Schizophrenia Bulletin - recent issues

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

Prognosis in Schizophrenia and the Role of Subjectivity

Strauss, J. S. — 2008-02-26

Beating the Odds--Nothing Is Impossible, Its Just a Road Less Traveled

Brady, M. — 2008-02-26

By contrasting students with learning disabilities and students with schizophrenia, it becomes conspicuously clear that they face many of the same hurdles. I know through personal experience because I have both. Postsecondary institutions are making great strides in balancing the scales for disabled students. Special education for learning-disabled students is more a hindrance than a benefit; mainstreaming many learning-disabled students seems a more appropriate option. Students need to take advantage of the services that are most beneficial to them. The least restrictive environment is predominantly, if not always, the correct choice.

Desire, Disease, and the Origins of the Dopaminergic System

Sillitoe, R. V., Vogel, M. W. — 2008-02-26

The dopaminergic neurons in the midbrain region of the central nervous system project an extensive network of connections throughout the forebrain, including the neocortex. The midbrain-forebrain dopaminergic circuits are thought to regulate a diverse set of behaviors, from the control of movement to modulation of cognition and desire—because they relate to mood, attention, reward, and addiction. Defects in these pathways, including neurodegeneration, are implicated in a variety of psychiatric and neurological diseases, such as schizophrenia, attention-deficit/hyperactivity disorder, drug addiction, and Parkinson disease. Based on the importance of the midbrain dopaminergic neurons to normal and pathological brain function, there is considerable interest in the molecular mechanisms that regulate their development. The goal of this short review is to outline new methods and recent advances in identifying the molecular networks that regulate midbrain dopaminergic neuron differentiation and fate. Midbrain dopaminergic neurons are descended from progenitor cells located near the ventral midline of the neural tube floor plate around the cephalic flexure. It is now clear that their initial formation is dependent on interactions between the signaling molecules Sonic hedgehog, WINGLESS 1, and FIBROBLAST growth factor 8, but there is still an extensive wider network of molecular interactions that must be resolved before the complete picture of dopaminergic neuron development can be described.

Does the Concept of "Sensitization" Provide a Plausible Mechanism for the Putative Link Between the Environment and Schizophrenia?

Collip, D., Myin-Germeys, I., Van Os, J. — 2008-02-26

Previous evidence reviewed in Schizophrenia Bulletin suggests the importance of a range of different environmental factors in the development of psychotic illness. It is unlikely, however, that the diversity of environmental influences associated with schizophrenia can be linked to as many different underlying mechanisms. There is evidence that environmental exposures may induce, in interaction with (epi)genetic factors, psychological or physiological alterations that can be traced to a final common pathway of cognitive biases and/or altered dopamine neurotransmission, broadly referred to as "sensitization," facilitating the onset and persistence of psychotic symptoms. At the population level, the behavioral phenotype for sensitization may be examined by quantifying, in populations exposed to environmental risk factors associated with stress or dopamine-agonist drugs, (1) the increased rate of persistence (indicating lasting sensitization) of normally transient developmental expressions of subclinical psychotic experiences and (2) the subsequent increased rate of transition to clinical psychotic disorder.

Psychosocial Treatment Programs for People With Both Severe Mental Illness and Substance Misuse

Cleary, M., Hunt, G. E., Matheson, S., Siegfried, N., Walter, G. — 2008-02-26

Over 50% of people with a severe mental illness also use illicit drugs and/or alcohol at hazardous levels. This review is based on the findings of 25 randomized controlled trials which assessed the effectiveness of psychosocial interventions, offered either as one-off treatments or as an integrated or nonintegrated program, to reduce substance use by people with a severe mental illness. The findings showed that there was no consistent evidence to support any one psychosocial treatment over another. Differences across trials with regard to outcome measures, sample characteristics, type of mental illness and substance used, settings, levels of adherence to treatment guidelines, and standard care all made pooling results difficult. More quality trials are required that adhere to proper randomization methods; use clinically valuable, reliable, and validated measurement scales; and clearly report data, including retention in treatment, relapse, and abstinence rates. Future trials of this quality will allow a more thorough assessment of the efficacy of psychosocial interventions for reducing substance use in this challenging population.

