Schizophrenia Bulletin - Advance Access

Measuring Specific, Rather than Generalized, Cognitive Deficits and Maximizing Between-Group Effect Size in Studies of Cognition and Cognitive Change

Silverstein, S. M. — 2008-05-08

While cognitive impairment in schizophrenia is easy to demonstrate, it has been much more difficult to measure a specific cognitive process unconfounded by the influence of other cognitive processes and noncognitive factors (eg, sedation, low motivation) that affect test scores. With the recent interest in the identification of neurophysiology-linked cognitive probes for clinical trials, the issue of isolating specific cognitive processes has taken on increased importance. Recent advances in research design and psychometric theory regarding cognition research in schizophrenia demonstrate the importance of (1) maximizing between-group differences via reduction of measurement error during both test development and subsequent research and (2) the development and use of process-specific tasks in which theory-driven performance indices are derived across multiple conditions. Use of these 2 strategies can significantly advance both our understanding of schizophrenia and measurement sensitivity for clinical trials. Novel data-analytic strategies for analyzing change across multiple conditions and/or multiple time points also allow for increased reliability and greater measurement sensitivity than traditional strategies. Following discussion of these issues, trade-offs inherent to attempts to address psychometric issues in schizophrenia research are reviewed. Finally, additional considerations for maximizing sensitivity and real-world significance in clinical trials are discussed.

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

2008-04-29

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.

Neurocognitive Allied Phenotypes for Schizophrenia and Bipolar Disorder

Hill, S. K., Harris, M. S. H., Herbener, E. S., Pavuluri, M., Sweeney, J. A. — 2008-04-29

Psychiatric disorders are genetically complex and represent the end product of multiple biological and social factors. Links between genes and disorder-related abnormalities can be effectively captured via assessment of phenotypes that are both associated with genetic effects and potentially contributory to behavioral abnormalities. Identifying intermediate or allied phenotypes as a strategy for clarifying genetic contributions to disorders has been successful in other areas of medicine and is a promising strategy for identifying susceptibility genes in complex psychiatric disorders. There is growing evidence that schizophrenia and bipolar disorder, rather than being wholly distinct disorders, share genetic risk at several loci. Further, there is growing evidence of similarity in the pattern of cognitive and neurobiological deficits in these groups, which may be the result of the effects of these common genetic factors. This review was undertaken to identify patterns of performance on neurocognitive and affective tasks across probands with schizophrenia and bipolar disorder as well as unaffected family members, which warrant further investigation as potential intermediate trait markers. Available evidence indicates that measures of attention regulation, working memory, episodic memory, and emotion processing offer potential for identifying shared and illness-specific allied neurocognitive phenotypes for schizophrenia and bipolar disorder. However, very few studies have evaluated neurocognitive dimensions in bipolar probands or their unaffected relatives, and much work in this area is needed.

Impairments in Cognition Across the Spectrum of Psychiatric Disorders: Evidence From a Swedish Conscript Cohort

David, A. S., Zammit, S., Lewis, G., Dalman, C., Allebeck, P. — 2008-04-25

It is well established that cognitive deficits are an almost invariable component of the schizophrenia syndrome. Much less is known about the association of cognitive deficits and the range of psychiatric disorders. The current study made use of a Swedish conscript cohort which included an IQ assessment and full psychiatric evaluation at conscription of all 18- to 19-year-old males. It was found that reduced intellectual functioning was found in association with psychosis and neurotic disorders including depression, personality disorders, alcoholism, and drug dependence. The effect was particularly strong for alcoholism. This presumably represents a combination of premorbid deficits (as demonstrated in those who developed schizophrenia some years later) plus coincident impairments. The direction of causality of this latter association is likely to be both forward and reverse. Different cognitive subtests showed varied strengths of association: "mechanical ability/knowledge," which might reflect planning and reasoning more than the other subtests, had the strongest effect. Cognitive deficits are widespread in psychiatric disorders and should be taken into account in clinical interactions.

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

Barbui, C., Signoretti, A., Mule, S., Boso, M., Cipriani, A. — 2008-04-23

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.

Anatomical Abnormalities of the Anterior Cingulate Cortex in Schizophrenia: Bridging the Gap Between Neuroimaging and Neuropathology

Fornito, A., Yucel, M., Dean, B., Wood, S. J., Pantelis, C. — 2008-04-23

The anterior cingulate cortex (ACC) is a functionally heterogeneous region involved in diverse cognitive and emotional processes that support goal-directed behaviour. Structural magnetic resonance imaging (MRI) and neuropathological findings over the past two decades have converged to suggest abnormalities in the region may represent a neurobiological basis for many of the clinical manifestations of schizophrenia. However, while each approach offers complimentary information that can provide clues regarding underlying patholophysiological processes, the findings from these 2 fields are seldom integrated. In this article, we review structural neuroimaging and neuropathological studies of the ACC, focusing on the unique information they provide. The available imaging data suggest grey matter reductions in the ACC precede psychosis onset in some categories of high-risk individuals, show sub-regional specificity, and may progress with illness duration. The available post-mortem findings indicate these imaging-related changes are accompanied by reductions in neuronal, synaptic, and dendritic density, as well as increased afferent input, suggesting the grey matter differences observed with MRI arise from alterations in both neuronal and non-neuronal tissue compartments. We discuss the potential mechanisms that might facilitate integration of these findings and consider strategies for future research.

