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Preview: Schizophrenia Bulletin - recent issues

Schizophrenia Bulletin - recent issues



Schizophrenia Bulletin - RSS feed of recent issues (covers the latest 3 issues, including the current issue)



 



Cover

2016-10-04T06:17:00-07:00




Editorial_Board

2016-10-04T06:17:00-07:00




Subscriptions

2016-10-04T06:17:00-07:00




Contents_Page

2016-10-04T06:17:00-07:00







The Importance of Talk Therapy

2016-10-04T06:17:00-07:00







The Journey

2016-10-04T06:17:00-07:00




Somatic Comorbidity in Schizophrenia: Some Possible Biological Mechanisms Across the Life Span

2016-10-04T06:17:00-07:00

Schizophrenia is associated with decreased life expectancy (15–25 y) compared to the general population, with comorbid somatic diseases and in particular cardiovascular diseases being a major cause. Life style and medication probably account for much of the increased mortality risk due to somatic diseases in schizophrenia, but the evidence implicating biological pathways potentially affecting both body and brain is increasing. This includes overlapping genes between schizophrenia and somatic diseases, prenatal risk factors such as hypoxia and infections, and increased cardiovascular disease risk in drug-naïve patients at illness onset. Although environmental bias increases throughout the disease course, there are also some studies on chronic schizophrenia and postmortem brain samples that warrant further attention. In the following, we will attempt to move beyond environmental impact and explore some of the shared pathophysiological mechanisms potentially underlying both schizophrenia and somatic diseases.




Wendan Decoction for Schizophrenia

2016-10-04T06:17:00-07:00







Gesture Performance in Schizophrenia Predicts Functional Outcome After 6 Months

2016-10-04T06:17:00-07:00

The functional outcome of schizophrenia is heterogeneous and markers of the course are missing. Functional outcome is associated with social cognition and negative symptoms. Gesture performance and nonverbal social perception are critically impaired in schizophrenia. Here, we tested whether gesture performance or nonverbal social perception could predict functional outcome and the ability to adequately perform relevant skills of everyday function (functional capacity) after 6 months. In a naturalistic longitudinal study, 28 patients with schizophrenia completed tests of nonverbal communication at baseline and follow-up. In addition, functional outcome, social and occupational functioning, as well as functional capacity at follow-up were assessed. Gesture performance and nonverbal social perception at baseline predicted negative symptoms, functional outcome, and functional capacity at 6-month follow-up. Gesture performance predicted functional outcome beyond the baseline measure of functioning. Patients with gesture deficits at baseline had stable negative symptoms and experienced a decline in social functioning. While in patients without gesture deficits, negative symptom severity decreased and social functioning remained stable. Thus, a simple test of hand gesture performance at baseline may indicate favorable outcomes in short-term follow-up. The results further support the importance of nonverbal communication skills in subjects with schizophrenia.




Protein Interaction Networks Link Schizophrenia Risk Loci to Synaptic Function

2016-10-04T06:17:00-07:00

Schizophrenia is a severe and highly heritable psychiatric disorder affecting approximately 1% of the population. Genome-wide association studies have identified 108 independent genetic loci with genome-wide significance but their functional importance has yet to be elucidated. Here, we develop a novel strategy based on network analysis of protein–protein interactions (PPI) to infer biological function associated with variants most strongly linked to illness risk. We show that the schizophrenia loci are strongly linked to synaptic transmission (P FWE < .001) and ion transmembrane transport (P FWE = .03), but not to ontological categories previously found to be shared across psychiatric illnesses. We demonstrate that brain expression of risk-linked genes within the identified processes is strongly modulated during birth and identify a set of synaptic genes consistently changed across multiple brain regions of adult schizophrenia patients. These results suggest synaptic function as a developmentally determined schizophrenia process supported by the illness’s most associated genetic variants and their PPI networks. The implicated genes may be valuable targets for mechanistic experiments and future drug development approaches.




Defeatist Performance Beliefs, Negative Symptoms, and Functional Outcome in Schizophrenia: A Meta-analytic Review

2016-10-04T06:17:00-07:00

Negative symptoms are a strong predictor of poor functional outcome in people with schizophrenia. Unfortunately there are few effective interventions for either negative symptoms or functional outcome, despite the identification of potential mechanisms. Recent research, however, has elucidated a new potential mechanism for negative symptoms and poor functional outcome: defeatist performance beliefs (DPB), or negative thoughts about one’s ability to successfully perform goal-directed behavior that can prevent behavior initiation and engagement. We conducted 2 meta-analyses examining the relationship between DPB and both negative symptoms (n = 10 studies) and functional outcome (n = 8 studies) in people with schizophrenia. We found a small effect size for the relationship between DPB and negative symptoms, regardless of how negative symptoms were measured. We also found a small effect size for the relationship between DPB and functional outcome, which was significantly moderated by the method of assessing DPB and moderated by the sex composition of the study at a trend level. These findings highlight the potential of targeting DPB in psychosocial interventions for both negative symptoms and functional outcome.




Stress Sensitivity and Psychotic Experiences in 39 Low- and Middle-Income Countries

2016-10-04T06:17:00-07:00

Stress has a central role in most theories of psychosis etiology, but the relation between stress and psychosis has rarely been examined in large population-level data sets, particularly in low- and middle-income countries. We used data from 39 countries in the World Health Survey (n = 176 934) to test the hypothesis that stress sensitivity would be associated with psychotic experiences, using logistic regression analyses. Respondents in low-income countries reported higher stress sensitivity (P < .001) and prevalence of psychotic experiences (P < .001), compared to individuals in middle-income countries. Greater stress sensitivity was associated with increased odds for psychotic experiences, even when adjusted for co-occurring anxiety and depressive symptoms: adjusted odds ratio (95% CI) = 1.17 (1.15–1.19) per unit increase in stress sensitivity (range 2–10). This association was consistent and significant across nearly every country studied, and translated into a difference in psychotic experience prevalence ranging from 6.4% among those with the lowest levels of stress sensitivity up to 22.2% among those with the highest levels. These findings highlight the generalizability of the association between psychosis and stress sensitivity in the largest and most globally representative community-level sample to date, and support the targeting of stress sensitivity as a potential component of individual- and population-level interventions for psychosis.




Environmental Social Stress, Paranoia and Psychosis Liability: A Virtual Reality Study

2016-10-04T06:17:00-07:00

The impact of social environments on mental states is difficult to assess, limiting the understanding of which aspects of the social environment contribute to the onset of psychotic symptoms and how individual characteristics moderate this outcome. This study aimed to test sensitivity to environmental social stress as a mechanism of psychosis using Virtual Reality (VR) experiments. Fifty-five patients with recent onset psychotic disorder, 20 patients at ultra high risk for psychosis, 42 siblings of patients with psychosis, and 53 controls walked 5 times in a virtual bar with different levels of environmental social stress. Virtual social stressors were population density, ethnic density and hostility. Paranoia about virtual humans and subjective distress in response to virtual social stress exposures were measured with State Social Paranoia Scale (SSPS) and self-rated momentary subjective distress (SUD), respectively. Pre-existing (subclinical) symptoms were assessed with the Community Assessment of Psychic Experiences (CAPE), Green Paranoid Thoughts Scale (GPTS) and the Social Interaction Anxiety Scale (SIAS). Paranoia and subjective distress increased with degree of social stress in the environment. Psychosis liability and pre-existing symptoms, in particular negative affect, positively impacted the level of paranoia and distress in response to social stress. These results provide experimental evidence that heightened sensitivity to environmental social stress may play an important role in the onset and course of psychosis.




Why Are Children in Urban Neighborhoods at Increased Risk for Psychotic Symptoms? Findings From a UK Longitudinal Cohort Study

2016-10-04T06:17:00-07:00

Background:

Urban upbringing is associated with a 2-fold adulthood psychosis risk, and this association replicates for childhood psychotic symptoms. No study has investigated whether specific features of urban neighborhoods increase children’s risk for psychotic symptoms, despite these early psychotic phenomena elevating risk for schizophrenia and other psychiatric disorders in adulthood.

Methods:

Analyses were conducted on over 2000 children from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally-representative cohort of UK-born twins. Neighborhood-level characteristics were assessed for each family via: a geodemographic discriminator indexing neighborhood-level deprivation, postal surveys of over 5000 residents living alongside the children, and in-home interviews with the children’s mothers. Children were interviewed about psychotic symptoms at age 12. Analyses were adjusted for important family-level confounders including socioeconomic status (SES), psychiatric history, and maternal psychosis.

Results:

Urban residency at age-5 (OR = 1.80, 95% CI = 1.16–2.77) and age-12 (OR = 1.76, 95% CI = 1.15–2.69) were both significantly associated with childhood psychotic symptoms, but not with age-12 anxiety, depression, or antisocial behavior. The association was not attributable to family SES, family psychiatric history, or maternal psychosis, each implicated in childhood mental health. Low social cohesion, together with crime victimization in the neighborhood explained nearly a quarter of the association between urbanicity and childhood psychotic symptoms after considering family-level confounders.

Conclusions:

Low social cohesion and crime victimization in the neighborhood partly explain why children in cities have an elevated risk of developing psychotic symptoms. Greater understanding of the mechanisms leading from neighborhood-level exposures to psychotic symptoms could help target interventions for emerging childhood psychotic symptoms.




A Psychometric Comparison of the Clinical Assessment Interview for Negative Symptoms and the Brief Negative Symptom Scale

2016-10-04T06:17:00-07:00

In 2005, the National Institute of Mental Health held a consensus development conference on negative symptoms of schizophrenia. Among the important conclusions of this meeting were that there are at least 5 commonly accepted domains of negative symptoms (blunted affect, alogia, avolition, anhedonia, asociality) and that new rating scales were needed to adequately assess these constructs. Two next-generation negative symptom scales resulted from this meeting: the Brief Negative Symptom Scale (BNSS) and Clinical Assessment Interview for Negative Symptoms (CAINS). Both measures are becoming widely used and studies have demonstrated good psychometric properties for each scale. The current study provides the first direct psychometric comparison of these scales. Participants included 65 outpatients diagnosed with schizophrenia or schizoaffective disorder who completed clinical interviews, questionnaires, and neuropsychological testing. Separate raters completed the BNSS and CAINS within the same week. Results indicated that both measures had good internal consistency, convergent validity, and discriminant validity. High correspondence was observed between CAINS and BNSS blunted affect and alogia items. Moderate convergence occurred for avolition and asociality items, and low convergence was seen among anhedonia items. Findings suggest that both scales have good psychometric properties, but that there are important distinctions among the items related to motivation and pleasure.