Questioning an Axiom: Better Prognosis for Schizophrenia in the Developing World?

Cohen, A., Patel, V., Thara, R., Gureje, O. — 2008-02-26

Introduction: That schizophrenia has a better course and outcome in developing countries has become an axiom in international psychiatry. This is based primarily on a series of cross-national studies by the World Health Organization (WHO). However, increasing evidence from other research indicates a far more complex picture. Methods: Literature review and tabulation of data from 23 longitudinal studies of schizophrenia outcomes in 11 low- and middle-income countries. Results: We reviewed the evidence about the following domains: clinical outcomes and patterns of course, disability and social outcomes (marital and occupational status, in particular), and untreated samples and duration of untreated psychosis. Outcomes varied across the studies and the evidence suggests a need to reexamine the conclusions of the WHO studies. Additionally, assessments of outcomes should take excess mortality and suicide into account. Conclusions: It is time to reexamine presumed wisdom about schizophrenia outcomes in low- and middle-income countries.

Is Prognosis in the Individual, the Environment, the Disease, or What?

Strauss, J. — 2008-02-26

Dissecting the Heterogeneity of Schizophrenia Outcomes

McGrath, J. — 2008-02-26

Commentary on Alex Cohen et al: "Questioning an Axiom: Better Prognosis for Schizophrenia in the Developing World"

Kleinman, A. — 2008-02-26

Comment on Paper by Cohen, Patel, Thara, and Gureje

Leff, J. — 2008-02-26

What Did the WHO Studies Really Find?

Jablensky, A., Sartorius, N. — 2008-02-26

Cross-National Comparisons: Problems in Interpretation When Studies Are Based on Prevalent Cases

Bromet, E. J. — 2008-02-26

Issues in Psychopharmacology

Kane, J. M., Leucht, S. — 2008-02-26

Cochrane Schizophrenia Group

2008-02-26

Randomized Controlled Trials for Schizophrenia: Study Designs Targeted to Distinct Goals

Stroup, T. S., Geddes, J. R. — 2008-02-26

Randomized controlled trials for antipsychotic drugs have a variety of design features suited to diverse purposes. Efficacy (or explanatory) trials seek to establish if a drug can reduce psychotic symptoms under ideal circumstances. To isolate drug effects, researchers enroll carefully selected patients. Specialized research personnel use rating scales of symptoms that are sensitive to drug effects as the study primary outcomes. Large simple trials (LSTs) are conducted at typical treatment settings with usual clinical personnel and enroll large numbers of participants so small but clinically important differences between treatment options can be detected. LSTs focus narrowly on clearly defined, patient-oriented outcomes. To some extent, practical trials can be conceptualized as hybrids of efficacy and large simple trials. Practical trials provide independent evidence to inform decision makers about the everyday effectiveness of clinically relevant alternative interventions. Practical trial researchers include a heterogeneous population of patients and collect data on a broad range of meaningful health outcomes at many types of practice settings intended to represent usual treatment. The designers of practical trials make trade-offs between internal validity, external validity, the breadth of issues addressed, and the ability to detect small differences. The different objectives of trials should be considered in the interpretation of the complete body of randomized evidence on antipsychotic drugs.

Methodological Issues in Current Antipsychotic Drug Trials

Leucht, S., Heres, S., Hamann, J., Kane, J. M. — 2008-02-26

Every year numerous reports on antipsychotic drug trials are being published in neuropsychiatric journals, adding new information to our knowledge in the field. The information however is often hard for the reader to interpret, sometimes contradictory to comparable available studies and leaves more questions open than it actually answers. Although the overall quality of the studies is rather good, there are manifold options for further improvement in the conception, conduct, and reporting of antipsychotic drug trials. In this survey, we address methodological challenges such as the limited generalizability of outcomes due to patient selection and sample size; the vague or even lacking definition of key outcome parameters such as response, remission or relapse, insufficient blinding techniques, the pitfalls of surrogate outcomes and their assessment tools; the varying complex statistical approaches; and the challenge of balancing various ways of reporting outcomes. The authors present practical examples to highlight the current problems and propose a concrete series of suggestions on how to further optimize antipsychotic drug trials in the future.

