SUPPLEMENT TO

Available at CurrentPsychiatry.com
A Q U A d r A N T H E A LT H c O M P U b L i c AT i O N

October 2011

Understanding the Complexities of Schizophrenia

A Supplement based on the Satellite Symposium Presented at A AcP 2011

Associate Clinical Professor Department of Psychiatry Washington University School of Medicine St. Louis, Missouri

Gregory W. Mattingly, MD

Program Moderator Professor of Psychiatry and Neuroscience University of Cincinnati Director, Schizophrenia Program UC Health University Hospital Cincinnati, Ohio

Henry A. Nasrallah, MD

Professor of Psychiatry Director, Psychotic Disorders Program University of Illinois Medical Center Chicago, Illinois

Peter J. Weiden, MD

This supplement is sponsored by

is a registered trademark of Dainippon Sumitomo Pharma Co., Ltd. Sunovion Pharmaceuticals Inc. is a U.S. subsidiary of Dainippon Sumitomo Pharma Co., Ltd. 2011 Sunovion Pharmaceuticals Inc. All rights reserved. 9/11 LUR519-11

Understanding the Complexities of Schizophrenia

A Precipitous Decline
Schizophrenia 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 series of acute episodes and relapses, during which symptoms persist and often worsen over time.1-3 The damage associated with schizophrenia begins during or even before the prodromal period and appears to continue throughout the course of the disease. However, the first 5 to 10 years after diagnosis appear to be particularly destructive to brain tissue.4

Gregory W. Mattingly, MD
Associate Clinical Professor Department of Psychiatry Washington University School of Medicine St Louis, Missouri

Henry A. Nasrallah, MD

Professor of Psychiatry and Neuroscience University of Cincinnati College of Medicine Director, Schizophrenia Program UC Health University Hospital Cincinnati, Ohio

Peter J. Weiden, MD

Structural Brain Abnormalities in Schizophrenia

Structural 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 cortex of the parahippocampal gyrus, superior temporal gyrus, and anterior cingulate gyrus. Abnormalities in prefrontal white matter may underlie an altered connection between the prefrontal cortex and anterior cingulate 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 patterns of 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 limitation 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 memories. The roles for the hippocampus postulated in schizophrenia are varied. Some investigators attribute memory impairments in schizophrenia to hippocampal pathology. Others cite its high concentration of NMDA
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Professor of Psychiatry Director, Psychotic Disorders Program University of Illinois Medical Center Chicago, Illinois Disclosures

Dr Mattingly receives research support from Astra Zeneca; Ayerst; Dainippon Sumitomo Pharma Co. Ltd.; Forest Laboratories, Inc.; GlaxoSmithKline; Janssen; Johnson & 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 Pharmaceuticals; 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 Pharmaceuticals; Janssen, L.P.; Otsuka; Roche; and Shire. In addition, Dr Nasrallah has served as a meeting participant/ leader for Genentech, Inc.; Merck; Novartis; and Sunovion Pharmaceuticals Inc. He has also conducted scientific 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-McNeilJanssen, 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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Figure 1

Loss of Grey Matter in Patients With Schizophrenia6

Normal Schizophrenic Difference

Significant, progressive grey matter loss in patients with schizophrenia

Thompson PM, et al. PNAS. 2001;98(20):11650-11655. Copyright 2001 National Academy of Sciences, U.S.A.

Although the exact location of 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.

(N-Methyl-D-aspartate) receptors and believe it is involved in the clinical symptoms of schizophrenia.7 Although the exact location of hippocampal pathology in schizophrenia is currently a topic of active research, a postmortem study by Benes and colleagues demonstrated alterations in one particular regionCA2and in one particular cell typenonpyramidal cells. The hippocampus 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 significant brain alterations in a complex disease such as schizophrenia (Figure 2).8