Diagnostic Stability of ICD/DSM First Episode Psychosis Diagnoses: Meta-analysis

2016-10-04T06:17:00-07:00

Background:

Validity of current International Classification of Disease/Diagnostic and Statistical Manual of Mental Disorders (ICD/DSM) first episode psychosis diagnoses is essential in clinical practice, research, training and public health.

Method:

We provide a meta-analytical estimate of prospective diagnostic stability and instability in ICD-10 or DSM-IV first episode diagnoses of functional psychoses. Independent extraction by multiple observers. Random effect meta-analysis conducted with the "metaprop," "metaninf," "metafunnel," "metabias," and "metareg" packages of STATA13.1. Moderators were tested with meta-regression analyses. Heterogeneity was assessed with the I 2 index. Sensitivity analyses tested robustness of results. Publication biases were assessed with funnel plots and Egger’s test.

Findings:

42 studies and 45 samples were included, for a total of 14 484 first episode patients and an average follow-up of 4.5 years. Prospective diagnostic stability ranked: schizophrenia 0.90 (95% CI 0.85–0.95), affective spectrum psychoses 0.84 (95% CI 0.79–0.89), schizoaffective disorder 0.72 (95% CI 0.61–0.73), substance-induced psychotic disorder 0.66 (95% CI 0.51–0.81), delusional disorder 0.59 (95% CI 0.47–0.71), acute and transient psychotic disorder/brief psychotic disorder 0.56 (95% CI 0.62–0.60), psychosis not otherwise specified 0.36 (95% CI 0.27–0.45, schizophreniform disorder 0.29 (95% CI 0.22–0.38). Diagnostic stability within schizophrenia spectrum psychoses was 0.93 (95% CI 0.89–0.97); changes to affective spectrum psychoses were 0.05 (95% CI 0.01–0.08). About 0.10 (95% CI 0.05–0.15) of affective spectrum psychoses changed to schizophrenia spectrum psychosis. Across the other psychotic diagnoses there was high diagnostic instability, mostly to schizophrenia.

Interpretation:

There is meta-analytical evidence for high prospective diagnostic stability in schizophrenia spectrum and affective spectrum psychoses, with no significant ICD/DSM differences. These results may inform the development of new treatment guidelines for early psychosis and impact drug licensing from regulatory agencies.




Cancer Immune Equilibrium and Schizophrenia Have Similar Interferon-{gamma}, Tumor Necrosis Factor-{alpha}, and Interleukin Expression: A Tumor Model of Schizophrenia

2016-10-04T06:17:00-07:00

For at least a century, a debate has continued as to whether cancer risk is reduced in schizophrenia. Genetic studies have also suggested the 2 conditions may share protein transcriptional pathways. The author predicted that if the pathophysiology of schizophrenia confers protection from cancer, then the immunology of schizophrenia should reflect a state of tumor suppression, ie, the opposite of tumor escape. To examine this possibility, the author performed a literature search for measurements of cytokines in drug-naïve first episode subjects with schizophrenia for comparison with cytokine expression in tumor escape vs tumor suppression. The comparison showed that instead of either tumor suppression or escape, schizophrenia appears to be in a state of tumor equilibrium. Based on this finding, the author hypothesized that the clinical presentation of schizophrenia may involve cell transformation similar to an early stage of cancer initiation or an attenuated tumorigenesis. While this condition could reflect the presence of an actual tumor such as an ovarian teratoma causing anti-NMDA receptor encephalitis, it would only explain a small percentage of cases. To find a more likely tumor model, the author then compared the cytokine profile of schizophrenia to individual cancers and found the best match was melanoma. To demonstrate the viability of the theory, the author compared the hallmarks, emerging hallmarks, and enabling characteristics of melanoma to schizophrenia and found that many findings in schizophrenia are understood if schizophrenia is a condition of attenuated tumorigenesis.




Pharmacogenetic Associations of Antipsychotic Drug-Related Weight Gain: A Systematic Review and Meta-analysis

2016-10-04T06:17:00-07:00

Although weight gain is a serious but variable adverse effect of antipsychotics that has genetic underpinnings, a comprehensive meta-analysis of pharmacogenetics of antipsychotic-related weight gain is missing. In this review, random effects meta-analyses were conducted for dominant and recessive models on associations of specific single nucleotide polymorphisms (SNP) with prospectively assessed antipsychotic-related weight or body mass index (BMI) changes (primary outcome), or categorical increases in weight or BMI (≥7%; secondary outcome). Published studies, identified via systematic database search (last search: December 31, 2014), plus 3 additional cohorts, including 222 antipsychotic-naïve youth, and 81 and 141 first-episode schizophrenia adults, each with patient-level data at 3 or 4 months treatment, were meta-analyzed. Altogether, 72 articles reporting on 46 non-duplicated samples (n = 6700, mean follow-up = 25.1wk) with 38 SNPs from 20 genes/genomic regions were meta-analyzed (for each meta-analysis, studies = 2–20, n = 81–2082). Eleven SNPs from 8 genes were significantly associated with weight or BMI change, and 4 SNPs from 2 genes were significantly associated with categorical weight or BMI increase. Combined, 13 SNPs from 9 genes (Adrenoceptor Alpha-2A [ADRA2A], Adrenoceptor Beta 3 [ADRB3], Brain-Derived Neurotrophic Factor [BDNF], Dopamine Receptor D2 [DRD2], Guanine Nucleotide Binding Protein [GNB3], 5-Hydroxytryptamine (Serotonin) Receptor 2C [HTR2C], Insulin-induced gene 2 [INSIG2], Melanocortin-4 Receptor [MC4R], and Synaptosomal-associated protein, 25kDa [SNAP25]) were significantly associated with antipsychotic-related weight gain (P-values < .05–.001). SNPs in ADRA2A, DRD2, HTR2C, and MC4R had the largest effect sizes (Hedges’ g’s = 0.30–0.80, ORs = 1.47–1.96). Less prior antipsychotic exposure (pediatric or first episode patients) and short follow-up (1–2 mo) were associated with larger effect sizes. Individual antipsychotics did not significantly moderate effect sizes. In conclusion, antipsychotic-related weight gain is polygenic and associated with specific genetic variants, especially in genes coding for antipsychotic pharmacodynamic targets.




Mortality Risk Associated With Long-acting Injectable Antipsychotics: A Systematic Review and Meta-analyses of Randomized Controlled Trials

2016-10-04T06:17:00-07:00

Long-acting injectable (LAI) antipsychotics (LAI-APs) have several advantages over oral medications, but deaths reported in Japan during the early post-marketing phase vigilance period have raised safety concerns. We conducted a series of meta-analyses to assess whether LAI-APs affect the mortality of patients with schizophrenia. Three categorical meta-analyses of randomized controlled trials (RCTs) were performed to compare all-cause death (primary outcome) and death due to suicide: individual and pooled LAI-APs vs placebo, individual and pooled LAI-APs vs oral antipsychotics (OAPs), and head-to-head comparisons of LAI-APs. The risk ratios (RRs) and 95% CIs were calculated. We identified 52 RCTs (53 comparisons; total participants = 17 416, LAI-APs = 11 360, OAP = 3910, and placebo = 2146; mean study duration [wk]: LAI-APs vs placebo = 28.9, LAI-APs vs OAPs = 64.5). Neither pooled nor individual LAI-APs (aripiprazole, fluphenazine, olanzapine, paliperidone, and risperidone) differed from the placebo regarding the incidences of all-cause death (pooled LAI-APs: RR = 0.64, P = .37) and death due to suicide (pooled LAI-APs: RR = 0.98, P = .98). However, in a subgroup meta-analysis of only short-duration RCTs (≤13wk), pooled LAI-APs exhibited a trend toward lower incidence of all-cause death than placebo (RR = 0.29, P = .08). Pooled LAI-APs (aripiprazole, fluphenazine, haloperidol, olanzapine, paliperidone, risperidone, and zuclopenthixol) did not differ from pooled OAPs regarding all-cause death (pooled LAI-APs: RR = 0.71, P = .30) and death due to suicide (pooled LAI-APs: RR = 0.94, P = .91). Individual LAI-APs and OAPs were associated with similar risks of death. Data for head-to-head comparisons of individual LAI-APs were insufficient. In conclusion, there was no significant difference between LAI-APs and placebo or OAPs regarding all-cause death and death due to suicide.




Globally Efficient Brain Organization and Treatment Response in Psychosis: A Connectomic Study of Gyrification

2016-10-04T06:17:00-07:00

Background:

Converging evidence suggests that patients with first-episode psychosis who show a poor treatment response may have a higher degree of neurodevelopmental abnormalities than good Responders. Characterizing the disturbances in the relationship among brain regions (covariance) can provide more information on neurodevelopmental integrity than searching for localized changes in the brain. Graph-based connectomic approach can measure structural covariance thus providing information on the maturational processes. We quantified the structural covariance of cortical folding using graph theory in first-episode psychosis, to investigate if this systems-level approach would improve our understanding of the biological determinants of outcome in psychosis.

Methods:

Magnetic Resonance Imaging data were acquired in 80 first-episode psychosis patients and 46 healthy controls. Response to treatment was assessed after 12 weeks of naturalistic follow-up. Gyrification-based connectomes were constructed to study the maturational organization of cortical folding.

Results:

Nonresponders showed a reduction in the distributed relationship among brain regions (high segregation, poor integration) when compared to Responders and controls, indicating a higher burden of aberrant neurodevelopment. They also showed reduced centrality of key regions (left insula and anterior cingulate cortex) indicating a marked reconfiguration of gyrification. Nonresponders showed a vulnerable pattern of covariance that disintegrated when simulated lesions removed high-degree hubs, indicating an abnormal dependence on highly central hub regions in Nonresponders.

Conclusions:

These findings suggest that a perturbed maturational relationship among brain regions underlies poor treatment response in first-episode psychosis. The information obtained from gyrification-based connectomes can be harnessed for prospectively predicting treatment response and prognosis in psychosis.




A Randomized Controlled Trial of Clinician-Supported Problem-Solving Bibliotherapy for Family Caregivers of People With First-Episode Psychosis

2016-10-04T06:17:00-07:00

Family interventions for first-episode psychosis (FEP) are an integral component of treatment, with positive effects mainly on patients’ mental state and relapse rate. However, comparatively little attention has been paid to the effects of family interventions on caregivers’ stress coping and well-being, especially in non-Western countries. We aimed to test the effects of a 5-month clinician-supported problem-solving bibliotherapy (CSPSB) for Chinese family caregivers of people with FEP in improving family burden and carers’ problem-solving and caregiving experience, and in reducing psychotic symptoms and duration of re-hospitalizations, compared with those only received usual outpatient family support (UOFS). A randomized controlled trial was conducted across 2 early psychosis clinics in Hong Kong, where there might be inadequate usual family support services for FEP patients. A total of 116 caregivers were randomly selected, and after baseline measurement, randomly assigned to the CSPSB or UOFS. They were also assessed at 1-week and 6- and 12-month post-intervention. Intention-to-treat analyses were applied and indicated that the CSPSB group reported significantly greater improvements in family burden and caregiving experience, and reductions in severity of psychotic symptoms and duration of re-hospitalizations, than the UOFS group at 6- and 12-month follow-up. CSPSB produces moderate long-term benefits to caregivers and FEP patients, and is a low-cost adjunct to UOFS.




