Schizophrenia Bulletin - current issue

Schizophrenia Bulletin and the Revised NIH Public Access Policy

Shepard, P. D. — 2008-08-20

Premorbid Adjustment, Onset Types, and Prognostic Scaling: Still Informative?

McGlashan, T. H. — 2008-08-20

Efforts emerged to describe, quantify, and predict prognosis once it became clear that the outcomes of Kraepelinian dementia praecox could vary. The concepts and scales that have evolved focus on types of premorbid adjustment and illness onset. Enduring highlights of this literature will be described, and its current and future utility will be discussed.

Genetic Research in Schizophrenia: New Tools and Future Perspectives

Bertram, L. — 2008-08-20

Genetically, schizophrenia is a complex disease whose pathogenesis is likely governed by a number of different risk factors. While substantial efforts have been made to identify the underlying susceptibility alleles over the past 2 decades, they have been of only limited success. Each year, the field is enriched with nearly 150 additional genetic association studies, each of which either proposes or refutes the existence of certain schizophrenia genes. To facilitate the evaluation and interpretation of these findings, we have recently created a database for genetic association studies in schizophrenia ("SzGene"; available at http://www.szgene.org). In addition to systematically screening the scientific literature for eligible studies, SzGene also reports the results of allele-based meta-analyses for polymorphisms with sufficient genotype data. Currently, these meta-analyses highlight not only over 20 different potential schizophrenia genes, many of which represent the "usual suspects" (eg, various dopamine receptors and neuregulin 1), but also several that were never meta-analyzed previously. All the highlighted loci contain at least one variant showing modest (summary odds ratios approximately 1.20 [range 1.06–1.45]) but nominally significant risk effects. This review discusses some of the strengths and limitations of the SzGene database, which could become a useful bioinformatics tool within the schizophrenia research community.

Haloperidol versus chlorpromazine for treatment of schizophrenia

Leucht, C., Kitzmantel, M., Chua, L., Kane, J., Leucht, S. — 2008-08-20

Emotion, Motivation, and Reward Processing in Schizophrenia Spectrum Disorders: What We Know and Where We Need to Go

Barch, D. M. — 2008-08-20

Emotional Response Deficits in Schizophrenia: Insights From Affective Science

Kring, A. M., Moran, E. K. — 2008-08-20

Our understanding of the emotional features of schizophrenia has benefited greatly from the adoption of methods and theory from the field of affective science. This article covers basic concepts and methods from affective science on the psychological and neural mechanisms contributing to emotions and reviews the ways in which this research has advanced our understanding of emotional response deficits in schizophrenia. We review naturalistic studies and elicitation studies that evoke emotion responses among participants, including emotion expression, experience, and autonomic physiology. We also consider how these emotion response measures correspond to schizophrenia symptoms, and we focus particular attention on the issue of sex differences in emotional responding and how this may influence our understanding emotional functioning among individuals with schizophrenia.

Reward Processing in Schizophrenia: A Deficit in the Representation of Value

Gold, J. M., Waltz, J. A., Prentice, K. J., Morris, S. E., Heerey, E. A. — 2008-08-20

Patients with schizophrenia demonstrate deficits in motivation and learning that suggest impairment in different aspects of the reward system. In this article, we present the results of 8 converging experiments that address subjective reward experience, the impact of rewards on decision making, and the role of rewards in guiding both rapid and long-term learning. All experiments compared the performance of stably treated outpatients with schizophrenia and demographically matched healthy volunteers. Results to date suggest (1) that patients have surprisingly normal experiences of positive emotion when presented with evocative stimuli, (2) that patients show reduced correlation, compared with controls, between their own subjective valuation of stimuli and action selection, (3) that decision making in patients appears to be compromised by deficits in the ability to fully represent the value of different choices and response options, and (4) that rapid learning on the basis of trial-to-trial feedback is severely impaired whereas more gradual learning may be surprisingly preserved in many paradigms. The overall pattern of findings suggests compromises in the orbital and dorsal prefrontal structures that play a critical role in the ability to represent the value of outcomes and plans. In contrast, patients often (but not always) approach normal performance levels on the slow learning achieved by the integration of reinforcement signals over many trials, thought to be mediated by the basal ganglia.

