Schizophrenia Bulletin - recent issues

Postmortem Brain Tissue for Drug Discovery in Psychiatric Research

Kim, S., Webster, M. J. — Fri, 16 Oct 2009 01:19:10 PDT

Silencing the Self: Schizophrenia as a Self-disturbance

Kean, C. — Fri, 16 Oct 2009 01:19:10 PDT

How High-Resolution Basal-State Functional Imaging Can Guide the Development of New Pharmacotherapies for Schizophrenia

Gaisler-Salomon, I., Schobel, S. A., Small, S. A., Rayport, S. — Fri, 16 Oct 2009 01:19:10 PDT

We describe here a coordinated brain imaging and animal models approach in which we have shown that the hippocampal CA1 region is a principal node in schizophrenia pathogenesis and have identified a novel treatment approach to the disorder based on inhibition of glutamate release. To identify biomarkers, we have focused on the putative prodromal period, typically lasting a few years, preceding the first onset of psychosis. About one-third of a high-risk cohort followed prospectively for 2.5 years will progress to threshold psychosis, making it possible to perform a relatively short prospective study. We have utilized a technological development in functional imaging techniques in which we measure cerebral blood volume (CBV), which allows for interrogation of subregions of the brain in the basal state at submillimeter resolution. Measurements of CBV in schizophrenia as well as in high-risk or prodromal stages can then pinpoint brain subregions differentially targeted during the earliest stages of the disorder. Our data suggest that the CA1 subfield of the hippocampal formation is most consistently implicated across disease stages, identifying a putative biomarker suitable for guiding drug development. Our studies in transgenic mice mutant in the glutamate synthetic enzyme glutaminase support the hypothesis that CA1 hyperfunction is due to altered glutamatergic neurotransmission. As a proof of principle, the glutaminase-deficient mice suggest that pharmacotherapies that reduce glutamatergic neurotransmission in the CA1 subfield may be a uniquely effective therapeutic strategy in schizophrenia and preventative in prodromal stages of the disorder.

Epigenetic Mediation of Environmental Influences in Major Psychotic Disorders

Rutten, B. P. F., Mill, J. — Fri, 16 Oct 2009 01:19:10 PDT

The major psychotic disorders schizophrenia and bipolar disorder are etiologically complex involving both heritable and nonheritable factors. The absence of consistently replicated major genetic effects, together with evidence for lasting changes in gene expression after environmental exposures, is consistent with the concept that the biologic underpinnings of these disorders are epigenetic in form rather than DNA sequence based. Psychosis-associated environmental exposures, particularly at key developmental stages, may result in long-lasting epigenetic alterations that impact on the neurobiological processes involved in pathology. Although direct evidence for epigenetic dysfunction in both schizophrenia and bipolar disorder is still limited, methodological technologies in epigenomic profiling have advanced. This means that we are at the exciting stage where it is feasible to start investigating molecular modifications to DNA and histones and examine the mechanisms by which environmental factors can act upon the genome to bring about epigenetic changes in gene expression involved in the etiology of these disorders. Given the dynamic nature of the epigenetic machinery and potential reversibility of epigenetic modifications, the understanding of such mechanisms is of key relevance for clinical psychiatry and for identifying new targets for prevention and/or intervention.

Day Hospital Vs Outpatient Care for People With Schizophrenia

Shek, E., Stein, A. T., Shansis, F. M., Marshall, M., Crowther, R., Tyrer, P. — Fri, 16 Oct 2009 01:19:11 PDT

Sensory Processing in Schizophrenia: Neither Simple nor Intact

Javitt, D. C. — Fri, 16 Oct 2009 01:19:11 PDT

This special issue focuses on the theme of sensory processing dysfunction in schizophrenia. For more than 50 years, from approximately the time of Bleuler until the early 1960s, sensory function was considered one of the few preserved functions in schizophrenia (Javitt1). Fortunately, the last several decades have brought a renewed and accelerating interest in this topic. The articles included in the issue range from those addressing fundamental bases of sensory dysfunction (Brenner, Yoon, and Turetsky) to those that examine how elementary deficits in sensory processing affect the sensory experience of individuals with schizophrenia (Butler, Kantrowitz, and Coleman) to the question of how sensory-based treatments may lead to improvement in remediation strategies (Adcock). Although addressing only a small portion of the current complex and burgeoning literature on sensory impairments across modalities, the present articles provide a cross-section of the issues currently under investigation. These studies also underscore the severe challenges that individuals with schizophrenia face when trying to decode the complex world around them.

Steady State Responses: Electrophysiological Assessment of Sensory Function in Schizophrenia

Fri, 16 Oct 2009 01:19:11 PDT

Persons with schizophrenia experience subjective sensory anomalies and objective deficits on assessment of sensory function. Such deficits could be produced by abnormal signaling in the sensory pathways and sensory cortex or later stage disturbances in cognitive processing of such inputs. Steady state responses (SSRs) provide a noninvasive method to test the integrity of sensory pathways and oscillatory responses in schizophrenia with minimal task demands. SSRs are electrophysiological responses entrained to the frequency and phase of a periodic stimulus. Patients with schizophrenia exhibit pronounced auditory SSR deficits within the gamma frequency range (35–50 Hz) in response to click trains and amplitude-modulated tones. Visual SSR deficits are also observed, most prominently in the alpha and beta frequency ranges (7–30 Hz) in response to high-contrast, high-luminance stimuli. Visual SSR studies that have used the psychophysical properties of a stimulus to target specific visual pathways predominantly report magnocellular-based deficits in those with schizophrenia. Disruption of both auditory and visual SSRs in schizophrenia are consistent with neuropathological and magnetic resonance imaging evidence of anatomic abnormalities affecting the auditory and visual cortices. Computational models suggest that auditory SSR abnormalities at gamma frequencies could be secondary to -aminobutyric acid–mediated or N-methyl-D-aspartic acid dysregulation. The pathophysiological process in schizophrenia encompasses sensory processing that probably contributes to alterations in subsequent encoding and cognitive processing. The developmental evolution of these abnormalities remains to be characterized.