The Impact of Supported Employment and Working on Clinical and Social Functioning: Results of an International Study of Individual Placement and Support

2008-04-21

Background: Concerns are frequently expressed that working might worsen the mental health of people with severe mental illness (SMI). Several studies of Individual Placement and Support (IPS), however, have found associations between working and better nonvocational outcomes. IPS has been found to double the return to work of people with SMI in 6 European countries. Aims: To explore separately associations between IPS, returning to work, and clinical and social outcomes. Methods: Patients (n = 312) in a randomized controlled trial of IPS in 6 European centers were followed up for 18 months. Results: There were no differences in clinical and social functioning between IPS and control patients at 18 months. Those who worked had better global functioning, fewer symptoms, and less social disability at final follow-up; greater job tenure was associated with better functioning. Working was associated with concurrently better clinical and social functioning, but this contrast was stronger in the control group, suggesting that IPS was better than the control service at helping more unwell patients into work. Working was associated with having been in remission and out of hospital for the previous 6 months. It was also associated with a slight decrease in depression and with being in remission over the subsequent 6 months. Conclusions: Concerns among clinicians about possible detrimental effects of working and supported employment have been misplaced. Although some of the associations found may have been selection effects, there is sufficient evidence of work having beneficial effects on clinical and social functioning to merit further exploration.

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. — 2008-04-21

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.

A Review of the Fetal Brain Cytokine Imbalance Hypothesis of Schizophrenia

Meyer, U., Feldon, J., Yee, B. K. — 2008-04-11

Maternal infection during pregnancy increases the risk of schizophrenia and other brain disorders of neurodevelopmental origin in the offspring. A multitude of infectious agents seem to be involved in this association. Therefore, it has been proposed that factors common to the immune response to a wide variety of bacterial and viral pathogens may be the critical link between prenatal infection and postnatal brain and behavioral pathology. More specifically, it has been suggested that the maternal induction of pro-inflammatory cytokines may mediate the neurodevelopmental effects of maternal infections. Here, we review recent findings from in vitro and in vivo investigations supporting this hypothesis and further emphasize the influence of enhanced anti-inflammatory cytokine signaling on early brain development. Disruption of the fetal brain balance between pro- and anti-inflammatory cytokine signaling may thus represent a key mechanism involved in the precipitation of schizophrenia-related pathology following prenatal maternal infection and innate immune imbalances.

Structural Cerebral Variations as Useful Endophenotypes in Schizophrenia: Do They Help Construct "Extended Endophenotypes"?

Prasad, K. M., Keshavan, M. S. — 2008-04-11

Endophenotypes represent intermediate phenotypes on the putative causal pathway from the genotype to the phenotype. They offer a potentially valuable strategy to examine the molecular etiopathology of complex behavioral phenotypes such as schizophrenia. Neurocognitive and neurophysiological impairments that suggest functional impairments associated with schizophrenia have been proposed as endophenotypes. However, few studies have examined the structural variations in the brain that might underlie the functional impairments as useful endophenotypes for schizophrenia. Over the past three decades, there has been an impressive body of literature supporting brain structural alterations in schizophrenia. We critically reviewed the extant literature on the neuroanatomical variations in schizophrenia in this paper to evaluate their candidacy as endophenotypes and how useful they are in furthering the understanding of etiology and pathophysiology of schizophrenia. Brain morphometric measures meet many of the criteria set by different investigators, such as being robustly associated with schizophrenia, heritable, quantifiable, and present in unaffected family members more frequently than in the general population. We conclude that the brain morphometric alterations appear largely to meet the criteria for endophenotypes in psychotic disorders. Some caveats for the utility of endophenotypes are discussed. A proposal to combine more than one endophenotype ("extended endophenotype") is suggested. Further work is needed to examine how specific genes and their interactions with the environment may produce alterations in brain structure and function that accompany psychotic disorders.

Secondary Effects of Antipsychotics: Women at Greater Risk Than Men

Seeman, M. V. — 2008-04-09

Context: The health burden of antipsychotic medication is well known, but the disproportionate effect on women as compared with men is underappreciated. Objective: The goal of this article is preventive—to better inform clinicians so that the risks to women and to their offspring can be diminished. Method: All PubMed sources in which the search term gender (or sex) was linked to a side effect of antipsychotic medication were reviewed. Result: There is general agreement in the literature on women's increased susceptibility to weight gain, diabetes, and specific cardiovascular risks of antipsychotics, with less consensus on malignancy risks and risks to the fetus. Cardiovascular death, to which men are more susceptible than women, is disproportionately increased in women by the use of antipsychotics. Sedating antipsychotics raise the risk of embolic phenomena during pregnancy, and postpartum. Prolactin-elevating drugs suppress gonadal hormone secretion and may enhance autoimmune proclivity. Conclusions: Clinicians need to be aware of the differential harm that women (and their offspring) can incur from the side effects of antipsychotics.