Functional Brain Abnormalities in Schizophrenia

In addition to a variety of structural alterations, patients with schizophrenia also show key functional abnormalities in brain activation during specific tasks. One such findinghypofrontalityrefers to the dysfunction in prefrontal brain regions associated 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 conducted 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 arranged in order of decreasing size. Cerebral perfusion 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 drugnave patients with schizophrenia showing the highest level of cerebral blood flow in both the control and active conditions. However, when the regional blood flow within predefined regions of interest was compared with overall brain perfusion, 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 colleagues correlated brain activation, as measured by fluorodeoxyglucose positron emission tomography (FDG-PET), with active verbal auditory hallucinations in patients 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 neuroleptic treatment. Observations included increases in activity in left superior and middle temporal gyri and hypoactivation in the bilateral hippocampi (Figure 3, page SA-6).10

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A Workout for the Hippocampus

In contrast to the many studies showing irreparable damage as schizophrenia wreaks havoc on the brain, a recent study reported the positive effects of a simple interventionmoderate exercise three times a weekon hippocampal volume in patients with schizophrenia. In this randomized, controlled study, patients 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 minutes three times a week (Figure 4, page SA-7).11 Patients with schizophrenia who exercised experienced hippocampal volume increases 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 volume correlated with improvement in aerobic fitness, as measured by change in maximum oxygen consumption. In the schizophrenia exercise group (but not in the controls), change in hippocampal volume was associated with a 35% increase in the ratio of N-acetylaspartate (NAA; a neuronal marker in magnetic resonance spectroscopy) to creatine in the hippocampus. Improvement in test scores for short-term memory in the combined exercise and nonexercise schizophrenia groups was correlated with change in hippocampal volume.11

Figure 2

Scatterplot of Hippocampal Neurons in the Stratum Pyramidale8

Control Schizophrenic

CA2

CA2

Pyramidal

Pyramidal

CA2

CA2

Nonpyramidal

Nonpyramidal

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 the hippocampal 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.

Approaches to Unlocking the Genetics of Schizophrenia

Over the last several decades of active research into the genetic causes of schizophrenia, 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 continues to look at the influence of candidate genes on specific symptoms, developmental trajectories, and pharmacologic outcomes.
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Particularly promising areas of schizophrenia research, known as pharmacogenomics, combine genetic information with pharmacologic treatment and evaluate genetic correlates with functional neuroimaging. Given the importance of dopamine for the pathophysiology of schizophrenia, much research has been devoted to examining 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 increased risk of psychosis. It is particularly concentrated in the extrasynaptic spaces of the prefrontal cortex and hippocampus two areas shown to sustain damage in patients with schizophrenia.15,16

It has become abundantly clear that schizophrenia is a complex polygenetic condition.

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Figure 3

Activation During Auditory Verbal Hallucinations

A2

10

Brain regions showing differences in relative glucose metabolic rate (rGMR) in patients with schizophrenia with auditory verbal hallucinations (multivariate analysis using partial least squares).
Horga G, et al. J Psychiatry Neurosci. 2011. doi: 10.1503/jpn.100085. [Epub ahead of print.] 2011 Canadian Medical Association.

COMT degrades catecholamine, including dopamine, and has been linked to an increased risk of psychosis.

Other genes related to dopamine functioning 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 signal transduction via G alpha-GTP binding; PPP1R1B, which encodes the dopamineand 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 noncanonical dopaminergic pathway.17-20 As the disease of schizophrenia becomes better understood, genes related to other neurotransmitters are receiving more attention. Dysbindin is one example. It is a protein whose gene is located at chromosome 6p22.3, one of the most promising susceptibility loci in schizophrenia linkage studies. In one animal study, overexpression of dysbindin increased extracellular basal glutamate levels and release of glutamate. Conversely, dysbindin protein knockout reduced 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 identification of genes through genome-wide association studies and investigation of epistatic relationships.15 Research examining the role of genetics in determining response to antipsychotics has yielded practical clinical information 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, and who uncover new aspects of this disease on a regular basis.

