Friday, April 30

Background: Opioid abuse and dependence are significant public health

problems. Methadone maintenance treatment (MMT) has been widely used for

decades in treating opiate addiction. Strict supervision in a specialized drug

treatment program has been the standard for MMT. But what about physician

opioid addicts, do they receive the same treatment?

Methods: For 5 years, we followed all physicians who were referred to Florida's

Professional Recovery Network (PRN) for opioid abuse/dependence. Twenty-

six physicians were identified in 1995-96; all but ten had intravenous opioid use.

They included 23 males and 3 females. Treatment referrals were made to

various addiction treatment facilities and outcomes were collected.

Results: All sign PRN contracts requiring them to attend a specialized

monitoring group, call a toll-free number for randomization to at least weekly

urine monitoring and regularly attend a local recovery support group program.

None were referred for MMT. None were treated with MMT. All were referred

for detoxification and drug-free long-term treatment. As reported previously,

physician addicts have a greater than 80% successful 5 year outcomes as

assessed by written counselor reports, physician/psychiatrist evaluations,

AA/NA attendance, return to work and regular random urine testing.

Conclusions: Unlike treatment referrals for non-physicians, opioid addict

physicians are referred to detox and long-term treatment rather than MMT.

Physicians may recommend MMT but NIMBY (not-in-my-backyard)

phenomenon applies for their colleagues. The physicians’ behavior is to vote for

detox and long-term treatment for themselves and colleagues and they may

prefer this option to MMT if available for other opiate addicts.

334. Pharmacological fMRI (pMRI) with Intravenous Citalopram: Direct Neuronal Effects

Ian M. Anderson1, Cristina M. Del-Ben

2, Shane McKie

1,

Nicola M. Delvai1, Steve Williams

3, Rebecca Elliott

1,

William Deakin1

1Neuroscience and Psychiatry Unit, University of Manchester,

Manchester, United Kingdom, 2Faculty of Medicine, University of Sao

Paulo, Ribeirao Preto, Brazil, 3Imaging Science and Biomedical

Engineering, University of Manchester, Manchester, United Kingdom

Background: The combination of serotonergic (5-HT) pharmacological

challenge and fMRI (pMRI) offers the possibility to measure 5-HT brain

function directly. Recently, we have demonstrated regional changes in blood

oxygen level dependent (BOLD) signal following infusion of the 5-HT2C

receptor agonist, mCPP, (Anderson et al, 2002 NeuroReport, 13:1547-51). This

study examined whether direct pMRI effects of intravenous infusion of the

SSRI, citalopram, could be detected.

Methods: 12 healthy males underwent two fMRI scanning sessions in a single-

blind, crossover design. Intravenous citalopram (7.5mg over 7.5 min) or saline

were infused in the middle of a single scan lasting 22.5 min. Images were

acquired on a 1.5T scanner, using single shot EPI. Data were analysed using

SPM2002, with a random effects model. The effects of the drug were modelled

using a priori regressors (including one based on subjective effects) entered into

a standard regression model.

Results: Citalopram infusion was associated with activation in the thalalmus,

hypothalamus, caudate nucleus, anterior cingulate gyrus, orbitofrontal cortex

and insula with attenuation seen in the right parahippocampal gyrus, right

precuneus, precentral gyri and pons.

Conclusions: Direct pMRI is controversial for theoretical and practical reasons.

The regional effects of citalopram infusion in areas believed to be involved in 5-

HT-mediated effects of antidepressants argues against non-specific effects of

the infusion. The good tolerability of citalopram presented a practical problem

in modelling the infusion based on subjective effects but preliminary sensitivity

analysis suggests the result is robust. Direct pMRI is likely to prove a valuable

tool for investigating neurotransmitter function.

335. Neurocognitive Enhancement Therapy and Work Therapy in Schizophrenia: Work Outcomes at 6 Months and 12 Month Follow-Up

Morris D. Bell1,2

, Gary Bryson1,2

, Joanna M. Fiszdon1,2

,Tamasine Greig

1, Bruce E. Wexler

1

1Psychiatry, Yale University School of Medicine, West Haven, CT,

2Rehabilitation Research and Development, Department of Veterans

Affairs, West Haven, CT

Background: Cognitive deficits in schizophrenia are strongly associated with

functional impairment. Neurocognitive Enhancement Therapy (NET) involves

computerized cognitive training and other methods to improve fundamental

cognitive processes of attention, memory and executive function. Previous

studies found that NET improved neuropsychological test performance and

that gains were sustained six-months after training. The present study examines

work outcomes when NET was added to a 6-month work rehabilitation

program.

Methods: 145 outpatients with DSM-IV Schizophrenia or Schizoaffective

disorder were randomly assigned to receive Work Therapy alone (WT) or

NET+WT. Work performance and cognitive impairments on the job were

evaluated biweekly using the Work Behavior Inventory (WBI) and the

Vocational Cognitive Rating Scale (VCRS) during the six-month active

rehabilitation phase. Hours worked during the six months prior to the study,

during rehabilitation, and during the six-months that followed were recorded.

Results: Both conditions demonstrated significant work performance

improvement during rehabilitation, but there were no significant group

differences. Mean hours worked for the two conditions were as follows: WT

Initial = 71, Rehabilitation = 270, 6-month follow-up = 191; NET+WT Initial

= 78, Rehabilitation = 210, 6-month follow-up = 306. Repeated measures

ANOVA for hours worked revealed a significant condition by time effect

favoring NET+WT.

Conclusions: Results suggest that there may be functional benefits to NET,

and that these effects appear after completion of training. Such findings are

consistent with models of neuroplasticity that predict gradual experience-based

changes in brain function. Findings support efficacy of cognitive training when

integrated into broader rehabilitation programs.

FRIDAY, APRIL 30

PLENARY SESSIONTreatment Research in Mental Illness: Update on the

NIMH Initiative in Treatment Development and

Effectiveness ResearchFriday, April 30, 8:30 AM-10:30 AM

Location: Grand Ballroom Chair: Harold A. Sackeim Co-Chair: J. John Mann

This session will begin with an overview of the NIMH plan for treatment

research beginning with treatment development extending through proof of

concept trials to the large practical clinical trials of treatment effectiveness.

336. The NIMH Roadmap for Treatment Development and Interventions Research

Thomas R. Insel

National Institute of Mental Health, National Institutes of Health,

Bethesda, MD

94S BIOL PSYCHIATRY 2004;55:1S–242S Thursday Abstracts

www.elsevier.com/locate/biopsych doi:10.1016/j.biopsych.2004.02.017

Thomas R. Insel, M.D., is Director of the National Institute of Mental Health

(NIMH). Prior to his NIMH appointment in November 2002, Dr. Insel was

Professor of Psychiatry at Emory University; founding director of the Center

for Behavioral Neuroscience, one of the largest NSF-funded science and

technology centers; director of an NIH-funded Center for Autism Research;

and director of the Yerkes Regional Primate Center in Atlanta. A focus of his

work has involved examining the role of the neuropeptides oxytocin and

vasopressin in social attachment – including, for example, maternal behavior

and pair-bond formation – and in aggressive behavior. Early in his career, while

at NIMH, Dr. Insel conducted clinical research on obsessive-compulsive

disorder, conducting some of the first treatment trials for OCD using the

selective serotonin reuptake inhibitors (SSRI) class of medications. A member

of the Institute of Medicine, his is also a Fellow of the ACNP and has served on

numerous academic, scientific, and professional committees.

337. Sequenced Treatment Alternatives to Relieve Depression (STAR*D): An Update on the Trial

A. John Rush

Psychiatry, UT Southwestern Medical Center, Dallas, TX

After graduating from Princeton University (A.B. 1964), he completed his MD

(1968) at Columbia College of Physicians & Surgeons, an internship (internal

medicine) at Northwestern University, and a residency in psychiatry at the

University of Pennsylvania. Dr. Rush is a Fellow of the American College of

Psychiatry, the American College of Neuropsychopharmacology, and the

American Psychiatric Association, and is former President of both the Society

of Biological Psychiatry and the Society of Psychotherapy Research. He chaired

the DSM-IV Work Group on Mood Disorders for the American Psychiatric

Association and the Panel on Practice Guidelines for Depression in Primary

Care for the Agency Health Care Policy and Research. Dr. Rush has also served

on review committees of the National Institute of Mental Health and the

Department of Veterans Affairs. He is an editorial board member or reviewer

for over a dozen psychiatric journals.

Honors include Exemplary Psychiatrist of the Year by the Texas Society of

Psytchiatric Physicians, the Gerald L. Klerman Lifetime Research Award

(National Depressive and Manic Depressive Association), the Strecker Award

(Institute of Pennsylvania Hospital), the Charles C. Burlingame Award (Institute

for Living), the Mood Disorder Research Award (American College of

Psychiatrists), the Edward J. Sachar Award (Columbia College of Physicians and

Surgeons) and the Award in Mood Disorders Research from NARSAD for his

research, teaching, and clinical work. For over 30 years, he has conducted

clinical investigations of both biological and psychosocial issues in mood

disorders in adults, children, and adolescents, and promoted the application of

clinical research findings to practice to improve the diagnosis and treatment of

these patients. Dr. Rush has authored over 450 papers and chapters, and 10

books.

338. Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)

Gary S. Sachs1,2

1Bipolar Treatment Center and Bipolar Mood Disorder Program,

Massachusetts General Hospital, Boston, MA, 2Psychiatry, Harvard

Medical School, Boston, MA

Gary S. Sachs, MD, is Director of the Bipolar Treatment Center, Director of the

Bipolar Mood Disorder Clinic and, Director of the Harvard Bipolar Research

Program, at Massachusetts General Hospital (MGH) in Boston, Massachusetts

and Associate Professor of Psychiatry at Harvard Medical School.

A 1982 graduate of the University of Maryland School of Medicine, Dr. Sachs

has held such distinguished positions as Chief Resident, Acute Psychiatry

Service, Clinical Fellow in Psychiatry, and Director of Chronobiology Section in

the Clinical Pyschopharmacology Unit at MGH. Among his many

achievements, Dr. Sachs has received the Dupont-Warren Fellow from the

Harvard Medical School, as well as the Dunlop Award for his achievements in

psychiatric research and writing.

Dr. Sachs has focused his career on improving understanding and treatment of

bipolar disorder. He is co-editor-in-chief of Clinical Approaches in Bipolar

Disorder and on the review board of such nationally recognized publications as

American Journal of Psychiatry,and The New England Journal of Medicine. In addition,

Dr. Sachs is currently a member of the American Psychiatric Association.

Dr. Sachs is principal investigator for the National Institute of Mental Health

(NIMH)-sponsored project titled, Systematic Treatment Enhancement Program

for Bipolar Disorder (STEP-BD). This project includes the largest NIMH

clinical studies conducted to date. In addition to several clinical trials examining

medication and psychosocial interventions STEP-BD conducts genetics

research, womens health studies and a disease management program that

emphasizes the continuity of care for all people with bipolar disorder.

339. The Role of Practical Clinical Trials and Treatment Research in Public Mental Health Care: The CATIE Project

Jeffrey A. Lieberman

Mental Health & Neuroscience Clinical Research Center, University of

North Carolina at Chapel Hill, Chapel Hill, NC

Jeffrey A. Lieberman, MD currently is the Thad and Alice Eure Distinguished

Professor of Psychiatry, Pharmacology, and Radiology and Director of the

Mental Health and Neuroscience Clinical Research Center at the University of

North Carolina, School of Medicine in Chapel Hill. He also serves as Adjunct

Professor of Psychiatry and Radiology at Duke University School of Medicine.

Dr. Lieberman’s research has focused on the neurobiology, pharmacology and

treatment of schizophrenia and related psychotic disorders. In this context, his

work has advanced our understanding of the natural history and

phenomenology of schizophrenia and its pathophysiological basis, and the

mechanism of action and clinical effectiveness of antipsychotic drugs. In terms

of the latter, he currently serves as the Principal Investigator of the Clinical

Antipsychotic Trials of Intervention Effectiveness Research Program (CATIE)

sponsored by the NIMH. He is also the Principal Investigator and Director of

an NIMH Silvio O. Conte Center for the Neuroscience of Mental Disorders

focusing on Schizophrenia at UNC.

Dr. Lieberman is a member of the National Academy of Sciences Institute of

Medicine and recipient of the Stanley R. Dean Award for Schziophrenia

Research from the American College of Psychiatry, the American Psychiatric

Association Research Award, the APA Kempf Award for Research in

Psychobiology, the APA Gralnick Award for Schizophrenia Research, the

Ziskind-Somerfeld Award of the Society of Biological Psychiatry, the Ernest

Strecker Award of the University of Pennsylvania and the Exemplary

Psychiatrist Award from the National Alliance of the Mentally Ill, Lilly

Neuroscience Award from the Collegium Internationale Neuro-

Psychopharmacologicum for Clinical Research.

340. Treatment Development: From Molecules to Proof of Concept

Wayne S. Fenton

Division of Mental Disorders, Behavioral Research and AIDS, National

Institute of Mental Health, Rockville, MD

Wayne S. Fenton, M.D., Associate Director for Clinical Affairs, National

Institute of Mental Health, Bethesda, Maryland is a graduate of George

Washington University School of Medicine. Following completion of post-

graduate training in Psychiatry at Yale University School of Medicine and a

National Research Service Award Fellowship at Yale’s Institution for Social and

Policy Studies, Fenton joined the staff of Chestnut Lodge Hospital where he

served in positions including Unit Chief, Director of Research, Medical Director

Friday Abstracts BIOL PSYCHIATRY 2004;55:1S–242S 95S

www.elsevier.com/locate/biopsych

and Chief Executive Officer between 1984 and 1998. Dr. Fenton’s research has

focused on the integration of biological, psychological and policy initiatives for

the treatment of severe mental illness. He has conducted clinical trials of

pharmacological and psychosocial interventions for schizophrenia and other

serious mental illnesses, is the author many publications related to this research,

and is the recipient of numerous awards including the Exemplary Psychiatrist

Award from the National Alliance for the Mentally Ill, the Maryland

Schizophrenia Service Award, the American Suicide Foundation’s Alexander

Gralnick Award, and the Research Award of the International Society for the

Psychological Treatment of Schizophrenia (ISPS). Dr. Fenton is a consultant to

the Special Litigation Section, Civil Rights Division of the United States Justice

Department. He is Deputy Editor of Schizophrenia Bulletin and is on the Editorial

Board of Acta Psychiatrica Scandinavica.

PRESIDENTIAL INVITED LECTURENeurobiology of Synaptic Transmission

Friday, April 30, 11:00 AM-12:00 PMLocation: Grand Ballroom Speaker: Paul Greengard

341. Neurobiology of Synaptic Transmission

Paul Greengard

Laboratory of Molecular and Cellular Neuroscience, The Rockefeller

University, NY

Dr. Paul Greengard is the Vincent Astor Professor of Molecular and Cellular

Neuroscience at The Rockefeller University. He began his exploration of nerve

cells in 1948 when he joined the Johns Hopkins biophysics laboratory then

headed by Detlev Bronk. After receiving his Ph.D. from Johns Hopkins in

1953, Greengard spent five years in England receiving advanced training in

brain biochemistry at the University of London, at Cambridge University, and at

the National Institute of Medical Research.

Upon his return to the United States, Greengard worked as Director of the

Department of Biochemistry at Geigy Research Laboratories, in Ardsley, New

York for eight years. He has remained intensely interested in the applications of

basic scientific knowledge to the development of therapeutic agents for

treatment of various neurological and psychiatric diseases. In 1967, he left the

pharmaceutical industry to return to academia. He spent one year as Visiting

Professor at Albert Einstein College of Medicine and Vanderbilt University

School of Medicine. From 1968 to 1983 Greengard served as Professor of

Pharmacology and Psychiatry at Yale University, at which time he moved to his

current position at The Rockefeller University.

Over the years, Greengard’s achievements have earned him many distinguished

awards including the Metropolitan Life Foundation Award for Medical

Research, The Charles A. Dana Award for Pioneering Achievements in Health,

the Ralph W. Gerard Prize in Neuroscience from the Society for Neuroscience,

The National Academy of Sciences Award in the Neurosciences, the Bristol-

Myers Award for Distinguished Achievement in Neuroscience Research, the 3M

Life Sciences Award of the Federation of American Societies for Experimental

Biology. In the year 2000, Greengard was awarded the Nobel Prize in

Physiology or Medicine.

LATE BREAKING/NEW SCIENCEMixed Topics

Friday, April 30, 12:30 PM-2:00 PMLocation: Grand Ballroom

Chair: J. John Mann

Complete abstract and author information will be included in the Program

Book (distributed at the meeting) and the online program beginning April 2,

2004 (www.sobp.org).

342. To Be Determined






SYMPOSIAPlasticity in Prefrontal-Amygdalar Neural Systems and its

Implications for Pediatric Bipolar DisorderFriday, April 30, 2:30 PM-5:00 PM

Location: Grand BallroomChair: Ellen Leibenluft

Co-Chair: Daniel P. Dickstein

348. Developmental Plasticity of the Amygdala: Lessons from Primates

Julie Fudge1, Crystal McClain

2

1Departments of Psychiatry, Neurobiology, and Anato, University of

Rochester Medical Center, Rochester, NY, 2Dept. of Psychiatry, and

Neurobiology and Anatomy, University of Rochester, Rochester, NY

Background: The primate amygdala is highly developed in primates compared

to lower species, and continues to develop postnatally. In the face of

accumulating evidence that there are functional and structural anomalies of the

amygdala in mood disorders, understanding the anatomy of the normal primate

amygdala is critical.

Methods: We used neuronal tract tracing studies and immunocytochemical

techniques to examine circuitry through the amygdala, and the distribution of

plasticity associated molecules in this structure.

Results: The amygdala projects strongly along a broad rostrocaudal extent of

the ventromedial striatum and to the extended amygdala. Through these

outputs, the amygdala is in a position to directly influence goal-directed

behaviors and responses to stress. Furthermore, neurons in specific

input/output paths contain a several neuroplasticity-associated molecules

known to be affected by psychiatric drugs. These include bcl-2 and

phosphorylated CREB. Immature-appearing neurons form a substantial

subpopulation of cells that contain these markers. Conclusions: The normal

function of amygdaloid circuitry in higher primates depends on growth and

plasticity-enhancing molecules. The circuit-specific distribution of these

molecules may provide clues into pathways influenced by therapeutic drugs.

349. Response Reversal and Social Cognition Deficits in Pediatric Bipolar Disorder: Evidence of Amygdala-OFC Dysfunction?

Ellen Leibenluft1, Erin B. McClure

2, Daniel P. Dickstein

2,

Tristan Gorrindo2, Julia Treland

2, Daniel S. Pine

2

1MAP, NIMH, Bethesda, MD,

2Map, NIMH, Bethesda, MD

96S BIOL PSYCHIATRY 2004;55:1S–242S Friday Abstracts


Background: The identification of neuropsychological deficits in children with

bipolar disorder (BPD) provides preliminary evidence regarding dysfunctional

neural circuitry; guides the development of behavioral paradigms for use in

fMRI; and identifies possible endophentypic markers.

Methods: 28 medicated children with BPD and 25 age/gender matched

controls received a broad battery of neuropsychological tests. On average, the

children with BPD were in a euthymic state. One of these tasks, the stop-change

task, was also used in an event-related fMRI study of children with BPD, as well

as normal adults and children.

Results: Despite preserved function in a number of areas (e.g. IQ, motor

inhibition) children with BPD had deficient performance on the ID/ED shift

task, a probabilistic response reversal task, and the stop-change task, all of

which assess response reversal. Statistical analyses indicate that these deficits

were not due to comorbid ADHD. The children with BPD also showed deficits

in pragmatic language and in facial emotion identification, important

components of social cognition. fMRI data in control adults using the stop-

change task indicates orbitofrontal cortical activation on “change” trials, which

require response reversal, as well as amygdala activation on successful (vs.

unsuccessful) “change” trials.

Conclusions: Both response reversal and social cognition tasks engage the

amygdala and orbitofrontal cortical regions. These behavioral deficits in children

with BPD are consistent with extensive literature implicating amygdala-OFC

dysfunction in adults with BPD. Further neuroimaging studies using response

reversal and social cognition tasks, as well as testing in adults with BPD and

their high-risk offspring, are warranted.

350. The Sequential Expression of Subcortical to Cortical Abnormalities in Juvenile Bipolar Disorder

Hilary P. Blumberg1,2

, John H. Krystal1,2

, Joan Kaufman

1, Andres Martin

3, Dennis S. Charney

4, Bradley

S. Peterson5

1Psychiatry, Yale University School of Medicine, New Haven, CT,

2Depression Research Center, Department of Veterans Affairs, West

Haven, CT, 3Child Study Center, Yale University School of Medicine,

New Haven, CT, 4Mood and Anxiety Disorders Research Program,

National Institute of Mental Health, Bethesda, MD, 5Psychiatry,

Columbia College of Physicians and Surgeons, New York, NY

Background: The neurobiology of juvenile bipolar disorder (BD) has received

little study and there is a paucity of information about potential

neurodevelopmental influences on the expression of brain abnormalities in

bipolar disorder (BD) over adolescence. The sequence of neurodevelopment of

structures implicated in BD, from prepubertal maturity of subcortical structures

such as amygdala to substantial developmental changes over adolescence in

ventral prefrontal cortex (VPFC), suggest that abnormalities in these structures

may be evident at different developmental stages.

Methods: Structural magnetic resonance imaging and functional magnetic

resonance imaging methods were utilized to measure the structure and function

of amygdala and VPFC in adolescents with BD as compared to healthy

adolescents.

Results: Amygdala abnormalities were found in adolescents and adults with

BD, whereas VPFC abnormalities were noted to progress over the course of

adolescence.

Conclusions: These data have implications for the consideration of methods to

identify biological and behavioral markers to detect BD early in its course, and

suggest brain regions that may be both especially vulnerable to the development

of neuropathology in adolescence and that may also be at a critical stage during

which interventions could positively influence the course of the disorder.

351. Neuroimaging in Phenotypes of Pediatric Bipolar Disorder

Daniel P. Dickstein

Pediatrics & Developmental Neuropsychiatry Branch, National

Institute of Mental Health, Bethesda, MD

Background: Previous magnetic resonance imaging (MRI) reports have treated

pediatric bipolar disorder (BPD) as a homogenous diagnostic entity. However,

studies suggest BPD in children may have considerable phenotypic variation.

Our group sought to examine neuroimaging findings in 2 groups representing

different phenotypes of pediatric BPD to determine how each differed from

normal children.

Methods: Our first study utilizes voxel-based morphometry (VBM) in children

with narrow phenotype BPD—i.e. meeting full DSM-IV criteria including

elevated, expansive mood lasting >4 days. Children with irritability alone or

episodes of shorter duration were excluded. Our second study uses 1H

magnetic resonance spectroscopy (MRS) in “broad phenotype” BPD children

participating in a double blind placebo controlled study of lithium. These

children have a chronic, rather than episodic, course of functionally impairing

irritability and hyper-arousal, without elevated or expansive mood.

Results: In our narrow phenotype BPD study, we found controls (N=20) had

significantly larger left amygdalar volume (p=0.003) versus BPD subjects

(N=20). In our broad phenotype BPD study, we obtained 1H MRS imaging

data on 8 subjects. These subjects were first imaged while medication free and

then after 6 weeks of either lithium or placebo to investigate previous adult

BPD findings that lithium increases N-acetyl-aspartate (a putative marker of

neuronal health) and decreases myoinositol (second messenger thought central

to lithium’s mechanism of action). The latter data are currently being analyzed.

Conclusions: We will link our 2 current neuroimaging studies in pediatric BPD

to previous adult and child BPD studies specifically emphasizing amygdala and

prefrontal cortex findings.

Neurogenesis: A Role in Learning, Learned Helplessness

or Depression?Friday, April 30, 2:30 PM-5:00 PM

Location: Astor SalonChair: Fritz A. Henn

352. Neurogenesis and the Makings of Memories

Tracey J. Shors

Psychology, Rutgers University, Piscataway, NJ

Background: The number of new neurons produced each day in the adult

brain is in the thousands if not tens of thousands (Gould et al., 1999, Cameron

and McKay, 2001). The vast majority of these new neurons are produced in the

hippocampus, a brain region known to be critical for certain types of learning.

Most of these new cells die within weeks of their birth. Given that so many cells

are born in the hippocampus, we have proposed that they may be involved in

the formation of new memories and have accumulated considerable evidence

that they are.

Methods: Animals were trained on learning tasks that either require the

hippocampus or are independent of its involvement. In the first set of studies,

we evaluated the effects of learning on the proliferation and the survival of new

neurons in the adult hippocampus. We also evaluated how long the effects of

learning persist. In a final set of studies, we depleted the population of new

neurons with an antimitotic agent and evaluated learning abilities.

Results: We found that animals that were trained on a learning task that

requires the hippocampus maintain many more of these new neurons than

animals exposed to a learning task that does not require the hippocampus

(Gould et al., 1999). We found no effects of training or learning on the



proliferation of new neurons. These data indicate that acquisition of

hippocampal-dependent types of memory can rescue newly generated neurons

from death. Also, once rescued from death by learning, the new neurons survive

for months and outlive the time when the hippocampus is involved in retention

of the memory (Leuner et al., 2004). Finally, we have found that a near

depletion of adult generated neurons impairs memory formation of very specific

types – those in which animals must associate events over time (Shors et al.,

2001, 2002, 2004).

Conclusions: Together, our results suggest that adult generated neurons are

affected by the formation of some types of new memories and may even be

involved in their production.

Supported by NIH (MH59740).

353. Role of Neurogenesis in Antidepressant Action

Luca Santarelli, René Hen

Center For Neurobiology and Behavior, Columbia University, New

York, NY

Background: Various chronic antidepressant treatments increase adult

hippocampal neurogenesis, but the functional importance of this phenomenon

remains unclear.

Methods: Two strategies were used in this study. The first consist of genetic

disruption of the serotonin 1A receptor and the second involves X-irradiation

of a small region of the brain containing the hippocampus.

Results: Serotonin 1A receptor null mice were insensitive to the neurogenic

and behavioral effects of fluoxetine, a serotonin selective reuptake inhibitor. X-

irradiation prevented the neurogenic and behavioral effects of two classes of

antidepressants.

Conclusions: These findings suggest that the behavioral effects of chronic

antidepressants may be mediated by the stimulation of neurogenesis in the

hippocampus.

354. Hippocampal Cellular Proliferation and Cognitive Outcome Following Magnetic Seizure Therapy and Electroconvulsive Shock

Sarah H. Lisanby1,2

, Harold A. Sackeim1,2

, Jason Scalia

3, Tammy Moscrip

4, Mark D. Underwood

1,3,

Andrew J. Dwork1,3,5

, Herbert Terrace4, Victorial

Arango1,3

1Psychiatry, Columbia University, New York, NY,

2Biological

Psychiatry, New York State Psychiatric Institute, New York, NY, 3Neuroscience, New York State Psychiatric Institute, New York, NY,

4Psychology, Columbia University, New York, NY,

5Pathology,

Columbia University College of Physicians & Surgeons, New York, NY

Background: Hippocampal neurogenesis has been hypothesized to play a role

in antidepressant action. Among antidepressants, electroconvulsive shock (ECS)

is the most robust inducer of neurogenesis in rodents, but the role of these new

cells in the therapeutic and adverse cognitive effects of ECT is not fully

understood. Magnetic seizure therapy (MST) is under development as a novel

antidepressant that may have fewer cognitive side effects than ECT by virtue of

its focality of stimulation and lesser impact on temporal lobe structures.

Previously we reported in 12 rhesus monkeys that MST fails to increase the

proliferation of new cells in the dentate gyrus. We now replicate this finding in

an additional group of monkeys, report on the 2 month survival of labeled cells,

and present the cognitive outcome of monkeys receiving MST or ECS.

Methods: Adolescent rhesus monkeys (n=24) were randomly assigned to

receive 6 wks of MST, ECS, or sham. Bromodeoxyuridine (BrdU, 100 mg/kg iv

qD x 6D) was injected 1 or 7 weeks prior to sacrifice. Brains were processed for

BrdU immunohistochemistry. BrdU positive nuclei were counted by masked

raters. To examine cognitive effects, a separate group of monkeys was exposed

to chronic MST, ECS, or sham in a within-subject cross-over design. Monkeys

were trained on a battery of tasks sampling anterograde and retrograde amnesia

using a touch screen monitor. Cognitive performance was assessed at baseline,

immediately and 3 hrs after each daily intervention, and during a 5 wk recovery

phase.

Results: More BrdU positive cells were seen in the dentate gyrus following ECS

than with MST or sham, both acutely post-BrdU injection (F (2,3) = 25.03, p =

0.013) and at 7 wk follow up (F (2,12) = 7.23, p = 0.008). Sham and MST did

not differ. Monkeys performed faster and more accurately on anterograde and

retrograde memory tasks following MST than ECS. This effect was most

marked for the short-term memory of a variable target and recall of previously

learned lists.

Conclusions: Unlike ECS, MST did not increase the proliferation of dentate

granular cells, and had less adverse impact on cognitive performance than ECS.

As a seizure model apparently devoid of effects on cellular proliferation, MST

represents a means for examining what role this aspect of hippocampal plasticity

may play in therapeutic and cognitive outcome following convulsive therapy.

Supported by R01 MH60884, K08 MH01577

355. Neurogenesis: Does it Play a Role in Learned Helplessness

Fritz A. Henn, Barbra Vollmayr

Central Institute of Mental Health, Mannheim, Germany

Background: The concept that decreased neurogenesis may be the cause of

depression is supported by the effects of stress on neurogenesis and the

demonstration that neurogenesis appears necessary for the action of most

antidepressant treatments.

Methods: Learned helplessness was induced in a paradigm that resulted in

about 20% of the stressed animals developing helplessness, while a further 20 %

showed no behavioral or physiological following this procedure.

Results: The helpless animals had changes in HPA axis activity consistent with

depression, as well as consistent REM sleep changes. Both the helpless and

non-helpless animals showed the same reduction in neurogensis following the

learned helplessness training paradigm, suggesting neurogenesis did not govern

the behavioral change. Inbred lines of learned helpless animals were bred and

the helpless line compared with the non-helpless line and no clear changes in

rates of neurogenesis were seen.

Conclusions: An analysis of all the dividing cell types suggests that the

difference between helpless and non helpless animals does not lie in different

rates of neuron formation or astrocyte formation.

Mechanisms of Stress-Induced Plasticity Friday, April 30, 2:30 PM-5:00 PM

Location: Basildon RoomChair: Bita Moghaddam

356. Molecular Basis of Individual Differences in Stress Responses

Guillome Drutel1, Sabine Spijker

2, Anton B. Smit

2, Pier

V. Piazza1

1Inserm u588, University de Bordeaux, Bordeaux Cedex, France,

2Molecular and Cellular Neurobiology, Faculty of Earth and Life

Sciences, Vrije Universiteit, Amsterdam, Netherlands

Background: Environmental and genetic factors play an important role in

determining the propensity of an individual to develop psychiatric deseases.

Although, a large number of data have shown the influence of genes and

environment separately very few studies have addressed the question of the



interaction between the genetic background of an individual and his sensitivity

to environmental influences.

Methods: We have compared the sensitivity of inbred strains of mice to

changes in environmental conditions. In particular we have analyzed the effect

of a period of food restriction on the behavioral responses of C57 and DBA2

mice. We also studied the expression of 250 relevant brain genes in the

prefrontal cortex and the extended amygdala of C57 and DBA in basal

condition and after food-restriction stress.

Results: It was found that in basal conditions the C57/bl6 strain is more

sensitive to amphetamine than the DBA/2 mice. However after a short period

of food-restriction DBA mice became equally or more sensitive, depending on

the parameter studied, than C57. Interestingly, whilst the behavioral phenotype

of DBA changed profoundly after stress no changes were observed in C57. In

parallel a much larger number of genes were regulated in C57 than in DBA and

one of the major effects of stress was to suppress preexisting strains differences

in gene expression.

Conclusions: In conclusion, the genetic back ground of the individual

determines largely his behavioral response to stress. Furthermore, profound

differences in gene expressions seem to mediate strain differences in stress-

induced changes in behavioral phenotypes.

357. Chronic Stress-Induced Alterations in Neuronal Excitability within the Amygdalo-Coerulear Circuit

Anthony A. Grace, Hank Jedema, Jeremy Amiel Rosenkranz, Cynthia J. Correll

Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA

Background: Stress exposure produces responses that are maladaptive or that

enable the organism to adapt more effectively to their environment. We

examined how chronic stress affected the amygdala, a region known to be

involved in both cognitive and physiological responses to stress.

Methods: Rats were exposed to chronic cold stress (shaved and housed at 5

degrees C for two weeks), and then tested 1-10 days after returning to room

temperature.

Results: Although initial exposure to cold caused physiological responses

indicative of stress (e.g., elevated plasma catecholamines), these parameters

returned to baseline after a few days of exposure. Nonetheless, after 10 days

removal from cold, the rats showed augmented acoustic startle response.

Neurons within the basolateral amygdala (BLA) of cold-stressed rats exhibited

baseline firing rates, but showed significantly greater activation in response to

footshock. In contrast, central amygdala (CeA) neurons, which receive BLA

input, were firing significantly slower and had a blunted response to footshock.

Although transection of prefrontal cortical (PFC) input did not alter CeA

neuron firing rate and responses in control rats, in the cold-stressed rats it

caused CeA neurons to return to baseline firing and exhibit significantly greater

response to footshock.

Conclusions: Following chronic cold stress, we propose that the PFC, via

activation of the intercalated GABAergic neurons in the amygdala, isolates BLA

hyper-responsivity from the CeA. Therefore, although the BLA-mediated

heightened cognitive/emotional correlates of chronic stress are preserved, the

autonomic CeA-modulated responses are blunted. In this way, the PFC can

circumvent potential damaging effects of chronic stress.

358. Stress-Induced Plasticity in the Prefrontal Cortex

Bita Moghaddam, Mark Jackson

Neuroscience, University of Pittsburgh, Pittsburgh, PA

Background: The prefrontal cortex (PFC) plays a critical role in response

selection that is driven by external and internal states. PFC dysfunction has been

implicated in most cognitive and affective disorders. Several lines of evidence

suggest that stress impairs executive functions associated with PFC; however,

the cellular basis of this disruption is not known.

Methods: Ensemble electrophysiological recordings were performed in

behaving animals that were exposed to acute and repeated disruptions in their

environment.

Results: During the first exposure to all stressors, most PFC neurons displayed

a biphasic response characterized by an initial increase followed by a decrease in

spontaneous activity. Once the stress was terminated, PFC neurons displayed a

prolonged period of firing rate potentiation. This latter response is relevant to

mechanisms that govern some forms of plasticity in neurons. Subsequent

exposure to the same stressor produced a muted or no significant effect on PFC

neurons suggesting that this region has a plastic response to stress.

Conclusions: Acute stress may interfere with PFC function by over-activating

its neurons, thus “over-engaging” the PFC so that it will not have the flexibility

to provide sufficient influence over behavior. However, PFC neurons appear to

habituate rapidly to repeated stress, allowing the organism to gain back

behavioral flexibility despite repeated exposure to the stressful situation.

Disruption of this plastic process in a dysfunctional PFC may lead to an

abnormal pattern of reactivity to stress.

359. Stress-Induced Synaptic Reorganization in Hippocampus

Ana M. Magarinos

Neuroendocrinology, Rockefeller University, New York, NY

Background: Chronic stress and the overactivity of glucocorticoids and

excitatory amino acids cause CA3 pyramidal hippocampal neurons to retract

their apical dendritic fields. Both rats and mice show similar plastic changes in

response to chronic stress. These adaptive plastic changes are associated with

some degree of declarative memory impairment. Neurotrophins such as brain

derived neurotrophic factor (BDNF) play an important role in structural

plasticity, dendritic remodeling and hippocampal dependent memory formation.

Methods: We examined the effects of 21 days of daily restraint stress (6h/day)

on the hippocampal morphology of wild type and BDNF deficient mice

Results: We observed that non-stressed BDNF deficient mice show a

significant decrease in the complexity and length of apical CA3 pyramidal

dendritic trees compared with non-stressed wild type animals. After 21 days of

repeated chronic restraint stress, the dendritic remodeling was not further

enhanced.

Conclusions: These results indicate that the partial deficiency of BDNF blocks

the stress-induced dendritic remodeling. Electron microscopic studies are in

progress to investigate whether the lack of plasticity observed in BDNF

heterozigous mice is associated with neuronal damage.

Imaging Amygdalo-Frontal Interactions: Implications for Mood and Anxiety Disorders

Friday, April 30, 2:30 PM-5:00 PMLocation: Conrad SuiteChair: Scott L. Rauch

360. Amygdalo-Frontal Interactions in Response to Ambiguously-Valenced Facial Expressions

Paul J. Whalen

Psychiatry, University of Wisconsin, Madison, WI

Background: Recent neuroimaging studies have examined response of the

human amygdala to facial expressions of emotion. We have suggested that

amygdala responsivity in these studies is best explained, not as a response to the

presence of these stimuli per se, but as a response to what these expressions do

or do not predict in terms of outcomes or their eliciting event.



Methods: 16 human subjects (eight female) passively viewed 16 sec blocks of

alternating Surprised and Neutral faces during two functional magnetic

resonance imaging (fMRI) scans.

Results: Subjects who offered more negative ratings of surprised expressions

showed higher amygdala and lower mPFC signal intensities, while subjects who

offered more positive interpretations showed the inverse pattern. Accordingly,

we observed evidence of functional connectivity between these regions in

response to surprised expressions. That is, there was a significant inverse

correlation between signal changes within amygdala and these vmPFC loci (right

vmPFC, r = -.69; p = .003; left vmPFC, r = -.58; p = .01).

Conclusions: A significant amount of variability in fMRI responses to an

expression whose predicted valence is ambiguous (e.g., surprised faces) is

explained by functional connectivity between the medial prefrontal cortex and

the amygdala. The present task may prove useful for the simultaneous

assessment of frontal and limbic regions in disorders where aberrations in this

circuitry are hypothesized to be critically involved (e.g., mood and anxiety

disorders).

361. Amygdalo-Frontal Interactions in Posttraumatic Stress Disorder

Lisa M. Shin1, Roger K. Pitman

2, Scott P. Orr

2,3, Scott L.

Rauch2

1Psychology, Tufts University, Medford, MA,

2Psychiatry,

Massachusetts General Hospital/Harvard Medical School, Boston,

MA,3Research Service, VAMC, Manchester, NH

Background: Recent functional neuroimaging studies have implicated the

amygdala and medial prefrontal cortex in the pathophysiology of PTSD.

Methods: In two separate studies, we used (1) PET and the script-driven

imagery paradigm and (2) fMRI and overtly presented fearful and happy facial

expressions to study amygdala and medial prefrontal cortex responses in

individuals with PTSD and in trauma-exposed comparison participants without

PTSD.

Results: In both studies, we observed exaggerated amygdala responses and

diminished medial prefrontal cortex responses in PTSD. In addition, we

observed an inverse correlation between amygdala and medial prefrontal cortex

responses in both studies.

Conclusions: These results suggest a reciprocal relationship between the

amygdala and medial prefrontal cortex in PTSD, consistent with current

functional neuroanatomical models of this disorder.

362. Amygdalo-Frontal Interactions in Major Depressive Disorders

Wayne C. Drevets

Mood & Anxiety Disorders Program, NIMH, Bethesda, MD

Background: Neuroimaging and neuropathological studies of depression

identified abnormalities of function and structure in amygdala and prefrontal

cortex (PFC) regions that modulate amygdala function. Dysfunction of these

PFC regions may disinhibit limbic activity mediating emotional responses. Siegle

et al (2002) reported amygdalar activity remained elevated for abnormally long

time in depressives viewing sad words, to an extent correlated with abnormal

activation in dorsolateral PFC. To determine whether this response to sad

verbal stimuli may also be reflected by abnormal habituation to sad visual

stimuli, we assessed habituation of amygdala responses to sad faces.

Methods: PET-CBF images were acquired in 10 depressives (5 female; age

=34 10) and 16 controls (8 female; mean age = 32 7.0) as they assigned gender

to human faces expressing fearful (FF), sad (SF), happy (HF) or “neutral” (NF)

expressions. Two scans were obtained for each condition, presented in blocks

of 70 stimuli from 10 actors (Eckman et al) at 1 Hz.

Results: Flow increased in left amygdala in both groups in SF and FF versus

NF and HF. In 2nd versus1st SF scan, left amygdala flow decreased (to

baseline) in controls, but not depressives [p(1t)<0.05]. Depressives and controls

did not differ in habituation to FF. Habituation of amygdala to SF and FF were

each associated with increased CBF in controls, but decreased CBF in

depressives, in pregenual anterior cingulate (ACC; p<.001).

Conclusions: Left amygdalar hemodynamic response showed impaired

habituation in depressives during repeated exposure to a sad faces, associated

with abnormal activity in pregenual ACC.

363. Orbitofrontal Cortex-Amygdala Interactions during Anger Induction in Patients with Major Depression with and without Anger Attacks

Darin D. Dougherty1, Scott L. Rauch

1, Thilo

Deckersbach1, Carl Marci

2, Rebecca Loh

1, Lisa M.

Shin1, Nathaniel M. Alpert

3, Alan J. Fischman

3, Maurizio

Fava2

1Psychiatry, Massachusetts General Hospital, Charlestown, MA,

2Psychiatry, Massachusetts General Hospital, Boston, MA,

3Nuclear

Medicine, Massachusetts General Hospital, Boston, MA

Background: Multiple lines of evidence suggest that hypofunctionality of the

prefrontal cortex (PFC) and amygdala is central to the pathophysiology of

impulsive aggression while, in contrast, increased ventral PFC and amygdala

activity are associated with major depressive disorder (MDD). Approximately

one-third of depressed outpatients present with anger attacks, a subgroup of

highly irritable and hostile depressed patients that provides a unique opportunity

for studying a population that exhibits symptoms of both depressed mood and

impulsive aggression.

Methods: For the current study, narrative scripts were used to induce Anger

states as well as Neutral states during a PET O15 study of regional cerebral

blood flow (rCBF) in ten unmedicated patients with MDD with anger attacks

(MDD+A), ten unmedicated patients with MDD without anger attacks (MDD-

A), and ten healthy control subjects. Voxel-wise and region of interest methods

were used for analyses of rCBF changes for the Anger vs. Neutral contrast

within and between groups.

Results: While healthy volunteers showed increased rCBF in the left

orbitofrontal cortex (OFC) during anger induction, MDD+A patients showed a

corresponding decrease in rCBF in this same region. In addition, while a

reciprocal relationship existed between rCBF changes during anger induction in

the left OFC and left amygdala in healthy volunteers and MDD-A patients, in

MDD+A patients this reciprocal relationship was not present.

Conclusions: These results suggest a pathophysiology of MDD+A patients

that is distinct from that of MDD-A patients and that may be responsible for

the unique clinical presentation of patients with this subtype of major

depression.

Schizophrenia Candidate Genes Regulating Cortical Development

Friday, April 30, 2:30 PM-5:00 PMLocation: West Foyer

Chair: Jeffrey A. LiebermanCo-Chair: Patricia F. Maness



364. Neuregulin 1- ErbB Signaling during Neuronal Migration in the Developing and Adult Cerebral Cortex

Eva Anton

Neuroscience, University of North Carolina School of Medicine,

Chapel Hill, NC

Background: Normal development of the mammalian cerebral cortex requires coordinated migration of post mitotic neurons from the ventricular zone to the outermost layer of the developing cortical plate along radial glia. However, the mechanisms that determine how radial glial cells are established, maintained, and transformed into astrocytes in the cerebral cortex are not well understood. Similarly, the molecular cues modulating the ongoing neuroblast migration and differentiation in the rostral migratory stream (RMS) of the adult brain remains unclear. We sought to determine if NRG-1 mediated signaling is involved in neuronal migration and glia differentiation in the cerebral cortex. Methods: We studied the function of NRG1 and its receptors erbB2 and 4 in these processes using NRG1, erbB2, and erbB4 deficient mice. Results: We found that neuregulin-1 (NRG-1) exerts a critical role in the establishment of radial glial cells. In vitro and in vivo, down regulation of expression and activity of erbB2, a member of the NRG-1 receptor complex, leads to the transformation of radial glial cells into astrocytes. These results suggest that developmental changes in neuregulin 1-erbB2 interactions modulate the establishment of radial glia and contribute to their appropriate transformation into astrocytes. Neuregulins and the receptor kinase ErbB4 play a similar role in the ongoing neuroblast migration and differentiation in the rostral migratory stream (RMS) of the adult brain. ErbB4 activation promotes progenitor cell division and helps to regulate the assembly of neuroblast chains that form the RMS. Conclusions: These results, together with the recent studies identifying NRG1 as a susceptibility gene for Schizophrenia (Stefansson, 2002a; Stefansson, 2002b) raises the intriguing possibility that impaired neuregulin-ErbB mediated neuronal precursor proliferation and migration, and the resultant changes in neural circuitry in the forebrain may enhance the sensitivity for neurodevelopmental disorders such as schizophrenia.