Principles of Antipsychotic Prescribing for Policy Makers, Circa 2008. Translating Knowledge to Promote Individualized Treatment

2008-04-02

Findings from 2 pivotal government-funded studies of comparative antipsychotic effectiveness undermine assumptions about the marked superiority of the more expensive second-generation "atypical" medications in comparison to the less expensive first-generation "typical" drugs. Because this assumption was the basis for the almost universal recommendation that these newer antipsychotics be used preferentially resulting in a 10-fold increase in state governmental expenditures on this class of medications over the past decade, a reassessment of policy is called for. To address the issue, the Medical Directors Council of the National Association of State Mental Health Program Directors critically reviewed findings of these studies in the context of other data and considered policy implications in the light of the obligations of state government to make available best possible and individually optimized treatment that is cost-effective. The Medical Directors Council unanimously adopted a set of recommendations to promote appropriate access, efficient utilization, and best practice use. We present our policy statement, in which we provide a succinct background, articulate general principles, and describe a set of 4 broad recommendations. We then summarize our understanding of the current state of knowledge about comparative antipsychotic effectiveness, best antipsychotic practice, and considerations for state policy that represent the basis of our position statement.

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

Venables, N. C., Bernat, E. M., Sponheim, S. R. — 2008-04-01

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.

Studying and Treating Schizophrenia Using Virtual Reality: A New Paradigm

Freeman, D. — 2008-03-28

Understanding schizophrenia requires consideration of patients’ interactions in the social world. Misinterpretation of other peoples’ behavior is a key feature of persecutory ideation. The occurrence and intensity of hallucinations is affected by the social context. Negative symptoms such as anhedonia, asociality, and blunted affect reflect difficulties in social interactions. Withdrawal and avoidance of other people is frequent in schizophrenia, leading to isolation and rumination. The use of virtual reality (VR)—interactive immersive computer environments—allows one of the key variables in understanding psychosis, social environments, to be controlled, providing exciting applications to research and treatment. Seven applications of virtual social environments to schizophrenia are set out: symptom assessment, identification of symptom markers, establishment of predictive factors, tests of putative causal factors, investigation of the differential prediction of symptoms, determination of toxic elements in the environment, and development of treatment. The initial VR studies of persecutory ideation, which illustrate the ascription of personalities and mental states to virtual people, are highlighted. VR, suitably applied, holds great promise in furthering the understanding and treatment of psychosis.

Extended Visual Simultaneity Thresholds in Patients With Schizophrenia

2008-03-21

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.

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

Thirthalli, J., Jain, S. — 2008-03-13

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.

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

2008-03-06

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.

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

Grant, P. M., Beck, A. T. — 2008-02-27

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.

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. — 2008-02-26

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.

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. — 2008-02-26

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.

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. — 2008-02-21

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.

Are Psychiatrist Characteristics Associated With Postdischarge Suicide of Schizophrenia Patients?

Lee, H.-C., Lin, H.-C. — 2008-02-16

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.

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

2008-02-16

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.

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. — 2008-02-14

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.

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. — 2008-01-31

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.

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

Bell, M., Tsang, H. W. H., Greig, T. C., Bryson, G. J. — 2008-01-31

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.

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

2008-01-31

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.

Effects of Bisphenol-A and Other Endocrine Disruptors Compared With Abnormalities of Schizophrenia: An Endocrine-Disruption Theory of Schizophrenia

Brown, J. S. — 2008-01-31

In recent years, numerous substances have been identified as so-called "endocrine disruptors" because exposure to them results in disruption of normal endocrine function with possible adverse health outcomes. The pathologic and behavioral abnormalities attributed to exposure to endocrine disruptors like bisphenol-A (BPA) have been studied in animals. Mental conditions ranging from cognitive impairment to autism have been linked to BPA exposure by more than one investigation. Concurrent with these developments in BPA research, schizophrenia research has continued to find evidence of possible endocrine or neuroendocrine involvement in the disease. Sufficient information now exists for a comparison of the neurotoxicological and behavioral pathology associated with exposure to BPA and other endocrine disruptors to the abnormalities observed in schizophrenia. This review summarizes these findings and proposes a theory of endocrine disruption, like that observed from BPA exposure, as a pathway of schizophrenia pathogenesis. The review shows similarities exist between the effects of exposure to BPA and other related chemicals with schizophrenia. These similarities can be observed in 11 broad categories of abnormality: physical development, brain anatomy, cellular anatomy, hormone function, neurotransmitters and receptors, proteins and factors, processes and substances, immunology, sexual development, social behaviors or physiological responses, and other behaviors. Some of these similarities are sexually dimorphic and support theories that sexual dimorphisms may be important to schizophrenia pathogenesis. Research recommendations for further elaboration of the theory are proposed.

Impaired Prepulse Inhibition and Prepulse-Elicited Reactivity but Intact Reflex Circuit Excitability in Unmedicated Schizophrenia Patients: a Comparison With Healthy Subjects and Medicated Schizophrenia Patients

2008-01-31

Deficient sensorimotor gating as indexed by prepulse inhibition (PPI) of the startle response has been reported repeatedly in patients suffering from schizophrenia. According to the widely accepted "protective hypothesis," PPI reflects the protection of ongoing information processing against interference by other stimuli. Alternatively, it has been proposed that PPI might be regulated by startle reflex circuit excitability. In the present study, we evaluated these 2 conceptually divergent approaches underlying the regulation of PPI. To this end, we assessed sensorimotor gating as indexed by PPI, the reactivity to the prepulse-alone stimulus indexed as prepulse-elicited reactivity (PPER), and acoustic blink reflex excitability in terms of paired pulse suppression (PPS) within a single recording session in 13 unmedicated and 24 medicated (11 first break) schizophrenia patients in comparison to 43 healthy control subjects. The results showed that PPI was significantly reduced in unmedicated, but not in medicated schizophrenia patients. Furthermore, unmedicated patients could be distinguished from the medicated patients and control subjects in terms of PPER. In contrast to PPI, PPS did not differ between patients and control subjects. These findings are in line with the "protective hypothesis" of PPI and indicate that reduced sensorimotor gating in schizophrenia patients might be based on a reduced perception and/or processing of the prepulse stimulus. The extent to which PPER may or may not be causally associated with sensorimotor gating in schizophrenia has to be further investigated in human and animal studies.

