Schizophrenia Bulletin - recent issues

Leaping Tall Buildings--The Science-to-Service Gap in Schizophrenia Treatment

Lehman, A. F. — 2009-06-15

Psychiatry and Oppression: A Personal Account of Compulsory Admission and Medical Treatment

Gray, B. — 2009-06-15

Toward a Model of Impaired Reality Testing in Rats

McDannald, M., Schoenbaum, G. — 2009-06-15

Schizophrenia is a chronic brain disorder that affects about 1.1% of the adult US population annually. Hallucinations, delusions, and impaired reality testing are prominent symptoms of the disorder. Modeling these symptoms is difficult because it is unclear how to assess impaired reality testing in animals. Animals cannot discuss their beliefs; however, a century of learning experiments has shown us that they, like us, construct complex internal representations of their world. Presumably, these representations can become confused with reality for animals in much the same way that they do for schizophrenic patients. Indeed, there is evidence from studies of Pavlovian conditioning that this happens even in normal animals. For example, early in training a cue that has been paired with reward elicits a highly realistic, sensory representation of that reward, which is to some extent indistinguishable from reality. With further training, this sensory hallucination of reward is replaced by a more abstract representation, termed a reward expectancy. Reward expectancies reflect the sensory and other qualities of the impending reward but are distinguishable from the actual reward. Notably, the hallucinatory representations depend on subcortical regions, such as amygdala, whereas reward expectancies require the progressive involvement of prefrontal areas, such as orbitofrontal cortex. Abnormal prefrontal function is associated with schizophrenia; impaired reality testing may result from a failure of the normal shift from highly realistic, sensory representations to more abstract, prefrontal expectancies. The Pavlovian procedures discussed here could be applied to animal models and schizophrenic patients to test this hypothesis.

From Real-World Events to Psychosis: The Emerging Neuropharmacology of Delusions

Morrison, P. D., Murray, R. M. — 2009-06-15

The earliest stages of delusion are characterized by an overabundance of meaningful coincidences impinging on the sufferer's existing worldview. Successive events are seen by him as pointing to, and then confirming, a fundamentally new reality that takes him over and engulfs his everyday life. Research over the last 4 decades has revealed the importance of dopamine (DA), D2 receptors, and the basal ganglia in psychotic thinking. Recent work has implicated the aberrant reward learning initiated by the excess release of striatal DA in the attribution of excessive importance or "salience" to insignificant stimuli and events. But our knowledge of what is happening beyond D2 receptors has remained scant. The gap is especially apparent at the cellular and microcircuit levels, encompassing the plastic changes, which are believed to be essential for new learning, and whose processes may go awry in major mental illness. Now new pharmacological findings are advancing our understanding of information processing and learning within the striatum. DA has an important role in setting the strength of individual striatal connections, but it does not act in isolation. Two other modulator systems are critical, the endocannabinoids and adenosine. Thus, at medium spiny neurons belonging to the indirect pathway, D2 stimulation evokes endocannabinoid-mediated depression of cortical inputs. Adenosine acting at A2A receptors elicits the opposite effect. Remarkably, drugs that target the endocannabinoid and purinergic systems also have pro- or antipsychotic properties. Here, we discuss how the 3 modulators regulate learning within the striatum and how their dysfunction may lead to delusional thinking.

Dance Therapy for People with Schizophrenia

Xia, J., Grant, T. J. — 2009-06-15

The Science-to-Service Gap in Real-World Schizophrenia Treatment: The 95% Problem

Drake, R. E., Essock, S. M. — 2009-06-15

Unmet Need for Mental Health Care in Schizophrenia: An Overview of Literature and New Data From a First-Admission Study

Mojtabai, R., Fochtmann, L., Chang, S.-W., Kotov, R., Craig, T. J., Bromet, E. — 2009-06-15

We present an overview of the literature on the patterns of mental health service use and the unmet need for care in individuals with schizophrenia with a focus on studies in the United States. We also present new data on the longitudinal course of treatments from a study of first-admission patients with schizophrenia. In epidemiological surveys, approximately 40% of the respondents with schizophrenia report that they have not received any mental health treatments in the preceding 6–12 months. Clinical epidemiological studies also find that many patients virtually drop out of treatment after their index contact with services and receive little mental health care in subsequent years. Clinical studies of patients in routine treatment settings indicate that the treatment patterns of these patients often fall short of the benchmarks set by evidence-based practice guidelines, while at least half of these patients continue to experience significant symptoms. The divergence from the guidelines is more pronounced with regard to psychosocial than medication treatments and in outpatient than in inpatient settings. The expansion of managed care has led to further reduction in the use of psychosocial treatments and, in some settings, continuity of care. In conclusion, we found a substantial level of unmet need for care among individuals with schizophrenia both at community level and in treatment settings. More than half of the individuals with this often chronic and disabling condition receive either no treatment or suboptimal treatment. Recovery in this patient population cannot be fully achieved without enhancing access to services and improving the quality of available services. The recent expansion of managed care has made this goal more difficult to achieve.

Disengagement From Mental Health Treatment Among Individuals With Schizophrenia and Strategies for Facilitating Connections to Care: A Review of the Literature

Kreyenbuhl, J., Nossel, I. R., Dixon, L. B. — 2009-06-15

Disengagement from mental health services can lead to devastating consequences for individuals with schizophrenia and other serious mental illnesses who require ongoing treatment. We review the extent and correlates of dropping out of mental health treatment for individuals with schizophrenia and suggest strategies for facilitating treatment engagement. Although rates vary across studies, reviews of the literature suggest that up to one-third of individuals with serious mental illnesses who have had some contact with the mental health service system disengage from care. Younger age, male gender, ethnic minority background, and low social functioning have been consistently associated with disengagement from mental health treatment. Individuals with co-occurring psychiatric and substance use disorders, as well as those with early-onset psychosis, are at particularly high risk of treatment dropout. Engagement strategies should specifically target these high-risk groups, as well as high-risk periods, including following an emergency room or hospital admission and the initial period of treatment. Interventions to enhance engagement in mental health treatment range from low-intensity interventions, such as appointment reminders, to high-intensity interventions, such as assertive community treatment. Disengagement from treatment may reflect the consumer's perspective that treatment is not necessary, is not meeting their needs, or is not being provided in a collaborative manner. An emerging literature on patient-centered care and shared decision making in psychiatry provides suggestive evidence that efforts to enhance client-centered communication and promote individuals’ active involvement in mental health treatment decisions can also improve engagement in treatment.

Implementing Evidence-Based Practices for People With Schizophrenia

Drake, R. E., Bond, G. R., Essock, S. M. — 2009-06-15

Over the last decade, a consensus has emerged regarding a set of evidence-based practices for schizophrenia that address symptom management and psychosocial functioning. Yet, surveys suggest that the great majority of the population of individuals with schizophrenia do not receive evidence-based care. In this article, we review the empirical literature on implementation of evidence-based practices for schizophrenia patients. We first examine lessons learned from implementation studies in general medicine. We then summarize the implementation literature specific to schizophrenia, including medication practices, psychosocial interventions, information technology, and state- and federal-level interventions. We conclude with recommendations for future directions.

Science to Practice: Making What We Know What We Actually Do

Sederer, L. I. — 2009-06-15

The perspective of the medical director of a large public mental health agency is provided regarding how to close the gap between what we know and what we do in mental health care. Tools for change, actions required, and key actors are identified. The author believes the moment is propitious for improving care systemically.

Multimedia Consent for Research in People With Schizophrenia and Normal Subjects: a Randomized Controlled Trial

2009-06-15

Limitations of printed, text-based, consent forms have long been documented and may be particularly problematic for persons at risk for impaired decision-making capacity, such as those with schizophrenia. We conducted a randomized controlled comparison of the effectiveness of a multimedia vs routine consent procedure (augmented with a 10-minute control video presentation) as a means of enhancing comprehension among 128 middle-aged and older persons with schizophrenia and 60 healthy comparison subjects. The primary outcome measure was manifest decisional capacity (understanding, appreciation, reasoning, and expression of choice) for participation in a (hypothetical) clinical drug trial, as measured with the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) and the University of California San Diego (UCSD) Brief Assessment for Capacity to Consent (UBACC). The MacCAT-CR and UBACC were administered by research assistants kept blind to consent condition. Additional assessments included standardized measures of psychopathology and cognitive functioning. Relative to patients in the routine consent condition, schizophrenia patients receiving multimedia consent had significantly better scores on the UBACC and on the MacCAT-CR understanding and expression of choice subscales and were significantly more likely to be categorized as being capable to consent than those in the routine consent condition (as categorized with several previously established criteria). Among the healthy subjects, there were few significant effects of consent condition. These findings suggest that multimedia consent procedures may be a valuable consent aid that should be considered for use when enrolling participants at risk for impaired decisional capacity, particularly for complex and/or high-risk research protocols.