365. Epigenetic Down-Regulation of Reelin (Reln) Expression in Schizophrenia

Dennis R. Grayson, Ying Chen, Erminio Costa, Alessandro Guidotti, Xiaomei Jia, Colin P. Mitchell, Rajiv P. Sharma, Marin Veldic

Psychiatry, University of Illinois at Chicago, Chicago, IL

Background: Reln and GAD67 mRNAs are co-expressed in adult cortical GABAergic neurons, and are also reduced in the brains of patients with schizophrenia. We have demonstrated that Reln is regulated by a combination of the transcription factors Sp1, Tbr1 and Pax6. In addition, human Reln is regulated by the methylation of its CpG island containing promoter. In human neuronal progenitors, histone deacetylase inhibitors, such as valproic acid, increase Reln expression and this is accompanied by a decrease in promoter methylation. New data shows that Dnmt1 mRNA is increased in GABAergic neurons in schizophrenia.Methods: We use a combination of promoter transfection and pharmacological manipulation of neuronal progenitors in vitro. In addition, we evaluate immunohistochemical data of post-mortem schizophrenia and non-psychiatric human brain slices and perform bisulfite modification of genomic DNA from these same preparations to determine the extent of human promoter methylation.Results: We have previously shown that reelin and GAD67 mRNAs are down regulated in schizophrenia post-mortem tissue. More recently, we have established that Dnmt1 mRNA is increased in GABAergic neurons of the

cortex of patients with schizophrenia. These are the same neurons in which we have observed decreases in reelin and GAD67 mRNA. Using a Dnmt1 antisense strategy we provide data implicating Dnmt1 protein in regulating Reln in mouse cortical neurons in vitro. Using methionine to induce an initial down-regulation of Reln, we show that antisense transfection decreased Dnmt1 mRNA and protein and increased Reln mRNA and blocked the methionine-induced down-regulation.Conclusions: Our findings suggest that Dnmt1 action regulates the expression of promoters in GABAergic neurons and that this action mediates changes in DNA methylation. We suggest that promoter hypermethylation may be a primary event responsible for gene down regulation in GABAergic neurons of the schizophrenia cortex. Dnmt1 represents a new target for the development of interventions in psychosis aimed at correcting the GABAergic neuron deficit that results in the hypermethylation of gene promoters.

366. Molecular Mechanisms Underlying Migration and Positioning of Neurons in the Developing Neocortex

Li-Huei Tsai

Pathology, Harvard Medical School, Boston, MA

Background: The mammalian neocortex is organized in six distinct layers that are assembled by postmitotic neurons migrating from the ventricular zone in the radial direction towards the pial surface. Layer assembly occurs in an inside-out manner, indicating that early and later born neurons occupy the deep and superficial layers, respectively. The type I lissencephaly gene Lis1 associates with and positively regulates cytoplasmic dynein. Another Lis1 interacting protein, Nudel, also binds cytoplasmic dynein. In this study, we set out to determine whether like Lis1, Nudel and dynein also regulate the positioning of neurons during brain development.Methods: We set out to silence the expression of Lis1, Nudel and dynein heavy chain (DHC) using DNA based interference RNA (RNAi) constructs.Results: Radial migration of neurons from the cortical ventricular zone to the upper layers of the cortex is impaired when Nudel, Lis1 and dynein RNAi constructs were introduced into mouse embryonic brains by electroporation in utero. In dissociated cortical neurons, silencing of Nudel, Lis1 and DHC expression caused abnormal nuclear movement and a net reduction of the total distance traveled. Furthermore, using a microtubule transport assay, we show that, like Lis1, Nudel is necessary to sustain the function of cytoplasmic dynein. Finally, silencing of Nudel reduced the association of Lis1 and dynein.Conclusions: These results indicate that the Nudel/Lis1/dynein pathway is essential for migration and proper layering of cortical neurons and that Nudel positively regulates cytoplasmic dynein by facilitating the interaction of Lis1 and dynein.

367. Neural Cell Adhesion Molecules as Modulators of Interneuron Differentiation and Cortical Neuron Migration

Patricia F. Maness

Biochemistry and Biophysics, University of North Carolina, Chapel

Hill, NC

Background: Transmembrane neural cell adhesion molecules of the Ig superfamily, NCAM and Close Homolog of L1 (CHL1), regulate neuronal cell migration, axon guidance, and synaptic plasticity. The extracellular region of NCAM (NCAM-EC) is abnormally secreted in schizophrenic brain, and an association between CHL1 alleles and schizophrenia have been reported.Methods: To study their function we generated a transgenic mouse line that secretes NCAM-EC in differentiating and mature neurons throughout the brain. We also produced CHL1-minus mice expressing yellow fluorescent protein in layer V pyramidal cells to study their development.



Results: Interneurons of the frontal cortex and amygdala of NCAM transgenic mice were impaired in the development of synaptic terminals, revealed by decreased GAD65, GAD67, and GAT1-labeled puncta surrounding neuronal soma. There was no change in the number of parvalbumin+ or calretinin+

interneurons. Transgenic mice displayed impaired sensorimotor gating (PPI), which was improved by clozapine but not haloperidol. Mice had increased locomotor and stereotypy activities, and could not be fear conditioned, indicative of learning/memory deficits.In the posterior but not anterior cortex of CHL1-minus mice, pyramidal neurons were displaced to lower layers and developed inverted apical dendrites. Radial migration of CHL1-minus neuronal precursors was strikingly perturbed in acute brain slice assays. Thus, CHL1 modulates area-specific migration and dendrite development, which may affect connectivity of pyramidal neurons in the neocortex.Conclusions: A novel mouse model that abnormally secretes NCAM during synaptic maturation may perturb brain circuitry and contribute to abnormal behaviors relevant to schizophrenia.

Role of Exogenous and Endogenous Cannabinoids in

Psychosis and CognitionFriday, April 30, 2:30 PM-5:00 PM

Location: JadeChair: Deepak Cyril D'Souza

368. Effects on Simulated Driving and Test of Visual Attention

Godfrey D. Pearlson

Psychiatry, Institute of Living/Yale University, Hartford, CT

Background: Effects of THC on cognition are not well studied using functional imaging methods.Methods: Oral doses of 10mg THC (dronabinol, Marinol) vs. placebo were given in a double blind crossover fashion to 10 healthy, screened non-marijuana using volunteer subjects. Subjective measures of intoxication and serial blood levels of THC and its metabolites were obtained. Subjects performed the Motor-Free Visual Perception Task (revised version – MVPTR) a test of complex visual perception, the Useful Field of View Task, a test of divided visual attention and a simulated driving paradigm with and without THC. All tasks were performed in an fMRI scanner.Results: For activation associated with the driving task, overall primary visual regions demonstrated the greatest modulation by drug. In sober subjects, active driving differentially activated these areas (likely due to modulation of visual areas), but not on THC. Additionally, orbitofrontal and anterior cingulate regions showed detectable differences between THC-intoxicated and sober states. We also performed this study with a different drug, (N = 10), alcohol which had profound effects on fronto-parietal but not visual regions during the driving task and thus had a very different imaging “signature” than THC.Conclusions: THC has measurable effects on driving-related attentional tasks and simulated driving. These differ from alcohol effects both behaviorally and in terms of fMRI activation.

369. Dose-Related Behavioral and Cognitive Effects of Intravenous Delta-9-THC in Schizophrenia Patients and Healthy Controls

Deepak Cyril D'Souza

Psychiatry, Yale University, West-Haven, CT

Background:Cannabis is a widely used psychoactive drug of abuse that has been associated with psychosis and the emergence of schizophrenia. The

literature associating cannabis and psychosis carries some limitations, some of which can be addressed in laboratory-based studies.Methods: Twenty two healthy subjects completed 3 test days under double-blind conditions in a randomized counterbalanced order during which the behavioral, cognitive and endocrine effects of intravenous infusion of 0, 2.5 mg and 5 mg delta-9-tetrahydrocannabinol were characterized. Prospective safety data was collected at 1, 3 and 6 months post-study. In a second study, healthy subjects (n=25) the effects of oral haloperidol on the behavioral nd cognitive effects of delta-9-THC were studied.Results: In a dose-dependent fashion, delta-9-THC produced 1) positive and negative symptoms; 2) perceptual alterations; 3) increases in euphoria; 4) impairments in recall, attention and working memory; 5) increases in plasma cortisol levels. However, haloperidol did not attenuate the behavioral or cognitive effects of delta-9-THC .Conclusions: The effects of delta-9-THC resemble many dimensions of endogenous psychoses, including schizophrenia. These data support the existing literature of an association between cannabis and psychosis and warrant further study of whether exogenous and endogenous cannabinoids contribute to the pathophysiology of schizophrenia. The mechanism by which delta-9-THC produces psychosis and cognitive deficts needs to be explored further.

370. Epidemiological Evidence Associating Cannabis and Psychosis

Robin M. Murray

Psychiatry, Institute of Psychiatry, London, United Kingdom

Background: Many schizophrenic patients consume cannabis but there has been dispute over this is causal to or consequent upon the psychosis. We set out to answer this question.Methods: Information was collected on cannabis consumprion at age 15 and 18 in a prospectively collected study of some 1000 children who were part of the Dunedin Birth Cohort. 96% of the sample were interviewed and diagnosed for DSMIV at 26 years.Results: Those who consumed cannabis at age 15 were 4.5 times more likely to develop a schizophreniform psychosis by 26 years than those who did not. Although those children who showed quasi-psychotic symptoms at 11 years were especially likely to use cannabis at 15, the risk increasing effect of cannabis remained when this group were excluded.Conclusions: Cannabis use is a contributory cause of schizophrenia.

371. Endogenous Cannabinoids and Their Neurobiological and Functional Role in Schizophrenia Spectrum Disorders

F. Markus Leweke1, Andrea Giuffrida

2, Christoph W.

Gerth1, Dagmar Koethe

1, Daniela Schreiber

1,3, Joachim

Klosterkötter1, Daniele Piomelli

3

1Dept. of Psychiatry and Psychotherapy, University of Cologne,

Cologne, Germany, 2Dept. of Pharmacology, University of Texas

Health Science Center, San Antonio, TX, 3Dept. of Pharmacology,

University of California, Irvine, Irvine, CA

Background: Activation of cannabinoid CB1 receptors produces intense emotional and cognitive responses, suggesting that dysfunction in the endocannabinoid system may contribute to the pathogenesis of mental disorders.Methods: We have examined the role of endocannabinoid signaling in psychotic states by measuring levels of the endocannabinoid anandamide in cerebrospinal fluid (CSF) and serum of various groups of healthy volunteers (n=84) and patients suffering from acute psychiatric disorders (n=187) by HPLC/MS.Results: The level of anandamide in CSF is significantly elevated in acute, antipsychotic-naive, first-episode schizophrenic patients (n=47) when compared



to controls. This is reversed by the administration of antipsychotics, which antagonize dopamine D2-like receptors (n=37), but not by those, which preferentially antagonize 5HT2A receptors (n=34). Furthermore, we found that, in antipsychotic-naïve, acute schizophrenics, CSF anandamide is negatively correlated with psychotic symptoms. Our findings were specific for schizophrenia spectrum disorders.Conclusions: Our results suggest that anandamide elevation in schizophrenia may reflect a compensatory adaptation to dopaminergic hyperactivity revealing an unexpected protective role for this endocannabinoid lipid in psychotic states.

New Insights into the Neurobiology of Bipolar Disorder Friday, April 30, 2:30 PM-5:00 PM

Location: Louis XVI CenterChair: Ghanshyam N. Pandey

Co-Chair: Victoria Arango

372. Molecular Alterations in the Brainstem of Subjects with Bipolar Disorder

Victoria Arango1,2

, Mark D. Underwood1,2

, Anna K. Wiste

1, J. John Mann

1,2

1Neuroscience, New York State Psychiatric Institute, New York, NY,

2Psychiatry, Columbia University, New York, NY

Background: There are abnormalities in the noradrenergic and serotonergic system in mood disorders. The locus coeruleus (LC) is the source of norepinephrine to the brain and receives a serotonergic innervation, which inhibits LC activity.Methods: We measured the area of LC neuropil occupied by tyrosine hydroxylase (TH) and by tryptophan hydroxylase (PH8) immunoreactive processes, and the optical density of their staining in three groups of subjects (n=6 per group: Bipolar and unipolar suicides and normal controls). Clinical diagnoses were determined by psychological autopsy.Results: The proportion of LC neuropil occupied by TH processes was reduced in depressed bipolars (27±6%) versus controls (51±3%;p=.002) and unipolars (53±3%;p=.001). Staining of TH processes relative to background was lighter in depressed bipolars, but not unipolars, versus controls. One manic bipolar had the highest proportion of stained processes (71%) and the darkest staining (4.6x bckgrd) observed. Unipolar depressed suicides had darker staining of serotonergic processes in the LC than bipolar suicides (Unipolars: ROD = .38±.05, Bipolars: ROD = .20±.01; p=.02), and the proportion of neuropil occupied by processes was greater in the unipolar group (Unipolars: 33±3%, Bipolars: 18±3%; p=.006). In controls, values were intermediate between unipolars and bipolars on both measures, but the differences between the controls and the psychiatric groups did not reach significance.Conclusions: Our data supports the hypothesis of reduced noradrenergic and serotonergic activity in bipolar depression and suggests that abnormalities in both systems may be of significance in the study of bipolar disorder.Supported by: MH40210, MH61285 and Stanley Foundation

373. Similarities and Differences in the Regulation of NMDA-Mediated Apoptotic Mechanisms in Anterior Cingulate Cortex of Subjects with Schizophrenia and Bipolar Disorder

Francine M. Benes, John P. Walsh, Wilson Woo

Program in Structural and Molecular Neuroscience, Mclean Hospital,

Mailman Research Center, Belmont, MA

Background: Recent postmortem studies of cingulate cortex in schizophrenia (SZ) and bipolar disorder (BD) have revealed similarities and differences in the

respective findings. For example, there is a much greater loss of GABA cells in ACCx-II of BDs (30%) when compared to SZs (15%).Methods: To assess whether an excitotoxic injury to GABA cells has occurred in ACCx of SZs and BDs, double in situ hybridization (DISH) has been used to co-localize mRNA for the NR2A subunit and GAD67. In addition, in situ end-labeling of single-stranded DNA breaks has been used as a specific marker for apoptosis.Results: A marked reduction in the number of GAD67-positive neurons that express the NR2A subunit was observed in ACCx-II of SZs and BDs. The reduction in SZs was much greater than that seen in earlier cell counting studies, while that seen for BDs is equivalent. An unexpected 72% reduction in DNA damage was also observed in SZs; BDs showed no difference.Conclusions: Taken together, these results suggest that both SZs and BDs are exposesd to NMDA-mediated excitotoxicity. However, apoptosis probably occurs in BDs and results in the death of GABAergic neurons. In contrast, SZs show significant GABAergic dysfunction, but this may be related to an interruption of normal signaling pathways associated with apoptosis. Overall, these findings suggest that novel pharmacologic treatments directed at changes in the regulation of apoptotic cascades may be designed to specifically and differentially treat SZ and BD.Supported by MH00423, MH42261, MH62822 and MH60450.

374. Protein Kinase C, Phospholipase C and MARCKS is Altered in the Platelets of Patients with Bipolar Disorder

Ghanshyam N. Pandey, Yogesh Dwivedi, Philip G. Janicak

Psychiatry, University of Illinois at Chicago, Chicago, IL

Background: Protein kinase C (PKC) is a key regulatory enzyme involved in important neuronal functions and is a key component of the PI signaling systems. There is some indirect evidence to suggests that it may play an important role in the pathophysiology of bipolar disorders. This is primarily derived from the observations that PKC may be the target for therapeutic actions for mood stabilizing drugs. However, direct evidence linking PKC to pathophysiology of bipolar illness is lacking.Methods: We have therefore studied PKC, MARCKS, an important substrate for phosphorylation by PKC, phospholipase C (PLC) and CREB, a transcription factor, in the platelets and neutrophils of patients with bipolar disorders and normal control subjects during a drug-free baseline period.Results: We observed that both PKC and PLC activity as well as the protein expression level for certain PKC and PLC isozymes were significantly decreased in platelets obtained from bipolar patients. We observed that protein expression levels of MARCKS in platelets obtained from bipolar patients were significantly increased. We also observed that CRE-DNA binding activity as well as the protein expression level of CREB, which is activated by PKC, were significantly lower in neutrophils of bipolar patients.Conclusions: These studies suggest an abnormality of PKC in bipolar patients and that this abnormality may lead to further abnormalities of phosphorylation of MARCKS and levels of CREB in patients with bipolar illness.

375. Fronto-Limbic Brain Abnormalities in Bipolar Disorder: Findings from Adult and Pediatric Studies

Jair C. Soares

Psychiatry, University of Texas Health Science Center at San Antonio,

San Antonio, TX

Background: Over the past two decades, brain imaging studies have begun to examine the pathophysiological mechanisms possibly involved in bipolar disorder. Methods: We have conducted a series of magnetic resonance imaging (MRI)



and spectroscopy (MRS) studies examining anatomical and neurochemical abnormalities in fronto-limbic brain regions in adult and pediatric bipolar patients. A 1.5T GE Signa magnet was used to acquire 3D SPGR MRIs (TR=25ms, TE=5ms, slice-thickness=1.5mm). Volumetric measures of amygdala, hippocampus, cingulate gyrus, sub-genual prefrontal cortex, and intra-cranial volumes (ICV) were obtained blindly by well-trained raters (ICC > 0.9). We also examined the DLPFC levels of NAA with 1H MRS and a STEAM sequence (TE= 20 ms, TM= 13.6 ms, TR= 1.5 sec, voxel dimension 2.0 x 2.0 x 2.0 cm3).Results: Our findings indicate subtle anatomical changes in sub-regions of the prefrontal cortex, medial temporal lobe, and corpus callosum. Furthermore, there is a reduction of NAA levels in dorsolateral PFC in bipolar patients. Conclusions: We will present our most recent findings and discuss its potential relevance for illness pathophysiology in the context of available literature from anatomical, functional, and neurochemical studies in bipolar disorder.

PAPER SESSIONSAnxiety and Eating Disorders

Friday, April 30, 2:30 PM-5:00 PMLocation: Conrad Suite

Chair: Walter Kaye

376. Neural Modulation of Adrenergic Function by PACAP via Ca+2 Signaling

Dona Lee Wong, T.C. Tai

Department of Psychiatry and Laboratory of Molecular and

Developmental Neurobiology, Harvard Medical School and McLean

Hospital, Belmont, MA

Background: Pituitary adenylate cyclase-activating polypeptide (PACAP) may be an important modulator of adrenergic function during stress. It activates the epinephrine-synthesizing enzyme, phenylethanolamine N-methyltransferase (PNMT) via cAMP-protein kinase A. The role of Ca+2, an important component of this signaling pathway, in PNMT gene regulation was therefore examined.Methods: PC12 cells transfected with PNMT promoter-luciferase reporter gene constructs were treated with PACAP or pre-treated with inhibitors, followed by PACAP and luciferase activity determined.Results: PACAP increased PNMT promoter-driven luciferase reporter gene expression 4.5-fold at 48 hr, through activation of PACAP type I receptors, shown by dose response curves for PACAP and VIP. The Ca+2 chelator BAPTA-AM attenuated PACAP induction by 30%. The L-Ca+2 channel inhibitors, D600 and nifedipine also attenuated PACAP stimulation while inhibitors of N-, P/Q- or T-Ca+2 channels had no effect. The L-channel activator FPL induced the PNMT promoter to the same extent as PACAP, which increased intracellular Ca+2 ~3-fold. Thapsigargin, an inhibitor of Ca+2-ATPase pump-mediated Ca+2 re-uptake into the ER, incrementally activated PNMT promoter induction by PACAP. While the Ca+2-calmodulin kinase inhibitor KN62 did not alter PACAP effects, the calcineurin inhibitor ascomycin reduced PACAP induction ~30%. Finally, mutation of the Egr-1 binding element in the PNMT promoter prevented PACAP induction of luciferase reporter gene activity.Conclusions: PACAP markedly activates PNMT promoter-driven gene expression, in part mediated via Ca+2 influx through L-channels and prevention of Ca+2 uptake into ER stores via the Ca+2-ATPase pump. Ca+2 effects further depend on calcineurin and the immediate early gene transcription factor Egr-1.

377. Mouse Strain Sensitivity to Autoimmune Disease Predicts Disturbances of Behavior and Brain Architecture Following Postnatal Thimerosal Exposure

Mady Hornig, David Chian, W. Ian Lipkin

Mailman School of Public Health, Columbia University, New York, NY

Background: Thimerosal, an ethylmercury-containing preservative formerly present in childhood vaccines, is implicated in the rising prevalence of autism, a highly genetic, disabling neuropsychiatric condition of unknown cause. Sensitivity of the prenatal central nervous system to methylmercury is well-established, and immune response genes predict risk in rodent models. Less is known about ethylmercury, postnatal exposures, or effects of repetitive, intramuscular administrations such as with vaccinations. If postnatal thimerosal causes neurodevelopmental damage, immunogenetic factors are likely to be important determinants of its neurotoxicity.Methods: To establish the biologic basis for susceptibility to adverse neurodevelopmental outcomes, we compared the effects of thimerosal, in doses and timing approximating the childhood immunization schedule, in mouse strains differing in autoimmune disease sensitivity (Balb, C57 and SJL).Results: Behavioral and neuropathologic disturbances were found to be strain-dependent. SJL mice, known to be sensitive to autoimmune disease in general and to mercury-induced autoimmunity in particular, were most prominently affected by postnatal thimerosal, with growth delay, impoverished behavioral responses with increased anxiety, and severe disturbances in architecture of hippocampus and glutamate receptor expression.Conclusions: These findings suggest that brain architecture and function may be altered in genetically susceptible hosts following postnatal thimerosal exposure, and support the utility and relevance of this model as a tool for identifying genetic and maturational factors underlying vulnerability to toxin-induced CNS injury and understanding the pathogenesis of human neurodevelopmental disorders.MIND Institute of UC Davis (MH); Coalition for Safe Minds (MH), HD37546 (MH, WIL)

378. Altered Serotonin 1 A Receptor Binding in Panic Disorder

Alexander Neumeister1, Earle E. Bain

1, Allison C.

Nugent1, Richard E. Carson

2, Omer Bonne

1, Dave

Luckenbaugh1, William C. Eckelman

2, Peter

Herscovitch2, Dennis S. Charney

1, Wayne C. Drevets

1

1Map, NIMH, Bethesda, MD,

2PET Department, NIH, Bethesda, MD

Background: Evidence suggests the possibility that disturbances in the 5-HT1AR and/or its downstream signaling pathway could contribute to the pathophysiology of panic disorder. The development of the selective 5-HT1AR radioligand, [18F]-FCWAY, permits in vivo assessment and characterization of central 5-HT1AR binding using positron emission tomography (PET).Methods: MRI and PET using FCWAY were performed in 15 unmedicated symptomatic outpatients with panic disorder (10 women, 5 men, age 35.5, SD 9.9 years) and 15 matched controls (10 women, 5 men, age 35.2, SD 9.9 years). Using quantitative PET image analysis, regional values were obtained for FCWAY volume of distribution (V), corrected for plasma protein binding, and K1, the delivery rate of FCWAY from plasma to tissue. The 5-HT1AR scans were acquired using intravenous bolus injection of 8 mCi of high-specific activity [18F]-FCWAY and a 120 minute dynamic PET scan. Analyses used independent t-tests with Bonferroni correction to correct for multiple comparisons. Post-hoc analysis included 3-group ANOVAs with Tukey post-hoc tests.Results: Panic disorder patients relative to controls showed lower V in the anterior cingulate (t=4.59, p<.001), posterior cingulate (t=4.20, p<.001), and the



raphe (t=3.09, p=.004). 5-HT1AR binding potentials were reduced in the panic disorder patients relative to controls in the anterior cingulate (t=4.59, p<.001), posterior cingulate (t=4.20, p<.001), and the raphe (t=3.83, p<.001). No significant between-group differences were seen in any region for K1.Conclusions: Our results substantiate the role of 5-HT1ARs in the pathophysiology of PD. However, the underlying mechanisms causing the reduction of 5-HT1AR remain unclear.

379. Alcohol Dependence is Associated with a Reduction in Mesolimbic Dopamine Transmission

Diana Martinez, Raj Narendran, W. Gordon Frankle, Dah-Ren Hwang, Yiyun Huang, Roberto B. Gil, Elizabeth Hackett, Audrey Perez, Marc Laruelle, Anissa Abi-Dargham

Psychiatry, Columbia University/NYSPI, New York, NY

Background: Alcohol dependence is associated with a reduction in D2 receptor availability in the striatum, however no studies have so far assessed presynaptic dopamine release. We measured D2 receptor availability and amphetamine induced dopamine release in the meso-limbic versus nigro-striatal subdivisions of the striatum using PET and [11C]raclopride.Methods: 15 alcohol dependent subjects (AD) and 15 healthy controls (HC) were scanned with [11C]raclopride before and after an amphetamine challenge (0.3 mg/kg). The regions of interest included the limbic striatum (LST), associative striatum (AST) and sensori-motor striatum (SMST). Measures of D2 receptor availability (V3”) and magnitude of dopamine release ( V3" ) were obtained.Results: AD subjects had a significant reduction in V3" compared to HC: 11% in the LST (1.81 ± 0.27 vs 2.04 ± 0.27 p = 0.02). 19% in the SMST (2.42 ± 0.32 vs 2.97 ± 0.38 p =0.002) and a 15% reduction in the AST (2.17 ± 0.27 vs 2.57 ± 0.31 , p = 0.001). Following amphetamine, AD displayed significantly lower

V3"in LST compared to HC (-5.2 ± 3.6% vs -14.2 ±8.3%, p = 0.001), with no significant difference in the SMST (-12.3 ±7.3% vs -15.3±8.4% , p =0.31) and AST (-4.6±5.8% vs -8.0±5.7% , p =0.14).Conclusions: Alcohol dependence is associated with a decrease in D2 receptor availability in all subregions of the striatum and a selective blunting of presynaptic dopamine release in the limbic striatum, a region involved in the brain reward circuitry. Funded by NIAAA.

380. 2-Adrenoreceptor (AR) Polymorphisms and Behavioral Responses to Yohimbine

Alexander Neumeister1, Marilla Geraci

2, Tamara Willis

3,

Inna Belfer4, Tanya J. Alim

5, Omer Bonne

1, William B.

Lawson5, David Goldman


1

1Mood and Anxiety Disorder Program, NIMH, Bethesda, MD,

2Mood

and Anxiety Disorders Program, NIMH, Bethesda, MD, 3Mood and

Anxiety Disorders Program, Howard University, Washington, DC, 4Nidcr, NIH, Bethesda, MD,

5Mood and Anxiety Disorder Program,

Howard University, Washington, DC, 6Niaaa, NIH, Bethesda, MD

Background: 2-adrenergic receptors ( 2-AR) are cell surface receptors for catecholamines that bind to the Gi/G0 family of G proteins. Recently, three 2-ARs subtypes designated 2A, 2B, and 2C have been defined. In human 2C-ARs,an in-frame deletion of a homologous repeat at codons 322-325 has been reported. Thus far, the possible functional consequences of this gene variant has not been studied in humans. This study evaluates whether altered behavioral responses occur in subjects homozygous and heterozygous for an in-frame deletion of a 2C-AR homologous repeat occurring at codons 322-325 relative to subjects without this deletion.Methods: Twenty seven healthy controls received an infusion of yohimbine hydrochloride (0.125 mg/kg bolus over 3 minutes, 0.001 mg/kg/min x 12

minutes infusion). Behavioral assessments used objective (Panic Disorder Symptom Scale, PDSS) and subjective ratings (visual analogue scales, VAS). Behavioral assessments were obtained at baseline before administration of yohimbine, and 15, 30, 45 and 60 minutes after administration of yohimbine. Raters and subjects were blinded regarding the genetic status of the study participants.Results: Administration of yohimbine resulted in significantly increased anxiety responses in subjects homozygous for an in-frame deletion in the 2C-ARrelative to carriers of the wild-type (PDSS total score: time X genotype interaction: F[8,92]=2.20, p=.035; VAS restlessness: time X genotype interaction: F[8,100]=2.39, p=.021). Peak behavioral effects were found 15 minutes after administration of yohimbine.Conclusions: These results suggest a functional role of an in-frame deletion of the 2C-AR in mediating behavioral responses to yohimbine

381. Altered 5-HT2A Receptor Binding after Recovery from Bulimia-Type Anorexia Nervosa

Ursula F. Bailer1, Julie C. Price

2, Carolyn C. Meltzer

2,

Guido K. Frank1, Chester A. Mathis

2, Lisa Weissfeld

3,

Walter H. Kaye1

1Psychiatry, University of Pittsburgh, Western Psychiatric Institute &

Clinic, Pittsburgh, PA, 2Radiology, University of Pittsburgh,

Presbyterian-University Hospital, Pittsburgh, PA, 3Biostatistics,

University of Pittsburgh, Department of Biostatistics, Pittsburgh, PA

Background: Several lines of evidence suggest that disturbances of serotonin function, such as 5-HT2A receptor activity, may contribute to the pathogenesis of anorexia nervosa (AN) and bulimia nervosa (BN), by effects on appetite and behavior.Methods: To avoid confounding effects of malnutrition, we studied 10 women recovered from bulimia-type AN (REC AN-BN, >1 year normal weight, regular menstrual cycles, no binging or purging, age: 25.2 ± 3.3) compared with 16 healthy control women (CW, age: 23.5 ± 3.0) using PET imaging and the 5-HT2A receptor antagonist [18F]altanserin.Results: REC AN-BN women had significantly reduced [18F]altanserin binding potential (BP) relative to CW in the left subgenual cingulate (1.47 ± 0.29 vs 1.82 ± 0.3; p = .01), the left parietal cortex (1.35 ± 0.15 vs 1.56 ± 0.20; p = .01), and the right occipital cortex (1.41 ± 0.19 vs 1.64 ± 0.25; p = .03). Cerebellar distribution volume (DV) values were similar between groups. [18F]altanserin BP was positively related to harm avoidance and negatively related to novelty seeking in cingulate and temporal regions only in REC AN-BN subjects.Conclusions: This study extends research suggesting that altered 5-HT neuronal system activity persists after recovery from bulimia-type AN, particularly in subgenual cingulate regions. Altered 5-HT neurotransmission after recovery supports the possibility that this may be a trait-related disturbance that contributes to the pathophysiology of eating disorders.

382. Positive Relationships between 5-HT2A

Receptor Activity in Frontal Cortical Regions after Recovery from Bulimia Nervosa

Shannan E. Henry1, Ursula F. Bailer

1, Guido K. Frank

1, Carolyn C.

Meltzer2, Julie C. Price

2, Chester A. Mathis

2, Angela Wagner

1, Walter

H. Kaye1

1Psychiatry, Western Psychiatric Institute and Clinic, University of

Pittsburgh, Pittsburgh, PA, 2Radiology, University of Pittsburgh,

Presbyterian University Hospital, Pittsburgh, PA

Background: Anxiety is common when individuals are ill with bulimia nervosa (BN). Anxiety may be a trait disturbance in this illness, as anxious mood often predates the onset of BN, and persists after recovery. Considerable data show that disturbed 5-HT function is present when BN are ill and persists after recovery. Limited evidence from imaging studies in humans supports the



possibility that 5-HT2A receptor activity is related to anxiety and is altered in BN.Methods: 5-HT2A receptor activity was assessed using PET imaging and [18F]altanserin binding potential in 9 women who had recovered from BN (REC AN-BN, >1 year normal weight, regular menstrual cycles, no bingeing or purging).Results: The REC BN subjects (22 ± 2 years old) showed significant positive relationships between Speilberger Trait Anxiety scores and the lateral orbital frontal (r=.70, p=.04), medial orbital frontal (r=.74, p=.02), and prefrontal (r=.77, p=.01) cortex.Conclusions: Trait anxiety is positively related to 5-HT2A receptor activity in frontal cortical regions in women recovered from BN. These findings add to a growing body of literature showing relationships between this receptor and measures of anxious mood in healthy subjects and behavioral disorders. Both 5-HT activity and frontal lobe function have been associated with behavioral disinhibition and extremes of self control. We postulate that inherent disturbance of orbital frontal 5-HT circuits in BN contributes to a vulnerability for imprecise and poorly modulated emotions.

383. Relationship between Central and Peripheral Stress Responses in Humans

Mary M. Heitzeg1, Christian S. Stohler

2, Jon-Kar

Zubieta1

1Psychiatry, University of Michigan, Ann Arbor, MI,

2School of

Dentistry, University of Maryland, Baltimore, MD

Background: The mu-opioid receptor system (MOR) has been implicated in the rewarding effects of drugs of abuse and in the pathophysiology of various illnesses, including depression. It is well know that stressful early life events have an effect on risk for both drug abuse and depression during adulthood. This relationship may be mediated by MOR modulation of responses to stress. We know that the activation of this system occurs in the context of sustained, or tonic, stressors. In the present study, we looked at whether measures of HPA system activation correlated with the activation of the MOR system.Methods: Controlled randomized studies with PET and the MOR tracer [11C]carfentanil in healthy volunteers were conducted (n=34) using sustained pain as a tonic stressor. Activation of the MOR system was estimated by subtracting saline-control minus pain scan MOR binding potential maps (BP, Bmax/Kd). Blood samples were taken every 10 minutes during baseline, saline-control and pain scans and assayed for cortisol and ACTH. Pixel-by-pixel correlations were conducted using SPM99.Results: Global MOR binding did not differ between conditions or groups of subjects. Both cortisol and ACTH correlated positively with MOR system activation in the ventral pallidum and nucleus accumbens, areas believed to be involved in stimulus salience and sensori-motor integration. Furthermore cortisol correlated negatively with MOR system activation in the posterior hypothalamus.Conclusions: These data demonstrate the interaction of the HPA axis and the MOR system in stress-responses in brain regions implicated in stress responses and the development of substance abuse.

384. Genomic Regions Controlling Corticosterone Levels in Rats

Marc N. Potenza1, Edward S. Brodkin

2, Bina Joe

3,

Xingguang Luo1, Elaine F. Remmers

3, Ronald L.

Wilder3, Eric J. Nestler

4, Joel Gelernter

1

1Department of Psychiatry, Yale University School of Medicine, New

Haven, CT, 2Department of Psychiatry and Center for Neurobiology

and Behavior, University of Pennsylvania, Philadelphia, PA, 3National

Institute of Arthritis and Musculoskeletal and Skin Diseases, National

Institutes of Health, Bethesda, MD, 4Department of Psychiatry and

Center for Basic Neuroscience, The University of Texas Southwestern

Medical Center, Dallas, TX

Background: The identification of genetic factors controlling stress-responsiveness should advance the understanding of susceptibility to psychiatric illness.Methods: Rat strains, F344/NHsd and LEW/NHsd, that differ in measures of stress-responsiveness and behaviors modeling psychiatric disorders, were bred to generate F2 progeny that were used in a quantitative trait loci (QTL) analysis to identify genomic regions influencing late-afternoon corticosterone levels.Results: Regions on chromosomes 4 and 10 previously identified as influencing autoimmune phenomena were the most significant QTLs observed, reaching suggestive significance at the genome-wide level. Congenic animals targeting these regions with F344/NHsd DNA on a DA/Bkl genomic background demonstrated corticosterone levels approximating those of F344/NHsd rats and differing significantly from DA/Bkl rats.Conclusions: Specific genomic regions influence both corticosterone levels and stress-related disease susceptibility. These findings not only represent the first identification of QTL controlling corticosterone levels, but also suggest a mechanism underlying genetic differences in stress-responsiveness.Supported by the NARSAD, APA, NIMH, NIDA, NIAAA, and US Dept of Veterans Affairs.

385. Family History and Alcohol Withdrawal Symptoms: Genetic ImplicationsThomas Beresford, Julie Alfers, Brandon Martin, Lori Clapp

Psychiatry, U of Colo/DVAMC, Denver, CO

Background: the central nervous system (CNS) hallmarks of alcohol dependence (AD) include withdrawal from ethanol. Very few reports address vulnerability to CNS withdrawal as a possible genetically based factor. Hypothesizing that alcohol withdrawal reflects a genetically based CNS vulnerability, we asked whether a positive AD family history (FH) associates with withdrawal symptom frequency.Methods: 1139 subjects of varying drinking histories who were interviewed in a study on AD screening described 1) subject perceived FH of a first-degree relative with alcoholism, and 2) subjects’ own lifetime alcohol withdrawal symptoms. Goodness-of-fit and correlation tests provided probability assessments of the relationship between FH positive status and the likelihood of AD withdrawal symptoms.Results: of the total, 41.5% (FH positive: 473) reported one or more first degree AD relative while 58.5% (FH negative: 666) did not. At the same time, 63.4% (722) of all subjects reported at least 1 withdrawal symptom and 36.6% (417) did not.

FH Positive (%) FH Negative (%) Probability

1 or > Symptom

all 331/472 (70.0) 391/666 (59.7) .001

males 186/239 (77.8) 243/552 (69.0) .025

females 145/234 (62.0) 148/314 (47.1) .001



Conclusions: positive family history appears to suggest greater vulnerability to alcohol withdrawal and may suggest a gender difference in this regard. While these data depend on subject reports of both FH status and withdrawal history, they point to further genetic investigation of CNS differences in withdrawal response. Further work must refine specific FH and withdrawal symptom associations in order to identify phenotypic forms.

Mood Disorders Friday, April 30, 2:30 PM-5:00 PM

Location: Herbert HooverChair: Monique Ernst

386. Tardive Dyskinesia Studies Highlight Pivotal Conceptual and Design Issues in the Pharmacogenetics of Psychotropic Drugs

Bernard Lerer1, Fabio Macciardi

2, Ronnen H. Segman

1

1Biological Psychiatry Laboratory, Hadassah - Hebrew University

Medical Center, Jerusalem, Israel, 2Department of Medical Genetics,

University of Milan, Milan, Italy

Background: Variability among individuals in their response to psychotropic drugs and in susceptibility to adverse effects is the focus of pharmacogenetics. Recent studies on genetic vulnerability to tardive dyskinesia (TD) highlight pivotal conceptual and design issues.Methods: Case control studies of candidate genes for TD susceptibility in Israeli schizophrenia patients (TD, n=59; non-TD, n=63) and in two large multicenter samples from (n=780 and 635 respectively) chronically treated with classical antipsychotic drugs .Results: 1) The importance of statistical power and appropriate consideration of confounders such as population origin, is underscored by the multicenter studies, which confirmed association of the dopamine D3 receptor (DRD3) ser9gly polymorphism and the serotonin 2A receptor (HTR2A) T102C polymorphism with TD susceptibility. 2) The polygenic basis of pharmacogenetic traits involves gene - gene interaction and is demonstrated by addititive association of a cys23ser polymorphism in the 5-HT2C (HTR2C) receptor gene with DRD3. Epistasis was shown by our finding that the A2-A2 genotype of the cytochrome P450 17 alpha-hydroxylase gene (CYP17) does not in itself confer susceptibility to TD but does so in those individuals who carry the gly allele of DRD3. 3) The expression of a pharmacogenetic trait may be age related. We have shown that the increased risk for TD conferred by the HTR2C ser23 allele and the HTR2A 102C allele is significant only in older subjects.Conclusions: Pharmacogenetic tests to predict response to and adverse effects of psychotropic drugs are highly feasible provided that pivotal conceptual and design issues are taken into consideration.

387. Interaction between the Serotonin Transporter Gene and Experiences of Maltreatment in Predicting Depression in Children

Joan Kaufman1, Heather Douglas-Palumberi

1, Eileen

Billlingslea1, Deborah Lipschitz

1, Shadi Houshyar

2,

Daryn David2, John H. Krystal

1, Joel Gelernter

1

1Psychiatry, Yale University, New Haven, CT,

2Psychology, Yale

University, New Haven, CT

Background: The purpose of this study was to determine if polymorphic variation in the gene encoding the serotonin transporter protein (locus SLC6A4) predicts the development of depression in maltreated children.Methods: Sample: 68 maltreated and 46 control children between 5 and 14 years of age. Depressive symptoms assessed with Mood and Feelings Questionnaire, and saliva specimens for DNA extraction collected at a day camp devised for research purposes. Genotypes obtained by agarose gel size fractionation; 8% of genotypes repeated at random, and no discrepancies identified.Results: In predicting children's depression scores, there was a significant main effect of genotype (F=3.09, p < .05), main effect of maltreatment history (F=10.9, p < .001), and significant gene by environment interaction (F=3.02, p < .05). Maltreated children homozygous for the long ("l") allele at the SLC6A4 locus had comparable depression scores to controls with the same genotype, maltreated children with the "s/l" genotype had slightly elevated depression scores, and maltreated children homozygous for the short ("s") allele had depression scores that were more than twice as high as controls with the same genotype, with 91% of maltreated children with this genotype scoring above the clinical threshold on the depression rating scale. This was a racially mixed group, and although the polymorphism studied is functional, we cannot yet exclude a contribution of population stratification.Conclusions: These results are consistent with findings reported in a large birth cohort investigation, and suggest this locus may moderate the effects of stress and confer a vulnerability to depression.

388. Association between Depression and 24-Hour Urinary Cortisol in Patients with Coronary Heart Disease: The Heart and Soul Study

Christian Otte1, Charles R. Marmar

1, Sharon Pipkin

2,

Rudolf Moos3, Warren S. Browner

4, Mary A. Whooley

4

1Psychiatry, University of California, San Francisco, CA,

2Medicine,

VA Medical Center, San Francisco, CA, 3Psychiatry, Stanford

University, Palo Alto, CA, 4Medicine, University of California, San

Francisco, CA

Background: Depression is associated with increased morbidity and mortality in patients with coronary heart disease. Increased activity of the hypothalamus-pituitary-adrenal (HPA) axis may contribute to this association.Methods: We examined the association between major depression according to the Computerized Diagnostic Interview Schedule and 24 hour urinary free cortisol in a cross-sectional study of 693 patients with stable coronary disease. We used logistic regression to determine the association between quartile of cortisol and major depression, adjusted for potential confounding variables.Results: Of the 693 participants, 138 (20%) had current depression. Participants with depression had greater mean cortisol levels than those without depression (42 ± 25 µg/day vs. 36 ± 20 µg/day, p<.01). With each quartile of cortisol concentration the frequency of depression increased (p<.01, figure). Participants in the highest quartile of cortisol had a two-fold increased odds of having major depression, compared with those in the lowest quartile of cortisol (Odds Ratio [OR] 2.1, 95% CI 1.2-3.6, p=.01). This association remained strong after adjusting for potential confounding variables (OR 2.4, 95% CI 1.3-4.4, p<.01).Conclusions: Depression is associated with increased levels of 24 hour urinary free cortisol in patients with coronary heart disease. Elevated cortisol may contribute to the worse outcomes associated with depression in patients with coronary disease.



