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Henry A. Nasrallah, MDProgram Moderator
Professor of Psychiatry and Neuroscience
University of Cincinnati
Director, Schizophrenia Program
UC Health University Hospital
Cincinnati, Ohio
Peter J. Weiden, MDProfessor of Psychiatry
Director, Psychotic Disorders ProgramUniversity of Illinois Medical Center
Chicago, Illinois
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Understanding the
Complexities of Schiophrenia
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SA-3CurrentPsychiatry.com Supplement to Current Psychiatry | Vol 10, No 9 | October 2011
Understanding the Complexitiesof Schizophrenia
A Precipitous DeclineSchizophrenia is a lifelong, degenerative disease that affects individuals
during the most productive period of their lives. Schizophrenia typically
begins during late adolescence, and the prodromal period is characterized
by social withdrawal and other subtle changes in behavior and emotional
responsiveness. What follows formal diagnosis of schizophrenia is a seriesof acute episodes and relapses, during which symptoms persist and often
worsen over time.1-3 The damage associated with schizophrenia begins dur-
ing or even before the prodromal period and appears to continue through-
out the course of the disease. However, the first 5 to 10 years after diagnosis
appear to be particularly destructive to brain tissue.4
Structural Brain Abnormalities in SchizophreniaStructural abnormalities associated with schizophrenia include enlarged
cerebral ventricles, a reduction in the size of the hippocampus and
amygdala, and alterations in other structures such as the entorhinal cor-
tex of the parahippocampal gyrus, superior temporal gyrus, and anteriorcingulate gyrus. Abnormalities in prefrontal white matter may underlie
an altered connection between the prefrontal cortex and anterior cingu-
late cortex or limbic regions. Unlike the hippocampus and amygdala,
which are smaller in patients with schizophrenia compared with the
general population, the size of basal ganglia structures is increased in
this population.5,6
The loss of grey matter is significant and progressive in patients with
schizophrenia, as illustrated by a study performed in patients with an early
onset of the disease (Figure 1, page SA-4). During the 5 years of the study,
grey-matter loss progressed anteriorly into temporal lobes, sensorimotor
and dorsolateral prefrontal cortices, and frontal eye fields. These patternsof loss correlated with psychotic symptom development and reflected the
neuromotor, auditory, visual search, and frontal executive impairments in
schizophrenia. It should be noted that subject choice was a notable limita-
tion of the study, as patients with very early onset of schizophrenia tend to
experience a more severe disease course.6
As previously noted, the hippocampus typically shows a decrease in
size and an alteration in shape in patients with schizophrenia. In humans,
this important structure is thought to mediate the formation of new mem-
ories. The roles for the hippocampus postulated in schizophrenia are var-
ied. Some investigators attribute memory impairments in schizophrenia
to hippocampal pathology. Others cite its high concentration of NMDA
Gregory W. Mattingly, MDAssociate Clinical ProfessorDepartment of PsychiatryWashington UniversitySchool of MedicineSt Louis, Missouri
Henry A. Nasrallah, MD
Professor of Psychiatry andNeuroscienceUniversity of Cincinnati College
of MedicineDirector, Schizophrenia ProgramUC Health University HospitalCincinnati, Ohio
Peter J. Weiden, MDProfessor of PsychiatryDirector, Psychotic Disorders ProgramUniversity of Illinois Medical CenterChicago, Illinois
Disclosures
Dr Mattingly receives research support from Astra
Zeneca; Ayerst; Dainippon Sumitomo Pharma Co. Ltd.;Forest Laboratories, Inc.; GlaxoSmithKline; Janssen; John-
son & Johnson; Eli Lilly and Company; Lundbeck A/S;
Ortho-McNeil-Janssen Pharmaceuticals, Inc.; Merck &
Co.; New River Pharmaceuticals Inc.; Novartis; Organon
Pharmaceuticals USA Inc.; Pfizer Inc; Sanofi-Synthelabo;
Schwabe/Ingenix; Sunovion Pharmaceuticals Inc.; Shire;
Solvay Pharmaceuticals, Inc.; Takeda Pharmaceuticals
North America, Inc.; Vanda Pharmaceuticals Inc.; and Wyeth
Pharmaceuticals Inc. He is or has served on speakers
bureaus for Abbott Laboratories; Forest Pharmaceuti-
cals; GlaxoSmithKline; Janssen; Eli Lilly and Company;
Ortho-McNeil-Janssen Pharmaceuticals, Inc.; and Shire. Dr
Mattingly is or has been a consultant for Forest; Eli Lilly and
Company; Ortho-McNeil-Janssen Pharmaceuticals, Inc.;
Pfizer Inc; Shire; and Vanda Pharmaceuticals Inc.