Diminished Orientation-Specific Surround Suppression of Visual Processing in Schizophrenia

Fri, 16 Oct 2009 01:19:11 PDT

Visual perception of a stimulus is a function of the visual context in which it is displayed. Surround suppression is a specific form of contextual modulation whereby the perceived contrast of a center stimulus is decreased by a high-contrast surround. Recent studies have demonstrated that individuals with schizophrenia are less prone to visual contextual effects, suggesting impairments in cortical lateral connectivity. We tested whether altered contextual modulation in schizophrenia is stimulus orientation selective. Participants viewed an annulus consisting of contrast-reversing sinusoidal gratings and determined if any one segment of the annulus had lower contrast relative to the other segments. Three stimulus configurations were tested: no surround (NS), parallel surround (PS), and orthogonal surround (OS). In the PS condition, the annulus was embedded in a 100% contrast grating parallel to the annulus gratings. In the OS condition, the surround grating was rotated 90° relative to the orientation of the annulus gratings. The main dependent measure was the suppression index—the change in contrast threshold in the OS and PS conditions relative to the NS condition. There was a group x condition interaction such that patients had significantly lower PS suppression index than controls, but there were no group differences in the OS suppression index. We conclude that individuals with schizophrenia possess an abnormality in surround suppression that is specific for stimulus orientation. In conjunction with physiological and anatomical evidence from basic and postmortem studies, our results suggest a deficit of inhibition in primary visual cortex in schizophrenia.

Seeing the World Dimly: The Impact of Early Visual Deficits on Visual Experience in Schizophrenia

Kantrowitz, J. T., Butler, P. D., Schecter, I., Silipo, G., Javitt, D. C. — Fri, 16 Oct 2009 01:19:11 PDT

Deficits in early visual processing are well documented in schizophrenia, using methods such as contrast sensitivity. Higher, integrative stages of functioning, such as susceptibility to visual illusions, have been evaluated less extensively. For example, patients show increased susceptibility to (ie, are more easily affected by) the Muller-Lyer illusion but decreased susceptibility (ie, are less easily affected by) to stereopsis based upon binocular disparity. The basis for pattern of illusion response and interaction between sensory and integrative stages of processing, however, is unclear. We tested a group of 38 patients and 28 control subjects in contrast sensitivity, the Muller-Lyer and Poggendorff illusions, as well as a subgroup in stereopsis and the Ponzo illusion, Sander parallelogram, and Hermann grid illusions. We predicted that patients would be more susceptible to tests that become more apparent with increased contrast (Muller-Lyer illusion), less susceptible to tests that become less apparent with increased contrast (stereopsis, Ponzo illusion, Hermann grid), and equally susceptible to contrast-insensitive tests (Poggendorff illusion). Additionally, the Hermann grid was tested at varying levels of contrast. Patients demonstrated significant deficits in contrast sensitivity, especially to brief, low spatial frequency stimuli, and the predicted differential response to the tested illusions. Additionally, poor performance on stereopsis and the Hermann grid significantly correlated with decreased contrast sensitivity (all P’s <.01). Muller-Lyer illusion and stereopsis performance were also inversely related (P < .01). This study replicates and expands upon previous findings with visual illusions. Our results offer a unifying explanation for disparate studies and suggest that deficits in early sensory gain affect subsequent integrative processes.

Sensory Contributions to Impaired Emotion Processing in Schizophrenia

Fri, 16 Oct 2009 01:19:11 PDT

Both emotion and visual processing deficits are documented in schizophrenia, and preferential magnocellular visual pathway dysfunction has been reported in several studies. This study examined the contribution to emotion-processing deficits of magnocellular and parvocellular visual pathway function, based on stimulus properties and shape of contrast response functions. Experiment 1 examined the relationship between contrast sensitivity to magnocellular- and parvocellular-biased stimuli and emotion recognition using the Penn Emotion Recognition (ER-40) and Emotion Differentiation (EMODIFF) tests. Experiment 2 altered the contrast levels of the faces themselves to determine whether emotion detection curves would show a pattern characteristic of magnocellular neurons and whether patients would show a deficit in performance related to early sensory processing stages. Results for experiment 1 showed that patients had impaired emotion processing and a preferential magnocellular deficit on the contrast sensitivity task. Greater deficits in ER-40 and EMODIFF performance correlated with impaired contrast sensitivity to the magnocellular-biased condition, which remained significant for the EMODIFF task even when nonspecific correlations due to group were considered in a step-wise regression. Experiment 2 showed contrast response functions indicative of magnocellular processing for both groups, with patients showing impaired performance. Impaired emotion identification on this task was also correlated with magnocellular-biased visual sensory processing dysfunction. These results provide evidence for a contribution of impaired early-stage visual processing in emotion recognition deficits in schizophrenia and suggest that a bottom-up approach to remediation may be effective.