Progression of Brain Volume Changes in Adolescent-Onset Psychosis

2008-01-24

Little is known about the changes that take place in the adolescent brain over the first few years following the onset of psychosis. The present longitudinal study builds on an earlier cross-sectional report demonstrating brain abnormalities in adolescent-onset psychosis patients with a recent-onset first episode of psychosis. Magnetic resonance imaging studies were obtained at baseline and 2 years later from 21 adolescents with psychosis and 34 healthy controls matched for age, gender, and years of education. Whole-brain volumes and gray matter (GM) and cerebrospinal fluid (CSF) volumes of the frontal, parietal, temporal, and occipital lobes were measured at baseline and at 2-year follow-up. In the frontal lobe, the rate of GM volume loss was significantly higher in male patients (2.9% and 2.0%, respectively, for left and right) than in controls (1.2% and 0.7%, respectively, for left and right). In the left frontal lobe, male patients showed a significantly higher rate of CSF volume increase than controls (8.6% vs 6.4%). These differences in rates of volume change were observed in male and female patients, although only males showed significant time x diagnosis interactions. This negative finding in females should be interpreted with caution as the study was underpowered to detect change in women due to limited sample size. An exploratory analysis revealed that schizophrenia and nonschizophrenia psychotic disorders showed similar volume change patterns relative to controls. Change in clinical status was not correlated with longitudinal brain changes. Our results support progression of frontal lobe changes in males with adolescent-onset psychosis.

Attention Shaping: a Reward-Based Learning Method to Enhance Skills Training Outcomes in Schizophrenia

2008-01-22

Disturbances in sustained attention commonly interfere with the ability of persons with schizophrenia to benefit from evidence-based psychosocial treatments. Cognitive remediation interventions have thus far demonstrated minimal effects on attention, as have medications. There is thus a gap between the existence of effective psychosocial treatments and patients' ability to effectively engage in and benefit from them. We report on the results of a multisite study of attention shaping (AS), a behavioral intervention for improving attentiveness and learning of social skills among highly distractible schizophrenia patients. Patients with chronic schizophrenia who were refractory to skills training were assigned to receive either the UCLA Basic Conversation Skills Module (BCSM) augmented with AS (n = 47) or in the standard format (n = 35). AS, a reward-based learning procedure, was employed to facilitate patients' meeting clearly defined and individualized attentiveness and participation goals during each session of a social skills training group. Primary outcome measures were observational ratings of attentiveness in each session and pre- and post-BCSM ratings of social skill and symptoms. Patients receiving social skills training augmented with AS demonstrated significantly more attentiveness in group sessions and higher levels of skill acquisition; moreover, significant relationships were found between changes in attentiveness and amount of skills acquired. Changes in attentiveness were unrelated to level or change in antipsychotic medication dose. AS is an effective example of supported cognition, in that cognitive abilities are improved within the environmental context where the patient is experiencing difficulty, leading to gains in both attention and functional outcome.

Impaired Flush Response to Niacin Skin Patch Among Schizophrenia Patients and Their Nonpsychotic Relatives: The Effect of Genetic Loading

2008-01-18

We previously reported familial aggregation in flush response to niacin skin patch among schizophrenia patients and their nonpsychotic relatives. However, little is known about whether this abnormal skin response is associated with genetic loading for schizophrenia. This study compared the niacin flush response in subjects from families with only one member affected with schizophrenia (simplex families) with those from families having a sib-pair with schizophrenia (multiplex families). Subjects were patients with schizophrenia and their nonpsychotic first-degree relatives from simplex families (176 probands, 260 parents, and 80 siblings) and multiplex families (311 probands, 180 parents, and 52 siblings) as well as 94 healthy controls. Niacin patches of 3 concentrations (0.001M, 0.01M, and 0.1M) were applied to forearm skin, and the flush response was rated at 5, 10, and 15 minutes, respectively, with a 4-point scale. More attenuated flush response to topical niacin was shown in schizophrenia probands and their relatives from multiplex families than in their counterparts from simplex families, and the differentiation was better revealed using 0.1M concentration of niacin than 0.01M or 0.001M. For the highest concentration of 0.1M and the longest time lag of 15 minutes, a subgroup of probands (23%), parents (27%), and siblings (19%) still exhibited nonflush response. Flush response to niacin skin patch is more impaired in schizophrenia patients and their relatives from families with higher genetic loading for schizophrenia, and this finding has implications for future genetic dissection of schizophrenia.