Dr Nasrallah is a consultant/advisor for AstraZeneca;
Janssen, L.P.; Merck; Novartis; Pfizer Inc.; and Sunovion
Pharmaceuticals Inc. He is an investigator for Forest Phar-
maceuticals; Janssen, L.P.; Otsuka; Roche; and Shire. In ad-
dition, Dr Nasrallah has served as a meeting participant/
leader for Genentech, Inc.; Merck; Novartis; and Sun-
ovion Pharmaceuticals Inc. He has also conducted scien-
tific study/trials for Forest Pharmaceuticals; Janssen, L.P.;
Otsuka; and Roche.
Dr Weiden has received grant support from The National
Institute of Mental Health (NIMH); Novartis; Ortho-McNeil-
Janssen, Inc.; and Sunovion Pharmaceuticals Inc. He has
served as a consultant for Biovail Corporation (now Valeant
Pharmaceuticals International, Inc); Bristol-Myers Squibb;
Delpor, Inc.; Genentech, Inc.; Lundbeck; Novartis; and
Ortho-McNeil-Janssen, Inc. He has also served as a speaker
for Merck; Novartis; Ortho-McNeil-Janssen, Inc.; Pfizer Inc;
and Sunovion Pharmaceuticals Inc.
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(N-Methyl-D-aspartate) receptors and be-
lieve it is involved in the clinical symptoms
of schizophrenia.7
Although the exact location of hip-pocampal pathology in schizophrenia is
currently a topic of active research, a post-
mortem study by Benes and colleagues
demonstrated alterations in one particular
regionCA2and in one particular cell
typenonpyramidal cells. The hippocam-
pus is a particularly complex structure,
and this study may also be instructive in
the kind of fine-grained analysis that may
be necessary to reveal functionally signifi-
cant brain alterations in a complex diseasesuch as schizophrenia (Figure 2).8
Functional Brain Abnormalitiesin SchizophreniaIn addition to a variety of structural al-
terations, patients with schizophrenia also
show key functional abnormalities in brain
activation during specific tasks. One such
findinghypofrontalityrefers to the dys-
function in prefrontal brain regions associat-
ed with linguistic and emotional expression,
planning and producing new ideas, and
mediating social interactions. The finding
of insufficient activation in this region was
elegantly illustrated by a classic study con-
ducted by Andreasen and colleagues.9
In this study, the Tower of London
task was used to engage prefrontal brain
function in drug-nave patients with
schizophrenia, nondrug-nave patients
with schizophrenia, and control subjects.