Clinical Challenges in the Treatment of Schizophrenia

The disease of schizophrenia is associated with severe disabilities and poses numerous treatment challenges. Research conducted by the World Health Organization, the World Bank, and the Harvard School of Public Health demonstrated that among developed 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 society, 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 with schizophrenia are unable to maintain independent living or gainful employment for any significant period of time after the onset of illness. The onset of schizophrenia is usually during adolescence, when individuals normally are beginning to achieve a firm sense of self, establish enduring relationships, and make productive contributions to society. Even during quiescent periods of the illness, patients continue to experience social disturbances that severely limit their

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capacity for recovery and integration into the community.24 Several factors contribute to the disease burden in schizophrenia, including persisting symptom burden, comorbid substance abuse, poor social skills, and unsupportive family and community environments.25 For these and other reasons, many patients with schizophrenia are nonadherent with pharmacotherapy, which can lead to poor outcomes, including relapse and hospitalization.26,27 In 2005, Andreasen and colleagues challenged the field of psychiatry by proposing a consensus definition of remission in schizophrenia, suggesting, although there is no cure, that this outcome is possible even in such a difficult population. This consensus definition of remission requires 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 much further research, but reported rates of remission have been varied (no higher than 38% in recent studies).29,30

Figure 4

Hippocampal Plasticity in Response to Exercise11

A B

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 in hippocampal 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 Shift in Clinical Concern

In addition to challenges to effective treatment, the management of side effects has been of paramount importance since atypical antipsychotics were introduced. At that time, the side effects of greatest concern to clinicians were the extrapyramidal 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 antipsychotics has increased the focus on other adverse events (Figure 5, page SA-8); those of great concern to clinicians include coronary heart disease, diabetes, hyperlipidemia, insulin resistance, weight change, and elevated glucose.31,32
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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, however, that metabolic disturbances in patients with schizophrenia are not solely the result of treatment with antipsychotic agents, as some increased risk factors were documented in this population before the advent of antipsychotics as well as in treatment-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 common cause of death in this population.36 In addition to increased metabolic and cardiovascular risk factors, patients with

Metabolic disturbances in patients with schizophrenia are not solely the result of treatment with antipsychotic agents.

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Figure 5

Shift in Concerns With Side-Effect Profile31,32

Side effects of greater historical concern Side effects of greater current concern

Diabetes Weight Gain

EPS and TD

Insulin Resistance
Weight Gain Insulin Resistance CHD Elevated Glucose Hyperlipidemia

Elevated Glucose

Hyperlipidemia

EPS and TD Coronary Heart Disease

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.

Even experts in schizophrenia may overestimate compliance in their patients.

schizophrenia also have a higher burden of medical illness.38,39 Unfortunately, despite the elevated risk factors and poor outcomes from comorbid cardiovascular and metabolic illnesses, patients with schizophrenia receive very little treatment for these disorders. In 2009, the UNITE survey found that many psychiatrists 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% reported 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 Problem

While nonadherence, or noncompliance, with pharmacotherapy is a common problem in medicine, the rate of compliance in

psychiatric patients is lower than in patients with physical disorders. A study by Cramer and colleagues found that, on average, patients receiving antipsychotics took approximately 58% of the recommended amount 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 responses of nearly 50 well-known researchers regarding the definition and rates of nonadherence in patients with schizophrenia. The authors of the study defined noncompliance in the following way42: Compliant: misses <20% of medication Partially compliant: misses 20%80% of medication Noncompliant: misses >80% of medication According to the above definition, the experts estimated that 43% of their patients were compliant. However, the average rate of compliance in the research literature is only 28%. The survey summary leading to the expert consensus guidelines demonstrates that even experts in schizophrenia may overestimate compliance in their patients, and that definitions of compliance may vary considerably. Nonadherence in patients with schizophrenia begins early and increases with time. Velligan and colleagues described their experience with the first 68 patients recruited 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-

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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 nonadherence in patients with schizophrenia noted that, by 1 year after hospital discharge, nonadherence rates rose to at least 50%, and by 2 years after discharge, to at least 75%.44 From the clinicians perspective, the perception 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 patients are going to take their medications as prescribed. Clinicians usually base their assessment of adherence on patient reports 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 adherent. This example of backward reasoning (ie, the patient is better so he/she must be taking the medication as prescribed) can have a significant consequence on prescribing behavior.