Executive Attention in Schizophrenic Males and the Impact of COMT Val108/158Met Genotype on Performance on the Attention Network Test

Opgen-Rhein, C., Neuhaus, A. H., Urbanek, C., Hahn, E., Sander, T., Dettling, M. — 2008-01-16

Background: Executive control of attention in schizophrenia has recently been assessed by means of the Attention Network Test (ANT). In the past, for tasks assessing executive attention, findings in schizophrenia have been contradictory, among others suggesting a lack of increased stimulus interference effects. Attention and executive functioning are substantially influenced by candidate genes of schizophrenia, including the functional single-nucleotide polymorphism catechol-o-methyltransferase (COMT) Val^108/158Met, with task-dependent, specific effects of Met allele load on cognitive function. Therefore, we aimed at investigating executive attention in schizophrenic patients (SZP) as compared with healthy controls (HC), and to assess the specific impact of COMT Val^108/158Met on executive attention, using ANT. Methods: We applied ANT to 63 SZP and 40 HC. We calculated a general linear model to investigate the influence of affection status and the COMT Val^108/158Met genotype on executive attention as assessed by the ANT. Results: Multivariate analysis of variance revealed a significant effect of group on executive attention. SZP exhibited smaller conflict effects in the ANT. Met allele load significantly modulated executive attention efficiency, with homozygous Met individuals showing low overall reaction time but increased effects conflicting stimulus information in executive attention. Conclusions: Our data suggest a disease-related dissociation of executive attention with reduced conflict effects in SZP. Furthermore, they support the hypothesis of differential tonic-phasic dopamine activation and specific dopamine level effects in different cognitive tasks, which helps interpreting contradictory findings of Met allele load on cognitive performance. Disease status seems to modulate the impact of COMT Val^108/158Met on cognitive performance.

Insight Into Neurocognitive Dysfunction in Schizophrenia

Medalia, A., Thysen, J. — 2008-01-16

Insight into psychotic symptoms is typically poor in schizophrenia; however, it is not known whether insight into neurocognitive impairment is similarly impaired. Most people with schizophrenia experience cognitive dysfunction, and the deficits in attention, memory, and critical thinking have been associated with poor functional outcome. As new treatments are developed for the cognitive impairments, it will be important to know whether patients will be receptive to yet another therapy. Insight is an important factor in treatment compliance and treatment outcome; however, it is not known if patients have insight into their cognitive dysfunction. In order to assess insight into neuro cognitive dysfunction, 75 subjects were administered the Measure of Insight into Cognition–Clinician Rated, a newly created measure based on the Scale to Access the Unawareness of Mental Disorder, that assesses insight into cognitive impairment. Subjects were also administered the Brief Assessment of Cognition in Schizophrenia and Independent Living Scale–Problem Solving to objectively assess neuropsychological status and problem-solving skills needed for independent living. Results demonstrated that virtually all subjects had cognitive impairment, yet insight into their neuro cognitive symptoms was limited. This finding has potential implications for treatment programs seeking to improve cognitive functioning in schizophrenia

Social Cognition in Schizophrenia: An NIMH Workshop on Definitions, Assessment, and Research Opportunities

2008-01-08

Social cognition has become a high priority area for the study of schizophrenia. However, despite developments in this area, progress remains limited by inconsistent terminology and differences in the way social cognition is measured. To address these obstacles, a consensus-building meeting on social cognition in schizophrenia was held at the National Institute of Mental Health in March 2006. Agreement was reached on several points, including definitions of terms, the significance of social cognition for schizophrenia research, and suggestions for future research directions. The importance of translational interdisciplinary research teams was emphasized. The current article presents a summary of these discussions.

The Concept of Psychosis: Historical and Phenomenological Aspects

Burgy, M. — 2008-01-03

The historical development of the concept of psychosis and its increasing differentiation from the neuroses up to the modern classification systems, Diagnostic and Statistical Manual of Mental Disorders and International Statistical Classification of Diseases, is initially presented. In portraying this development, the struggle surrounding the clinical relevance of concepts on the one hand and their reliability and validity on the other are reflected. Thus far, diagnostic reliability has primarily been improved by focusing on externally observable symptoms in connection with expression and behavior. The identification of disease-specific symptoms, however, is principally achieved through the differential description of subjective experience. How this experience is to be explored and assessed remains for the most part unclear. With reference to its founder Karl Jaspers, the phenomenological method is presented as the decisive instrument for the assessment of experience. It is shown that a return to the legacy of phenomenology and a reformulation of the long-standing question concerning the specific symptoms of the schizophrenic psychosis are currently in progress. The revival of historical knowledge and a focus on direct clinical phenomena continue to provide inspiration for further advancement in modern psychiatry.