Motivational Context Modulates Prediction Error Response in Schizophrenia

2016-10-04T06:17:00-07:00

Background:

Recent findings demonstrate that patients with schizophrenia are worse at learning to predict rewards than losses, suggesting that motivational context modulates learning in this disease. However, these findings derive from studies in patients treated with antipsychotic medications, D2 receptor antagonists that may interfere with the neural systems that underlie motivation and learning. Thus, it remains unknown how motivational context affects learning in schizophrenia, separate from the effects of medication.

Methods:

To examine the impact of motivational context on learning in schizophrenia, we tested 16 unmedicated patients with schizophrenia and 23 matched controls on a probabilistic learning task while they underwent functional magnetic resonance imaging (fMRI) under 2 conditions: one in which they pursued rewards, and one in which they avoided losses. Computational models were used to derive trial-by-trial prediction error responses to feedback.

Results:

Patients performed worse than controls on the learning task overall, but there were no behavioral effects of condition. FMRI revealed an attenuated prediction error response in patients in the medial prefrontal cortex, striatum, and medial temporal lobe when learning to predict rewards, but not when learning to avoid losses.

Conclusions:

Patients with schizophrenia showed differences in learning-related brain activity when learning to predict rewards, but not when learning to avoid losses. Together with prior work, these results suggest that motivational deficits related to learning in schizophrenia are characteristic of the disease and not solely a result of antipsychotic treatment.




Mild Reinforcement Learning Deficits in Patients With First-Episode Psychosis

2016-10-04T06:17:00-07:00

Numerous studies have identified reinforcement learning (RL) deficits in schizophrenia. Most have focused on chronic patients with longstanding antipsychotic treatment, however, and studies of RL in early-illness patients have produced mixed results, particularly regarding gradual/procedural learning. No study has directly contrasted both rapid and gradual RL in first-episode psychosis (FEP) samples. We examined probabilistic RL in 34 FEP patients and 36 controls, using Go/NoGo (GNG) and Gain vs Loss-Avoidance (GLA) paradigms. Our results were mixed, with FEP patients exhibiting greater impairment in the ability to use positive, as opposed to negative, feedback to drive rapid RL on the GLA, but not the GNG. By contrast, patients and controls showed similar improvement across the acquisition. Finally, we found no significant between-group differences in the postacquisition expression of value-based preference in both tasks. Negative symptoms were modestly associated with RL measures, while the overall bias to engage in Go-responding correlated significantly with psychosis severity in FEP patients, consistent with striatal hyperdopaminergia. Taken together, FEP patients demonstrated more circumscribed RL impairments than previous studies have documented in chronic samples, possibly reflecting differential symptom profiles between first-episode and chronic samples. Our finding of relatively preserved gradual/procedural RL, in briefly medicated FEP patients, might suggest spared or restored basal ganglia function. Our findings of preserved abilities to use representations of expected value to guide decision making, and our mixed results regarding rapid RL, may reflect a lesser degree of prefrontal cortical functional impairment in FEP than in chronic samples. Further longitudinal research, in larger samples, is required.




Prediction of Neurocognitive Deficits by Parkinsonian Motor Impairment in Schizophrenia: A Study in Neuroleptic-Naïve Subjects, Unaffected First-Degree Relatives and Healthy Controls From an Indigenous Population

2016-10-04T06:17:00-07:00

Background:

Neurocognitive deficits are among the most debilitating and pervasive symptoms of schizophrenia, and are present also in unaffected first-degree relatives. Also, multiple reports reveal parkisonian motor deficits in untreated subjects with schizophrenia and in first-degree relatives of affected subjects. Yet, the relation between motor and cognitive impairment and its value as a classifier of endophenotypes has not been studied.

Aims:

To test the efficacy of midbrain hyperechogenicity (MHE) and parkinsonian motor impairment (PKM) as predictors of neurocognitive impairment in subjects with or at risk for schizophrenia, that could be used to segregate them from first-degree relatives and healthy controls.

Method:

Seventy-six subjects with chronic schizophrenia never exposed to antipsychotic medication, 106 unaffected first-degree relatives, and 62 healthy controls were blindly assessed for cognitive and motor function, and transcranial ultrasound.

Results:

Executive function, fluid intelligence, motor planning, and hand coordination showed group differences. PKM and MHE were significantly higher in untreated schizophrenia and unaffected relatives. Unaffected relatives showed milder impairment, but were different from controls.

Conclusions:

PKM and MHE predict cognitive impairment in neuroleptic-naive patients with schizophrenia and their unaffected first-degree relatives and may be used to segregate them from first-degree relatives and healthy controls.




Cognitive Function in Individuals With Psychosis: Moderation by Adolescent Cannabis Use

2016-10-04T06:17:00-07:00

Prior cannabis use, compared to nonuse, is reported to be associated with less cognitive impairment in schizophrenia. The age of cannabis use and the persistent influence of cannabis use on cognitive function has not been examined across the psychosis dimension. Ninety-seven volunteers with psychosis (schizophrenia, schizoaffective, or bipolar psychosis) and 64 controls were recruited at the Dallas site of the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium. Cannabis use history obtained in a semi-structured manner was used to categorize subjects into nonusers, adolescent-onset users, and late-onset users. The a priori hypothesis tested was that individuals with psychosis and a history of adolescent cannabis use (ACU) would have better global neuropsychological performance, as measured by the Brief Assessment of Cognition in Schizophrenia (BACS) battery, compared to those with psychosis and no cannabis use history. BACS Composite scores were significantly higher in individuals with psychosis with ACU compared to individuals with psychosis and no prior cannabis use. In subgroup analyses, ACU influenced global cognition in the schizophrenia/schizoaffective (SCZ) subgroup but not the bipolar psychosis subgroup. Exploratory analyses within the SCZ group, suggest that ACU was associated with better performance in specific domains compared to non-ACU groups. There are distinct associations between age of cannabis use and neuropsychological function across psychotic illnesses. Specifically, ACU is associated with better cognitive function in SCZ but not bipolar psychosis. This age-dependent and diagnosis-specific influence of cannabis may need to be factored into the design of future cognitive studies in SCZ.




A Meta-analytic Review of Auditory Event-Related Potential Components as Endophenotypes for Schizophrenia: Perspectives From First-Degree Relatives

2016-10-04T06:17:00-07:00

Introduction:

As endophenotypes bridge the gap between genetics and phenotypic disease expression, identifying reliable markers is important for fostering understanding of pathophysiology. The present aim was to conduct current meta-analyses of 3 key auditory event-related potential (ERP) components that have been held as potential endophenotypes for schizophrenia: P50, P300 amplitude and latency, and mismatch negativity (MMN), reflective of sensory gating, attention and classification speed, and perceptual discrimination ability, respectively. In order to assess endophenotype viability, these components were examined in unaffected relatives of patients with schizophrenia and healthy controls.

Methods:

Effect sizes (ES) were examined between relatives and controls for P50 suppression (10 studies, n = 360 relatives, 473 controls), P300 amplitude (20 studies, n = 868 relatives, 961 controls), P300 latency (17 studies, n = 674 relatives, 792 controls), and MMN (11 studies, n = 377 relatives, 552 controls).

Results:

Reliable differences in P50 suppression (ES = 0.86, P < .001), P300 amplitude (ES = –0.52, P < .001), and P300 latency (ES = 0.44, P < .05) were found between unaffected relatives and controls. A trend was found between relatives and controls for MMN (ES = 0.21, P = 0.06), and the use of extraneous channels was found to be a significant moderator (P = 0.01). When MMN was analyzed using frontocentral channel Fz, a significant difference was found (ES = 0.26, P < 0.01).

Discussion:

The results indicate that P50 suppression, P300 amplitude and P300 latency, and MMN may serve as viable endophenotypes for schizophrenia.




Predictive Motor Timing and the Cerebellar Vermis in Schizophrenia: An fMRI Study

2016-10-04T06:17:00-07:00

Abnormalities in both time processing and dopamine (DA) neurotransmission have been observed in schizophrenia. Time processing seems to be linked to DA neurotransmission. The cognitive dysmetria hypothesis postulates that psychosis might be a manifestation of the loss of coordination of mental processes due to impaired timing. The objective of the present study was to analyze timing abilities and their corresponding functional neuroanatomy in schizophrenia. We performed a functional magnetic resonance imaging (fMRI) study using a predictive motor timing paradigm in 28 schizophrenia patients and 27 matched healthy controls (HC). The schizophrenia patients showed accelerated time processing compared to HC; the amount of the acceleration positively correlated with the degree of positive psychotic symptoms and negatively correlated with antipsychotic dose. This dysfunctional predictive timing was associated with BOLD signal activity alterations in several brain networks, especially those previously described as timing networks (basal ganglia, cerebellum, SMA, and insula) and reward networks (hippocampus, amygdala, and NAcc). BOLD signal activity in the cerebellar vermis was negatively associated with accelerated time processing. Several lines of evidence suggest a direct link between DA transmission and the cerebellar vermis that could explain their relevance for the neurobiology of schizophrenia.




Cover

2016-08-17T08:54:49-07:00




Editorial_Board

2016-08-17T08:54:49-07:00




Subscriptions

2016-08-17T08:54:49-07:00




Contents_Page

2016-08-17T08:54:49-07:00










Relating to a Schizophrenic

2016-08-17T08:54:49-07:00










Engaging Research Domain Criteria (RDoC): Neurocircuitry in Search of Meaning

2016-08-17T08:54:49-07:00

The Research Domain Criteria (RDoC) initiative was implemented to reorient the approach to mental health research from one focused on Diagnostic and Statistical Manual of Mental Disorders (DSM) nosology to one oriented to psychological constructs constrained by neurocircuitry and molecular entities. The initiative has generated significant discussion and valuable reflection on the moorings of psychiatric research. The purpose of this article is to illustrate how a basic or clinical investigator can engage RDoC to explore the neurobiological underpinnings of psychopathology and how a research question can be formulated in RDoC’s framework. We utilize a brain region with significant growing interest, the habenula, as an example for probing RDoC’s utility. Opportunities to enhance neurocircuitry-psychological construct associations and problems associated with neuronal populations that enable bidirectional circuitry influence are discussed. The exercise reveals areas for further development that could move RDoC from a promising research idea to a successfully engaged foundation for catalyzing clinically relevant discoveries.