Schizophrenia Patients Show Deficits in Shifts of Attention to Different Levels of Global-Local Stimuli: Evidence for Magnocellular Dysfunction

Fri, 16 Oct 2009 01:19:11 PDT

Abnormalities of attention and visual perception are well documented in schizophrenia. The global-local task is a measure of attention and perceptual organization that utilizes visual stimuli comprised of large letters (global level) made up of smaller letters (local level). Subjects identify target letters appearing at either the global or local level of the stimulus. In this study, we used a version of the global-local task specifically designed to examine lateralized hemispheric processing and attention shifting in 30 schizophrenia patients and 24 normal controls. Global-local stimuli were presented in couplets (consecutive pairs). Reaction time for the second target in a couplet was compared under conditions in which the target remained at the same level (global-global, local-local) and when the target changed levels (global-local, local-global). Level-specific priming (ie, global to global and local to local) and the local-to-global level shift were similar in both groups. Schizophrenia patients were significantly slower, however, shifting attention from the global to the local level. These results implicate an impairment in shifting attentional resources from predominantly right lateralized magnocellular/dorsal stream processing of global targets to predominantly left lateralized parvocellular/ventral stream processing of local targets. Local interference effects in global processing provide further support for impaired magnocellular processing in schizophrenia patients.

Scents and Nonsense: Olfactory Dysfunction in Schizophrenia

Turetsky, B. I., Hahn, C.-G., Borgmann-Winter, K., Moberg, P. J. — Fri, 16 Oct 2009 01:19:11 PDT

Among the sensory modalities, olfaction is most closely associated with the frontal and temporal brain regions that are implicated in schizophrenia and most intimately related to the affective and mnemonic functions that these regions subserve. Olfactory probes may therefore be ideal tools through which to assess the structural and functional integrity of the neural substrates that underlie disease-related cognitive and emotional disturbances. Perhaps more importantly, to the extent that early sensory afferents are also disrupted in schizophrenia, the olfactory system—owing to its strategic anatomic location—may be especially vulnerable to such disruption. Olfactory dysfunction may therefore be a sensitive indicator of schizophrenia pathology and may even serve as an "early warning" sign of disease vulnerability or onset. In this article, we review the evidence supporting a primary olfactory sensory disturbance in schizophrenia. Convergent data indicate that structural and functional abnormalities extend from the cortex to the most peripheral elements of the olfactory system. These reflect, in part, a genetically mediated neurodevelopmental etiology. Gross structural and functional anomalies are mirrored by cellular and molecular abnormalities that suggest decreased or faulty innervation and/or dysregulation of intracellular signaling. A unifying mechanistic hypothesis may be the epigenetic regulation of gene expression. With the opportunity to obtain olfactory neural tissue from live patients through nasal epithelial biopsy, the peripheral olfactory system offers a uniquely accessible window through which the pathophysiological antecedents and sequelae of schizophrenia may be observed. This could help to clarify underlying brain mechanisms and facilitate identification of clinically relevant biomarkers.

When Top-Down Meets Bottom-Up: Auditory Training Enhances Verbal Memory in Schizophrenia

Fri, 16 Oct 2009 01:19:11 PDT

A critical research priority for our field is to develop treatments that enhance cognitive functioning in schizophrenia and thereby attenuate the functional losses associated with the illness. In this article, we describe such a treatment method that is grounded in emerging research on the widespread sensory processing impairments of schizophrenia, as described elsewhere in this special issue. We first present the rationale for this treatment approach, which consists of cognitive training exercises that make use of principles derived from the past 2 decades of basic science research in learning-induced neuroplasticity; these exercises explicitly target not only the higher order or "top-down" processes of cognition but also the content building blocks of accurate and efficient sensory representations to simultaneously achieve "bottom-up" remediation. We then summarize our experience to date and briefly review our behavioral and serum biomarker findings from a randomized controlled trial of this method in outpatients with long-term symptoms of schizophrenia. Finally, we present promising early psychophysiological evidence that supports the hypothesis that this cognitive training method induces changes in aspects of impaired bottom-up sensory processing in schizophrenia. We conclude with the observation that neuroplasticity-based cognitive training brings patients closer to physiological patterns seen in healthy participants, suggesting that it changes the brain in an adaptive manner in schizophrenia.

Imaging Genetic Liability to Schizophrenia: Systematic Review of fMRI Studies of Patients' Nonpsychotic Relatives

MacDonald, A. W., Thermenos, H. W., Barch, D. M., Seidman, L. J. — Fri, 16 Oct 2009 01:19:11 PDT

There is a growing literature on brain activity in the nonpsychotic first-degree relatives of patients with schizophrenia as measured using functional imaging. This systematic review examined 20 studies in 4 domains of cognition, including cognitive control (7 samples), working memory (5 samples), long-term memory (4 samples), and language (4 samples). While the literature was widely divergent, these studies did consistently find activation differences between patients’ relatives and controls. The most consistent increases in activation within hemisphere were found in right ventral prefrontal cortex (PFC) and right parietal cortex. Abnormal activity, defined as significant increases or decreases in activation relative to controls irrespective of hemisphere, was found in about two-thirds of contrasts in the cerebellum, dorsal prefrontal, lateral temporal, and parietal cortices, and thalamus, with basal ganglia and ventral PFC showing abnormalities in approximately half of those contrasts. Anterior cingulate was generally spared in patients’ relatives. The diversity of findings in studies of patients’ relatives may derive from differences between the cognitive demands across studies. We identify avenues for building a more accurate and cumulative literature, including symmetrical inclusion criteria for relatives and controls, recording in-scanner responses, using both a priori and whole-brain tests, explicitly reporting threshold values, reporting main effects of task, reporting effect sizes, and quantifying the risk of false negatives. While functional imaging in the relatives of schizophrenia patients remains a promising methodology for understanding the impact of the unexpressed genetic liability to schizophrenia, no single region or mechanism of abnormalities has yet emerged.