Leptin and Ghrelin Levels in Patients With Schizophrenia During Different Antipsychotics Treatment: A Review

Sentissi, O., Epelbaum, J., Olie, J.-P., Poirier, M.-F. — 2007-12-28

Energy homeostasis is achieved by the integration of peripheral metabolic signals by the neural circuits involving specific hypothalamic nuclei and brain stem regions. These neural circuits mediate many of the effects of the adipocyte-derived hormone leptin and gut-derived hormone ghrelin. The former is strongly anorexigenic while the latter is the only orexigenic agent active when administered by a peripheral route. Abnormal regulation of these 2 antagonistic regulatory peptides in patients with schizophrenia could play a role in the impairment in the regulation of food intake and energy balance. This bibliographical analysis aims to compare 27 prospective and cross-sectional studies published on circulating leptin and ghrelin levels during acute and chronic administration of antipsychotics treatment, especially atypical ones. Fasting morning leptin levels of schizophrenic patients increase rapidly in the first 2 weeks after atypical antipsychotic (AAP) treatment (mostly olanzapine and clozapine) and remain somehow elevated after that period up to several months. On the contrary, conventional antipsychotics (such as haloperidol) do not interfere with leptin levels. In contrast to leptin, fasting morning ghrelin levels decrease during the first few weeks after the beginning of AAPs treatment while they increase in the longer run. Surprisingly, body weight gain and correlations between the variation of these 2 peptides and adiposity and metabolism-related parameters such as the body mass index and abdominal perimeter were not systematically considered. Finally, an objective evaluation of feeding behavior during antipsychotic treatment remains to be determined.

Is Schizophrenia a Syndrome of Accelerated Aging?

Kirkpatrick, B., Messias, E., Harvey, P. D., Fernandez-Egea, E., Bowie, C. R. — 2007-12-21

Schizophrenia is associated with a number of anatomical and physiological abnormalities outside of the brain, as well as with a decrease in average life span estimated at 20% in the United States. Some studies suggest that this increased mortality is not entirely due to associated causes such as suicide and the use of psychotropic medications. In this article, in order to focus greater attention on the increased mortality associated with schizophrenia, we present a special case of the hypothesis that physiological abnormalities associated with schizophrenia make a contribution to the increased mortality of schizophrenia: specifically, the hypothesis that schizophrenia is a syndrome of accelerated aging. Evidence consistent with this hypothesis comes from several areas. The biological plausibility of the hypothesis is supported by the existence of established syndromes of accelerated aging and by the sharing of risk factors between schizophrenia and other age-related conditions. We propose methods for testing the hypothesis.

Results From a Hypothesis Generating Case-Control Study: Herpes Family Viruses and Schizophrenia Among Military Personnel

Niebuhr, D. W., Millikan, A. M., Yolken, R., Li, Y., Weber, N. S. — 2007-12-21

Background: Herpes family viruses can cause central nervous system inflammatory changes that can present with symptoms indistinguishable from schizophrenia and therefore are of interest in schizophrenia research. Most existing studies of herpes viruses have used small populations and postdiagnosis specimens. As part of a larger research program, we conducted a hypothesis-generating case-control study of selected herpes virus antibodies among individuals discharged from the US military with schizophrenia and pre- and postdiagnosis sera. Methods: Cases (n = 180) were servicemembers hospitalized and discharged from military service with schizophrenia. Controls, 3:1 matched on several factors, were members not discharged. The military routinely collects and stores members' serum specimens. We used microplate enzyme immunoassay to measure immunoglobulin G (IgG) antibody levels to 6 herpes viruses in pre- and postdiagnosis specimens. Conditional logistic regression was used, and the measure of association was the hazard ratio (HR). Results: Overall, we found a significant association between human herpes virus type 6 and schizophrenia, with an HR of 1.17 (95% confidence interval [CI] = 1.04, 1.32). Women and blacks had significant negative associations with herpes simplex virus type 2 and cytomegalovirus; among blacks, there was a significant positive association with herpes simplex virus type 1. Among men, there was a HHV-6 temporal effect with an HR of 1.41 (95% CI = 1.02, 1.96) for sera drawn 6–12 months before diagnosis. Discussion: Findings from previous studies of herpes family viruses and schizophrenia have been inconsistent. Our study is based on a larger population than most previous studies and used serum specimens collected before onset of illness. This study adds to the body of knowledge and provides testable hypotheses for follow-on studies.

Estrogen and Comprehension of Metaphoric Speech in Women Suffering From Schizophrenia: Results of a Double-Blind, Placebo-Controlled Trial

Bergemann, N., Parzer, P., Jaggy, S., Auler, B., Mundt, C., Maier-Braunleder, S. — 2007-12-21

Objective: The effects of estrogen on comprehension of metaphoric speech, word fluency, and verbal ability were investigated in women suffering from schizophrenia. The issue of estrogen-dependent neuropsychological performance could be highly relevant because women with schizophrenia frequently suffer from hypoestrogenism. Method: A placebo-controlled, double-blind, crossover study using 17β-estradiol for replacement therapy and as an adjunct to a naturalistic maintenance antipsychotic treatment was carried out over a period of 8 months. Nineteen women (mean age = 38.0 years, SD = 9.9 years) with schizophrenia were included in the study. Comprehension of metaphoric speech was measured by a lexical decision paradigm, word fluency, and verbal ability by a paper-and-pencil test. Results: Significant improvement was seen for the activation of metaphoric meaning during estrogen treatment (P = .013); in contrast, no difference was found for the activation of concrete meaning under this condition. Verbal ability and word fluency did not improve under estrogen replacement therapy either. Conclusions: This is the very first study based on estrogen intervention instead of the physiological hormone changes to examine the estrogen effects on neuropsychological performance in women with schizophrenia. In addition, it is the first time that the effect of estrogen on metaphoric speech comprehension was investigated in this context. While in a previous study estrogen therapy as adjunct to a naturalistic maintenance treatment with antipsychotics did not show an effect on psychopathology measured by a rating scale, a significant effect of estrogen on the comprehension of metaphoric speech and/or concretism, a main feature of schizophrenic thought and language disturbance, was found in the present study. Because the improvement of formal thought disorders and language disturbances is crucial for social integration of patients with schizophrenia, the results may have implications for the treatment of these individuals.