The Association of Dropout and Outcome in Trials of Antipsychotic Medication and Its Implications for Dealing With Missing Data

Rabinowitz, J., Davidov, O. — 2008-02-26

Objective: The extent to which noncompletion of a clinical trial relates to outcomes has implications for choosing the most appropriate method for contending with missing data due to dropout. We examined whether dropout relates to outcome in clinical trials of antipsychotic medication. Methods: Data from 5 large clinical trials of schizophrenia (n = 3483) were examined separately. Patients were aggregated into groups based on their final study visit. Group mean Positive and Negative Syndrome Scale (PANSS) total scores for each visit were computed and graphed. Change from baseline to end point for each group was computed and examined using ANCOVA. Cox regression modeling was used to examine baseline PANSS total and change as predictors of time to dropout. Results: In all 5 trials there was a statistically significantly relationship between time in trial and improvement. The longer the patients remained in the trial the more that they improved, with trial completers showing the most improvement at each time point. Higher baseline PANSS scores and symptom deterioration indicated by increased PANSS preceding the final study visit prior to dropout corresponded significantly with a greater likelihood of dropout. Conclusions: Dropout in clinical trials of antipsychotic medications corresponds with efficacy outcomes, the dynamics of symptom change and baseline symptom severity. Therefore, methods for statistical analysis should examine both efficacy and dropout and cannot assume that missing data due to dropout are completely at random.

Feasibility of Reducing the Duration of Placebo-Controlled Trials in Schizophrenia Research

2008-02-26

Use of placebo-controlled trials in medical and psychiatric research has been controversial, although a consensus is emerging about conditions under which placebo-controlled trials are ethical. In schizophrenia research, the paradigm of slow onset of antipsychotic effects has led to a model in which placebo-controlled trials of 6–8 weeks duration have been used to demonstrate efficacy. Recent evidence that the largest symptom reductions are typically seen in the first weeks of treatment suggests that shorter placebo-controlled studies to demonstrate antipsychotic efficacy are possible. In a pilot study of the feasibility of shortening placebo-controlled studies, we reanalyzed data from placebo-controlled registry trials of olanzapine and risperidone and found that trials as short as 4 weeks could have similar power to longer term 6–8 week studies, given the estimated time course of treatment effects. Although fuller evaluation is required, the results suggest future antipsychotic trials could be shortened from 6–8 weeks to 3–4 weeks with a relatively low increase in sample size requirements. Shortening placebo-controlled trials would reduce patient burden and ethical objections to prolonged administration of placebo and reduce potential bias due to high dropout rates in longer clinical trials.

Unanswered Questions in Schizophrenia Clinical Trials

Kane, J. M., Leucht, S. — 2008-02-26

Progressive Brain Changes in Schizophrenia

Arango, C., Kahn, R. — 2008-02-26

The Concept of Progressive Brain Change in Schizophrenia: Implications for Understanding Schizophrenia

DeLisi, L. E. — 2008-02-26

Kraepelin originally defined dementia praecox as a progressive brain disease, although this concept has received various degrees of acceptance and rejection over the years since his famous published textbooks appeared. This article places an historical perspective on the current renewal of Kraepelin's concept in brain imaging literature that supports progressive brain change in schizophrenia from its earliest stages through its chronic course. It is concluded that a great deal of future research is needed focusing on the longitudinal course of change, the extent to the regions of change within each individual and the underlying mechanism and implications of brain change through functional and neurochemical imaging, combined with structural studies in the same individuals.

