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Preview: Schizophrenia Bulletin - current issue

Schizophrenia Bulletin Current Issue





Published: Thu, 15 Jun 2017 00:00:00 GMT

Last Build Date: Thu, 15 Jun 2017 11:46:39 GMT

 



Contents_Page

2017-06-15




Cover

2017-06-15




Editorial_Board

2017-06-15




Subscriptions

2017-06-15




A Transdiagnostic Review of Negative Symptom Phenomenology and Etiology

2017-06-15

Abstract
In the DSM5, negative symptoms are 1 of the 5 core dimensions of psychopathology evaluated for schizophrenia. However, negative symptoms are not pathognomonic—they are also part of the diagnostic criteria for other schizophrenia-spectrum disorders, disorders that sometimes have comorbid psychosis, diagnoses not in the schizophrenia-spectrum, and the general “nonclinical” population. Although etiological models of negative symptoms have been developed for chronic schizophrenia, there has been little attention given to whether these models have transdiagnostic applicability. In the current review, we examine areas of commonality and divergence in the clinical presentation and etiology of negative symptoms across diagnostic categories. It was concluded that negative symptoms are relatively frequent across diagnostic categories, but individual disorders may differ in whether their negative symptoms are persistent/transient or primary/secondary. Evidence for separate dimensions of volitional and expressive symptoms exists, and there may be multiple mechanistic pathways to the same symptom phenomenon among DSM-5 disorders within and outside the schizophrenia-spectrum (ie, equifinality). Evidence for a novel transdiagnostic etiological model is presented based on the Research Domain Criteria (RDoC) constructs, which proposes the existence of 2 such pathways—a hedonic pathway and a cognitive pathway—that can both lead to expressive or volitional symptoms. To facilitate treatment breakthroughs, future transdiagnostic studies on negative symptoms are warranted that explore mechanisms underlying volitional and expressive pathology.






Primary, Enduring Negative Symptoms: An Update on Research

2017-06-01

Abstract
We previously proposed that people with schizophrenia who have primary, enduring negative symptoms have a disease—deficit schizophrenia (DS)—that is separate from that affecting people with schizophrenia without these features. Additional evidence consistent with the separate disease hypothesis has accumulated in recent years. White matter changes may be widespread in deficit compared to nondeficit patients and may relate to problems in early brain migration. These 2 patient groups also appear to differ on metabolic measures prior to antipsychotic treatment. Studies of reward and defeatist beliefs provide the basis for future treatment trials. The 2 factors or groups within negative symptoms broadly defined (both primary and secondary) have also been found in DS, and recent evidence suggests these 2 symptom groups have different correlates and reflect the existence of 2 groups with in DS. Negative symptoms are found in disorders other than schizophrenia, and excess summer birth, a deficit risk factor, has been found in a non-patient group with deficit-like features. It may be useful in future research to determine whether findings in DS extend to patients with other neuropsychiatric disorders who also have negative symptoms.



Negative Symptom Therapeutics

2017-05-30

This issue of the Bulletin continues the emphasis on the 5 Criteria A symptoms that have played a central role in the diagnosis of psychotic disorders. In previous 2017 issues, hallucinations, delusions and thought disorder have been viewed in the context of porous diagnostic boundaries. We seek clarity regarding critical variables that are common to several disorders and those variables that may be discriminating between disorders. Negative symptom psychopathology is the focus in this issue. The lead article1 and commentaries2–4 cover the concepts and science related to the negative symptom construct. This psychopathology, when viewed as a manifestation of schizophrenia, remains an unmet therapeutic challenge. Here we briefly address the shortfall in treatment development and issues that complicate the design and interpretation of therapeutic studies.