Clinical, Functional, and Economic Ramifications of Early Nonresponse to Antipsychotics in the Naturalistic Treatment of Schizophrenia

2007-12-21

Objective: Early nonresponse to antipsychotics appears to predict subsequent nonresponse to treatment when assessed in randomized controlled trials of predominately acute inpatients treated for schizophrenia. This study assessed the predictive accuracy of early nonresponse to treatment and its clinical, functional, and economic ramifications in the naturalistic treatment of predominately chronic outpatients treated for schizophrenia. Methods: This post hoc analysis used data from a 1-year, randomized, open-label study of olanzapine, risperidone, and typical antipsychotics in the treatment of schizophrenia. If clinically warranted, patients could switch antipsychotics following 8 weeks of treatment. Patients completing 8 weeks of treatment (n = 443 of 664 enrollees) were included. Patients with early response (≥20% improvement from baseline on the Positive and Negative Syndrome Scale at 2 weeks) were compared with early nonresponders on symptom remission, functionality, perceptions of medication influence, and total health care costs at 8 weeks. Results: Early response/nonresponse at 2 weeks predicted subsequent response/nonresponse at 8 weeks with a high level of accuracy (72%) and specificity (89%). After 8 weeks, early nonresponders were less likely to achieve symptom remission (P < .001), improved less on functional domains (P < .05), perceived medication as less beneficial (P = .004), and incurred total heath care costs over twice that of early responders ($4349 vs $2102, P = .010). Conclusions: In the usual care of schizophrenia patients, early nonresponse appears to reliably predict subsequent nonresponse to continued treatment with the same medication to be associated with poorer outcomes and higher health care costs. Identifying early nonresponders may minimize prolonging exposure to suboptimal or ineffective treatment strategies.

Use of Depot Antipsychotic Medications for Medication Nonadherence in Schizophrenia

West, J. C., Marcus, S. C., Wilk, J., Countis, L. M., Regier, D. A., Olfson, M. — 2007-12-18

Objectives: To describe factors associated with initiation of depot antipsychotic medications in psychiatric outpatients with schizophrenia and recent medication nonadherence. Methods: A national sample of psychiatrists reported on adult outpatients with schizophrenia who were nonadherent with oral antipsychotic medications in the last year. Results: In total, 17.6% of psychiatrists initiated depot antipsychotic injections. Initiation was significantly and positively associated with public insurance, prior inpatient admission, proportion of time nonadherent, average or above average intellectual functioning, and living in a mental health residence. Use was inversely associated with using second-generation antipsychotics and other oral psychotropic medications prior to medication nonadherence. Psychiatrists who were male, nonwhite, and more optimistic about managing nonadherence were more likely to initiate depot injections. Conclusions: Initiation of depot injections is a joint function of patient, physician, treatment, and setting factors. Use of long-acting preparations in this population is uncommon despite clinical recommendations urging their use.

Hypothesis: Grandiosity and Guilt Cause Paranoia; Paranoid Schizophrenia is a Psychotic Mood Disorder; a Review

Lake, C. R. — 2007-12-01

Delusional paranoia has been associated with severe mental illness for over a century. Kraepelin introduced a disorder called "paranoid depression," but "paranoid" became linked to schizophrenia, not to mood disorders. Paranoid remains the most common subtype of schizophrenia, but some of these cases, as Kraepelin initially implied, may be unrecognized psychotic mood disorders, so the relationship of paranoid schizophrenia to psychotic bipolar disorder warrants reevaluation. To address whether paranoia associates more with schizophrenia or mood disorders, a selected literature is reviewed and 11 cases are summarized. Comparative clinical and recent molecular genetic data find phenotypic and genotypic commonalities between patients diagnosed with schizophrenia and psychotic bipolar disorder lending support to the idea that paranoid schizophrenia could be the same disorder as psychotic bipolar disorder. A selected clinical literature finds no symptom, course, or characteristic traditionally considered diagnostic of schizophrenia that cannot be accounted for by psychotic bipolar disorder patients. For example, it is hypothesized here that 2 common mood-based symptoms, grandiosity and guilt, may underlie functional paranoia. Mania explains paranoia when there are grandiose delusions that one's possessions are so valuable that others will kill for them. Similarly, depression explains paranoia when delusional guilt convinces patients that they deserve punishment. In both cases, fear becomes the overwhelming emotion but patient and physician focus on the paranoia rather than on underlying mood symptoms can cause misdiagnoses. This study uses a clinical, case-based, hypothesis generation approach that warrants follow-up with a larger representative sample of psychotic patients followed prospectively to determine the degree to which the clinical course observed herein is typical of all such patients. Differential diagnoses, nomenclature, and treatment implications are discussed because bipolar patients misdiagnosed with schizophrenia are severely misserved.