Schizophrenia Susceptibility Genes Directly Implicated in the Life Cycles of Pathogens: Cytomegalovirus, Influenza, Herpes simplex, Rubella, and Toxoplasma gondii

Carter, C.J. — Fri, 16 Oct 2009 01:19:11 PDT

Many genes implicated in schizophrenia can be related to glutamatergic transmission and neuroplasticity, oligodendrocyte function, and other families clearly related to neurobiology and schizophrenia phenotypes. Others appear rather to be involved in the life cycles of the pathogens implicated in the disease. For example, aspartylglucosaminidase (AGA), PLA2, SIAT8B, GALNT7, or B3GAT1 metabolize chemical ligands to which the influenza virus, herpes simplex, cytomegalovirus (CMV), rubella, or Toxoplasma gondii bind. The epidermal growth factor receptor (EGR/EGFR) is used by the CMV to gain entry to cells, and a CMV gene codes for an interleukin (IL-10) mimic that binds the host cognate receptor, IL10R. The fibroblast growth factor receptor (FGFR1) is used by herpes simplex. KPNA3 and RANBP5 control the nuclear import of the influenza virus. Disrupted in schizophrenia 1 (DISC1) controls the microtubule network that is used by viruses as a route to the nucleus, while DTNBP1, MUTED, and BLOC1S3 regulate endosomal to lysosomal routing that is also important in viral traffic. Neuregulin 1 activates ERBB receptors releasing a factor, EBP1, known to inhibit the influenza virus transcriptase. Other viral or bacterial components bind to genes or proteins encoded by CALR, FEZ1, FYN, HSPA1B, IL2, HTR2A, KPNA3, MED12, MED15, MICB, NQO2, PAX6, PIK3C3, RANBP5, or TP53, while the cerebral infectivity of the herpes simplex virus is modified by Apolipoprotein E (APOE). Genes encoding for proteins related to the innate immune response, including cytokine related (CCR5, CSF2RA, CSF2RB, IL1B, IL1RN, IL2, IL3, IL3RA, IL4, IL10, IL10RA, IL18RAP, lymphotoxin-alpha, tumor necrosis factor alpha [TNF]), human leukocyte antigen (HLA) antigens (HLA-A10, HLA-B, HLA-DRB1), and genes involved in antigen processing (angiotensin-converting enzyme and tripeptidyl peptidase 2) are all concerned with defense against invading pathogens. Human microRNAs (Hsa-mir-198 and Hsa-mir-206) are predicted to bind to influenza, rubella, or poliovirus genes. Certain genes associated with schizophrenia, including those also concerned with neurophysiology, are intimately related to the life cycles of the pathogens implicated in the disease. Several genes may affect pathogen virulence, while the pathogens in turn may affect genes and processes relevant to the neurophysiology of schizophrenia. For such genes, the strength of association in genetic studies is likely to be conditioned by the presence of the pathogen, which varies in different populations at different times, a factor that may explain the heterogeneity that plagues such studies. This scenario also suggests that drugs or vaccines designed to eliminate the pathogens that so clearly interact with schizophrenia susceptibility genes could have a dramatic effect on the incidence of the disease.

Passive and Active Schizophrenia: Toward a New Descriptive Micropsychopathology

Moscarelli, M. — Fri, 16 Oct 2009 01:19:11 PDT

The "experiences" reported by individuals affected by schizophrenia are fundamental components of the descriptive approach adopted by current diagnostic systems for mental disorders and by clinical diagnostic interviews and rating scales for the assessment of the symptoms of schizophrenia. However, the technical literature does not rely on a specific definition of experiences in schizophrenia. This article introduces a specific, restrictive, operationalized definition of the "experiential substrate" of schizophrenia, defined by the "self-giving" "passive experiences" of the disorder that break into the consciousness of the affected individual, and are distinguished from the "active" acts of judgment formulation and conviction/belief attainment. The experiential substrate of schizophrenia may be considered similar to the experiential substrate of pain. The operationalization of the definition of passive experiences can enable the experiential substrate of schizophrenia to be acknowledged as an independent domain with a specific role in the assessment of the disorder, a role that is substantially omitted or ignored by current research and practice. The term "descriptive micropsychopathology" is proposed for this new method aimed to describe passive experiences and active judgments as independent domains to enhance the reformulation of criteria for symptom assessment and, consequently, reformulation of the criteria for the assessment of the efficacy and effectiveness of interventions aimed at prevention, care, and rehabilitation in schizophrenia. A new measure focusing on the evaluation of the passive experiences of schizophrenia and on the disturbance they cause to patients is also described.