The Link Between the Immune System, Environment, and Psychosis

2017-05-17

Abstract
The last decade has witnessed a burgeoning interest in studies exploring the link between psychosis spectrum disorders (PSD) and altered immune function. While epidemiological and clinical studies point to evidence for increased peripheral inflammatory markers in PSD, it is not clear whether peripheral inflammation correlates with central inflammation in the brain. Furthermore, these studies are confounded by multiple methodological and disorder-related factors such as antipsychotic medications, smoking, obesity, and metabolic syndrome, all of which independently contribute to altered inflammation. Clinical and animal studies provide encouraging evidence that inflammatory processes can define trans-diagnostic neuropsychiatric domains such as positive/negative valence, affective dysregulation, and cognitive impairment. In this commentary, we speculate on whether inflammation-mediated pathways may serve as a final-common pathway for environmental risk factors of early-childhood adversity, adolescent cannabis use, social exclusion, and on the possible mechanisms mediating the pathophysiology of PSD. We propose an integrative framework and suggest future research strategies that may help disentangle the link between immune dysfunction and PSD.



Paradigms for Assessing Hedonic Processing and Motivation in Humans: Relevance to Understanding Negative Symptoms in Psychopathology

2017-05-17

Abstract
Clinicians and researchers have long known that one of the debilitating aspects of psychotic disorders is the presence of “negative symptoms,” which involve impairments in hedonic and motivational function, and/or alterations in expressive affect. We have a number of excellent clinical tools available for assessing the presence and severity of negative symptoms. However, to better understand the mechanisms that may give rise to negative symptoms, we need tools and methods that can help distinguish among different potential contributing causes, as a means to develop more targeted intervention pathways. Using such paradigms is particularly important if we wish to understand whether the causes are the same or different across disorders that may share surface features of negative symptoms. This approach is in line with the goals of the Research Diagnostic Criteria Initiative, which advocates understanding the nature of core dimensions of brain-behavior relationships transdiagnostically. Here we highlight some of the emerging measures and paradigms that may help us to parse the nature and causes of negative symptoms, illustrating both the research approaches from which they emerge and the types of constructs that they can help elucidate.



Embodiment and Schizophrenia: A Review of Implications and Applications

2017-03-03

Abstract
In recent decades, embodiment has become an influential concept in psychology and cognitive neuroscience. Embodiment denotes the study of the reciprocal (causal) relationships between mind and body, with the mind not only affecting the body but also vice versa. Embodied cognition comes to the fore in sensorimotor coupling, predictive coding, and nonverbal behavior. Additionally, the embodiment of the mind constitutes the basis of social interaction and communication, as evident in research on nonverbal synchrony and mimicry. These theoretical and empirical developments portend a range of implications for schizophrenia research and treatment. Sensorimotor dysfunctions are closely associated with affective and psychotic psychopathology, leading to altered timing in the processing of stimuli and to disordered appraisals of the environment. Problems of social cognition may be newly viewed as disordered embodied communication. The embodiment perspective suggests novel treatment strategies through psychotherapy and body-oriented interventions, and may ultimately provide biomarkers for diagnosis.



The Effect of Substance Use on 10-Year Outcome in First-Episode Psychosis

2017-02-11

Abstract
Substance use is common in first-episode psychosis (FEP) and has been linked to poorer outcomes with more severe psychopathology and higher relapse rates. Early substance discontinuation appears to improve symptoms and function. However, studies vary widely in their methodology, and few have examined patients longitudinally, making it difficult to draw conclusions for practice and treatment. We aimed to investigate the relationship between substance use and early abstinence and the long-term course of illness in a representative sample of FEP patients. Out of 301 included patients, 266 could be divided into 4 groups based on substance use patterns during the first 2 years of treatment: persistent users, episodic users, stop-users and nonusers. Differences in clinical and functional measures during the follow-up period were assessed using linear mixed effects models for the analysis of repeated measures data. Patients who stopped using substances within the first 2 years after diagnosis had outcomes similar to those who had never used with fewer symptoms than episodic or persistent users. Both episodic and persistent users had lower rates of symptom remission than nonusers, and persistent users also had more negative symptoms than those who stopped using. Our findings emerge from one of very few long-term longitudinal studies examining substance use cessation in FEP with 10-year follow-up. The results convey hope that the detrimental effects of substance abuse on mental health may be significantly reversed if one stops the abuse in time. This can help patients who struggle with addiction with their motivation to embrace abstinence.