Worth the Risk? Relationship of Incentives to Risk and Benefit Perceptions and Willingness to Participate in Schizophrenia Research

Dunn, L. B., Kim, D. S., Fellows, I. E., Palmer, B. W. — 2009-06-15

Objective: Providing incentives for research participation is widely practiced but minimally studied. In schizophrenia research, questions about capacity to consent and potential vulnerability may raise concerns when offering incentives for participation. Despite empirical attention focused on consent and decision-making capacity in schizophrenia, the issue of incentives has been essentially ignored. We examined willingness to participate in research, in relation to perceived risks and benefits, among people with schizophrenia and schizoaffective disorder. Method: Forty-six people with schizophrenia or schizoaffective disorder rated perceived risks and benefits of 5 hypothetical research vignettes. They also indicated whether they would be willing to participate at each of 5 incentive levels (including no compensation). Cognition was assessed with Mattis Dementia Rating Scale. Results: Ratings of risk and potential personal benefit were inversely correlated. For all scenarios, significant correlations were found between perceived risk and willingness to participate for greater compensation. Conversely, lower perceived likelihood of benefit was associated with a higher compensation threshold for participation in each scenario. Even at the highest proffered payment level for each scenario, however, a substantial proportion of respondents were not willing to participate. Risk assessment and willingness to participate (at all levels of compensation) were not associated with demographic variables or cognitive status. Conclusions: Determining whether incentives impede voluntarism remains an important task for empirical ethics research. Assessing potential research participants’ understanding and perceptions of risks, benefits, and alternatives to participation will help ensure that informed consent fulfills its mission—embodying the ethical principle of respect for persons.

Neurocognition, Social Cognition, Perceived Social Discomfort, and Vocational Outcomes in Schizophrenia

Bell, M., Tsang, H. W. H., Greig, T. C., Bryson, G. J. — 2009-06-15

Social cognition has been suggested to be an important mediating variable in the relationship between neurocognition and functional outcome. The present study tested this model in relation to work rehabilitation outcome and added self-reported social discomfort as a possible mediator. One hundred fifty-one participants with schizophrenia or schizoaffective disorder participated in a 26-week work therapy program. Neurocognition was constructed as a latent construct comprised of selected variables from our intake test battery representing executive functioning, verbal memory, attention and working memory, processing speed, and thought disorder. Social cognition at intake was the other latent construct comprised of variables representing affect recognition, theory of mind, self-reported egocentricity, and ratings of rapport. The 2 latent constructs received support from confirmatory factor analysis. Social discomfort on the job was based on their self-report on a weekly questionnaire. In addition, we constructed a composite rehabilitation outcome that was based on how many hours they worked, how well they worked, and how complex was the job that they were doing. Path analysis showed direct effects of neurocognition on rehabilitation outcome and indirect effects mediated by social cognition and social discomfort. This model proved to be a good fit to the data and far superior to another model where only social cognition was the mediating variable between neurocognition and rehabilitation outcome. Findings suggest that neurocognition affects social cognition and that poorer social cognition leads to social discomfort on the job, which in turn leads to poorer rehabilitation outcomes. Implications for rehabilitation interventions are discussed.

Neuroleptic Drugs Revert the Contextual Fear Conditioning Deficit Presented by Spontaneously Hypertensive Rats: A Potential Animal Model of Emotional Context Processing in Schizophrenia?

2009-06-15

Schizophrenia, bipolar disorder, and attention deficit/hyperactivity disorder (ADHD) present abnormalities in emotion processing. A previous study showed that the spontaneously hypertensive rats (SHR), a putative animal model of ADHD, present reduced contextual fear conditioning (CFC). The aim of the present study was to characterize the deficit in CFC presented by SHR. Adult male normotensive Wistar rats and SHR were submitted to the CFC task. Sensitivity of the animals to the shock and the CFC performance after repeated exposure to the task were investigated. Pharmacological characterization consisted in the evaluation of the effects of the following drugs administered previously to the acquisition of the CFC: pentylenetetrazole (anxiogenic) and chlordiazepoxide (anxiolytic); methylphenidate and amphetamine (used for ADHD); lamotrigine, carbamazepine, and valproic acid (mood stabilizers); haloperidol, ziprasidone, risperidone, amisulpride, and clozapine (neuroleptic drugs); metoclopramide and SCH 23390 (dopamine antagonists without antipsychotic properties); and ketamine (a psychotomimmetic). The effects of paradoxical sleep deprivation (that worsens psychotic symptoms) and the performance in a latent inhibition protocol (an animal model of schizophrenia) were also verified. No differences in the sensitivity to the shock were observed. The repeated exposure to the CFC task did not modify the deficit in CFC presented by SHR. Considering pharmacological treatments, only the neuroleptic drugs reversed this deficit. This deficit was potentiated by proschizophrenia manipulations. Finally, a deficit in latent inhibition was also presented by SHR. These findings suggest that the deficit in CFC presented by SHR could be a useful animal model to study abnormalities in emotional context processing related to schizophrenia.

Are Psychiatrist Characteristics Associated With Postdischarge Suicide of Schizophrenia Patients?

Lee, H.-C., Lin, H.-C. — 2009-06-15

Information on the relationship between characteristics of mental healthcare providers, including hospitals and psychiatrists, and postdischarge suicide is scanty. This study aims to identify the risk factors for suicide among schizophrenia patients in the 3-month postdischarge period. The study cohort comprised all patients with a principal diagnosis of schizophrenia discharged from psychiatric inpatient care from 2002 to 2004 who committed suicide within 90 days of discharge. The control cohort consisted of all surviving schizophrenia patients discharged from psychiatric inpatient care in the same period and were matched to cases for age, gender, and date of discharge. There were 87 and 348 cases in the study and control cohorts, respectively. For suicide cases, death most frequently occurred on the first day after leaving the hospital (16.1%). The adjusted hazard ratios for committing suicide during the 90-day postdischarge period were 2.639 times greater for patients without previous psychiatric admission than for those hospitalized more than 3 times in the year preceding the index hospitalization. The adjusted suicide hazard for schizophrenia patients treated by male psychiatrists was significantly higher than for patients treated by female psychiatrists, by a multiple of 5.117 (P = .032). The adjusted suicide hazard among patients treated by psychiatrists over age 44 years was 2.378 times (P = .043) that for patients treated by psychiatrists aged younger than 35 years. Risk factors related to psychiatric hospitalization, including number of psychiatric admissions in the previous year and length of stay, together with gender and age of the psychiatrist providing inpatient care, are identified.

Subjective Experience of Cognitive Failures as Possible Risk Factor for Negative Symptoms of Psychosis in the General Population

Pfeifer, S., van Os, J., Hanssen, M., Delespaul, P., Krabbendam, L. — 2009-06-15

Objective: The aim of this study was to examine whether proneness to subjective cognitive failure (cognitive based mistakes) increases the risk for the development of symptoms of psychosis and to what degree any association was familial. Methods: At baseline, the Cognitive Failure Questionnaire (CFQ) and the Community Assessment of Psychic Experiences (CAPE) questionnaire were administered in a general population sample of genetically related individuals (n = 755). Individuals scoring high (>75th percentile) or average on the CAPE (between 40th and 60th percentile) (n = 488) were reinterviewed with the CAPE and Structured Interview for Schizotypy—Revised (SIS-R) at follow-up (mean interval = 7.7 months, SD = 4.8 months). Results: Cross-trait, within-relative analysis showed a significant association between the CFQ and the negative dimension, assessed with both the CAPE and SIS-R, whereas no association was found between the CFQ and the positive dimension. Cross-trait, between-relative analyses showed no association between the CFQ in one relative and any of the dimensions of the subclinical psychosis phenotype in the other relative. Conclusion: Proneness to subjective cognitive failure possibly contributes to the development or persistence of negative symptoms and can be seen as potential risk factor for negative symptoms of psychosis. This overlap is due to individual effects rather than familial liability.

Dropout Rates in Randomized Clinical Trials of Antipsychotics: A Meta-analysis Comparing First- and Second-Generation Drugs and an Examination of the Role of Trial Design Features

Rabinowitz, J., Levine, S. Z., Barkai, O., Davidov, O. — 2009-06-15

Dropout is often used as an outcome measure in clinical trials of antipsychotic medication. Previous research is inconclusive regarding (a) differences in dropout rates between first- and second-generation antipsychotic medications and (b) how trial design features reduce dropout. Meta-analysis of randomized controlled trials (RCTs) of antipsychotic medication was conducted to compare dropout rates for first- and second-generation antipsychotic drugs and to examine how a broad range of design features effect dropout. Ninety-three RCTs that met inclusion criteria were located (n = 26 686). Meta-analytic random effects models showed that dropout was higher for first- than second-generation drugs (odds ratio = 1.49, 95% confidence interval: 1.31–1.66). This advantage persisted after removing study arms with excessively high dosages, in flexible dose studies, studies of patients with symptom exacerbation, nonresponder patients, inpatients, and outpatients. Mixed effects models for meta-analysis were used to identify design features that effected dropout and develop formulae to derive expected dropout rates based on trial design features, and these assigned a pivotal role to duration. Collectively, dropout rates are lower for second- than first-generation antipsychotic drugs and appear to be partly explained by trial design features thus providing direction for future trial design.