Progressive Changes in the Development Toward Schizophrenia: Studies in Subjects at Increased Symptomatic Risk

2008-02-26

Although the underlying neurobiology of emerging psychotic disorders is not well understood, there is a growing conviction that the study of patients at clinical high risk for the illness will provide important insights. Further, a better understanding of the transition period may help the development of novel therapies. In this review, we summarize the extant neuroimaging and neuropsychological studies of people at clinical high risk for psychosis. By and large, there are few definitive markers that distinguish those who go on to develop the illness from those who do not. The 2 most consistently abnormal brain regions in schizophrenia research, the hippocampi and the lateral ventricles, are not significantly different from healthy controls prior to psychosis onset. However, frontal lobe measures (eg, cortical thickness in the anterior cingulate) do show promise, as do cognitive measures sensitive to prefrontal cortex dysfunction. Further, longitudinal magnetic resonance imaging findings in individuals at ultrahigh risk for developing a psychotic illness show that there are excessive neuroanatomical changes in those who convert to psychosis. These aberrant changes are observed most prominently in medial temporal and prefrontal cortical regions. While the pathological processes underlying such changes remain unclear, speculatively they may reflect anomalies in genetic and/or other endogenous mechanisms responsible for brain maturation, the adverse effects of intense or prolonged stress, or other environmental factors. Active changes during transition to illness may present the potential to intervene and ameliorate these changes with potential benefit clinically.

Brain Structure and Function Changes During the Development of Schizophrenia: The Evidence From Studies of Subjects at Increased Genetic Risk

Lawrie, S. M., McIntosh, A. M., Hall, J., Owens, D. G.C., Johnstone, E. C. — 2008-02-26

This article reviews the evidence for changes in the structure and function of the brain in subjects at high risk of schizophrenia for genetic reasons during the genesis of the disorder. We first highlight the structural and functional abnormalities in schizophrenia and whether any similar or lesser abnormalities are apparent in unaffected relatives. There is good evidence for subtle abnormalities of hippocampal and ventricle volume in relatives that are not as marked as the deficits in schizophrenia. In addition, the functional imaging literature suggests that prefrontal cortex function may deteriorate in those at risk who go on to develop the disorder. We then review the findings from longitudinal imaging studies of those at high risk, particularly the Edinburgh High-Risk Study, which report gray matter density reductions in medial and lateral temporal lobe because people develop schizophrenia, as well as functional abnormalities which precede onset. We conclude by quoting our own and others’ imaging studies of the associations of genetic and other risk factors for schizophrenia, including stressful life events and cannabis use, which provide mechanistic examples of how these changes may be brought about. Overall, the literature supports the view that there are measurable changes in brain structure and function during the genesis of the disorder, which provide opportunities for early detection and intervention.

Longitudinal Brain Changes in Early-Onset Psychosis

2008-02-26

Progressive losses of cortical gray matter volumes and increases in ventricular volumes have been reported in patients with childhood-onset schizophrenia (COS) during adolescence. Longitudinal studies suggest that the rate of cortical loss seen in COS during adolescence plateaus during early adulthood. Patients with first-episode adolescent-onset schizophrenia show less marked progressive changes, although the number of studies in this population is small. Some studies show that, although less exaggerated, progressive changes are also present in nonschizophrenia early-onset psychosis. The greater loss of brain tissue seen in COS, even some years after the first episode, as compared to adolescent- or adult-onset schizophrenia may be due to variables such as sample bias (more severe, treatment refractory sample of childhood-onset patients studied), a process uniquely related to adolescent development in COS, differential brain effects of drug treatment in this population, clinical outcome, or interactions among these variables. Findings from both cross-sectional studies of first-episode patients and longitudinal studies in COS and adolescent onset support the concept of early-onset schizophrenia as a progressive neurodevelopmental disorder with both early and late developmental abnormalities. Future studies should look for correlates at a cellular level and for pathophysiological explanations of volume changes in these populations. The association of risk genes involved in circuitries associated with schizophrenia and their relationship to developmental trajectories is another promising area of future research.