What Is the Link Between Hallucinations, Dreams, and Hypnagogic-Hypnopompic Experiences?

2016-08-17T08:54:49-07:00

By definition, hallucinations occur only in the full waking state. Yet similarities to sleep-related experiences such as hypnagogic and hypnopompic hallucinations, dreams and parasomnias, have been noted since antiquity. These observations have prompted researchers to suggest a common aetiology for these phenomena based on the neurobiology of rapid eye movement (REM) sleep. With our recent understanding of hallucinations in different population groups and at the neurobiological, cognitive and interpersonal levels, it is now possible to draw comparisons between the 2 sets of experiences as never before. In the current article, we make detailed comparisons between sleep-related experiences and hallucinations in Parkinson’s disease, schizophrenia and eye disease, at the levels of phenomenology (content, sensory modalities involved, perceptual attributes) and of brain function (brain activations, resting-state networks, neurotransmitter action). Findings show that sleep-related experiences share considerable overlap with hallucinations at the level of subjective descriptions and underlying brain mechanisms. Key differences remain however: (1) Sleep-related perceptions are immersive and largely cut off from reality, whereas hallucinations are discrete and overlaid on veridical perceptions; and (2) Sleep-related perceptions involve only a subset of neural networks implicated in hallucinations, reflecting perceptual signals processed in a functionally and cognitively closed-loop circuit. In summary, both phenomena are non-veridical perceptions that share some phenomenological and neural similarities, but insufficient evidence exists to fully support the notion that the majority of hallucinations depend on REM processes or REM intrusions into waking consciousness.




Auditory Hallucinations and the Brains Resting-State Networks: Findings and Methodological Observations

2016-08-17T08:54:50-07:00

In recent years, there has been increasing interest in the potential for alterations to the brain’s resting-state networks (RSNs) to explain various kinds of psychopathology. RSNs provide an intriguing new explanatory framework for hallucinations, which can occur in different modalities and population groups, but which remain poorly understood. This collaboration from the International Consortium on Hallucination Research (ICHR) reports on the evidence linking resting-state alterations to auditory hallucinations (AH) and provides a critical appraisal of the methodological approaches used in this area. In the report, we describe findings from resting connectivity fMRI in AH (in schizophrenia and nonclinical individuals) and compare them with findings from neurophysiological research, structural MRI, and research on visual hallucinations (VH). In AH, various studies show resting connectivity differences in left-hemisphere auditory and language regions, as well as atypical interaction of the default mode network and RSNs linked to cognitive control and salience. As the latter are also evident in studies of VH, this points to a domain-general mechanism for hallucinations alongside modality-specific changes to RSNs in different sensory regions. However, we also observed high methodological heterogeneity in the current literature, affecting the ability to make clear comparisons between studies. To address this, we provide some methodological recommendations and options for future research on the resting state and hallucinations.




Are Hallucinations Due to an Imbalance Between Excitatory and Inhibitory Influences on the Brain?

2016-08-17T08:54:50-07:00

This review from the International Consortium on Hallucinations Research intends to question the pertinence of the excitatory-to-inhibitory (E/I) imbalance hypothesis as a model for hallucinations. A large number of studies suggest that subtle impairments of the E/I balance are involved in neurological and psychiatric conditions, such as schizophrenia. Emerging evidence also points to a role of the E/I balance in maintaining stable perceptual representations, suggesting it may be a plausible model for hallucinations. In support, hallucinations have been linked to inhibitory deficits as shown with impairment of gamma-aminobutyric acid transmission, N-methyl-d-aspartate receptor plasticity, reductions in gamma-frequency oscillations, hyperactivity in sensory cortices, and cognitive inhibition deficits. However, the mechanisms by which E/I dysfunctions at the cellular level might relate to clinical symptoms and cognitive deficits remain unclear. Given recent data advances in the field of clinical neuroscience, it is now possible to conduct a synthesis of available data specifically related to hallucinations. These findings are integrated with the latest computational frameworks of hallucinations, and recommendations for future research are provided.




Differential Patterns of Dysconnectivity in Mirror Neuron and Mentalizing Networks in Schizophrenia

2016-08-17T08:54:50-07:00

Impairments of social cognition are well documented in patients with schizophrenia (SCZ), but the neural basis remains poorly understood. In light of evidence that suggests that the "mirror neuron system" (MNS) and the "mentalizing network" (MENT) are key substrates of intersubjectivity and joint action, it has been suggested that dysfunction of these neural networks may underlie social difficulties in SCZ patients. Additionally, MNS and MENT might be associated differently with positive vs negative symptoms, given prior social cognitive and symptom associations. We assessed resting state functional connectivity (RSFC) in meta-analytically defined MNS and MENT networks in this patient group. Magnetic resonance imaging (MRI) scans were obtained from 116 patients and 133 age-, gender- and movement-matched healthy controls (HC) at 5 different MRI sites. Network connectivity was analyzed for group differences and correlations with clinical symptoms. Results demonstrated decreased connectivity within the MNS and also the MENT in patients compared to controls. Notably, dysconnectivity of the MNS was related to symptom severity, while no such relationship was observed for the MENT. In sum, these findings demonstrate that differential patterns of dysconnectivity exist in SCZ patients, which may contribute differently to the interpersonal difficulties commonly observed in the disorder.




Reduced Frontoparietal Activity in Schizophrenia Is Linked to a Specific Deficit in Goal Maintenance: A Multisite Functional Imaging Study

2016-08-17T08:54:50-07:00

Patients with schizophrenia (SZ) previously demonstrated specific deficits in an executive function known as goal maintenance, associated with reduced middle frontal gyrus (MFG) activity. This study aimed to validate a new tool—the Dot Pattern Expectancy (DPX) task—developed to facilitate multisite imaging studies of goal maintenance deficits in SZ or other disorders. Additionally, it sought to arrive at recommendations for scan length for future studies using the DPX. Forty-seven SZ and 56 healthy controls (HC) performed the DPX in 3-Tesla functional magnetic resonance imaging (fMRI) scanners at 5 sites. Group differences in DPX-related activity were examined with whole brain voxelwise analyses. SZs showed the hypothesized specific performance deficits with as little as 1 block of data. Reduced activity in SZ compared with HC was observed in bilateral frontal pole/MFG, as well as left posterior parietal lobe. Efficiency analyses found significant group differences in activity using 18 minutes of scan data but not 12 minutes. Several behavioral and imaging findings from the goal maintenance literature were robustly replicated despite the use of different scanners at different sites. We did not replicate a previous correlation with disorganization symptoms among patients. Results were consistent with an executive/attention network dysfunction in the higher levels of a cascading executive system responsible for goal maintenance. Finally, efficiency analyses found that 18 minutes of scanning during the DPX task is sufficient to detect group differences with a similar sample size.




Hyperdeactivation of the Default Mode Network in People With Schizophrenia When Focusing Attention in Space

2016-08-17T08:54:50-07:00

When studying selective attention in people with schizophrenia (PSZ), a counterintuitive but replicated finding has been that PSZ display larger performance benefits than healthy control subjects (HCS) by cues that predicts the location of a target stimulus relative to non-predictive cues. Possible explanations are that PSZ hyperfocus attention in response to predictive cues, or that an inability to maintain a broad attentional window impairs performance when the cue is non-predictive. Over-recruitment of regions involved in top-down focusing of spatial attention in response to predictive cues would support the former possibility, and an inappropriate recruitment of these regions in response to non-predictive cues the latter. We probed regions of the dorsal attention network while PSZ (N = 20) and HCS (N = 20) performed a visuospatial attention task. A central cue either predicted at which of 4 peripheral locations a target signal would appear, or it gave no information about the target location. As observed previously, PSZ displayed a larger reaction time difference between predictive and non-predictive cue trials than HCS. Activity in frontoparietal and occipital regions was greater for predictive than non-predictive cues. This effect was almost identical between PSZ and HCS. There was no sign of over-recruitment when the cue was predictive, or of inappropriate recruitment when the cue was non-predictive. However, PSZ differed from HCS in their cue-dependent deactivation of the default mode network. Unexpectedly, PSZ displayed significantly greater deactivation than HCS in predictive cue trials, which may reflect a tendency to expend more processing resources when focusing attention in space.




Genetic Variation in Schizophrenia Liability is Shared With Intellectual Ability and Brain Structure

2016-08-17T08:54:50-07:00

Background:

Alterations in intellectual ability and brain structure are important genetic markers for schizophrenia liability. How variations in these phenotypes interact with variance in schizophrenia liability due to genetic or environmental factors is an area of active investigation. Studying these genetic markers using a multivariate twin modeling approach can provide novel leads for (genetic) pathways of schizophrenia development.

Methods:

In a sample of 70 twins discordant for schizophrenia and 130 healthy control twins, structural equation modeling was applied to quantify unique contributions of genetic and environmental factors on human brain structure (cortical thickness, cortical surface and global white matter fractional anisotropy [FA]), intellectual ability and schizophrenia liability.

Results:

In total, up to 28.1% of the genetic variance (22.8% of total variance) in schizophrenia liability was shared with intelligence quotient (IQ), global-FA, cortical thickness, and cortical surface. The strongest contributor was IQ, sharing on average 16.4% of the genetic variance in schizophrenia liability, followed by cortical thickness (6.3%), global-FA (4.7%) and cortical surface (0.5%). Furthermore, we found that up to 57.4% of the variation due to environmental factors (4.6% of total variance) in schizophrenia was shared with IQ (34.2%) and cortical surface (13.4%).

Conclusions:

Intellectual ability, FA and cortical thickness show significant and independent shared genetic variance with schizophrenia liability. This suggests that measuring brain-imaging phenotypes helps explain genetic variance in schizophrenia liability that is not captured by variation in IQ.