Cortical Dopamine D2/D3 Receptors Are a Common Site of Action for Antipsychotic Drugs--An Original Patient Data Meta-analysis of the SPECT and PET In Vivo Receptor Imaging Literature

Stone, J. M., Davis, J. M., Leucht, S., Pilowsky, L. S. — 2009-06-15

Subject numbers in neuroreceptor imaging studies of antipsychotic treatment in schizophrenia are generally insufficient to directly test the relationship of regional D₂/D₃ and 5HT_2A receptor binding to clinical efficacy. We selected positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies of antipsychotic dose vs occupancy at both temporal cortex and striatal D₂/D₃ receptors. We selected corresponding SPECT and PET studies of 5HT_2A receptor occupancy. We also selected randomized double-blind clinical trials of antipsychotics, where patients were treated with randomly assigned fixed doses. For each antipsychotic drug, we compared the optimum effective antipsychotic dose with the dose inducing maximal occupancy of D₂/D₃ receptors in striatum and in temporal cortex as well as at 5HT_2A receptors. Both first- and second-generation antipsychotic (FGA, SGA) drugs produced high temporal cortex D₂/D₃ occupancy. Only FGA produced high striatal D₂/D₃ receptor occupancy. The clinically effective dose showed correlation with doses inducing maximal dopamine D₂/D₃ receptor occupancy both in striatum and in temporal cortex, the strongest correlation being with temporal cortex binding. Extrapyramidal side effects (EPSE) were primarily related to striatal D₂/D₃ receptor occupancy. There was no correlation between 5HT_2A occupancy and clinically effective dose. We conclude that cortical dopamine D₂/D₃ receptor occupancy is involved in antipsychotic efficacy, with striatal D₂/D₃ occupancy having a likely therapeutic role while also inducing EPSE. We found no evidence for 5HT_2A blockade involvement in antipsychotic action, although we cannot exclude this possibility.

Defeatist Beliefs as a Mediator of Cognitive Impairment, Negative Symptoms, and Functioning in Schizophrenia

Grant, P. M., Beck, A. T. — 2009-06-15

Poor social and vocational outcomes have long been observed in schizophrenia. Two of the most consistent predictors are negative symptoms and cognitive impairment. We investigate the hypothesis that cognitive content—defeatist beliefs regarding performance—provides a link between cognitive impairment, negative symptoms, and poor functioning in schizophrenia. A total of 77 individuals (55 patients diagnosed with schizophrenia or schizoaffective disorder and 22 healthy controls) participated in a cross-sectional study of psychopathology. Tests of memory, abstraction, attention, and processing speed, as well as current psychopathology, functioning, and endorsement of defeatist beliefs, were employed. Greater neurocognitive impairment was associated with elevated defeatist belief endorsement, higher negative symptom levels, and worse social and vocational functioning. Notably, statistical modeling indicated that defeatist belief endorsements were mediators in the relationship between cognitive impairment and both negative symptoms and functioning. These effects were independent of depression and positive symptom levels. The results add to the emerging biopsychosocial understanding of negative symptoms and introduce defeatist beliefs as a new psychotherapeutic target.

Errorless Learning for Training Individuals With Schizophrenia at a Community Mental Health Setting Providing Work Experience

2009-06-15

The effects of errorless learning (EL) on work performance, tenure, and personal well-being were compared with conventional job training in a community mental health fellowship club offering 12-week time-limited work experience. Participants were 40 clinically stable schizophrenia and schizoaffective disorder outpatients randomly assigned to EL vs conventional instruction (CI) at a thrift-type clothing store. EL participants received training on how to perform their assigned job tasks based on principles of EL, such as error reduction and automation of task performance. CI participants received training common to other community-based entry-level jobs that included verbal instruction, a visual demonstration, independent practice, and corrective feedback. Participants were scheduled to work 2 hours per week for 12 weeks. For both groups, job training occurred during the first 2 weeks at the worksite. Work performance (assessed using the Work Behavior Inventory, WBI) and personal well-being (self-esteem, job satisfaction, and work stress) were assessed at weeks 2, 4, and 12. Job tenure was defined as the number of weeks on the job or total number of hours worked prior to quitting or study end. The EL group performed better than the CI group on the Work Quality Scale from the WBI, and the group differences were relatively consistent over time. Results from the survival analyses of job tenure revealed a non-significant trend favoring EL. There were no group differences on self-esteem, job satisfaction, or work stress. The findings provide modest support for the extensions of EL to community settings for enhancing work performance.

Extended Visual Simultaneity Thresholds in Patients With Schizophrenia

2009-06-15

Clinical observations suggest that the experience of time phenomenology is disturbed in schizophrenia, possibly originating disorders in dynamic cognitive functions such as language or motor planning. We examined the subjective evaluation of temporal structure using an experimental approach involving judgments of simultaneity of simple, visually presented stimuli. We included a priming procedure, ie, a subthreshold presentation of simultaneous or asynchronous stimuli. This allowed us to evaluate the effects of subthreshold synchrony and to check for bias effects, ie, changes in the criteria used by the subjects to rate the stimuli. Primes were adapted to the responses of the subjects. Bias effects were thus expected to yield a change in the efficiency of the prime and to induce a change in the amplitude of the priming effect. Nineteen outpatients with schizophrenia and their individually matched controls participated in the study. In all tests, patients required longer delays between stimuli to detect that they were asynchronous. In other words, they judged stimuli to be synchronous even when their onset was separated by delays of 100 milliseconds and even more in some cases. These results contrasted with preserved effects of subthreshold synchrony. Our findings argue against the hypothesis that the patients’ responses were influenced by biases. We conclude that the subjective evaluation of simultaneity/asynchrony is impaired in schizophrenia, thus leading to impairment in the phenomenology of event-structure coding. The method used in the present study provides a novel approach to the assessment of those disturbances related to time in patients with schizophrenia.

Genetic and Disorder-Specific Aspects of Resting State EEG Abnormalities in Schizophrenia

Venables, N. C., Bernat, E. M., Sponheim, S. R. — 2009-06-15

We evaluated whether abnormal frequency composition of the resting state electroencephalogram (EEG) in schizophrenia was associated with genetic liability for the disorder by studying first-degree biological relatives of schizophrenia patients. The study included a data-driven method for defining EEG frequency components and determined the specificity of resting state EEG frequency abnormalities by assessing schizophrenia patients, bipolar disorder patients, and relatives of both patient groups. Schizophrenia patients and their relatives, but not bipolar patients or their relatives, exhibited increased high-frequency activity (beta) providing evidence for disturbances in resting state brain activity being specific to genetic liability for schizophrenia. Schizophrenia patients exhibited augmented low-frequency EEG activity (delta, theta), while bipolar disorder patients and the 2 groups of relatives generally failed to manifest similar low-frequency EEG abnormalities. The Val¹⁵⁸Met polymorphism for the catechol-O-methyl transferase (COMT) gene was most strongly associated with delta and theta activity in schizophrenia patients. Met homozygote schizophrenia patients exhibited augmented activity for the 2 low-frequency bands compared with control subjects. Excessive high-frequency EEG activity over frontal brain regions may serve as an endophenotype that reflects cortical expression of genetic vulnerability for schizophrenia. Low-frequency resting state EEG anomalies in schizophrenia may relate to disorder-specific pathophysiology in schizophrenia and the influence of the COMT gene on tonic dopamanergic function.

Substance Use Disorders in Schizophrenia--Clinical Implications of Comorbidity

Volkow, N. D. — 2009-04-16

Nearly half of the people suffering from schizophrenia also present with a lifetime history of substance use disorders (SUD), a rate that is much higher than the one seen among unaffected individuals. This phenomenon suggests that the factors influencing SUD risk in schizophrenia may be more numerous and/or complex than those modulating SUD risk in the general population. It is critically important to address this comorbidity because SUD in schizophrenic patients is associated with poorer clinical outcomes and contributes significantly to their morbidity and mortality.

Metaphorical Stories for Education About Mental Health Challenges and Stigma

Rofe, T. — 2009-04-16

In 1989, my psychiatrist convinced me to present to a small group of parents of people with mental health challenges. I had terrible stage fright, but I coped well. It was such a success that I was invited to present to other groups. Thus, I started presenting to groups and other audiences. In this article, I want to share my experience using metaphorical stories when presenting. The more I presented to different audiences, the more I found I was trying to explain complicated matters. It is not enough to want to communicate with someone, and it is not enough that he or she wants to communicate with oneself. Suitable conditions are required for communication. Because I was captivated in my childhood by the fables of Aesop, La-Fontaine, and Krilov, I used in my presentations various fables and other types of metaphorical stories to bridge the gap of knowledge and to enable communication. When I could not find metaphorical stories to suit my presentations, I made them up.