What Happens After the First Episode? A Review of Progressive Brain Changes in Chronically Ill Patients With Schizophrenia

Hulshoff Pol, H. E., Kahn, R. S. — 2008-02-26

Numerous imaging studies have revealed structural brain changes in schizophrenia. Decreases in brain tissue are accompanied by increases in ventricle volumes and cerebrospinal fluid. Whether or not these brain changes are progressive beyond the first episode is subject to debate. To assess if progressive brain changes occur in chronically ill patients, 11 longitudinal magnetic resonance imaging and computed tomography studies were reviewed. Patients were ill for on average 10 years at their initial scan. Follow-up intervals varied between 1 and 10 years. Overall, the findings suggest continuous progressive brain tissue decreases and lateral ventricle volume increases in chronically ill patients, up to at least 20 years after their first symptoms. The extent of progressive brain tissue decrease in patients (–0.5% per year) is twice that of healthy controls (–0.2% per year). These findings are consistent with the extent of postmortem brain tissue loss in schizophrenia. Progressive volume loss seems most pronounced in the frontal and temporal (gray matter) areas. Progressive lateral ventricle volume increases are also found. More pronounced progressive brain changes in patients is associated with poor outcome, more negative symptoms, and a decline in neuropsychological performance in one or some of the studies, but not consistently so. Higher daily cumulative dose of antipsychotic medication intake is either not associated with brain volume changes or with less prominent brain volume changes. The progressive brain changes present in chronic schizophrenia may represent a continuous pathophysiological process taking place in the brains of these patients that warrants further study.

Inefficient Face Detection in Schizophrenia

Chen, Y., Norton, D., Ongur, D., Heckers, S. — 2008-02-26

Background: Higher levels of facial processing, such as recognition of the individuality and emotional expression of faces, are abnormal in schizophrenia. It is unknown, however, whether the visual detection of a face as face is impaired as well. Methods: We examined the performance of schizophrenia patients (n = 29) and normal controls (n = 28) in locating a line-drawn face on the left or the right side of a larger line drawing. To prevent the normal formation of general facial impressions, stimulus presentations were brief (13–104 ms). The face stimuli were either displayed upright or inverted in order to study the face inversion effect, ie, the specific effect of stimulus inversion on face processing. Results: Schizophrenia patients showed a significantly reduced face inversion effect, resulting primarily from significantly lower accuracy in detecting upright faces than normal controls. In tree detection, a comparison task that was also administered, the stimulus inversion effect was similarly small in both groups. Conclusion: Given the primitive nature and brief duration of the stimuli, and the simplicity of the task, these results indicate that at the initial visual detection stage, facial processing is inefficient in schizophrenia. By isolating face detection from other aspects of face recognition, this study identifies a face-specific visual deficit in schizophrenia, which may ultimately contribute to impaired face-related cognitive and emotional processing and social interaction.

Rethinking Antipsychotic Formulary Policy

Rosenheck, R.A., Leslie, D.L., Busch, S., Rofman, E. S., Sernyak, M. — 2008-02-26

In this commentary, we review recent research suggesting that (a) second-generation antipsychotics (SGAs) may be no more effective than first-generation antipsychotics (FGAs), (b) the reduced risk of EPS and tardive dyskinesia with SGAs is more weakly supported by the research literature than has been appreciated, and (c) benefits may be offset by greater metabolic risks of some SGAs and their substantially greater cost. Bearing in mind, as well, that risperidone, currently the least expensive SGA, will soon be available as an even less expensive generic drug, we propose a new algorithm for maintenance antipsychotic therapy. We further outline a cautious implementation procedure that relies on standardized documentation and feedback, without a restrictive formulary that would limit physician choice. The algorithm outlined here and the process for its implementation are intended as a stimulus for discussion of potential policy responses, not as a finalized proposition.