Brain activation was measured with single
photon emission computed tomography
(SPECT) imaging. The Tower of London
task requires shifting balls of varying size
between several pegs until they are ar-
ranged in order of decreasing size. Cerebralperfusion with xenon 133 was measured
during the task with a SPECT scanner.9
During the Tower of London task, the
difference in regional cerebral blood flow
between active and control conditions
increased in all three groups, with drug-
nave patients with schizophrenia show-
ing the highest level of cerebral blood
flow in both the control and active condi-
tions. However, when the regional blood
flow within predefined regions of interestwas compared with overall brain perfu-
sion, control subjects showed the greatest
increase in blood flow in the left mesial
frontal region. Neither drug-nave nor
drug-exposed patients with schizophrenia
showed this increase.9
A more recent study by Horga and col-
leagues correlated brain activation, as
measured by fluorodeoxyglucose positron
emission tomography (FDG-PET), with ac-
tive verbal auditory hallucinations in pa-tients with schizophrenia. This study used
patients with schizophrenia without verbal
auditory hallucinations as a control group,
and all patients were drug-naveallowing
the investigators to examine the neurologic
correlates of the disease of schizophrenia
without the confounding factor of neuro-
leptic treatment. Observations included in-
creases in activity in left superior and middle
temporal gyri and hypoactivation in the bi-
lateral hippocampi (Figure 3, page SA-6).10
Although the
exact locationof hippocampal
pathology in
schizophrenia is
currently a topic of
active research, a
postmortem study by
Benes and colleagues
demonstrated
alterations in one
particular region
CA2and in one
particular cell type
nonpyramidal cells.
Figure 1
Loss of Grey Matter in Patients With Schizophrenia6
Thompson PM, et al. PNAS. 2001;98(20):11650-11655.
Copyright 2001 National Academy of Sciences, U.S.A.
Normal Schizophrenic Difference
Significant, progressive grey matter loss in patients with schizophrenia
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SA-5CurrentPsychiatry.com Supplement to Current Psychiatry | Vol 10, No 9 | October 2011
A Workout for the HippocampusIn contrast to the many studies show-
ing irreparable damage as schizophre-
nia wreaks havoc on the brain, a recent
study reported the positive effects of asimple interventionmoderate exercise
three times a weekon hippocampal
volume in patients with schizophrenia.
In this randomized, controlled study, pa-
tients with schizophrenia and normal
control subjects exercised in a gym for
30 minutes three times a week for a period of
3 months. The nonexercising control groups
of patients with schizophrenia and healthy
volunteers played table foosball for 30 min-
utes three times a week (Figure 4, page SA-7).11
Patients with schizophrenia who exer-
cised experienced hippocampal volume in-
creases of 12% compared with a further 1%
shrinkage among the nonexercising patients.
Healthy subjects who exercised experienced
a 16% increase in hippocampal volume.
Furthermore, changes in hippocampal vol-
ume correlated with improvement in aerobic
fitness, as measured by change in maximum
oxygen consumption. In the schizophre-
nia exercise group (but not in the controls),change in hippocampal volume was as-
sociated with a 35% increase in the ratio of
N-acetylaspartate (NAA; a neuronal marker
in magnetic resonance spectroscopy) to cre-
atine in the hippocampus. Improvement
in test scores for short-term memory in the
combined exercise and nonexercise schizo-
phrenia groups was correlated with change
in hippocampal volume.11
Approaches to Unlocking theGenetics of SchizophreniaOver the last several decades of active re-
search into the genetic causes of schizo-
phrenia, it has become abundantly clear
that schizophrenia is a complex polygenetic
condition.12-14 Certainly, no one gene has
ever been successfully linked with its onset
or treatment. In the meantime, research con-
tinues to look at the influence of candidate
genes on specific symptoms, developmental
trajectories, and pharmacologic outcomes.
Particularly promising areas of schizophre-
nia research, known as pharmacogenomics,
combine genetic information with pharma-
cologic treatment and evaluate genetic cor-
relates with functional neuroimaging.
Given the importance of dopamine for
the pathophysiology of schizophrenia,
much research has been devoted to exam-
ining genes related to dopamine transport,connectivity, or signal transduction. For
example, the catechol-O-methyltransferase
(COMT) gene is by far the most frequently
studied in association with schizophrenia.