389. Pet Correlates of Neuropsychological Impairment in Depression and Suicide

John G. Keilp, Matthew Milak, Ramin V. Parsey, Maria A. Oquendo, J. John Mann

Neuroscience/Psychiatry, NYSPI/Columbia University Medical College,

New York, NY

Background: We previously identified independent multivariate neuropsychological dimensions that characterize (1) attention/memory function typically impaired in depression, and (2) executive function uniquely impaired in highly lethal past suicide attempters. In this study, we examined the relationship between these neuropsychological dimensions and resting cerebral glucose metabolism, to determine if distinct patterns of regional cerebral activity were associated with these neuropsychological dimensions.Methods: Twenty-seven unmedicated, unipolar depressed subjects received a battery of neuropsychological tests and an [18F]-flourodeoxyglucose (FDG) PET scan. Neuropsychological discriminant functions were computed for each subject based on previously published algorithms, and results correlated with PET data using SPM-99.Results: Each neuropsychological dimension correlated with metabolism in a large prefrontal region. The attention/memory dimension correlated negatively with metabolism in a superior, anterior region of left prefrontal cortex (1,819 pixels; primarily Brodman areas 9 & 10). The executive function dimension correlated positively with metabolism in a superior, lateral region in right prefrontal cortex (2,553 pixels; primarily Brodman areas 8, 9 & 10).Conclusions: Association of depression-related impairments in attention/memory with higher left prefrontal metabolism is consistent with published data linking presence of depression to higher prefrontal metabolism and/or blood flow. Association of executive function impairment with lower right prefrontal activity is consistent with our previous findings of reduced metabolism in this region in highly lethal past attempters. The distinctiveness of these regional correlations supports the independence of these neuropsychological dimensions, and the possibility of finding patterns of regional brain dysfunction and related cognitive impairment associated with risk for severe suicidal behavior.

390. High Probability Candidate Genes, Pathways and Mechanisms for Bipolar and Related Disorders Identified through a Comprehensive Convergent Functional Genomics Approach

Cory Ogden1,2,3

, Michael Rich1,2,3

, Nicholas Schork1,

Martin P. Paulus1,2

, Mark A. Geyer1,2

, James B. Lohr1,2

,Ronald Kuczenski

1, Alexander B. Niculescu

1,2,3

1Psychiatry, UC San Diego, La Jolla, CA,

2VAMC San Diego, La Jolla,

CA,3Laboratory of Neurophenomics, UC San Diego, La Jolla, CA

Background: We have used an expanded version of the convergent functional genomics approach (Niculescu et al. 2000) to identify candidate genes for bipolar and related disorders.Methods: Mice were treated with either a bipolar disorder mimicking agent, methamphetamine, a bipolar disorder treating agent, valproate, or co-treated with both drugs. Gene expression analysis of multiple brain regions was carried out, in parallel with behavioral studies. Genes whose expression was changed by both drugs individually, and whose change was prevented by co-treatment, were deemed higher probability candidate genes. As external cross-validation, gene expression data was cross-matched against linkage loci from human genetic studies, reports from the literature regarding biological roles, and changes in post-mortem brains from patients.Results: By integrating multiple internal and external lines of evidence, a list of candidate genes was generated, with three genes at the top: TAC1 (substance P), PENK (preproenkephalin) and DARPP-32. Other findings include clock genes, neurotransmitter genes, myelin genes, and neurotrophic genes, as well as their clustering into pathways and mechanisms.Conclusions: We propose that our approach is useful in helping unravel the genetic code of bipolar and related disorders.

391. Motor Retardation is Associated with Greater D2 Binding Potential in Depression

Jeffrey H. Meyer, Heather McNeely, Sandra Sagrati, Anahita Boovariwala, Alan Wilson, Sylvain Houle

Department of Psychiatry, Clarke Site, Centre for Addiction and

Mental Health, Toronto, ON, Canada

Background: It has been proposed that specific symptoms of depression may be mediated via distinct neurochemical phenomena. The [11C] raclopride binding potential (BP) found with positron emission tomography (PET) is an index of D2 receptors and is also sensitive to levels of extracellular dopamine such that higher D2BP occurs when dopamine is lower. It was hypothesized that putamen D2BP will be higher in motor retarded depressed subjects. The putamen region was chosen because indices of low dopamine in the putamen are associated with motor retardation in Parkinson’s disease.Methods: 20 drug free (i.e.>3 months), non-smoking depressed patients and 20 healthy age matched controls were recruited. Striatal D2 BP was found with [11C] raclopride PET. Motor retardation was measured with the finger tapping test and each subject also received a standard neuropsychological test battery.Results: The depressed group were significantly slower than healthy controls.(F1,38=5.5, p=0.02). In depressed subjects, putamen D2 BP was significantly associated with performance speed on the finger tapping test, after covarying out effects of age upon both variables (r=-0.48, p=0.03). In healthy subjects, putamen D2 BP was not significantly associated with performance speed (r=-0.27, p=0.2). The 10 depressed subjects with greater motor retardation had a significantly greater D2BP as compared to healthy subjects (F1,28=4.1, p=0.05).Conclusions: Abnormally elevated putamen D2 BP is associated with motor retardation during depressive episodes and it is likely that extracellular dopamine is lower in the putamen in motor retarded depressed patients. This has important implications for the treatment of motor retardation in depression.



392. Increased GABA in the Anterior Cingulate Cortex (ACC) of Children and Adolescents with Bipolar Affective Disorder (BD): A 4. 0 T MRS Study

Constance M. Moore1, Jean A. Frazier

2, Katrin Seifert

2,

Mary S. Ahn2, Jacob J. Venter

2, Martha R. Herbert

2,

Perry F. Renshaw1

1Brain Imaging Center, McLean Hospital/Harvard Medical School,

Belmont, MA, 2Child And Adolescent Psychiatry, McLean

Hospital/Harvard Medical School, Belmont, MA

Background: Short echo 4.0 T proton MRS data were acquired from the ACC (8cm3) of 7 children with BD (age:11.9Â±2.3 y.o.; F 4; M:3) and 7 HealthyComparisons (HC) (age:13.0Â±2.2 y.o.; F:5; M:2).Methods: All children were interviewed with the KSADS-PL. Two of the children with BD had a diagnosis of ADHD. Five of the BD children were medicated. Absolute peak areas were estimated using LCModel. The model included, but was not limited to: Ino, Gly, Cho, Cr, GABA, Glu, Gln and NAA. Voxel gray matter and white matter content were estimated.Results:

% Difference between the BD and HC

Measure % Difference

Cr -2.33

Cho 2.54

GABA 19.60

Glu 5.06

Ino -11.62

NAA -14.07

Age -8.77

Gray Matter .59

White Matter 2.01

GABA levels were higher in the ACC of subjects with BD. Excluding the two subjects on GABAergic medication (valproate) yielded GABA levels significantly higher in the BD group (p < 0.02: t-test).Conclusions: Increased GABA may be associated with BD. Given that there was little difference between the two groups glutamate levels these results suggest a dysregulation in the synthesis of GABA, to other compounds such as SSADH and NADH. It has been reported that at therapeutic concentrations valproate may enhance the activity of neuronal and glial GABA transporters. This would suggest that these drugs operate by removing GABA from synaptic vesicles.There was no difference in the voxel tissue content between the two groups.In addition, reduced NAA and Ino were associated with BD: these results are in agreement with the work of other groups.

393. Dopamine D2 Receptors in the Ventral Striatum in Major Depression

Franklin R. Schneier1,2

, Diana Martinez2,3

, Anissa Abi-Dargham

2,3, Peter S. Talbot

2,3, Henry Huang

2,3, Dah-

Ren Hwang2,3

, Michael R. Liebowitz1,2

, Marc Laruelle2,3

1Therapeutics, New York State Psychiatric Institute, New York, NY,

2Psychiatry, Columbia University College of Physicians and Surgeons,

New York, NY, 3Functional Brain Mapping, New York State

Psychiatric Institute, New York, NY

Background: The relationship of major depression to striatal dopamine dysfunction has appeared inconsistent in brain imaging studies. Prior studies have been limited, however, by insufficient resolution to image functional subregions of the striatum and little characterization of clinical features (e.g. depression subtype, anhedonia) that might be associated with ventral striatal motivation/reward circuitry.

Methods: Eight unmedicated outpatients with non-psychotic unipolar major depression were compared to 18 healthy control subjects matched for age, sex, and tobacco use. A high resolution PET camera was used to assess availability of D2 receptors (V3”, defined by ratio of [11C]raclopride binding in ventral striatum/ binding in cerebellum) at equilibrium.Results: Subjects with major depression had lower D2 receptor availability in the ventral striatum (V3” = 1.87 vs. 2.16 for controls, p = 0.028). The groups differed less in sensorimotor and associative subregions of the striatum. D2 receptor availability in the ventral striatum was further decreased among subjects with the melancholic subtype (n = 5) vs. matched controls (n = 11) (V3” = 1.77 vs. 2.11, p = 0.022). D2 receptor availability was associated with measures of usual mood reactivity (r = 0.66, p = 0.076), maximal mood reactivity (r = 0.84, p = 0.009), and to a lesser extent with the anhedonia subscale of the SANS (r = 0.49, p = 0.22).Conclusions: These findings suggest that major depression is associated with decreased D2 receptor availability in the ventral striatum. This difference may reflect dysfunction of ventral striatal reward circuitry associated with symptoms of anhedonia.

394. Associations of Age and Length of Illness with Hippocampus and Amygdala Volumes in Mood Disorder Patients

Sheila C. Caetano1,2,3

, Mark A. Nicoletti1, John P.

Hatch1, Paolo Brambilla

4, Roberto B. Sassi

2, Alan G.

Mallinger5,6

, Ellen Frank7, David J. Kupfer

5,7, Matcheri S.

Keshavan5, Jair C. Soares

1,3,8

1Department of Psychiatry, The University of Texas Health Science

Center at San Antonio, San Antonio, TX, 2Department of Psychiatry,

University of Sao Paulo School of Medicine, Sao Paulo, Brazil, 3South

Texas Veterans Health Care System, Audie L. Murphy Division, San

Antonio, TX, 4Department of Medicine and Public Health Section of

Psychiatry, University of Verona, Verona, Italy, 5Department of

Psychiatry, Western Psychiatric Institute and Clinic, University of

Pittsburgh School of Medicine, Pittsburgh, PA, 6Department of

Pharmacology, University of Pittsburgh School of Medicine,

Pittsburgh, PA, 7Department of Psychology, University of Pittsburgh,

Pittsburgh, PA, 8Department of Radiology, The University of Texas

Health Science Center at San Antonio, San Antonio, TX

Background: Hippocampus has been reported to be smaller in unipolar patients, while the amygdala seems to be enlarged in bipolar individuals. It has not been established if these abnormalities occur at an early phase or later during illness course. We hypothesized that length of illness would inversely correlate with hippocampal volumes in unipolar patients, whereas in bipolar patients it would directly correlate with amygdala volumes. Also, we predicted that the association between age and these structures volumes would be stronger in patients compared to healthy controls.Methods: 51 bipolar patients (mean age±S.D.= 29.7 ±13y, range= 10-61; 27 females), 31 unipolar patients (mean age±S.D.= 39.2 ±11.9y, range= 18-58; 24 females), and 71 healthy controls (mean age±S.D.= 30.1±11.6y, range= 11-53; 31 females) were studied. Hippocampus and amygdala were traced on high resolution MRIs. Partial correlation coefficients were adjusted by ICV and gender. Length of illness was log transformed to better fit normal distribution.Results: In unipolar patients, the left hippocampal volumes were inversely correlated with age (r= -0.57, p= 0.001) and a trend towards length of illness (r= - 0.35, p= 0.06). In bipolar patients, left amygdala volumes were directly correlated with age (r= 0.30, p= 0.035) and length of illness (r= 0.31, p= 0.03).Conclusions: Our findings support the involvement of neurodegenerative and/or compensatory mechanisms in the pathophysiology of amygdala and hippocampus abnormalities in bipolar and unipolar mood disorders.



This work was partly supported by MH01736, MH29618, MH30915, NARSAD, Veterans Administration, the Krus Endowed Chair in Psychiatry, and CAPES Foundation (Brazil).

395. Loss of Subicular Dendritic Spines in Major Psychiatric Disorders

Gorazd Rosoklija1, Snezana Rauski

2, Branislav

Mancevski1, Tereza Serafimova

3, Aleksej Duma

4, J.

John Mann5, Andrew J. Dwork

6

1Neuroscience / Psychiatry, New York State Psychiatric Institute /

Columbia University, New York, NY, 2Neuroscience, New York State

Psychiatric Institute, New York, NY, 3Psychiatry, School of Medicine,

Skopje, The former Yugoslav Republic of Macedonia, 4Neuroscience /

Psychiatry, Institute for Forensic Medicine, School of Medicine/

Columbia University, Skopje / New York, The former Yugoslav

Republic of Macedonia, 5Neuroscience / Psychiatry and Radiology,

New York State Psychiatric Institute / Columbia University, New York,

NY, 6Neuroscience / Pathology and Psychiatry, New York State

Psychiatric Institute / Columbia University, New York, NY

Background: Postmortem studies have consistently found loss of dendritic spines in schizophrenia. Most have focused on frontal cortex. We wished to determine the reproducibility of our earlier finding of pronounced loss of spines on apical dendrites of pyramidal cells in the subiculum of chronically institutionalized schizophrenia patients and some chronically institutionalized mood disorder patients.Methods: Golgi-Kopsch impregnations were performed on the left hippocampi of subjects autopsied at the Institute for Forensic Medicine in Skopje, Macedonia. Psychiatric diagnoses (or their absence) were determined by standardized interviews with relatives and by review of psychiatric records with the modified Diagnostic Evaluation After Death. This preliminary report includes 6 schizophrenia cases (mean age 44), six mood disorder cases (mean age 58; all suicides), and 4 nonpsychiatric cases (mean age 34).Results: A severe loss of dendritic spines (~80%) was found in both schizophrenia and mood disorders (F=260, p<.0005), including one mood disorder case who was treatment-naïve. Three mood disorder cases had never been institutionalized. The schizophrenia subjects had all been treated with antipsychotic drugs, but the mood disorder subjects had not.Conclusions: A profound loss of subicular spines in schizophrenia and mood disorders is confirmed . The subjects in this study were relatively young. Postmortem intervals were short (13±7 hours). All autopsies were performed in a single institution. Conditions for Golgi impregnation were optimal. The loss of spines appears to be unrelated to medication or institutionalization.MH64168, MH60877. NARSAD, American Foundation for Suicide Prevention, Lieber Center for Schizophrenia Research.

POSTER SESSION Mixed Topics

Friday, April 30, 5:30 PM-7:00 PM Location: Verrazano Ballroom, Metropolitan Hotel,

569 Lexington Avenue

396. Anterior Cingulate and Subgenual Prefrontal Cortical Changes in Regional Cerebral Blood Flow Following Rapid Tryptophan Depletion in Healthy Humans: A SPECT Study Using [

99mTc]HMPAO

Peter S. Talbot, Stephen J. Cooper

Department of Mental Health, Queen's University, Belfast, United

Kingdom

Background: In healthy humans, there is an apparent dissociation between cognitive and affective consequences of the reduced brain serotonin (5-HT) associated with rapid tryptophan depletion (RTD), as RTD gives rise to alterations in a consistent constellation of cognitive processes in the general absence of a change in mood. This study aimed to investigate possible brain mechanisms underlying the effects of reduced 5-HT on mood and cognition and their relative dissociation.Methods: 16 healthy, euthymic male subjects (mean age 39±9 yr) without a personal or family history of affective disorder had mood ratings and SPECT scans with the cerebral blood flow (rCBF) tracer [99mTc]HMPAO under reduced 5-HT (RTD) and control conditions, in a within-subject, double-blind, counterbalanced, crossover design.Results: There were 2 main findings: i) as expected, RTD was not associated with a significant mean change in mood across the group. However, across individuals there was significant covariation between the changes in mood and rCBF attributable to RTD in the subgenual (affective) anterior cingulate cortex (ACC) and associated regions (BA25 and posterior BA11 & 47; SPM99 p<0.05, corrected for multiple comparisons). The covariation was such that increasing sadness was associated with increased rCBF and vice versa; ii) when these mood-associated rCBF changes were removed, RTD was associated with reduced rCBF in the rostrodorsal (cognitive) ACC (BA32; SPM99 p<0.05, corrected).Conclusions: The results suggest that the dissociation between affective and cognitive consequences of RTD may be attributable to differential effects of RTD on the affective and cognitive functional subdivisions of the ACC.

397. FMRI of Amygdala Activation during Emotion Processing in Patients with Schizophrenia

Gabriele Sachs1, Simon Robinson

2, Rainer Strobl

1,

Ewald Moser3, Raquel E. Gur

4, Heinz Katschnig

1

1Psychiatry, University of Vienna, Vienna, Austria,

2Medical Physics,

University of Vienna, Vienna, Austria, 3Radiodiagnostics, University of

Vienna, Vienna, Austria, 4Psychiatry, University of Pennsylvania,

Philadelphia, PA

Background: Recent fMRI studies have indicated limbic activation in response to emotional stimuli, albeit with imaging methods which have recently been called into question. The present study employs a high resolution EPI protocol optimised for the amygdala and 3 T to investigate possible differences in emotion processing between patients with schizophrenia and healthy controls.Methods: 18 patients with schizophrenia (DSM-IV, SCID) and 18 age and sex-matched healthy controls viewed images of faces displaying happiness, sadness, anger, fear as well as neutral faces. FMRI was used to measure BOLD signal changes as subjects alternated between tasks requiring discrimination of emotional valence of the faces (positive or negative) and age (over 30 or under 30). All measurements were carried out using a 3 T Medspec S300 whole-body system. An optimised EPI protocol was employed; oblique axial slices of 2mm thickness,128x128 matrix, TEeff=46ms, 12 axial slices in TR=2s.Results: Activation in the bilateral amygdalae and fusiform gyrus was detected in patients with schizophrenia and controls when both tasks (emotional and age discrimination) were considered in combination. Group analysis showed a significant difference between patients with schizophrenia and controls for the emotion - age contrast in the bilateral amygdala and left hippocampus.Conclusions: A high resolution EPI protocol combined with high field strength (3T) has proved capable of detecting activiation in the amygdala and the fusiform gyrus. These results provide evidence for diminished amygdala activation in patients with schizophrenia that may play a key role in the impairment of emotion recognition in schizophrenia.



398. Abnormal Amygdala Volumes in Pediatric Bipolar Disorder


, Rene Olvera1, Kristina Hunter

1,

Mark A. Nicoletti1,2

, Manish Dalwani1,2

, Oswaldo Ortiz2,4

,John P. Hatch

1, Carlos Bazan

4, Charles L. Bowden

1,

Steven R. Pliszka1, Jair C. Soares

1,2,4



South Texas Veterans Health Care System, Audie L. Murphy Division,

San Antonio, TX, 3Department of Psychiatry, University of Sao Paulo

School of Medicine, Sao Paulo, Brazil, 4Department of Radiology, The

University of Texas Health Science Center at San Antonio, San

Antonio, TX

Background: Amygdala enlargement and normal hippocampal volumes have been reported in most studies in adult bipolar subjects. Preliminary studies in pediatric bipolar populations suggest smaller amygdala volumes. We examined the amygdala and hippocampal volumes in children and adolescents with bipolar disorder to attempt to replicate prior findings of smaller amygdala in pediatric bipolar individuals.Methods: 14 children and adolescent bipolar patients (mean age±S.D.=12.6±2.9y, range=8-17y, 8 males) and 8 healthy controls (mean age±S.D.=14.9±3y, range=12-19y, 7 males) were studied on an 1.5T Philips Intera 8.1.1. scanner.Results: Bipolar patients had significantly smaller left (F=11.13, df=1/17, p= 0.004) and right (F=6.39, df=1/17, p= 0.022) amygdala compared to healthy controls (ANCOVA with ICV, age and gender as covariates). In bipolar patients, left amygdala volumes had a trend towards direct correlation with the Young Mania Rating Scale (YMRS) scores (rho= 0.52, p= 0.055). We did not find any significant difference in hippocampal volume.Conclusions: Children and adolescents with bipolar disorder have smaller amygdala volumes compared to healthy controls. Moreover, left amygdala volumes may be directly correlated with measures of illness severity, such as YMRS scores. The amygdala in bipolar patients appears to be smaller in an early phase of the illness, but as it progresses, a continuing over-drive of this structure during brain development could possibly result in its enlargement in adulthood, as a result of compensatory mechanisms.This work was partly supported by MH 01736, M01-RR-01346, the Krus Endowed Chair in Psychiatry, the Veterans Administration, and CAPES Foundation (Brazil).

399. BDNF Serum Concentrations in Healthy Volunteers are Associated with Depression-Related Personality Traits

Undine Lang, Rainer Hellweg

Department of Psychiatry, Charité University Medicine Berlin, Campus

Benjamin Franklin, Berlin, Germany

Background: Neuroticism is a strong marker for vulnerability to depression, and a personality trait accompanied with anxiety, low mood and hostility. The issue of neurotrophins is recognized as a new lead in the quest for a deeper understanding of mood disorders. This hypothesis has emerged from experimental evidence suggesting that antidepressant drugs might work by a neuroprotective effect through stimulation of the neurotrophin expression in distinct regions of the brain.Methods: Endogenous levels of brain-derived neurotrophic factor (BDNF) were measured in the serum samples of 118 healthy unrelated volunteers (64 male, 54 female, age: 42.1±13.0), and the NEO Five Factor Inventory (NEO-FFI) that is a psychometrically sound and widely used instrument assessing five global personality domains (including neuroticism) has been performed in all subjects.

Results: BDNF serum values amounted to 16.3± 7.3 ng/ml. BDNF concentration correlated significantly with age (r=0.182, p=0.048), but showed no gender differences (male 16.1± 7.2, female 16.5± 7.4 ng/ml). A negative correlation between the BDNF serum concentration and the depression-related factor neuroticism has been found (r=-0.212, p=0.022).Conclusions: Low BDNF levels in healthy humans with depressive personality traits might constitute a risk marker, reflecting a personality profile, which is linked to vulnerability to mood disorders. These results provide further support for the hypothesis that BDNF may be central to the development of depressive mood states.

400. Neural Basis for Heritable Differences in Startle Gating-Disruptive Effects of Dopamine Agonists in Rats

Neal R. Swerdlow1, Jana Goins

1, Shanda Gomes

2,

Orrin Franko1, Lillian Ma

1, Sarah Crain

1, Jody M.

Shoemaker1

1Psychiatry Department, University of California, San Diego, La Jolla,

CA,2Neuroscience, Amherst College, Amherst, MA

Background: Sprague Dawley (SD) rats are significantly more sensitive than Long Evans (LE) rats to the disruption of prepulse inhibition (PPI) of startle by systemically-administered dopamine agonists. This strain difference is heritable and insensitive to cross-fostering. Inherited differences in the ability of elevated dopamine activity to disrupt PPI may be useful for understanding the neural basis for PPI deficits in schizophrenia and other neuropsychiatric disorders. For this reason, we are studying the neural basis for these SD vs. LE differences.Methods: PPI was assessed in male SD and LE rats after amphetamine administered either: 1) systemically; 2) into the nucleus accumbens core (NAC); 3) into the anteromedial striatum (AMS); or 4) into both the NAC+AMS.Results: SD > LE sensitivity to the PPI-disruptive effects of amphetamine was observed after systemic and intra-NAC administration, though qualitatively this effect appeared more robust after systemic vs. intra-accumbens administration. PPI disruption was evident after intra-NAC infusion of 10, 20 or 40 µgamphetamine in SD rats, and after 20 µg amphetamine in LE rats. PPI was not significantly reduced in either strain after intra-AMS infusion of amphetamine; combined infusion in the NAC+AMS resulted in significant PPI reduction in SD but not LE rats.Conclusions: SD > LE strain differences in PPI-disruptive effects of amphetamine are reproduced after intra-NAC but not intra-AMS amphetamine infusion. The involvement of other brain regions (accumbens shell, basolateral amygdala) in this heritable difference is under investigation. Supported by MH68366, MH01436.

401. Are Proteins Expressed Differently in Postmortem Brain of Schizophrenia Patients Affected in Brain of Animal Models of Obstetric Complications?

Galila Agam1, Carmit Nadri

2, Barbara K. Lipska

3, Daniel

R. Weinberger4, R. H. Belmaker

1

1Stanley Research Center, Ben-Gurion University, Beer-Sheva, Israel,

2Stanley Foundation Research Center, Ben-Gurion University, Beer-

Sheva, Israel, 3Clinical Brain Disorders Branch, NIMH, Bethesda, MD,

4Clinical Brain Disorders Branch MD, NIMH, Bethesda, MD

Background: Glycogen synthase kinase-3 (GSK-3) is a protein kinase highly abundant in brain and involved in signal transduction cascades. Its activity, protein levels and mRNA levels have been found to be ~40% lower in postmortem frontal cortex of schizophrenic patients but not in occipital cortex, suggesting regional specificity. No reduction was found in lymphocyte GSK-3 parameters in schizophrenic patients.



Methods: Protein levels were determined by Western blotting.Results: In the schizophrenia-related neonatal ventral hippocampal lesion rat model GSK-3beta protein levels were significantly lower than in sham rats, favoring perinatal insult as a cause of low GSK-3 in schizophrenia. In rats, cold restraint stress did not change GSK-3beta protein levels. Chronic treatment of rats with lithium, valproate, haloperidol or clozapine did not change cortical GSK-3beta protein levels ex-vivo, suggesting that low GSK-3 in schizophrenia is not secondary to stress or drug treatment.Conclusions: Taken together, these studies suggest that low GSK-3 in post-mortem brain of schizophrenic patients is a late consequence of neurodevelopmental insult in schizophrenia and not a genetic marker of schizophrenia. Indeed, neither GSK-3alpha nor GSK-3beta are coded by chromosomal regions for which linkage has been implicated for schizophrenia. Further studies are now aiming at determining whether nonspecific neonatal damage or only specific factors cause low GSK-3 as a late effect. The results will be compared with other proteins found to be altered in postmortem brain of schizophrenic patients (synaptophysin, reelin, neuregulin1) but mapped to chromosomal regions for which linkage with schizophrenia has been reported.

402. Differential Long-Term Effects of Multiple Doses of Risperidone on Dopamine Receptors in Juvenile Animals

Taylor Moran-Gates, Christopher Grady, Ross J. Baldessarini, Frank I. Tarazi

Psychiatry, Harvard Medical School, Belmont, MA

Background: Atypical antipsychotic drug risperidone (RISP) is increasingly prescribed to pediatric patients with psychotic disorders. Since the effects of RISP on dopamine (DA) receptors in juvenile subjects remain unclear, we studied the long-term effects of low, moderate and high doses of RISP in young rats.Methods: Four groups of juvenile rats [age 22d] received daily injections of vehicle or three doses of RISP (0.3, 1.0 or 3.0 mg/kg). Subjects were sacrificed at age 42d and their brains were processed for in vitro DA receptor autoradiography.Results: Moderate and high doses of RISP (1.0 and 3.0 mg/kg) significantly increased DA D1 receptors in nucleus accumbens [NAc; by 34% and 64%] and caudate-putamen [CPu; 53%, 75%]. RISP (0.3, 1.0 and 3.0 mg/kg) dose-dependently increased D2 receptors in medial prefrontal cortex [MPC; 21%, 41%, 55%] and hippocampus [HIPP; 24%, 57%, 90%] and D4 receptors in HIPP [28%, 37%, 52%]. In addition, high dose of RISP increased D4 receptors in NAc [26%] and CPu [28%]. In contrast, only moderate and high doses of RISP increased D2 receptor levels in CPu [20%, 36%]. D3 receptors in forebrain regions were unaltered by any treatment.Conclusions: Long-term treatment with different doses of RISP exerts differential effects on DA receptors. Low dose of RISP mediates its beneficial therapeutic effects by selectively targeting DA receptors in cortical and limbic brain regions while sparing extrapyamidal system. High dose of RISP, although clinically effective, has the ability to induce extrapyramidal side effects in juvenile patients.Supported by Janssen Pharmaceutica & NARSAD

403. Chronic Lipopolysaccharide Results in Tolerance to Alterations to Basic Reward Behavior, Body Weight, and Food and Water Consumption

Richard De La Garza1, Erika Pedrosa

1, Cordelia

Stearns1, Gregory M. Asnis

2

1Psychiatry and Neuroscience, Albert Einstein College of Medicine,

Bronx, NY, 2Psychiatry, Albert Einstein College of Medicine, Bronx,

NY

Background: Acute lipopolysaccharide (LPS) exposure has been shown to induce robust disturbances in basic reward behavior (termed anhedonia). We sought to determine the effects of repeated LPS exposure on sucrose pellet self-administration (SA) behavior, neuroendocrine and neuroimmune activation, and monoamine turnover.Methods: Male, Wistar rats (N=8/grp) were trained to press a lever for sucrose pellet reward and then treated with saline (1 ml/kg, ip) or LPS (100 µg/kg, ip) for 6 days, followed by a final injection of LPS or saline on day 7. Brain tissue was extracted for gene expression and tissue monoamine analysis, and plasma isolated for corticosterone analysis.Results: Acute LPS significantly reduced sucrose pellet SA behavior and total reinforcers obtained. Importantly, repeated exposure to LPS resulted in a tolerance to the acute behavioral effects. In addition, tolerance developed to acute LPS-induced decreases in body weight, and home cage food and water consumption. Alterations to hippocampus and pituitary gene expression (pro-inflammatory cytokines and stress hormones) and an analysis of tissue monoamines (via HPLC) will be provided.Conclusions: Overall, the data are expected to contribute to an understanding of the effects of acute and repeated LPS exposure on brain and behavior. Although behavioral changes showed rapid adaptation in this model, a critical future question is whether some of the long-term neurobiological changes that persist after repeated exposure are capable of altering behavior some time later, which may have greater relevance to an animal model of depression.

404. Selective 5-HT or NA Reuptake Inhibitors vs Mixed 5-HT/NA Reuptake Inhibitors in Animal Models of Pain

Connie Sanchez

Pharmacology, H Lundbeck A/S, Copenhagen, Denmark

Background: Antidepressants are frequently used as adjuvants for analgesic treatment of pain1. Furthermore the somatic complaints accompanying depression are often relieved by antidepressants. The pharmacological mechanisms by which such pain relief is mediated remain unclear. We investigated the analgesic potential of the most selective serotonin reuptake inhibitor, escitalopram2, the non-selective 5-HT reuptake inhibitors, venlafaxine and duloxetine, and the tricyclic antidepressant, desimipramine, which has a high degree of selectivity for noradrenaline versus 5-HT reuptake inhibition in the mouse grid shock and formalin models of acute pain.Methods: Male mice NMRI and C57/Black were used for the grid shock and formalin tests, respectively. The floor of the grid shock box consists of metal wires and tolerance to increasing milliamperage is measured before and after drug treatment. The current stops in response to a mouse squeak. In the formalin test, the duration of paw licking behaviour is measured for 0-5 and 20-30 min (phase 1 and 2) after intra-plantar injection of 20µL formalin (2.5%) in a hind paw.Results: The antidepressants had minimal effects in the grid shock test, whereas all drugs significantly reduced the paw licking response to formalin, particularly in phase 2, where ED50 values were 0.71, 5.4, 0.69, and 0.68 mg/kg for escitalopram, venlafaxine, duloxetine, and desimipramine, respectively.Conclusions: Escitalopram and desimipramine were as effective as the non-selective 5-HT reuptake inhibitors in a rodent model of acute pain.1.Sindrup SH, Jensen TS. Pain 1999; 83: 389-400.2.Sánchez C et al., Psychopharmacology. 2003;167:353-362.



405. Cortical NK1 Receptor Expression in a Rat Model for Tardive Dyskinesia

Megan E. Dunning, Blair L. Bowers, Susan E. Bachus

Psychology Department & Krasnow Institute, George Mason

University, Fairfax, VA

Background: Both frontal cortical damage (Gunne et al., Psychopharmacology

77:134, 1982) and intracranial administration of substance P receptor agonists (Liminga & Gunne, Behav. Brain Res. 57:93, 1993) have been found to exacerbate chronic haloperidol (HAL)-induced vacuous chewing movements (VCMs), a rat model for tardive dyskinesia (TD). We assessed cortical NK1 receptor mRNA in rats treated with chronic HAL to determine whether effects of HAL on these receptors might play a role in the induction of VCMs.Methods: Group-housed male Long-Evan rats (starting weights 90-165 g) were monitored over 7 weeks for baseline VCMs in two-minute samples weekly, and for 24 weeks during chronic HAL decanoate (28.5 mg/kg/ml, i.m., at 3 week intervals; n=43) or vehicle (sesame oil; n=20) under both quiet and noisy conditions. Subsequently, brains were frozen and sectioned onto slides for assay of NK1 mRNA in frontal and parietal cortices by in situ hybridization.Results: There was not a statistically significant effect of chronic HAL on cortical NK1 receptor mRNA. However, there was a positive correlation between the NK1 receptor expression in the frontal cortex and VCMs (r=0.262, p<0.04) under noisy conditions, but not under quiet conditions. This relationship was not significant in the control region (parietal cortex) or among the vehicle-treated control rats.Conclusions: Thus, while individual variability obscured an overall drug effect, the parallel effects across the HAL-treated rats, on both VCMs and frontal cortical NK1 mRNA, do implicate this regionally specific neurotransmitter system in the etiology of VCMs, and by analogy, TD.

406. Specific Alterations of Cerebral Hemodynamics during a Planning Task: A Transcranial Doppler Sonography Study

Daniel Schuepbach1, Beat A. Frauenfelder

1, Ralf W.

Baumgartner2, Daniel Hell

1

1Psychiatry, Psychiatric University Hospital, Zurich, Switzerland,

2Department of Neurology, University of Zurich, Zurich, Switzerland

Background: Planning forms part of the executive functions, whose main neurological correlate, the central executive, is located in the dorsolateral prefrontal cortex (DLPFC).Methods: The Stockings of Cambridge (SOC), a test originally designed to distinguish between automated (routine) and active (no routine) processes of planning, was introduced to twenty-one healthy subjects while they underwent bilateral transcranial Doppler sonography (TCD) of the middle (MCA) and anterior (ACA) cerebral arteries. Different levels of difficulty were applied during continuous registration of peak mean cerebral blood flow velocity (CBFV). A specific test procedure allowed separating the actual planning from the execution phase. There was also a similar control task, which did not involve planning.Results: CBFV differed between the planning, execution and control conditions (MCA: P<0.01; ACA: P<0.001) but did not show a significant difference between the MCA and ACA (P>0.1). Easy tasks yielded a more rapid increase of CBFV in the MCA compared to difficult problems during planning (P<0.05).Conclusions: Specific patterns of cerebral blood flow velocity support the idea of different cognitive challenges for planning and control and between easy and difficult conditions.

407. Reward Prediction, Learning and the Mesolimbic Dopamine System - Testing a Computational Model of Pavlovian Learning Using fMRI in Humans

Jimmy Jensen1, Andrew J. Smith

2, Matthaeus Willeit

1,

Irina Vitcu1, Shitij Kapur

1

1PET Centre, Centre for Addiction and Mental Health, Toronto, ON,

Canada,2Psychology, McMaster University, Hamilton, ON, Canada

Background: Learning occurs according to the discrepancy or “prediction error” between the expected outcome and the actual outcome - computationally operationalized as a temporal difference (TD) learning algorithm The firing of the midbrain dopamine neurons projecting to the ventral striatum (VS) conforms to the predictions of this algorithm during learning in monkeys. We wanted to test how the TD-model fares in understanding brain changes during learning in humans.Methods: Ten subjects were exposed to a conditioning paradigm in which a neutral visual stimulus predicted winning money (appetitive), while another predicted unpleasant cutaneous electrical stimulation (aversive). SPM analysis was used to assess whether brain activations, especially in the mesolimbic dopamine projections, conformed to the predictions of the TD algorithm.Results: As subjects learnt to associate visual stimuli with appetitive and aversive events it led to an activation in the ventral striatum. During appetitive learning activity in the ventral striatum covaried as predicted by TD algorithm. However, aversive learning also led to changes in the VS that correlated positively with TD-algorithm.Conclusions: The activations of the VS in this paradigm are consistent with it representing a reward-prediction error signal for learning. However, while the standard TD-model predicts a positive response when things are ‘better than expected’ and a negative response when things are ‘worse than expected’ – we find a positive response whenever things are “different from expected.” These results suggest that the ventral striatum activations in humans reflect prediction of salience rather than the prediction of positive reward alone.

408. Declarative and Procedural Memory Consolidation during REM-Sleep in Aging

Orla P. Hornung1, Francesca Regen

1, Heidi Danker-

Hopfe1, Michael Schredl

2, Isabella Heuser

1

1Department of Psychiatry, Charité - University Medicine Berlin,

Campus Benjamin Franklin, Berlin, Germany, 2Sleep Laboratory,

Central Institute of Mental Health in Mannheim, Mannheim, Germany

Background: Aging is accompanied by changes on many different levels including memory processing and sleep. Negative effects of aging on declarative and procedural memory as well as on REM-sleep characteristics such as REM-sleep percentage have been repeatedly shown. In light of recent findings which underline the importance of REM-sleep for memory consolidation in young adults, memory-promoting effects of REM-sleep in older adults are of particular interest. A better understanding of the function of REM-sleep in memory processing with aging may also further our knowledge of mechanisms involved in Alzheimer’s disease where declining memory function is paralleled by a reduction in REM-sleep percentage.Methods: Participants (60-85y/o) spend one adaptation night in our sleep laboratory. Apart from applying a REM-sleep deprivation paradigm in two groups during the study night, REM-sleep augmentation is achieved physiologically through REM-rebound and pharmacologically by a placebo-controlled AchE-Inhibitor in two more groups. Performance in a procedural, i.e. mirror-tracing, and declarative learning task, i.e. paired-associate-list, is investigated before and after the study night.Results: Results are based on n=47 in the augmentation groups. The most pronounced association of REM-sleep with morning memory performance,



after statistically controlling for evening trials, was found concerning performance-time in the procedural learning task (test1: r=-.310*[p=.019]; test2: r=-.274*[p=.035]; test3: r=-.441**[p=.001]; test5: r=-.349*[p=.022]; test6: r=-.247†[p=.055]). In contrast, there was no significant correlation between REM-sleep percentage and declarative learning.Conclusions: REM-sleep seems to be clearly associated with procedural memory consolidation in aging. Increasing REM-sleep percentage may therefore be a strategy to enhance procedural learning in older adults.

409. Differences in Performance on Neuropsychological Tests between people with Asperger’s Syndrome and those with High Functioning Autism

Fiona Z. Ambery1, Ailsa J. Russell

2, Lindsay

Richardson1, Declan G. M. Murphy

1

1Psychological Medicine, Institute of Psychiatry, London, United

Kingdom,2Clinical Psychology, Institute of Psychiatry, London, United

Kingdom

Background: With the aim of securing a clear diagnostic differentiation between Asperger’s Syndrome (AS) and High-Functioning Autism (HFA), previous studies have investigated neuropsychological functioning in the two groups. It is difficult to determine if typical patterns of neuropsychological function have been found, owing to differences in the diagnostic criteria used, the use of children rather than adults, and the limited range of tests administered.Methods: A comprehensive neuropsychological battery of tests was administered to a group of adults of normal intellect with AS (N=11), a group with HFA (N=11) and healthy controls (N=11). The AS and HFA groups were diagnosed using ICD-10 criteria by experienced clinicians with the majority receiving an ADOS or ADI. Subjects were pair-matched for VIQ and age. There were no significant differences on measures of PIQ between the groups.Results: Analysis of variance showed significant differences between the groups on measures of verbal and visual memory. People with AS were significantly better than controls on verbal memory tasks but performed significantly less well than the HFA group on visual memory tests. The AS group did not exhibit a VIQ-PIQ differential in favour of VIQ. However, the HFA group was found to be significantly more likely to have a PIQ greater than VIQ.Conclusions: We reported measurable differences in the cognitive profiles of people with HFA and those with AS. Relative to HFA, the AS profile is characterised by strong verbal memory skills and impaired visual memory. These differences support a diagnostic distinction between the two disorders.

410. The Role of the N-Methyl-D-Aspartate Receptor (NMDAR) in the CA3 Field of the Hippocampus in Context Information Processing

Tarek K. Rajji1,2

, David Chapman1, Howard B.

Eichenbaum3, Robert W. Greene

1,2

1Psychiatry, University of Texas Southwestern Medical Center at

Dallas, Dallas, TX, 2Mental Health, North Texas VA Health Care

System, Dallas, TX, 3Psychology, Boston University, Boston, MA

Background: Context information processing deficit is believed to be core pathology in schizophrenia. The hippocampus has been shown to mediate contextual learning in animal models, while computational analyses have suggested a critical role for the CA3 region. Thus, we examined the role of CA3 NMDAR’s in contextual learning.Methods: We used the Cre-loxP system and the adeno-associated viral (AAV) vector, to mediate a focal NMDAR-NR1 knockout in CA3 of adult male mice. We designed a paradigm of contextual appetitive conditioning of two olfactory

cues, A and B. Depending on whether two cups filled with scented-sand were presented in context X or Y, the A- or B-scented cup was baited, respectively. After learning one set of contexts/odors, mice were microinjected with AAV-Cre, bilaterally into CA3. Ten days later, they were tested on recalling the same set, and then on acquiring a new set. The knockout sites were verified with Cre immunocytochemistry and NR1 in situ hybridization. Whole-cell patch-clamp recordings confirmed that NMDAR’s were functionally absent. AAV-lacZ injections were used in controls.Results: Compared to controls, and to themselves before the injections, AAV-Cre mice were impaired in acquiring new contextual associations, but not in recalling old ones. NMDAR-dependent LTP and NMDAR evoked currents were selectively absent at CA3- commissural/associational synapses in AAV-Cre injected mice.Conclusions: Functional NMDAR’s in CA3 fields of the hippocampus are essential for the acquisition of context information, but not recall. This finding might advance our understanding of the pathophysiology of schizophrenia, especially with respect to the cognitive impairment.

411. Memory Induced Gamma Band Activation

Colleen A. Brenner, Brian F. O'Donnell, William P. Hetrick

Department of Psychology, Indiana University, Bloomington, IN

Background: It has been hypothesized that the synchronous activation of neural ensembles, particularly in the gamma band (24-60 Hz), may be associated with the binding of features of a visual scene to create a coherent representation of the stimulus. The present study examined whether the maintenance of a visual stimulus in short-term memory throughout the delay in a delayed match-to-sample task would induce sustained oscillatory gamma band activity.Methods:19 healthy subjects were presented with a visual delayed match-to-sample task in which they had to remember the spatial configuration of the stimulus. A staircase method was used to modulate the difficulty of the task, maintaining accuracy at approximately 88%. A control task in which subjects did not need to remember the stimulus was also presented. EEG activity was recorded from 61 sensors during the experiment, and single trial event-related spectral perturbation (ERSP) was calculated.Results: Increased induced gamma band activity was observed during the delay in the memory condition, compared to the no-memory condition, at frontal and central electrode sites beginning 200 ms post stimulus offset and continuing until the onset of the second stimulus. There were no differences between the memory and no-memory condition when averaged data was used, indicating that increased activity in the gamma range was induced, and not stimulus locked.Conclusions: These analyses provide preliminary support for the role of high frequency oscillatory activity in the maintenance of a visual stimulus representation in short-term memory.

412. Role of P1 and N1 Neocortical Brain Generators in Auditory Sensory Gating.

Oleg A. Korzyukov1, Martin Kurthen

2, Christian Elger

2,

Thomas Grunwald2, Thomas Dietl

2, Mario Staedtgen

2,

Peter Trauthner2, Nashaat N. Boutros

1

1Psychiatry, Yale University, West Haven, CT,

2Department of

Epileptology, University of Bonn, Bonn, Germany

Background: Inhibition of the response to incoming irrelevant sensory input (sensory-gating) is a fundamental protective mechanism of the CNS. Sensory gating is usually measured in the paired-click paradigm (S1-S2) as the degree of amplitude reduction of the S2 auditory P50/N100 responses. The neuronal generators of P50/N100 responses and their role in sensory gating are not well known.



