Schizophrenia Bulletin - current issue

Has Research Informed Us on the Practical Drug Treatment of Schizophrenia?

Davis, J. M., Leucht, S. — 2008-04-14

Emerging From Schizophrenia

Cohen, M. — 2008-04-14

Social Cognition in Schizophrenia: An Overview

Penn, D. L., Sanna, L. J., Roberts, D. L. — 2008-04-14

The purpose of this column is to provide an overview of social cognition in schizophrenia. The column begins with a short introduction to social cognition. Then, we describe the application of social cognition to the study of schizophrenia, with an emphasis on key domains (i.e., emotion perception, Theory of Mind, and attributional style). We conclude the column by discussing the relationship of social cognition to neurocognition, negative symptoms, and functioning, with an eye toward strategies for improving social cognition in schizophrenia.

Gene Expression in the Etiology of Schizophrenia

Bray, N. J. — 2008-04-14

Gene expression represents a fundamental interface between genes and environment in the development and ongoing plasticity of the human brain. Individual differences in gene expression are likely to underpin much of human diversity, including psychiatric illness. In the past decade, the development of microarray and proteomic technology has enabled global description of gene expression in schizophrenia. However, it is difficult on the basis of gene expression assays alone to distinguish between those changes that constitute primary etiology and those that reflect secondary pathology, compensatory mechanisms, or confounding influences. In this respect, tests of genetic association with schizophrenia will be instructive because changes in gene expression that result from gene variants that are associated with the disorder are likely to be of primary etiological significance. However, regulatory polymorphism is extremely difficult to recognize on the basis of sequence interrogation alone. Functional assays at the messenger RNA and/or protein level will be essential in elucidating the molecular mechanisms underlying genetic association with schizophrenia and are likely to become increasingly important in the identification of regulatory variants with which to test for association with the disorder and related traits. Once established, etiologically relevant changes in gene expression can be recapitulated in model systems in order to elucidate the molecular and physiological pathways that may ultimately give rise to the condition.

Paliperidone for Treatment of Schizophrenia

Nussbaum, A. M., Stroup, T. S. — 2008-04-14

In short-term studies, oral paliperidone is an antipsychotic that is more efficacious than placebo. We found its adverse effects to be similar to those of its parent compound, risperidone, with movement disorders, weight gain, and tachycardia all more common with paliperidone than placebo. In addition, paliperidone is associated with substantial increases in serum prolactin that may be associated with sexual dysfunction, although sexual functioning outcomes were not reported. At doses greater than 3 mg per day, oral paliperidone appears comparable in efficacy to oral olanzapine 10 mg per day. Regarding the critical comparison of oral paliperidone to risperidone, we have no information and are thus unable to determine if paliperidone has any advantages or disadvantages compared to its well-known parent compound.

Less Unique Variance Than Meets the Eye: Overlap Among Traditional Neuropsychological Dimensions in Schizophrenia

Dickinson, D., Gold, J. M. — 2008-04-14

The magnitude of the overlap among dimensions of neuropsychological test performance in schizophrenia has been the subject of perennial controversy. This issue has taken on renewed importance with the recent focus on cognition as a treatment target in schizophrenia. A substantial body of factor analytic literature indicates that dimensions are separable in schizophrenia. However, this literature is generally uninformative as to whether the separable dimensions are independent, weakly correlated, or strongly correlated. Factor analyses have often used methods (ie, principal components analysis with orthogonal rotation) that preclude this determination, and correlations among factor-based domain composites and underlying measures have been reported infrequently in these studies. Current meta-analyses of reported "between-dimension" correlations for individual neuropsychological measures and for cognitive domain composite variables indicate that cognition variables in schizophrenia are correlated, on average, at a "medium" level of r = 0.37 for individual measures from different cognitive dimensions and r = 0.45 for domain composites. Because these are mean bivariate correlations, the multiple correlation of an individual measure with all the other measures in a cognitive battery is likely to be higher. Measure reliabilities of 0.80 or less also imply greater commonality among traditional neuropsychological measures. In short, there are underappreciated constraints on the amount of reliable cognitive performance variance in traditional neuropsychological test batteries that is free to vary independently. The ability of such batteries to reveal cognitive domain–specific treatment effects in schizophrenia may be much more limited than is generally assumed.

