Research in the treatment and causes of schizophrenia

Vishwajit L Nimgaonkar, MD, PhDProfessor of Psychiatry and Human Genetics,

University of Pittsburghnimga@pitt.edu

Disclosure statement

Vishwajit L. Nimgaonkarhas no conflict of interest in this

presentation

Outline (vignettes)• Diagnosis• Treatment• Causation• Research at Pittsburgh• Request for your help

Outline

• Diagnosis• Treatment• Causation• Research at Pittsburgh• Request for your help

Empirical Diagnosis (DSM IV)

• Two or more psychotic features: > 1 month

• Impaired social / occupational function• Duration (6 months)• Exclude:

• Mood disorder, possible causative medical condition, substance abuse.

Coming soon …• DSM V criteria (due 2012)

– Lifespan diagnostic approach.– Emphasis on dimensional concepts.– Diagnostic specificity.– Interface between psychiatric and general

medicine.– Gender and cross-cultural issues. – Remove schizoaffective disorder?

Outline:• Diagnosis• Treatment• Causation• Research at Pittsburgh• Request for your help

Patient Outcomes Research Team (PORT, Lehman et al, 1995 ….)

• Medications: Buchanan et al, 2010.http://www.ncbi.nlm.nih.gov/pubmed/19955390?dopt=Citation

• Psychosocial Rx: Dixon et al, 2010. http://schizophreniabulletin.oxfordjournals.org/content/36/1/48.full.pdf+html

• Levels of adherence?

Antipsychotic drugs• Most significant benefit:

PREVENTION OF RELAPSE• Symptomatic improvement• Modest improvement:

• ‘negative’ symptoms• cognitive features• social function

• Efficacy / side effect profiles vary between patients.

Classical: first generation antipsychotic drugs

• Chlorpromazine (Largactil)• Haloperidol (Haldol)• Fluphenazine (Prolixin)• Ziprasidone (Geodon)• Clozapine (Clozaril): treatment

resistant schizophrenia

Second generation antipsychotic drugs

• Risperidone (Risperdal)• Olanzapine (Zyprexa)• Quetiapine (Seroquel)

Most recent antipsychotic drugs

• Aripiprazole (Abilify)• Paliperidone (Invega)*• Asenapine (Saphris)• Iloperidone (Fanapt)• Lurasidone (Latuda)

* Risperidone metabolite

‘Newest’ antipsychotic drugs*Drug Advantages Side effects/concerns

Asenapine(Saphris)

Sublingual, rapid absorption. Akathisia, oral hypoesthesia,somnolence.? Hemodynamics.

Iloperidone(Fanapt)

Low EPS, low akathisia, little weight gain.

Dizziness, orthostasis.? QT prolongation.

Lurasidone(Latuda)

Pregnancy category B, low weight gain, low extra pyramidal symptoms.

Akathisia, nausea.? Use in moderate / severe renal impairment.

* Cindy Holway, PharmD, MBA

Adjunctive treatments (PORT, Dixon et al, 2010)

• Assertive Community Treatment• Supported Employment• Skills training• Cognitive Behavioral Therapy (+/-)• Token Economy Interventions (old data)• Family-Based Services• Alcohol and Substance Use Disorders• Weight Management

More evidence needed (PORT, Dixon et al, 2010)

• Cognitive remediation• Peer Support and Peer-Delivered

Services• Interventions to Increase Adherence to

Antipsychotic Medication• Psychosocial Treatments for Recent

Onset Schizophrenia

Outline• Diagnosis• Treatment• Causation• Research at Pittsburgh• Request for your help

Genetics: ‘tsunami’• Increased number of polymorphisms:

• genome-wide association studies (GWAS) ~1 million SNPs / person

• Coming soon: Whole genome sequencing.

GWAS: HLA variants and schizophrenia

HLA variants in schizophrenia: Pittsburgh studies

Copy number variations in schizophrenia

Odds ratios ~ 7 – 13– Chromosome 22q11.2– Chr. 1q21.1– Chr.15q11.2– Chr. 15q13.3 (autism / Angelman-Prader

Willi S)

Antibodies to Toxoplasma gondii in Patients with Schizophrenia: Meta-Analysis

Torrey et al., Schizophr Bulletin (2007), 33 (3): 729-736.

Forty-two studies: 17 countries over 5 decades; 23 met selection criteria.

Combined odds ratio (OR): 2.73 (95% C.I., 2.10 to 3.60; p < .000001).

Outline• Diagnosis• Treatment• Causation• Research at Pittsburgh• Request for your help

Abnormalities in the auditory cortex

Robert A. Sweet, M.D.(Professor of Psychiatry and Neurology, Co-

Associate Director for Research, MIRECC, VA Pittsburgh Healthcare System)

Small molecule modulation of dendritic spine structural

plasticity to enhance persistence and prevent loss

Prevention

Auditory

Cortex

Clinical Feature

Pathophysiology

Pathology

Affective Impairment

Vocal Emotion Discrimination

Pitch Discrimination

Pathogenesis

K.N. Roy Chengappa, MD.(Professor of Psychiatry, University of Pittsburgh)

L-Carnosine – A potent antioxidant has shown benefits for improving cognitive set-shifting and decreasing perseverative errors in a subgroup of people with schizophrenia.– Unpublished.

Cognitive remediation: medications

Anti-herpes virus specific treatment and cognition in schizophrenia: a test-of-

concept randomized double blind placebo controlled trial

K M Prasad MDAssistant Professor of Psychiatry

University of Pittsburgh

(unpublished)

Changes in neuropsychological scores with Valacyclovir ‘add on’ N-back

(Total Accuracy) Immediate Verbal Memory

(Processing Speed) Delayed Verbal Memory

(Processing Speed)

Immediate Face Memory (Processing Speed)

Spatial Processing (Processing Speed)

Delayed Visual Memory (Total Accuracy)

Yoga for cognitive remediation

Bhatia et al, in press, Acta Psychiatrica Scandinavica

Federally funded trial in India– conventional exercise as comparison– random allocation to treatment cells– ‘blind’ evaluation

Pilot studies in the USA?

Outline• Diagnosis• Treatment• Causation• Research at Pittsburgh• Request for your help

A Family Study of Schizophrenia A Family Study of Schizophrenia and Related Conditionsand Related Conditions

Comprehensive study of causation and pathogenesis– Includes patients, relatives, controls– Diagnostic studies– Computerized cognitive evaluation– MRI studies– Genetic and environmental studies– Federally funded (NIMH)

Participation details

• Families with > 2 closely related members with schizophrenia / schizoaffective disorder

• Parent / child; siblings

• All relatives eligible

• Caucasian ethnicity

• Voluntary and confidential.

• No change in treatment.

• One time.

• Participant receive $ 175 + travel costs.

A Family Study of Schizophrenia A Family Study of Schizophrenia and Related Conditionsand Related Conditions

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TOLL FREE: 1-877-363-5895

Fax: (412) 246 6350

WEB SITE: www.pitt.edu/~nimga