COMT degrades catecholamine, including
dopamine, and has been linked to an in-
creased risk of psychosis. It is particularly
concentrated in the extrasynaptic spaces of
the prefrontal cortex and hippocampus
two areas shown to sustain damage in pa-
tients with schizophrenia.15,16
Figure 2
Scatterplot of Hippocampal Neurons in the StratumPyramidale8
P=0.037
A scattergram plot of the x,y coordinates of every pyramidal neuron (upper panel) and
nonpyramidal neuron (lower panel) in the stratum pyramidale of sectors CA14 in thehippocampal formation of a normal control (left) and schizophrenic (right) subject. There
was on average approximately 2000 pyramidal neurons (small dots) and 200 nonpyramidal
neurons (filled circles) throughout the cornu ammonis subfields of the subjects in both groups.
Benes FM, et al. Biol Psychiatry. 1998;44:88-97. 1998 Society of Biological Psychiatry.
CA2 CA2
CA2 CA2
It has become
abundantly clear that
schizophrenia is a
complex polygenetic
condition.
Control Schizophrenic
Pyramidal Pyramidal
Nonpyramidal Nonpyramidal
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SA-6 October 2011 | Vol 10, No 9 | Supplement to Current Psychiatry
Other genes related to dopamine func-
tioning currently under investigation in
schizophrenia areto name a fewDRD2,
which encodes the dopamine receptors
D2 subtype and enhances engagement of
prefrontal-striatal pathways; RGSR, which
encodes the RGS protein, which is thought
to modulate postsynaptic dopamine sig-
nal transduction via G alpha-GTP binding;
PPP1R1B, which encodes the dopamine-and cAMP-regulated phosphoprotein of
molecular weight 32 kDa (DARPP-32),
which is a key integrator of information
in dopaminoceptive neurons; and AKT1,
which encodes the AKT1 protein putatively
involved in signal transduction in the non-
canonical dopaminergic pathway.17-20
As the disease of schizophrenia becomes
better understood, genes related to other
neurotransmitters are receiving more atten-
tion. Dysbindin is one example. It is a pro-tein whose gene is located at chromosome
6p22.3, one of the most promising suscep-
tibility loci in schizophrenia linkage stud-
ies. In one animal study, overexpression
of dysbindin increased extracellular basal
glutamate levels and release of glutamate.
Conversely, dysbindin protein knockout re-
duced the release of glutamate, suggesting
that dysbindin may affect glutamate release
by upregulating molecules in presynaptic
machinery.21
Other approaches to understanding the
genetic basis of schizophrenia include identi-
fication of genes through genome-wide asso-
ciation studies and investigation of epistatic
relationships.15
Research examining the roleof genetics in determining response to anti-
psychotics has yielded practical clinical in-
formation about potential dose adjustments
and side effects modulated via CYP enzyme
metabolization.22
As a clinical and neuropathologic entity,
schizophrenia currently may be as difficult
to characterize as it is to treat. However, all of
its complexities and challenges also provide
enticement for researchers and clinicians
who work at the forefront of psychiatry, andwho uncover new aspects of this disease on
a regular basis.
Clinical Challenges in theTreatment of SchizophreniaThe disease of schizophrenia is associated
with severe disabilities and poses numer-
ous treatment challenges. Research con-
ducted by the World Health Organization,
the World Bank, and the Harvard School of
Public Health demonstrated that among de-veloped regions schizophrenia ranks fourth
in diseases contributing to global burden of
disease for ages 15 through 44 years.23 These
years are typically the most productive for
individuals and their contributions to so-
ciety, so the personal and societal costs of
schizophrenia must be appreciated in this
context.24
Both patients with schizophrenia and the
clinicians who treat them face substantial
challenges. A large majority of patients withschizophrenia are unable to maintain inde-
pendent living or gainful employment for
any significant period of time after the onset
of illness. The onset of schizophrenia is usu-
ally during adolescence, when individuals
normally are beginning to achieve a firm
sense of self, establish enduring relation-
ships, and make productive contributions
to society. Even during quiescent periods of
the illness, patients continue to experience
social disturbances that severely limit their
COMT degrades
catecholamine,
including dopamine,
and has been linked
to an increased risk
of psychosis.