First Aid Recommendations for Psychosis: Using the Delphi Method to Gain Consensus Between Mental Health Consumers, Carers, and Clinicians

Langlands, R. L., Jorm, A. F., Kelly, C. M., Kitchener, B. A. — 2008-04-14

Background: Members of the general public often lack the knowledge and skills to intervene effectively to help someone who may be developing a psychotic illness before appropriate professional help is received. Methods: We used the Delphi method to determine recommendations on first aid for psychosis. An international panel of 157 mental health consumers, carers, and clinicians completed a 146-item questionnaire about how a member of the public could help someone who may be experiencing psychosis. The panel members rated each questionnaire item according to whether they believed the statement should be included in the first aid recommendations. The results were analyzed by comparing consensus rates across the 3 groups. Three rounds of ratings were required to consolidate consensus levels. Results: Eighty-nine items were endorsed by ≥80% of panel members from all 3 groups as essential or important for psychosis first aid. These items were grouped under the following 9 headings: how to know if someone is experiencing psychosis; how to approach someone who may be experiencing psychosis; how to be supportive; how to deal with delusions and hallucinations; how to deal with communication difficulties; whether to encourage the person to seek professional help; what to do if the person does not want help; what to do in a crisis situation when the person has become acutely unwell; what to do if the person becomes aggressive. Conclusions: These recommendations will improve the provision of first aid to individuals who are developing a psychotic disorder by informing the content of training courses.

The Dimensional Structure of the Wisconsin Schizotypy Scales: Factor Identification and Construct Validity

Kwapil, T. R., Barrantes-Vidal, N., Silvia, P. J. — 2008-04-14

The present study examined the factor structure underlying the Wisconsin Schizotypy Scales and the validity of these dimensions. Confirmatory factor analysis with 6137 nonclinical young adults supported a 2-factor model with positive and negative schizotypy dimensions. As predicted, the schizotypy dimensions were differentially related to psychopathology, personality, and social impairment. Both dimensions were related to schizotypal and paranoid symptoms. Positive schizotypy was uniquely related to psychotic-like experiences, substance abuse, mood disorders, and mental health treatment, whereas negative schizotypy was associated with negative and schizoid symptoms. Both dimensions were associated with poorer overall and social functioning, but negative schizotypy was associated with decreased likelihood of intimate relationships. The findings support the construct validity of a multidimensional model of schizotypy and the use of psychometric inventories to assess these dimensions.

Systematic Association Studies of Mitochondrial DNA Variations in Schizophrenia: Focus on the ND5 Gene

2008-04-14

Postmortem studies, as well as genetic association studies, have implicated mitochondrial dysfunction in schizophrenia (SZ). We conducted multistaged analysis to assess the involvement of mitochondrial DNA (mtDNA) variations in SZ. Initially, the entire mtDNA genome was sequenced in pools of DNA from SZ cases and controls (n = 180 in each group, set 1). Two polymorphisms localized to the NADH dehydrogenase subunit 5 (ND5) gene demonstrated suggestive case control allele frequency differences (mtDNA 13368 G/A, p = .019 and mtDNA 13708G/A, p = .043). Hence, the ND5 gene was sequenced in individual samples from the initial panel of cases and controls. Additional subjects from another independent set of cases and controls (set 2, cases, n = 244, controls n = 508) were also sequenced individually. No significant differences in allele frequencies for mtDNA 13368 G/A, and mtDNA 13708G/A were observed. However, we identified 216 other rare variants, 53 of which were reported earlier in association studies of other mitochondrial disorders. We compared the distribution of polymorphisms in both sets of cases and controls. No significant case-control differences were observed in the smaller, first set. In the second set, cases had more variants overall (p = 0.014), as well as synonymous variants (p = 0.02), but the difference for nonsynonymous variants was not significant (p = 0.19). Screening available first-degree relatives (n = 10) revealed 10 maternally inherited variations, suggesting that not all the variants are somatic mutations. Further investigations are warranted.