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

Fri, 16 Oct 2009 01:19:11 PDT

Issue 35(5) Cover Image: Woman with guitar

Fri, 16 Oct 2009 01:19:11 PDT

Anticipating DSM-V: Should Psychosis Risk Become a Diagnostic Class?

Carpenter, W. T. — Tue, 18 Aug 2009 18:07:41 PDT

Recovery as Discovery

Scotti, P. — Tue, 18 Aug 2009 18:07:41 PDT

This first person account describes recovery as discovery of new meanings and opportunities in life. It travels through a journey from illness to wellness, from darkness and despair to light and hope, from futility to fruitfulness, as well as, from a state of death and loss to new life.

Who Is at Risk for a Psychotic Disorder?

Heckers, S. — Tue, 18 Aug 2009 18:07:41 PDT

Accurate assessment of the individual risk for psychotic disorders has great value. We need to determine the reliability and rate of conversion to a psychotic disorder in clinical samples before we can recommend a risk syndrome diagnosis for general practice. The assessment of risk carries its own risks, including stigmatization and inappropriate treatment, potentially leading to adverse outcomes.

Neurexin 1 (NRXN1) Deletions in Schizophrenia

Tue, 18 Aug 2009 18:07:41 PDT

Zuclopenthixol Dihydrochloride for Schizophrenia

Kumar, A., Strech, D. — Tue, 18 Aug 2009 18:07:41 PDT

Cognitive Behavior Therapy for Psychosis: Where Have We Been and Where Are We Going?

Velligan, D. I. — Tue, 18 Aug 2009 18:07:41 PDT

Predictors of Outcome in Brief Cognitive Behavior Therapy for Schizophrenia

Brabban, A., Tai, S., Turkington, D. — Tue, 18 Aug 2009 18:07:41 PDT

Antipsychotic medications, while effective, often leave patients with ongoing positive and negative symptoms of schizophrenia. Guidelines recommend using cognitive behavior therapy (CBT) with this group. Clearly, mental health professionals require training and supervision to deliver CBT-based interventions. This study tested which antipsychotic-resistant patients were most likely to respond to brief CBT delivered by psychiatric nurses. Staff were trained over 10 consecutive days with ongoing weekly supervision. Training for carers in the basic principles of CBT was also provided. This article represents the secondary analyses of completer data from a previously published randomized controlled trial (Turkington D, Kingdon D, Turner T. Effectiveness of a brief cognitive-behavioural therapy intervention in the treatment of schizophrenia. Br J Psychiatry. 2002;180:523–527) (n = 354) to determine whether a number of a priori variables were predictive of a good outcome with CBT and treatment as usual. Logistic regression was employed to determine whether any of these variables were able to predict a 25% or greater improvement in overall symptoms and insight. In the CBT group only, female gender was found to strongly predict a reduction in overall symptoms (P = .004, odds ratio [OR] = 2.39, 95% confidence interval [CI] = 1.33, 4.30) and increase in insight (P = .04, OR = 1.84, 95% CI = 1.03, 3.29). In addition, for individuals with delusions, a lower level of conviction in these beliefs was associated with a good response to brief CBT (P = .02, OR = 0.70, 95% CI = 0.51, 0.95). Women with schizophrenia and patients with a low level of conviction in their delusions are most likely to respond to brief CBT and should be offered this routinely alongside antipsychotic medications and other psychosocial interventions.

The Evolution of Cognitive Behavior Therapy for Schizophrenia: Current Practice and Recent Developments

Tai, S., Turkington, D. — Tue, 18 Aug 2009 18:07:41 PDT

Cognitive behavior therapy (CBT) evolved from behavioral theory and developed to focus more on cognitive models that incorporated reappraisal of thinking errors and schema change strategies. This article will describe the key elements of CBT for schizophrenia and the current evidence of its efficacy and effectiveness. We conclude with a description of recent concepts that extend the theoretical basis of practice and expand the range of CBT strategies for use in schizophrenia. Mindfulness, meta-cognitive approaches, compassionate mind training, and method of levels are postulated as useful adjuncts for CBT with psychotic patients.

Social Disinterest Attitudes and Group Cognitive-Behavioral Social Skills Training for Functional Disability in Schizophrenia

Granholm, E., Ben-Zeev, D., Link, P. C. — Tue, 18 Aug 2009 18:07:41 PDT

The majority of clinical trials of cognitive-behavioral therapy (CBT) for schizophrenia have used individual therapy to target positive symptoms. Promising results have been found, however, for group CBT interventions and other treatment targets like psychosocial functioning. CBT for functioning in schizophrenia is based on a cognitive model of functional outcome in schizophrenia that incorporates dysfunctional attitudes (eg, social disinterest, defeatist performance beliefs) as mediators between neurocognitive impairment and functional outcome. In this report, 18 clinical trials of CBT for schizophrenia that included measures of psychosocial functioning were reviewed, and two-thirds showed improvements in functioning in CBT. The cognitive model of functional outcome was also tested by examining the relationship between social disinterest attitudes and functional outcome in 79 people with schizophrenia randomized to either group cognitive-behavioral social skills training or a goal-focused supportive contact intervention. Consistent with the cognitive model, lower social disinterest attitudes at baseline and greater reduction in social disinterest during group therapy predicted better functional outcome at end of treatment for both groups. However, the groups did not differ significantly with regard to overall change in social disinterest attitudes during treatment, suggesting that nonspecific social interactions during group therapy can lead to changes in social disinterest, regardless of whether these attitudes are directly targeted by cognitive therapy interventions.