The Phenomenological Critique and Self-disturbance: Implications for Ultra-High Risk ("Prodrome") Research

Nelson, B., Yung, A. R., Bechdolf, A., McGorry, P. D. — 2008-02-26

Recent years have witnessed widespread interest in the early phase of schizophrenia and other psychotic disorders. Strategies have been introduced to attempt to identify individuals in the prepsychotic or prodromal phase. The most widely used of these approaches is the ultra-high risk (UHR) approach, which combines known trait and state risk factors for psychotic disorder. However, researchers guided by phenomenological theory have argued that modern psychiatry's neglect of subjective experience has compromised researchers’ understanding of psychotic disorder and has thereby limited efforts at prospective and early identification. Phenomenological research indicates that disturbance of the basic sense of self may be a core marker of psychotic vulnerability, particularly of schizophrenia spectrum disorders. It is argued that identifying self-disturbance in the UHR population may provide a means of further "closing in" on individuals truly at high risk of psychotic disorder, thus supplementing the UHR identification approach. This would be of practical value in the sense of reducing inclusion of "false-positive" cases in UHR samples and of theoretical value in the sense of shedding light on core features of psychotic pathology. The strong explanatory power and empirical findings to date invite further research into the role of self-disturbance as a phenotypic vulnerability marker for psychotic disorder.

Patterns of Structural MRI Abnormalities in Deficit and Nondeficit Schizophrenia

2008-02-26

Negative symptoms of schizophrenia have generally been found in association with ventricular enlargement and prefrontal abnormalities. These relationships, however, have not been observed consistently, most probably because negative symptoms are heterogeneous and result from different pathophysiological mechanisms. The concept of deficit schizophrenia (DS) was introduced by Carpenter et al to identify a clinically homogeneous subgroup of patients characterized by the presence of primary and enduring negative symptoms. Findings of brain structural abnormalities reported by magnetic resonance imaging (MRI) studies focusing on DS have been mixed. The present study included 34 patients with DS, 32 with nondeficit schizophrenia (NDS), and 31 healthy comparison subjects, providing the largest set of MRI findings in DS published so far. The Schedule for the Deficit Syndrome was used to categorize patients as DS or NDS patients. The 2 patient groups were matched on age and gender and did not differ on clinical variables, except for higher scores on the negative dimension and more impaired interpersonal relationships in DS than in NDS subjects. Lateral ventricles were larger in NDS than in control subjects but were not enlarged in patients with DS. The cingulate gyri volume was smaller in NDS but not in DS patients as compared with healthy subjects. Both groups had smaller dorsolateral prefrontal cortex and temporal lobes than healthy subjects, but DS patients had significantly less right temporal lobe volume as compared with NDS patients. These findings do not support the hypothesis that DS is the extreme end of a severity continuum within schizophrenia.

Editorial: More Changes for the Schizophrenia Bulletin

Carpenter, W. T. — 2007-12-13

This Way to School... Lessons From the Classroom

Erwin, E. J. — 2007-12-13

Remission and Recovery in Schizophrenia: Practitioner and Patient Perspectives

Davidson, L., Schmutte, T., Dinzeo, T., Andres-Hyman, R. — 2007-12-13

Schizophrenia remains a complex, dynamic, multi-dimensional, and poorly understood condition. Although the concept of heterogeneity in outcome has conceptually overturned the post Kraepelinian legacy of progressive deterioration, a number of factors appear to contribute to perpetuating a pessimistic attitude toward outcome within the field. These include the limited access people with schizophrenia have to effective interventions and the phenomenon of the "clinician's illusion," which refers to the tendency of practitioners to assume that patients remain seriously ill when outside of the clinical care settings in which they are typically seen. Longitudinal studies, however, continue to point to a large number of people who experience improvements in their condition over time. Pressure from patients and their families, who experience periods of symptomatic relief and enhanced functioning first-hand, has led to the introduction of such concepts as "remission" and being "in" recovery with schizophrenia, in addition to the conventional notion of recovering "from" schizophrenia. These developments are consistent with recent policy initiatives by the U.S. and other governments around the world and aim to re-orient research and clinical practice from a traditional focus on effecting cure to exploring ways to encourage and assist people with schizophrenia to live meaningful lives in the face of an enduring illness.