The Key to Reducing Duration of Untreated First Psychosis: Information Campaigns

2008-04-14

The TIPS early intervention program reduced the duration of untreated psychosis (DUP) in first-episode schizophrenia from 16 to 5 weeks in a health care sector using a combination of easy access detection teams (DTs) and a massive information campaign (IC) about the signs and symptoms of psychosis. This study reports what happens to DUP and presenting schizophrenia in the same health care sector when the IC is stopped. Methods: Using an historical control design, we compare 2 cohorts of patients with first-episode Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, non-affective psychosis at admission to treatment. The first cohort (N = 108) was recruited from January 1997 to December 2000, using an IC to raise awareness about recognizing psychosis to the public, the schools, and to general practitioners. The second cohort (N = 75) was recruited from January 2002 to June 2004 with no-IC. Easy access DTs were available to both cohorts. Results: In the no-IC period, DUP increased back up to 15 weeks (median) and fewer patients came to clinical attention through the DTs. No-IC patients were diagnosed less frequently with schizophreniform disorder, more Positive and Negative Syndrome Scale positive and total symptoms, and poorer Global Assessment of Functioning (symptom) Scale scores. Conclusions: Intensive education campaigns toward the general public, the schools, and the primary health care services appear to be an important and necessary part of an early detection program. When such a campaign was stopped, there was a clear regressive change in help-seeking behavior with an increase in DUP and baseline symptoms.

Neural Evidence for Faster and Further Automatic Spreading Activation in Schizophrenic Thought Disorder

Kreher, D. A., Holcomb, P. J., Goff, D., Kuperberg, G. R. — 2008-04-14

It has been proposed that the loose associations characteristic of thought disorder in schizophrenia result from an abnormal increase in the automatic spread of activation through semantic memory. We tested this hypothesis by examining the time course of neural semantic priming using event-related potentials (ERPs). ERPs were recorded to target words that were directly related, indirectly related, and unrelated to their preceding primes, while thought-disordered (TD) and non-TD schizophrenia patients and healthy controls performed an implicit semantic categorization task under experimental conditions that encouraged automatic processing. By 300–400 milliseconds after target word onset, TD patients showed increased indirect semantic priming relative to non-TD patients and healthy controls, while the degree of direct semantic priming was increased in only the most severely TD patients. By 400–500 milliseconds after target word onset, both direct and indirect semantic priming were generally equivalent across the 3 groups. These findings demonstrate for the first time at a neural level that, under automatic conditions, activation across the semantic network spreads further within a shorter period of time in specific association with positive thought disorder in schizophrenia.

The Use of Individually Tailored Environmental Supports to Improve Medication Adherence and Outcomes in Schizophrenia

2008-04-14

Cognitive adaptation training (CAT) is a psychosocial treatment that uses environmental supports such as signs, checklists, alarms, and the organization of belongings to cue and sequence adaptive behaviors in the home. Ninety-five outpatients with schizophrenia (structured clinical interview for diagnosis, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) were randomly assigned to (1) Full-CAT (CAT focused on many aspects of community adaptation including grooming, care of living quarters, leisure skills, social and role performance, and medication adherence), (2) Pharm-CAT (CAT focused only on medication and appointment adherence), or (3) treatment as usual (TAU). Treatment lasted for 9 months, and patients were followed for 6 months after the withdrawal of home visits. Medication adherence (assessed during unannounced, in-home pill counts) and functional outcomes were assessed at 3-month intervals. Results of mixed-effects regression models indicated that both CAT and Pharm-CAT treatments were superior to TAU for improving adherence to prescribed medication (P < .0001). Effects on medication adherence remained significant when home visits were withdrawn. Full-CAT treatment improved functional outcome relative to Pharm-CAT and TAU (P < .0001). However, differences for functional outcome across groups decreased following the withdrawal of home visits and were no longer statistically significant at the 6-month follow-up. Survival time to relapse or significant exacerbation was significantly longer in both CAT and Pharm-CAT in comparison to TAU (.004). Findings indicate that supports targeting medication adherence can improve and maintain this behavior. Comprehensive supports targeting multiple domains of functioning are necessary to improve functional outcomes. Maintenance of gains in functional outcome may require some form of continued intervention.