Figure 6

Clinical Stability in Patients With Schizophrenia Who Discontinued Oral Medication45

% Remaining stable

100 90 % Remaining stable 80 70 60 50 40 30 20 0 24

100 90 80 70 60 50 0 4 8 12 16 20 24 28 Weeks after stopping neuroleptic therapy 32 Time to 50% risk

48 72 96 120 144 168 Weeks after stopping oral neuroleptic therapy abruptly

192

Computed survival functions based on findings from studies that discontinued maintenance oral neuroleptic drugs in patients with schizophrenia. Data are the percentage of patients whose conditions remained stable vs the weeks after the abrupt stoppage of treatment (n=1006). Dashed lines indicate 95% confidence intervals. 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.

The Consequences of Nonadherence

Poor adherence to antipsychotic medications can contribute to a vicious cycle of poor outcomes for patients with schizophrenia. Within 3 to 10 months of discontinuing 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 to 6 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 colleagues, 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 patients who remained adherent.47 The impact of nonadherence on outcome cuts across different phases of illness. In recently diagnosed first-episode patients,
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where adherence was carefully tracked over follow-up, Subotnick and colleagues demonstrated that periods of partial adherence (50%75% of prescribed dosage) and relatively brief periods (24 weeks) of partial or full 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 likelihood 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 colleagues demonstrated that, in patients with schizophrenia with partial adherence to oral antipsychotic therapy, the length of the therapy 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 several 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.

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Figure 7

Risk for Rehospitalization Increases With Length of Therapy Gap49

% Patients rehospitalized 25 20 15 10 5 0 0 1-10 11-30 >30 6 12 16 22

tients life. Because the patients subjective experience can affect adherence, it is important for clinicians to also take both objective safety and subjective distress very seriously in overall pharmacologic management.50

Strategies for Improving Adherence

Numerous strategies have been proposed for improving adherence to treatment in patients with schizophrenia. In 2003, Dolder and colleagues reviewed the recent literature to evaluate which interventions were most successful. They concluded that, of the psychosocial interventions using a single approach, educational strategies were least successful. The most successful strategies used a combination of educational, affective, and behavioral approaches. These combined approaches also were more likely to improve secondary outcomes (eg, medication knowledge, insight into treatment, 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 in a group setting, demonstrating the importance 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 affecting adherence require different interventions by the clinician. For example, if a patient has an unfavorable attitude toward taking or staying on medication, it is important to: routinely assess adherence; 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

Maximum therapy gap, days within 1 year

Weiden PJ, et al. Psychiatr Serv. 2004;55:886-891. Adapted with permission from Psychiatric Services (Copyright 2004). American Psychiatric Association.

It is important for clinicians to also take both objective safety and subjective distress very seriously in overall pharmacologic management.

schizophrenia summarized the research literature on this topic. Incorrect inferences by the clinician can result in inappropriate treatment plans for the patient. When a patient appears to not respond to treatment with a particular agent, the psychiatrist may conclude that the patient needs augmentation or switching, whereas the poor response may be due to the patient simply not taking his or her medication.27 It is also important to consider the effect that nonadherence can have on the physician/patient relationship. If the psychiatrist approaches adherence as a type of behavior in which the patient obeys the clinician, the therapeutic relationship may be damaged, 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-