Psychosis as a Disorder of Reduced Cathectic Capacity: Freud's Analysis of the Schreber Case Revisited

McGlashan, T. H. — 2009-04-16

Approximately 100 years ago, a prominent German public figure name Daniel Schreber wrote memoirs of his experiences in asylums. His case was diagnosed Dementia Praecox at times and Paranoia at others by his treaters. Freud analyzed Schreber's memoirs from the perspective of his "libido" theory of developmentally organized mental "cathexes" or ideational/emotional investments in self and others. Revisiting Freud's analysis of the Schreber case suggests that it may represent the first theoretical articulation that the pathophysiologic core of psychosis is one of deficit, i.e., of diminished (organic) cathectic capacity for normal mental and affective investments in life.

Psychosis Genetics: Modeling the Relationship Between Schizophrenia, Bipolar Disorder, and Mixed (or "Schizoaffective") Psychoses

Craddock, N., O'Donovan, M. C., Owen, M. J. — 2009-04-16

As a result of improving technologies and greatly increased sample sizes, the last 2 years has seen unprecedented advances in identification of specific genetic risk factors for psychiatric phenotypes. Strong genetic associations have been reported at common polymorphisms within ANK3 and CACNA1C in bipolar disorder and ZNF804A in schizophrenia and a relatively specific association between common variation in GABA_A receptor genes and cases with features of both bipolar disorder and schizophrenia. Further, the occurrence of rare copy number variants (CNVs) has been shown to be increased in schizophrenia compared with controls. These emerging data provide a powerful resource for exploring the relationship between psychiatric phenotypes and can, and should, be used to inform conceptualization, classification, and diagnosis in psychiatry. It is already clear that, in general, genetic associations are not specific to one of the traditional diagnostic categories. For example, variation at ZNF804A is associated with risk of both bipolar disorder and schizophrenia, and some rare CNVs are associated with risk of autism and epilepsy as well as schizophrenia. These data are not consistent with a simple dichotomous model of functional psychosis and indicate the urgent need for moves toward approaches that (a) better represent the range of phenotypic variation seen in the clinical population and (b) reflect the underlying biological variation that gives rise to the phenotypes. We consider the implications for models of psychosis and the importance of recognizing and studying illness that has prominent affective and psychotic features. We conclude that if psychiatry is to translate the opportunities offered by new research methodologies, we must finally abandon a 19th-century dichotomy and move to a classificatory approach that is worthy of the 21st century.

Chlorpromazine Dose for People With Schizophrenia

de Haan, S., Liu, X. — 2009-04-16

What We Know: Findings That Every Theory of Schizophrenia Should Explain

MacDonald, A. W., Schulz, S. C. — 2009-04-16

The article summarizes the process used to distill schizophrenia science into 22 facts. These facts consist of 6 basic facts, 3 etiological facts, 6 pharmacological and treatment facts, 5 pathology facts, and 2 behavioral facts that were critically reviewed by the scholarly community through a special initiative in cooperation with the Schizophrenia Research Forum. A subset of 10 of these facts was selected to form a common set of findings to be explained from the different theoretical perspectives included in this special section of Schizophrenia Bulletin. The rationale for this exercise is to distinguish more precisely the areas of agreement and disagreement between theories of schizophrenia and to highlight where more thought and data can make the greatest impact for understanding this disease.

Dysconnection in Schizophrenia: From Abnormal Synaptic Plasticity to Failures of Self-monitoring

Stephan, K. E., Friston, K. J., Frith, C. D. — 2009-04-16

Over the last 2 decades, a large number of neurophysiological and neuroimaging studies of patients with schizophrenia have furnished in vivo evidence for dysconnectivity, ie, abnormal functional integration of brain processes. While the evidence for dysconnectivity in schizophrenia is strong, its etiology, pathophysiological mechanisms, and significance for clinical symptoms are unclear. First, dysconnectivity could result from aberrant wiring of connections during development, from aberrant synaptic plasticity, or from both. Second, it is not clear how schizophrenic symptoms can be understood mechanistically as a consequence of dysconnectivity. Third, if dysconnectivity is the primary pathophysiology, and not just an epiphenomenon, then it should provide a mechanistic explanation for known empirical facts about schizophrenia. This article addresses these 3 issues in the framework of the dysconnection hypothesis. This theory postulates that the core pathology in schizophrenia resides in aberrant N-methyl-D-aspartate receptor (NMDAR)–mediated synaptic plasticity due to abnormal regulation of NMDARs by neuromodulatory transmitters like dopamine, serotonin, or acetylcholine. We argue that this neurobiological mechanism can explain failures of self-monitoring, leading to a mechanistic explanation for first-rank symptoms as pathognomonic features of schizophrenia, and may provide a basis for future diagnostic classifications with physiologically defined patient subgroups. Finally, we test the explanatory power of our theory against a list of empirical facts about schizophrenia.

The Neurodevelopmental Hypothesis of Schizophrenia, Revisited

Fatemi, S. H., Folsom, T. D. — 2009-04-16

While multiple theories have been put forth regarding the origin of schizophrenia, by far the vast majority of evidence points to the neurodevelopmental model in which developmental insults as early as late first or early second trimester lead to the activation of pathologic neural circuits during adolescence or young adulthood leading to the emergence of positive or negative symptoms. In this report, we examine the evidence from brain pathology (enlargement of the cerebroventricular system, changes in gray and white matters, and abnormal laminar organization), genetics (changes in the normal expression of proteins that are involved in early migration of neurons and glia, cell proliferation, axonal outgrowth, synaptogenesis, and apoptosis), environmental factors (increased frequency of obstetric complications and increased rates of schizophrenic births due to prenatal viral or bacterial infections), and gene-environmental interactions (a disproportionate number of schizophrenia candidate genes are regulated by hypoxia, microdeletions and microduplications, the overrepresentation of pathogen-related genes among schizophrenia candidate genes) in support of the neurodevelopmental model. We relate the neurodevelopmental model to a number of findings about schizophrenia. Finally, we also examine alternate explanations of the origin of schizophrenia including the neurodegenerative model.

The Dopamine Hypothesis of Schizophrenia: Version III--The Final Common Pathway

Howes, O. D., Kapur, S. — 2009-04-16

The dopamine hypothesis of schizophrenia has been one of the most enduring ideas in psychiatry. Initially, the emphasis was on a role of hyperdopaminergia in the etiology of schizophrenia (version I), but it was subsequently reconceptualized to specify subcortical hyperdopaminergia with prefrontal hypodopaminergia (version II). However, these hypotheses focused too narrowly on dopamine itself, conflated psychosis and schizophrenia, and predated advances in the genetics, molecular biology, and imaging research in schizophrenia. Since version II, there have been over 6700 articles about dopamine and schizophrenia. We selectively review these data to provide an overview of the 5 critical streams of new evidence: neurochemical imaging studies, genetic evidence, findings on environmental risk factors, research into the extended phenotype, and animal studies. We synthesize this evidence into a new dopamine hypothesis of schizophrenia—version III: the final common pathway. This hypothesis seeks to be comprehensive in providing a framework that links risk factors, including pregnancy and obstetric complications, stress and trauma, drug use, and genes, to increased presynaptic striatal dopaminergic function. It explains how a complex array of pathological, positron emission tomography, magnetic resonance imaging, and other findings, such as frontotemporal structural and functional abnormalities and cognitive impairments, may converge neurochemically to cause psychosis through aberrant salience and lead to a diagnosis of schizophrenia. The hypothesis has one major implication for treatment approaches. Current treatments are acting downstream of the critical neurotransmitter abnormality. Future drug development and research into etiopathogenesis should focus on identifying and manipulating the upstream factors that converge on the dopaminergic funnel point.

What Is the Role of Theories in the Study of Schizophrenia?

Cannon, T. D. — 2009-04-16

As an epilogue to the themed papers on "Theories of Schizophrenia" in this issue of Schizophrenia Bulletin, this article reviews some basic philosophy of science principles in regard to the role of theories in the evolving state of a natural science discipline. While in early phases inductive and abductive logic are the primary vehicles for organizing observations and developing models, when a critical set of "facts" have been elucidated which can be explained by competing theoretical perspectives, hypothetico-deductive logic provides a more robust and efficient approach to scientific progress. The key principle is to determine where two or more theories predict different observations and then to devise studies that collect critical observations—correlations or experimental outcomes that are predicted differentially by the competing theories. To a large extent, current theories of schizophrenia (eg, focusing on aberrant dopaminergic signaling, neural dysconnectivity, and disrupted neural development) are not (and are not intended by their authors to be) mutually exclusive of each other. Rather, they provide explanations that differ in relative emphases, eg, on distal vs proximal causes and on broad vs narrow behavioral end points. It is therefore possible for all of them to be "right" at least in a general sense. This non-exclusivity is problematic when considered in light of the strong inferences principles characteristic of a mature natural science discipline. The contrast points are likely to be found in constructions that integrate influences across different levels of analysis, as in additive vs interactive models, direct effects vs mediation models, and developmental vs deteriorative models.