Multimodal Cognitive Therapy: Combining Treatments That Bypass Cognitive Deficits and Deal With Reasoning and Appraisal Biases

Tue, 18 Aug 2009 18:07:41 PDT

The process of recovery in schizophrenia involves resolving persistent symptoms, addressing cognitive impairments, and improving functional outcomes. Our research group has demonstrated the efficacy of cognitive adaptation training (CAT)—a home-based psychosocial treatment utilizing environmental supports such as medication containers, signs, checklists, and the organization of belongings to bypass deficits in cognitive functioning and cue and sequence adaptive behavior) for improving adherence to medications and functional outcomes in schizophrenia. Early CAT pilot studies utilizing some therapists with training in cognitive behavior therapy (CBT) techniques for psychosis found significant improvements in positive symptoms. More recent larger scale randomized clinical trials failed to replicate this finding with CAT therapists not trained in CBT techniques. Persistent psychotic symptoms substantially impair patients’ ability to adapt to life in the community. Cognitive behavior therapy for psychosis (CBTp) is an evidence-based practice for addressing persistent positive symptoms and the distress associated with them. CBTp decreases symptomatology and minimizes the negative effect of persisting symptoms upon individuals with this disorder. We now describe a home-delivered, multimodal cognitive treatment targeting functional outcomes and persistent positive symptoms for individuals with schizophrenia by utilizing both CAT and CBT techniques. We discuss the advantages and challenges of combining these 2 interventions, present a small retrospective data analysis to support their combination into a multimodal treatment, and describe the design of an ongoing randomized trial to investigate efficacy.

Validity of the Prodromal Risk Syndrome for First Psychosis: Findings From the North American Prodrome Longitudinal Study

Tue, 18 Aug 2009 18:07:41 PDT

Treatment and prevention studies over the past decade have enrolled patients believed to be at risk for future psychosis. These patients were considered at risk for psychosis by virtue of meeting research criteria derived from retrospective accounts of the psychosis prodrome. This study evaluated the diagnostic validity of the prospective "prodromal risk syndrome" construct. Patients assessed by the Structured Interview for Prodromal Syndromes as meeting criteria of prodromal syndromes (n = 377) from the North American Prodrome Longitudinal Study were compared with normal comparison (NC, n = 196), help-seeking comparison (HSC, n = 198), familial high-risk (FHR, n = 40), and schizotypal personality disorder (SPD, n = 49) groups. Comparisons were made on variables from cross-sectional demographic, symptom, functional, comorbid diagnostic, and family history domains of assessment as well as on follow-up outcome. Prodromal risk syndrome patients as a group were robustly distinguished from NC subjects across all domains and distinguished from HSC subjects and from FHR subjects on most measures in many of these domains. Adolescent and young adult SPD patients, while distinct from prodromal patients on definitional grounds, were similar to prodromals on multiple measures, consistent with SPD in young patients possibly being an independent risk syndrome for psychosis. The strong evidence of diagnostic validity for the prodromal risk syndrome for first psychosis raises the question of its evaluation for inclusion in Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition).

Is Early Intervention in Psychosis Cost-Effective Over the Long Term?

Mihalopoulos, C., Harris, M., Henry, L., Harrigan, S., McGorry, P. — Tue, 18 Aug 2009 18:07:41 PDT

Objective: This study assesses the long-term cost-effectiveness of a comprehensive model of mental health care for first-episode psychosis. The study is an extension of a previous economic evaluation of the Early Psychosis Prevention and Intervention Centre (EPPIC) that assessed the first-year costs and outcomes of treatment. Method: The current study used a matched, historical control group design with a follow-up of approximately 8 years. Complete follow-up data were available for 65 of the original 102 participants. Direct public mental health service costs incurred subsequent to the first year of treatment and symptomatic and functional outcomes of 32 participants initially treated for up to 2 years at EPPIC were compared with a matched cohort of 33 participants initially treated by generic mental health services. Treatment-related resource use was measured and valued using Australian published prices. Results: Almost 8 years after initial treatment, EPPIC subjects displayed lower levels of positive psychotic symptoms (P = .007), were more likely to be in remission (P = .008), and had a more favorable course of illness (P = .011) than the controls. Fifty-six percent of the EPPIC cohort were in paid employment over the last 2 years compared with 33% of controls (P = .083). Each EPPIC patient costs on average A$3445 per annum to treat compared with controls, who each costs A$9503 per annum. Conclusions: Specialized early psychosis programs can deliver a higher recovery rate at one-third the cost of standard public mental health services. Residual methodological limitations and limited sample size indicate that further research is required to verify this finding.