Reinforcement and Reversal Learning in First-Episode Psychosis

2008-08-20

Background: Abnormalities in reinforcement learning and reversal learning have been reported in psychosis, possibly secondary to subcortical dopamine abnormalities. Methods: We studied simple discrimination (SD) learning and reversal learning in a sample of 119 first-episode psychosis patients from the Cambridge early psychosis service (CAMEO) and 107 control participants. We used data on reinforcement learning and reversal learning extracted from the Cambridge Neuropsychological Test Automated Battery Intradimensional-Extradimensional shift task, which measures cognitive flexibility but also involves simple reinforcement learning (SD learning) and reversal learning stages. We also gathered diagnostic information to examine whether there were any differences between patients ultimately diagnosed with schizophrenia-spectrum disorders and those diagnosed with affective psychosis. Results: Psychosis patients demonstrated deficits in simple reinforcement learning (SD learning) and in reversal learning, with no differences between affective psychosis and schizophrenia-spectrum psychosis. There was a significant modest correlation between reversal errors and negative symptoms (Spearman = 0.3, P = .02). Conclusions: There are reinforcement learning abnormalities in first-episode psychosis, which correlate with negative symptoms, suggesting a possible role for orbitofrontal cortex and ventral striatal pathology in the pathogenesis of motivational deficits in psychosis.

Affective Traits in Schizophrenia and Schizotypy

Horan, W. P., Blanchard, J. J., Clark, L. A., Green, M. F. — 2008-08-20

This article reviews empirical studies of affective traits in individuals with schizophrenia spectrum disorders, population-based investigations of vulnerability to psychosis, and genetic and psychometric high-risk samples. The review focuses on studies that use self-report trait questionnaires to assess Negative Affectivity (NA) and Positive Affectivity (PA), which are conceptualized in contemporary models of personality as broad, temperamentally-based dispositions to experience corresponding emotional states. Individuals with schizophrenia report a pattern of stably elevated NA and low PA throughout the illness course. Among affected individuals, these traits are associated with variability in several clinically important features, including functional outcome, quality of life, and stress reactivity. Furthermore, evidence that elevated NA and low PA (particularly the facet of anhedonia) predict the development of psychosis and are detectable in high-risk samples suggests that these traits play a role in vulnerability to schizophrenia, though they are implicated in other forms of psychopathology as well. Results are discussed in terms of their implications for treatment, etiological models, and future research to advance the study of affective traits in schizophrenia and schizotypy.

Emotional Memory in Schizophrenia

Herbener, E. S. — 2008-08-20

Emotional memories play an important role in our day-to-day experience, informing many of our minute-to-minute decisions (eg, where to go for dinner, what are the likely consequences of not attending a meeting), as well as our long-term goal setting. Individuals with schizophrenia appear to be impaired in memory for emotional experiences, particularly over longer delay periods, which may contribute to deficits in goal-related behavior and symptoms of amotivation and anhedonia. This article reviews factors that are known to influence emotional memory in healthy subjects, applies these factors to results from emotional memory studies with individuals with schizophrenia, and then uses extant neurobiological models of emotional memory formation to develop hypotheses about biological processes that might particularly contribute to emotional memory impairment in schizophrenia.

Emotion Processing in Persons at Risk for Schizophrenia

Phillips, L. K., Seidman, L. J. — 2008-08-20

Evidence suggests that individuals with schizophrenia demonstrate emotion-processing deficits. However, the nature and extent of emotion abnormalities in individuals considered at risk for schizophrenia have not been previously summarized. This article provides a review of the recent literature pertaining to emotion processing in 3 at-risk populations: those at familial high risk, those with schizotypal characteristics, and those in the putative prodrome to psychosis. Studies are reviewed across the components of emotion perception, experience, and expression. Further, we discuss investigations into psychophysiology, brain structure, and brain function that employ emotion probes. Review of the literature suggests that individuals at high risk demonstrate similar abnormalities to those with schizophrenia but at an attenuated level. The most robust findings in at-risk groups are in the areas of reduced emotion perception, self-reported anhedonia, and increased negative affect. We conclude with an agenda for future research.