Figure 3
Activation During Auditory Verbal Hallucinations10
Brain regions showing differences in relative glucose metabolic rate (rGMR) in patients
with schizophrenia with auditory verbal hallucinations (multivariate analysis using partialleast squares).
Horga G, et al.J Psychiatry Neurosci. 2011. doi: 10.1503/jpn.100085. [Epub ahead of print.]
2011 Canadian Medical Association.
A2
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SA-7CurrentPsychiatry.com Supplement to Current Psychiatry | Vol 10, No 9 | October 2011
capacity for recovery and integration into
the community.24
Several factors contribute to the disease
burden in schizophrenia, including persist-
ing symptom burden, comorbid substanceabuse, poor social skills, and unsupportive
family and community environments.25
For these and other reasons, many pa-
tients with schizophrenia are nonadherent
with pharmacotherapy, which can lead
to poor outcomes, including relapse and
hospitalization.26,27
In 2005, Andreasen and colleagues chal-
lenged the field of psychiatry by propos-
ing a consensus definition of remission
in schizophrenia, suggesting, althoughthere is no cure, that this outcome is pos-
sible even in such a difficult population.
This consensus definition of remission re-
quires scores of mild or less for a period
of 6 or more months on select items of the
Brief Psychiatric Rating Scale (BPRS), the
Positive and Negative Syndrome Scale
(PANSS), the Scale for the Assessment of
Negative Symptoms (SANS), and the Scale
for the Assessment of Positive Symptoms
(SAPS).28
This definition did spur muchfurther research, but reported rates of re-
mission have been varied (no higher than
38% in recent studies).29,30
A Shift in Clinical ConcernIn addition to challenges to effective treat-
ment, the management of side effects
has been of paramount importance since
atypical antipsychotics were introduced.
At that time, the side effects of great-
est concern to clinicians were the extra-pyramidal symptoms (EPS) and tardive
dyskinesia (TD) thought to be associated
with the more typical antipsychotics.
Although these particular issues are still
important, the use of atypical antipsy-
chotics has increased the focus on other
adverse events (Figure 5, page SA-8); those
of great concern to clinicians include coro-
nary heart disease, diabetes, hyperlipid-
emia, insulin resistance, weight change,
and elevated glucose.31,32
Elevated cardiovascular risk factors
in patients with schizophrenia include
elevated body-mass index, smoking,
diabetes, hypertension, and metabolic
syndrome.33-35 It should be noted, how-
ever, that metabolic disturbances in pa-
tients with schizophrenia are not solely
the result of treatment with antipsychotic
agents, as some increased risk factors were
documented in this population before theadvent of antipsychotics as well as in treat-
ment-nave patients.31
The consequences of increased metabolic
and cardiovascular risk factors in patients
with schizophrenia are severe. Compared
with the general population, patients with
schizophrenia die as many as 30 years
earlier.36,37 Heart disease is the most com-
mon cause of death in this population.36
In addition to increased metabolic and
cardiovascular risk factors, patients with
Figure 4
Hippocampal Plasticity in Response to Exercise11
Metabolic
disturbances
in patients with
schizophrenia
are not solely the
result of treatment
with antipsychotic
agents.
T1-weighted magnetic resonance images in the sagittal and coronal plane, with the
right hippocampus marked in blue, comparing baseline (A and B) and endpoint (C
and D) of the patient in the schizophrenia exercise group with the largest increase inhippocampal volume (from 3.898 cm3 to 4.667 cm3; +19.7%).
Pajonk F-G, et al.Arch Gen Psychiatry. 2010;67(2):133-143. 2010 American Medical
Association. All Rights Reserved.
A B
C D
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SA-8 October 2011 | Vol 10, No 9 | Supplement to Current Psychiatry
schizophrenia also have a higher burden of
medical illness.38,39
Unfortunately, despite the elevated riskfactors and poor outcomes from comorbid
cardiovascular and metabolic illnesses, pa-
tients with schizophrenia receive very little
treatment for these disorders. In 2009, the
UNITE survey found that many psychia-
trists who treat patients with schizophrenia
do not follow guidelines for the monitoring
of cardiovascular and metabolic disorders.