Genome-Wide Association Studies Suggest Limited Immune Gene Enrichment in Schizophrenia Compared to 5 Autoimmune Diseases

2016-08-17T08:54:50-07:00

There has been intense debate over the immunological basis of schizophrenia, and the potential utility of adjunct immunotherapies. The major histocompatibility complex is consistently the most powerful region of association in genome-wide association studies (GWASs) of schizophrenia and has been interpreted as strong genetic evidence supporting the immune hypothesis. However, global pathway analyses provide inconsistent evidence of immune involvement in schizophrenia, and it remains unclear whether genetic data support an immune etiology per se. Here we empirically test the hypothesis that variation in immune genes contributes to schizophrenia. We show that there is no enrichment of immune loci outside of the MHC region in the largest genetic study of schizophrenia conducted to date, in contrast to 5 diseases of known immune origin. Among 108 regions of the genome previously associated with schizophrenia, we identify 6 immune candidates (DPP4, HSPD1, EGR1, CLU, ESAM, NFATC3) encoding proteins with alternative, nonimmune roles in the brain. While our findings do not refute evidence that has accumulated in support of the immune hypothesis, they suggest that genetically mediated alterations in immune function may not play a major role in schizophrenia susceptibility. Instead, there may be a role for pleiotropic effects of a small number of immune genes that also regulate brain development and plasticity. Whether immune alterations drive schizophrenia progression is an important question to be addressed by future research, especially in light of the growing interest in applying immunotherapies in schizophrenia.




Genetic Polymorphism Associated Prefrontal Glutathione and Its Coupling With Brain Glutamate and Peripheral Redox Status in Early Psychosis

2016-08-17T08:54:50-07:00

Background:

Oxidative stress and glutathione (GSH) metabolism dysregulation has been implicated in the pathophysiology of schizophrenia. GAG-trinucleotide repeat (TNR) polymorphisms in the glutamate-cysteine ligase catalytic gene (GCLC), the rate-limiting enzyme for GSH synthesis, are associated with schizophrenia. In addition, GSH may serve as a reserve pool for neuronal glutamate (Glu) through the -glutamyl cycle. The aim of this study is to investigate brain [GSH] and its association with GCLC polymorphism, peripheral redox indices and brain Glu.

Methods:

Magnetic resonance spectroscopy was used to measure [GSH] and [Glu] in the medial prefrontal cortex (mPFC) of 25 early-psychosis patients and 33 controls. GCLC polymorphism was genotyped, glutathione peroxidases (GPx) and glutathione reductase (GR) activities were determined in blood cells.

Results:

Significantly lower [GSHmPFC] in GCLC high-risk genotype subjects were revealed as compared to low-risk genotype subjects independent of disease status. In male subjects, [GSHmPFC] and blood GPx activities correlate positively in controls (P = .021), but negatively in patients (P = .039). In GCLC low-risk genotypes, [GlumPFC] are lower in patients, while it is not the case for high-risk genotypes.

Conclusions:

GCLC high-risk genotypes are associated with low [GSHmPFC], highlighting that GCLC polymorphisms should be considered in pathology studies of cerebral GSH. Low brain GSH levels are related to low peripheral oxidation status in controls but with high oxidation status in patients, pointing to a dysregulated GSH homeostasis in early psychosis patients. GCLC polymorphisms and disease associated correlations between brain GSH and Glu levels may allow patients stratification.




Shared Etiology of Psychotic Experiences and Depressive Symptoms in Adolescence: A Longitudinal Twin Study

2016-08-17T08:54:50-07:00

Psychotic disorders and major depression, both typically adult-onset conditions, often co-occur. At younger ages psychotic experiences and depressive symptoms are often reported in the community. We used a genetically sensitive longitudinal design to investigate the relationship between psychotic experiences and depressive symptoms in adolescence. A representative community sample of twins from England and Wales was employed. Self-rated depressive symptoms, paranoia, hallucinations, cognitive disorganization, grandiosity, anhedonia, and parent-rated negative symptoms were collected when the twins were age 16 (N = 9618) and again on a representative subsample 9 months later (N = 2873). Direction and aetiology of associations were assessed using genetically informative cross-lagged models. Depressive symptoms were moderately correlated with paranoia, hallucinations, and cognitive disorganization. Lower correlations were observed between depression and anhedonia, and depression and parent-rated negative symptoms. Nonsignificant correlations were observed between depression and grandiosity. Largely the same genetic effects influenced depression and paranoia, depression and hallucinations, and depression and cognitive disorganization. Modest overlap in environmental influences also played a role in the associations. Significant bi-directional longitudinal associations were observed between depression and paranoia. Hallucinations and cognitive disorganization during adolescence were found to impact later depression, even after controlling for earlier levels of depression. Our study shows that psychotic experiences and depression, as traits in the community, have a high genetic overlap in mid-adolescence. Future research should test the prediction stemming from our longitudinal results, namely that reducing or ameliorating positive and cognitive psychotic experiences in adolescence would decrease later depressive symptoms.




Disruptions of Sleep/Wake Patterns in the Stable Tubule Only Polypeptide (STOP) Null Mouse Model of Schizophrenia

2016-08-17T08:54:50-07:00

Disruption of sleep/wake cycles is common in patients with schizophrenia and correlates with cognitive and affective abnormalities. Mice deficient in stable tubule only polypeptide (STOP) show cognitive, behavioral, and neurobiological deficits that resemble those seen in patients with schizophrenia, but little is known about their sleep phenotype. We characterized baseline sleep/wake patterns and recovery sleep following sleep deprivation in STOP null mice. Polysomnography was conducted in adult male STOP null and wild-type (WT) mice under a 12:12 hours light:dark cycle before, during, and after 6 hours of sleep deprivation during the light phase. At baseline, STOP null mice spent more time awake and less time in non-rapid eye movement sleep (NREMS) over a 24-hour period, with more frequent transitions between wake and NREMS, compared to WT mice, especially during the dark phase. The distributions of wake, NREMS and REMS across the light and the dark phases differed by genotype, and so did features of the electroencephalogram (EEG). Following sleep deprivation, both genotypes showed homeostatic increases in sleep duration, with no significant genotype differences in the initial compensatory increase in sleep intensity (EEG delta power). These results indicate that STOP null mice sleep less overall, and their sleep and wake periods are more fragmented than those of WT mice. These features in STOP null mice are consistent with the sleep patterns observed in patients with schizophrenia.




Disturbances of the Basic Self and Prodromal Symptoms Among Young Adolescents From the Community: A Pilot Population-Based Study

2016-08-17T08:54:50-07:00

Background and Goal:

Recent findings have provided preliminary support for the notion that basic self-disturbances (SD) are related to prodromal symptoms among nonpsychotic help-seeking adolescents. As a sizable proportion of adolescents who are at risk do not seek help, this study attempts to assess the extent to which these findings can be generalized to the entire population of adolescents who are at risk for psychosis.

Method:

The concurrent relationship between SD and prodromal symptoms was explored in a sample of 100 non-help-seeking adolescents (age 13–15) from the community. SD were assessed with the Examination of Anomalous Self-Experience (EASE); prodromal symptoms and syndromes were assessed with the Structured Interview for Prodromal Syndromes (SIPS); psychosocial functioning was assessed with the "Social and Role Global Functioning Scales"; and level of distress with the Mood and Anxiety States Questionnaire (MASQ).

Results:

SD significantly correlated with sub-clinical psychotic symptoms (r = .70, P < .0001). This correlation was significantly stronger than those of SD with mood symptoms and social functioning. Finally, SD was the single best concurrent predictor of prodromal symptoms and syndromes.

Conclusions:

These results provide preliminary support for the generalizability of the association between SD and prodromal symptoms for the entire population of adolescents who are clinically at high risk for psychosis. In addition, they further support the notion that this association is both specific and unique.




The "Insight Paradox" in Schizophrenia: Magnitude, Moderators and Mediators of the Association Between Insight and Depression

2016-08-17T08:54:50-07:00

The so-called "insight paradox" posits that among patients with schizophrenia higher levels of insight are associated with increased levels of depression. Although different studies examined this issue, only few took in account potential confounders or factors that could influence this association. In a sample of clinically stable patients with schizophrenia, insight and depression were evaluated using the Scale to assess Unawareness of Mental Disorder and the Calgary Depression Scale for Schizophrenia. Other rating scales were used to assess the severity of psychotic symptoms, extrapyramidal symptoms, hopelessness, internalized stigma, self-esteem, and service engagement. Regression models were used to estimate the magnitude of the association between insight and depression while accounting for the role of confounders. Putative psychological and sociodemographic factors that could act as mediators and moderators were examined using the PROCESS macro. By accounting for the role of confounding factors, the strength of the association between insight into symptoms and depression increased from 13% to 25% explained covariance. Patients with lower socioeconomic status (F = 8.5, P = .04), more severe illness (F = 4.8, P = .03) and lower levels of service engagement (F = 4.7, P = .03) displayed the strongest association between insight and depression. Lastly, hopelessness, internalized stigma and perceived discrimination acted as significant mediators. The relationship between insight and depression should be considered a well established phenomenon among patients with schizophrenia: it seems stronger than previously reported especially among patients with lower socioeconomic status, severe illness and poor engagement with services. These findings may have relevant implications for the promotion of insight among patients with schizophrenia.




Functional Capacity Assessed by the Map Task in Individuals at Clinical High-Risk for Psychosis

2016-08-17T08:54:50-07:00

Objectives:

Recent studies have recognized that signs of functional disability in schizophrenia are evident in early phases of the disorder, and, as a result, can potentially serve as vulnerability markers of future illness. However, functional measures in the psychosis prodrome have focused exclusively on real-world achievements, rather than on the skills required to carry-out a particular real-world function (ie, capacity). Despite growing evidence that diminished capacity is critical to the etiology of the established disorder, virtually no attention has been directed towards assessing functional capacity in the pre-illness stages. In the present study, we introduce the Map task, a measure to assess functional capacity in adolescent and young-adult high-risk populations.

Methods:

The Map task was administered to 609 subjects at Clinical High-Risk (CHR) for psychosis and 242 Healthy Controls (HCs) participating in the North American Prodrome Longitudinal Study (NAPLS2). Subjects were required to efficiently complete a set of specified errands in a fictional town.

Results:

CHR participants showed large impairments across major indices of the Map task, relative to the HCs. Most importantly, poor performance on the Map task significantly predicted conversion to psychosis, even after adjusting for age, IQ, clinical state, and other potential confounders.

Conclusions:

To the best of our knowledge, the Map task is one of the first laboratory-based measures to assess functional capacity in high-risk populations. Functional capacity deficits prior to the onset of psychosis may reflect a basic mechanism that underlies risk for psychosis. Early intervention targeting this domain may help to offset risk and independently improve long-term outcome.




Four-Year Follow-up of Cognitive Behavioral Therapy in Persons at Ultra-High Risk for Developing Psychosis: The Dutch Early Detection Intervention Evaluation (EDIE-NL) Trial

2016-08-17T08:54:50-07:00

Background:

Previously, we demonstrated that cognitive behavior therapy for ultra-high risk (called CBTuhr) halved the incidence of psychosis over an 18-month period. Follow-up data from the same study are used to evaluate the longer-term effects at 4 years post-baseline.