Can Antistigma Campaigns Be Improved? A Test of the Impact of Biogenetic Vs Psychosocial Causal Explanations on Implicit and Explicit Attitudes to Schizophrenia

Lincoln, T. M., Arens, E., Berger, C., Rief, W. — 2007-12-01

Antistigma campaigns have been promoting a medical view of schizophrenia. Given the growing body of research finding negative associations between biogenetic (BG) causal attributions and stigmatizing attitudes, this approach must be reappraised. The present study investigates the impact of different psychoeducational interventions on the etiology of schizophrenia (BG and psychosocial [PS], vs a neutral condition) and on stigmatizing attitudes in medical (n = 60) and psychology students (n = 61). Information was presented via information brochures and a video presentation. Attitudes were assessed before and after the interventions on an explicit level using the stereotype questionnaire and the Social Distance Scale as well as on an implicit level, using the Implicit Association Test. Both educational interventions produced a significant decrease in several stereotype components, which was not the case in the neutral condition. The BG intervention decreased the attribution of blame in both groups. It also decreased the stereotype unpredictability/incompetence and social distance in the medical students but increased the negative outlook on prognosis in the psychology students. The PS intervention reduced the widespread stereotype of dangerousness as well as social distance in the group of medical students. While further research into antistigma interventions is necessary, the proposal for antistigma campaigns is to take a multidimensional and balanced approach, which is adapted to target groups and provides additional facts that challenge the myths maintaining stigma.

Schizophrenia, Psychiatric Genetics, and Darwinian Psychiatry: An Evolutionary Framework

Pearlson, G. D., Folley, B. S. — 2007-11-21

The evolutionary origins of one of the most dramatic and seemingly deleterious behavioral phenotypes, the syndrome known as schizophrenia, are mysterious. Schizophrenia occurs in all cultures and is inherited. Although most phenotypes are said to be "selected for" based on adaptive qualities, it is difficult to understand how the genetic basis of schizophrenia could have operated under a similar framework. This has lead several theorists analyzing the proposed evolutionary origins of other disease states to that of schizophrenia. To date, several models have been applied. We have tried to conceptualize schizophrenia in a compensatory advantage framework whereby incomplete penetrance of the full disorder, or alternatively, the inheritance of risk alleles insufficient in number to manifest as the classic clinical syndrome, may manifest as a behavioral phenotype with adaptive advantages (eg, creative behavior or novel illuminating ideas). The idea that even full penetrance can also be advantageous has been offered as applied to religious experience and ancient social standing, but is unlikely. Can complex behavioral phenotypes such as schizophrenia, and particularly those that seem purely deleterious, be explained by mechanisms of Darwinian psychiatry? Can models from other disease classes be applied successfully to schizophrenia? Such ideas have generated intense speculation, but often in the absence of testable models. In this article, we will examine some of these proposed ideas and offer suggestions for future research.

Validity of the Premorbid Adjustment Scale

Brill, N., Reichenberg, A., Weiser, M., Rabinowitz, J. — 2007-11-20

Background: The aim of the current study was to test the predictive and concurrent validity of the Premorbid Adjustment Scale (PAS) by comparing it with another similar but more elaborate retrospective measure and with data collected during late adolescence. Methods: We compared PAS late adolescence scores (age 16–18 years) of 91 males with schizophrenia or schizoaffective disorder with data on behavior collected in adolescence, before the first psychotic episode as part of standardized Draft Board screening, and with the same measure readministered during adulthood and modified to collect the same data again retrospectively. Results: The correlation of the PAS social withdrawal and social relations items with the social behavior scale of the Draft Board were .76 and .80, respectively, for the concurrent ratings and .52 and .53, respectively, for the data collected at age 17 years. The correlation of the PAS school achievements and school adjustment items with the functioning in structured environments scale of the Draft Board were .71 and .72, respectively, for the concurrent ratings and .43 and .47, respectively, for the data collected at age 17 years. Conclusions: Our results support the predictive and concurrent validity of the PAS and the validity of self-reported data on premorbid functioning in persons with schizophrenia.

A Composite Approach That Includes Dropout Rates When Analyzing Efficacy Data in Clinical Trials of Antipsychotic Medications

Rabinowitz, J., Davidov, O. — 2007-09-29

Background: Often, outcomes in clinical trials of antipsychotic medications are examined using last observation carried forward (LOCF). One limitation of LOCF and other common approaches is that they overlook the meaning underpinning trial completion and noncompletion. Noncompletion often relates to lack of drug tolerability. Because long-term treatment is often indicated, noncompletion is an important outcome. An alternative approach is to test the composite hypothesis of the difference between (a) completion rates and (b) efficacy of complete cases. Studies to date have not applied this relatively new method. Objective: To illustrate the composite approach, we applied it to a systematic review of studies and compared the results with the reported LOCF analysis. Methods: A systematic search of the Schizophrenia Module of the Cochrane Library and Medline was conducted that identified 127 relevant randomized clinical trials of antipsychotic medications conducted since 1995. Extracted from study reports were the P values of a difference in dropout and the P value of a difference in improvement among complete cases. These P values were combined using standard approaches. Results: We identified 11 trials with 5339 participants that provided the necessary information to adequately apply the composite approach. In 2 trials, (18.2%) in which the LOCF results were not significant, the composite results were significant. Conclusions: The composite approach was more sensitive to change than LOCF and conceptually answers a more relevant question. It is likely that applying the composite approach would change how results of many trials are interpreted.