Prenatal Malnutrition and Adult Schizophrenia: Further Evidence From the 1959-1961 Chinese Famine

2009-04-16

Objective: Evidence from the 1944–1995 Dutch Hunger Winter and the 1959–1961 Chinese famines suggests that those conceived or in early gestation during famines, have a 2-fold increased risk of developing schizophrenia in adult life. We tested the hypothesis in a second Chinese population and also determined whether risk differed between urban and rural areas. Method: The risk of schizophrenia was examined in Liuzhou prefecture of Guangxi autonomous region. Rates were compared among those conceived before, during, and after the famine years. Based on the decline in birth rates, we predicted that those born in 1960 and 1961 would have been exposed to the famine during conception or early gestation. All psychiatric case records in Liuzhou psychiatric hospital for the years 1971 through 2001 were examined and clinical/sociodemographic data extracted by psychiatrists blind to exposure status. Data on births and deaths in the famine years were also available, and cumulative mortality was estimated from later demographic surveys. Evidence of famine was verified, and results were adjusted for mortality. Relative risks (RRs) for schizophrenia were calculated for the region as a whole and for urban and rural areas separately. Results: Mortality-adjusted RR for schizophrenia was 1.5 (1960) and 2.05 (1961), respectively. However, the effect was exclusively from the rural areas RR = 1.68 (1960) and RR = 2.25 (1961). Conclusions: We observe a 2-fold increased risk of schizophrenia among those conceived or in early gestation at the height of famine with risk related to severity of famine conditions.

Why Schizophrenia Epidemiology Needs Neurobiology--and Vice Versa

McGrath, J. J., Richards, L. J. — 2009-04-16

Schizophrenia epidemiology can provide us with valuable information to guide research directions. However, while epidemiology is useful for generating candidate risk factors, it can not always deliver studies that prove causality. We argue that the field needs more translational research that links schizophrenia epidemiology with molecular, cellular, and behavioral neuroscience. Cross-disciplinary projects related to candidate genetic or nongenetic risk factors not only can address the biological plausibility of these factors, but they can serve as catalysts for discovery in neuroscience. This type of cross disciplinary research is likely to be more efficient compared to clinically dislocated basic neuroscience. Examples of this type of translational research are provided based on (a) the impact of prenatal nutrition and prenatal infection on brain development and (b) understanding the causes and consequences of agenesis of the corpus callosum. We need to build shared discovery platforms that encourage greater cross-fertilization between schizophrenia epidemiology and basic neuroscience research.

Relation of Schizophrenia Prevalence to Latitude, Climate, Fish Consumption, Infant Mortality, and Skin Color: A Role for Prenatal Vitamin D Deficiency and Infections?

2009-04-16

Previous surveys found a large (>10-fold) variation in schizophrenia prevalence at different geographic sites and a tendency for prevalence to increase with latitude. We conducted meta-analyses of prevalence studies to investigate whether these findings pointed to underlying etiologic factors in schizophrenia or were the result of methodological artifacts or the confounding of sites’ latitude with level of healthcare at those sites. We found that these patterns were still present after controlling for an index of healthcare—infant mortality—and focusing on 49 studies that used similar diagnostic and ascertainment methods. The tendencies for schizophrenia prevalence to increase with both latitude and colder climate were still large and significant and present on several continents. The increase in prevalence with latitude was greater for groups with low fish consumption, darker skin, and higher infant mortality—consistent with a role of prenatal vitamin D deficiency in schizophrenia. Previous research indicates that poor prenatal healthcare and nutrition increase risk for schizophrenia within the same region. These adverse conditions are more prevalent in developing countries concentrated near the equator, but schizophrenia prevalence is lowest at sites near the equator. This suggests that schizophrenia-producing environmental factors associated with higher latitude may be so powerful they overwhelm protective effects of better healthcare in industrialized countries. The observed patterns of correlations of risk factors with prevalence are consistent with an etiologic role for prenatal vitamin D deficiency and exposure to certain infectious diseases. Research to elucidate environmental factors that underlie variations in schizophrenia prevalence deserves high priority.

Incidence of Schizophrenia Among Second-Generation Immigrants in the Jerusalem Perinatal Cohort

2009-04-16

Objective: Increased incidence of schizophrenia is observed among some immigrant groups in Europe, with the offspring of immigrants, ie "second-generation" immigrants particularly vulnerable. Few contemporary studies have evaluated the risk of schizophrenia among second-generation immigrants in other parts of the world. Methods: We studied the incidence of schizophrenia in relation to parental immigrant status in a population-based cohort of 88 829 offspring born in Jerusalem in 1964–1976. Parental countries of birth were obtained from birth certificates and grouped together as (1) Israel, (2) Other West Asia, (3) North Africa, and (4) Europe and industrialized countries. Cox proportional hazards methods were used in adjusting for sex, parents’ ages, maternal education, social class, and birth order. Results: Linkage with Israel's Psychiatric Registry identified 637 people admitted to psychiatric care facilities with schizophrenia-related diagnoses, before 1998. Incidence of schizophrenia was not increased among second-generation immigrants in this birth cohort, neither overall nor by specific group. Conclusions: The difference in risk of schizophrenia among second-generation immigrants in Europe and in this Israeli birth cohort suggests that the nature of the immigration experience may be relevant to risk, including reasons for migration, the nature of entry, and subsequent position in the host country for immigrants and their offspring. Minority status may be of importance as, in later studies, immigrants to Israel from Ethiopia had increased risk of schizophrenia.

The Antecedents of Schizophrenia: A Review of Birth Cohort Studies

Welham, J., Isohanni, M., Jones, P., McGrath, J. — 2009-04-16

Background: Birth cohort (BC) studies demonstrate that individuals who develop schizophrenia differ from the general population on a range of developmental indices. The aims of this article were to summarize key findings from BC studies in order to identify areas of convergence and to outline areas requiring further research. Method: We define BC studies as studies based on general population BCs where data are collected prospectively from birth or childhood and which identify schizophrenia or related disorders as an outcome. To identify such studies, we searched various electronic databases using the search parameters (schizo* OR psych*) AND (birth cohort). We also checked the references of relevant articles and previous reviews. Results: We identified 11 BCs from 7 countries that have examined schizophrenia as an outcome in adulthood. There is relatively consistent evidence that, as a group, children who later develop schizophrenia have behavioral disturbances and psychopathology, intellectual and language deficits, and early motor delays. Evidence with respect to alterations in language, educational performance, and physical growth has also been identified in some studies. BC studies have also contributed evidence about a wide range of putative risk factors for schizophrenia. Conclusions: BC studies have provided important, convergent insights into how the developmental trajectory of individuals who develop schizophrenia differs from their peers. The combination of new paradigms and larger cohorts, with the tools of modern epidemiology and biomedical science, is advancing our understanding of the developmental pathways to schizophrenia.

Association Between Paternal Schizophrenia and Low Birthweight: A Nationwide Population-Based Study

Lin, H.-C., Tang, C.-H., Lee, H.-C. — 2009-04-16

Using a nationwide population-based dataset, the aim of the present study was to investigate the association between paternal schizophrenia and the risk of low birthweight (LBW). This study linked the 2001 Taiwan National Health Insurance Research Dataset with Taiwan's birth and death certificate registries. In total, 220 465 singleton live births were included. The key dependent variable was whether or not an infant's father was diagnosed with schizophrenia, while the independent variable of interest was whether an infant had LBW. Multivariate logistic regression analysis was performed to explore the relationship between paternal schizophrenia and the risk of LBW, after adjusting for the infant and parents’ characteristics. The results show that infants whose fathers had schizophrenia were more likely to have LBW than those whose fathers did not (12.6% vs 8.0%). Infants whose fathers had schizophrenia were found to be 1.58 (95% confidence interval = 1.10–2.52, P < .05) times more likely to have LBW than their counterparts whose fathers did not have schizophrenia, following adjustment for gestational week at birth, parity, paternal age and highest educational level, family monthly incomes, and marital status. We conclude that the offspring whose fathers had a diagnosis of schizophrenia had increased risk of LBW compared with those whose fathers had no schizophrenia. This finding paves the way for further studies and suggests that there may be potential benefit to early intervention to prevent LBW in pregnant women with husbands with schizophrenia.