Method:

The Dutch Early Detection and Intervention Evaluation study was a randomized controlled trial of 196 UHR patients comparing CBTuhr with treatment-as-usual (TAU) for comorbid disorders with TAU only. Of the original 196 patients, 113 consented to a 4-year follow-up (57.7%; CBTuhr = 56 vs TAU = 57). Over the study period, psychosis incidence, remission from UHR status, and the effects of transition to psychosis were evaluated.

Results:

The number of participants in the CBTuhr group making the transition to psychosis increased from 10 at 18-month follow-up to 12 at 4-year follow-up whereas it did not change in the TAU group (n = 22); this still represents a clinically important (incidence rate ratio [IRR] = 12/22 = 0.55) and significant effect (F(1,5) = 8.09, P = .03), favoring CBTuhr. The odds ratio of CBTuhr compared to TAU was 0.44 (95% CI: 0.24–0.82) and the number needed to treat was 8. Moreover, significantly more patients remitted from their UHR status in the CBTuhr group (76.3%) compared with the TAU group (58.7%) [t(120) = 2.08, P = .04]. Importantly, transition to psychosis was associated with more severe psychopathology and social functioning at 4-year follow-up.

Conclusions:

CBTuhr to prevent a first episode of psychosis in persons at UHR of developing psychosis is still effective at 4-year follow-up. Our data also show that individuals meeting the formal criteria of a psychotic disorder have worse functional and social outcomes compared with non-transitioned cases. Trial registration: The trial is registered at Current Controlled Trials as trial number ISRCTN21353122 (http://controlled-trials.com/ISRCTN21353122/gaag).




Prefrontal Transcranial Direct Current Stimulation for Treatment of Schizophrenia With Predominant Negative Symptoms: A Double-Blind, Sham-Controlled Proof-of-Concept Study

2016-08-17T08:54:50-07:00

Negative symptoms are highly relevant in the long-term course of schizophrenia and are an important target domain for the development of novel interventions. Recently, transcranial direct current stimulation (tDCS) of the prefrontal cortex has been investigated as a treatment option in schizophrenia. In this proof-of-concept study, 20 schizophrenia patients with predominantly negative symptoms were randomized to either 10 sessions of add-on active (2 mA, 20min) or sham tDCS (anode: left DLPFC/F3; cathode: right supraorbital/F4). Primary outcome measure was the change in the Scale for the Assessment of Negative Symptoms (SANS) sum score; secondary outcomes included reduction in Positive and Negative Syndrome Scale (PANSS) scores and improvement of depressive symptoms, cognitive processing speed, and executive functioning. Sixteen patients underwent 4 functional connectivity magnetic resonance imaging (fcMRI) scans (pre and post 1st and pre and post 10th tDCS) to investigate changes in resting state network connectivity after tDCS. Per-protocol analysis showed a significantly greater decrease in SANS score after active (–36.1%) than after sham tDCS (–0.7%). PANSS sum scores decreased significantly more with active (–23.4%) than with sham stimulation (–2.2%). Explorative analysis of fcMRI data indicated changes in subgenual cortex and dorsolateral prefrontal cortex (DLPFC) connectivity within frontal-thalamic-temporo-parietal networks. The results of this first proof-of-concept study indicate that prefrontal tDCS may be a promising intervention for treatment of schizophrenia with predominant negative symptoms. Large-scale randomized controlled studies are needed to further establish prefrontal tDCS as novel treatment for negative symptoms in schizophrenia.




Meta-analysis of the Association Between the Level of Cannabis Use and Risk of Psychosis

2016-08-17T08:54:50-07:00

Cannabis use has been reported to induce long-lasting psychotic disorders and a dose-response relationship has been observed. We performed a systematic review of studies that investigate the association between the degree of cannabis consumption and psychosis and a meta-analysis to quantify the magnitude of effect. Published studies were identified through search of electronic databases, supplemented by manual searches of bibliographies. Studies were considered if they provided data on cannabis consumption prior to the onset of psychosis using a dose criterion (frequency/amount used) and reported psychosis-related outcomes. We performed random effects meta-analysis of individual data points generated with a simulation method from the summary data of the original studies. From 571 references, 18 studies fulfilled inclusion criteria for the systematic review and 10 were inserted in the meta-analysis, enrolling a total of 66 816 individuals. Higher levels of cannabis use were associated with increased risk for psychosis in all the included studies. A logistic regression model gave an OR of 3.90 (95% CI 2.84 to 5.34) for the risk of schizophrenia and other psychosis-related outcomes among the heaviest cannabis users compared to the nonusers. Current evidence shows that high levels of cannabis use increase the risk of psychotic outcomes and confirms a dose-response relationship between the level of use and the risk for psychosis. Although a causal link cannot be unequivocally established, there is sufficient evidence to justify harm reduction prevention programs.




Dietary Fructose and GLUT5 Transporter Activity Contribute to Antipsychotic-Induced Weight Gain

2016-08-17T08:54:50-07:00

Receptors for antipsychotics in the hypothalamus contribute to antipsychotics-induced weight gain; however, many of these receptors are also expressed in the intestine. The role of these intestinally-expressed receptors, and their potential modulation of nutrient absorption, have not been investigated in the context of antipsychotics-induced weight gain. Here we tested the effect of dietary fructose and intestinal fructose uptake on clozapine-induced weight gain in mice. Weight gain was determined in wild type mice and mice lacking the GLUT5 fructose transporter that were "orally-administered" 20mg/kg clozapine for 28 days. To assess the role of dietary fructose, clozapine-treated mice were fed controlled diets with different levels of fructose. Effect of clozapine treatment on intestinal fructose transport activity and expression levels of various receptors that bind clozapine, as well as several genes involved in gluconeogenesis and lipogenesis were measured using real-time RT-PCR and western blotting. Oral administration of clozapine significantly increased body weight in wild type C57BL/6 mice but not in GLUT5 null mice. The clozapine-induced weight gain was proportional to the percentage of fructose in the diet. Clozapine-treated mice increased intestinal fructose uptake without changing the intestinal expression level of GLUT5. Clozapine-treated mice expressed significantly higher levels of intestinal H1 histamine receptor in the wild type but not GLUT5 null mice. Clozapine also increased the intestinal expression of fructokinase and several genes involved in gluconeogenesis and lipogenesis. Our results suggest that increased intestinal absorption and metabolism of fructose contributes to clozapine-induced weight gain. Eliminating dietary fructose might prevent antipsychotics-induced weight gain.




Awareness of Pre-diabetes or Diabetes and Associated Factors in People With Psychosis

2016-08-17T08:54:50-07:00

Objective: To estimate awareness of pre-diabetes or type 2 diabetes and associated factors in people with psychosis, a known high-risk group. Methods: Cross sectional analysis of a national sample with psychosis who were aged 18–64 years, gave a fasting blood sample (n = 1155), had pre-diabetes or diabetes based on testing (n = 359) and reported if they knew they had high blood sugar or diabetes at survey (n = 356). Logistic regression was used to identify factors associated with awareness of pre-diabetes or diabetes prior to testing. Results: The prevalence of pre-diabetes (19.0% 219/1153) or type 2 diabetes (12.1%, 140/1153) was 31.1% (359/1153); 45% (160/356) were known prior to testing. Factors associated with detection were higher fasting blood glucose, older age, a perception of poor health, severe obesity, dyslipidaemia or treatment with a lipid regulating drug, a family history of diabetes, Aboriginal or Torres Strait Islander descent, decreased cognitive functioning, regional economic disadvantage, treatment with an antihypertensive drug, and an elevated 5-year risk for cardiovascular disease. The prevalence of undiagnosed pre-diabetes/diabetes was highest in those aged 25–34 years at 34.2%. Conclusions: Clinical detection of pre-diabetes or diabetes in people with psychosis was strongly dependent on established risk factors for type 2 diabetes in the population but not on current antipsychotic drug treatment or psychiatric case management which should ensure regular screening. Screening must become a clinical priority and should not wait until age 40.




Chronic Peripheral Inflammation is Associated With Cognitive Impairment in Schizophrenia: Results From the Multicentric FACE-SZ Dataset

2016-08-17T08:54:50-07:00

Objectives:

Inflammation, measured by abnormal blood C-reactive protein (CRP) level, has been described in schizophrenia (SZ), being inconsistently related to impaired cognitive functions. The aim of the present study is to investigate cognitive impairment associated with abnormal CRP levels in a large multi-centric sample of community-dwelling SZ patients, using a comprehensive neuropsychological battery.

Method:

Three hundred sixty-nine community-dwelling stable SZ subjects (76.2% men, mean age 32.7 y) were included and tested with a comprehensive battery of neuropsychological tests. Abnormal CRP level was defined as >3mg/L.

Results:

Multiple factor analysis revealed that abnormal CRP levels, found in 104 patients (28.2%), were associated with impaired General Intellectual Ability and Abstract Reasoning (aOR = 0.56, 95% CI 0.35–0.90, P = .014), independently of age, sex, education level, psychotic symptomatology, treatments, and addiction comorbidities. Abnormal CRP levels were also associated with the decline of all components of working memory (respectively effect size [ES] = 0.25, P = .033; ES = 0.27, P = .04; ES = 0.33, P = .006; and ES = 0.38, P = .004) and a wide range of other impaired cognitive functions, including memory (ES = 0.26, P = .026), learning abilities (ES = 0.28, P = .035), semantic memory (ES = 0.26, P = .026), mental flexibility (ES = 0.26, P = .044), visual attention (ES = 0.23, P = .004) and speed of processing (ES = 0.23, P = .043).

Conclusion:

Our results suggest that abnormal CRP level is associated with cognitive impairment in SZ. Evaluating the effectiveness of neuroprotective anti-inflammatory strategies is needed in order to prevent cognitive impairment in SZ.




Erratum

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Erratum

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Special Supplement Introduction: The Fourth Kraepelin Symposium--Cognitive Dysfunction in Schizophrenia: Origins and Innovative Treatment

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This Special Supplement presents reports from working groups meeting at the Fourth Kraepelin Symposium in Munich, Germany, in September 2014. It covers the origins and therapy of cognitive dysfunction in schizophrenia. Cognitive deficits are core symptoms of schizophrenia being decisive for the long-term prognosis only improved moderately by antipsychotic treatment, however, showing more evidence for cognitive remediation. The authors refer to neurobiological and psychological underpinnings of cognitive deficits and to innovative treatment interventions aimed at improving cognitive dysfunction in order to improve outcome and to support coping with the illness. Therapeutic approaches include aerobic exercise, cognitive training, psychoeducation, cognitive therapy, noninvasive brain stimulation and pharmacotherapy in acute to post-acute patients. The supplement also presents novel diagnostic tools for early recognition, such as biomarkers, as well as cognitive training to prevent worsening of symptoms in individuals at clinical high risk for psychosis. In recent years there has been progress in basic science and outcomes research as well as psychopharmacological and psychological treatment options. Despite of this, treatment of cognitive deficits needs significant improvement and further research is needed.