Oculomotor and Neuropsychological Effects of Antipsychotic Treatment for Schizophrenia

Hill, S. K., Reilly, J. L., Harris, M. S. H., Khine, T., Sweeney, J. A. — 2008-04-14

Cognitive enhancement has become an important target for drug therapies in schizophrenia. Treatment development in this area requires assessment approaches that are sensitive to procognitive effects of antipsychotic and adjunctive treatments. Ideally, new treatments will have translational characteristics for parallel human and animal research. Previous studies of antipsychotic effects on cognition have relied primarily on paper-and-pencil neuropsychological testing. No study has directly compared neurophysiological biomarkers and neuropsychological testing as strategies for assessing cognitive effects of antipsychotic treatment early in the course of schizophrenia. Antipsychotic-naive patients with schizophrenia were tested before treatment with risperidone and again 6 weeks later. Matched healthy participants were tested over a similar time period. Test-retest reliability, effect sizes of within-subject change, and multivariate/univariate analysis of variance were used to compare 3 neurophysiological tests (visually guided saccade, memory-guided saccade, and antisaccade) with neuropsychological tests covering 4 cognitive domains (executive function, attention, memory, and manual motor function). While both measurement approaches showed robust neurocognitive impairments in patients prior to risperidone treatment, oculomotor biomarkers were more sensitive to treatment-related effects on neurocognitive function than traditional neuropsychological measures. Further, unlike the pattern of modest generalized cognitive improvement suggested by neuropsychological measures, the oculomotor findings revealed a mixed pattern of beneficial and adverse treatment-related effects. These findings warrant further investigation regarding the utility of neurophysiological biomarkers for assessing cognitive outcomes of antipsychotic treatment in clinical trials and in early-phase drug development.

Feasibility and Validity of Computerized Ecological Momentary Assessment in Schizophrenia

Granholm, E., Loh, C., Swendsen, J. — 2008-04-14

Background: Computerized Ecological Momentary Assessment (EMAc) techniques permit the assessment of daily life behaviors and experiences. The present investigation examined the feasibility and validity of this assessment methodology in outpatients with schizophrenia. Methods: Outpatients with schizophrenia or schizoaffective disorder (n = 54) received a battery of standard laboratory clinical and functional outcome measures and then completed electronic questionnaires on a personal digital assistant (PDA) microcomputer 4 times per day for 1 week. Results: Generally good compliance (87%) with EMAc was found, and participants rated their experience with the study positively. The data collected in daily life demonstrated expected patterns across the assessment week and were significantly associated with scores from standard laboratory instruments measuring similar constructs. Conclusions: EMAc is a feasible and valid approach to data collection in community-dwelling people with schizophrenia, and it may provide important information that is inaccessible via standard clinical and functional outcome measures administered in the laboratory.

The Dream as a Model for Psychosis: An Experimental Approach Using Bizarreness as a Cognitive Marker

2008-04-14

Many previous observers have reported some qualitative similarities between the normal mental state of dreaming and the abnormal mental state of psychosis. Recent psychological, tomographic, electrophysiological, and neurochemical data appear to confirm the functional similarities between these 2 states. In this study, the hypothesis of the dreaming brain as a neurobiological model for psychosis was tested by focusing on cognitive bizarreness, a distinctive property of the dreaming mental state defined by discontinuities and incongruities in the dream plot, thoughts, and feelings. Cognitive bizarreness was measured in written reports of dreams and in verbal reports of waking fantasies in 30 schizophrenics and 30 normal controls. Seven pictures of the Thematic Apperception Test (TAT) were administered as a stimulus to elicit waking fantasies, and all participating subjects were asked to record their dreams upon awakening. A total of 420 waking fantasies plus 244 dream reports were collected to quantify the bizarreness features in the dream and waking state of both subject groups.

Two-way analysis of covariance for repeated measures showed that cognitive bizarreness was significantly lower in the TAT stories of normal subjects than in those of schizophrenics and in the dream reports of both groups.