Methods: Intracranial Event-related potentials (ERPs) were measured from 19 epilepsy patients undergoing invasive presurgical evaluation. Four of them had grid electrodes covering areas of the parietal and/or temporal lobe.Results: Neocortically recorded ERP revealed Posterior-Temporal lobe junction (PTj) as one of the brain areas that contribute to generation of P50. This was evidenced by polarity inversions of P50 at neighboring electrodes. Sensory habituation of P50 response was most evident at the same electrodes where P50 to S1 were measured. Polarity inversions of N100 response was found in temporal lobe areas in the vicinity of the auditory cortex. Unlike the P50, N100 sensory gating was not evident in all brain regions where N100 seems to be generated.Conclusions: Present data suggest that PTj region contributes to P50 generation and P50 auditory sensory gating. Our data also suggest that in spite of partial anatomical overlapping of P50 and N100 brain generators sensory gating that occur during time ranges specific to these two responses might have distinct brain mechanisms. Neocortical generators of P50 demonstrate a great deal of involvement in the process of sensory gating while not all generators of N1 exhibited sensory gating.

413. Topographic Quantitative EEG Effects Immediately Following Tobacco Exposure and at 24 Hours Post Smoking Abstinence

Harold Pinkofsky1, Frederick A. Struve

2, Gloria Patrick

3

1Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, PA,

2Psychiatry, Psychiatry, Yale Medical School & VA CT Healthcare

System, CT, 3Medical Research, Overton Brooks VAMC, Shreveport,

LA

Background: The addictive properties of tobacco are recognized. Achieving abstinence is difficult, particularly for psychiatric patients. While subjective withdrawal effects are recognized, a delineation of the electrophysiological effects of withdrawal remains incomplete.Methods: Twenty-one channel eyes closed EEGs were obtained from 9 normal smokers before and after smoking and following 24 hours of abstinence. Sixty alert artifact free 2.5-sec EEG epochs per subject were quantified yielding estimates of total mean frequency, and mean frequency, absolute power, and relative power within each traditional EEG band at all scalp locations. Coherence and power asymmetry measures were also obtained. Changes across conditions were assessed using repeated measures ANOVAs.Results: Tobacco smoking and 24 hours of abstinence produced profound electrophysiological effects. Smoking produced significantly increased total mean frequency and alpha frequency, significantly decreased absolute and relative theta power, and significantly decreased delta absolute power. Abstinence produced significant effects opposite in direction to those of acute smoking. These included decreased total mean frequency, decreased alpha and beta mean frequency, decreased beta relative power and extreme increases in theta absolute and relative power and delta absolute power. Coherence and asymmetry measures did not significantly change. EEG effects involved widespread cortical regions.Conclusions: The EEG spectra is substantially altered by both acute smoking and tobacco withdrawal. Previously reported findings of tobacco related changes in alpha are replicated and extended by results involving all quantitative EEG variables. Topographic quantitative EEG effects of tobacco withdrawal may be a electrophysiological substrate of subjective tobacco withdrawal symptoms.

414. Transient Frontal EEG Theta Produced by Laboratory Marijuana Smoking Mimics Persistent Frontal Theta Seen in Extremely Long (Mean 19. 6 years) Marijuana Users

Frederick A. Struve1, Barbara R. Manno

2, Gloria

Patrick3

1Psychiatry, Yale Medical School and VA Connecticut Healthcare

System, West Haven, CT, 2Psychiatry, Louisiana State University

Health Sciences Center, Shreveport, LA, 3Medical Research, Overton

Brooks VAMC, Shreveport, LA

Background: Previously we documented elevated alpha absolute and relative power and coherence over frontal cortex ("alpha hyperfrontality") in chronic marijuana users. Marijuana causality was confirmed by producing "alpha hyperfrontality" as a transient effect following double-blind placebo controlled marijuana smoking. When subsequent pilot data showed elevated frontal theta in extremely long duration (mean = 19.6 years) marijuana users we wished to determine if this excess frontal theta could also be duplicated as a transient effect with an experimental design using controlled marijuana smoking.Methods: On three days spaced one week apart eight subjects smoked either a low (1.77% THC), high (3.54% THC) or placebo marijuana "joint" under double-blind counterbalanced conditions. A total "theta hyperfrontality" score was obtained by averaging Z-scores for theta absolute power, relative power, and coherence separately across three frontal electrode groups and then combining these averages into a grand average. The total theta hyperfrontality score and three component scores (absolute power, relative power, coherence) were computed before, during, and at various time points following smoking.Results: High dose marijuana significantly increased frontal theta absolute power (p<0.01) and coherence (p<0.009) but not relative power. In a larger sample of 18 daily marijuana users, frontal theta relative power correlated with duration in years of marijuana use (r=0.57, p=0.01)Conclusions: The theta hyperfrontality seen in extremely long-term marijuana users was successfully duplicated in an acute smoking experimental design. This supports the contention that marijuana was causal in generating the frontal theta activity seen in the chronic user.

415. A Major Role for Glutamatergic Synapses in Autism

Stephane Jamain1, Hélène Quach

1, Catalina Betancur

2,

Maria Rastam3, Catherine Collineaux

2, Carina Gillberg

4,

Henrik Soderstrom5, Bruno Giros

6, Marion Leboyer

6,

Christopher Gillberg3, Thomas Bourgeron

1,7

1Human Genetics and Cognitive Functions, Institut Pasteur, Paris,

France,2Neurobiology and psychiatry, INSERM U513, Paris, France,

3Child and adolescent psychiatry, Göteborg University, Göteborg,

Sweden, 43Department of Child and Adolescent Psychiatry, Göteborg

University, Göteborg, Sweden, 5Department of Child and Adolescent

Psychiatry, Göteborg University, Göteborg, Sweden, 6Neurobiologie et

psychiatrie, INSERM U513, Paris, France, 7Human Genetics and

Cognitive Functions, University Paris 7, Paris, France

Background: Autism is characterised by impairments in reciprocal social interaction and communication as well as restricted and stereotyped patterns of interests and activities. Several chromosomal regions are candidate for predisposition to these syndromes. On the basis of linkage analyses and/or chromosomal rearrangements, we analysed three regions on chromosome 6q16, Xq13 and Xp22.3.Methods: We characterised three genes (GRIK2, NLGN3 and NLGN4) and examined the nucleotide diversity of these genes in families with autism.Results: On chromosome 6q16, one haplotype (P = 0,0004) and one variation M867I (P = 0,007) of the GRIK2 gene are more maternally transmitted to the



affected children. On chromosome X, we identified a de novo frameshift mutation in NLGN4, an X-linked neuroligin, segregating in a familial case of autism and Asperger syndrome (AS). In a second family with two affected brothers, one with typical autism and the other with AS, we identified a R451C mutation in NLGN3 inherited from the mother and changing a highly conserved arginine residue into cysteine within the esterase domain of this cell adhesion molecule.Conclusions: Both GRIK2 and Neuroligins share common binding partners and seem to be specific to glutamatergic synapses. Among the various proteins involved in the establishment of the neural networks, cell adhesion molecules and kainate receptors are crucial factors for the formation of a functional synapse. Therefore, we hypothesise that a defect in these proteins may abolish formation, stabilisation and/or recognition of specific synapses essential for the communication processes that are deficient in subjects with autistic spectrum disorder.

416. Lack of Association HTR3A and HTR4 Polymorphisms with Antipsychotic Response to Risperidone (RIS)

Yoshio Yamanouchi1, Nakao Iwata

1, Tatsuyo Suzuki

1,

Tsuyoshi Kitajima1, Masashi Ikeda

2, Norio Ozaki

2

1Psychiatry, Fujita Health Univeristy School of Medicine, Toyoake,

Aichi, Japan, 2Psychiatry, Nagoya Univeristy Graduate School of

Medicine, Nagoya, Aichi, Japan

Background: We previously reported that D2 receptor gene haplotype could predict the antipsychotic response of RIS in Japanese schizophrenia. In this study, we furtherer examined association between RIS response and two serotonergic candidate genes, 5-HT3A receptor gene (HTR3A) and 5-HT4 receptor gene (HTR4).Methods: 80 Japanese patients with schizophrenia were given RIS for 8 weeks. Clinical symptoms were evaluated using by the Positive and Negative Syndrome Scale (PANSS). Candidate polymorphisms in HTR3A and HTR4 were genotyped. Multiple linear regressions were used to analyze the effects of these genotypes and other clinical factors on reduction rate of PANSS. This study was approved by the ethics committee of Fujita Health University and Nagoya University. Written informed consent was obtained from all participants in this study.Results: After adjustment for the effects of confounding factors such as age, gender, and the dose of RIS, the genotypes of HTR3A and HTR4 polymorphisms, as well as other clinical factors, did not significantly influence reduction rate of PANSS.Conclusions: HTR3A and HTR4 genes were not associated with antipsychotic response of RIS in this study. Further investigation needed because the type II error due to small sample size may cause this negative association study.

417. Schizophrenia and the Syntaxin 1a Gene

Albert H. Wong1, Joseph Trakalo

2, Olga Likhodi

2,

Muneeb Yusuf1, Antonio Macedo

3, Maria-Helena

Azevedo3, Tim Klempen

1, Michelle T. Pato

4, William G.

Honer5, Carlos M. Pato

4, Hubert H.M. Van Tol

1, James

L. Kennedy1

1Psychiatry, University of Toronto, Toronto, ON, Canada,

2Psychiatry,

Centre for Addiction and Mental Health, Toronto, ON, Canada, 3Psychiatry, University of Coimbra, Coimbra, Portugal,

4Psychiatry,

SUNY, Buffalo, NY, 5Psychiatry, University of British Columbia,

Vancouver, BC, Canada

Background: Both microarray and candidate molecule studies have demonstrated that protein and mRNA expression of syntaxin and other genes involved in synaptic function are altered in the cerebral cortex of patients with schizophrenia.Methods: Genetic association between polymorphic markers in the syntaxin1a (STX1a) gene and schizophrenia was assessed in a matched case-control sample of 192 pairs, and in an independent sample of 186 nuclear families. STX1a mRNA levels were measured in post-mortem samples of dorso-lateral prefrontal cortex (BA46) from patients with schizophrenia, bipolar disorder and unaffected controls (35 subjects each).Results: In the family-based sample, a significant genetic association was found between schizophrenia and one of the four polymorphisms tested: an intron7 SNP (Chi square=5.898; df=1; p=0.015). In the case-control sample, the same allele of the intron7 SNP showed a trend towards association with schizophrenia (Chi square=1.82; df=1; p=0.177). When the two samples were combined, the association was stronger (N=378; z=2.67; p=0.0076). Haplotype analysis did not reveal any significant associations. No significant mRNA expression differences were seen in the post-mortem tissue.Conclusions: The results should be treated with caution until replicated, but this is the first report of a genetic association between syntaxin 1a and schizophrenia.

418. Dysbindin Protein is Decreased in the Dorsolateral Prefrontal Cortex of Schizophrenia Patients

Richard E. Straub, Benjamin W. McClintock, Nader D. Halim, Barbara K. Lipska, Thomas M. Hyde, Mary M. Herman, Daniel R. Weinberger, Joel E. Kleinman, Cynthia Shannon Weickert

Clinical Brain Disorders Branch, IRP, NIMH, NIH, Bethesda, MD

Background: The mechanism by which dysbindin (DTNBP1; 6p22.3) increases the risk of schizophrenia is unknown. In previous studies, we found a 15-20% decrease in dysbindin mRNA in multiple layers of the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia.Methods: We produced a polyclonal antibody (dys755), directed against Exon 10 amino acids 320-333 of protein NP_115498, which is translated from transcript BC011912. Protein levels were estimated by Western blotting of homogenates from DLPFC from 21 controls and 18 schizophrenic patients.Results: We applied a previously characterized antibody to mouse dysbindin (m10CT-FP in Benson et al., J Biol Chem 276, 24232-41, 2001) to human and rat tissues, and observed multiple bands, all of roughly equal intensity, including one at 50KDa. Antibody dys755 produced a very strong band at 50kDa, and a second, much fainter band, both of which were absent if dys755 was pre-incubated with the peptide antigen. We found a 16% decrease in dysbindin protein in patients with schizophrenia (t = -2.50, p = .017). Dysbindin protein level did not correlate with age, pH, or postmortem interval. By immunocytochemistry, the two antibodies produced a similar staining pattern in all layers of monkey prefrontal cortex, with prominent staining of the nucleus, cytoplasm, and neuropil of pyramidal neurons. Haloperidol had no effect on dysbindin immunoreactivity in rats.Conclusions: Dysbindin protein expression in the DLPFC of patients with schizophrenia is decreased by about the same percentage as the mRNA, and this reduction is unlikely to be due to neuroleptics such as haloperidol.



419. RNA Editing and Alternative Splicing of Human Serotonin 2C Receptor in Schizophrenia

Stella Dracheva1,2

, Sharif L. Elhakem1,2

, Sue M. Marcus

1,2, Larry J. Siever

1,2, Susan R. McGurk

1,2,

Vahram Haroutunian1,2

1Department of Psychiatry, Bronx VA Medical Center, Bronx, NY,

2Departments of Psychiatry, Mount Sinai School of Medicine, New

York, NY

Background: Serotonin 2C receptor (5-HT2CR) heterogeneity in brain occurs from two different sources: 1) 5-HT2CR mRNA undergoes adenosine-to-inosine editing events at five positions which leads to amino acid substitutions that produce receptor variants with different pharmacological properties. 2) 5-HT2CR mRNA is alternatively spliced, resulting in a truncated mRNA that encodes a non-functional serotonin receptor.Methods: 5-HT2CR mRNA editing efficiencies and the expression of the full-length and the truncated mRNA splice isoforms were analyzed in the dorsolateral prefrontal cortex (DLPFC) of elderly subjects with schizophrenia vs. matched normal controls (ns=15). 5-HT2CR mRNA editing efficiencies were measured by sequence analysis of individual clones (at least 32 per each subject), permitting an accurate examination at all five edited positions. Real-Time RT-PCR was used to perform relative quantitation of the full-length and the truncated mRNAs.Results: Quantitation of the full-length and truncated mRNA variants revealed that in the DLPFC the expression of 5-HT2CR-tr was ~ 50% of that observed for the full-length isoform. No significant differences were found in the editing or in the expression of 5-HT2CR mRNA isoforms between patients with schizophrenia and normal controls.Conclusions: The results indicate that there are no alterations in editing or alternative splicing of the 5-HT2CR that are associated with schizophrenia in the DLPFC of persons treated with antipsychotic medications. However, given the involvement of 5-HT2CR in regulating mood, appetite, and sexual behavior, alterations in 5-HT2CR mRNA editing could be found in other brain regions and/or could contribute to other psychopathologies such as affective disease and suicide.

420. Antipsychotic-Induced Acetylcholine Release is Mediated by Muscarinic Receptor Antagonism: Microdialysis Studies on Olanzapine, Clozapine, Thioridazine and Ziprasidone

David E. Johnson, Hans Rollema, Frank M. Nedza, Douglas K. Spracklin, Karen M. Ward, Anne W. Schmidt, Philip A. Iredale

Neuroscience and Pharmacokinetics/Drug Metabolism, Pfizer Global

Research and Development, Groton, CT

Background: Olanzapine and clozapine robustly increase hippocampal ACh release during acetylcholinesterase inhibition, whereas ziprasidone and thioridazine have only small effects (Shirazi-Southall, Neuropsycho-pharmacology 26:583,2002). Since thioridazine has, like olanzapine and clozapine, high affinity for muscarinic receptors, Shirazi-Southall et al. concluded that the ACh increase is not mediated by muscarinic receptor blockade. We present microdialysis and functional data that explain thioridazine’s lack of effect and show that the olanzapine-induced ACh increase is mediated by muscarinic receptor antagonism.Methods: Microdialysis of ACh was performed in rat hippocampus in the presence of 100 nM neostigmine. Binding affinities and functional potencies were determined in CHO cells expressing M1 or M2 receptors. Rat brain and plasma levels were determined by LC-MSResults: Clozapine and olanzapine produced dose-dependent ACh increases, while local perfusions demonstrated that olanzapine does not act at cholinergic

septum cell bodies, but at hippocampal terminals. At 10 mg/kg sc thioridazine only slightly elevated ACh release, but higher s.c. doses and high perfusing concentrations produced robust increases in ACh levels. In vivo, thioridazine is ~20 fold less potent than olanzapine, consistent with its significantly lower in vitro functional M2 potencyConclusions: Thioridazine has weaker M2 antagonist functional potency, reduced affinity for rat muscarinic receptors and lower brain levels than olanzapine, which explains that only high thioridazine doses markedly increase ACh. The high correlation between a compound’s in vitro M2 antagonist potency and in vivo ACh increasing potency suggests that the olanzapine/clozapine-induced ACh increase is mediated by M2 autoreceptor blockade. Potential clinical implications will be discussed.

421. White Matter Development during Childhood and Adolescence: A Cross-Sectional Diffusion Tensor Imaging Study

Naama Barnea-Goraly1, Vinod Menon

1, Leanne Tamm

2,

Mark Eckert1, Roland Bammer

3, Asya Karchemskiy

1,

Chris Dant1, Allan L. Reiss

1

1Psychiatry, Stanford University, Palo Alto, CA,

2Psychology,

Children's Hospital of Orange County, Orange, CA, 3Radiology,

Stanford University, Palo Alto, CA

Background: Maturation of brain white matter pathways is an important factor in cognitive, behavioral, emotional, and motor development during childhood and adolescence. In this study, we investigate white matter maturation as reflected by changes in anisotropy with age. To elucidate the processes underlying white matter development during childhood and adolescence, we further compare age-related variation in anisotropy to a measure of white matter density with age.Methods: Thirty-four children and adolescents aged 6-19 years received diffusion-weighted MRI scans. Among these, thirty children and adolescents also received high-resolution T1-weighed anatomical scans. A linear regression model was used to correlate fractional anisotropy (FA) values with age on a voxel-by-voxel basis. Within the regions that showed significant FA changes with age, a post-hoc analysis was performed to investigate white matter density changes.Results: FA values increased in prefrontal regions, in the internal capsule as well as in basal ganglia and thalamic pathways, the ventral visual pathways, and the corpus callosum. The posterior limb of the internal capsule, intrathalamic connections and the corpus callosum showed the most significant overlaps between white matter density and FA changes with age.Conclusions: During childhood and adolescence,white matter anisotropy changes in brain regions that are important for attention, motor skills, cognitive ability, and memory. This typical developmental trajectory may be altered in individuals with disorders of development, cognition, and behavior.

422. Age-Related Regional Expression Patterns of Estrogen Receptor alpha and Glucocorticoid Receptor mRNA in the Human Hippocampus

William R. Perlman1, Maree J. Webster

2, Mary M.

Herman1, Joel E. Kleinman

1, Cynthia Shannon

Weickert1

1Clinical Brain Disorders Branch, NIMH/NIH/DHHS, Bethesda, MD,

2Department of Psychiatry, Uniformed Services University of Health

Sciences, Stanley Foundation Laboratory of Brain Research,

Bethesda, MD

Background: Age related changes in hippocampal steroid hormone receptor expression may underlie age related changes in cognition and stress responsivity.



Methods: We employed quantitative film autoradiography following in situ

hybridization with a previously characterized 2.8kb cDNA spanning exons 1-8 of the human GR gene and a 495bp cDNA spanning exons 1 and 2 of the human ER gene. Measurements of the levels of hippocampal GR and ERmRNA were taken from adjacent sections in 6 age groups (N=6 neonates, 4 infants, 8 adolescents, 6 young adults, 9 adults, and 6 aged).Results: Densitometric quantification of mRNAs by hippocampal subfield yielded the following patterns in descending order: ER - dentate gyrus > CA3 > CA4 = CA1 > subiculum; GR- dentate gyrus > CA3 = CA1 > subiculum > CA4. Correlations between ER mRNA and age revealed significant, subfield specific, decreases across the lifespan in CA4 (r=-0.33, p=0.04), the subiculum (r=-0.46, p=0.004), and a trend towards reduction in CA1 (r=-0.3, p=0.064). Correlations between GR mRNA and age did not reveal significant differences across the lifespan when all subjects were considered, possibly because the GR mRNA profile is more dynamic, initially increasing and then decreasing with age. When only neonates and infants were considered, a strong positive correlation between GR mRNA and age was detected in CA4 (r=0.87, p=0.0053).Conclusions: Our results suggest that these steroid hormone receptor mRNAs decrease with aging and that CA4, CA1 and the subiculum are the most affected subfields, potentially through neurodegeneration or steroid hormone dysregulation.

423. Effects of Ovarian Steroids and Raloxifene on Monoamine Oxidase A and B (MAO-A; MAO-B) Protein Expression in the Raphe Region of Rhesus Macaques

Lisa J. Smith1, Creed W. Abell

2, Cynthia L. Bethea

1

1Reproductive Sci and Neurosci, Oregon National Primate Research

Center, Beaverton, OR, 2Institute for Neuroscience, University of

Texas, Austin, TX

Background: We previously reported that 1-month (mo) of estrogen (E) replacement, with or without progesterone (P) supplementation for 14 days, significantly decreased MAO-A mRNA, but had no effect on MAO-B mRNA in the dorsal raphe nucleus. We questioned what effect would E ±P or the SERM, raloxifene, have on MAO-A and -B protein?Methods: We examined MAO-A and –B protein levels in the dorsal raphe region of spayed monkeys treated with E, E+P or raloxifene for 1 or 5 mo by western blotting. The membranes were probed with an antibody to MAO-A (A6E5; 1/100), then re-probed with an antibody to MAO-B (B1C2; 1/100). The optical densities of the signals were measured with NIH Image and analyzed by ANOVA.Results: 1 mo of E or E+P caused a significant reduction in MAO-A. After 5 mo of E or E+P, MAO-A was not different from spayed controls. Neither 1 nor 5 mo of E had any effect on MAO-B. However, addition of P for 1 or 5 mo caused a significant increase in MAO-B. Raloxifene for 5 mos had no effect.Conclusions: In the raphe region, MAO-A protein was suppressed by short term E, and P had no further effect. MAO-B protein was not affected by E, but was increased when P was added to the E regimen. Together these data indicate that E could briefly decrease serotonin degradation without affecting NE degradation. Addition of P may enhance NE degradation. With longer treatment, serotonin degradation may rebound but NE degradation may continue.

424. Memantine and Neramexane Protect against Semi-Chronic 3-NP Toxicity in Organotypic Hippocampal Cultures

Andrea S. Baude1, Ben A. Bahr

2, Gary Samoriski

3,

Chris G. Parsons1

1Preclinical Research & Development, Merz Pharmaceuticals GmbH,

Frankfurt/Main, Germany, 2Department of Pharmaceutical Sciences,

University of Connecticut, Storrs, CT, 3Department of Pharmacology

and Toxicology, Forest Research Institute, Jersey City, NJ

Background: Memantine, an NMDA-receptor antagonist, has been approved in the U.S. for moderate-to-severe Alzheimer’s disease (AD). Clinical data indicate the symptomatic utility of this moderate-affinity, uncompetitive NMDA-receptor antagonist in AD. Unfortunately, proof of the predicted neuroprotective effects of such agents is difficult to obtain in clinical trials. While memantine has been shown to be neuroprotective in several in vivo tests modeling prolonged disturbances in glutamatergic transmission, no in vitro

models have adequately addressed this.Methods: Neuroprotective potencies of memantine and another NMDA-receptor antagonist, neramexane (MRZ 2/579), against mitochondrial toxin-induced, semi-chronic excitotoxicity in organotypic hippocampal slice cultures was assessed over 4-20 days [1, 3, 10µM against 35-60µM 3-nitropropionate (3-NP)]. For biochemical quantification, calpain-mediated spectrin breakdown product, post- and presynaptic marker immunoreactivity (GluR1 and synapsin II), and LDH-release were measured.Results: Neuroprotective effects of neramexane on 3-NP-induced cytotoxicity (LDH-release) were seen in several independent assays, with mean IC50 values of 1.68±0.04µM, 1.74±0.16µM and 2.34±0.23µM following 35µM 3-NP exposure on days 7, 9 and 12, respectively. Under similar conditions, neramexane was neuroprotective with respective IC50 values of 1.16±0.51µM, 1.79±0.44µM and 2.52±0.71µM. Additionally, memantine significantly reduced 3-NP-induced spectrin breakdown and loss of synaptic markers (GluR1 and synapsin II). For memantine and neramexane effects at days 7-12 of exposure, phase contrast as well as PI fluorescence images and cresyl violet staining confirmed neuroprotection.Conclusions: Both memantine and neramexane are likely to slow the progression of human diseases including AD, vascular dementia, Parkinson’s and Huntington’s disease, and ALS, which are hypothesised to involve chronic excitotoxic processes.

425. Prenatal Exposure to Infection: Inflammatory Cytokines Reduce Dendritic Complexity

John H. Gilmore1, L. Fredrik Jarskog

1, Swarooparani

Vadlamudi1, Jean M. Lauder

2

1Department of Psychiatry, University of North Carolina School of

Medicine, Chapel Hill, NC, 2Department of Cell and Developmental

Biology, University of North Carolina School of Medicine, Chapel Hill,

NC

Background: We have hypothesized that inflammatory cytokines, generated in response to maternal infection, alter neuron development and increase risk for schizophrenia (Gilmore and Jarskog, 1997). The regulation of dendritic development of cortical neurons by IL-1 , TNF , and IL-6 was determined.Methods: Primary mixed cortical neuronal cultures, obtained from E18 rats, were exposed to 0, 100 or 1000 U/ml of IL-1 , TNF , and IL-6 or IL-1 + TNF for 44 hours. Immunohistochemistry for IL-1 receptor, IL-6 receptor, TNF-I receptor and TNF-II receptor, and MAP-2 was performed. 10 MAP-2 positive neurons from 9 cultures were randomly identified for each condition (n=90) and the number of primary dendrites, nodes, and total dendrite length was determined using the Neurolucida imaging program.



Results: Each cytokine receptor was expressed by embryonic cortical neurons. 100 U of TNF significantly reduced the number of nodes (27%, p = 0.02) and total dendritic length (14%, p=0.04). 100 U IL-1 + TNF significantly reduced the number of primary dendrites (17%, p=0.006), nodes (32%, p=0.001) and total dendritic length (30%, p<0.0001). At 1000 U, each cytokine significantly reduced the number of primary dendrites (14-24%), nodes (28-37%), as well as total dendritic length (25-30%).Conclusions: These results indicate that inflammatory cytokines can significantly reduce dendritic development and complexity in developing cortical neurons, consistent with the reductions of synaptic connectivity observed in schizophrenia. These findings support the hypothesis that cytokines play a key mechanistic role in the link between prenatal exposure to infection and risk for schizophrenia.

426. Increased Amygdalar Activation after Secretin Administration

Staci A. Gruber1, Jadwiga Rogowska

1, Patrice Rioux

2,

Karen Juaregui2, James Rusche

2, Deborah A.

Yurgelun-Todd1

1Cognitive Neuroimaging Laboratory, McLean Hospital/ Harvard

Medical School, Belmont, MA, 2Repligen, Repligen Corporation,

Waltham, MA

Background: Neuroimaging studies indicate that brain regions associated with affective processing of visual stimuli, such as the amygdala, are sensitive to pharmacologic manipulation. Recent investigations suggest that secretin, a peptide found in gut and brain tissue, activates gene expression in the central nucleus of the amygdala in rats. To better understand the neurophysiological effects of secretin on cortical activation, we applied fMRI techniques to healthy subjects during the viewing of affective faces following secretin administration.Methods: Functional magnetic resonance imaging (fMRI) BOLD scans of 12 healthy adult male subjects were acquired during the presentation of happy, fearful, and neutral faces both before and one hour post infusion with either secretin or placebo.Results: Within the secretin group, subtraction of the treatment from the baseline activation during the fear condition yielded significant (p = .001) activation in the right amygdala. In contrast, when viewing happy or neutral faces, no significant differences were seen between pre and post infusion within the amygdala. Within the placebo group, no significant differences were detected for any facial affect. To further map regions of the brain involved in social cognition processes, we examined additional brain areas including the prefrontal cortex, fusiform face area and cerebellum during this paradigm.Conclusions: Results from this investigation indicate a BOLD signal increase in response to fearful face stimuli, supporting the hypothesis that secretin alters amygdala responsiveness to affective stimuli. Moreover, changes within related brain regions suggest that this altered amygdalar response may be mediated by a variety of neural networks.

427. Tobacco Smoking Chronic Effects: Enhanced Event-Related Gamma 40 Hz Synchronization

Dennis McClain-Furmanski1, Neal Castagnoli

2, Kay

Castagnoli2, Helen Crawford

3

1Psychiatry, Yale Medical School, West Haven, CT,

2Chemistry,

Virginia Tech, Blacksburg, VA, 3Psychology, Virginia Tech,

Blacksburg, VA

Background: The stimulus-bound auditory transient 40 Hz response, an event-related synchronization in gamma EEG, occurs within about 100 msec post-stimulus. It is increased by attention to stimuli, and is increased or decreased by substances which enhance or impair perceptual or attentional processes

respectively. Smoking tobacco’s impact on gamma band oscillations yet to be investigated. Smoking produces activation of the dopaminergic system via cholinergic innervation of dopaminergic neurons in the ventral tegmentum. Also, smokers have chronically reduced levels of monoamine oxidase which catabolize dopamine. We proposed that the chronic dopaminergic action of smoking tobacco may enhance gamma band oscillations.Methods: 26 males, mean age 26, were tested twice with an auditory oddball paradigm. 13 smokers were tested after overnight abstention and again after smoking. 13 never-smokers were tested similarly, without smoking. Stimuli were 475 tone pips (400 each 1000 Hz, 75 each 1200 Hz, 50 msec duration) with 25 visual stimuli used as an attentional control. Transient 40 Hz responses were analyzed as mean absolute value amplitude (MAVA) and compared within 20 msec windows.Results: Smokers generated significantly more synchronized gamma activity as a main effect across the two conditions than never-smokers. This was particularly evident at fronto-central sites, between 40 and 80 msec.Conclusions: Smoking tobacco chronically enhances the transient 40 Hz response. The results here replicate findings from an earlier study on P50 sensory gating (Crawford et al., 2002). This seems to support the hypothesis of enhanced dopaminergic activity due to chronic MAO inhibition.

428. Contribution of High Affinity Binding at Alpha2-Delta Protein to the Anxiolytic Action of Pregabalin

Charles P. Taylor

CNS Pharmacology, Pfizer Global R & D, Ann Arbor, MI

Background: Pregabalin shows anxiolytic actions in animal models. It also is a specific ligand at alpha2-delta ( 2– ) protein, a membrane-bound subunit of voltage-gated calcium channels. The role of 2– binding in the pharmacology of pregabalin has been uncertain, but a knockout mutation to 2– type 1 caused lethality in mice.Methods: A single amino acid mutation was incorporated into the native 2–type 1 gene sequence to convert arginine 217 to alanine (R217A). Wildtype and R217A mice were compared with: 2– brain membrane radioligand binding, autoradiography, release of [3H]noradrenaline from neocortex slices, activity of drugs in the rat Vogel conflict test and drugs in a nerve ligation model of neuropathic pain. A series of compounds related to pregabalin were compared for activity in the Vogel test and for 2– binding affinity.Results: The R217A mutation reduced binding affinity for [3H]gabapentin by 20×. R217A mice had reduced binding of radioligand to neocortex, hippocampus and other forebrain structures, but relatively unchanged binding in cerebellum. Brain tissues from R217A mice had reduced pregabalin effect on [3H]NA release. R217A mice had little effect of pregabalin in the Vogel test or pain models. Experiments with compounds structurally related to pregabalin showed a correlation between affinity for binding to 2– and in vivo activity in the Vogel test.Conclusions: These results suggest that high affinity binding to the 2–protein is required for the pharmacological activity of pregabalin and defines a novel class of anxiolytic drugs.

429. Antipsychotic Treatment and Apoptosis in Synapses in Rat Cortex

Leisa A. Glantz, John H. Gilmore, Jeffrey A. Lieberman, L. Fredrik Jarskog

Psychiatry, University of North Carolina, Chapel Hill, NC

Background: Given neuroimaging and clinical evidence for progression of illness, neuropathological findings including reduced neuropil and somal volumes, apoptotic protein alterations and decreased synaptic markers in the cortex of subjects with schizophrenia suggest that a subtle deterioration may be



occurring in the cortex of these subjects. Apoptosis, a form of cell death that can also act locally at synapses, may be involved in this deterioration. Because antipsychotics improve long-term outcome in schizophrenia, these medications are thought to exert neuroprotective effects. However, the mechanism through which antipsychotics work is poorly understood. The hypothesis of this study is that antipsychotics inhibit apoptotic activity at the level of the synapse, through alterations in apoptotic regulatory protein levels.Methods: Rats (n=7) were treated with i.p. haloperidol (1 mg/kg) daily for 1 week and compared to saline-treated rats (n=6). Brain homogenates were from medial prefrontal cortical blocks or from synaptosomes from lateral prefrontal cortex. Western blotting was used to assess the levels of Par-4, Bax, activated Caspase-3 (all pro-apoptotic) and Bcl-2 (anti-apoptotic) proteins.Results: There were no significant differences in the levels of Par-4, activated Caspase-3, or Bcl-2 in the cortical homogenates or in the synaptosomes of haloperidol-treated compared to saline-treated rats. (Bax results pending.)Conclusions: These findings suggest that Par-4, activated Caspase-3, and Bcl-2 are not altered with short-term antipsychotic treatment. We are currently conducting a similar study using a longer course (1 month) of antipsychotic treatment with both conventional and atypical antipsychotics in order to determine if these apoptotic proteins are altered synaptically.

430. The Effects of Acute and Chronic Treatment with S(+)- and R(-)-Citalopram, Given Alone and in Combination, on the Agonistic Behaviour of Resident Rats

Paul J. Mitchell1, Sandy Hogg

2, Connie Sanchez

3

1Pharmacy and Pharmacology, University of Bath, Bath, United

Kingdom,2Psychopharmacology Depression, H. Lundbeck A/S,

Copenhagen, Denmark, 3Psychpharmacology, H. Lundbeck A/S,

Copenhagen, Denmark

Background: Antidepressant drugs induce common changes in the behaviour of resident rats expressed during social encounters with unfamiliar intruder rats. Acute antidepressant treatment selectively suppresses the aggressive behaviour (a measure of assertive behaviour) of resident rats, whereas chronic treatment increases aggressive behaviour reflecting the increased assertiveness observed during the recovery from depressive illness. Recent studies suggest that the antidepressant effect of citalopram resides in the S(+)-enantiomer (escitalopram) and that R(-)-citalopram counteracts the effects of escitalopram.Methods: Resident-intruder studies were performed with escitalopram, citalopram, R(-)-citalopram and escitalopram in combination with R(-)-citalopram (0.5 plus 2.0 mg/kg, respectively). Additional studies examined the effect of chronic treatment with escitalopram, citalopram, R-citalopram and escitalopram in combination with R(-)-citalopram (0.5 plus 2.0 mg/kg/day, respectively).Results: Acute treatment with escitalopram or citalopram selectively reduced the aggressive behaviour of resident rats (ID50= 0.26 and 1.28 mg/kg, respectively). R(-)-citalopram (4.0 mg/kg) failed to modify rodent aggression. R(-)-citalopram (2.0 mg/kg) attenuated the reduction of aggressive behaviour induced by escitalopram (0.5 mg/kg). In chronic treatment studies, escitalopram and citalopram (0.5 and 1.0 mg/kg/day, respectively) significantly increased aggressive behaviour from day 1 and 4 respectively, while R(-)-citalopram (2 mg/kg/day) was inactive and a combination of R(-)-citalopram with escitalopram (2.0 plus 0.5 mg/kg/day) only increased aggressive behaviour from day 7 of treatment.Conclusions: These data demonstrate that R(-)-citalopram significantly attenuates the antidepressant activity of escitalopram both following acute and during chronic treatment and, most importantly, delays the behavioural changes induced by chronic treatment with escitalopram alone.

431. An Economic Analysis of Antipsychotic Treatment for Schizophrenia

Gordon G. Liu1, Shawn Sun

1, Dale Christensen

1,

Zhongyun Zhao2

1Pharmaceutical Policy and Evaluative Sciences, University of North

Carolina at Chapel Hill, Chapel Hill, NC, 2Outcomes Research, Eli Lilly

and Company, Indianapolis, IN

Background: This study was designed to evaluate direct healthcare costs associated with olanzapine and risperidone treatment for patients with schizophrenia.Methods: Using the North Carolina Medicaid Claims database, patients diagnosed with schizophrenia (ICD9-CM: 295.xx) were assigned to olanzapine or risperidone cohort on the basis of which drug was received first. Medication, medical service and total healthcare costs were examined for schizophrenia-related, mental health-related, and all-cause services using multivariate models controlling for possible confounding factors including demographics, types of schizophrenia, co-morbidities, and prior use of medications and medical services.Results: 498 patients (286 olanzapine and 212 risperidone) were identified with available data for three-month prior and eighteen-month after antipsychotic treatment. During 18-month treatment, olanzapine patients incurred significantly higher drug expenditures (+$1,235, p<0.0001) than risperidone patients. Patients on olanzapine, however, had significantly lower medical service costs (-$3,212, p=0.02) than risperidone patients, leading to no statistical difference in total healthcare costs between the two groups (-$1,976 lower for olanzapine, p=0.16). The findings are consistent with the schizophrenia-related and mental health-related cost models. Additionally, age, race, type of schizophrenia, co-morbidities, and prior use of inpatient services were also found to impact treatment costs.Conclusions: This study finds that compared to risperidone, olanzapine is associated with increased drug expenditures but reduced medical service costs. Although total costs are similar, results suggest that schizophrenia patients might benefit from olanzapine due to reduced medical service use.

432. Effects of 5 Daily Injections of the Neurotensin-Mimetic NT69L on Dopamine Release and Expression of Neurotensin Receptors in Rat

Rui Wang1, Mona Boules

2, Elisa Gollatz

2, William

Tiner2, Katrina Williams

2, Elliott Richelson

2

1State Key Laboratory of Drug Research, Shanghai Institute of

Materia Medica, Shanghai, China, 2Department of Neuroscience,

Mayo Clinic, Jacksonville, FL

Background: NT69L is a neurotensin (NT) receptor agonist. Rapid tolerance to some, but not all its effects occurs. We investigated possible mechanisms of this selective tolerance.Methods: NT69L (2 mg/kg i.p.) or saline was injected for 5 days into rats. DA release in striatal slices was measured in vitro. Expression of NT and DA receptors, tyrosine hydroxylase (TH), and DOPA decarboxylase (DDC) was investigated by immunohistochemistry and real-time RT-PCR.Results: (1) In saline-treated animals, in vitro NT69L significantly increased K+- and electrically-evoked [3H]DA release. In slices from animals pretreated with NT69L for 5 days, in vitro NT69L perfusion still caused a robust increase in K+-evoked DA release, but its effect on electrically-evoked [3H]DA release was significantly reduced. (2) With two successive treatments of NT69L in vitro on slices from untreated rats, the second NT69L perfusion significantly increased electrically-evoked [3H]DA release, with no effect on K+-evoked [3H]DA release. (3) one NT69L injection had no effect on NT receptor expression. 5 daily NT69L injections down-regulated striatal NTR-1. NTR-2 and NTR-3 were not significantly affected in 1 or 5 NT69L injections in most



brain regions. (4) 5 daily injections of NT69L significantly down-regulated TH and DDC expression, up-regulated Nurr1 in striatum but down-regulated in prefrontal cortex.Conclusions: Distinct neurotensin receptors were involved in NT69L effects. Down-regulation of NTR-1 might contribute to rapid tolerance to some effects of NT69L. Modulation of NT receptor sensitivity in intact brain may involve the interactions of NT69L with both neural networks and cellular proteins. (Supported by Mayo Foundation)

433. Chemical Structure-Activity Relationship (SAR) Model of Drug-Induced QT Prolongation and Tosades de Pointes (TdP)

Tibor Szekely1, Michael B. Heller

2

1Con-search, Independent Research Group, Con-search, Woodside,

NY, 2Con-search, Con-search, Woodside, NY

Background: The chemical structure of drugs can play an essential role in receptor binding. While QT/TdP risk is linked to a wide variety of pharmacotherapeutics, this study focuses on the common chemical underpinning.Methods: 3D structures of 92 drugs from the Arizona CERT database and two additional withdrawn drugs were generated. The pharmaceutical agents were associated with varying degrees of QT/TdP risks. When applicable the distance between aromatic rings as well as the coplanarity was calculated using Chem3D software. SAR was used to project QT risk.Results: In addition to the known quinidine like and certain phosphorous compounds, aliphatic sulfur as well as adjacent aromatic ring structure was identified as putative QT associated structures. SAR based QT risk assessment correlated with the Arizona CERT database (p=0.192; r=0.800) and the FDA 054 study of antipsychotics (significant p<0.01; r=0.956, Spearman). While the sulfur in olanzapine is metabolically stable, a ziprasidone’s metabolite contains a thioalkyl group similar to thioridazine, an agent with increased QT/TdP risk. Insufficient study covers quetiapine’s metabolism and risperidone aromatic-partial aromatic structure may limits it's QT risk. The tricyclic structure in antidepressants contains fixed rings and is associated with non-QT cardiac side-effects. While the structure of SSRIs suggests QT risk, their antidepressive effect may compensate for it. Conclusions: Aliphatic sulfur-organic molecules may form GDP[S] in a dose-dependent way, leading to irreversible G-protein binding. Genetics, HERG K+

ion channels, and drug’s effects all could be linked to altered aromatic hydrophobic structures. Dose, duration and risk-factors all contributes to the clinical side-effect.

434. Can Substance Use Predict Gambling Behavior?

Vinodh Jeevanantham1, Nathan A. Shapira

2, Giselle D.

Mann3, MaryAnn Ferguson

4, Kimberly Frost-Pineda

2,

Mark S. Gold5

1Public Health, University of Florida, Gainesville, FL,

2Psychiatry,

University of Florida, Gainesville, FL, 3Communicative Disorders,

University of Florida, Gainesville, FL, 4Journalism and

Communications, University of Florida, Gainesville, FL, 5Psychiatry,

Neuroscience, Community Health and Family Medicine, University of

Florida, Gainesville, FL

Background: A number of studies have reported on a variety of relationships between substance use and gambling. But is there a relationship between specific substances (tobacco, alcohol, marijuana, cocaine, stimulants, tranquilizers), use patterns (i.e. binge drinking), and gambling behavior?Methods: Lifetime Lower-risk (n= 1160) and Higher-risk gamblers (n = 106) were identified as part of a random epidemiological telephone survey of adult Florida residents.Results: Univariate analysis showed a statistically significant correlation between higher-risk gambling and past-year alcohol, marijuana, cocaine, stimulants and tranquilizer use. In this analysis, the higher-risk category (at risk + problem + pathological gamblers) had one or more DSM-IV criteria for pathological gambling. After controlling for each of the substances by using logistic regression analysis, only marijuana use and stimulant use predicted higher-risk gambling behavior. Higher-risk gamblers were 2.6 times more likely than lower-risk gamblers to be marijuana users [OR 2.6, 95% CI 1.6 to 4.3] and 4.3 times more likely than lower risk gamblers to use stimulants [OR 4.3, CI 1.9 to 9.8].Conclusions: Casinos and other gaming establishments often allow smoking and encourage alcohol consumption. Our data indicate substance use correlates with higher-risk gambling, particularly marijuana and stimulants. Identifying the predictors of higher-risk gambling behavior may help improve public health prevention strategies and impact treatment outcomes.Research completed under contract with the Florida Council on Compulsive Gambling, Inc.