Decreased Oligodendrocyte and Neuron Number in Anterior Hippocampal Areas and the Entire Hippocampus in Schizophrenia: A Stereological Postmortem Study

2016-07-25T23:37:14-07:00

The hippocampus is involved in cognition as well as emotion, with deficits in both domains consistently described in schizophrenia. Moreover, the whole volumes of both the anterior and posterior region have been reported to be decreased in schizophrenia patients. While fewer oligodendrocyte numbers in the left and right cornu ammonis CA4 subregion of the posterior part of the hippocampus have been reported, the aim of this stereological study was to investigate cell numbers in either the dentate gyrus (DG) or subregions of the anterior hippocampus. In this design-based stereological study of the anterior part of the hippocampus comparing 10 patients with schizophrenia to 10 age- and gender-matched healthy controls were examined. Patients showed a decreased number of oligodendrocytes in the left CA4, fewer neurons in the left DG and smaller volumes in both the left CA4 and DG, which correlated with oligodendrocyte and neuron numbers, respectively. When exploring the total hippocampus, keeping previously published own results from the posterior part of the same brains in mind, both decreased oligodendrocyte numbers in the left CA4 and reduced volume remained significant. The decreased oligodendrocyte number speaks for a deficit in myelination and connectivity in schizophrenia which may originate from disturbed maturational processes. The reduced neuron number of the DG in the anterior hippocampus may well point to a reduced capacity of this region to produce new neurons up to adulthood. Both mechanisms may be involved in cognitive dysfunction in schizophrenia patients.




Aberrant Functional Whole-Brain Network Architecture in Patients With Schizophrenia: A Meta-analysis

2016-07-25T23:37:14-07:00

Findings from multiple lines of research provide evidence of aberrant functional brain connectivity in schizophrenia. By using graph-analytical measures, recent studies indicate that patients with schizophrenia exhibit changes in the organizational principles of whole-brain networks and that these changes relate to cognitive symptoms. However, there has not been a systematic investigation of functional brain network changes in schizophrenia to test the consistency of these changes across multiple studies. A comprehensive literature search was conducted to identify all available functional graph-analytical studies in patients with schizophrenia. Effect size measures were derived from each study and entered in a random-effects meta-analytical model. All models were tested for effects of potential moderator variables as well as for the presence of publication bias. The results of a total of n = 13 functional neuroimaging studies indicated that brain networks in patients with schizophrenia exhibit significant decreases in measures of local organization (g = –0.56, P = .02) and significant decreases in small-worldness (g = –0.65, P = .01) whereas global short communication paths seemed to be preserved (g = 0.26, P = .32). There was no evidence for a publication bias or moderator effects. The present meta- analysis demonstrates significant changes in whole brain network architecture associated with schizophrenia across studies.




Molecular Signatures of Psychosocial Stress and Cognition Are Modulated by Chronic Lithium Treatment

2016-07-25T23:37:14-07:00

Chronic psychosocial stress is an important environmental risk factor of psychiatric diseases such as schizophrenia. Social defeat in rodents has been shown to be associated with maladaptive cellular and behavioral consequences including cognitive impairments. Although gene expression changes upon psychosocial stress have been described, a comprehensive transcriptome profiling study at the global level in precisely defined hippocampal subregions which are associated with learning has been lacking. In this study, we exposed adult C57Bl/6N mice for 3 weeks to "resident-intruder" paradigm and combined laser capture microdissection with microarray analyses to identify transcriptomic signatures of chronic psychosocial stress in dentate gyrus and CA3 subregion of the dorsal hippocampus. At the individual transcript level, we detected subregion specific stress responses whereas gene set enrichment analyses (GSEA) identified several common pathways upregulated upon chronic psychosocial stress related to proteasomal function and energy supply. Behavioral profiling revealed stress-associated impairments most prominent in fear memory formation which was prevented by chronic lithium treatment. Thus, we again microdissected the CA3 region and performed global transcriptome analysis to search for molecular signatures altered by lithium treatment in stressed animals. By combining GSEA with unsupervised clustering, we detected pathways that are regulated by stress and lithium in the CA3 region of the hippocampus including proteasomal components, oxidative phosphorylation, and anti-oxidative mechanisms. Our study thus provides insight into hidden molecular phenotypes of chronic psychosocial stress and lithium treatment and proves a beneficial role for lithium treatment as an agent attenuating negative effects of psychosocial stress on cognition.




Psychological Mechanisms Mediating Effects Between Trauma and Psychotic Symptoms: The Role of Affect Regulation, Intrusive Trauma Memory, Beliefs, and Depression

2016-07-25T23:37:14-07:00

Evidence suggests a causal role for trauma in psychosis, particularly for childhood victimization. However, the establishment of underlying trauma-related mechanisms would strengthen the causal argument. In a sample of people with relapsing psychosis (n = 228), we tested hypothesized mechanisms specifically related to impaired affect regulation, intrusive trauma memory, beliefs, and depression. The majority of participants (74.1%) reported victimization trauma, and a fifth (21.5%) met symptomatic criteria for Posttraumatic Stress Disorder. We found a specific link between childhood sexual abuse and auditory hallucinations (adjusted OR = 2.21, SE = 0.74, P = .018). This relationship was mediated by posttraumatic avoidance and numbing (OR = 1.48, SE = 0.19, P = .038) and hyperarousal (OR = 1.44, SE = 0.18, P = .045), but not intrusive trauma memory, negative beliefs or depression. In contrast, childhood emotional abuse was specifically associated with delusions, both persecutory (adjusted OR = 2.21, SE = 0.68, P = .009) and referential (adjusted OR = 2.43, SE = 0.74, P = .004). The link with persecutory delusions was mediated by negative-other beliefs (OR = 1.36, SE = 0.14, P = .024), but not posttraumatic stress symptoms, negative-self beliefs, or depression. There was no evidence of mediation for referential delusions. No relationships were identified between childhood physical abuse and psychosis. The findings underline the role of cognitive-affective processes in the relationship between trauma and symptoms, and the importance of assessing and treating victimization and its psychological consequences in people with psychosis.




Enhancing Cognitive Training Through Aerobic Exercise After a First Schizophrenia Episode: Theoretical Conception and Pilot Study

2016-07-25T23:37:14-07:00

Cognitive training (CT) and aerobic exercise have separately shown promise for improving cognitive deficits in schizophrenia. Aerobic exercise releases brain-derived neurotrophic factor, which promotes synaptic plasticity and neurogenesis. Thus, aerobic exercise provides a neurotrophic platform for neuroplasticity-based CT. The combination of aerobic exercise and CT may yield more robust effects than CT alone, particularly in the initial course of schizophrenia. In a pilot study, 7 patients with a recent onset of schizophrenia were assigned to Cognitive Training & Exercise (CT&E) and 9 to CT alone for a 10-week period. Posit Science programs were used for CT. Neurocognitive training focused on tuning neural circuits related to perceptual processing and verbal learning and memory. Social cognitive training used the same learning principles with social and affective stimuli. Both groups participated in these training sessions 2d/wk, 2h/d. The CT&E group also participated in an aerobic conditioning program for 30 minutes at our clinic 2d/wk and at home 2d/wk. The effect size for improvement in the MATRICS Consensus Cognitive Battery Overall Composite score for CT&E patients relative to CT patients was large. Functional outcome, particularly independent living skills, also tended to improve more in the CT&E than in the CT group. Muscular endurance, cardiovascular fitness, and diastolic blood pressure also showed relative improvement in the CT&E compared to the CT group. These encouraging pilot study findings support the promise of combining CT and aerobic exercise to improve the early course of schizophrenia.




Treatment of Cognition in the Schizophrenia Spectrum: The Context of Psychiatric Rehabilitation

2016-07-25T23:37:14-07:00

Evidence-based approaches and modalities for targeting and treating the cognitive impairments of schizophrenia have proliferated over the past 15 years. The impairments targeted are distributed across the cognitive spectrum, from elemental perception, attention, and memory, to complex executive and social-cognitive functioning. Cognitive treatment is most beneficial when embedded in comprehensive programs of psychiatric rehabilitation. To personalize comprehensive treatment and rehabilitation of schizophrenia spectrum disorders, practitioners and participants must select from a rapidly expanding array of particular modalities and apply them in the broad context of the participant’s overall recovery. At present, no particular treatment, cognitive or otherwise, can be considered more important or primary than the context in which it is applied. Persistent difficulty in dissemination of new technology for severe and disabling mental illness compounds the significance of the context created by a full treatment array. In this article, a case-study of a mental health service system is described, showing the broad-ranging effects of degrading the rehabilitative context of treatments, obviating the benefits of cognitive treatment and other modalities. To realize the promise of cognitive treatment, the problems that prevent dissemination and maintenance of complete psychiatric rehabilitation programs have to be addressed.




Psychoeducation Improves Compliance and Outcome in Schizophrenia Without an Increase of Adverse Side Effects: A 7-Year Follow-up of the Munich PIP-Study

2016-07-25T23:37:14-07:00

Psychoeducation improves adherence and motivates patients to accept a maintenance therapy as recommended by the guidelines. This would mean a daily consumption of at least 300 chlorpromazine (CPZ) units in the long run and should lead to an increase of the antipsychotic dosage in comparison to patients with treatment as usual (TAU). This raises 2 important questions: whether more side effects are provoked and do the patients have a corresponding benefit with a better outcome. A total of 41 patients with a diagnosis of schizophrenic or schizoaffective disorder were randomized at study entry, either to bifocal psychoeducation (21), or to standard treatment (20). They were compared concerning compliance, type of medication, dosage (CPZ equivalents), motor side effects and number of days in hospital. The average daily antipsychotic medication 2 and 7 years after index discharge was 365 and 354 CPZ-units respectively in the intervention group (IG), but 247 and 279, respectively in the control group (CG). The extent of motor side effects was slightly smaller in the IG, but they showed a small and statistically not significant increase in the rate of tardive dyskinesia (TD) after 7 years. At the 7-year follow-up the patients in the IG had spent 74.7 days in hospital compared to 243.4 days for the patients in the CG (P < .05). The course of illness was significantly better in the IG without increasing motor side-effects. Therefore, psychoeducation should be integrated more systematically into the routine treatment. These data are part of a previous study, published 2007, with a sample size of 48 patients. Seven patients—3 of the IG and 4 of the CG—could not be included, because they were not able to complete the very complex "Computer-based kinematic analysis of motor performance." In this article all conclusions are referred to the new sample size, therefore some results are slightly different in comparison to the previous data.