The differences between the 2 groups indicated that, under experimental conditions, the waking cognition of schizophrenic subjects shares a common degree of formal cognitive bizarreness with the dream reports of both normal controls and schizophrenics. Though very preliminary, these results support the hypothesis that the dreaming brain could be a useful experimental model for psychosis.

Cognitive Behavior Therapy for Schizophrenia: Effect Sizes, Clinical Models, and Methodological Rigor

Wykes, T., Steel, C., Everitt, B., Tarrier, N. — 2008-04-14

Background: Guidance in the United States and United Kingdom has included cognitive behavior therapy for psychosis (CBTp) as a preferred therapy. But recent advances have widened the CBTp targets to other symptoms and have different methods of provision, eg, in groups. Aim: To explore the effect sizes of current CBTp trials including targeted and nontargeted symptoms, modes of action, and effect of methodological rigor. Method: Thirty-four CBTp trials with data in the public domain were used as source data for a meta-analysis and investigation of the effects of trial methodology using the Clinical Trial Assessment Measure (CTAM). Results: There were overall beneficial effects for the target symptom (33 studies; effect size = 0.400 [95% confidence interval {CI} = 0.252, 0.548]) as well as significant effects for positive symptoms (32 studies), negative symptoms (23 studies), functioning (15 studies), mood (13 studies), and social anxiety (2 studies) with effects ranging from 0.35 to 0.44. However, there was no effect on hopelessness. Improvements in one domain were correlated with improvements in others. Trials in which raters were aware of group allocation had an inflated effect size of approximately 50%–100%. But rigorous CBTp studies showed benefit (estimated effect size = 0.223; 95% CI = 0.017, 0.428) although the lower end of the CI should be noted. Secondary outcomes (eg, negative symptoms) were also affected such that in the group of methodologically adequate studies the effect sizes were not significant. Conclusions: As in other meta-analyses, CBTp had beneficial effect on positive symptoms. However, psychological treatment trials that make no attempt to mask the group allocation are likely to have inflated effect sizes. Evidence considered for psychological treatment guidance should take into account specific methodological detail.

Dysfunction in Configural Face Processing in Patients With Schizophrenia

Shin, Y.-W., Na, M. H., Ha, T. H., Kang, D.-H., Yoo, S.-Y., Kwon, J. S. — 2008-04-14

Background: Face recognition has important implications for patients with schizophrenia, who exhibit poor interpersonal and social skills. Previous reports have suggested that patients with schizophrenia have deficits in their ability to recognize faces, and because face recognition relies heavily on information about the configuration of faces, we hypothesized that patients with schizophrenia would have specific problems in processing configural information. Methods: We measured the performance of 20 patients with schizophrenia and 20 normal subjects in a face-discrimination task, using upright and inverted pairs of face photographs that differed in featural or configural information. Results: The patients with schizophrenia showed disproportionately poorer performance in discriminating configural compared with featural face sets. Conclusion: The result suggests that the face-recognition deficit in schizophrenic patients is due to specific impairments in configural processing of faces.

Cognition in Young Schizophrenia Outpatients: Comparison of First-Episode With Multiepisode Patients

2008-04-14

Cognitive impairments are recognized as a central feature of schizophrenia (SZ), largely independent of other symptoms, and a major cause of poor functioning. Studies indicate cognitive deterioration in the first years after the onset of SZ. These studies, however, have been criticized for using a small sample size, for having limited monitoring of confounding variables, and for the inclusion of cohorts of different ages. The current study compared the cognitive profile of first-episode schizophrenia patients, multi-episode schizophrenia patients and healthy controls (n = 44, n = 39, and n = 44; respectively). The study focused on the early stages of the disorder, recruiting only young patients. All subjects underwent an extensively validated computerized cognitive assessment (Cambridge Neuropsychological Test Automated Battery). The results revealed widespread cognitive impairments in SZ patients, compared with healthy control subjects. The multiepisode SZ patients were significantly more impaired than the first-episode ones, with deficits mainly related to psychomotor speed, pattern memory, and executive functioning. The functioning in other cognitive domains (ie, attention and spatial memory) was deficient even at an early stage of the disorder. These findings can help clarify the course of cognitive decline in young-aged SZ patients and aid in the development of phase-appropriate interventions.