435. Decaffeinated Coffee: An Oxymoron

Bruce A. Goldberger1, Rachel R. McCusker

2, Kimberly

Frost-Pineda3, Mark S. Gold

4

1Pathology, Immunology and Laboratory Medicine and Psychiatry,

University of Florida, Gainesville, FL, 2Pathology, Immunology and

Laboratory Medicine, University of Florida, Gainesville, FL, 3Psychiatry, University of Florida, Gainesville, FL,

4Psychiatry,

Neuroscience, Community Health and Family Medicine, University of

Florida, Gainesville, FL

Background: Caffeine is the most commonly used psychostimulant worldwide. Caffeine is usually safe when taken in moderate doses (about 250 milligrams/day), however, an excessive dose increases blood pressure and heart rate. Individuals with hypertension, insomnia, panic and anxiety disorders should be especially cautious regarding their caffeine consumption. Caffeine withdrawal can cause headache, increased irritability and aggressiveness.Methods: As a follow-up to our pilot study reported at last year's SOBP meeting, a wide variety of coffee samples were collected from seven specialty coffee shops in two cities and caffeine levels were analyzed by GC-NPD. Quantification of caffeine content was based on an internal standardization method.Results: The dose of caffeine varied considerably, even in coffee of the same size and brand purchased on different days. Some samples were as high as 564 mg and even decaffeinated coffees had considerable caffeine present. In comparison, 16 ounces of a caffeinated soft-drink has about 64 milligrams of caffeine.Conclusions: Decaffeinated coffee drinkers may be caffeine dependent and may wait in line for caffeine rather than for euphoric recall or the taste. Women with cystic disease of the breast, individuals with hypertension or arrhythmias, and those with sleep problems, panic or anxiety, who are advised by their physicians to abstain from caffeine should not assume that they can drink decaffeinated coffee. Documentation of caffeine exposure, and when possible, total caffeine (mg/ day), should be made in the medical history.



436. Regional Cerebral Blood Flow Correlates of Neuroendocrine Responses to Aversive Emotional Stimuli in PTSD

Israel Liberzon1,2

, Anthony P. King1,2

, K. Luan Phan3,

Jennifer Britton4, Stephan F. Taylor

1


2Psychiatry, Ann

Arbor VA Medical Center, Ann Arbor, MI, 3Psychiatry, Wayne State

University, Detroit, MI, 4Neuroscience Program, University of

Michigan, Ann Arbor, MI

Background: Posttraumatic stress disorder (PTSD) is associated with altered HPA axis activity, and imaging studies have implicated limbic and paralimbic cortical regions in PTSD. However, less is known about involvement of cortical structures in regulation of HPA axis activity and the sites of action of cortisol in human cortex.Methods: Subjective emotion, SCR, plasma ACTH and cortisol, and regional cerebral blood flow ([15O]H2O PET) were measured in 16 combat veteran PTSD patients, 15 combat veterans without PTSD, and 14 normal controls following exposure to aversive images and traumatic autobiographic narratives. Whole brain, voxel-by-voxel, analyses of covariance were performed in each group using plasma ACTH and cortisol levels.Results: Plasma ACTH response was detected to traumatic narratives in PTSD and combat control groups. In PTSD patients, plasma ACTH correlated with rCBF in right insula and superior temporal sulcus. In contrast, in combat controls, ACTH correlated with activity in dmPFC and left parahippocampal gyrus. Cortisol positively correlated with negative emotion in all groups. Pre-scan plasma cortisol correlated with rCBF in anterior cingulate and temporal pole in PTSD patients and combat controls.Conclusions: These results suggest paralimbic cortical regions are involved in regulation of HPA axis responses to emotional recall. Insular cortex and dmPFC are implicated in neuroendocrine responses to traumatic memories. In turn, temporal pole and anterior cingulate are implicated as regions possibly modulated by circulating levels of cortisol. Differential patterns of correlation between stress hormones and brain activities suggest potential areas of dysregulation in PTSD.Supported by VA-DoD Award to IL

437. Elevated Disgust Sensitivity in Washing OCD: A Clinical and fMRI Study

David Mataix-Cols1, Natalia S. Lawrence

1, Sarah C.

Wooderson1, Anne Speckens

2, Vincent Giampietro

3,

Michael J. Brammer3, Mary L. Phillips

1


Kingdom,2Psychology, Institute of Psychiatry, London, United

Kingdom,3Biostatistics, Institute of Psychiatry, London, United

Kingdom

Background: Some studies suggest that disgust sensitivity may be specifically elevated in patients with Obsessive-compulsive disorder (OCD) who have contamination/washing but not other types of concerns.Methods: 16 OCD patients and 16 matched healthy controls were administered Haidt’s (1994) Disgust Scale and also participated in 2 fMRI experiments consisting of the provocation of contamination-related and generally aversive (symptom-unrelated) anxiety. Disgust sensitivity scores were correlated with OCD symptom dimension scores derived from the Yale-Brown Obsessive-Compulsive Scale Symptom Checklist and patterns of brain activation.Results: Patients as a whole had higher disgust sensitivity scores than controls. In the patient group, disgust sensitivity was specifically associated with contamination/washing but not other types of symptoms. During the washing experiment, disgust sensitivity correlated positively with activation in bilateral ventral prefrontal regions (BA32, BA47, BA10), caudate nucleus, visual regions

(BA18) and the right anterior insula. As predicted, there were no positive correlations in the control (symptom-unrelated) experiment. Unexpectedly, disgust sensitivity correlated negatively with activation in bilateral dorsolateral regions (BA44, BA6) and right middle occipital gyrus (BA19) in this experiment.Conclusions: In OCD, disgust sensitivity is specifically associated with contamination concerns and activation in regions important for emotion and disgust processing. Negative correlations in dorsolateral regions during the aversive control experiment might reflect compensatory emotional regulation mechanisms. Given the small sample size, the results should be taken as preliminary.

438. Anxiety Responses to CO2 Inhalation in Subjects at High Risk for Panic Disorder

William H. Coryell

Psychiatry, University of Iowa, Iowa City, IA

Background: Three earlier studies have shown that well individuals who have first-degree relatives with panic disorder experience more anxiey following CO2 inhalation then do controls. The following was undertaken to confirm and extend these findings.Methods: Well subjects at high risk for panic disorder (HR-P, n=132) had a first-degree family member with treated panic disoder but no personal history of panic attacks. Low-risk subjects (LR-C, n=85) had no such family history. All underwent a diagnostic interview, completed self-rating scales, and underwent two CO2 challenges. One involved a single vital capacity breath of air and then of 35% CO2 and the other five minutes of air and then five minutes of 5% CO2.Results: HR-P subjects had higher scores on self-ratings of anxiety and depression and were more likely to have a lifetime diagnosis of MDD or of an anxiety disorder. As predicted, the HR-P subjects experienced more anxiety following 35% CO2 exposure. The removal of individuals with lifetime diagnoses of MDD or an anxiety disorder eliminated the relationship of neuroticism to CO2-induced anxiety and strengthened the relationship between CO2 response and a familty history of panic disorder. Five minutes of 5% CO2 revealed a dose-by-group interaction suggesting that increasing CO2 exposure increases anxiety preferentially in high-risk subjects.Conclusions: These resluts confirm earlier findings indicating that a family history of panic disorder conveys a liability to experience anxiety with CO2 exposure. They also suggest that this anxiety may reflect several discrete diatheses of relevance to the heritability of panic disorder.

439. Acute HPA Axis Responses to Major Abdominal Surgery and Post-Operative Psychiatric and Medical Outcomes

Bardia Gholami1,2

, Anthony P. King1,2

, Yvette M. Harden

1,2, Samir A. Khan

1,2, Peter K. Henke

3, Gilbert R.

Upchurch3, Linda Graham

4, Israel Liberzon

1,2


2Psychiatry, Ann

Arbor VA Medical Center, Ann Arbor, MI, 3Vascular Surgery,

University of Michigan, Ann Arbor, MI, 4Cardiovascular Medicine,

Cleveland Clinic, Ann Arbor, MI

Background: Major abdominal surgery in humans is a severe psychological and physical stressor, and is associated with de novo post-operative PTSD and depression. Peri-traumatic neuroendocrine responses may predict development of post-traumatic psychiatric symptoms. The present study investigates the role of acute HPA axis responses to surgery in development of stress-related psychiatric morbidity.Methods: We studied 50 patients undergoing major abdominal surgery,12 received etomidate. Blood samples at check-in, during surgery, and 3 and 9 hrs after surgery, and 24 hr post-surgical urine were obtained. Plasma ACTH and



cortisol were measured by radioimmunoassays. Psychiatric symptoms (CAPS, IES, BDI), plasma, salivary, and 24 hr urine cortisol, and dexamethasone suppression (DST, 0.25 mg) were measured 4 days before and 3 months after surgery.Results: Patients without etomidate had robust cortisol responses during surgery (mean increase 20.8±2.5µg/dl); with etomidate had no acute cortisol response, but increased cortisol (15.8±2.7µg/dl) by 9 hrs post surgery. ACTH response was higher with etomidate (525±102 vs. 311±42 pg/ml), consistent with a lack of cortisol feedback. Pre-surgical DST predicted initial plasma cortisol (r= -.39 and r= -.78, p<.05 respectively), and without etomidate, cortisol response (r= -.36, p=.03). Patients treated with etomidate had significantly higher 3 month post-operative DST (75±6% vs. 47±9%, p<.05). Post-operative psychiatric symptom severity and medical outcomes continue to be collected.Conclusions: Preliminary data suggest DST predicts cortisol response to surgery, and manipulation of HPA responses to stress may result in altered negative feedback.Supported by VA Advanced Research Career Development Award and NIMH RO1MH63092 to Israel Liberzon, M.D.

440. The Characteristics of Heart Rate Variability Inpatients with Panic Disorder

Jong-Min Woo, Woo-Yeon Cho, Young-Hee Choi, Haye-Young Yoon

Neuropsychiatry, Inje University Seoul Paik Hospital, Seoul, Republic

of Korea

Background: This study is to assess the difference in autonomic nervous system function using heart rate variability(HRV) between patients with panic disorder (PD) and normal controls(NC).Methods: 82 PD patients and 82 healthy, age- and gender-matched controls were included in this study. We gathered 5-minute short-term HRV in a structured setting. Both time and frequency domain measures were calculated.Results: Mean age of PD and NC was 34.0 and 34.8, respectively. Body mass index did not show significant difference. PD showed higher mean heart rate (73.62 vs. 70.22, t=-2.06, p<0.05) and HRV index (58.88 vs. 40.95, t=-2.47, p<0.05). SDNN, RMSSD, LF, HF were lower in PD but without statistical significance.Conclusions: These results indicate decreased HRV in PD patients than normal controls. The analysis of HRV revealed an autonomic substrate for the symptoms of panic.

441. Familial and Sporadic Subtypes of Early-Onset Obsessive-Compulsive Disorder

Gregory L. Hanna, Daniel J. Fischer, Kristin R. Chadha, Joseph A. Himle, Michelle Van Etten

Psychiatry, University of Michigan, Ann Arbor, MI

Background: Family studies of obsessive-compulsive disorder (OCD) indicate some cases are familial and other cases have no family history of OCD. This study was done to determine whether there are differences between familial and sporadic OCD probands with early-onset OCD in lifetime obsessive-compulsive (OC) symptom categories and lifetime comorbid psychiatric diagnoses.Methods: We ascertained 50 OCD probands ranging in age from 10 to 19 years with an onset of OC symptoms before age 15 years. All probands were directly assessed with semi-structured diagnostic interviews, and their first-degree and second-degree relatives were directly or indirectly assessed with similar diagnostic instruments. Discriminant function analysis was used to compare 33 familial and 17 sporadic OCD probands.

Results: There was no difference between the two groups in seven lifetime obsession categories. However, there was a significant difference between the two groups in seven lifetime compulsion categories. Ordering and touching maximally separated the two groups. There was a significant difference between the two groups in seven lifetime comorbid psychiatric diagnoses. Phobic disorders and nailbiting/skin picking maximally separated the two groups.Conclusions: The results suggest that familial and sporadic OCD can be discriminated by lifetime OC symptom categories and lifetime comorbid psychiatric diagnoses.

442. Effects of Maltreatment and Psychiatric Diagnosis on Identification of Emotional Facial Expressions in Children

Carrie L. Masten1, Amanda E. Schweder

1, Hilary B.

Hodgdon1, Erin B. McClure

1, Girma Woldehawariat

1,

Dennis S. Charney1, Monique Ernst

1, Joan Kaufman

2,

Daniel S. Pine1, Christopher S. Monk

1

1Mood and Anxiety Disorders Program, National Institute of Mental

Health, Bethesda, MD, 2Psychiatry, Yale University, New Haven, CT

Background: Abuse and neglect during childhood are associated with increased risk for psychopathology. Thought processes underlying this risk, however, are not clearly understood. Altered judgments of social context, resulting from maltreatment, may contribute to symptoms of depression, post-traumatic stress disorder, and other anxiety disorders. This study set out to more clearly identify the effects of maltreatment on social perception and cognition during childhood and adolescence, and to find out how mental processing differs between maltreated adolescents and controls.Methods: We examined the effects of abuse and neglect on the accuracy and reaction time of facial expression identification in adolescents. Our sample consisted of 32 abused and/or neglected adolescents and 22 controls, ranging in age from 8 to 15 years, (M = 11.47; SD = 1.69). Subjects viewed faces that varied in degree of happiness and fear. Subjects were asked to identify the expression on each face as happy, neutral or fearful.Results: Maltreated adolescents were faster than controls at categorizing emotional facial expressions, F(9,450) = 2.198 p < .05. These results were driven primarily by the fearful faces. Classification of faces during this task was equivalent for maltreated adolescents and controls. Analyses of the effects of psychiatric diagnosis on this task are underway.Conclusions: Maltreated adolescents identified emotional facial expressions faster than controls. An explanation for these results is that maltreated adolescents adapt to their environments and become hypervigilant at identifying potential social threats.

443. Randomized, Double-Blind Study of SR142801 (Osanetant), a Novel Neurokinin-3 (NK3) Receptor Antagonist in Panic Disorder with Pre- and Posttreatment Cholecystokinin Tetrapeptide (CCK-4) Challenges

Golo Kronenberg, Isabella Heuser



Background: The present study was designed to examine the efficacy and tolerability of the non-peptide neurokinin-3 (NK3) receptor antagonist SR142801 in out-patients suffering from panic disorder.Methods: In a pilot study, 52 patients who were responders to a cholecystokinin tetrapeptide (CCK-4) challenge were randomized to four weeks of treatment with SR142801 (n=36) or placebo (n=16). Panic symptoms were assessed on weekly visits and a second CCK-4 challenge was performed at the end of the double-blind placebo controlled treatment period.



Results: Tolerability of SR142801 was generally good. The proportion of patients who had at least one adverse event (AE) in the SR142801 group and the placebo group was similar (58,3 and 50%, respectively). Independent of treatment group, patients’ overall panic symptomatology was substantially improved by the end of treatment. With regard to efficacy outcomes, the compound was not significantly different from placebo. However, post-CCK-4 plasma prolactin concentrations showed a significant difference between placebo and SR142801.Conclusions: This study indicates that although SR142801 at a dose of 200mg/day failed to affect CCK-4-induced psychopathology, it demonstrated an effect on the endocrine stress response. Since the compound was well tolerated in this study and phase I clinical studies with doses up to 1000 mg/day have been conducted successfully, further studies are warranted.

444. Integrating Functional MRI and Electrophysiological Data to Characterize the Pathophysiology Associated with Schizophrenia and its Progression

Aysenil Belger1,2

1Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill,

NC,2Duke-UNC Brain Imaging and Analysis Center, Duke University,

Durham, NC

Background: Using multimodal neuroimaging, including functional MRI and electrophysiology, we examined prefrontal activation and event-related potentials associated with visual and auditory executive processes in three cross-sectional groups representing disease progression of schizophrenia spectrum psychotic disorders.Methods: Fifty-three individuals from four groups (control, high-risk, first episode and chronic schizophrenia) were studied with functional MRI and event-related potentials while performing an auditory-visual oddball task.Results: FMRI findings revealed that individuals at high-risk for schizophrenia showed significantly smaller activation to task-relevant target events in frontal regions (anterior cingulate gyrus, inferior frontal gyrus, middle frontal gyrus) compared to controls. Activation associated with target stimuli demonstrated a linear stepwise decline in activation over the cross sectional groups representing disease progression. The chronic and first episode groups showed significantly lower activation than the control group while the high-risk group showed activation trending towards that of the first episode group. Electrophysiological indices of target detection showed a similar decline with disease progression, with group differences emerging in high-risk individuals, and further declining with disease progression.Conclusions: These results suggest that prefrontal function declines prior to illness and hence may represent a vulnerability marker in assessing the risk of developing psychotic disorders among high-risk individuals. These findings also represent the first multimodal imaging of high-risk individuals, as compared to first episode and chronic patients, and indicate that fronto-striate function declines progressively during the course of illness.

445. Withdrawn

446. Abnormal Working Memory with Prefrontal Hypo- and Hyperactivity in First-Episode Schizophrenia

Hao-Yang Tan1, Wei-Chieh Choo

2, Steve Graham

2,

Calvin SL Fones1, Michael W. L. Chee

2

1Psychological Medicine, National University of Singapore, Singapore,

Singapore,2Cognitive Neuroscience Laboratory, Singhealth Research

Laboratories, Singapore, Singapore

Background: Aberrant prefrontal activity in response to working memory tasks in schizophrenia could be affected by variations in clinical status, task design and behavioral performance. This study aims to clarify, using fMRI and a set of verbal working memory tasks, the prefrontal activity in first-episode schizophrenia, minimizing confounders due to chronic illness.Methods: We studied 11 first-episode schizophrenia patients with less than 1 year duration of psychosis and who were treated with atypical antipsychotics. They were compared to 11 matched healthy controls. Each group performed two verbal working memory tasks while undergoing fMRI: one required maintenance of letters (LTR); the other required manipulation in addition to maintenance (PLUS).Results: Performance in both tasks was poorer but not slower in patients. Both patients and controls activated a predominantly left-sided frontal-parietal network, with PLUS eliciting activity of greater magnitude and spatial extent. With both tasks, patients showed less dorsolateral prefrontal cortex (DLPFC) activity, and greater ventrolateral prefrontal cortex (VLPFC) activity relative to controls. In patients but not in controls, performance was correlated with right VLPFC activation. Further, in patients, the task requiring manipulation resulted in greater VLPFC and less anterior cingulate activity than controls.Conclusions: In patients with first-episode schizophrenia, tasks engaging verbal working memory reveal hypo- and hyperactivity in several prefrontal regions compared to controls, reflecting abnormal prefrontal circuitry and compensation effects present relatively early in the illness.

447. Absence of Anterior Cingulate Activation in Schizophrenic Individuals during a Semantic Feature-Binding Task

Paul Rivkin1, Michael Yassa

1, Michael Kraut

2, Richard

Kanaan3, Sarah A. J. Reading

1, Vince D. Calhoun

1,4,

John Hart5, Godfrey D. Pearlson

1,4

1Psychiatry and Behavioral Sciences, Johns Hopkins University,

Baltimore, MD, 2Radiology, Johns Hopkins University, Baltimore, MD,

3Section of Neuroimaging, Institute of Psychiatry, London, United

Kingdom,4Psychiatry, Yale University, Hartford, CT,

5GRECC of

CAVHS, Geriatrics, University of Arkansas for Medical Sciences, Little

Rock, AR

Background: Functional MRI (fMRI) was used to determine whether brain activation associated with semantic binding is disrupted in schizophrenic individuals.Methods: Thirteen individuals diagnosed with either schizophrenia or schizoaffective disorder (8M, 5F; mean age 41.0, SD 9.1) were recruited from the Johns Hopkins Hospital. Positive and negative symptoms were evaluated using the Scales for Assessment of Positive and Negative Symptoms (SAPS and SANS). Functional MRI scans were acquired using an event-related design. During the task, subjects were instructed to press a button if the two words presented on the screen were features of a single object (bind) and another button if they were not (non-bind). Functional data were preprocessed and analyzed using Statistical Parametric Mapping (SPM99).Results: Patients showed increased rCBF in left thalamic nuclei during binding events when compared to non-binding events (p<0.01, uncorrected). No other activation was observed.Conclusions: Prior studies of semantic binding in normal individuals using this specific experiment (Kraut et al. JOCN, 2002; JINS, 2003) showed focal activation in the thalamus and supplementary motor area/anterior cingulate. Our current results suggest that individuals with schizophrenia have no activation of SMA/anterior cingulate during performance of this semantic binding task. The SMA/anterior cingulate region has been postulated to set the target search criteria for feature-binding, monitoring neural processes subserving task performance, or perhaps determining whether the feature-



binding criteria have been met. With impaired semantic binding likely associated with formal thought disorder (FTD), these findings may have important implications for neural mechanisms of FTD.

448. In Vivo1H Spectroscopy Evidence of Increased

Macromolecule Signal in Younger First-Episode Never-Medicated Patients with Schizophrenia

Jeffrey A. Stanley1, Madhuri Vemulapalli

2, Debra M.

Montrose2, John A. Sweeney

3, Jay W. Pettegrew

1,

Matcheri S. Keshavan1

1Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh,

PA,2Psychiatry, Western Psychiatric Institute and Clinic, Pittsburgh,

PA,3Psychiatry, University of Illinois at Chicago, Chicago, IL

Background: In vivo 31P spectroscopy studies have shown increased signal of broader spectral peaks in the prefrontal region of first-episode, never-medicated schizophrenia (FESCH) subjects; a finding that may suggest increased synaptic/transport vesicles, and/or phosphorylated proteins. Interestingly, in

vivo, short echo time 1H spectroscopy also contains broader peaks due to macromolecules (MM). The assignment of the MM resonances is unclear; however, glycolipids such as gangliosides can contribute to the MM signal. Gangliosides are developmentally regulated and are enriched in grey matter (e.g., synaptic membranes). The purpose of this study is to investigate whether increased MM levels also are observed in FESCH, which would support prior 31P spectroscopy studies.Methods: 1H metabolite levels and levels of lipid and MM resonances were quantified in the left dorsolateral prefrontal cortex of 19 FESCH subjects (13M and 6F; 23.1Â±6.4 years) and 61 healthy controls (HC; 40M and 21F; 24.1Â±6.5 years) using LC Model for quantification.Results: FESCH subjects showed decreased N-acetyl-aspartate (NAA) compared to controls (p=0.033); a finding more pronounced in the younger subjects (age-interaction: p=0.0013). There were no group differences for MM or lipid; however, there was a significant age-interaction with MM (p=0.0086). The MM levels were higher in the younger subjects compared to age-matched controls (p=0.0055 for subjects < 24 years).Conclusions: Lower NAA suggests an underdevelopment of neuronal processes and synapses in FESCH. Increased MM in the younger FESCH subjects is consistent with 31P spectroscopy findings and may suggest an alteration in the ganglioside environment specially in synaptosomal membranes.

449. PET 18-F-Fallypride and FDG Ipairs in Never-Medicated Schizophrenics and Normal Volunteers

Monte S. Buchsbaum1, Brad T. Christian

2, Douglas S.

Lehrer3

1Psychiatry, Mount Sinai School of Medicine, New York, NY,

2Department of Nuclear Medicine, Kettering Medical Center, Dayton,

OH,3Psychiatry, Wright State University School of Medicine, Dayton,

OH

Background: Because neuroleptic treatment may cause long-lasting changes in brain structure and function, we recruited a sample of never-previously medicated patients with schizophrenia to examine dopaminergic physiology in the frontal-striatum-thalamus circuitMethods: We obtained positron emission tomography with 18F-fallypride and 18F-deoxyglucose on 13 never previously medicated patients with schizophrenia and 12 normal volunteers. During FDG uptake, patients carried out a spatial attention task previously demonstrated to activate the pulvinar as assessed with FDG PET and recently confirmed with fMRI.Results: Patients with schizophrenia had lower relative metabolic rates in the prefrontal cortex, striatum, and thalamus and lower binding potential for Fallypride in the thalamus.

Conclusions: Dysfunction of the fronto-striato-thalamic pathway is implicated in schizophrenia.

450. Is the NMDA Receptor Relevant to Antipsychotic Drug Action?

Lyn S. Pilowsky1, Rodrigo A. Bressan

1, Kjell

Erlandsson2, Rachel S. Mulligan

1, Jonathan Owens

3,

James Stone1, Vincent J. Cunningham

4, Roger N.

Gunn5, Peter J. Ell

2

1Institute of Psychiatry and Institute of Nuclear Medicine, King's

College London and University College London, London, United

Kingdom,2Institute of Nuclear Medicine, University College London,

London, United Kingdom, 3Department of Clinical Physics, University

of Glasgow, Glasgow, United Kingdom, 4Methodology,

GlaxoSmithKline, Harlow, United Kingdom, 5Montreal Neurological

Institute, McGill University, Montreal, PQ, Canada

Background: There are many lines of evidence supporting NMDA dysfunction in schizophrenia. NMDA receptors are heteromeric ion channels composed of multiple protein subunits. These receptors are essential for synaptic initiation, strengthening and plasticity. Blockade of the open channel by phencyclidine or ketamine results in a psychotomimetic profile similar to schizophrenia. NMDA function is difficult to measure accurately post mortem. We have validated [123I] CNS 1261, the first useful SPET tracer for the MK-801/PCP/ketamine site in living humans (1,2).Methods: We studied healthy volunteers, drug free schizophrenic patients, typical antipsychotic and clozapine treated patients. SPET studies were performed using either a bolus protocol and kinetic analysis or a bolus/infusion protocol and equilibrium analysis. Receptor binding was quantified by the total volume of distribution (VT), and also, to control for the effect of non-specific binding, by the alternative outcome measures BP1(binding potential1)= VT-VR, and BP2 (binding potential 2)= (VT-VR)/VR.VR, was obtained from whole cortex. ROI and voxel based analyses were performed.Results: Decreased NMDA binding (BP1 and BP2) was observed in frontal, temporal and striatal regions in drug free patients relative to healthy volunteers. Increased binding was seen in cerebellar regions in drug free patients. These abnormalities were not observed in drug treated patients.Conclusions: Antipsychotic drug treatment may be normalising NMDA dysfunction in schizophrenia. The data supports glutamatergic hypotheses of schizophrenia and suggests novel directions for drug discovery.1. Erlandsson K et al, Nucl. Med. Biol., 30(4), 441-4542. Bressan RA et al. Nucl. Med. Biol. (in press)

451. Volumetric MRI Study in Childhood and Adolescent Psychoses

Mohamed Elsayed1, Linmarie Sikich

1, Cecil Charles

2,

Sarang Joshi3, Guido Gerig

4, Jeffrey A. Lieberman

1

1Psychiatry Department, UNC-CH, Chapel Hill, NC,

2Radiology

Department, Duke University, Durham, NC, 3Biomedical Engineering

Department, UNC-CH, Chapel Hill, NC, 4Computer Science

Department, UNC-CH, Chapel Hill, NC

Background: Numerous studies have found that patients with schizophrenia have structural brain abnormalities. Less marked structural brain abnormalities have also been described in affective disorders. Volumetric imaging studies of young psychotic individuals may provide an alternative way to assess whether structural brain changes are present as chronic psychotic illnesses begin to develop or whether structural brain changes appear to be more related to ongoing psychotic illness.



Methods: 29 psychotic patients (16 with schizophrenic spectrum disorders and

13 with affective psychoses) and 17 healthy controls were included in this study.

Subjects had a thorough diagnostic and clinical evaluation. High-resolution MRI

was done on a GE SIGNA Advantage System operating at 1.5T. Measurement

of the intra-cranial volume components was performed using Automatic brain

tissue segmentation and brain parcellation. Measurements of the hippocampus

were performed using newly modified large-deformation-based segmentation.

Volumes of the selected structured measured were normalized by the ICV.

Sixteen of the subjects were rescanned after 2-6 months of antipsychotic

treatment.

Results: A significant decrease in frontal and parietal grey matter was found in

the schizophrenic spectrum group but not in the psychotic affective group

compared to healthy controls. The hippocampul volume was decreased in the

psychotic group compared to the healthy controls. In patients rescanned after 2-

6 months, the left hippocampus volume was significantly decreased after 2-6

months of treatment.

Conclusions: Youth with schizophrenic spectrum disorders had significant less

frontal and parietal grey matter than those with affective psychoses and healthy

controls. Psychotic youth had smaller hippocampus than healthy controls.

452. Reduced Cortical Folding in Individuals at High Risk for Schizophrenia

Roger J. Jou, Antonio Y. Hardan, Matcheri S. Keshavan

Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA

Background: The gyrification index (GI), the total cortical contour divided by

the outer contour, is a measure of cerebral cortical folding. Studies have

documented its reduction in individuals with schizophrenia, and this

investigation attempts to examine gyrification patterns in individuals at high risk

for schizophrenia.

Methods: Using MRI scans and the Brains2 software, GIs were calculated for

17 high-risk children/adolescents (at least one first-degree relative with

schizophrenia) and 15 controls (no family history of schizophrenia). Using the

coronal slice anterior to the corpus callosum, total and outer contours were

manually traced to allow GI calculation.

Results: No significant differences between the two groups were observed with

regard to gender composition (high-risk: 10 males, 7 females; control: 13 males,

2 females) or age (high-risk=15.2±3.0 years; control=14.5±5.4 years). Left GI

was lower in the high-risk group compared to controls (high-risk=2.95±0.30;

control=3.21±0.35; t=2.19, df=30, p=0.036). No significant difference in the

right GI was observed (high-risk=3.03±0.35; control=3.11±0.24; t=0.746,

df=30, p=0.461). Negative correlations were observed in the high-risk group

between right GI and perceptual aberrations as measured by the Chapman scale

(R=-0.503; p= 0.047) and the number of nonperseverative errors on the

Wisconsin Card Sorting test (R=-0.512; p=0.036).

Conclusions: These results suggest reduced cortical gyrification in the left

frontal lobes of young relatives at high risk for schizophrenia. This finding is

consistent with studies of schizophrenic patients and supports genetic and

neurodevelopmental models of the disorder. Longitudinal studies can elucidate

predictive value of this abnormality for later emergence of psychotic disorders

in individuals at risk.

453. An MR-DTI Study of Thalamo-Cortical Connections in Schizophrenia

James J. Levitt1, Hal Ersner-Hershfield

1, Marek

Kubicki1, Carl-Frederik Westin

2, Ron Kikinis

2, Ferenc A.

Jolesz2, Robert W. McCarley

1, Martha E. Shenton

1

1Psychiatry, VA Boston Healthcare System, Harvard Medical School,

Brockton, MA, 2Radiology, Brigham and Women's Hospital, Harvard

Medical School, Boston, MA

Background: Frontal-subcortical cognitive and limbic feedback loops play an

important modulatory role in higher cognitive functioning. The final step in

these higher cognitive feedback loops is the thalamo-cortical projection through

the anterior limb of the internal capsule (AL-IC). Hence, we assessed the AL-IC

fiber tract, using diffusion tensor imaging (DTI) in schizophrenic subjects, for

any abnormalities which might disrupt these higher cognitive circuits.

Methods: In 16 chronic schizophrenics and 19 male, normal controls matched

for handedness, age, and parental SES, we measured: 1) water diffusion

fractional anisotropy (FA; a measure of disturbances in fiber density, thickness

and/or coherence) in the AL-IC; and 2) the volume of the AL-IC, manually

segmented on water diffusion FA images. Four-mm thick coronal images

covering the whole brain were acquired on a 1.5 Tesla GE Echospeed system

using MR line scan diffusion imaging. FA was calculated based on derived

diffusion tensor eigenvalues estimating the degree of anisotropy of the tensor in

each voxel.

Results: Results showed that mean FA did not differ between groups for either

left or right AL-IC (p=0.3; p=0.14). However, there were significant bilateral

group differences in mean volume of AL-IC, traced on FA map images.

Schizophrenics, in comparison with controls, had significantly decreased left

and right volumes of the AL-IC (p<0.02; p=0.005).

Conclusions: The bilaterally decreased volume in the AL-IC in schizophrenics,

in comparison with controls, is consistent with a reduction in number of fibers

in the AL-IC whose cell bodies originate either in the prefrontal cortex or in the

thalamus.

454. Anterior Ventromedial Temporal Lobe Volume Decrements In Family Members of Patients with Schizophrenia

Adrienne D. Mishkin, Paul J. Moberg, David Roalf, Bruce I. Turetsky

Psychiatry, University of Pennsylvania, Philadelphia, PA

Background: In a volumetric MRI study of the anterior ventromedial temporal

lobe (AVMT) in schizophrenia, we observed bilateral reductions in gray matter

in both the perirhinal and entorhinal regions, and an association between

reduced perirhinal volume and olfactory threshold sensitivity deficits. Olfactory

dysfunction and its associated neurobiological abnormalities have been

considered possible endophenotypic markers of genetic vulnerability to

schizophrenia. We therefore undertook a parallel investigation of AVMT

volumes in unaffected family members of schizophrenia patients.

Methods: MRI scans were acquired from 22 healthy first-degree relatives of

schizophrenia patients and 22 age and gender-matched comparison subjects.

Transitional landmarks derived from histological analysis were used to parse the

AVMT into discrete temporopolar, perirhinal and entorhinal cortical regions.

Gray matter volumes within each region was determined as a percent of total

cranial volume, separately for left and right hemispheres.

Results: There were no abnormalities in the temporal polar cortex. Family

members had bilateral reductions of the entorhinal cortex, which were more

severe in the right hemisphere. Female relatives had increased volumes of the left

perirhinal cortex; male relatives did not differ from controls. Relatives also had

reduced right nostril UPSIT scores.

Conclusions: Reduced volume of the entorhinal cortex in unaffected family

members parallels our earlier finding in patients, indicating that this is a

genetically-mediated structural brain abnormality. Family members differed

from patients in having larger rather than smaller perirhinal cortical volumes.

Reduced perirhinal volume may therefore be a manifestation of disease

progression, with possible compensatory or protective mechanisms active in the

unaffected relatives.



455. Cognitive Function and Brain Anatomy in Adults with VCFS with and without Psychosis

Therese van Amelsvoort1, Eileen M. Daly

2, Jayne

Henry3, Robin Morris

3, Michael J. Owen

4, Kieran C.

Murphy5, Declan G. M. Murphy

6

1Psychiatry, Academic Medical Center, Amsterdam, Netherlands,

2Psychological Medidicine, Institute of Psychiatry, London, United

Kingdom,3Psychology, Institute of Psychiatry, London, United

Kingdom,4Psychological Medicine, University College of Wales,

Cardiff, United Kingdom, 5Psychiatry, Royal College of Surgeons in

Ireland, Dublin, Ireland, 6Psychological Medicine, Institute of

Psychiatry, London, United Kingdom

Background: Velo-cardio-facial syndrome (VCFS) is associated with interstitial

deletions of chromosome 22q11, mild/borderline learning disability,

characteristic dysmorphology, and a high prevalence of of schizophrenia. The

biological basis to this high prevalence of schizophrenia is unknown.

Methods: We studied brain anatomy and cognitive function in a group of 28

adults with VCFS. Structural MRI and a comprehensive neuropsychological

testbattery were employed to acquire data to measure total and regional brain

volumes, regional grey and white matter densities, and to assess intellectual

function, memory, executive function, visuospatial function and attention.

Within-VCFS group comparisons between those who developed schizophrenia

and those who did not were made.

Results: There were no between group differences in age, gender and IQ.

Compared to VCFS adults without schizophrenia, those with schizophrenia had

significant impairments on tests of executive function and attention, and

reduced total brain and white matter volume and increased total cerebrospinal

fluid volume.

Conclusions: Within VCFS the presence of schizophrenia is accompanied by

neurocognitive impairments and structural brain abnormalities. Our results

suggest that schizophrenia in VCFS is a progessive neurodevelopmental

disorder that might affect white matter and prefrontal function in particular.

456. Correlates of Cannabis Misuse in Adolescents with Treatment-Refractory Schizophrenia

Emily P. Thaden1, Joseph Rhinewine

1, Harvey N.

Kranzler2, Ginny Gerbino-Rosen

2, Marjorie

McMeniman1, Courtney Dethomas

1, Sanjiv Kumra

1

1Psychiatry Research, Zucker Hillside Hospital, North Shore-Long

Island Jewish Health System, Glen Oaks, NY, 2Psychiatry, Albert

Einstein College of Medicine, Bronx, NY

Background: The authors conducted a retrospective chart review to evaluate

whether repeated exposure to cannabis might have an impact on symptom

presentation and clozapine treatment response in consecutively admitted

treatment-refractory adolescents (ages 15 to 18 years) with schizophrenia (295.x)

or schizoaffective disorder (295.7).

Methods: The following information was extracted from the medical records:

past history of cannabis misuse, demographic data, closest available IQ test

result, and baseline Brief Psychiatric Rating Scale (BPRS) ratings prior to

clozapine initiation. Clinical ratings of clozapine response after 6 months of

treatment.

Results: Twelve of 28 (40%) adolescents were found to have documented

evidence of a significant history of cannabis misuse. Dual diagnosis patients

were found to have significantly higher full-scale, verbal IQ , and a higher

baseline severity of positive and negative symptoms prior to clozapine initiation

compared to schizophrenic adolescents with no history of cannabis misuse.

Twenty of 28 (71%) patients were rated as very much/much improved at the

completion of 6 months of clozapine treatment compared to their baseline

status.

Conclusions: Treatment-refractory adolescents with schizophrenia and a

history of cannabis misuse have higher intellectual functioning, which may

reflect higher premorbid cognitive functioning. Also, these preliminary data

suggest that repeated exposure to cannabis may contribute to the morbidity of

schizophrenia leading to worsening of clinical symptoms. Additional long-term,

controlled studies are needed to assess whether clozapine reduces the likelihood

of recurrence of cannabis abuse and psychotic relapse once adolescents with

schizophrenia are discharged from the hospital to less restrictive settings.

457. Predicting Schizophrenia: The Convergence of Clinical, Genetic and Vulnerability Marker Risk Assessment

Kristin Cadenhead, Kathleen Shafer, Gregory A. Light

Psychiatry, University of California San Diego, La Jolla, CA

Background: Schizophrenia is often a devastating illness with a chronic course.

Early identification of individuals at risk for the development of schizophrenia

is an important endeavor because early intervention improves the course and

prognosis of the illness and may prevent further neuropathological changes.

Methods: Through community outreach and education, 43 individuals with

early signs of psychosis and/or a high genetic risk for schizophrenia were

referred to the CARE (Cognitive Assessment and Risk Evaluation) program at

UCSD for longitudinal follow-up. The primary aim of the CARE program is to

predict which individuals are at greatest risk for conversion to psychosis using a

combination of clinical, genetic and vulnerability marker assessment. All at-risk

subjects receive a monthly clinical assessment as well as a biannual assessment

using psychophysiological and neurocognitive measures that are candidate

endophenotypes for schizophrenia spectrum illness including the P50 event

related potential paradigm.

Results: As predicted, the at-risk subjects had P50 gating performance that was

intermediate to normal subjects (N=25) and a group of patients experiencing

their first psychotic break (N=15). Those at-risk subjects who were not

receiving antipsychotic medication or who had a first degree relative with

schizophrenia had the most deficient gating.

Conclusions: Longitudinal follow-up will allow assessment of the predictive

validity of P50 gating alone and in combination with other measures in

determining which individuals are at greatest risk for schizophrenia.

Additionally, the potential role of antipsychotic medication on P50 gating as

well as the prevention of schizophrenia needs further investigation.

458. Cortical Amplification Failure as a Unifying Model of Cognitive ERP Dysfunction in Schizophrenia

Daniel C. Javitt1,2

, David Leitman1, Marina Shpaner

1,

Beth Higgins1, Gail Silipo

1, John J. Foxe

1

1Program in Cognitive Neuroscience and Schizophrenia, Nathan Kline

Institute for Psychiatric Research, Orangeburg, NY, 2Psychiatry, New

York University School of Medicine, New York, NY

Background: Patients with schizophrenia show deficits in the generation of

early auditory potentials, including N100 (N1). N1 normally increases in

amplitude as a function of interstimulus interval (ISI). The gain function is non-

linear, with an initial rapid increase followed by plateau. The present study

investigates characteristics of non-linear gain of the N1 amplification function

in schizophrenia.

Methods: N1 was elicited in response to repetitive tones bursts delivered at

intervals ranging from 0.3 to 6 s in separate blocks. Amplitudes and surface

voltage distributions were determined by repeated measures ANOVA. Cortical

gain parameters were conducted using non-linear curve fitting to the Michaelis-

Menton equation. Dipole mapping was used conducted using BESA.



Results: Patients showed normal N1 amplitude at 300 ms ISI, with progressive

increase in deficit thereafter leading to a significant group X ISI interaction

(p<.0001). There were no significant between-group topographic differences.

Non-linear curve fitting demonstrated differences in the slope and plateau

values of the N1 amplification curve in schizophrenia, with no alteration in

semi-saturation point. Dipole mapping demonstrated deficits in auditory cortical

ERP generation leading to dysfunction in higher order circuits.

Conclusions: This study confirms prior reports of N1 generation deficits in

schizophrenia. The pattern of dysfunction closely resembles the pattern

observed following blockade of N-methyl-D-aspartate (NMDA) receptors in

monkeys, suggesting that deficits may reflect underlying NMDA dysfunction.

Dipole mapping suggests that dysfunction of auditory cortical N1 generators

leads to failure of higher order cortical activations.

459. Physiologic Responses to Pleasant and Unpleasant Odors in Patients with Schizophrenia

Kiana Owzar, Paul J. Moberg, David Roalf, Raquel E. Gur, Bruce I. Turetsky

Psychiatry, University of Pennsylvania, Philadelphia, PA

Background: Deficits in emotional perception and processing are well known

in schizophrenia. Olfactory impairments have also been identified. Olfaction

has been associated with emotional experience, and overlapping limbic system

structures are involved in both olfactory and emotional stimulus processing.

Physiological probes of the olfactory system may therefore be particularly

sensitive to deficits in emotional reactivity. Surprisingly, there has been little

direct investigation of this aspect of olfactory function in schizophrenia.

Methods: Chemosensory event-related potentials were used to examine the

basic physiological response to pleasant and unpleasant odors. The sample

included 23 patients with schizophrenia and 20 healthy comparison subjects.

Vanillin and hydrogen sulfide (H2S) were used as olfactory nerve stimulants that

differed in hedonic valence. Rght and left nostrils were activated separately to

assess lateralized brain responses.

Results: Patients exhibited reduced N1 and P2 component amplitudes,

independent of the odorant class. This was most prominent following left

nostril stimulation. Healthy controls, but not patients, displayed increased N2

amplitude and prolonged P3 latency when exposed to H2S as compared to

vanillin.

Conclusions: Abnormal N1 and P2 responses indicate lateralized early sensory

deficits in the olfactory pathway. The enhanced N2 and prolonged P3 responses

in controls, to H2S, indicate greater depth of processing of unpleasant odors;

patients' failure to exhibit similar enhanced responses indicates deficient

processing of “unpleasantness.” Functional imaging studies have demonstrated

amygdala activation in response to negative valence odors, and structural

imaging data indicate reduced amygdala volumes in patients. Physiological

impairments in processing unpleasant odors may, therefore, indicate amygdala

dysfunction.

460. Prenatal Infection and Immune Abnormalities in Adult Schizophrenia

Alan S. Brown1, Catherine A. Schaefer

2, Stefan

Gravenstein3, Melissa D. Begg

4, Charles P.

Quesenberry2, Vicki Babulas

1, Jack M. Gorman

5, Ezra

S. Susser6

1Department of Psychiatry, Columbia University, New York, NY,

2Research Division, Kaiser Permanente, Oakland, CA,

3Department of

Medicine, Eastern Virginia Medical School, Norfolk, VA, 4Department

of Biostatistics, Columbia University, New York, NY, 5Department of

Psychiatry, Mt. Sinai School of Medicine, New York, NY, 6Department

of Epidemiology, Columbia University, New York, NY

Background: Previous studies have suggested associations between prenatal

infectious exposures and risk of schizophrenia. Most prior investigations,

however, relied upon epidemics in populations to define exposure status. We

sought to improve upon this work by quantifying exposure status using archived

prenatal serum specimens.

Methods: In 3 separate studies on a large birth cohort born from 1959-1967,

we examined the relationship between schizophrenia and prenatal exposure to

influenza, cytokines, and toxoplasmosis. Serologic assays for each of these

infectious and immune factors were obtained in maternal serum specimens

from pregnancies giving rise to cases of schizophrenia and other schizophrenia

spectrum disorders and matched controls.

Results: The risk of schizophrenia was increased threefold for exposure to

influenza during early to mid-pregnancy (OR=3.0, 95% CI=0.9-10.1, p=.052).

Second trimester interleukin-8 levels were significantly elevated in

schizophrenia/spectrum disorder cases as compared to matched controls

(p=.02). Preliminary results indicate a greater than twofold increased risk of

schizophrenia/spectrum disorders in subjects with elevated antibody titers to

toxoplasmosis (OR=2.6, 95% CI=1.0- 6.8, p=.051).