Neural Synchrony in Schizophrenia

Ford, J. M., Mathalon, D. H. — 2008-08-20

Basic neuroscience research suggests that neural assemblies communicate with each other in the temporal domain and rely on the coincidence of neural activity to detect phasic relationships between groups of neurons. Clinical neuroscience research suggests that communication and coordination failures between different brain regions may account for a wide range of problems in schizophrenia, from psychosis to cognitive dysfunction. This theme issue presents: an overview of time-frequency analyses that are used by clinical neuroscientists studying neural oscillations in schizophrenia; a comprehensive review of the literature on schizophrenia and neural asynchrony; data supporting dysfunction of both the GABA and glutamate systems in contributing to neural synchrony dysfunction in schizophrenia; and an example of how neural activity oscillating at different frequencies can form a code, which when disrupted could account for various symptoms of the illness. These papers illustrate approaches to translational neuroscience that will increase our understanding of schizophrenia and provide neurobiological endpoints for developing novel treatments.

Event-Related EEG Time-Frequency Analysis: An Overview of Measures and An Analysis of Early Gamma Band Phase Locking in Schizophrenia

Roach, B. J., Mathalon, D. H. — 2008-08-20

An increasing number of schizophrenia studies have been examining electroencephalography (EEG) data using time-frequency analysis, documenting illness-related abnormalities in neuronal oscillations and their synchronization, particularly in the gamma band. In this article, we review common methods of spectral decomposition of EEG, time-frequency analyses, types of measures that separately quantify magnitude and phase information from the EEG, and the influence of parameter choices on the analysis results. We then compare the degree of phase locking (ie, phase-locking factor) of the gamma band (36–50 Hz) response evoked about 50 milliseconds following the presentation of standard tones in 22 healthy controls and 21 medicated patients with schizophrenia. These tones were presented as part of an auditory oddball task performed by subjects while EEG was recorded from their scalps. The results showed prominent gamma band phase locking at frontal electrodes between 20 and 60 milliseconds following tone onset in healthy controls that was significantly reduced in patients with schizophrenia (P = .03). The finding suggests that the early-evoked gamma band response to auditory stimuli is deficiently synchronized in schizophrenia. We discuss the results in terms of pathophysiological mechanisms compromising event-related gamma phase synchrony in schizophrenia and further attempt to reconcile this finding with prior studies that failed to find this effect.

The Role of Oscillations and Synchrony in Cortical Networks and Their Putative Relevance for the Pathophysiology of Schizophrenia

Uhlhaas, P. J., Haenschel, C., Nikolic, D., Singer, W. — 2008-08-20

Neural oscillations and their synchronization may represent a versatile signal to realize flexible communication within and between cortical areas. By now, there is extensive evidence to suggest that cognitive functions depending on coordination of distributed neural responses, such as perceptual grouping, attention-dependent stimulus selection, subsystem integration, working memory, and consciousness, are associated with synchronized oscillatory activity in the theta-, alpha-, beta-, and gamma-band, suggesting a functional mechanism of neural oscillations in cortical networks. In addition to their role in normal brain functioning, there is increasing evidence that altered oscillatory activity may be associated with certain neuropsychiatric disorders, such as schizophrenia, that involve dysfunctional cognition and behavior. In the following article, we aim to summarize the evidence on the role of neural oscillations during normal brain functioning and their relationship to cognitive processes. In the second part, we review research that has examined oscillatory activity during cognitive and behavioral tasks in schizophrenia. These studies suggest that schizophrenia involves abnormal oscillations and synchrony that are related to cognitive dysfunctions and some of the symptoms of the disorder. Perspectives for future research will be discussed in relationship to methodological issues, the utility of neural oscillations as a biomarker, and the neurodevelopmental hypothesis of schizophrenia.