Thus, according to this study, only 30% of
patients with schizophrenia reported ever
having been weighed, and only 12% report-ed ever having had their waist measured.40
Both patients with schizophrenia and their
psychiatrists face significant challenges when
it comes to treating the disorder and caring
for the individuals overall physical health.
Adherence Considerations:Scope of the ProblemWhile nonadherence, or noncompliance,
with pharmacotherapy is a common prob-
lem in medicine, the rate of compliance in
psychiatric patients is lower than in pa-
tients with physical disorders. A study by
Cramer and colleagues found that, on aver-
age, patients receiving antipsychotics took
approximately 58% of the recommendedamount of medication, whereas patients
with physical disorders took 76%.41 In the
treatment of schizophrenia, nonadherence
presents a particularly challenging barrier
to improving patient outcomes, because
some elements of the disease itselfsuch
as poor insightcontribute to a lack of
adherence.26
Expert consensus clinical guidelines
published in 2003 reported the surveyed re-
sponses of nearly 50 well-known researchersregarding the definition and rates of nonad-
herence in patients with schizophrenia. The
authors of the study defined noncompliance
in the following way42:
Compliant: misses 80% of
medication
According to the above definition, the
experts estimated that 43% of their patientswere compliant. However, the average rate
of compliance in the research literature is
only 28%. The survey summary leading to
the expert consensus guidelines demon-
strates that even experts in schizophrenia
may overestimate compliance in their pa-
tients, and that definitions of compliance
may vary considerably.
Nonadherence in patients with schizo-
phrenia begins early and increases with
time. Velligan and colleagues describedtheir experience with the first 68 patients re-
cruited into a 5-year study of adherence in
patients with schizophrenia.43 During the
first 2 weeks after hospital discharge, 25% of
patients with schizophrenia, including those
living in group homes, missed one or more
doses of antipsychotic medications. This rate
of nonadherence was demonstrated even
under close supervision (staff monitoring,
pill counts, and blood-level analysis). Home
visits by the investigators revealed numer-
Even experts in
schizophrenia
may overestimate
compliance in their
patients.
EPS=extrapyramidal symptoms; TD=tardive dyskinesia.
Nasrallah HA, Smeltzer DJ. Contemporary Diagnosis and Management of the Patient
With Schizophrenia. Newtown, PA: Handbooks in Health Care; 2003.
Young AS, et al. Schizophr Bull. 2010;36:732-739.
Shift in Concerns With Side-Effect Profile31,32
Figure 5
Side effects of greater
historical concern
Side effects of greater
current concern
EPS and TD
CoronaryHeart Disease
EPS and TD
ElevatedGlucose
InsulinResistance
WeightGain
Diabetes
Hyperlipidemia
WeightGain
CHD
Hyper-lipidemia
ElevatedGlucose
InsulinResistance
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SA-9CurrentPsychiatry.com Supplement to Current Psychiatry | Vol 10, No 9 | October 2011
ous barriers to adherence, including poor
understanding of drug regimen and the roles
of prior and current medications, as well as
chaotic living arrangements.43 A review of
the literature regarding outpatient nonad-herence in patients with schizophrenia noted
that, by 1 year after hospital discharge, non-
adherence rates rose to at least 50%, and by
2 years after discharge, to at least 75%.44
From the clinicians perspective, the per-
ception of good adherence in their practice
may not be consistent with the reality that
many patients who seem adherent are in
fact not. It is difficult to predict which pa-
tients are going to take their medications
as prescribed. Clinicians usually base theirassessment of adherence on patient re-
ports and apparent clinical state. However,
it is not always the case that, if a patient is
in a good clinical state, he or she is adher-
ent. This example of backward reasoning
(ie, the patient is better so he/she must be taking
the medication as prescribed) can have a signifi-
cant consequence on prescribing behavior.