Association Between Prenatal Exposure to Bacterial Infection and Risk of Schizophrenia

Sorensen, H. J., Mortensen, E. L., Reinisch, J. M., Mednick, S. A. — 2009-04-16

Recent research suggests that prenatal exposure to nonviral infection may be associated with increased risk of schizophrenia, and we hypothesized an association between maternal bacterial infection during pregnancy and elevated offspring risk of schizophrenia. Data on maternal infections from the Copenhagen Perinatal Cohort were linked with the Danish National Psychiatric Register. Offspring cases of narrowly defined schizophrenia (International Classification of Diseases, Eighth Revision [ICD-8]) and more broadly defined schizophrenia (ICD-8 and ICD-10) were identified before the ages of 32–34 and 45–47 years, respectively. The effect of prenatal exposure to bacterial infections was adjusted for prenatal exposure to analgesics and parental social status. In a risk set of 7941 individuals, 85 cases (1.1%) of ICD-8 schizophrenia were identified by the age of 32–34 years and 153 cases (1.9%) of more broadly defined schizophrenia by the age of 45–47 years. First-trimester exposure conferred an elevated risk of ICD-8 schizophrenia (odds ratio 2.53; 95% confidence interval [CI] 1.07–5.96) and also of broadly defined schizophrenia (odds ratio 2.14; 95% CI 1.06–4.31). Second-trimester exposure also conferred a significantly elevated risk of schizophrenia but only in unadjusted analyses. These findings suggest a relationship between maternal bacterial infection in pregnancy and offspring risk of schizophrenia, and this effect was somewhat stronger for ICD-8 schizophrenia with earlier onset. Post hoc analyses showed that upper respiratory tract and gonococcal infections were associated with elevated risk of the disease. An association between risk of schizophrenia and prenatal exposure to bacterial infections might be mediated through transplacental passage of maternally produced cytokines in response to bacterial infections.

Life Events and High-Trait Reactivity Together Predict Psychotic Symptom Increases in Schizophrenia

Docherty, N. M., St-Hilaire, A., Aakre, J. M., Seghers, J. P. — 2009-04-16

Psychotic symptoms are exacerbated by stressful life events in schizophrenia patients as a group. Some individuals appear to be more vulnerable than others in this regard. This study tested whether schizophrenia patients are highly emotionally reactive compared with controls and whether the level of trait emotional reactivity in patients influences the degree to which they respond to life stressors with exacerbations of psychosis. Schizophrenic outpatients and nonpsychiatric controls were assessed for levels of trait emotional reactivity, arousability, and trait anxiety. Severity of symptoms was also rated in the patients. Patients were then followed up 9 months later, assessed for independent stressful life events occurring during the month before the follow-up session, and reassessed for symptom levels. The patients scored higher than the control subjects on all 3 measures of reactivity at the initial assessment. At follow-up, the occurrence of potentially stressful life events predicted increases in psychotic symptoms in patients, and there was a significant interaction between level of initial trait reactivity and the occurrence of life events in the prediction of these increases. High-trait–reactive patients showed increases in psychotic symptoms in response to life stressors, whereas low-trait–reactive patients did not. These findings support the idea that patients as a group have higher than normal levels of trait reactivity and also that patients with very high levels of trait reactivity are at elevated risk of psychotic relapse under stress. Such patients might benefit particularly from interventions designed to assist them in coping with potentially stressful life events and circumstances.

Clinical Course and Outcome of Schizophrenia in a Predominantly Treatment-Naive Cohort in Rural Ethiopia

2009-04-16

The established view that schizophrenia may have a favorable outcome in developing countries has been recently challenged; however, systematic studies are scarce. In this report, we describe the clinical outcome of schizophrenia among a predominantly treatment-naive cohort in a rural community setting in Ethiopia. The cohort was identified in a 2-stage sampling design using key informants and measurement-based assessment. Follow-up assessments were conducted monthly for a mean duration of 3.4 years (range 1–6 years). After screening 68 378 adults, ages 15–49 years, 321 cases with schizophrenia (82.7% men and 89.6% treatment naive) were identified. During follow-up, about a third (30.8%) of cases were continuously ill while most of the remaining cohort experienced an episodic course. Only 5.7% of the cases enjoyed a near-continuous complete remission. In the final year of follow-up, over half of the cases (54%) were in psychotic episode, while 17.6% were in partial remission and 27.4% were in complete remission for at least the month preceding the follow-up assessment. Living in a household with 3 or more adults, later age of onset, and taking antipsychotic medication for at least 50% of the follow-up period predicted complete remission. Although outcome in this setting appears better than in developed countries, the very low proportion of participants in complete remission supports the recent observation that the outcome of schizophrenia in developing countries may be heterogeneous rather than uniformly favorable. Improving access to treatment may be the logical next step to improve outcome of schizophrenia in this setting.

Better Outcome of Schizophrenia in India: A Natural Selection Against Severe Forms?

Thirthalli, J., Jain, S. — 2009-04-16

Regional variations are observed in outcome of schizophrenia, but reasons remain unclear. Outcome of schizophrenia is reported to be better in India. In this report based on census data, we highlight substantially greater mortality observed among the mentally ill than among the general population during famines in India in the 19th century. A possible selection against the most severe forms of schizophrenia could account for greater occurrence of better-outcome phenotypes. Population histories and environmental influences, including epigenetics, need to be considered to further investigate differences between schizophrenia phenotypes.

Retracted: First Person Account: My Dream Life, a Normal Life

2009-04-16

Editorial: Understanding and Measuring Recovery

Essock, S., Sederer, L. — 2009-03-20

Editorial: Clustering of Schizophrenia With Other Comorbidities--What Can We Learn?

Mitchell, B. D. — 2009-03-20

Psychological Causes of Schizophrenia

MacPherson, M. — 2009-03-20

This article outlines not only the path of my recovery but also the conclusions of my therapeutic journal that developed over a period of several years. This journal evolved into the following structure: description of personal pain body, moving forward with transformations, and active living—implementation of intention and desire that continues. My journal has evolved from the written word to transformation, current lived experience, and the expectation of good things yet to come. Many transformations were integrated into my thinking and emotions over the years. As I developed solutions to my pain body, the structure of the psychological causes of my paranoid schizophrenia became clear. The voices and interference are at bay, hallucinations and delusions are understood, and paranoid disposition transformed to a more normal way of thinking and reacting. I continue on a low maintenance dose of atypical antipsychotic medication. My hope is that my conclusions will inspire researchers and clinicians and help other peers with their recovery. An open mind, moving forward in work, self-direction, and transformative learning have contributed significantly to my recovery.

Drug Discovery in Psychiatric Illness: Mining for Gold

Elmer, G. I., Kafkafi, N. — 2009-03-20

The discovery of truly efficacious treatments that lead to full recovery is a daunting task in psychiatric illness. A systems-based orientation to in vivo pharmacology has been suggested as a way to transform psychiatric drug discovery and development. A critical catalyst in the success of recent systems biology efforts has been the incorporation of data mining strategies. Our approach to the drug discovery problem has been to utilize the whole animal to provide a systems response that is subsequently mined for predictive attributes with known psychopharmacological value. Our in vivo data mining approach, termed Pattern Array, establishes a framework for screening novel chemical entities based upon a response that represents the net pharmacological effect on the system of interest, namely the central nervous system (CNS). Large scale screening of small molecules by non-conventional approaches such as this at a systems level may improve the identification of novel chemical entities with psychiatric utility. This type of approach will compliment the more labor-intensive models based upon construct validity. It will take the collective effort of many disciplines and numerous strategies in close association with clinical colleagues to address quality of life issues and breakthrough treatment barriers in psychiatric illness.

Stigmatization as an Environmental Risk in Schizophrenia: A User Perspective

van Zelst, C. — 2009-03-20

Stigmatization represents a chronic negative interaction with the environment that most people with a diagnosis of schizophrenia face on a regular basis. Different types of stigma—public stigma, self-stigma, and label avoidance—may each have detrimental effects. In the present article, the possible consequences of stigma on onset, course, and outcome of schizophrenia are reviewed. Stigmatization may be conceptualized as a modifiable environmental risk factor that exerts its influence along a variety of different pathways, not only after the illness has been formally diagnosed but also before, on the basis of subtle behavioral expressions of schizophrenia liability. Integrating stigma-coping strategies in treatment may represent a cost-effective way to reduce the risk of relapse and poor outcome occasioned by chronic exposure to stigma. In addition, significant gains in quality of life may result if all patients with schizophrenia routinely receive information about stigma and are taught to use simple strategies to increase resilience vis-à-vis adverse, stigmatizing environments.

Atypical Antipsychotics for People With Both Schizophrenia and Depression

Furtado, V. A, Srihari, V., Kumar, A. — 2009-03-20

Functional Recovery in Schizophrenia: Raising the Bar for Outcomes in People with Schizophrenia

Harvey, P. D. — 2009-03-20

Toward a Terminology for Functional Recovery in Schizophrenia: Is Functional Remission a Viable Concept?