Conclusions: These findings provide further support for a substantive role of

in utero infection in the etiology of schizophrenia.

461. Gene Expression Analyses in the Cerebellum of Patients with Schizophrenia Suggest that a GABAergic Dysfunction in Golgi Cells Leads to Hyperactivity of Glutamatergic Granule Cells

Rodrigo D. Paz1, Melissa A. Merhege

1, Rosalinda C.

Roberts2, Robert R. Conley

2, Nancy C. Andreasen

3,4,

Nora I. Perrone-Bizzozero1

1Department of Neurosciences, University of New Mexico School of

Medicine, Albuquerque, NM, 2Department of Psychiatry, University of

Maryland School of Medicine, Baltimore, MD, 3Department of

Psychiatry, University of Iowa College of Medicine, Iowa City, IA, 4MIND Imaging Center, MIND Institute, Albuquerque, NM

Background: Neuroimaging studies have demonstrated an increased cerebellar

blood flow and glucose uptake in the cerebellum of patients with schizophrenia.

Our goal is to identify the molecular and cellular substrates of this metabolic

hyperactivity.

Methods: RNA was isolated from post-mortem human tissues from the

Maryland Brain Collection. We used DNA microarray technologies and real

time PCR to examine the pattern of gene expression in lateral regions of the

cerebellum from patients with schizophrenia and controls without a psychiatric

disorder. Both groups of subjects were further subdivided into those with and

without a history of alcohol abuse or dependence.

Results: Patients without alcohol abuse showed a pattern of disinhibited

granule cell activity as revealed by the significant increases in BDNF and GAP-

43 mRNAs, which are selectively expressed by these neurons. The levels of the

delta sub-unit of the GABA-A receptor mRNA were also increased in cerebellar

granule cells, suggesting a deficit in the GABAergic tone provided by Golgi

interneurons. Patients with schizophrenia and ethanol abuse did not show any

of these abnormalities.

Conclusions: Considering recent studies indicating that ethanol is a potent

activator of extrasynaptic GABA-A receptors containing the delta subunit, our

results are consistent with the hypothesis that the metabolic hyperactivity

reported by functional neuroimaging studies has its molecular substrate in a

dysfunction of Golgi interneurons. This deficit, in turn, could result in increased

granule cell firing leading to a hyperglutamatergic state in the cerebellar cortex

of patients with schizophrenia.



462. RGS4 Polymorphism and the Dorsolateral Prefrontal Cortex Morphometry in First Episode Schizophrenia

Konasale M. Prasad, Kodavali V. Chowdari, Michael E. Talkowski, Vishwajit L. Nimgaonkar, Matcheri S. Keshavan

Psychiatry, Western Psychiatric Institute and Clinic, Pittsburgh, PA

Background: The precise mechanism by which the candidate genes associated

with schizophrenia confer susceptibility is poorly understood. We studied the

regulator of G-protein signaling subtype 4 (RGS4) gene that was reported in

postmortem studies to be underexpressed in the prefrontal cortex (PFC) of

patients but not control subjects. RGS4 gene has been reported to confer

susceptibility to schizophrenia in five independent samples. We examined the

DLPFC gray matter in antipsychotic naïve first episode schizophrenia patients

and control subjects with RGS4 polymorphisms hypothesizing that the DLPFC

volume would be different across RGS4 genotypes.

Methods: Fifty-seven RGS4 genotyped subjects (schizophrenia=30; matched

control subjects=27) were scanned on a 1.5T GE whole body scanner. We

performed voxel-based morphometry (VBM) to examine whole brain

differences and measured the DLPFC using region-of-interest approach blind to

the diagnosis and the genotype data.

Results: VBM showed reduced volumes in the prefrontal cortex and

cerebellum. ROI analyses showed robust volumetric differences across the

genotypes in the pooled sample of patients and controls as well as within the

patient group (n=30) but not in controls (n=27) (see Table).

Conclusions: Our observations suggest that RGS4 polymorphisms may

contribute to DLPFC structural alterations, perhaps by affecting the synaptic

density, and neuronal or glial number. Genotype effect restricted to the patients

suggests that other susceptibility genes may be interacting with RGS4

polymorphism.

Comparison of DLPFC across RGS4 genotypes in the pooled sample

of patients and control subjects.

Left DLPFC Right DLPFC SNP

F (2,57) p F(2,57) p

1 4.32 .019 3.04 .057

4 8.33 .001 5.65 .006

7 3.67 .032 2.02 .14

18 7.58 .001 5.51 .007

463. Rostral Entorhinal Region in Schizophrenia: Heterotopic Malformations in Correlation with Clinical Symptomatology

Helmut Beckmann1, Dieter Senitz

1, Hermann Jakob

2

1Psychiatry and Psychotherapy, University of

Wuerzburg, Wuerzburg, Germany,2State Hospital,

Department of Pathology, Wiesloch/Heidelberg, Germany

Background: Heterotopic malformations in the rostral entorhinal region of

schizophrenic brains: discussion of problems and possible reasons for divergent

findings.

Methods: Description of processing of the material, exact topology of the

sections of both hemispheres. Collection of brains of 20 schizophrenics

diagnosed acc. to DSM IV R and 20 controls of approximately the same age.

Both rostral hemispheres in series of 20 µm sections. "Heterotopic

malformation": 1. Cell clusters of narrowly or even unseperably lying nerve cells

in pre-ß and pre- . 2. Often striking differences of volume of these cells within

the clusters. 3. Loss of normal layering with severe thinning or the complete loss

of single layers particularly layers IV and V. 4. Striking interhemispherical

differences in the cytoarchitectural pattern.

Results: All 20 schizophrenics: heterotopic malformations in contrast to 20

controls. Case 1: the typical heterotopic malformation on both sides, but to a

different degree, both sides with different location (patient suffered from a

chronic form of paranoid-hallucinatory schizophrenia, paranoid type (DSM IV

R 295.30)). Case 2 (so called negativistic catatonia (Leonhard) (DSM IV R

295.20) or chronic catatonia disorganized type): the heterotopic malformation

was only on one side with its characteristic pattern, whereas the other side was

completely free.

Conclusions: Important finding as schizophrenia - already stated by Bleuler - is

very different in its clinical pictures as far as cross sectional, long-term courses

and outcomes are concerned. The findings that different locations and sizes of

the migrational malformations may be causative for different clinical pictures is

obvious.

464. Cannabis and Multiple Substance Abuse Raise the Serum Concentrations of Brain Derived Neurotrophic Factor (BDNF) in Drug-Naive Schizophrenic Patients

Maria Christiane Jockers-Scherübl, Uta Matthies, Heidi Danker-Hopfe, Franziska Selig, Undine Lang



Background: Long-term cannabis abuse may increase the risk for

schizophrenia. Nerve growth factor (NGF) and brain-derived neurotrophic

factor (BDNF) play a crucial role concerning growth, differentiation and

maintenance of function in the central and peripheral nervous system. In a

previous study we found a high correlation between cannabis consumption (or

additional substances) in drug-naïve schizophrenic patients and their NGF

serum-concentrations. They also had an earlier onset of disease when compared

to patients without a history of cannabis consumption. We postulated NGF as a

marker of neuronal damage and tested BDNF likewise to substantiate our

previous findings.

Methods: The BDNF serum levels of 156 drug-naïve schizophrenic patients

(according to DSM IV) were measured, compared to those of healthy controls

and then correlated to the long-term intake of cannabis and other illegal drugs.

Results: BDNF serum levels of 61 controls (13246 ± 5158 pg/ml) and 102

schizophrenics not consuming drugs (13134 ± 5911 pg/ml) did not differ

significantly. Schizophrenic patients with regular cannabis intake in the past (n=

34) had significantly raised BDNF serum levels (17584 ± 7369 pg/ml) in

comparison to controls and schizophrenics not consuming cannabis (p< 0.001).

The same was true for schizophrenics who abused not only cannabis but

additional substances (n=20) (16969 ± 6005 pg/ml, p<0.003). Again the

cannabis abusers suffered their first schizophrenic episode earlier than those

abstaining from drugs.

Conclusions: BDNF serum concentrations correlate positively with cannabis-

and additional drug-consumption in schizophrenic patients thereby possibly

representing a marker for neurotoxicity.



465. A Neuropsychological Investigation into Violence and Mental Illness

Ian Barkataki1, Veena Kumari

2, Mrigendra Das

3, Mary

Hill4, Robin Morris

2, Pamela Taylor

3, Tonmoy Sharma

5

1Section of Cognitive Psychopharmacology, Institute of Psychiatry,

London, United Kingdom, 2Department of Psychology, Institute of

Psychiatry, London, United Kingdom, 3Forensic Psychiatry,

Broadmoor Hospital, Crowthorne, United Kingdom, 4Department of

Psychology, Broadmoor Hospital, Crowthorne, United Kingdom, 5Research, Clinical Neuroscience Research Centre, Dartford, , United

Kingdom

Background: Previous research has reported cognitive impairment in

schizophrenia and antisocial personality disorder, the two mentally disordered

groups most implicated in violent behaviour. Until now, studies have focussed

on either group exclusively and have been criticised for procedural inadequacies

and sample heterogeneity. This study investigated neuropsychological profiles of

individuals with antisocial personality disorder and violent and non-violent

schizophrenia.

Methods: Individuals who had a history of violent behaviour diagnosed with

antisocial personality disorder (n=14) or schizophrenia (n=13), non-violent

schizophrenia (n=15) and healthy control subjects (n=15) were compared on a

neuropsychological battery designed to assess general intellectual function,

executive function, attention and cognitive processing speed.

Results: Cognitive deficits were more widespread in schizophrenia patients

regardless of a history of violence compared to those with antisocial personality

disorder, with the latter group displaying significant impairment only in

cognitive processing. Violent schizophrenia patients demonstrated greater levels

of impairment than non-violent schizophrenia counterparts, specifically in

executive functioning.

Conclusions: The findings demonstrate that selective cognitive impairments

are implicated in violence in schizophrenia and antisocial personality disorder,

implying differences in underlying pathology. Furthermore, cognitive

impairment appears more affected by the incidence of schizophrenia than

violent history, although there is evidence that a combination of both

exacerbates such deficits.

466. Memory-Delineated Subtypes of Schizophrenia: Performance in Biological Relatives

Monica E. Calkins, Paul J. Moberg, Ruben C. Gur, Raquel E. Gur, Bruce I. Turetsky

Neuropsychiatry Program, University of Pennsylvania School of

Medicine, Philadelphia, PA

Background: Schizophrenia is clinically heterogeneous, and this likely reflects

heterogeneity in underlying genetic vulnerability and disease pathology. Despite

this presumed heterogeneity, most schizophrenia research investigates overall

group differences between patients and healthy individuals. Recent efforts to

move beyond this have revealed neuropsychologically or psychophysiologically

distinct patient subgroups. Using the California Verbal Learning Test (CVLT),

Turetsky et al. (2002; Neuropsychology, 16, 481-490) derived three memory-

delineated schizophrenia subgroups fitting cortical, subcortical, or unimpaired

performance profiles and differing in clinical and neuroanatomical features. To

determine whether these subgroups are also genetically informative, we

examined the memory performance of the biological relatives of patients in each

subgroup.

Methods: First-degree biological relatives (n=27) of schizophrenia patients and

healthy participants (n=90) were administered the CVLT. Relatives were

grouped according to the subgroup status of their ill family member.

Results: As shown in the figure, relatives were more impaired than controls

across most CVLT indices. However, the relatives of cortical patients were

more impaired than relatives of subcortical or unimpaired patients.

Conclusions: The biological relatives of schizophrenia patients exhibited

performance heterogeneity. Verbal learning and memory deficits were especially

pronounced in the unaffected relatives of patients with a cortical dementia

profile. The results are thus supportive of (1) heterogeneity of memory

impairment in schizophrenia families (2) validity of the cortical-subcortical

distinction in schizophrenia (3) utility of subtyping strategies.

467. Speed of Processing and Olfaction in Schizophrenia

Nora Goudsmit, Rachel Wolitzky, Anna Regine Seckinger, Cheryl Corcoran, Arielle D. Stanford, Eileen Alexander, Raymond R. Goetz, Dolores Malaspina

Medical Genetics, New York State Psychiatric Institute, New York, NY

Background: Amid the various neurocognitive impairments documented in

schizophrenia, smell identification deficits (SID) remain an undisputed and

compelling finding. To determine how speed of processing is related to SID, we

examined performance on the Trail Making Test.

Methods: Our sample included 60 inpatients from the New York State

Psychiatric Institute’s Schizophrenia Research Unit. We considered age, deficit

syndrome, verbal IQ, and education in our analyses due to the documented

relationship to smell identification ability. Smell identification was tested with

the University of Pennsylvania Smell Identification Test (UPSIT), a forced-

choice scratch-and-sniff odor identification task. The Trail Making Test

primarily taps simple information processing and motor speed. Success on the

test requires, sustained visual attention and effort, sequencing and aspects of

working memory.

Results: UPSIT and Trails test mean scores respectively were 32.12 (SD =

4.60), Trails A seconds = 50.23 (SD = 29.09), Trails A errors = .17 (SD = .46),

Trails B seconds = 140.92 (SD = 77.59), Trails B errors = 1.44 (SD = 2.82).

Trails A errors and Trails A seconds accounted for a significant amount of the

variance in UPSIT scores in regression analyses (R2 = .098, p = .008 and R2 =

.051, p = .040).

Conclusions: Our novel finding that Trails A scores strongly and

independently predict to UPSIT scores adds to the developing understanding of

how neuropsychological performance and smell identification ability are linked

in schizophrenia. Connecting neurocognition to SID may prove to be an

essential marker for schizophrenia research.



468. Sex Differences in Cognitive Response to Medication in First Episode Schizophrenia

Pauline M. Maki1, Leah H. Rubin

2, Gretchen L. Haas

3,

Matcheri S. Keshavan3, John A. Sweeney

4

1Psychiatry and Psychology, University of Illinois at Chicago, Chicago,

IL,2Psychology, University of Illinois at Chicago, Chicago, IL,

3Psychiatry, Western Psychiatric Institute and Clinic, Pittsburgh, PA,

4Psychiatry, Psychology, and Neurology, University of Illinois at

Chicago, Chicago, IL

Background: Sex differences in the presentation of diseases and in cognition

may reflect the activational and/or organizational effects of gonadal hormones

on brain function. Here we report the first study to examine sex differences in

cognitive responses to antipsychotic medication in treatment naïve

schizophrenic patients as a way of exploring hormone effects on cognitive

deficits.

Methods: Primary outcomes were scores on neuropsychological tasks that

typically favor either men (Finger Tapping, Judgment of Line Orientation) or

women (Grooved Pegboard, Digit Symbol, California Verbal Learning Test).

Participants included 94 men and women participating in the University of

Pittsburgh First Episode Project. Pre-treatment and post-treatment (5 weeks)

cognitive testing was performed in men (n = 32) and women (n = 16) with

schizophrenia, and in matched healthy men (n = 28) and women (n = 18) at a

similar time interval.

Results: Multivariate analyses of variance of the effects of sex, group, and time

on "female" tasks showed advantages for females, controls, and the second

session. Female patients showed significant differential improvement on

"female tests" following treatment (sex x group x time interaction). A similar

analysis of "male tasks" showed an advantage for male patients and controls,

but male patients did not show differential improvement on these tasks after

treatment.

Conclusions: Results show specific sex differences in treatment response in

favor of females on female tests. Findings suggest that early organizational

effects of estrogen on brain structure or activational effects of gonadal

hormones on brain function might influence response to antipsychotic

treatment.

469. Depressed Mood and Functional Correlates in Institutionalized Schizophrenia Patients

Nina Rieckmann1, Abraham Reichenberg

1, Christopher

R. Bowie1, Michael J. Parrella

2, Leonard White

2, Philip

D. Harvey1

1Psychiatry, Mount Sinai School of Medicine, New York, NY,

2Clinical

Neuroscience Center, Pilgrim Psychiatric Center, West Brentwood,

NY

Background: Depressed mood is common in schizophrenia, but its relation to

the functional status of chronic patients is unclear. We determined the

frequency of depressed mood symptoms in institutionalized schizophrenia

patients and their cross-sectional relation to demographic, illness-related and

functional variables.

Methods: Cross-sectional data from 657 patients from the Pilgrim Psychiatric

Institute Longitudinal Study was analyzed. Patients with moderate to high

depressed mood ratings on both the Positive and Negative Syndrome Scale (a

score of 4 and above) and the Alzheimer's Disease Assessment Scale-Late

clinician rating (a score of 2 and above) were identified and compared to a

group of non-depressed patients matched on demographic variables. A second

comparison was done matching the groups for negative symptoms.

Results: 47 (7.2%) patients received moderate to high depressed mood ratings

on both scales. They were younger, more educated and had fewer years since

their first hospitalization than the non-depressed. Matching for those variables,

depressed patients exhibited better social and cognitive functioning than non-

depressed patients, with more positive and fewer negative symptoms. After

matching for negative symptoms, depressed patients still had more positive

symptoms, but there were no group differences in self-care, social and cognitive

functioning.

Conclusions: It appears that depressed mood in chronic schizophrenia patients

is associated with better functioning. Even when controlling for negative

symptoms, there is no indication of worse cognitive or self-care functioning in

depressed patients.

470. Learning Potential as a Predictor of Readiness for Psychosocial Rehabilitation in Schizophrenia

Thomas E. Smith1,2

, Joanna M. Fiszdon3,4

, Joel F. McClough

1,2, Steven M. Silverstein

5, Justin R.

Jaramillo2, Morris D. Bell

3,4

1Psychiatry, Columbia University College of Physicians & Surgeons,

New York, NY, 2Psychiatry, Hall-Brooke Behavioral Health Services,

Westport, CT, 3Psychiatry, Yale University School of Medicine, New

Haven, CT, 4Psychology, VA Connecticut Healthcare System, West

Haven, CT, 5Psychiatry, Center for Cognitive Medicine, University of

Illinois at Chicago, Chicago, IL

Background: Cognitive function in schizophrenia has repeatedly been

demonstrated to correlate with functional outcome. It has also been suggested

that a patient’s ability to benefit from training and practice, known as learning

potential, may moderate the relationship between cognition and functional

outcomes. Several studies have indicated that assessments of learning potential

may be better predictors of readiness for psychosocial rehabilitation than

traditional, static neurocognitive measures. The aim of the current study was to

determine whether performance on a verbal memory measure of learning

potential is associated with readiness for psychosocial rehabilitation.

Methods: Fifty outpatients with schizophrenia or schizoaffective disorder were

administered three different versions of a list learning test (CVLT-II), spaced 15

minutes apart. Based on CVLT-II performance across the three assessments,

participants were categorized as “learners”, “high scorers”, and “non-retainers”.

Participants were also administered a measure that has been shown to predict

performance in manualized skill training groups, the Micromodule Learning

Test (MMLT).

Results: Results indicate that learning potential categorization is significantly

associated with performance on the MMLT, F (2, 48) = 5.81, p < .01.

Conclusions: Dynamic measures of learning may provide valuable information

regarding an individual’s rehabilitation readiness. Further analyses are currently

underway to determine the demographic, symptom, and cognitive profiles

associated with learning potential classification.

471. The Role of Masking Effects on the Attentional Blink in Schizophrenia Patients

Jonathan K. Wynn1, Michael F. Green

2

1Department of Psychology, UCLA, Los Angeles, CA,

2Department of

Psychiatry and Biobehavioral Science, Geffen School of Medicine at

UCLA, Los Angeles, CA

Background: Identification of a second target is poorer when it follows the

first target by 200-500 ms during a rapid presentation of visual stimuli, resulting

in an attentional blink (AB). Only one study to date has examined AB in

schizophrenia finding that schizophrenia patients had enhanced AB. However,

it is unclear whether the enhanced effect is due to working memory deficits, to

greater susceptibility to masking effects, or a combination of both.



Methods: Fifteen schizophrenia patients and 6 normal controls participated in

an AB paradigm. AB was administered under two conditions: In the standard

condition the duration was kept constant for all stimuli (targets and distractors).

In the masking condition, duration for the distractors immediately following the

targets was either increased or decreased systematically, resulting in four

different combinations of post-target distractor length.

Results: In the standard condition, we replicated the finding that schizophrenia

patients showed an enhanced AB effect. In the masking condition,

schizophrenia patients’ had an augmented AB effect with a longer distractor

immediately following the first target. For both groups, increasing the length of

the distractor after the second target, regardless of the length of the distractor

after the first target, produced an enhanced AB effect.

Conclusions: In this preliminary study, schizophrenia patients’ showed an

exaggerated AB that appears to be due, at least in part, to greater susceptibility

to backward masking effects. These results suggest performance on the AB task

reflects both a deficit in working memory, and also greater susceptibility to

interruption by masking stimuli.

472. The Iron Metabolism in Acute Schizophrenic In-Patients

Jan Di Pauli1, Peter König

1, Zeyneb Vetter

1, Michael

Prapotnik1, Armand Hausmann

2, Roland Waschgler

3,

Andreas Conca1

1Psychiatry I, Regional Hospital Rankweil, Rankweil, Austria,

2General

Psychiatry, University of Innsbruck, Innsbruck, Austria, 3Medical

Laboratory Feldkirch, Medical Laboratory Feldkirch, Feldkirch, Austria

Background: Dopamine transmission plays a important role in the

pathogenesis of schizophrenia. In human beings and animals iron metabolism

effects the dopamine mediated behaviour. In patients affected by schizophrenia

post mortem examinations of the brain revealed abnormal iron deposits.

Furthermore low levels of serum iron have been reported in schizophrenics.

The aim of our study was to investigate the iron metabolism in a large number

of acute schizophrenic in-patients.

Methods: We used a naturalistic and prospective study design. During a 24-

months period, patients suffering from schizophrenia with catatonic symptoms

were consecutively admitted to the study. Age, gender, and diagnoses according

to ICD 10 were assessed. Blood samples were drawn immediately after

admission.

Results: 238 (114 females) patients with a mean age of 37.6 years (± 13.0) were

recruited. 32.1% of the patients displayed a absolute hypoferremia and 3.8% a

hyperferremia. The risk for hypoferremia was twofold for females (44.5% vs

18.9%). 26.9% of patients revealed a low transferrin saturation level, whereas

hypoferritinemia and hypotransferrinemia in 8.9 % respectively in 19.1% were

observed.

Conclusions: Our results indicate important changes of serum iron in acute

schizophrenics, predominately in women. Possible therapeutic consequences of

iron substitution therapy are under investigation.

473. Cannabis Use and Attenuated Positive Symptoms of Schizophrenia in Putatively Prodromal Adolescents and Young Adults

Andrea M. Auther, Emilie Y. Nakayama, Christopher W. Smith, Todd Lencz, Barbara A. Cornblatt

Psychiatry Research, The Zucker Hillside Hospital, Lake Success, NY

Background: The role cannabis abuse plays in the etiology of schizophrenia

remains unresolved. Competing hypotheses suggest that cannabis is used

primarily to self-medicate emerging symptoms vs. more recent views that it is a

risk factor or “trigger” for illness. Most data addressing this issue is

retrospective, making it difficult to disentangle these two possibilities. The

Recognition and Prevention (RAP) Program is a longitudinal prospective study

of adolescents prodromal for schizophrenia. Participants enter the RAP

Program at relatively young ages, when cannabis use is low and symptoms are

attenuated. As a result, the data is uniquely suited to examine the relationship of

cannabis use to emerging symptomatology.

Methods: Initial data analysis examined baseline rates of cannabis use measured

by structured clinical interview (K-SADS) and level of positive and negative

symptoms rated on the Structured Interview for Prodromal Symptoms (SIPS)

for 86 prodromal adolescents.

Results: Preliminary findings suggest that: 1) overall rates of cannabis use in the

total prodromal sample are comparable to normal population estimates, in

contrast to findings of high rates of cannabis use in schizophrenic populations;

2) self-reported cannabis use is not associated with higher attenuated positive

and negative symptoms at baseline.

Conclusions: The cross-sectional finding of lack of relationship between

cannabis use and symptoms is only suggestive and will need to be confirmed

with longitudinal data. Nevertheless, these results are consistent with the

Phillips et al. (2002) finding in a similar high risk sample, both of which cast

suspicion on cannabis use as a risk factor for psychosis.

474. Delusions in Individuals with Schizophrenia: Factor Structure and Clinical Correlates

David Kimhy1,2

, Raymond R. Goetz1,2

, Scott Yale1,2

,Cheryl Corcoran

1,2, Dolores Malaspina

1,2

1Psychiatry, Columbia University, New York, NY,

2Medical Genetics,

New York State Psychiatric Institute, New York, NY

Background: It is remain unclear whether delusions are unique from other

psychotic symptoms, or even if different delusions reflect a unitary

phenomenon with common neurobiological underpinnings.

Methods: We examined the factor structure of delusions in 83 neuroleptic-free

subjects with DSM-IV schizophrenia/schizoaffective disorder using the Scale

for Assessment of Positive Symptoms (SAPS), Scale for Assessment of

Negative Symptoms (SANS) and the Schedule for the Deficit Syndrome (SDS).

Results: Factor analysis of the individual delusions symptoms revealed three

distinct and interpretable factors (58.3% of variance). Factor 1 (26.1%) was

comprised by delusions of being controlled, thought withdrawal, thought

broadcasting, thought insertion, and mind reading. It was significantly related to

hallucinations (r=.459), avolition/apathy (r=.368), severity of deficit syndrome

(r=.334) and attention (r=.275). Factor 2 (20.8%) was comprised by grandiose,

religious, guilt/sin delusions, and delusions of reference and was significantly

related to bizarre behavior (r=.437), avolition/apathy (r=.311), and positive

formal thought disorder (r=.269). Factor 3 (11.4%) was comprised by

persecutory delusions and was not related to other clinical phenomena.

Conclusions: The three subtypes of delusions likely reflect distinct phenomena.

Future research can examine their links neurobiological mechanisms.

475. Proteome Analysis of the Anterior Cingulate Cortex in Major Psychiatric Disorders

Kyla Pennington1,2

, Clare Beasley3, Mike Dunn

2, David

Cotter1

1Department of Psychiatry, Royal College of Surgeons in Ireland,

Dublin, Ireland, 2Department of Neuroscience, Institute of Psychiatry,

London, United Kingdom, 3Department of Psychological Medicine,

Institute of Psychiatry, London, United Kingdom

Background: Marked alterations in neuronal and glial size and density have

been observed in the anterior cingulate cortex (ACC) in schizophrenia, major

depressive disorder (MDD) and bipolar disorder (BPD). The basis for these

morphological changes is unknown but may be revealed through proteomic

analysis.



Methods: Two dimensional electrophoresis (2DGE) and mass spectrometry

were used in this study to compare and identify disease-specific protein changes

in schizophrenia, MDD and BPD in the ACC. We applied immobilised pH

gradients (IPG) 4-7 and 6-9 to the Stanley Foundation Brain Consortium brain

series (comprising 15 subjects per group from each of MDD, BPD and

schizophrenia). Gel image analysis of the protein profile acquired from the post-

mortem tissue was undertaken using Progenesis 2003.1 (Nonlinear Dynamics).

Data was analysed by ANCOVA.

Results: Within the two pH ranges 51 spots, present in 40 or more cases, were

found to be differentially expressed in the disease groups. Of these 20 have so

far been identified using peptide mass profiling by MALDI-TOF-MS. These

include alteration in expression of the DRP family, creatine kinase, succinyl

coenzyme A, various isoforms of tubulin and carbonic anhydrase.

Conclusions: These findings replicate and extend previous observations of

altered protein expression in psychiatric disorders. The role of these proteins in

the pathophysiology of these brain disorders needs to be explored further.

Research supported by the Stanley Medical Research Institute and the Wellcome

Trust.

476. Long-Term Cognitive Improvement in Patients Switched to Ziprasidone

Antony Loebel1, Philip D. Harvey

2, Stephen Murray

1

1CNS/Medical, Pfizer Inc, New York, NY,

2Psychaitry, Mt. Sinai School

of Medicine, New York, NY

Background: Memory impairment in schizophrenia is associated with

functional impairment. We examined improvement in memory functions

associated with ziprasidone in patients switched from other antipsychotics.

Methods: Three open-label, flexible-dose continuation studies enrolled patients

who completed 6-week trials wherein they had been switched to ziprasidone

from conventional antipsychotics, risperidone, or olanzapine due to suboptimal

antipsychotic efficacy or tolerability. Learning and memory were assessed at last

visit with the Rey Auditory Verbal Learning Test (RAVLT). Changes from the

core study baseline to endpoint in the ITT population are reported.

Results: Overall, median treatment duration was 215 days. Patients in all three

studies demonstrated significant improvement in multiple components of the

RAVLT. Patients switched from conventional antipsychotics (n=71)

demonstrated improvement in performance on first learning trial (P<0.001),

Total Learning over five learning trials (P<0.05), and Long Delay Recall

(P<0.05) components. Patients switched from olanzapine (n=71) exhibited

improvement in Trial One Performance (P<0.0005), Total Learning

(P<0.0001), and Long Delay Recall (P<0.005). Patients switched from

risperidone (n=43) improved significantly on Total Learning (P<0.05) and Long

Delay Recall (P<0.01).

Conclusions: Patients switched to ziprasidone may experience improvement in

learning and memory over a long-term period. The functional consequences of

the improvements are yet to be determined.

477. Mifepristone (RU-486) in the Treatment of Schizophrenia

Peter Gallagher, Margaret Smith, Stuart Watson, Bruce Owen, Navdeep Malik, Paul Mackin, I. Nicol Ferrier, Allan H. Young

Psychiatry, Newcastle University, Newcastle, United Kingdom

Background: Antiglucocorticoids hold promise in the treatment of severe

psychiatric disorder. Corticosteroid synthesis inhibitors are antidepressant in

some patients with mood disorders and glucocorticoid receptor antagonists

including mifepristone and Org 34517 may have cognitive enhancing and

antidepressant effects in both unipolar and bipolar depression. It has also

recently been demonstrated that augmentation with the antiglucocorticoid,

DHEA has efficacy in positive and negative symptoms of schizophrenia. We

hypothesised that treatment with mifepristone would improve positive, negative

and affective symptoms in patients with schizophrenia and that treatment would

improve neurocognitive performance by a selective effect on executive function.

Methods: 20 schizophrenic outpatients (18 male and 2 post-menopausal

female) received treatment with 600 mg of mifepristone and placebo in a 7 week

randomised balanced order crossover design. Outcome measures consisted of

neurocognitive performance, psychiatric symptoms determined by standard

rating scales and plasma cortisol levels at half-hourly intervals between 1pm and

4pm.

Results: Mifepristone was well tolerated. The 2 female patients developed a

transient rash during the trial-neither were taking mifepristone at the time.

Plasma cortisol levels were elevated immediately after cessation of treatment

and returned to normal after 2 weeks (see fig). ANOVA revealed a main effect

of visit (F=35, P<0.0005) and a time by visit interaction (F=3.3, P=0.002).

Conclusions: Mifepristone is associated with a temporary robust rise in cortisol

levels. Further results will be reported.

478. A Wellness Intervention Program for Patients with Serious and Persistent Mental Illness

Vicki P. Hoffmann1, Lara Jensen

1, Jacques Thierry

2,

Jonna Ahl1

1Neuroscience, Eli Lilly and Company, Indianapolis, IN,

2Research,

HealthAnswers, Pennington, NJ

Background: Obesity is prevalent in patients with serious and persistent mental

illness (SPMI), and they have substantial risk for weight gain during

psychopharmacological treatment. Obesity is difficult to reverse, but behavioral

programs have been successful sometimes. Solutions For Wellness Personalized

Program (SWFPP) provides individualized education and support for improving

overall wellness.

Methods: Patients with any SPMI treated with any antipsychotic medication

and living in the community were enrolled voluntarily into SFWPP. Participants

completed an enrollment survey providing information for the creation of

individualized weight management plans that included nutrition, exercise, stress

management, and sleep improvement. Weight and body mass index (BMI) were

assessed at baseline and monthly for 6 months. Behavior and attitudes were

assessed regularly.

Results: Over 7000 patients were enrolled. BMI at baseline was >25 in 83% of

the participants. After 6 months, participants (n=3,341) reported positive

changes in diet (90.2%), exercise (85.0%), handling stress (93.8%), and

improved sleep (92.9%). Individuals who made positive changes in diet, also

reported weight loss and reduced BMI (-0.93 kg/m2, mean change). In addition,

97% of participants reported having gained confidence in the ability to maintain

life style changes.



Conclusions: Patients suffering from SPMI reported positive changes in diet,

exercise, handling stress, improved sleep, and increased confidence in

maintaining lifestyle changes after participating in the Solutions for Wellness

Personalized Program.

479. Do Short Sleepers Eat More?

Gregor Hasler1, Daniel J. Buysse

2, Richard Klaghofer

3,

Alex Gamma4, Vladeta Ajdacic

4, Dominique Eich

4, Wulf

Rössler4, Jules Angst

4

1Madp, NIMH, Bethesda, MD,

2Department of Psychiatry, University of

Pittsburgh School of Medicine, Pittsburgh, PA, 3Department of

Psychosocial Medicine, University of Zurich, Zurich, Switzerland, 4Department of Psychiatry, University of Zurich, Zurich, Switzerland

Background: Experimental reduction of sleep duration results in a number of

metabolic alterations such as glucose intolerance. Informed by this biological

finding and based on preliminary evidence from epidemiological studies, we

hypothesized a negative association between sleep duration and both body

weight and body weight gain in young adults.

Methods: A prospective community-based single-aged cohort study of young

adults (N=496) was conducted. Data was collected through four interviews

when participants were ages 27, 29, 34, and 40.

Results: There was a virtually monotonic trend toward higher BMI and higher

average weight gain over 13 years among those with shorter sleep duration. A

random effects model for BMI including a variety of covariates yielded a

significant association between sleep duration categories and BMI. This

association decreased with age. Short sleep duration (<6h) considerably

increased the risk for obesity (at age 27, odds ratio: 7.4, 95% confidence

interval: 1.3-43.1). Other sleep characteristics including sleep quality, awakenings

during the sleep episode, insomnia and daytime sleepiness were not associated

with BMI in this model.

Conclusions: This study shows a negative age-modified association between

sleep duration and BMI, and it demonstrates that this association has clinical

significance. The finding that sleep disturbances including awakenings during

sleep episode and daytime sleepiness are not associated with BMI tempers the

plausible explanation that weight related sleep disturbances (e.g., obstructive

sleep apnea) mediate this BMI-sleep duration relationship.

480. Symmetry/Order Symptoms of Obsessive-Compulsive Disorder Correlate with Perseveration Scores on the Wisconsin Card Sorting Test

Sarah C. Wooderson, Natalia S. Lawrence, David Mataix-Cols, Anne Speckens, Mary L. Phillips

Neuroscience & Emotion, Institute of Psychiatry, London, United

Kingdom

Background: Previous studies have inconsistently reported poor performance

on the Wisconsin Card Sorting Test (WCST) in patients with obsessive-

compulsive disorder (OCD). The clinical heterogeneity of the disorder might

explain such inconsistent findings. Factor-analytic studies have reduced the

complex clinical picture of OCD into a few replicable symptom dimensions:

contamination/washing, obsessions/checking, hoarding, symmetry/ordering,

and sexual/religious obsessions.

Methods: 34 OCD patients and 38 matched controls were administered the

WCST as part of a larger battery of executive function tasks. Multiple regression

models assessed the relationship between OCD symptom dimension scores

derived from the short version of the Obsessive-Compulsive Inventory and the

various WCST indexes, controlling for depression, anxiety and overall OCD

severity.

Results: The variance within the OCD group was statistically greater than that

of the control group. Non-parametric tests indicated that patients performed

more poorly than controls on all the WCST indexes (perseverative and non-

perseverative errors and categories). Within the patient group, greater

order/symmetry scores correlated positively with perseverative errors (partial r

= 0.52, p<0.01) and negatively with categories (partial r = -0.05, p <0.01). These

results were independent from depression, state anxiety and overall OCD

severity, which were also included in the regression models.

Conclusions: In OCD, perseveration and thus poor performance on the

WCST is associated with order/symmetry but not other types of symptoms.

These results could help explain previous inconsistent WCST findings in OCD

but should be taken as preliminary given the sample size.

481. Functional Magnetic Resonance Imaging Study of Visuospatial Working Memory in Children and Adolescents with Velo-Cardio-Facial Syndrome

Rayna Azuma1, Linda Campbell

1, Eileen M. Daly

1,

Declan G. M. Murphy1, Vincent Giampietro

1, Kieran C.

Murphy2


Kingdom,2Psychiatry, Royal College of Surgeons in Ireland,

Beaumont Hospital, Dublin, Ireland

Background: Velo-cardio-facial syndrome (VCFS) is a genetic disorder that is

associated with a microdeletion in the Chromosome 22q11. Children with

VCFS typically have mild learning disabilities and show deficiencies in specific

cognitive areas such as visuospatial, working memory, mathematics abilities and

executive functions. Recent imaging studies showed that the VCFS patients

have structural abnormalities in various brain regions, including parietal and

frontal lobes that are known to be involved in visuospatial and mathematical

processing. In this study, we investigated visuospatial working memory

processing in VCFS, using the functional Magnetic Resonance Imaging (fMRI),

to see how the cognitive deficits are related to the structural brain abnormalities.

Methods: Twelve children and adolescents with VCFS and twelve control

children (aged 9-17 for both groups) were scanned while performing a

visuospatial working memory task.

Results: Both groups showed task related activation in right dorsolateral

prefrontal cortex (DLPFC) and bilateral parietal association cortices that are

associated with working memory. In addition, the normal group showed

activation in cerebellum, premotor cortex and SMA that are related to decision

making processes.

Conclusions: Previous studies suggested structural abnormalities in these areas

in the VCFS population. The results from the current study seemed to be in line

with the conjecture that the anatomical and functional abnormalities underlie

the cognitive disorder in VCFS.

482. An MRI Study of Minor Physical Abnormalities in Autism

Antonio Y. Hardan, Matcheri S. Keshavan, Sucheta Sreedhar, Madhuri Vemulapalli, Nancy J. Minshew

Psychiatry, Western Psychiatric Institute and Clinic, University of

Pittsburgh, Pittsburgh, PA

Background: Limited number of minor physical anomalies (MPA) have been

reported in autism. The most replicated finding consists of increased head size,

which appears to be associated with increased brain size. No other physical

abnormalities have consistently been reported to date. The objective of the

current investigation was to examine the existence of MPA in autism by

assessing the existence of hypo or hypertelorism.

Methods: The inter-orbital and inter-lens distances were measured on MRI

scans obtained from a sample of 40 non-mentally retarded individuals with

autism and 40 gender, IQ, and age group-matched healthy controls.



Results: No differences were observed between the two groups on any of the

measurements. However, when the analysis was conducted using a split median

procedure, individuals with autism and either low FSIQ, or PIQ had shorter

inter-orbital distances when compared to controls. Additionally, negative

correlations were observed between the inter-orbital and inter-lens distances

and FSIQ, PIQ, and VIQ in the control group but not in the patients group.

Conclusions: Hypotelorism is a MPA that may be present in individuals with

autism and limited cognitive abilities. This observation points to the genetic and

neurodevelopmental heterogeneity of this severe and pervasive disorder, and

warrants the search for other midline craniofacial malformations. Replication of

the current findings are needed in larger sample sizes with a wide range of

intellectual functioning and stratified by such factors as age and other related

disorders such as Asperger’s disorder and pervasive developmental disorder,

NOS.

483. Response-Type SpecificWorking Memory Deficits in Children with ADHD

Nicholas D. Davenport1, Canan Karatekin

2

1Psychology, University of Minnesota, Minneapolis, MN,

2Child

Development, University of Minnesota, Minneapolis, MN

Background: Attention-Deficit/Hyperactivity Disorder (ADHD) is commonly

associated with working memory impairments. The current study seeks to

characterize these impairments by comparing recall and recognition of spatial

information across three delay periods in an oculomotor delayed-response task.

Methods: Participants are children 9-13 years of age either with or without a

diagnosis of ADHD. The task consists of one dot appearing at a location on a

computer screen while the participant maintains central fixation; a lexical

distraction task lasting 2, 8, or 20 sec (delay); and a response cue. The

participant indicates where the initial dot had appeared by making a saccade

either towards one of three possible locations (recognition) or towards the

correct location with no external guidance (recall). In control conditions for

both tasks, the dot appears in the same location on each trial. Response time

and spatial accuracy of the saccades, and errors and manual response times on

the distraction task are used to assess performance.

Results: Preliminary results from 32 controls and 20 children with ADHD

suggest that the ADHD group is not impaired relative to the comparison group

on recognition or control-recognition trials at any delay. In contrast, the ADHD

group makes larger distance errors than the comparison group during both the

recall and control-recall tasks, especially at 20 sec delays.

Conclusions: The lack of recognition deficits indicates that individuals with

ADHD can encode and retrieve information when given cues at retrieval.

However, they may have difficulty recalling the information without external

landmarks, especially at long delays.

484. Withdrawn

485. A Controlled Trial of Extended-Release Bupropion in Adult ADHD

James J. Hudziak1, Timothy E. Wilens

2, Daniel F.

Connor3, Barbara R. Haight

4, Joseph P. Horrigan

4,

Kenneth D. Hampton4, Nathalie E. Richard

5, Jack G.

Modell4

1Department of Psychiatry, University of Vermont College of Medicine,

Burlington, VT, 2Pediatric Psychopharmacology Clinic, Massachusetts

General Hospital, Boston, MA, 3Department of Psychiatry, University

of Massachusetts Memorial Medical Center, Worcester, MA, 4Psychiatry, GlaxoSmithKline, Research Triangle Park, NC,

5Biomedical Data Sciences, GlaxoSmithKline, Research Triangle

Park, NC

Background: To evaluate the efficacy and tolerability of a once-daily

preparation of a nonstimulant, extended-release bupropion (bupropion XL), in

adults with attention-deficit/hyperactivity disorder (ADHD).

Methods: A multi-site, placebo-controlled, parallel-group, 8-week prospective

study of 162 subjects (ages 18-60 years) was undertaken in DSM IV diagnosed

adults with all subtypes of ADHD. Subjects were treated with up to 450 mg/d

of bupropion XL and were rated on multiple outcomes weekly.

Results: Subjects receiving bupropion XL manifested significant improvement

on the primary outcome measure, a reduction of 30% in the ADHD Rating

Scale as assessed by investigators, over subjects receiving placebo as early as

week 2 (p = 0.01), which persisted through week 8 (p = 0.004). At endpoint, the

self-reported Connors Rating Scale scores revealed that bupropion XL provided

sustained benefit throughout the day compared to placebo (morning p = 0.033,

afternoon p = 0.004, and evening p = 0.024). Only 5% of subjects discontinued

because of adverse effects related to the medication. There was no significant

difference between bupropion XL and placebo in the incidence of adverse

effects.

Conclusions: Once-daily bupropion XL is an effective and well-tolerated

nonstimulant treatment for adults with ADHD.

486. Cerebral Blood Volume Changes during Cognitive and Motor Activation in Bipolar Disorder: A Multichannel Near-Infrared Spectroscopy Study

Masaki Kameyama, Tomohiro Suto, Yutaka Yamagishi, Makoto Ito, Toru Uehara, Masato Fukuda, Masahiko Mikuni

Department of Psychiatry and Human Behavior, Gunma University

Graduate School of Medicine, Gunma, Japan

Background: Near-infrared spectroscopy (NIRS) is an optical technique that

enables the noninvasive and continuous monitoring of regional cerebral blood

volume (rCBV) changes by measuring oxy- and deoxy-hemoglobin

concentrations. In the present study, we investigated rCBV changes during

cognitive and motor tasks in patients with bipolar disorder using multichannel

NIRS machines.

Methods: The present study has been approved by the Institute Research

Board of Gunma University Hospital. Twenty-three patients with bipolar

disorder in the subdepressive state, six patients with bipolar disorder in the

hypomanic or mixed state, seventeen patients with major depressive disorder

and seventeen healthy subjects, participated in the study after giving their

written informed consent. Oxy-hemoglobin concentration ([oxy-Hb]) changes

were monitored over the subjects’ frontal and temporal regions during a word

fluency task and a finger-tapping task using two sets of 24-channel NIRS

machines.