The Consequences of
NonadherencePoor adherence to antipsychotic medica-
tions can contribute to a vicious cycle of
poor outcomes for patients with schizo-
phrenia. Within 3 to 10 months of discon-
tinuing their medication, approximately
50% of patients experience a relapse.45-47
In a meta-analysis of published studies of
antipsychotic medication discontinuation
in patients with schizophrenia (N=1,006),
time-to-relapse, and indicator of clinical
stability, deteriorated markedly within 3 to6 months (Figure 6). Risk of relapse reached
25% within 10.2 weeks and 50% within
30.3 weeks.45 In a study by Morken and col-
leagues, patients who were not adherent to
oral antipsychotics (those with more than
1 month of missed medications) relapsed
at a rate of 64% compared with 11% for pa-
tients who remained adherent.47
The impact of nonadherence on outcome
cuts across different phases of illness. In re-
cently diagnosed first-episode patients,
where adherence was carefully tracked over
follow-up, Subotnick and colleagues dem-
onstrated that periods of partial adherence
(50%75% of prescribed dosage) and rela-
tively brief periods (24 weeks) of partial orfull nonadherence with oral antipsychotic
therapy put patients with schizophrenia
at significant risk for relapse (hazard ratio,
3.728.5).48
Even relatively smaller medication gaps in
otherwise stable patients with schizophrenia
can have a noticeable impact on the likeli-
hood of relapse. In a pharmacy refill study
of Medicaid patients with schizophrenia
chosen for their relative stability during the
previous year, a study by Weiden and col-leagues demonstrated that, in patients with
schizophrenia with partial adherence to oral
antipsychotic therapy, the length of the ther-
apy gap predicted rehospitalization(Figure 7,
page SA-10).49
In addition to directly affecting patient
outcomes by allowing psychotic symptoms
to continue unabated, nonadherence has sev-
eral indirect but deleterious effects. The 2009
consensus guidelines that addressed the
problem of nonadherence in patients with
Even relatively
smaller medication
gaps in otherwise
stable patients with
schizophrenia can
have a noticeable
impact on the
likelihood of relapse.
Computed survival functions based on findings from studies that discontinuedmaintenance oral neuroleptic drugs in patients with schizophrenia. Data are thepercentage of patients whose conditions remained stable vs the weeks after the
abrupt stoppage of treatment (n=1006). Dashed lines indicate 95% confidenceintervals. Inset: time to a 50% relapse risk (7.5 months).
Viguera AC, et al.Arch Gen Psychiatry. 1997;54:49-55. 1997 American Medical Association.
All Rights Reserved.
Clinical Stability in Patients With Schizophrenia WhoDiscontinued Oral Medication45
Figure 6
100
90
80
70
60
50
40
30
20
100
90
80
70
60
50
%R
emainingstable
%Remainingstable
Weeks after stopping oral neuroleptic therapy abruptly
Weeks after stopping neuroleptic therapy
Time to 50% risk
0
0 4 8 12 16 20 24 28 32
24 48 72 96 120 144 168 192
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schizophrenia summarized the research lit-
erature on this topic. Incorrect inferences by
the clinician can result in inappropriate treat-
ment plans for the patient. When a patient
appears to not respond to treatment with a
particular agent, the psychiatrist may con-
clude that the patient needs augmentation or
switching, whereas the poor response may
be due to the patient simply not taking his orher medication.27
It is also important to consider the effect
that nonadherence can have on the physi-
cian/patient relationship. If the psychiatrist
approaches adherence as a type of behavior
in which the patient obeys the clinician,
the therapeutic relationship may be dam-
aged, leading to potential further negative
repercussions for the patients treatment.27
Patient and clinician responses to factors
that affect adherence can differ considerably.As shown in Figure 8, when a potentially
troublesome side effect emerges, the patient
can experience acute distress and respond
by reducing adherence to the antipsychotic
regimen. The clinician may focus more on
the objective severity of the side effect rather
than on the subjective distress it causes the
patient. The clinicians behavior typically is
motivated by evaluating the safety concern
that the particular side effect poses, rather