Harvey, P. D., Bellack, A. S. — 2009-03-20

Recovery in schizophrenia is receiving increasing attention. Part of the increased focus is based on the recent working criteria for clinical remission in schizophrenia and the realization that many people with schizophrenia meet these criteria for remission. In this article, we consider whether functional disability can also be evaluated in a "remission" model. In so doing, we evaluate the concept of clinical remission, evaluate the possibility of remission of other generally stable features of schizophrenia such as negative symptoms, and make some heuristic terminological recommendations. We also propose a "level and breadth" model for the definition of functional remission and examine some of the alternate influences that could produce suboptimal everyday functioning, including effort, motivation, and societal barriers toward functional achievement.

A Review of Instruments for Measuring Functional Recovery in Those Diagnosed With Psychosis

Mausbach, B. T., Moore, R., Bowie, C., Cardenas, V., Patterson, T. L. — 2009-03-20

The task of judging an individual's functional recovery is not an easy one for healthcare professionals. Indeed, increasing one's accuracy in predicting one's ability to self-maintain would be of great value for determining if functional recovery has or is occurring. The purpose of this review is to examine existing measures for assessing remission/normalization of functional status among people with psychosis. Our review evaluates 8 measures of functional ability encompassing self-report, clinical, and performance-based measures. We elected to utilize a grading system to aid readers in understanding the merit of a scale for use in assessing functional recovery. In this approach, a letter grade (A, B, or C) was assigned to each of 4 domains we deemed important to professionals in electing to use specific assessments: (1) Ease of Administration, (2) Reliability, (3) Validity/Relationship to Real-World Outcomes, and (4) Sensitivity to Change/Use in Clinical Trials. Results indicated that no "gold standard" measure has been developed to date, but performance-based measures appear to have the most evidence for predicting concurrent self-maintenance abilities (eg, residing independently or maintaining work). More research on existing measures is needed, and greater funding for developing new measures of functional recovery is strongly recommended.

Work, Recovery, and Comorbidity in Schizophrenia: A Randomized Controlled Trial of Cognitive Remediation

McGurk, S. R., Mueser, K. T., DeRosa, T. J., Wolfe, R. — 2009-03-20

Employment is central to the concept of recovery in severe mental illness. However, common comorbid conditions present significant obstacles to consumers seeking employment and benefiting from vocational rehabilitation. We review research on the effects of three common comorbid conditions on work and response to vocational rehabilitation, including cognitive impairment, substance abuse, and medical conditions, followed by research on vocational rehabilitation. We then present the results of a randomized controlled trial evaluating the effects of adding cognitive remediation to a vocational rehabilitation program compared with vocational rehabilitation alone in 34 consumers with severe mental illness. Consumers who received both cognitive remediation and vocational rehabilitation demonstrated significantly greater improvements on a cognitive battery over 3 months than those who received vocational rehabilitation alone and had better work outcomes over the 2-year follow-up period. Substance abuse was associated with worse employment outcomes, but did not interact with treatment group, whereas medical comorbidity was not related to work outcomes. More research is warranted to evaluate the interactions between substance abuse and medical comorbidity with vocational rehabilitation and cognitive remediation.

Cross-sectional and Longitudinal Relationships Between Insight and Attitudes Toward Medication and Clinical Outcomes in Chronic Schizophrenia

Mohamed, S., Rosenheck, R., McEvoy, J., Swartz, M., Stroup, S., Lieberman, J. A. — 2009-03-20

Background: We evaluated the cross-sectional and longitudinal association of measures of both insight and attitudes toward medication to outcomes that included psychopathology and community functioning. Methods: Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) was a large 18-month follow-up study pharmacotherapy of people with schizophrenia. Insight was measured using the Insight and Treatment Attitudes Questionnaire and attitudes toward medication by the Drug Attitude Inventory. Widely known scales were used to assess symptoms of schizophrenia and depression and community functioning. Medication adherence was globally assessed by the treating psychiatrist using several sources of information. Bivariate correlations and mixed model regression analyses were used to test the relationship of insight and medication attitudes to outcomes at baseline and during the follow-up period. Regression models were used to evaluate the relationship between change in insight and medication attitudes and changes outcomes. Results: There was a significant relationship at baseline between insight and drug attitudes and symptoms of schizophrenia and depression, as well as with community functioning. Higher levels of insight at baseline were significantly associated with lower levels of schizophrenia symptoms at follow-up while more positive medication attitudes were significantly associated with both lower symptom levels and better community functioning. Change in insight scores over time was associated with declining schizophrenia symptoms but increasing levels of depression. Change toward more positive medication attitudes was associated, independently of changes in insight, with significant decreases in psychopathology, improvement in community functioning, and greater medication compliance. Conclusion: Greater patient understanding of their illness and more positive attitudes toward medication may improve outcomes. Educational interventions that affect these attitudes may be an important part of psychosocial rehabilitation and/or recovery-oriented services.

Psychosocial Treatments to Promote Functional Recovery in Schizophrenia

Kern, R. S., Glynn, S. M., Horan, W. P., Marder, S. R. — 2009-03-20

A number of psychosocial treatments are available for persons with schizophrenia that include social skills training, cognitive behavioral therapy, cognitive remediation, and social cognition training. These treatments are reviewed and discussed in terms of how they address key components of functional recovery such as symptom stability, independent living, work functioning, and social functioning. We also review findings on the interaction between pharmacological and psychosocial treatments and discuss future directions in pharmacological treatment of schizophrenia. Overall, these treatments provide a range of promising approaches to helping patients achieve better outcomes far beyond symptom stabilization.

Clinical Recovery in First-Episode Psychosis

Wunderink, L., Sytema, S., Nienhuis, F. J., Wiersma, D. — 2009-03-20

Introduction: Generally agreed outcome criteria in psychosis are required to evaluate the effectiveness of new treatment strategies. The aim of this study is to explore clinical recovery in first-episode patients, defined by meeting criteria for both symptomatic and functional remission. Method: In a sample of first-episode patients (N = 125), symptomatic and functional remission during the last 9 months of a 2-year follow-up period were examined, as well as recovery and its predictors. Results: Half the patients (52.0%) showed symptomatic remission and a quarter (26.4%) functional remission, while one-fifth (19.2%) met both criteria sets and were considered recovered. Recovery was significantly associated with short duration of untreated psychosis and better baseline functioning. Conclusion: Most functionally remitted patients were also symptomatically remitted, while a minority of symptomatically remitted patients were also functionally remitted. Treatment delay may affect chance of recovery.

Recovery From Schizophrenia: With Views of Psychiatrists, Psychologists, and Others Diagnosed With This Disorder

Frese, F. J., Knight, E. L., Saks, E. — 2009-03-20

As the concept of schizophrenia began to develop over a century ago, it was accompanied by little hope of recovery. As the second half of the 20th century began, new treatments and changing social conditions resulted in most long-term patients being discharged into the community. Many of these expatients showed more improvement than had been expected. Treatment approaches evolved to help these persons live better lives in the community. In the recent past, psychosocial and psychiatric rehabilitation approaches to treatment have increasingly incorporated perspectives of persons in recovery. These perspectives are explored with emphasis on how they have helped drive federal government and other perspectives on recovery. Particular attention is given to the varying views of psychiatrists, psychologists, and other highly trained persons who have themselves been diagnosed and treated for schizophrenia.

Schizophrenia as A Systemic Disease

Kirkpatrick, B. — 2009-03-20

Psychiatric Comorbidities and Schizophrenia

Buckley, P. F., Miller, B. J., Lehrer, D. S., Castle, D. J. — 2009-03-20

Psychiatric comorbidities are common among patients with schizophrenia. Substance abuse comorbidity predominates. Anxiety and depressive symptoms are also very common throughout the course of illness, with an estimated prevalence of 15% for panic disorder, 29% for posttraumatic stress disorder, and 23% for obsessive-compulsive disorder. It is estimated that comorbid depression occurs in 50% of patients, and perhaps (conservatively) 47% of patients also have a lifetime diagnosis of comorbid substance abuse. This article chronicles these associations, examining whether these comorbidities are "more than chance" and might represent (distinct) phenotypes of schizophrenia. Among the anxiety disorders, the evidence at present is most abundant for an association with obsessive-compulsive disorder. Additional studies in newly diagnosed antipsychotic-naive patients and their first-degree relatives and searches for genetic and environmental risk factors are needed to replicate preliminary findings and further investigate these associations.

Systemic Hypotheses for Generalized Cognitive Deficits in Schizophrenia: A New Take on An Old Problem

Dickinson, D., Harvey, P. D. — 2009-03-20

The schizophrenia research community, including government, industry, and academia, has made development of procognitive treatment strategies a priority. Much current research is directed at dividing broad impairments in cognition into more delineated components that might correspond to relatively specific neural systems and serve as targets for intervention. Sometimes overlooked in this ambitious agenda is the substantial neuropsychological literature that signals a more broadly generalized dysfunction in higher order cognitive functions in this illness. In this article, we argue that a generalized cognitive deficit is at the core of the disorder, is not a methodological artifact, and deserves more focused consideration from cognitive specialists in the field. Further, we weigh evidence that this broad deficit may have systemic biological underpinnings. At the level of the central nervous system, examples of findings that might help to account for broad cognitive impairment include gray and white matter irregularities, poor signal integration by neurons and neural networks, and abnormalities in glutamate and -aminobutyric acid neurotransmission. Other, more speculative hypotheses focus on even broader somatic systems, including energy metabolism and inflammatory processes. Treatment implications of systemic conceptualizations of schizophrenia are also considered.