Shared Neurocognitive Dysfunctions in Young Offspring at Extreme Risk for Schizophrenia or Bipolar Disorder in Eastern Quebec Multigenerational Families

Tue, 18 Aug 2009 18:07:41 PDT

Background: Adult patients having schizophrenia (SZ) or bipolar disorder (BP) may have in common neurocognitive deficits. Former evidence suggests impairments in several neuropsychological functions in young offspring at genetic risk for SZ or BP. Moreover, a dose-response relation may exist between the degree of familial loading and cognitive impairments. This study examines the cognitive functioning of high-risk (HR) offspring of parents having schizophrenia (HRSZ) and high-risk offspring of parents having bipolar disorder (HRBP) descending from densely affected kindreds. Methods: The sample consisted of 45 young offspring (mean age of 17.3 years) born to a parent having SZ or BP descending from large multigenerational families of Eastern Québec that are densely affected by SZ or BP and followed up since 1989. The offspring were administered a lifetime best-estimate diagnostic procedure (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV]) and an extensive standard neuropsychological battery. Raw scores were compared with age- and gender-matched controls. Results: The offspring displayed differences in memory and executive functions when compared with controls. Moderate to large effect sizes (Cohen d) ranging from 0.65 to 1.25 (for IQ and memory) were observed. Several of the cognitive dysfunctions were present in both HRSZ and HRBP, even when considering DSM-IV clinical status. Conclusions: HRSZ and HRBP shared several aspects of their cognitive impairment. Our data suggest that the extremely high genetic and familial loading of these HRs may have contributed to a quantitatively increased magnitude of the cognitive impairments in both HR subgroups, especially in memory. These offspring at heightened risk present difficulties in processing information that warrant preventive research.

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

Tue, 18 Aug 2009 18:07:41 PDT

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

Secondary Effects of Antipsychotics: Women at Greater Risk Than Men

Seeman, M. V. — Tue, 18 Aug 2009 18:07:41 PDT

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

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

Tue, 18 Aug 2009 18:07:41 PDT

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

A Review of the Fetal Brain Cytokine Imbalance Hypothesis of Schizophrenia

Meyer, U., Feldon, J., Yee, B. K. — Tue, 18 Aug 2009 18:07:41 PDT

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

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

Fornito, A., Yucel, M., Dean, B., Wood, S. J., Pantelis, C. — Tue, 18 Aug 2009 18:07:42 PDT

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

Attributional Style in Delusional Patients: A Comparison of Remitted Paranoid, Remitted Nonparanoid, and Current Paranoid Patients With Nonpsychiatric Controls

Aakre, J. M., Seghers, J. P., St-Hilaire, A., Docherty, N. — Tue, 18 Aug 2009 18:07:42 PDT

Many studies have found that people experiencing persecutory delusions have a marked tendency to use external-personal attributions when establishing the causes of negative events. Although nonclinical populations also tend to attribute negative events to external causes, those causes are typically believed to be universal in nature, rather than personal. The central goal of the present study was to investigate whether individuals with remitted persecutory delusions would display this external-personal bias regarding negative events, in comparison to remitted patients whose delusions were not paranoid in nature and to nonpsychiatric controls. Results indicate that currently paranoid patients were significantly more likely than all other groups, including the remitted paranoid group, to use external-personal attributions in negative events. Interestingly, all patient groups also were found to be significantly more likely than the controls to use internal-personal and internal-universal attributions when explaining negative events.

Taking the Perspective of the Other Contributes to Awareness of Illness in Schizophrenia

Langdon, R., Ward, P. — Tue, 18 Aug 2009 18:07:42 PDT

Two approaches dominate research on the lack of awareness of illness that characterizes schizophrenia. The "deficit" approach uses standardized neuropsychological batteries to identify the neural underpinnings of intact insight; the "nondeficit" approach investigates the psychological defense mechanisms that motivate denial of illness. We adopt, instead, a cognitive neuropsychological approach to model the cognitive processes which underpin insight and which might be either damaged (because of neuropathology) or not used (because of motivational forces). We conceive of these processes in terms of a metacognitive capacity "to see ourselves as others see us." We predict that a general difficulty with adopting other mental perspectives (with "seeing the world as others do"), indexed by performance deficits on theory of mind (ToM) tasks, will impair insight in schizophrenia. Thirty schizophrenic patients (also assessed for insight) and 26 healthy controls completed a battery of ToM tasks which varied presentation modality, response mode and instruction type (picture sequencing, joke appreciation and story comprehension tasks). While patients performed more poorly than controls on all ToM tasks, impairment in patients was not concordant across tasks. ToM scores from the picture sequencing and joke appreciation tasks, and not the story comprehension task, intercorrelated significantly in patients and predicted insight. Findings support the view that insight relies upon a cognitive capacity to adopt the other perspective, which, if intact, contributes to the metacognitive capacity to reflect upon "one's own" mental health from the other perspective. Findings also suggest that the nature of perspective-taking difficulty which disrupts insight in schizophrenia is best revealed using ToM tasks with "indirect" instructions.

Major Self-mutilation in the First Episode of Psychosis

Large, M., Babidge, N., Andrews, D., Storey, P., Nielssen, O. — Tue, 18 Aug 2009 18:07:42 PDT

Major self-mutilation (MSM) is a rare but catastrophic complication of severe mental illness. Most people who inflict MSM have a psychotic disorder, usually a schizophrenia spectrum psychosis. It is not known when in the course of psychotic illness, MSM is most likely to occur. In this study, the proportion of patients in first episode of psychosis (FEP) was assessed using the results of a systematic review of published case reports. Histories of patients who had removed an eye or a testicle, severed their penis, or amputated a portion of a limb and were diagnosed with a schizophrenia spectrum psychosis were included. A psychotic illness was documented in 143 of 189 cases (75.6%) of MSM, of whom 119 of 143 (83.2%) were diagnosed with a schizophrenia spectrum psychosis. The treatment status of a schizophrenia spectrum psychosis could be ascertained in 101 of the case reports, of which 54 were in the FEP (53.5%, 95% confidence interval = 43.7%–63.2%). Patients who inflict MSM in FEP exhibited similar symptoms to those who inflict MSM later in their illness. Acute psychosis, in particular first-episode schizophrenia, appears to be the major cause of MSM. Although MSM is extremely uncommon, earlier treatment of psychotic illness may reduce the incidence of MSM.