Results: The patterns of [oxy-Hb] change during the word fluency task were

characterized by a rapid increase and a gradual decrease in the control and

hypomanic/mixed bipolar groups, a gradual increase in the depressive bipolar

group, and the lack of a clear increase in the depression group, although task

performance was not statistically different among the four groups.

Conclusions: The difference in the pattern of [oxy-Hb] change observed

among the groups in the present study suggests the various characteristics of

frontal lobe functions in each group. If these findings are confirmed, NIRS data

can be employed as a clinically useful biological marker for the diagnosis and

treatment of bipolar disorders.



487. Reduced N-Acetyl-Aspartate Levels in the Dorsolateral Prefrontal Cortex of Adolescent Bipolar Patients

Roberto B. Sassi1,2

, Jeffrey A. Stanley3, David Axelson

3,

Paolo Brambilla4, Mark A. Nicoletti

5, Matcheri S.

Keshavan3, Renato T. Ramos

2, Neal D. Ryan

3, Boris

Birmaher3, Jair C. Soares

5,6


2Psychiatry, University of Sao Paulo School of Medicine, Sao Paulo,

Brazil, 3Psychiatry, Western Psychiatric Institute and Clinic,

Pittsburgh, PA, 4Psychiatry, University of Verona, Verona, Italy,

5Psychiatry, University of Texas Health Science Center, San Antonio,

TX,6Audie L. Murphy Division, South Texas Veterans Health Care

System, San Antonio, TX

Background: Proton spectroscopy (1H-MRS) studies performed in adult

bipolar patients assessing prefrontal regions have suggested decreased levels of

N-acetyl-aspartate (NAA), a putative marker of neuronal integrity. In order to

test if these abnormalities would also be found in younger patients, we

conducted a 1H-spectroscopy study focusing in the dorsolateral prefrontal

cortex (DLPFC) of children and adolescents with bipolar disorder.

Methods: We examined the levels of NAA, creatine plus phosphocreatine and

choline-containing compounds in the left DLPFC of 14 bipolar disorder

patients (15.5±3 years old; 8 female) and 18 healthy controls (17.3±3.7 years

old; 7 female) using a short echo time, single voxel, in vivo 1H-spectroscopy

technique. Absolute metabolite levels were determined using water signal as an

internal reference.

Results: Bipolar patients presented significantly lower NAA levels (ANCOVA,

age and gender as covariates, F=5.3, df=1,28, p=0.03) compared to healthy

controls and a significant inverse correlation of choline-containing compounds

and number of previous affective episodes (Pearson’s correlation r=-0.86,

p=0.0001). No differences were found for other metabolites.

Conclusions: These preliminary findings suggest that even younger bipolar

disorder patients have decreased NAA levels in the DLPFC, similarly to what

was reported in adult patients. If replicated in larger samples, these results may

reflect an underdevelopment of dendritic arborizations and synaptic

connections. These neuronal abnormalities in DLPFC in bipolar patients are

unlikely to represent long-term degenerative processes, at least in the sub-group

of patients where the illness had relatively early onset.

Grant support: MH-01736, MH-55123, MH-30915, and MH-59929 from the

NIMH, NARSAD, and CAPES (Brazil).

488. MRI Study of the Cerebellum and Vermis in Children and Adolescents with Bipolar Disorder

E. Serap Monkul1,2,3

, Roberto B. Sassi4, David Axelson

5,

Paolo Brambilla6, Mark A. Nicoletti

1, John P. Hatch

1,

Matcheri S. Keshavan5, Neal D. Ryan

5, Boris Birmaher

5,

Jair C. Soares1,3,7

1Department of Psychiatry, Mood and Anxiety Disorders Division,

University of Texas Health Science Center at San Antonio, San

Antonio, TX, 2Department of Psychiatry, Dokuz Eylul University

School of Medicine, Izmir, Turkey, 3South Texas VA Health Care

System, Audie L. Murphy Division, San Antonio, TX, 4Department of

Psychiatry, University of Sao Paulo School of Medicine, Sao Paulo,

Brazil, 5Department of Psychiatry, Western Psychiatric Institute and

Clinic, University of Pittsburgh Medical Center, Pittsburgh, PA, 6Department of Medicine and Public Health, Section of Psychiatry,

University of Verona School of Medicine, Verona, Italy, 7Department

of Radiology, The University of Texas Health Science Center at San

Antonio, San Antonio, TX

Background: Although the cerebellum and vermis are important regions in the

neuroanatomic model of mood disorders, the presence of structural

abnormalities in these regions early in illness course has not been studied. We

examined possible structural abnormalities in cerebellum and vermis in children

and adolescents with bipolar disorder.

Methods: Sixteen children and adolescents with bipolar disorder (mean age±

S.D.=15.5±3.4 years) and 21 healthy controls (mean age±S.D.=16.9±3.8 years)

were examined. The patients met DSM-IV diagnostic criteria for bipolar type I

(n=12), bipolar type II (n=3), and bipolar not otherwise specified (n=1). Two

were in a depressive episode and fourteen euthymic at the time of the study. A

1.5 T GE Signa Imaging System running version Signa 5.4.3 software was used

to acquire the MRI scans. We measured the volumes of right, left and total

cerebellum, vermis and vermal areas V1 (lobules I-V), V2 (lobules VI-VII), and

V3 (lobules VIII-X).

Results: Analysis of covariance with age, gender, and intra-cranial brain volume

as covariates revealed no significant differences in cerebellum or vermis

measures between patients and controls. However, there were significant

inverse correlations between age and vermis area V3 in the bipolar patient

group (partial correlation coefficient=-0.55, P=0.042), and between number of

previous affective episodes and vermis area V2 (partial correlation coefficient=-

0.58, P=0.036).

Conclusions: Our findings suggest that neurodegenerative mechanisms in the

cerebellar vermis may be operating in bipolar patients, and that those are already

present in children and adolescents suffering from this disorder.

489. Temperament and Character Traits in Bipolar Disorder

Shay T. Loftus1,2

, John J. Cecero2, Cristina Gomes

1,

Anil K. Malhotra3, Judith Jaeger

1

1Center for Neuropsychiatric Outcome and Rehabilitation Research,

The Zucker Hillside Hospital, Glen Oaks, NY, 2Psychology

Department, Fordham University, Bronx, NY, 3Psychiatry Research,

The Zucker Hillside Hospital, Glen Oaks, NY

Background: Temperament and character traits have been related to course of

illness in affective disorders. The presence of an affective episode, however,

likely precludes reliable detection of these traits due to state-trait interactions.

Thus, while the optimal time to evaluate these traits in patients with bipolar

disorder would be when clinically recovered, not all patients recover fully

between episodes. According to Kraepelin, enduring temperamental traits were

characteristic in 37% of manic depressive patients.

Methods: 60 patients with bipolar I or II confirmed by SCID-DSM-IV, were

administered the Temperament and Character Inventory (TCI) when their

symptoms recovered to within the mild range. Symptom severity was assessed

using the HRSD-17 and Clinician-Administered Rating Scale for Mania.

Results: A MANOVA was used to compare patients’ TCI scores with those of

a matched group of healthy controls. Bipolar patients scored significantly higher

on Harm Avoidance and Self-Transcendence, and significantly lower on Self-

Directedness and Cooperativeness. Harm Avoidance (r=.53, p<.01) and Self-

Directedness (r=-.33, p< 01) were correlated with subsyndromal depressive

symptoms, and Persistence (r=.30, p<.05) and Self-Transcendence (r=.40,

p<.01) were correlated with subsyndromal manic symptoms. 58% of patients

had co-occurring substance abuse; 19% anxiety; and 5% eating disorders.

Novelty Seeking was positively correlated with a substance abuse diagnosis.

Conclusions: Bipolar patients show elevated Harm Avoidance and Self-

Transcendence, and decreased Self-Directedness and Cooperativeness, although

these results may be influenced by residual symptoms. Consistent with the

findings in other populations, high Novelty Seeking is associated with substance

use, and may distinguish patients with a more complicated clinical course.



490. Intrafamilial Correlation of Physical Anhedonia in Normothymic Bipolar Patients and their First-Degree Relatives

Bruno Etain1,2

, Frank Bellivier1,2

, Isabelle Roy1, Chantal

Henry3, Angela Rousseva

1, Marion Leboyer

1,2,4

1Service de Psychiatrie, Hôpital Henri Mondor, Créteil, France,

2Laboratoire Neurobiologie et Psychiatrie, INSERM U513, Créteil,

France,3Service de Psychiatrie, Hôpital Charles Perrens, Bordeaux,

France,4Service de Psychiatrie, Hôpital Albert Chenevier, Créteil,

France

Background: Bipolar disorder is a psychiatric disorder with genetic

component. However, the valid heritable phenotype remains unclear. New

methodologies have been proposed to identify homogeneous forms of the

disease (candidate symptom approach) and intermediate traits (endophenotype)

in non affected relatives. In schizophrenia, physical anhedonia (PA) might

represent a candidate symptom and/or an endophenotype. However, PA might

be poorly specific of schizophrenia and has never been studied in bipolar

disorder.

Methods: We compared the PA scores of 351 normothymic bipolar patients,

130 first-degree relatives and 170 healthy controls. We tested the existence of an

intrafamilial correlation for PA and compared the clinical characteristics of

anhedonic versus hedonic bipolar patients.

Results: PA is a stable trait in normothymic bipolar patients. We found a

significant intrafamilial correlation of PA scores among families. PA scores

obtained for non-affected relatives were similar to those obtained for controls.

Clinical characteristics of anhedonic and hedonic patients were not significantly

different. Patients with a high level of PA had not a greater familial risk for

bipolar disorder.

Conclusions: We demonstrated the familial nature of PA in bipolar families.

PA did not represent an endophenotype, as it did not allow to differenciate non-

affected relatives from controls. It did not represent a candidate symptom, as it

did not help to identify a more homogeneous group of patients, especially those

with a greater familial risk of bipolar disorder. Thus, PA is not a valid candidate

symptom and/or endophenotype in bipolar disorder and may be specific to

schizophrenia.

491. Context Processing Performance in Bipolar Disorder Patients

Paolo Brambilla1,2

, Angus W. McDonald3, Roberto B.

Sassi4, Melissa K. Johnson

3, Alan G. Mallinger

5, Ellen

Frank5, David J. Kupfer

5, Cameron S. Carter

6, Jair C.

Soares7

1Psychiatry, University of Verona, Verona, Italy,

2Department of

Pathology and Experimental and Clinical Medicine, Section of

Psychiatry, University of Udine, Udine, Italy, 3Psychology, University

of Minnesota, Minneapolis, MN, 4Psychiatry, Harvard Medical School,

Boston, MA, 5Psychiatry, University of Pittsburgh, Pittsburgh, PA,

6Psychiatry, University of California, Davis, CA,

7Psychiatry, University

of Texas, San Antonio, TX

Background: Previous studies indicate that, compared to schizophrenia

patients, bipolar disorder patients display a similar, but less severe

neuropsychological pattern of impairment. Context processing is the adaptive

control of current behavior through the use of prior context information and

has been found to be impaired in schizophrenia. It is a neuropsychological

dimension that has not yet been examined in bipolar disorder in existing

literature. We investigated context processing performance in bipolar patients

and healthy individuals. We also examined the effects of lithium in context

processing in a group of healthy individuals treated with lithium.

Methods: Fifteen bipolar patients (6 males, 9 males) and 26 healthy controls

(10 males, 16 females) were studied (mean-age±S.D.=22.67±12.34 and

25.50±9.75, respectively). Eleven healthy subjects (mean-age=27.00±10.49; 6

males, 5 females) were studied before and after 4 weeks of lithium treatment.

An expectancy version of the AX continuous performance test was

administered, in which a non-target response to the cue (A) is followed by a

prepotent target response to the probe (X).

Results: Bipolar patients had significantly increased mean error for AX-delay

and BY-delay compared to healthy controls (F= 6.73, p=0.01; F= 4.42, p=0.04,

respectively). Healthy individuals had significantly decreased mean error for BX-

immediate (t=2.39, p=0.04) and significantly increased d'-context immediate

(t=-2.87, p=0.02) after lithium administration.

Conclusions: This study suggests a mild generalized deficit in task performance

in patients with bipolar disorder, in contrast to patients with schizophrenia who

present specific context processing abnormality. Moreover, acute lithium

treatment does not appear to cause context processing performance

impairments.

492. Facial Expression Recognition and Response Bias Differentiates Bipolar Disorder from Unipolar Disorder

Natalie Kerr, Mary L. Phillips

Psychological Medicine, Institute of Psychiatry, London, United

Kingdom

Background: Ability to recognize emotional markers in facial expression

determine an individuals success in cooperative behaviors. We therefore

examined differences between unipolar and bipolar episodes in ability to

determine emotional expression of other people unfamiliar to each subject.

Methods: Recognition accuracy (RA) and response bias (RB) of 20 manic, 15

depressed and 20 euthymic patients in addition to 20 unipolar and 20 normal

controls was examined using morphed faces of unfamilar others showing either

happy, sad or neutral facial expression. Faces were presented at 25%, 50% and

100% intensity, and at 100msec and 2000 msec duration.

Results: Bipolar depressed showed greater impairments in RA towards sad

faces of others than unipolar subjects. Overall, manic subjects showed

significantly greater impairments in RA towards sad faces (p = <.005), with

euthymic subjects falsely labelleling more neutral faces as sad faces than

unipolar subjects. For RB, both euthymic and unipolar subjects showed greater

RB towards sad faces than manic and controls. Manic subjects showed greater

RB towards happy faces.

Conclusions: We have shown that differences exist between facial expression

recognition and emotional bias in euthymia and between depressed and manic

mood states. Furthermore, we have identified that differences exist between

bipolar depressed and unipolar depressed episodes. Therefore, identification of

ability in cooperative behaviors with others may be compromised between

mood states, especially in euthymic bipolar subjects. We suggest that poor social

functioning in euthymic bipolar patients is reflective of impairments in

recognition of emotions of others leading to maintenance of undercooperative

behaviors.

493. Diagnosing Bipolar Disorder in Research: Comparing two Methods

Judith Jaeger1, George Petrides

2, Rebecca Wagner

Iannuzzo1, Stefanie M. Berns

1, Donna O'Shea

1, Sarah

Uzelac1, Anil K. Malhotra

3

1Center for Neuropsychiatric Outcome and Rehabilitation Research,

North Shore Long Island Jewish Health System, Glen Oaks, NY, 2Department of Psychiatry, UMDNJ - New Jersey Medical School,

Newark, NJ, 3Department of Psychiatry Research, North Shore Long

Island Jewish Health System, Glen Oaks, NY



Background: Methods for establishing diagnostic inclusion criteria for bipolar

disorder (BPD) research participants vary between studies. Most typically for

clinical trials, the psychiatrist’s clinical diagnosis (CD) based on DSM-IV criteria

is used. Less frequently diagnosis is based on a SCID interview, but only rarely

is this supplemented by historical records. The reliability of the CD method in

BPD has not been previously investigated. We report on the relationship

between CD and a Consensus Lifetime SCID Method (CLSM).

Methods: 81 cases recruited to a BPD study received diagnoses using CLSM,

which involves a SCID interview supplemented with current/past inpatient

records and collateral interviews. Case reviews are prepared and presented at a

Diagnostic Conference attended by expert faculty. Lifetime Axis I consensus

diagnoses are determined and confidence ratings are assigned on a four-point

scale (where the confidence rating <4, reasons for less than full confidence are

recorded).

Results: Among 67 patients having CD of BPI, 54 had equivalent CLSM

diagnosis. Of 72 patients with CD’s within the bipolar spectrum, 62 had

subsequent bipolar spectrum CLSM diagnoses. Agreement between CD/CLSM

for BPI was associated with higher confidence CLSM diagnosis. Reasons for

low confidence varied and included atypical presentation, substance abuse

history, unreliable patient report and signs of co-occurring Axis II disorder.

Conclusions: Approximately 20 percent of recruits to a BPD study proved not

to meet criteria for the target disease. BPD studies may be subject to

considerable sample dilution when less rigorous diagnostic methods are used.

494. Association of Psychotic Symptoms and Suicidal Plans in Pediatric Bipolar patients


, Rene Olvera1, Kristina Hunter

1,

Pablo Najt1, John P. Hatch

1, Charles L. Bowden

1,

Steven R. Pliszka1, Jair C. Soares

1,2,4



South Texas Veterans Health Care System, Audie L. Murphy Division,

San Antonio, TX, 3Department of Psychiatry, Institute of Psychiatry,

University of Sao Paulo School of Medicine, Sao Paulo, Brazil, 4Department of Radiology, The University of Texas Health Science

Center at San Antonio, San Antonio, TX

Background: Psychosis in pediatric mood disorder patients is associated with a

higher prevalence of suicidal ideation. Bipolar (BP) adolescents are at a high risk

of completed suicide. We studied the association between psychotic symptoms

and suicidality in pediatric BP patients, to examine the hypothesis that psychotic

patients have higher prevalence of suicidalidity than non-psychotic ones.

Methods: Psychiatric diagnoses were established with the K-SADS-PL

interview. We studied 16 (37.2%) BP patients with lifetime psychotic symptoms

(mean age ±S.D= 11.6 ± 2.7y; range= 8-17y, 10 males, 11 BP type1, 5 BP

NOS) and 27 (62.8%) BP patients without psychotic symptoms (mean age

±S.D= 11± 2.9y; range= 8-17y, 15 males, 12 BP type1, 2 BP type2, 13 BP

NOS).

Results: There were no significant differences in age (t= -0.60, df= 41, p=

0.56) or gender (t= 0.44, df= 41, p= 0.67) between psychotic and non-psychotic

BP patients. Pediatric BP patients with psychotic symptoms were more likely to

have thoughts of death (100% versus 70.4%, X2=5.82, p= 0.02), suicidal

ideation (93.8% versus 44.4%, X2=10.5, p= 0.001) and suicidal plans (68.8%

versus 14.8%, X2=12.9 , p= 0.001) compared to non-psychotic ones.

Conclusions: Psychotic symptoms in pediatric BP patients are associated with

suicidal ideation and plans. These are a risk factor for suicidality amongst

pediatric bipolar populations, and may constitute a clinical indicator of

significant value in trying to prevent suicide in this patient group.

This work was partly supported by MH01736, M01-RR-01346, the Krus

Endowed Chair in Psychiatry, the Veterans Administration, and CAPES

Foundation (Brazil).

495. Quetiapine Monotherapy for Mania Associated with Bipolar Disorder

Martin Brecher1, Karin Huizar

2

1Seroquel Global Publications, AstraZeneca, Wilmington, DE,

2Department of Biostatistics, AstraZeneca, Södertälje, Sweden

Background: Quetiapine (QTP) is an atypical antipsychotic with a favorable

weight profile, low risk of extrapyramidal symptoms (including akathisia), and

placebo-level effects on serum prolactin levels. Preliminary studies suggest that

QTP is an effective, well-tolerated treatment of bipolar mania in adolescents

and adults. The purpose of this study was to evaluate the efficacy and safety of

QTP monotherapy for mania associated with bipolar disorder.

Methods: Patients (bipolar I disorder, manic episode) were randomized to 12

weeks' double-blind treatment with QTP (up to 800 mg/d), placebo (PBO), or

an internal standard (haloperidol [HAL]). The primary endpoint was change

from baseline in Young Mania Rating Scale (YMRS) score at Day 21 (QTP vs

PBO).

Results: 53.9% (55/102) of QTP- vs 41.6% (42/101) of PBO-treated patients

completed the study. Quetiapine-treated patients had a significant improvement

in YMRS score vs PBO at Day 21 (–12.29 vs –8.32; P=0.0096), that increased

by Day 84 (P<0.0001). Significantly more QTP patients achieved a YMRS

response ( 50% decrease from baseline) at Day 84 (QTP 61.4%; PBO 39.0%;

P=0.0015). Significant improvements in YMRS score at Days 21 and 84 for

HAL were also observed. Extrapyramidal symptoms (EPS) were consistently

higher in the HAL group (any EPS event: HAL 60.6%; QTP 12.7%; PBO

16.8%), as were discontinuations due to adverse events (HAL 10.1%; QTP

4.9%; PBO 5.9%). Mean last-week QTP dose in responders at Day 21 was 559

mg/d.

Conclusions: Quetiapine monotherapy is well tolerated and significantly more

effective than placebo in the treatment of mania associated with bipolar

disorder.

496. Initial Symptoms of Manic Relapse

Ilya Lipkovich, John P. Houston, Saeed Ahmed, Jonna Ahl, Matthew Rotelli, Robert W. Baker

Neuroscience, Eli Lilly and Company, Indianapolis, IN

Background: To identify manic symptoms as early predictors (within 2 weeks)

of manic relapse in a double-blind, randomized relapse prevention study of

olanzapine versus lithium.

Methods: Post hoc analysis of Young Mania Rating Scale (YMRS) items prior to

manic relapse (YMRS >15 or hospitalization) was conducted using bi-weekly

data from 398 initially euthymic (YMRS <12) patients with bipolar I disorder

randomized to olanzapine (OLZ, n=199, 5-20 mg/day) or lithium (Li, n=199,

serum level of 0.6 to 1.2 mEq/L). Relapses were captured 3 to 16 weeks after

randomization. Repeated-measures logistic regression analysis of detectable

changes in clinical symptoms (increase in an item score of >1) during 2 weeks

prior to relapse was used to estimate odds of relapse by the next visit.

Results: A total of 32 subjects relapsed within this study period (OLZ, n=15;

Li, n=17, respectively).YMRS items that increased most frequently preceding

manic relapses (OLZ vs Li, respectively) were: increased motor activity/energy

(46.6%, 17.7%), decreased need for sleep (26.7%, 17.7%), irritability (20.0%,

17.7%), and rapid speech (20.0%, 17.7%).YMRS items with largest odds ratios

for predicted relapse were: increased motor activity/energy (14.1, p<.001),

disheveled appearance (9.2, p=.021), and irritability (7.24, p=.002) in

olanzapine-treated patients, and disruptive-aggressive behavior (6.9, p=.022) in

lithium-treated patients. Overall, 73.3% olanzapine-treated vs. 58.8% lithium-

treated patients had pre-relapse increases in at least one YMRS item.

Conclusions: Increases in manic symptoms two weeks prior to relapse were

found more often with olanzapine- than lithium-treated patients. Early

detection of these symptoms may permit clinical interventions to help avert

relapse.



497. Olanzapine versus Placebo in the Prevention of Relapse for Mixed Index Versus Manic Index Episode Patients

Mauricio Tohen1,2

, Charles L. Bowden3, Richard

Risser1, Holland C. Detke

1, Joseph R. Calabrese

4

1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN,

2Department of Psychiatry, Harvard Medical School/McLean Hospital,

Belmont, MA, 3Department of Psychiatry, University of Texas Health

Science Center, San Antonio, TX, 4Department of Psychiatry, Case

Western Reserve University School of Medicine, Cleveland, OH

Background: Type of index episode may differentially affect long-term

outcome for bipolar patients.1 The following post-hoc analyses looked at

patterns of relapse for mixed vs. manic index episode patients receiving

olanzapine or placebo.

Methods: Bipolar patients who achieved remission (YMRS 12 and HAMD-21

8) following 6–12 weeks of open-label olanzapine (5–20 mg/day) were

randomly assigned to double-blind treatment with olanzapine (5–20 mg/day,

mixed index n=76, manic index n=144) or placebo (mixed index n=45, manic

index n=88) for up to 48 weeks. Relapse was defined as a YMRS 15 or

HAMD-21 15 or hospitalization.

Results: For patients entering with a mixed episode, olanzapine treatment was

associated with lower rates of relapse (59.2% vs. 91.1% for placebo patients,

p<.001) and a longer median estimated time to relapse (46 days vs. 15 days for

placebo patients; p<.001). For patients entering with a manic episode,

olanzapine was again associated with lower rates of relapse (39.6% vs. 73.9% for

placebo, p<.001) and longer time to relapse (median not estimable vs. 43 days

for placebo patients, p<.001). Separate analyses examining specific types of

relapse revealed that mixed index episode patients receiving olanzapine had

significantly longer times to manic (p<.001) and depressed (p=.001) but not

mixed relapse (p=.485), while manic index episode patients receiving olanzapine

had significantly longer times to manic (p<.001), depressed (p=.002), and mixed

relapse (p<.001).

Conclusions: Olanzapine was associated with reductions in overall relapse rates

and longer time spent free from any relapse for both manic and mixed index

episode patients.

498. Effects of APOE Genotype on Beta-Amyloid1-42 Levels in Young Adults

Deepa Bhupali1, Nadeem Mirza

1, Irene Dustin

1, James

A. Levy1, Holly D. Soares

2, Georgy Csako

3, Karen

Putnam1, Robert M. Cohen

1, Trey Sunderland

1

1Geriatric Psychiatry Branch, NIMH, Bethesda, MD,

2Pharmacogenomics and Clinical Biochemical Measurements

Division, Pfizer Central Research, Groton, CT, 3Department of

Laboratory Medicine, Clinical Center, NIH, Bethesda, MD

Background: Cerebrospinal fluid (CSF) -amyloid1-42 is reduced in Alzheimer’s

disease (AD) subjects when compared to controls despite the large overall

increase in -amyloid in the brains of AD subjects (Sunderland et al., JAMA

2003). We have recently discovered that CSF -amyloid1-42 levels are also lower

in middle-aged controls who are “at-risk” for developing AD by virtue of

having at least one copy of the APOE 4 risk allele (Sunderland et al,

submitted). We were interested in determining if CSF -amyloid1-42 levels are

already decreased in young adulthood.

Methods: CSF samples were collected from 25 younger controls [mean age

(SD), mean age=27 ± 4.5 years). Within this group, 14 controls were APOE 4

+ and 11 were APOE 4 -. CSF -amyloid1-42 levels were measured with a

sandwich ELISA assay.

Results: All subjects were cognitively normal at the time of testing. There was

no difference found in CSF -amyloid1-42 levels between those who are APOE

4 + and APOE 4- [1826 (598) vs. 1900 (523) pg/ml respectively, t=0.32,

p=0.75].

Conclusions: This data is consistent with the notion that the effects of APOE

4 on CSF -amyloid1-42 do not occur before young adulthood. One

interpretation of this finding is that late-onset changes of CSF -amyloid1-42

levels are a “state” dependent variable associated with an AD prodrome or the

disease itself rather than a “trait” variable that is present throughout life. Further

study of this potential biomarker with a larger sample size is needed to confirm

this finding.

499. Reciprocity of Dorsal and Ventral Limbic and Paralimbic Brain Regions During Mood Induction in Healthy Volunteers and Patients with Major Depression

Darin D. Dougherty1, Thilo Deckersbach

1, Scott L.

Rauch1, Carl Marci

2, Rebecca Loh

1, Nathaniel M.

Alpert3, Alan J. Fischman

3, Maurizio Fava

2

1Psychiatry, Massachusetts General Hospital, Charlestown, MA,


3Radiology, Massachusetts General Hospital, Boston, MA

Background: There is substantial evidence that a reciprocal relationship exists

between dorsal and ventral brain regions during affective and cognitive tasks.

One goal of the current study was to demonstrate this reciprocal relationship

during emotion induction in healthy control subjects. We also included patients

with major depressive disorder (MDD) and hypothesized that this normal

reciprocal relationship may be dysfunctional in the MDD patients.

Methods: For the current study, narrative scripts were used to induce Happy

and Sad states as well as Neutral states during a PET O15 study of regional

cerebral blood flow (rCBF) in twenty unmedicated patients with MDD and ten

healthy control subjects. Statistical parametric mapping techniques were used

for analysis.

Results: Happy minus Neutral state contrasts within groups demonstrated

decreased rCBF in the DLPFC for both groups, although the decrease was left-

sided for the control group and right-sided for the MDD group. Additionally, a

right amygdala rCBF decrease was observed during the Happy state for the

MDD group only. Sad minus Neutral state contrasts within groups

demonstrated increased insular cortex rCBF for both groups, although the

increase was left-sided in the control group and right-sided for the MDD group.

Involvement of frontal regions during the Sad state was observed for the MDD

group only.

Conclusions: These findings suggest specific limbic disturbances that may play

important roles in the pathophysiology of MDD.

500. Investigation of Dorso-Lateral Prefrontal Cortex in Unipolar Disorder Patients with

1H Magnetic

Resonance Spectroscopy

Paolo Brambilla1,2

, Jeffrey A. Stanley3, Roberto B.

Sassi4, Alan G. Mallinger

3, David J. Kupfer

3, Ellen

Frank3, Matcheri S. Keshavan

3, Jair C. Soares

5,6

1Department of Medicine and Public Health, Section of Psychiatry,

University of Verona, Verona, Italy, 2Department of Pathology and

Experimental and Clinical Medicine, Section of Psychiatry, University

of Udine, Udine, Italy, 3Department of Psychiatry, University of

Pittsburgh, Pittsburgh, PA, 4Department of Psychiatry, Harvard

Medical School, Boston, MA, 5Department of Psychiatry, University of

Texas, San Antonio, TX, 6South Texas Veterans Health Care System,

Audie L. Murphy Division, San Antonio, TX



Background: In recent years, neuroimaging and postmortem studies suggested

the involvement of the dorsolateral prefrontal cortex (DLPFC) in the

pathophysiology of unipolar disorder. We examined with 1H magnetic

resonance spectroscopy (MRS) the levels of specific brain metabolites in the

DLPFC of adult patients with unipolar disorder and healthy controls, and

investigated the role of illness chronicity in DLPFC biochemistry.

Methods: Nineteen DSM-IV patients with unipolar depression who were

unmedicated for at least 2 weeks (mean age of 37.4±12.0; 13 females, 6 males; 9

chronically ill, 10 non-chronically ill; 13 depressed, 6 euthymic) and 19 age- and

gender-matched healthy controls (mean age of 37.0±11.5; 13 females, 6 males)

underwent a short echo-time 1H spectroscopy session (8cm3 voxel placed in the

left DLPFC). The metabolite levels were expressed in mmol/kg wet weight.

Results: There were no significant differences between unipolar and healthy

subjects for N-acetyl-aspartate (NAA), choline-containing molecules, and

creatine-phosphocreatine levels (Student t-test, p>0.05). NAA levels were

significantly decreased in patients with chronic illness compared to non-chronic

patients and healthy controls (ANCOVA, age as covariate, p<0.05). No

significant differences were found among depressed, euthymic, and healthy

individuals for any metabolites (ANCOVA, age as covariate, p>0.05).

Conclusions: This study found abnormally reduced levels of NAA in left

DLPFC of chronically ill patients with unipolar depression, suggesting a

possible progression of the dysfunction in neuronal processes and synapses in

DLPFC in unipolar disorder. This could possibly be accounted by

neurodegenerative processes arising with the progression of the illness.

501. Tryptophan Depletion Does not Lead to Measurable Extracellular Serotonin Loss in Remitted Patients with Unipolar Depression

Nicole Praschak-Rieder, Alan Wilson, Sylvain Houle, Jeffrey H. Meyer

PET Centre, Department of Psychiatry, Centre for Addiction and

Mental Health, University of Toronto, Toronto, ON, Canada

Background: Recurrence of depressive symptoms after tryptophan depletion

(TD) in SSRI-treated subjects with major depressive disorder (MDD) is an

important, unexplored phenomenon. The authors measured serotonin1A

receptor binding potential (5-HT1A BP), an index that is sensitive to

extracellular serotonin (5-HT) levels, in multiple brain regions with [18F] MPPF

PET. This was done in SSRI-treated remitted patients with MDD after TD. In a

competition model, an increase in 5-HT1A BP after TD would be an index of

5-HT1A receptors unoccupied by 5-HT due to lowering of extracellular 5-HT.

Therefore, we hypothesized that 5-HT1A BP as found with [18F] MPPF PET

would be greater in the TD condition as compared to the sham depletion (SD)

condition.

Methods: Eight remitted patients with MDD currently taking citalopram as

monotherapy were recruited. Patients received [18F] MPPF PET scans twice,

once after TD, and once after SD in a counterbalanced order. Behavioural

measures were evaluated with the Hamilton Depression Rating Scale and Visual

Analog Scales.

Results: No effect on regional 5-HT1A BP was observed after TD in all

regions examined despite an 86% decrease in total plasma tryptophan and

significant mood effects in 5 of 8 patients.

Conclusions: Our findings argue that large magnitude changes in extracellular

5-HT are not crucial for the mood effects observed after TD. Therefore, greater

consideration should be given to other mechanisms that could contribute to

lower mood, e.g. changes on the level of signal transduction pathways..

502. Brain MRI White Matter Hyperintensities, Cardiovascular Risk Factors, One-Carbon Cycle Metabolism as Predictors of Outcome in Major Depressive Disorder

George I. Papakostas1, Dan V. Iosifescu

1, Perry F.

Renshaw2, Jonathan E. Alpert

1, Maurizio Fava

1


2Psychiatry, McLean Hospital, Boston, MA

Background: The purpose of this study was to investigate the relative impact

of brain white matter hyperintensities (WMH), cardiovascular risk factors, and

elements of the one-carbon cycle metabolism (including serum folate, vitamin

B12 and homocysteine levels) on clinical response in non-elderly subjects with

major depressive disorder (MDD) enrolled in an 8-week open trial of 20mg

fluoxetine.

Methods: 50 subjects meeting DSM-III-R criteria for major depressive disorder

were administered brain magnetic resonance imaging (MRI) scans at 1.5T to

detect T2 white matter hyperintensities. The severity of brain white matter

hyperintensities was classified with the Fazekas scale (range = 0-3). We assessed

cardiovascular risk factors in all MDD subjects (age, gender, smoking, diabetes,

family history, hypertension, cholesterol). MDD patients also had serum folate,

vitamin B12 and homocysteine levels measured. WMH severity, cardiovascular

risk factors and elements of one carbon cycle metabolism were entered in a

logistic regression as independent variables, with clinical response and then

remission as the dependent variables.

Results: The severity of subcortical WMH and hypofolatemia were

independent predictors of lack of clinical response (HAM-D reduction > 50%)

with antidepressant treatment. Separately, hypofolatemia also predicted lack of

remission (final HAM-D < 7). The other variables were not independent

predictors of either outcome.

Conclusions: Subcortical brain white matter hyperintensities and

hypofolatemia appear to have independent negative impact on the outcome of

SSRI antidepressant treatment in non-elderly subjects with MDD.

503. Circadian Endocrine Profiles and Bonemineral Density in Premenopausal Women with Major Depression and a Comorbid Diagnosis of Post Traumatic Stress Disorder

Andrea Horvath Deak1, Sahel Meftah

1, Pedro E.

Martinez1, Farideh Eskandari

1, Sara Torvik

1, Sejal

Mistry1, Donna Ronsaville

1, Jimy Reynolds

1, Philip W.

Gold1, Esther Sternberg

1, Giovanni Cizza

2

1National Institute of Mental Health, National Institute of Health,

Bethesda, MD, 2National Institutes of Mental Health, National Institute

of Health, Bethesda, MD

Background: Major Depressive Disorder (MDD) has been indicated as a risk

factor for osteoporosis (Cizza G. et al., 2001). Although, Post Traumatic Stress

Disorder (PTSD) is often observed in patients with MDD, no research has

determined whether patients with both diagnoses are also at higher risk of

developing osteoporosis. The goal of this study was to establish whether

women with both disorders are at different risk of developing osteoporosis and

to characterize their neuroendocrine features.

Methods: 90 depressed and 44 normal control premenopausal women

participated in this study. Diagnoses were based on the SCID for DSM-IV. 13

patients had MDD and also a lifetime history of PTSD. BMD measurements

were performed by DEXA. Blood sample were collected hourly for

determinations of plasma ACTH, cortisol and TSH, and for biochemical

markers of bone turn over (BBTO).

Results:The prevalence of osteoporosis was significantly higher in the MDD

group than the control group. Mean 24hs ACTH and TSH were lower in the



PTSD+MDD group (<0.0001) compared to the MDD or the control groups.

TSH 24hs mesor and amplitude were also lower in the PTSD +MDD group.

No differences were observed, however, in plasma cortisol. BMD and BBTO

were similar in the 3 groups.

Conclusions: Lower 24hs plasma ACTH and TSH in PTSD+MDD

underscore the biological impact of the comorbidity, even after remission of the

symptoms. The diagnosis of PTSD in addition to MDD in this sample had no

clinical repercussion on bone status, possibly because of unchanged plasma

cortisol levels.

504. An Investigation of the Neural Correlates of Episodic Memory in Drug-Free Depression

Hamid A. Alhaj, R. Hamish McAllister-Williams

Psychobiology Research Group, School of Neurology, Neurobiology

and Psychiatry, University of Newcastle, Newcastle upon Tyne, United

Kingdom

Background: Depressed patients experience neuropsychological impairments

encompassing learning and memory. In addition, abnormal asymmetric cortical

activity has been shown in depression with relatively less activity over the left

regions. The chief objective of the current study was to investigate the neural

correlates of episodic memory using an event-related potentials (ERP)

technique, and the differential lateralization across the cerebral hemispheres in

patients with depression.

Methods: Twenty-five right-handed drug-free depressed patients and twenty-

one age, sex and IQ matched healthy controls took part in the study. In a study

phase subjects heard words spoken in a male or female voice. ERPs were

recorded during a test phase when old and new words were presented visually.

Memory retrieval was confirmed by correct identification of old words with

accurate gender recollection.

Results: The behavioural analysis demonstrated that response times were

significantly longer in depressed patients p=0.04. However, there was no

significant difference in memory performance between the two groups. Control

subjects showed highly significant hemispheric asymmetries due to a relatively

higher voltages between 200 and 500 msec post-stimulus over the right

hemisphere [F(1,20) =20.4, p<0.001]. Strikingly, depressed patients did not

show this difference [F(1,24)=0.44, p=0.51]. There was a significant group by

hemisphere effect, which was independent of memory retrieval.

Conclusions: The results show a lack of normal cortical asymmetry in

depressed patients when performing an episodic memory task. This may reflect

a general cortical asymmetry abnormality in depression rather than a specific

defect in the neural correlates of episodic memory.

505. Apolipoprotein E Polymorphism: A Gender-Linked Risk Factor for Depression?

Eleanor Spoor, James A. Levy, Robert M. Cohen, Judy Bergeson, Karen Putnam, Edward Huey, Brenda Phillips, Nadeem Mirza, Irene Dustin, Trey Sunderland

Lab of Geriatric Psychiatry, NIMH, Bethesda, MD

Background: The Apolipoprotein E-4 allele (APOE-4) may be a risk factor for

Alzheimer's Disease (AD) and early-onset coronary heart disease. The role of

APOE-4 as a risk factor for depression is unclear. Recent work in AD patients

reports an association in women, but not in men. We examined the relationship

between APOE-4 and depression in normal subjects deemed genetically "at

risk" for AD.

Methods: Eighty-six cognitively normal subjects (age 58.9 +/- 5.8) were

selected from a long-term study on risk factors in AD. Half had a history of

clinical depression based on retrospective chart review.

Results: Overall, subjects with a positive history of clinical depression did not

differ significantly in the frequency of APOE-4 from subjects without a history

of depression, although a trend was evident (p=0.07). When separated by

gender, however,a significant association was observed for women (p=0.03).

Neither mean age of onset of depression (40.1+/- 12.6) nor chronicity were

significantly related to APOE-4.

Conclusions: Our data support previous findings suggesting that APOE-4 may

be a risk factor for depression in women, but not in men. While late-onset

depression has been associated with subsequent AD, it is unclear whether the

association between depression and APOE-4 in the present study reflects a risk

factor for depression itself, or for a prodromal form of AD. The average age of

onset of depression in our cohort suggests that the latter may be less likely.

Further study is needed and is currently ongoing in a longitudinal follow-up of

these subjects.

506. Elevated Serum Copper Levels in Women with a History of Post-Partum Depression

John W. Crayton1, William J. Walsh

2

1Psychiatry, Loyola Medical School, Maywood, IL,

2Research, Health

Research Institute, Warrenville, IL

Background: Alterations of zinc and copper have been associated with a

diagnosis of depression in several recent studies, although the findings across

these studies are not consistent.

Methods: We studied zinc and copper circulating levels in patients attending a

large private clinic. Blood samples from 574 women and 328 men with a

primary complaint of depression were studied and compared with age and sex

matched controls.

Results: Women had significantly higher copper levels than men (116±29.8 vs.

92.4±16.9 µl/dl). Levels of zinc were not significantly different between the

sexes. Levels of copper were significantly higher in women-but not men-with

depression compared with non-depressed subjects (116.2±30.8 in depressed

women vs. 106.7±20.7, non-depressed). Zinc levels were not significantly

different in depressed vs. non-depressed women. Among a number of variables

studied, high copper levels were most clearly associated with a history of post-

partum depression. Seventy-eight women with a history of post-partum

depression had a mean serum Cu level of 131.2±39.0 µl/dl compared with a

level of 111.4±24.7 in normal controls. (p < 0.001) Sixty-six percent of women

with copper levels more than two standard deviations above the normal group

mean gave a history of post-partum depression, compared with 24% of those

with copper levels below this level.

Conclusions: This finding supports a role for copper in the expression of

depression, and, in particular, post-partum depression. Possible mechanisms

suggested by these elevated copper levels include dysregulation in biochemical

pathways related to second messenger signaling, biogenic amine synthesis,

oxidative stress, and inflammatory or auto-immune phenomena.

507. Weekly Mood Stability Over 6 Months with Lamotrigine or Placebo in Bipolar Rapid Cycling

Joseph F. Goldberg1, Anil K. Malhotra

1, Joseph R.

Calabrese2, Charles L. Bowden

3, Trisha Suppes

4, Mark

A. Frye5, Terence A. Ketter

6

1Psychatry Research, The Zucker Hillside Hospital, Glen Oaks, NY,

2Psychatry, Case Western Reserve University, Cleveland, OH,

3Psychiatry and Pharmacology, Univ. of Texas Health Science Center

at San Antonio, San Antonio, TX, 4Psychiatry, Univ. of Texas

Southwestern Medical Center, Dallas, TX, 5Psychatry and

Biobehavioral Sc iences, UCLA School of Medicine, Los Angeles, CA, 6Psychatry, Stanford University School of Medicine, Stanford, CA

Background: Traditional definitions of "mood stabilization" have focused

mainly on the acute treatment or prevention of manic or depressive syndromes.

However, in practice, clinicians often conceptualize mood stabilizers as



interventions able to ameliorate fluctuations in mood over time. The FDA

approval of lamotrigine for the maintenance treatment of bipolar disorder

suggests its value for relapse prevention, but little empirical data exists to assess

its utility for mood instability on a week-by-week basis.

Methods: In this secondary analysis of a previously reported clinical trial,

prospective Life Chart Method (LCM) data were examined for 182 bipolar

outpatients with DSM-IV rapid cycling who had initially stabilized with open

label lamotrigine and were then randomized to receive either lamotrigine

monotherapy or placebo for up to 6 months. Proportions of time spent with

euthymia, as well as patterns of mood variation, were examined by GEE

analyses.

Results: Significantly more time was spent with euthymia during the study

period for subjects taking lamotrigine than placebo. Those taking lamotrigine

spent significantly less time with mild hypomania or with moderate levels of

depression, as well as less time with dysphoric mania. Weekly polarity

fluctuations also were less frequent with lamotrigine than placebo for

approximately one-quarter of the study period. Results were comparable for

subjects with bipolar I and bipolar II disorder.

Conclusions: The present findings lend support to the potential mood

stabilizing properties of lamotrigine monotherapy for bipolar disorder, with

more sustained periods of euthymia seen on a continual basis after achieving

initial remission.

508. Birth Seasonality in Seasonal Depression

Edda Pjrek, Dietmar Winkler, Anastasios Konstantinidis, Angela Heiden, Siegfried Kasper

Department of General Psychiatry, University of Vienna, Vienna,

Austria

Background: Season of birth is a putative etiological factor for several

psychiatric illnesses [1]. The aim of this investigation was to examine seasonal

differences in the frequency of birth in a sample of patients with seasonal

affective disorder (SAD).

Methods: 553 outpatients suffering from SAD, winter type, were included in

this evaluation. We compared the observed number of births in our sample with

expected values calculated from the general population.