Neurological Signs and Involuntary Movements in Schizophrenia: Intrinsic To and Informative on Systems Pathobiology

Whitty, P. F., Owoeye, O., Waddington, J. L. — 2009-03-20

While it has long been considered whether the pathobiology of schizophrenia extends beyond its defining symptoms to involve diverse domains of abnormality, in the manner of a systemic disease, studies of neuromotor dysfunction have been confounded by treatment with antipsychotic drugs. This challenge has been illuminated by a new generation of studies on first-episode schizophrenia before initiation of antipsychotic treatment and by opportunities in developing countries to study chronically ill patients who have remained antipsychotic naive due to limitations in provision of psychiatric care. Building from studies in antipsychotic-naive patients, this article reviews 2 domains of neuromotor dysfunction in schizophrenia: neurological signs and involuntary movements. The presence and characteristics of neurological signs in untreated vis-à-vis treated psychosis indicate a vulnerability marker for schizophrenia and implicate disruption to neuronal circuits linking the basal ganglia, cerebral cortex, and cerebellum. The presence and characteristics of involuntary movements in untreated vis-à-vis treated psychosis indicate an intrinsic feature of the disease process and implicate dysfunction in cortical-basal ganglia-cortical circuitry. These neuromotor disorders of schizophrenia join other markers of subtle but pervasive cerebral and extracerebral, systemic dysfunction, and complement current concepts of schizophrenia as a disorder of developmentally determined cortical-basal ganglia-thalamo-cortical/cerebellar network disconnectivity.

Physical Manifestations of Neurodevelopmental Disruption: Are Minor Physical Anomalies Part of the Syndrome of Schizophrenia?

Compton, M. T., Walker, E. F. — 2009-03-20

The well-documented excess of minor physical anomalies (MPAs) among individuals with schizophrenia generally supports the neurodevelopmental model, which posits that both genetic and environmental factors contribute to structural and functional brain changes in the intrauterine and perinatal periods that predispose one to developing schizophrenia. This review synthesizes select areas of research findings on MPAs to address the question, Are MPAs part of the syndrome of schizophrenia? Although MPAs are not specific to schizophrenia, their presence in some patients indicates that aberrations in the development of the nervous system contribute to risk for the disorder. The broadly defined, heterogeneous MPA construct may be of limited value in further elucidating the specific pathophysiology of schizophrenia, though particular anomalies, such as those pertaining to nasal volumes, palatal abnormalities, or craniofacial morphology, may be informative. Given the availability of more sophisticated microarray technologies, and in light of recent findings on spontaneous mutations in patients with schizophrenia, it is possible that MPAs will prove to be useful in identifying etiologic subtypes and/or the loci of genetic risk factors. It remains to be determined whether MPAs—which, of course, are fixed markers present throughout childhood and adolescence well before the onset of the prodrome and psychosis—may have utility in terms of risk stratification for future preventive efforts. Taken together, research findings on MPAs indicate that these minor anomalies are indeed part of some schizophrenia syndromes, representing a stable systemic or physical set of manifestations of the underlying neurodevelopmental processes that lead to the illness.

Telomere Length and Pulse Pressure in Newly Diagnosed, Antipsychotic-Naive Patients With Nonaffective Psychosis

2009-03-20

Introduction: Recent studies suggest that in addition to factors such as treatment side effects, suicide, and poor health habits, people with schizophrenia may have an increased risk of diabetes prior to antipsychotic treatment. Diabetes is associated with an increased pulse pressure (PP) and a shortened telomere. We tested the hypothesis that prior to antipsychotic treatment, schizophrenia and related disorders are associated with a shortened telomere, as well as an increased PP. Methods: Telomere content (which is highly correlated with telomere length) and PP were measured in newly diagnosed, antipsychotic-naive patients with schizophrenia and related disorders on first clinical contact and in matched control subjects. Both groups were also administered an oral glucose tolerance test. Results: Compared with control subjects, the patients with psychosis had decreased telomere content and an increased PP. As previously reported, they also had increased glucose concentrations at 2 hours. These differences could not be attributed to differences in age, ethnicity, smoking, gender, body mass index, neighborhood of residence, socioeconomic status, aerobic conditioning, or an increased cortisol concentration in the psychotic subjects. Discussion: These results suggest that prior to antipsychotic use, nonaffective psychosis is associated with reduced telomere content and increased PP, indices that have been linked to an increased risk of diabetes and hypertension.

Antipsychotic Combinations vs Monotherapy in Schizophrenia: A Meta-analysis of Randomized Controlled Trials

Correll, C. U., Rummel-Kluge, C., Corves, C., Kane, J. M., Leucht, S. — 2009-03-20

Context: Despite lacking evidence for its safety and efficacy, antipsychotic cotreatment is common in schizophrenia.

Objective: To evaluate therapeutic and adverse effects of antipsychotic cotreatment vs monotherapy in schizophrenia.

Data Sources: Cochrane Schizophrenia Group register and hand searches of relevant journals/conference proceedings.

Study Selection: Randomized controlled trials comparing antipsychotic monotherapy to cotreatment with a second antipsychotic.

Data Extraction and Analysis: Two authors independently extracted data. For homogenous dichotomous data, we calculated random effects, relative risk (RR), 95% confidence intervals (CIs), and numbers needed to treat (NNT). For continuous data, weighted mean differences were calculated.

Results: In 19 studies (1229 patients) with 28 monotherapy and 19 cotreatment arms, antipsychotic cotreatment was superior to monotherapy regarding 2 a priori defined coprimary outcomes: less study-specific defined inefficacy (N = 22, n = 1202, RR = 0.76, CI = 0.63–0.90, P = .002, NNT = 7, CI = 4–17, P = .0008, I² = 78.9%) and all-cause discontinuation (N = 20, n = 1052, RR = 0.65, CI = 0.54–0.78, P < .00001). Results were consistent using Clinical Global Impressions thresholds of less than much (P = .006) and less than minimally (P = .01) improved. Specific psychopathology and adverse event data were insufficient to yield meaningful results. In sensitivity analyses, 5 efficacy moderators emerged: concurrent polypharmacy initiation, clozapine combinations, trial duration >10 weeks, Chinese trials, and second-generation + first-generation antipsychotics. In a meta-regression, similar dose combinations, second-generation + first-generation antipsychotics and concurrent polypharmacy initiation remained significant.

Conclusions: In certain clinical situations, antipsychotic cotreatment may be superior to monotherapy. However, the database is subject to possible publication bias and too heterogeneous to derive firm clinical recommendations, underscoring the need for future research.

Does the Addition of a Second Antipsychotic Drug Improve Clozapine Treatment?

Barbui, C., Signoretti, A., Mule, S., Boso, M., Cipriani, A. — 2009-03-20

In patients with schizophrenia who do not have an optimal response to clozapine, it remains unclear if there is an evidence base to support a second antipsychotic in combination with clozapine. The present systematic review was therefore carried out to determine the efficacy of various clozapine combination strategies with antipsychotics. Relevant studies were located by searching the Cochrane Schizophrenia Group Trials Register, Medline, and Embase (up to November 2007). Only studies randomly allocating patients to clozapine plus another antipsychotic vs clozapine monotherapy were included. The search yielded 21 studies suitable for reanalysis. In 3 trials, clozapine was combined with a phenothiazine, in 8 trials with a benzamide, and in the remaining trials with risperidone. While the majority of randomized trials were not double blind, 6 studies were double-blind placebo-controlled trials. A total of 14 randomized open studies significantly favored clozapine combination strategy in terms of mean difference (random effect standardized mean difference [SMD] = –0.80, 95% confidence interval [CI] = –1.14 to –0.46); however, data extracted from 6 randomized double-blind studies did not show a statistically significant positive effect of this combination strategy in terms of mean difference (SMD = –0.12, 95% CI = –0.57 to 0.32). In terms of percentage of patients failing to show an improvement, a total of 10 randomized open studies significantly favored clozapine combination strategy (random effect relative risk [RR] = 0.64, 95% CI = 0.42 to 0.97), but data extracted from 6 randomized double-blind studies did not show a statistically significant positive effect of this combination strategy (RR = 0.91, 95% CI = 0.75 to 1.11). We conclude that the evidence base supporting a second antipsychotic in addition to clozapine in partially responsive patients with schizophrenia is weak. This weak evidence indicates modest to absent benefit.