Neuropsychological Function and Dysfunction in Schizophrenia and Psychotic Affective Disorders

Tue, 18 Aug 2009 18:07:42 PDT

Background: Mounting evidence suggests that compromised neurocognitive function is a central feature of schizophrenia. There are, however, schizophrenia patients with a normal neuropsychological (NP) performance, but estimates of the proportion of NP normal patients vary considerably between studies. Neurocognitive dysfunction is also a characteristic of other psychotic disorders, yet there are inconsistencies in the literature regarding the similarity to impairments in schizophrenia. NP normality in psychotic affective disorders has not been systematically studied.

Methods: Data came from the Suffolk County Mental Health Project, an epidemiological study of first-admission patients with psychotic disorders. Respondents with a diagnosis of schizophrenia (N = 94) or schizoaffective disorder (N = 15), bipolar disorder (N = 78), and major depressive disorder (N = 48) were administered a battery of NP tests assessing 8 cognitive domains 2 years after index admission. Patients’ performance profile was compared, and their NP status was classified based on 3 previously published criteria that vary in their stringency.

Results: The 4 diagnostic groups had comparable NP performance profile patterns. All groups demonstrated impairments in memory, executive functions, and attention and processing speed. However, schizophrenia patients were more impaired than the other groups on all cognitive domains. Results were not attenuated when IQ was controlled. Prevalence of NP normality ranged between 16% and 45% in schizophrenia, 20% and 33% in schizoaffective disorder, 42% and 64% in bipolar disorder, and 42% and 77% in depression, depending on the criterion employed.

Conclusions: Evidence suggests that differences in NP performance between schizophrenia and psychotic affective disorders are largely quantitative. NP impairment is also common in psychotic affective disorders. A significant minority of schizophrenia patients are NP normal.

Theory of Mind and Schizophrenia: A Positron Emission Tomography Study of Medication-Free Patients.

Tue, 18 Aug 2009 18:07:42 PDT

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

Lehman, A. F. — Mon, 15 Jun 2009 08:36:21 PDT

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

Gray, B. — Mon, 15 Jun 2009 08:36:21 PDT

Toward a Model of Impaired Reality Testing in Rats

McDannald, M., Schoenbaum, G. — Mon, 15 Jun 2009 08:36:21 PDT

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

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

Morrison, P. D., Murray, R. M. — Mon, 15 Jun 2009 08:36:21 PDT

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

Dance Therapy for People with Schizophrenia

Xia, J., Grant, T. J. — Mon, 15 Jun 2009 08:36:21 PDT

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

Drake, R. E., Essock, S. M. — Mon, 15 Jun 2009 08:36:21 PDT

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

Mojtabai, R., Fochtmann, L., Chang, S.-W., Kotov, R., Craig, T. J., Bromet, E. — Mon, 15 Jun 2009 08:36:22 PDT

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

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

Kreyenbuhl, J., Nossel, I. R., Dixon, L. B. — Mon, 15 Jun 2009 08:36:22 PDT

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

Implementing Evidence-Based Practices for People With Schizophrenia

Drake, R. E., Bond, G. R., Essock, S. M. — Mon, 15 Jun 2009 08:36:22 PDT

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

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

Sederer, L. I. — Mon, 15 Jun 2009 08:36:22 PDT

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

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

Mon, 15 Jun 2009 08:36:22 PDT

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

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

Dunn, L. B., Kim, D. S., Fellows, I. E., Palmer, B. W. — Mon, 15 Jun 2009 08:36:22 PDT

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

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

Bell, M., Tsang, H. W. H., Greig, T. C., Bryson, G. J. — Mon, 15 Jun 2009 08:36:22 PDT

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

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

Mon, 15 Jun 2009 08:36:22 PDT

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

Are Psychiatrist Characteristics Associated With Postdischarge Suicide of Schizophrenia Patients?

Lee, H.-C., Lin, H.-C. — Mon, 15 Jun 2009 08:36:22 PDT

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

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

Pfeifer, S., van Os, J., Hanssen, M., Delespaul, P., Krabbendam, L. — Mon, 15 Jun 2009 08:36:22 PDT

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

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

Rabinowitz, J., Levine, S. Z., Barkai, O., Davidov, O. — Mon, 15 Jun 2009 08:36:22 PDT

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

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

Stone, J. M., Davis, J. M., Leucht, S., Pilowsky, L. S. — Mon, 15 Jun 2009 08:36:22 PDT

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

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

Grant, P. M., Beck, A. T. — Mon, 15 Jun 2009 08:36:22 PDT

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

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

Mon, 15 Jun 2009 08:36:22 PDT

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

Extended Visual Simultaneity Thresholds in Patients With Schizophrenia

Mon, 15 Jun 2009 08:36:22 PDT

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

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

Venables, N. C., Bernat, E. M., Sponheim, S. R. — Mon, 15 Jun 2009 08:36:22 PDT

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