Tobacco Use Among Individuals With Schizophrenia: What Role Has the Tobacco Industry Played?

Prochaska, J. J., Hall, S. M., Bero, L. A. — 2008-04-14

Rates of tobacco use among individuals diagnosed with schizophrenia have been estimated as high as 80%. A variety of hypotheses have been proposed to explain the high rate of tobacco use among this vulnerable group. This study examined the tobacco industry's efforts to establish and promulgate beliefs about schizophrenic individuals’ need to smoke and the hazards of quitting. The current study analyzed previously secret tobacco industry documents. The initial search was conducted during January–July 2005 in the Legacy Tobacco Documents Library. The search yielded 280 records dating from 1955 to 2004. Documents indicate the tobacco industry monitored or directly funded research supporting the idea that individuals with schizophrenia were less susceptible to the harms of tobacco and that they needed tobacco as self-medication. The tobacco industry promoted smoking in psychiatric settings by providing cigarettes and supporting efforts to block hospital smoking bans. The tobacco industry engaged in a variety of direct and indirect efforts that likely contributed to the slowed decline in smoking prevalence in schizophrenia via slowing nicotine dependence treatment development for this population and slowing the rate of policy implementation vis-à-vis smoking bans on psychiatric units.

Childhood Trauma and Psychotic Disorders: a Systematic, Critical Review of the Evidence

Bendall, S., Jackson, H. J., Hulbert, C. A., McGorry, P. D. — 2008-04-14

There is controversy over whether childhood trauma (CT) is a causal factor in the development of psychosis. This review aims to identify and critically analyze the association between CT and psychotic disorders. Studies investigating CT and psychotic disorder were identified by searches of electronic databases and manual searches of references lists, and 46 studies were identified. Forty studies had no control group, only psychiatric control groups, or unmatched, nonpopulation control groups and thus had methodologies that were inadequate to determine the relationship between CT and psychosis. Six studies used appropriate control groups. Three studies found an association between CT and psychosis, 2 found potentially real associations that failed to reach statistical significance, and 1 found no association, tentatively suggesting a relationship between CT and psychotic disorders. Several methodological problems were found in the studies in the review, including the highest quality studies, which limit the strength of the conclusions that can be drawn from them. These were lack of statistical power, lack of attention to moderating or mediating variables, the way in which CT was measured, and the use of cross-sectional research designs. These problems, some of which may be unavoidable in CT research, suggest the need for new and innovative methodologies in the investigation of CT and psychosis. Directions for further research are explored.

Childhood Sexual Abuse, Early Cannabis Use, and Psychosis: Testing an Interaction Model Based on the National Comorbidity Survey

Houston, J. E., Murphy, J., Adamson, G., Stringer, M., Shevlin, M. — 2008-04-14

Previous research investigating the etiology of psychosis has identified risk factors such as childhood sexual abuse and cannabis use. This study investigated the multiplicative effect of these variables on clinically assessed diagnoses of psychosis based on a large community sample (the National Comorbidity Survey). Demographic variables (sex, age, urbanicity, ethnicity, education, employment, and living arrangements) and depression were used as predictors in the first block of a binary logistic regression. In the second block, the variables representing early cannabis use, childhood sexual trauma, and the interaction between these variables were entered. There was no significant main effect for early cannabis use or childhood sexual trauma. The interaction was statistically significant (odds ratio [OR] = 6.93, 95% confidence interval [CI] = 1.39–34.63, P = .02). The effect for the sexual trauma variable was statistically significant for those who used cannabis under 16 years (OR = 11.96, 95% CI = 2.10–68.22, P = .01) but not for those who had not used cannabis under 16 years (OR = 1.80, 95% CI = 0.91–3.57, P = .09). Many factors have been shown to be significant in the etiology of psychosis; however, the current research augments previous findings by examining psychosis in terms of an interaction between 2 of these factors.

Corrigendum

2008-04-14