GABA Neurons and the Mechanisms of Network Oscillations: Implications for Understanding Cortical Dysfunction in Schizophrenia

Gonzalez-Burgos, G., Lewis, D. A. — 2008-08-20

Synchronization of neuronal activity in the neocortex may underlie the coordination of neural representations and thus is critical for optimal cognitive function. Because cognitive deficits are the major determinant of functional outcome in schizophrenia, identifying their neural basis is important for the development of new therapeutic interventions. Here we review the data suggesting that phasic synaptic inhibition mediated by specific subtypes of cortical -aminobutyric acid (GABA) neurons is essential for the production of synchronized network oscillations. We also discuss evidence indicating that GABA neurotransmission is altered in schizophrenia and propose mechanisms by which such alterations can decrease the strength of inhibitory connections in a cell-type–specific manner. We suggest that some alterations observed in the neocortex of schizophrenia subjects may be compensatory responses that partially restore inhibitory synaptic efficacy. The findings of altered neural synchrony and impaired cognitive function in schizophrenia suggest that such compensatory responses are insufficient and that interventions aimed at augmenting the efficacy of GABA neurotransmission might be of therapeutic value.

Region-Specific Changes in Gamma and Beta2 Rhythms in NMDA Receptor Dysfunction Models of Schizophrenia

2008-08-20

Cognitive disruption in schizophrenia is associated with altered patterns of spatiotemporal interaction associated with multiple electroencephalogram (EEG) frequency bands in cortex. In particular, changes in the generation of gamma (30–80 Hz) and beta2 (20–29 Hz) rhythms correlate with observed deficits in communication between different cortical areas. Aspects of these changes can be reproduced in animal models, most notably those involving acute or chronic reduction in glutamatergic synaptic communication mediated by N-methyl D-aspartate (NMDA) receptors. In vitro electrophysiological and immunocytochemical approaches afforded by such animal models continue to reveal a great deal about the mechanisms underlying EEG rhythm generation and are beginning to uncover which basic molecular, cellular, and network phenomena may underlie their disruption in schizophrenia. Here we briefly review the evidence for changes in -aminobutyric acidergic (GABAergic) and glutamatergic function and address the problem of region specificity of changes with quantitative comparisons of effects of ketamine on gamma and beta2 rhythms in vitro. We conclude, from available evidence, that many observed changes in markers for GABAergic function in schizophrenia may be secondary to deficits in NMDA receptor–mediated excitatory synaptic activity. Furthermore, the broad range of changes in cortical dynamics seen in schizophrenia—with contrasting effects seen in different brain regions and for different frequency bands—may be more directly attributable to underlying deficits in glutamatergic neuronal communication rather than GABAergic inhibition alone.

A Neural Coding Scheme Formed by the Combined Function of Gamma and Theta Oscillations

Lisman, J., Buzsaki, G. — 2008-08-20

Brain oscillations are important in controlling the timing of neuronal firing. This process has been extensively analyzed in connection with gamma frequency oscillations and more recently with respect to theta frequency oscillations. Here we review evidence that theta and gamma oscillations work together to form a neural code. This coding scheme provides a way for multiple neural ensembles to represent an ordered sequence of items. In the hippocampus, this coding scheme is utilized during the phase precession, a phenomenon that can be interpreted as the recall of sequences of items (places) from long-term memory. The same coding scheme may be used in certain cortical regions to encode multi-item short-term memory. The possibility that abnormalities in theta/gamma could underlie symptoms of schizophrenia is discussed.

Validity of the Premorbid Adjustment Scale

Brill, N., Reichenberg, A., Weiser, M., Rabinowitz, J. — 2008-08-20

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

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

Lincoln, T. M., Arens, E., Berger, C., Rief, W. — 2008-08-20

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

Use of Depot Antipsychotic Medications for Medication Nonadherence in Schizophrenia

West, J. C., Marcus, S. C., Wilk, J., Countis, L. M., Regier, D. A., Olfson, M. — 2008-08-20

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