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Preview: Schizophrenia Bulletin - current issue

Schizophrenia Bulletin - current issue



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Cover

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




Editorial_Board

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




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Contents_Page

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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

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




Erratum

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