Results: There was a significant deviation of the observed number of births

from the expected values on a monthly basis (p<0.01). We also found less births

than expected in the first quarter of the year and a slight excess of births in the

second and third quarter (p<0.05). Interestingly, patients with melancholic

depression were more frequently born in fall/winter and less often in

spring/summer compared to patients with atypical depression (p<0.01).

Conclusions: For the pathogenesis of SAD genetic factors [2] and also

environmental circumstances such as birth seasonality seem to be important. In

addition birth effects seem to be dependent on the symptom profile of the

patients, but further studies are needed to elucidate the underlying mechanisms

of these observations.

[1] Torrey EF, Rawlings RR, Ennis JM, Merrill DD, Flores DS. Birth seasonality

in bipolar disorder, schizophrenia, schizoaffective disorder and stillbirths.

Schizophrenia Res 1996; 21:141-149

[2] Lam RW, Levitan RD. Pathophysiology of seasonal affective disorder: a

review. J Psychiatry Neurosci 2000; 25:469-80

509. Children’s Decision-Making in the Context of Risk-Taking: The Role of Maltreatment and Psychiatric Disorders

Amanda E. Schweder1, Hilary B. Hodgdon

1, Carrie L.

Masten1, Sandra Jazbec


1, Joan

Kaufman2, Daniel S. Pine

1, Monique Ernst

1

1Mood and Anxiety Disorders Program, NIMH, Bethesda, MD,

2Department of Psychiatry, Yale University, New Haven, CT

Background: Responses to rewards and punishments represent a strong

neuropsychological correlate of adult depressive disorders. Childhood

maltreatment is a known risk factor for developing mood and anxiety disorders,

yet specific mechanisms linking maltreatment and psychopathology are relatively

unknown. The current study hypothesizes that alterations in reward processing

may be associated with maltreatment and in turn contribute to depressive

and/or anxiety symptoms in children.

Methods: We used a computerized two-choice decision-making task involving

probabilistic monetary outcomes to examine choice selection and reward

anticipation in 32 maltreated children and 21 controls between the ages of 8 and

15. Participants selected either a high probability choice of winning a small

amount of money or a low probability choice of winning a greater amount of

money. Participants indicated their degree of confidence in winning their

selection.

Results: Maltreated children selected low risk choices more often than did

controls, t(1,51) = 2.02, p < .05, given a 30% or 70% chance of winning.

Compared to controls, maltreated children were more variable in their

confidence level of winning after selecting either 30% or 70% options, t(1,49) =

-2.06, p < .05 and t(1,40) = -2.96, p < .01, respectively. Analyses examining

group differences in relation to psychiatric diagnosis are in progress.

Conclusions: Recent conceptualizations view adult depressive disorders as

developmental conditions based on data linking adult depression to high levels

of depressive symptoms and adversity in childhood. This study lays the

groundwork for research on neurodevelopmental aspects of reward processes in

relation to psychopathology and maltreatment.

510. The Role of Brain-Derived Neurotrophic Factor (BDNF) in Increased Neuronal and Glial Density in Hippocampus in Major Depressive Disorder (MDD)

Craig A. Stockmeier1, Gouri J. Mahajan

1, Emer

Hennessy1, Wendy Martin

1, Lisa C. Konick

2, James C.

Overholser3, George J. Jurjus

2, Herbert Y. Meltzer

4,

Jose Javier Miguel-Hidalgo1, Lee Friedman

5, Grazyna

Rajkowska1

1Psychiatry, University of Mississippi Medical Center, Jackson, MS,

2Psychiatry, Case Western Reserve University, Cleveland, OH,

3Psychology, Case Western Reserve University, Cleveland, OH,

4Psychopharmcology, Psychiatric Hospital at Vanderbilt, Nashville,

TN,5Psychiatry, The MIND Institute, Albuquerque, NM

Background: Imaging studies report that hippocampal volume is decreased in

MDD. The cellular basis for a change in volume has not been established.

Diminished BDNF may play a role in hippocampal changes in MDD.

Methods: Sections of frozen right anterior hippocampus were histologically or

immunohistochemically processed in 19 subjects with MDD and 21 normal

control subjects. Seven depressives had a recent antidepressant drug

prescription. Neuronal and glial number, as well as somal area was measured in

randomly placed 3-dimensional counting boxes in 3 sections/subject. In 3

adjacent sections, the areal fraction of BDNF immunohistochemistry was

assessed.

Results: The density of granule cells in the dentate gyrus (DG) and pyramidal

neurons in all CA subfields is significantly increased by ~35% in MDD. In

MDD, glial density is significantly increased by ~30% across hippocampal

subfields and the granule cell layer of the DG. The average soma size of

pyramidal neurons is significantly decreased by about 20% in MDD. BDNF

immunoreactivity is significantly correlated with age (negatively), but not with

PMI, or neuronal or glial density. Regardless of antidepressant drug history,

there was no significant difference between cohorts in total sampled area or

BDNF areal fraction.



Conclusions: Changes in neuron and glial packing density and neuronal soma

size detected postmortem may be the basis of decreased hippocampal volume

noted by some in MDD. BDNF may not play a role in these changes.

Supported by NARSAD, P20 RR17701, MH63187, MH61578, MH67996.

511. Comparison of Sexual Functioning in Patients Receiving Duloxetine or Paroxetine: Acute and Long-Term Data

Madelaine Wohlreich1, Stephen Brannan

2, Michael J.

Detke1, Fujun Wang

1, Craig Mallinckrodt

1, Pierre V.

Tran1, Pedro Delgado

3

1Neuroscience, Eli Lilly and Company, Indianapolis, IN,

2Neuroscience, Cyberonics, Houston, TX,

3Psychiatry, Case Western

Reserve University, Cleveland, OH

Background: Evaluate sexual functioning following acute- and long-term

treatment with duloxetine, paroxetine or placebo.

Methods: Acute-phase data obtained from four 8-week, double-blind studies,

with patients randomized to duloxetine (20-60 mg BID; n=736), paroxetine (20

mg QD; n=359), or placebo (n=371). Long-term data obtained from extension

phases, in which acute treatment responders received duloxetine (40 or 60 mg

BID; n=297), paroxetine (20 mg QD; n=140), or placebo (n=129) for 26

additional weeks. Sexual function evaluated using the Arizona Sexual

Experience Scale (ASEX).

Results: In patients without initial sexual dysfunction, the probability of acute

phase sexual dysfunction onset was significantly lower for duloxetine-treated

patients compared with those receiving paroxetine (p=.015), although both rates

were significantly higher than placebo (p=.007 and <.001, respectively). Long-

term data revealed that sexual function improved (ASEX total score reduced) in

70.9% of duloxetine-treated patients between baseline and endpoint, compared

with 57.6% for paroxetine (p=.060). For ASEX Questions 1 and 2, a

significantly greater proportion of duloxetine-treated patients reported

improvement compared to paroxetine (p=.050 and .037, respectively). No

significant differences were found in Questions 3, 4, or 5.

Conclusions: In these studies, the incidence of acute phase sexual dysfunction

development among patients receiving duloxetine across its dose range (40-120

mg/d) was significantly lower than that of paroxetine at the low end of its dose

range (20 mg/d). On certain ASEX questions, a significantly higher percentage

of duloxetine-treated patients reported improvement in sexual functioning

compared with paroxetine.

512. Dehydroepiandrosterone Treatment of Anorexia Nervosa - Effects on Eating Behavior, Mood and Bone Metabolism

Miki Bloch1, Yael Latzer

2, Zofia Ish-Shalom

2, Ehud

Klein2

1Psychiatry, Tel Aviv Sourski Medical Center, Tel Aviv, Israel,

2Psychiatry, Rambam Medical Center, Haifa, Israel

Background: Anorexia Nervosa (AN) is characterized by low plasma levels of

Dehydroepiandrosterone (DHEA) and hypercortisolemia. DHEA ameliorate

depressed mood in some mood disorders.

Methods: We studied the effect of DHEA treatment on mood, weight, body

composition, eating behavior, bone mass density (BMD) and bone metabolic

parameters in 26 female AN patients. Patients were treated with DHEA

50mgX2\d + calcium\vit.D (Caltrate 600IU) and the control group with

placebo + Caltrate for 6 months. Outcome measures were: psychological –

BDI, EDI and CGI and biological - weight, BMD (by DPX), total body fat%,

cortical bone mass (CBM, ultrasound). Blood measures - PTH, OHD3, cortisol,

BAP, DPD, urine Ca/creatinin, testosterone, estradiol and DHEAS.

Results: Mean baseline weight for the group was 45.5 kg (SD 4.7). Mood and

eating behavior was significant improved for the whole group after 6 months

without a treatment by time interaction. At 6 months, the treatment group

showed a significant increase in DHEAS levels and testosterone and a decrease

in cortisol and DPD compared to controls with significant interactions. No

significant weight gain was observed in both groups but an initial increase in

BMI was observed in the DHEA group at 4 months (8.9%, p=0.05). No

treatment or time effects were observed for BMD, total fat% or CBM.

Improvement of mood was significantly correlated with weight in the DHEA

group only.

Conclusions: DHEA treatment may enhance initial weight gain in AN patients

but was not associated with improvement in bone metabolism, mood or eating

behavior after 6 months treatment.

513. Continuous D2 Receptor Occupancy with Olanzapine Also Induces Vacuous Chewing Movements (VCMs) in Rats

Peter Turrone1, Gary Remington

1, Shitij Kapur

1, Jose

Nobrega2

1Schizophrenia Program, Centre for Addiction and Mental

Health/Institute of Medical Science; University of Toronto, Toronto,

ON, Canada, 2Brain Imaging Program, Centre for Addiction and

Mental Health; University of Toronto, Toronto, ON, Canada

Background: High levels of continuous, but no transient, D2 occupancy by a

conventional antipsychotic (haloperidol) can trigger the vacuous chewing

movement (VCM) syndrome in subgroups of rats. The objective of this

experiment is to determine whether transient (achieved through daily

subcutaneous (SC) injections) versus continuous (achieved through minipump,

MP) D2 receptor occupancy using olanzapine, an atypical antipsychotic, will

differentially affect the development of VCMs.

Methods: Experiment 1: Animals were treated with 7.5 mg/kg/day of

olanzapine (OLZ) or vehicle (VEH) via either MP or daily SC injections for 8

weeks. Experiment 2: A separate group of rats were treated with 15 mg/kg/day

of olanzapine or 1 mg/kg/day of haloperidol (HAL) or VEH via MP for 8

weeks. D2 occupancy levels were measured in vivo using 3H-raclopride.

Results: Experiment 1: Only VCMs in the OLZ MP-treated rats were

significantly different than VEH (p=0.02). Experiment 2: Both OLZ and HAL

led to similar increases in VCMs compared to VEH (p=0.005).

Conclusions: This study strongly suggests that even an atypical antipsychotic

like olanzapine can lead to the VCM syndrome in a subgroup of animals if the

drug is administered in a method (MP) that leads to moderate (51-67%) but

continuous D2 occupancy. The 5-HT/D2 model has been proposed to account

for various clinical advantages attributable to these newer antipsychotics,

including their decreased risk of motoric side effects. The present findings

suggest that other mechanisms may play a role.

514. A Comparison of Structural Brain Deficits in Antisocial Personality Disorder and Violent Schizophrenia: An MRI Investigation

Ian Barkataki1, Veena Kumari

2, Mrigendra Das

1, Pamela

Taylor3, Tonmoy Sharma

4


Kingdom,2Psychology and Psychological Medicine, Institute of

Psychiatry, London, United Kingdom, 3Forensic Mental Health

Sciences, Institute of Psychiatry, London, United Kingdom, 4Clinical

Research, Clinical Research Neuroscience Centre, Dartford, United

Kingdom



Background: Brain abnormalities are found in antisocial personality disorder

and schizophrenia, the two groups most implicated in violent behaviour in

mentally disordered populations.

Methods: Structural magnetic resonance imaging was used to investigate the

whole brain, cerebellum, temporal lobe, lateral ventricles, caudate nucleus,

putamen, thalamus hippocampus, amygdala and the prefrontal, pre-motor,

sensorimotor, occipito-parietal regions in 14 men with antisocial personality

disorder, 13 men with schizophrenia and a history of violence, 15 men with

schizophrenia without violent history and 15 healthy non-violent men. Clinical

groups were compared against each other and healthy controls to examine

general (found in all clinical groups) and specific brain abnormalities (evident in

particular clinical groups).

Results: Compared to controls, the antisocial personality disorder group

displayed reductions in whole brain volume, temporal lobe and pre-motor

region and increases in putamen volume, both non-violent and violent

schizophrenia groups exhibited increased lateral ventricles, with the violent

schizophrenia group demonstrating further abnormalities as reduced whole

brain and hippocampal volumes and increased putamen size.

Conclusions: Individuals with antisocial personality disorder and violent

schizophrenia suffer from different as well as common neural deficits.

Temporal lobe reductions are prevalent in APD whereas hippocampal reduction

is seen in violent schizophrenia, but both groups have reduced whole brain

volumes.

515. Prepulse Inhibition Deficits in Violent Mentally Disordered Subjects

Veena Kumari1, Mrigendra Das

2, Elizabeth Zachariah

2,

Ian Barkataki2, Pamela Taylor

3, Tonmoy Sharma

4

1Psychology and Psychological Medicine, Instititute of Psychiatry,

London, United Kingdom, 2Psychological Medicine, Instititute of

Psychiatry, London, United Kingdom, 3Forensic Mental Health,

Instititute of Psychiatry, London, United Kingdom, 4Clinical Research

Neuroscience Centre, Clinical Research Neuroscience Centre,

Dartford, Kent, United Kingdom

Background: Violent behaviour has a strong association with schizophrenia

and antisocial personality disorder and impacts on patients’ lives as well as on

society. The emergence of violence involves a complex interaction between

neurobiological and environmental factors. Although developments in the

understanding of socio-environmental factors cannot be ignored, advances in

prevention and treatment of violent behaviour need to include a full

understanding of its neurobiological and cognitive basis. This study therefore

investigated deficits in prepulse inhibition (PPI) of the startle response in

violent mentally disordered individuals. Neural regions underlying PPI, such as

the prefrontal cortex, hippocampus and amygdala, are implicated in both

violence and schizophrenia.

Methods: PPI was measured in 14 non-violent healthy men, 14 men with

schizophrenia but no history of violence, 9 men with schizophrenia and a

history of violence, and 9 men with antisocial personality disorder and a history

of violence.

Results: Compared to controls, severe PPI deficits were found in men with

antisocial personality disorder. Both violent and non-violent men with

schizophrenia also showed impaired PPI, with more severe deficits apparent in

the violent group.

Conclusions: Given the established neural circuitry of PPI from animal and

human studies, these observations help to increase current understanding of the

neuropsychobiology of schizophrenia and extreme violence. Furthermore, given

the sensitivity of PPI to a number of pharmacological manipulations (e.g.

disrupted by dopamine agonists and improved by some antipsychotics), the

present findings may have implications for developing more effective

psychopharmacological approaches to treating mentally ill violent offenders.

516. The Point Subtraction Aggression Paradigm; Correlations with Self-Report Measures in Subjects with Personality Disorders

Marianne Goodman1,2

, Antonia S. New1,2

, Harold W. Koenigsberg

1,2, Larry Sprung

2, Larry J. Siever

1,2

1Psychiatry, Bronx VAMC, Bronx, NY,

2Psychiatry, Mount Sinai School

of Medicine, New York, NY

Background: Impulsive aggression is a core feature of Borderline Personality

Disorder (BPD). Newer methods of assessment of impulsive aggression include

the Point Subtraction Aggression Paradigm (PSAP), a computer game that

involves provocation of impulsive aggression as participants win money against

a factitious other. Minimal data exists for the PSAP in personality-disordered

subjects, and its relationship to self-report measures of hostility, impulsivity, and

affect. We hypothesized that PSAP results would correlate with indices of

hostility and in BPD subjects only, indices of affective instability.

Methods: 68 personality disordered (PD) and normal control subjects

completed a PSAP at a pfi of 62.5 and self-report measures including: Buss-

Durkee Hostility Inventory (BDHI), Barrett Impulsivity scale (BIS), Affective

Lability Scale (ALS), and the Affect Intensity Measure (AIM). Analytic methods

included Pearson’s correlations of PSAP (pfi 62.5), with self-report measures in

the total population, by gender and by PD.

Results: 35 controls, 33 PD including 19 BPD were studied. Total population

PSAP results correlate with BDHI negativity scales (r=.27, p<.03). In PD

female but not male subjects, BDHI negativity remained significant (r=.75,

p<.02) and ALS cyclothymia scores (r=.83, p<.005), and BIS motor responses

(r=.85, p<.005) were also significant. In BPD subjects, ALS cyclothymic scores

(r=.51, p<.03) and BDHI negativity (r=.76, p<.001) were positively correlated

with PSAP results. In males but not females, suspiciousness (r=.58, p<.05)

correlated with PSAP results.

Conclusions: These preliminary results suggest that the PSAP correlated with

measures of negativity, suspiciousness and for PD subjects, indices of unstable

affect. Updated results will be provided.

517. Effects of Vagus Nerve Stimulation on Early Sensory Information Processing in Major Depressive Disorder

Andres Neuhaus, Johannes Rentzsch, Peter Neu, Malek Bajbouj

Department of Psychiatry, Charité - University Medicine Berlin,

Campus Benjamin Franklin, Berlin, Germany

Background: Vagus nerve stimulation (VNS) is a new therapy option for the

treatment of therapy-resistant major depressive disorder, yet the mechanism of

central nervous anti-depressive action is largely unknown. Electrophysiological

studies are of particular interest since peripheral current application to afferent

fibers may well exert certain effects on central electrical activity. In an

exploratory study design we investigated effects of VNS on sensory information

processing by recording auditory evoked potentials (AEP) in the

electroencephalogram (EEG).

Methods: Seven patients receiving VNS for therapy of a major depressive

disorder were investigated prior to implantation and 10 weeks after stimulation

onset with the pulse generator turned off 1h prior to investigation. Event-

related potentials were elicited using an auditory oddball paradigm recorded

with 29-channel EEG.

Results: After VNS, the auditory evoked potential showed a significant increase

in amplitude of an early positive component peaking approximately 30ms after

the target stimulus onset (P30) at electrode positions Fz and Cz (p<.05).

Conclusions: Auditory evoked potentials are a useful tool for investigating

VNS-induced changes in early sensory information processing. The

modification of the P30 component is supposed to reflect long-term effects of



VNS and might indicate altered perceptive functions in the course of the

therapy. This result may be a relevant finding for the understanding of the

neurophysiological mechanism of action of VNS and for the pathophysiology

of depression.

518. Left vs. Right 1 Hz Prefrontal rTMS in Pharmacotherapy-Resistant Depressed Patients: Preliminary Results

Robin Ella, Peter Zwanzger, Thomas C. Baghai, Cornelius Schule, Tobias Deiml, Rainer Rupprecht, Hans-Jürgen Möller, Frank Padberg

Dept. of Psychiatry, Ludwig-Maximilian-University, Munich, Munich,

Germany

Background: In spite of the growing number of clinical trials investigating the

efficacy of rTMS in psychiatric disorders, the relationship between stimulation

parameters and efficacy is still not fully understood. Two groups discovered

therapeutic effects of right 1 Hz rTMS (Klein et al. 1999, Fitzgerald et al. 2003).

Preliminary results of imaging studies of rTMS-related effects also showed an

amelioration of depressive symptoms after left prefrontal 1 Hz rTMS (Kimbrell

et al. 1999).

The aim of the current study is to compare the efficacy of the left with the right

prefrontal rTMS.

Methods: 36 of a planned 48 patients suffering from a major depressive

episode were included.

All patients received a stable medication for at least three weeks prior to and

during stimulation.

Patients were randomly assigned to rTMS of the left or right dorsolateral

prefrontal cortex and treated 5 times per week over three weeks with 1200

stimuli/d at 1 Hz and 110% of motor threshold intensity.

Results: An interim analysis of 36 of the planned 48 patients showed a

3.94±2.9 point difference in the HRSD scores after week three between left and

right prefrontal stimulation to the benefit of the right side. After left rTMS, 21%

of the patients were responders and 42% showed a reduction of at least 25% of

the baseline HRSD score. Under right rTMS, 24% were responders and 71%

partial responders. These differences were not statistically significant.

Conclusions: A side dependence of clinical effects of 1 Hz prefrontal rTMS

cannot be supported as yet.

519. Relative Efficacy of High Dose Right Unilateral, Moderate Dose Right Unilateral and Low Dose Bilateral Electroconvulsive Therapy

Isaac Schweitzer1,2

, Anna Ingram1,2,3

, Chee Ng1,2

,Michael Saling

3, Greg Savage

1,4

1Department of Psychiatry, The University of Melbourne, Victoria,

Australia, 2The Professorial Unit, The Melbourne Clinic, Richmond,

Australia, 3Department of Psychology, The University of Melbourne,

Victoria, Australia, 4Department of Psychology, Monash University,

Clayton, Australia

Background: Debate persists over which type of electroconvulsive therapy

(ECT) is optimal. While electrode placement is an important determinant of

efficacy and side effects (e.g., bilateral [BL] or right unilateral [RUL]), dosage

relative seizure threshold (ST) also influences outcome. Importantly, the dose-

response relationship appears to be unique to RUL ECT. BL ECT, by contrast,

has similar levels of efficacy at different dosages (e.g., 1.5 x ST and 2.5 x ST) but

has greater cognitive side effects compared with RUL ECT. Accordingly, high

dose RUL ECT shows promise as an optimal type of ECT but has not been

thoroughly compared with other standard ECT types using an adequate dose

titration procedure.

Methods: In a double-blind randomized design, the efficacies of high dose

RUL ECT (5 x ST), moderate dose RUL ECT (2.5 x ST) and low dose BL ECT

(1.5 x ST) were compared in patients suffering from Major Depression (N=40)

before, immediately after and one month after ECT endpoint, using an adequate

dose titration procedure.

Results: Response rates were similar for the different ECT types immediately

after treatment but high dose RUL ECT and low dose BL ECT had significantly

better sustained therapeutic responses (up to one month follow up) compared

with moderate dose RUL ECT (p=. 036).

Conclusions: These findings suggest that moderate RUL ECT is less favorable

than either of the other treatments given its high level of relapse. They also add

weight to previous evidence that high dose RUL ECT as a possible optimal type

of ECT.

520. Caudate Nuclei Volume during Treatment with Quetiapine in First Episode Schizophrenia

Sitra Tauscher-Wisniewski1, Shitij Kapur

2, Bruce K.

Christensen2, Robert B. Zipursky

2

1Dept. of Neuropsychiatry for Children and Adolescents, Medical

University Vienna, Vienna, Austria, 2Center for Addiction and Mental

Health, University of Toronto, Toronto, ON, Canada

Background: Magnetic resonance imaging (MRI) studies suggest that

antipsychotics may alter basal ganglia volume early in the course of treatment.

We treated patients experiencing their first episode of schizophrenia with

quetiapine and investigated whether caudate nuclei volumes (CNV) changed

after 3 months of treatment.

Methods: We used a GE Signa 1.5 T MRI scanner to obtain a coronal three-

dimensional SPGR sequence to measure CNV in 10 patients with a first episode

of schizophrenia (N=8) or schizophreniform disorder (N=2) at baseline and

after 12 weeks of treatment with quetiapine. All were neuroleptic naïve at the

time of the first scan. Mean duration of untreated psychosis (DUP) was 17.8

months (SD=20.4). Mean age at baseline was 23.4 years (SD=4.0). Mean dose

after 12 weeks of treatment was 494 mg (SD=130).

Results: The patients showed a mean CNV of 8.42 cc (SD=1.27) at baseline,

and 8.29 cc (SD=1.10) at endpoint. The CNV declined on average by -.13 cc

(SD= .33) during 12 weeks of treatment with quetiapine, but this change was

not statistically significant (P= .265). There was no significant correlation of the

CNV change with age or DUP.

Conclusions: There was no evidence for an alteration in CNV after 12 weeks

of treatment with quetiapine in a sample of neuroleptic naïve patients suffering

from a first episode of schizophrenia. This data support the notion that

treatment with atypical antipsychotics may not lead to increase in caudate

volume in the very early treatment phase of a first episode of schizophrenia.

521. Extrastriatal D2 Imaging with PET

Tetsuya Suhara1, Fumihiko Yasuno

1, Yoshiro Okubo

1,

Yasuhiko Sudo1, Makoto Inoue

1, Tetsuya Ichimiya

1,

Akihiro Takano1, Kazuhiko Nakayama

1, Christer

Halldin2, Lars Farde

2

1Brain Imaging Project, National Institute of Radiological Sciences,

Chiba, Japan, 2Clinical Neuroscience/Psychiatry Section, Karolinska

Institutet, Stockholm, Sweden

Background: An increasing body of evidence favors a crucial role of

extrastriatal regions in the pathophysiology of positive symptoms, and we have

recently reported lower D2 receptor binding in the anterior cingulated cortex

and its correlation with positive symptoms. The trend of lower D2 receptor

binding was observed in the whole thalamus. Several structural and functional

brain imaging studies point to a disturbance of subnuclei of the thalamus in

schizophrenia.



Methods: Positron emission tomography (PET) and [11C]FLB 457 was used to

examine dopamine D2 receptor in thalamic subregions of 10 drug-naïve patients

with schizophrenia. Comparisons were made with 19 healthy controls.

Subregions of interest were defined on individual magnetic resonance images

(MRI) using a percentage-based operational approach.

Results: The binding potential (BP) of [11C]FLB457 was lower in the central

medial and posterior subregions of the thalamus in patients with schizophrenia.

At a functional level there was a significant negative correlation between BP and

the positive symptom scores on BPRS.

Conclusions: The subregions with low D2 receptor binding comprise primarily

the dorsomedial nucleus and pulvinar, two important components in circuitries

previously suggested in the pathophysiology of schizophrenia. Aberrant

dopaminergic neurotransmission in thalamic subregions might be a mechanism

underlying positive symptoms in schizophrenia.

522. Determining Optimum Medication in Schizophrenic Patients: Implication of Using a Statistical Model

David L. Van Brunt1, Hong Liu-Seifert

1, P. Joseph

Gibson2, Robert L. Obenchain

1, Saeeduddin Ahmed

3

1Outcomes Research, Eli Lilly and Company, Indianapolis, IN,

2Epidemiology, Health and Hospital Corporation of Marion County,

Indianapolis, IN, 3Neuroscience, Eli Lilly and Company, Indianapolis,

IN

Background: This study was designed to assess the implications of using a

statistical model for selecting optimal antipsychotic treatment among

schizophrenics using randomized trials comparing olanzapine and risperidone.

Methods: Logistic regression models were developed to predict treatment

response from pooled baseline data from two randomized clinical trials. These

models were used to obtain probabilities of response to both olanzapine and

risperidone for every subject (N=529). Treatment response was defined as

>20% reduction in total score on the Positive and Negative Syndrome Scale at 8

weeks. “Preferred” treatment was the drug with a higher probability of

response. Contingency tables compared response rates based on match to

preferred treatment, independent of drug received, to see if matching was

associated with better response rates.

Results: The group of patients randomized to their preferred treatment showed

a 53% response rate, while those receiving the other treatment showed a 41%

response rate. The difference in response rate was significant (p < .01).

Conclusions: Our findings suggest that baseline characteristics can be used to

determine likelihood of response to specific antipsychotic medications, and that

using these models for treatment selection may improve response rates.

Refinement is needed to address alternative treatment goals and generalizability

outside of trial settings.

523. Improvement of Cognitive Functioning with Atypical Antipsycotic Treatment in Non-Schizophrenic Adolescent Inpatients

Laura M. Coraci1,2

, Liza A. Maldari1,2

, David L. Pogge1,2

,John Stokes

2,3, Nicholas J. deSpoelberch

2, Philip D.

Harvey4

1Psychology, Fairleigh Dickinson University, Teaneck, NJ,

2Psychology, Four Winds Hospital, Katonah, NY,

3Psychology, Pace

University, New York, NY, 4Psychology, Mt. Sinai School of Medicine,

New York, NY

Background: Atypical antipsychotic medications have been found to lead to

moderate improvements in aspects of cognitive functions in patients with

schizophrenia. These medications are also commonly used in conditions other

than schizophrenia. It is not clear whether these medications have similar

cognitive benefits in individuals who do not have schizophrenia.

Methods: In an ongoing study, adolescent psychiatric inpatients were examined

with a cognitive assessment prior to being treated with atypical antipsychotic

medications. They were re-tested at discharge, and then followed up 120 days

after discharge for functional status assessment.

To date, 41 inpatients have been assessed. They had a variety of psychiatric

diagnoses, including depression, conduct problems, and psychotic disorders.

All participants were examined with measures of working memory, vigilance,

episodic memory, verbal fluency, and executive functioning, as well as

assessments of intellectual functioning.

Results: Statistically significant improvements in episodic memory (P<.001),

vigilance (p<.05), working memory (p<.05), executive functioning (p<.05), and

verbal fluency (p<.05) were detected. These changes were not correlated with

baseline intellectual functioning. Preliminary correlational analyses indicated that

improvements in cognitive functions were associated with followup functional

skills (e.g.,social functioning), but not residual symptom status.

Conclusions: In this ongoing study, changes in cognitive functioning similar to

those reported for patients with schizophrenia were found. The cognitive

functions improved were consistent with previous research, although this is an

open-label study. The correlations of these inpatient changes with 120 day

follow-up data regarding functional status will be presented as well, in order to

validate these open-label observations.

524. Pharmacokinetic/Pharmacodynamic Evaluation of Continuous versus Pulsatile Methylphenidate Treatment

Ann Polcari1, Martin H. Teicher

1,2, Mary Foley

1,

Elizabeth Valente1, Cynthia E. McGreenery

1

1Developmental Biopsychiatry Research Program, McLean Hospital,

Belmont, MA, 2Psychiatry, Harvard Medical School, Cambridge, MA

Background: Recent studies indicate that the sustained efficacy of

methylphenidate depends on pharamacokinetics, and that constant blood levels

produce rapid tolerance and waning benefits. To overcome this problem

methylphenidate preparations need to be pulsatile with periods of falling levels

to restore sensitivity, or need to produce constantly increasing blood levels to

surmount an underlying emerging tolerance.

Methods: Forty-eight boys (10.6±1.1 yr) with ADHD combined subtype, who

were all methylphenidate responsive, were randomly assigned to one of four

medication regimen groups. Each subject received divided doses of a total of 1

mg/kg/day methylphenidate administered to produce either pulsatile kinetics,

steady-state blood levels, or a bolus + rising blood level pattern similar to

Concerta™. Subjects had blood drawn for d-methylphenidate levels and

computer testing for attention and hyperactivity (infrared motion analysis) at

hourly intervals over the course of 12 hours in our clinical lab.

Results: Methylphenidate exerted effects on attention and activity that

correlated strongly with d-methylphenidate blood levels. A pulsatile three times

a day dosing pattern (0.4, 0.4 and 0.2 mg/kg) produced maximal peak and

overall benefits on activity and attention.

Conclusions: Pulsatile delivery minimized development of tolerance and

produce greater efficacy at moderate doses than continuously increasing

delivery. Continuously increasing regimens may require higher total doses to

produce comparable benefits.



525. The Effect of Dehydroepiandrosterone (DHEA) Administration on Response to the Gamma-Aminobutyric Acid (GABA) Agonist, Alprazolam

M. Margaret Folan1, John A. Sweeney

2, Frank J.

Kroboth3, Tanya J. Fabian

1, Gretchen L. Haas

4, Kristin

L. Bigos1, Patricia D. Kroboth

1

1Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA,

2Psychiatry, Neurology and Psychology, University of Illinois, Chicago,

IL,3Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA,

4Psychiatry, University of Pittsburgh, Pittsburgh, PA

Background: DHEA is antagonistic at the GABA-receptor complex.

Alprazolam has GABA-agonist activity and produces concentration-dependent

decreases in psychomotor performance. The elderly are more sensitive to these

GABA-agonist effects and have lower DHEA concentrations than young

individuals. The concentration of DHEA may be related to the intensity of

response from GABA-agonist effects.

Methods: Healthy women (20 young; 16 older) and men (16 young; 14 older)

participated in a two-way crossover study of placebo plus alprazolam (PL/ALP)

and DHEA plus alprazolam (DHEA/ALP). Saccadic eye movements (SEMs)

and psychomotor tasks were used as measures of intensity of response prior to

administration of PL or DHEA at 0 hour, and at 2, 3.5, 4.5, 5.5, 7, 8.5, 10, 11.5

and 12.5 hours after. Alprazolam was administered at 2.5 h.

Results: A greater number of subjects were unable to complete the SEM task

than the digit symbol substitution (DSST) tasks due to alprazolam effects. The

number of older subjects unable to do the SEM task was greater in the

DHEA/ALP treatment, p 0.0006; there were no differences between

treatments for the young. For DSST, there were no differences between

treatments for either age group.

Conclusions: The number of older subjects capable of performing the SEM

task under the influence of alprazolam was decreased during the DHEA

treatment, indicating greater GABA-agonist activity. More subjects

demonstrated impairment at a level where they were unable to complete the

SEM tasks though were capable of doing the DSST, implying SEMs are a more

sensitive measure of GABA-agonist effect.

526. Withdrawn

527. Risperidone and 9-OH-Risperidone Plasma Levels and Clinical Response in Schizophrenia Patients

Martin T. Strassnig1, Markus J. Schwarz

2, Ilja

Spellmann2, Anette Mueller-Arends

2, Sandra Dehning

2,

Hans-Jürgen Möller2, Norbert Mueller

2, Michael Riedel

2

1Western Psychiatric Institute and Clinic, University of Pittsburgh

Medical Center, Pittsburgh, PA, 2Department of Psychiatry and

Psychotherapy, LMU University of Munich, Munich, Germany

Background: Assessment of the relation between oral neuroleptic dose, serum

drug levels and clinical response may provide important information for rational

treatment decisions. CYP2D6 isoenzyme polymorphisms may influence plasma

levels and clinical response parameters.

Methods: Risperidone monotherapy was administered to schizophrenia

patients in a 6-week open dose clinical trial. Weekly assessments including CGI

and PANNS ratings to assess psychopathology; Extrapyramidal Symptom

Rating Scale (ESRS) and Barnes Akathisia Scale (BAS) to assess medication side

effects; and blood draws to quantify steady state plasma levels of Risperidone

and 9-OH-Risperidone were carried out. Additionally, major CYP2D6

polymorphisms were genotyped.

Results: Seventy two patients were recruited. Mean oral dose of Risperidone

was 4.3 ±1.2 mg. Mean plasma levels of Risperidone were 25.4 ±22.3 ng/ml,

and 54.4 ±31.3 ng/ml of 9-OH-Risperidone, respectively. Significant

improvements in the various PANNS scales/subscales ensued. There was a

positive linear correlation between Risperidone plasma levels and oral dose

(r=0.32, p 0.05), but no correlation between Risperidone and 9-OH-

Risperidone levels. Additionally, a curvilinear correlation of plasma levels and

therapeutic response was found. EPS and plasma levels were not correlated;

however, patients initially receiving higher oral doses of risperidone were

significantly more likely to develop extrapyramidal side effects.

Conclusions: Oral Risperidone doses from 4 to 6 mg predicted the best clinical

responses, roughly corresponding to combined Ris/9-OH-Ris plasma levels of

20 to 40 ng/ml. 9-OH-Risperidone levels were not correlated to Risperidone

plasma levels, and were likely determined by CYP2D6 polymorphisms. It is

important to measure both Ris/9-OH-Ris levels for plasma drug monitoring.

528. Changes in Body Composition in Children and Adolescents Treated with Second Generation Antipsychotics

Christoph U. Correll, Umesh H. Parikh, John M. Kane, Anil K. Malhotra

Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY

Background: Although widely utilized, limited data exist on second-generation

antipsychotic (SGA)-induced effects on body composition in children and

adolescents.

Methods: 12-week, prospective, open-label study in subjects 5-18 years old

with a DSM-IV diagnosis of psychotic, mood and/or aggressive disorders

necessitating initiation of SGA-treatment. Monthly, height, weight, body mass

index (BMI), fat mass and percentage (bioimpedance), and waist circumference

were measured. At baseline, 4 and 12 weeks, leptin and SGA levels were

assessed.

Results: In 141 youngsters (mean age: 14.1±3.3 years, 60.1% male, 49.0%

Caucasian) who completed 8 (mean: 12.0±1.5) weeks of SGA-treatment,

weight, BMI, fat mass, fat percentage, and waist circumference increased

significantly (p<.0001, respectively). All measures increased with olanzapine the

most (e.g., 15.3±10.9lbs=2.4±1.7BMI points, n=50), followed by risperidone

(10.7±8.2lbs=1.6±1.3BMI points, n=52) and quetiapine (5.0±11.4lbs=0.6±2.0

BMI points, n=41) (p<.0001, respectively). Extreme weight gain ( 7%)

occurred in 76.0%, 60.0% and 36.6% of patients (p<0.001). In antipsychotic-

naïve youngsters (n=74), olanzapine caused significantly higher increases only in

fat percentage and abdominal circumference compared to quetiapine (p<.05,

respectively). Correlates of weight gain at endpoint were weight gain at 4 weeks

and baseline-to-endpoint increases in leptin (p<.0001, respectively), co-

treatment with divalproex (p<.01), antipsychotic-naïveté (p=.03) and diagnosis

of schizophrenia-spectrum disorders (p<.05).

Conclusions: In youth, SGAs adversely affect cardiovascular risk factors, such

as weight, BMI, fat mass, fat percentage, and waist circumference. High-risk

individuals are antipsychotic-naive, leptin resistant youngsters with

schizophrenia-spectrum disorders, co-treated with divalproex who experience

largest early weight gain. Careful use of SGAs, regular monitoring of these side

effects, and pre-treatment dietary/lifestyle counseling are warranted.



529. Who Responds to Cognitive Behavioral Therapy for Obsessive Compulsive Disorder? A Retrospective fMRI Symptom Provocation Study

Anne Speckens1, David Mataix-Cols

2, Sarah C.

Wooderson2, Natalia S. Lawrence

2, Michael J.

Brammer3, Mary L. Phillips

2

1Psychology, Institute of Psychiatry, London, United Kingdom,


Kingdom,3Biostatistics, Institute of Psychiatry, London, United

Kingdom

Background: Different symptoms dimensions of obsessive compulsive

disorder (OCD) may be mediated by distinct neural systems. In an earlier study

of neuroimaging predictors of response to cognitive behavioral therapy (CBT)

in OCD, increased activation of the left orbitofrontal cortex was found to

correlate positively with clinical improvement. We retrospectively examined the

neural correlates of improvement with CBT of different symptom dimensions

of OCD.

Methods: Thirteen OCD patients participated in four functional magnetic

resonance experiments consisting of provocation of washing, checking,

hoarding, and symptom-unrelated anxiety during an open trial of CBT. Patterns

of brain activity were correlated with reduction of obsessive compulsive

symptoms after treatment, controlling for reduction of depressive sympoms and

level of obsessive compulsive and depressive symptoms at the time of the scan.

Results: In the washing experiment, improvement was positively correlated

with activation in bilateral striatum, bilateral dorsomedial frontal and right

precentral gyri. In the checking experiment, improvement was negatively

correlated with activation in left dorsolateral prefrontal and lateral occipital

regions. In the hoarding experiment, improvement was positively correlated

with activation in right orbitofrontal cortex. In the aversive control experiment,

improvement was positively correlated with activation in left thalamus and

negatively correlated with activation in lateral occipital regions.

Conclusions: Different symptom dimensions of OCD may be associated with

different neural predictors of outcome of CBT, but the results need replication

in a prospective controlled study.

530. Aripiprazole as an Adjunct to Clozapine Therapy in Chronic Schizophrenia

David C. Henderson1,2

, Tara B. Daley1, Dana Nguyen

1,

Laura Kunkel1,2

, Pearl Louie1,2

, Donald C. Goff1,2


2Psychiatry, Harvard Medical School, Boston, MA

Background: Clozapine remains the most effective agent for the treatment

resistant schizophrenia population. However, treatment options for patients

who do not fully respond to clozapine or who have significant side effects have

not been fully clarified. This six week open label trial of Aripiprazole added to

clozapine examines the overall efficacy against the symptoms of schizophrenia.

Methods: Ten clozapine-treated subjects participated in this open trial and 80

% were male. The mean age was 38.7 ± 8.9 years and the mean clozapine dose

was 455 ± 83 mg daily.

Results: Baseline mean PANSS total score was 63.8 ± 7.9. There was a

nonsignificant reduction in Total PANSS scores (p > .05) with 7 out of 10

subjects showing a decrease. There was a nonsignificant improvement in the

Quality of Life scale, with 7 subjects showing improvements. Finally, there was

a significant improvement on the Fatigue Symptom Inventory (p=.015)

comparing baseline to endpoint. In addition, there was a significant decrease in

weight comparing baseline to study endpoint (p=.003) and body mass index

(BMI) (p=.004). There was a significant decrease in fasting total serum

cholesterol (p=.002) and total triglycerides (p=.04) comparing baseline to

endpoint. Seven of ten subjects experienced a decrease in fasting serum

triglyceride and all ten subjects experienced a decrease in total cholesterol.

Conclusions: This combination may be useful for some symptomatic

clozapine-treated patients and must be studied in a placebo-controlled double-

blind randomized trial to determine efficacy and safety.

531. Effects of Dopamine Depletion on Working Memory Function in Healthy Volunteers

Youssef Hassoun, Faith Gunning-Dixon, Katharine Nassauer, Kelly Dillon, John A. Bates, Anil K. Malhotra

Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY

Background: Dopaminergic function has been implicated in the regulation of

working memory (WM). Preclinical studies suggest that dopaminergic

perturbation influences WM function, and a limited number of clinical studies

have indicated that dopaminergic augmentation may enhance performance on

WM tasks. Clinical data on the effects of dopamine depletion in healthy subjects

has been limited, however, by the lack of suitable pharmacological probes of the

dopamine system. We are utilizing a branch chain amino acid (BCAA)

preparation with demonstrable effects on dopaminergic activity to test the

relationship between dopaminergic depletion and cognitive function in healthy

volunteers.

Methods: 7 healthy male volunteers (mean age = 38.5 ± 9.2 years) were

administered a BCAA drink in a randomized double blind placebo controlled

design. Cognitive testing was conducted at baseline, 4 hours after BCAA (or

placebo) administration, and 6 hours after BCAA administration on 2 separate

days. Cognitive battery included tests of sustained attention, working memory,

and executive function. Serial serum prolactin levels were obtained as a marker

for dopamine level alterations.

Results: Preliminary data analysis indicates that BCAA administration was

associated with a diminution in performance on the delayed match to sample

task (DMST), a putative measure of WM function, with no effects observed on

other measures. Serum prolactin levels were significantly increased during the

period of WM impairment.

Conclusions: These results provide preliminary evidence that dopamine

depletion is associated with WM dysfunction in healthy volunteers. Larger

studies assessing the relationship between BCAA administration and effects on

a comprehensive neurocognitive battery are underway.

532. Sustained Release Bupropion in the Treatment of Pathological Gambling - A Pilot Study

Pinhas N. Dannon1,2

1Psychiatry, Rehovot Community Mental Health Care Clinic, Rehovot,

Israel,2Tel Aviv University, Sackler School of Medicine, Tel Aviv,

Israel

Background: Pathological Gambling (PG) is a highly prevalent and diabling

impulse control disorder. Recent studies demonstrated the effectiveness of

SSRI's, mood stabilizers and opioid agonists. These findings have supported the

observation that PG is strongly associated with both mood and addictive

disorders. The aim of the study to show the effectiveness of bupropion SR in

PG

Methods: Fifteen male gamblers that failed to respond to two SSRI trials

included. The patients screened for symptoms of gambling, anxiety and

depression by a blind rater. In addition, the patients completed self-report

questionnaires about their treatment status.

Resuts: Twelve patients completed the twelve week bupropion up to 450 mg/d

program. Ten out of twelve patients responded with full recovery and two

others were partial responders.

Conclusions: Bupropion SR could be effective in the treatment of pathological

gambling.



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