A Randomized Controlled Trial of Group Coping-Oriented Therapy vs Supportive Therapy in Schizophrenia: Results of a 2-Year Follow-up

2016-07-25T23:37:14-07:00

Objective:

Over the past 30 years, illness management programs and cognitive-behavioral therapy for psychosis have gained prominence in the treatment of schizophrenia. However, little is known about the long-term benefits of these types of programs when delivered during inpatient treatment following a symptom exacerbation. To evaluate this question, we conducted a randomized controlled trial comparing the long-term effects of a group-based coping-oriented program (COP) that combined the elements of illness management with cognitive behavioral-therapy for psychosis, with an equally intensive supportive therapy (SUP) program.

Method:

196 inpatients with DSM-IV schizophrenia were randomized to COP or SUP, each lasting 12 sessions provided over 6–8 weeks. Outcome measures were collected in the hospital at baseline and post-assessment, and following discharge into the community 1 and 2 years later. We compared the groups on rehospitalizations, symptoms, psychosocial functioning, and knowledge about psychosis.

Results:

Intent-to-treat analyses indicated that patients in COP learned significantly more information about psychosis, and had greater reductions in overall symptoms and depression/anxiety over the treatment and follow-up period than patients in SUP. Patients in both groups improved significantly in other symptoms and psychosocial functioning. There were no differences between the groups in hospitalization rates, which were low.

Conclusions:

People with schizophrenia can benefit from short-term COPs delivered during the inpatient phase, with improvements sustaining for 2 years following discharge from the hospital. More research is needed to evaluate the long-term impact of coping-oriented and similar programs provided during inpatient treatment.




Psychoeducational and Cognitive Behavioral Treatment Programs: Implementation and Evaluation From 1995 to 2015 in Kraepelins Former Hospital

2016-07-25T23:37:14-07:00

Objective:

Programs that view individuals as capable of taking an active role in managing their illness have gained importance in Europe and the United States. This article describes the implementation and evaluation of group psychoeducational and cognitive behavioral treatment programs at the Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Munich, Germany, over the past 20 years.

Methods:

Implementing psychoeducational programs was the first step to establish cognitive behavioral psychotherapy and dispel the myth of schizophrenia for patients. Programs are also provided for patients with mood disorders, substance use disorders, or both. These groups include topics such as psychoeducation about the illness, establishing rewarding activities, stress management, cognitive therapy, and relapse prevention.

Results:

More than 1000 patients with schizophrenia or mood disorders (380 schizophrenia, 563 major depression, and 110 bipolar) have participated in illness management groups to learn about their illness and its treatment, and to learn skills to manage their illness. Patients have expressed satisfaction with the programs, and research has supported their effectiveness.

Conclusions:

Individuals with severe disorders can benefit from psychoeducational and cognitive treatment programs if the programs are adapted to the level of neuropsychological functioning and compensate for cognitive deficits and emotional overload. These findings suggest that providing information about the illness and coping skills for patients and relatives are important for treatment outcome.




Dose Equivalents for Antipsychotic Drugs: The DDD Method

2016-07-25T23:37:14-07:00

Background:

Dose equivalents of antipsychotics are an important but difficult to define concept, because all methods have weaknesses and strongholds.

Methods:

We calculated dose equivalents based on defined daily doses (DDDs) presented by the World Health Organisation’s Collaborative Center for Drug Statistics Methodology. Doses equivalent to 1mg olanzapine, 1mg risperidone, 1mg haloperidol, and 100mg chlorpromazine were presented and compared with the results of 3 other methods to define dose equivalence (the "minimum effective dose method," the "classical mean dose method," and an international consensus statement).

Results:

We presented dose equivalents for 57 first-generation and second-generation antipsychotic drugs, available as oral, parenteral, or depot formulations. Overall, the identified equivalent doses were comparable with those of the other methods, but there were also outliers.

Conclusions:

The major strength of this method to define dose response is that DDDs are available for most drugs, including old antipsychotics, that they are based on a variety of sources, and that DDDs are an internationally accepted measure. The major limitations are that the information used to estimate DDDS is likely to differ between the drugs. Moreover, this information is not publicly available, so that it cannot be reviewed. The WHO stresses that DDDs are mainly a standardized measure of drug consumption, and their use as a measure of dose equivalence can therefore be misleading. We, therefore, recommend that if alternative, more "scientific" dose equivalence methods are available for a drug they should be preferred to DDDs. Moreover, our summary can be a useful resource for pharmacovigilance studies.




Repetitive Noninvasive Brain Stimulation to Modulate Cognitive Functions in Schizophrenia: A Systematic Review of Primary and Secondary Outcomes

2016-07-25T23:37:14-07:00

Despite many years of research, there is still an urgent need for new therapeutic options for the treatment of cognitive deficits in schizophrenia. Noninvasive brain stimulation (NIBS) has been proposed to be such a novel add-on treatment option. The main objective of this review was to systematically evaluate the cognitive effects of repetitive NIBS in schizophrenia. As most studies have not been specifically designed to investigate cognition as primary outcome, we have focused on both, primary and secondary outcomes. The PubMed/MEDLINE database (1985–2015) was systematically searched for interventional studies investigating the effects of repetitive NIBS on schizophrenia symptoms. All interventional clinical trials using repetitive transcranial stimulation, transcranial theta burst stimulation, and transcranial direct current stimulation for the treatment of schizophrenia were extracted and analyzed with regard to cognitive measures as primary or secondary outcomes. Seventy-six full-text articles were assessed for eligibility of which 33 studies were included in the qualitative synthesis. Of these 33 studies, only 4 studies included cognition as primary outcome, whereas 29 studies included cognitive measures as secondary outcomes. A beneficial effect of frontal NIBS could not be clearly established. No evidence for a cognitive disruptive effect of NIBS (temporal lobe) in schizophrenia could be detected. Finally, a large heterogeneity between studies in terms of inclusion criteria, stimulation parameters, applied cognitive measures, and follow-up intervals was observed. This review provides the first systematic overview regarding cognitive effects of repetitive NIBS in schizophrenia.




Classifying Schizophrenia Using Multimodal Multivariate Pattern Recognition Analysis: Evaluating the Impact of Individual Clinical Profiles on the Neurodiagnostic Performance

2016-07-25T23:37:14-07:00

Previous studies have shown that structural brain changes are among the best-studied candidate markers for schizophrenia (SZ) along with functional connectivity (FC) alterations of resting-state (RS) patterns. This study aimed to investigate effects of clinical and sociodemographic variables on the classification by applying multivariate pattern analysis (MVPA) to both gray matter (GM) volume and FC measures in patients with SZ and healthy controls (HC). RS and structural magnetic resonance imaging data (sMRI) from 74 HC and 71 SZ patients were obtained from a Mind Research Network COBRE dataset available via COINS (http://coins.mrn.org/dx). We used a MVPA framework using support-vector machines embedded in a repeated, nested cross-validation to generate a multi-modal diagnostic system and evaluate its generalizability. The dependence of neurodiagnostic performance on clinical and sociodemographic variables was evaluated. The RS classifier showed a slightly higher accuracy (70.5%) compared to the structural classifier (69.7%). The combination of sMRI and RS outperformed single MRI modalities classification by reaching 75% accuracy. The RS based moderator analysis revealed that the neurodiagnostic performance was driven by older SZ patients with an earlier illness onset and more pronounced negative symptoms. In contrast, there was no linear relationship between the clinical variables and neuroanatomically derived group membership measures. This study achieved higher accuracy distinguishing HC from SZ patients by fusing 2 imaging modalities. In addition the results of RS based moderator analysis showed that age of patients, as well as their age at the illness onset were the most important clinical features.




Intensive Auditory Cognitive Training Improves Verbal Memory in Adolescents and Young Adults at Clinical High Risk for Psychosis

2016-07-25T23:37:14-07:00

Objective: Individuals at clinical high risk (CHR) for psychosis demonstrate cognitive impairments that predict later psychotic transition and real-world functioning. Cognitive training has shown benefits in schizophrenia, but has not yet been adequately tested in the CHR population. Methods: In this double-blind randomized controlled trial, CHR individuals (N = 83) were given laptop computers and trained at home on 40 hours of auditory processing-based exercises designed to target verbal learning and memory operations, or on computer games (CG). Participants were assessed with neurocognitive tests based on the Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative (MATRICS) battery and rated on symptoms and functioning. Groups were compared before and after training using a mixed-effects model with restricted maximum likelihood estimation, given the high study attrition rate (42%). Results: Participants in the targeted cognitive training group showed a significant improvement in Verbal Memory compared to CG participants (effect size = 0.61). Positive and Total symptoms improved in both groups over time. Conclusions: CHR individuals showed patterns of training-induced cognitive improvement in verbal memory consistent with prior observations in schizophrenia. This is a particularly vulnerable domain in individuals at-risk for psychosis that predicts later functioning and psychotic transition. Ongoing follow-up of this cohort will assess the durability of training effects in CHR individuals, as well as the potential impact on symptoms and functioning over time. Clinical Trials Number: NCT00655239. URL: https://clinicaltrials.gov/ct2/show/NCT00655239?term=vinogradov&rank=5. [...]



Brain Biomarkers of Vulnerability and Progression to Psychosis

2016-07-25T23:37:15-07:00

Identifying predictors and elucidating the fundamental mechanisms underlying onset of psychosis are critical for the development of targeted preemptive interventions. This article presents a selective review of findings on risk prediction algorithms and potential mechanisms of onset in youth at clinical high-risk for psychosis, focusing principally on recent findings of the North American Prodrome Longitudinal Study (NAPLS). Multivariate models incorporating risk factors from clinical, demographic, neurocognitive, and psychosocial assessments achieve high levels of predictive accuracy when applied to individuals who meet criteria for a prodromal risk syndrome. An individualized risk calculator is available to scale the risk for newly ascertained cases, which could aid in clinical decision making. At risk individuals who convert to psychosis show elevated levels of proinflammatory cytokines, as well as disrupted resting state thalamo-cortical functional connectivity at baseline, compared with those who do not. Further, converters show a steeper rate of gray matter reduction, most prominent in prefrontal cortex, that in turn is predicted by higher levels of inflammatory markers at baseline. Microglia, resident immune cells in the brain, have recently been discovered to influence synaptic plasticity in health and impair plasticity in disease. Processes that modulate microglial activation may represent convergent mechanisms that influence brain dysconnectivity and risk for onset of psychosis and thus may be targetable in developing and testing preventive interventions.