than how much it interferes with the pa-
tients life. Because the patients subjective
experience can affect adherence, it is impor-
tant for clinicians to also take both objective
safety and subjective distress very seriously
in overall pharmacologic management.50
Strategies for ImprovingAdherenceNumerous strategies have been proposed
for improving adherence to treatment in pa-
tients with schizophrenia. In 2003, Dolder
and colleagues reviewed the recent litera-
ture to evaluate which interventions were
most successful. They concluded that, of
the psychosocial interventions using a sin-
gle approach, educational strategies wereleast successful. The most successful strate-
gies used a combination of educational, af-
fective, and behavioral approaches. These
combined approaches also were more
likely to improve secondary outcomes (eg,
medication knowledge, insight into treat-
ment, hospitalization, psychopathology,
and functioning) in addition to adherence
to antipsychotic therapy. Interventions that
led to improvements in adherence tended
to be of longer duration and performed ina group setting, demonstrating the impor-
tance of sufficient intensity and length of
therapy as well as a large enough sample
size for evaluation.51
As with pharmacologic interventions
with antipsychotics, matching behavioral
interventions to increase adherence with
pharmacotherapy to the needs of specific
patients is desirable. Different factors af-
fecting adherence require different inter-
ventions by the clinician. For example,if a patient has an unfavorable attitude
toward taking or staying on medication,
it is important to: routinely assess adher-
ence; emphasize the therapeutic alliance;
use a patient-centered approach, starting
with the patients point of view; and stay
symptom-focused rather than relying on
the disease-model of interaction, in which
the clinician lectures the patient. Specific
interventions include: cognitive-behavioral
therapy (CBT) to emphasize working on
Risk for Rehospitalization Increases With Lengthof Therapy Gap49
Figure 7
25
20
15
10
5
0
%P
atientsrehospitalized
Maximum therapy gap, days within 1 year
0
6
1-10
12
11-30
16
>30
22
It is important for
clinicians to also
take both objective
safety andsubjective
distress very
seriously in overall
pharmacologic
management.
Weiden PJ, et al. Psychiatr Serv. 2004;55:886-891. Adapted with permission from PsychiatricServices (Copyright 2004). American Psychiatric Association.
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SA-11CurrentPsychiatry.com Supplement to Current Psychiatry | Vol 10, No 9 | October 2011
problems as identified by the patient rather
than the clinician; motivational interview-
ing to help facilitate motivation for positive
change; and family intervention to help ed-
ucate and motivate family members in en-couraging ongoing medication adherence.
In fact, involving family members in treat-
ment and offering family psychoeducation
may encourage adherence and reduce hos-
pitalizations and relapses.52
It is also important to appreciate the po-
tential role of persistent symptoms as bar-
riers to adherence and to address them not
only with pharmacotherapy but also with
effective behavioral interventions. Likewise,
many patients have environmental barriersto adherence, such as difficulty remember-
ing to take medication without supervision,
getting to appointments, and refilling pre-
scriptions. Interventions such as cognitive
adaptation training (CAT) may be helpful
in addressing these barriers, together with
good case management.52
Although adherence is driven by multiple
factors, recent research provides some guid-
ance for understanding and addressing this
complex component of improved outcomesin patients with schizophrenia.
Acknowledgement
The faculty wish to acknowledge Katia Zalkind,
MS, for her contributions to this manuscript.
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Many patients haveenvironmental
barriers to adherence,
such as difficulty
remembering to take
medication without
supervision.
An Example of How Patient and Clinician ResponsesMay Differ50
Figure 8
Inuenci
ngpatien
trespons
e
Inuencingclinicianresponse
Reverberations from side effects
Side Effect
Appears
Subjective
Distress
Objective
Severity
Adherence
Impact
Safety and
Risk
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