Neuregulin 1 Genotype and Schizophrenia

Munafo, M. R., Attwood, A. S., Flint, J. — 2007-12-13

The neuregulin 1 (NRG1) gene has been the subject of considerable excitement within the psychiatric genetics literature since it was originally identified as a potential susceptibility locus for schizophrenia. Here we provide an update of our first meta-analysis of this association. Case-control and family-based genetic association studies of the NRG1 gene in healthy control groups and clinically diagnosed schizophrenia patients were included. We repeated the search strategy in our earlier meta-analysis for studies published between December 31, 2005, and September 30, 2007, and updated the results of our original meta-analysis accordingly. Superficially, the results of our updated meta-analysis are consistent with those in our previous report, although it is notable that the strength of evidence as based on our haplotype analysis has weakened over this period. The evidence for association of the SNP8NRG221533 polymorphism continued to be nonsignificant. We discuss a number of problems in the interpretation of a disparate and inconsistent gene-disease association literature, including the difficulties associated with determining what constitutes replication across studies which vary in their methods, marker sets employed, phenotype definition, and other study characteristics.

Cessation of Medication for People With Schizophrenia Already Stable on Chlorpromazine

Almerie, M. Q., El-Din Matar, H., Essali, A., Alkhateeb, H., Rezk, E. — 2007-12-13

Editorial: Research Progress in Early-Onset Schizophrenia

Kumra, S., Charles Schulz, S. — 2007-12-13

A substantial proportion of patients with schizophrenia experience the onset of their illness by age 18. Data from phenomenological, cognitive, neuroimaging, and genetic studies suggest a similar profile of clinical and neurobiological abnormalities between early- and adult-onset patients. However, children and adolescents with schizophrenia have been found to have more severe premorbid neurodevelopmental abnormalities, worse long-term outcome, more cytogenetic anomalies, and potentially greater loading of family histories for schizophrenia and associated spectrum disorders than their adult counterparts. Together, these data support a hypothesis that early-onset schizophrenia may reflect a more severe form of the disorder associated with a greater genetic predisposition. It is anticipated that future imaging and genetic studies of this cohort will provide further insight into the neurodevelopmental origins of schizophrenia and the complexity by which genetic and environmental factors interact to modulate susceptibility and/or disease phenotype. The articles on this theme provide updated findings from brain magnetic resonance imaging, neurocognition, and clinical trials in this unique cohort.

Limbic Structures and Networks in Children and Adolescents With Schizophrenia

2007-12-13

Studies of adults with schizophrenia provide converging evidence for abnormalities in the limbic system. Limbic structures that show consistent patient/control differences in both postmortem and neuroimaging studies include the anterior cingulate and hippocampus, although differences in the amygdala, parahippocampal gyrus, and fornix have also been observed. Studies of white matter in children and adolescents with schizophrenia tend to show findings that are more focal than those seen in adults. Interestingly, these focal abnormalities in early-onset schizophrenia tend to be more localized to limbic regions. While it is unclear if these early limbic abnormalities are primary in the etiology of schizophrenia, there is evidence that supports a developmental progression with early limbic abnormalities evolving over time to match the neuroimaging profiles seen in adults with schizophrenia. Alternatively, the aberrations in limbic structures may be secondary to a more widespread or global pathological processes occurring with the brain that disrupt neural transmission. The goal of this article is to provide a review of the limbic system and limbic network abnormalities reported in children and adolescents with schizophrenia. These findings are compared with the adult literature and placed within a developmental context. These observations from neuroimaging studies enrich our current understanding of the neurodevelopmental model of schizophrenia and raise further questions about primary vs secondary processes. Additional research within a developmental framework is necessary to determine the putative etiologic roles for limbic and other brain abnormalities in early-onset schizophrenia.