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problems as identified by the patient rather than the clinician; motivational interviewing to help facilitate motivation for positive change; and family intervention to help educate and motivate family members in encouraging ongoing medication adherence. In fact, involving family members in treatment and offering family psychoeducation may encourage adherence and reduce hospitalizations and relapses.52 It is also important to appreciate the potential role of persistent symptoms as barriers to adherence and to address them not only with pharmacotherapy but also with effective behavioral interventions. Likewise, many patients have environmental barriers to adherence, such as difficulty remembering to take medication without supervision, getting to appointments, and refilling prescriptions. 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 guidance for understanding and addressing this complex component of improved outcomes in patients with schizophrenia. Acknowledgement The faculty wish to acknowledge Katia Zalkind, MS, for her contributions to this manuscript.
References
1. Lieberman JA. Atypical antipsychotic drugs as a first-line treatment of schizophrenia: a rationale end hypothesis. J Clin Psychiatry. 1996;57(suppl 11):68-71. 2. Lieberman J, Jody D, Geisler S, et al. Time course and biologic correlates of treatment response in first-episode schizophrenia. Arch Gen Psych. 1993;50:369-376. 3. Lewis DA, Lieberman JA. Catching up on schizophrenia: natural history and neurobiology. Neuron. 2000;28: 325-334. 4. Lieberman JA, Perkins D, Belger A, et al. The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches. Biol Psychiatry. 2001;50:884-897. 5. Carpenter WT, Buchanan RW. Schizophrenia. N Engl J Med. 1994;330(10):681-690. 6. Thompson PM, Vidal C, Giedd JN, et al. Mapping adolescent brain change reveals dynamic wave of accelerated grey matter loss in very early-onset schizophrenia. PNAS. 2001; 98(20):11650-11655. 7. Heckers S, Conradi C. Hippocampal pathology in schizophrenia. Curr Top Behav Neurosci. 2010;4:529-553. 8. Benes FM, Kwok EW, Vincent SL, Todtenkopf MS. A reduction of nonpyramidal cells in sector CA2 of

Figure 8

An Example of How Patient and Clinician Responses May Differ50

Reverberations from side effects

enc In u

in

tien g pa

t res

pons

Subjective Distress Side Effect Appears Objective Severity

In u encin g clin

Adherence Impact

ician

Safety and Risk

resp o nse

Weiden PJ, Buckley PF. J Clin Psychiatry. 2007;68(suppl 6):14-23.

schizophrenics and manic depressives. Biol Psychiatry. 1998; 44:88-97. 9. Andreasen NC, Rezai K, Alliger R, et al. Hypofrontality in neuroleptic nave patients and in patients with chronic schizophrenia: assessment with xenon 133 single-photon emission computed topography and the Tower of London. Arch Gen Psychiatry. 1992;49(12):943-958. 10. Horga G, Parellada E, Lomea F, et al. Differential brain glucose metabolic patterns in antipsychotic-nave firstepisode schizophrenia with and without auditory verbal hallucinations. J Psychiatry Neurosci. 2011. doi: 10.1503/ jpn.100085. [Epub ahead of print.] 11. Pajonk F-G, Wobrock T, Gruber O, et al. Hippocampal plasticity in response to exercise in schizophrenia. Arch Gen Psychiatry. 2010;67(2):133-143. 12. Harrison PJ, Owen MJ. Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet. 2003; 361:417-419. 13. Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry. 2005;10:40-68. 14. Norton N, Williams HJ, Owen MJ. An update on the genetics of schizophrenia. Curr Opin Psychiatry. 2006;19:158-164. 15. Meyer-Lindenberg A. Translational research. Imaging genetics of schizophrenia. Dialogues Clin Neurosci. 2010; 12:449-456. 16. Gogos JA, Morgan M, Luine V, et al. Catechol-Omethyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc Natl Acad Sci U S A. 1998;95:9991-9996. 17. Bertolino A, Fazio L, Caforio G, et al. Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia. Brain. 2009;132:417-425. 18. Buckholtz JW, Meyer-Lindenberg A, Honea RA, et al. Allelic variation in RGS4 impacts functional and structural connectivity in the human brain. J Neurosci. 2007;27: 1584-1593. 19. Meyer-Lindenberg A, Straub RE, Lipska BK, et al. Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition. J Clin Invest. 2007;117: 672-682.

Many patients have environmental barriers to adherence, such as difficulty remembering to take medication without supervision.

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October 2011 | Vol 10, No 9 | Supplement to Current Psychiatry