Cortical Brain Development in Schizophrenia: Insights From Neuroimaging Studies in Childhood-Onset Schizophrenia

Gogtay, N. — 2007-12-13

Childhood-onset schizophrenia (COS; defined as onset by age 12 years) is rare, difficult to diagnose, and represents a severe and chronic phenotype of the adult-onset illness. A study of childhood-onset psychoses has been ongoing at the National Institute of Mental Health (NIMH) since 1990, where children with COS and severe atypical psychoses (provisionally labeled "multidimensionally impaired" or MDI by the NIMH team) are studied prospectively along with all first-degree relatives. COS subjects have robust cortical gray matter (GM) loss during adolescence, which appears to be an exaggeration of the normal cortical GM developmental pattern and eventually mimics the pattern seen in adult-onset cases as the children become young adults. These cortical GM changes in COS are diagnostically specific and seemingly unrelated to the effects of medications. Furthermore, the cortical GM loss is also shared by healthy full siblings of COS probands suggesting a genetic influence on the abnormal brain development.

Diagnostic and Sex Effects on Limbic Volumes in Early-Onset Bipolar Disorder and Schizophrenia

2007-12-13

Objective: The limbic structures in early-onset schizophrenia-spectrum illness (SZ) and bipolar disorder (BPD) were studied to discern patterns associated with diagnosis and sex. Methods: Thirty-five youths with DSM-IV BPD without psychosis, 19 with BPD with psychosis, 20 with SZ, and 29 healthy controls (HC), similar in age (6-17 years) and sex, underwent structured and clinical interviews, neurological examination, and cognitive testing. Structural magnetic resonance images (MRIs) were acquired on a 1.5 Tesla, General Electric Signa Scanner. Differences in subcortical brain volumes, including the amygdala and hippocampus, were evaluated using two-way (diagnosis, sex) univariate analyses covarying for total cerebral volume and age. Results: Youth with SZ and BPD showed no differences in amygdala and hippocampal volumes. However, boys with SZ had smallest left amygdala and girls with BPD had the smallest left hippocampal volumes. In exploratory analyses, SZ showed reduced thalamic volumes bilaterally and both BPD groups had larger right nucleus accumbens (NA) volumes relative to HC. Conclusion: There were no limbic volumetric differences between BPD and SZ. However, there were diagnosis-by-sex interactions in the amygdala and hippocampus, structures that are rich in sex hormone receptors. In addition, smaller thalamus was associated with SZ while larger right NA volumes were most related to BPD. This study underscores the importance of assessing diagnostic effects and sex effects on the brain in future studies and provides evidence that boys and girls with SZ and BPD may have differential patterns of neuropathology associated with disease expression.

The Stability of Inhibitory and Working Memory Deficits in Children and Adolescents Who are Children of Parents With Schizophrenia

Ross, R. G., Wagner, B., Heinlein, S., Zerbe, G. O. — 2007-12-13

Cognitive deficits are a central feature of schizophrenia and occur in first-degree relatives of schizophrenic probands, even in the absence of psychotic symptoms. A number of cognitive domains have been implicated including measures of response inhibition and working memory. While the stability of cognitive deficits has been demonstrated in individuals with schizophrenia, stability of deficits has not been explored in first-degree relatives. This report focuses on 25 children (ages 6–15 years), all with at least one schizophrenic parent. The children were assessed twice, utilizing inhibitory and working memory tasks, with a mean 2.6 years between visits. Stop reaction time (a measure of motor inhibition) and performance on a counting span task (a measure of verbal working memory) were borderline to mildly impaired (compared with a typically developing comparison group) at both visits with similar effect sizes (stopping task time 1, effect size = 0.46, time 2 effect size = 0.50; counting span time 1 effect size = 0.53, time 2 effect size = 0.42). For these 2 tasks, individual age-adjusted scores also correlated across both time points (r = 0.41–0.76) suggesting that individual children maintained deficits across time. As etiologically driven strategies are developed for the cognitive deficits of schizophrenia, expansion of these treatments to relatives who share the cognitive but not the psychotic symptoms may be worth exploring.