Kynurenic Acid in Schizophrenia: A Systematic Review and Meta-analysis

2017-02-10

Abstract
Kynurenic acid (KYNA) is an endogenous antagonist of N-methyl-D-aspartate and α7 nicotinic acetylcholine receptors that is derived from astrocytes as part of the kynurenine pathway of tryptophan degradation. Evidence suggests that abnormal KYNA levels are involved in the pathophysiology of schizophrenia. However, this has never been assessed through a meta-analysis. A literature search was conducted through Ovid using Embase, Medline, and PsycINFO databases (last search: December 2016) with the search terms: (kynuren* or KYNA) and (schizophreni* or psychosis). English language studies measuring KYNA levels using any method in patients with schizophrenia and healthy controls (HCs) were identified. Standardized mean differences (SMDs) were calculated to determine differences in KYNA levels between groups. Subgroup analyses were separately performed for nonoverlapping participant samples, KYNA measurement techniques, and KYNA sample source. The influences of patients’ age, antipsychotic status (%medicated), and sex (%male) on study SMDs were assessed through a meta-regression. Thirteen studies were deemed eligible for inclusion in the meta-analysis. In the main analysis, KYNA levels were elevated in the patient group. Subgroup analyses demonstrated that KYNA levels were increased in nonoverlapping participant samples, and centrally (cerebrospinal fluid and brain tissue) but not peripherally. Patients’ age, %medicated, and %male were each positively associated with study SMDs. Overall, KYNA levels are increased in patients with schizophrenia, specifically within the central nervous system. An improved understanding of KYNA in patients with schizophrenia may contribute to the development of novel diagnostic approaches and therapeutic strategies.



Autonomic Regulation and Auditory Hallucinations in Individuals With Schizophrenia: An Experience Sampling Study

2017-02-08

Abstract
Auditory Hallucinations (AH) cause substantial suffering and dysfunction, yet remain poorly understood and modeled. Previous reports have linked AH to increases in negative emotions, suggesting a role for the autonomic nervous system (ANS) in underlying this link. Employing an Experience Sampling Method (ESM) approach, 40 individuals with schizophrenia completed a 36-hour ambulatory assessment of AH and cardiac autonomic regulation. Participants carried mobile electronic devices that prompted them to report 10 times/d the severity of their momentary AH, along with a Holter monitor that continuously recorded their cardiac autonomic regulation. The clocks of the devices and monitors were synchronized, allowing for high time-resolution temporal linking of the AH and concurrent autonomic data. Power spectral analysis was used to determine the relative vagal (parasympathetic) contribution to autonomic regulation during 5 minutes prior to each experience sample. The participants also completed interview-based measures of AH (SAPS; PSYRATS). The ESM-measured severity of AH was significantly correlated with the overall SAPS-indexed AH severity, along with the PSYRATS-indexed AH frequency, duration, loudness, degree of negative content, and associated distress. A mixed-effect regression model indicated that momentary increases in autonomic arousal, characterized by decreases in vagal input, significantly predicted increases in ESM-measured AH severity. Vagal input averaged over the 36-hour assessment displayed a small but significant inverse correlation with the SAPS-indexed AH. The results provide preliminary support for a link between ANS regulation and AH. The findings also underscore the highly dynamic nature of AH and the need to utilize high time-resolution methodologies to investigate AH.



A Neural “Tuning Curve” for Multisensory Experience and Cognitive-Perceptual Schizotypy

2017-02-07

Abstract
Our coherent perception of external events is enabled by the integration of inputs from different senses occurring within a range of temporal offsets known as the temporal binding window (TBW), which varies from person to person. A relatively wide TBW may increase the likelihood that stimuli originating from different environmental events are erroneously integrated and abnormally large TBW has been found in psychiatric disorders characterized by unusual perceptual experiences. Despite strong evidence of inter-individual differences in TBW, both within clinical and nonclinical populations, the neurobiological underpinnings of this variability remain unclear. We adopted an integrated strategy linking TBW to temporal dynamics in functional magnetic resonance imaging (fMRI)-resting-state activity and cortical excitation/inhibition (E/I) balance. E/I balance was indexed by glutamate/Gamma-AminoButyric Acid (GABA) concentrations and common variation in glutamate and GABA genes in a healthy sample. Stronger resting-state long-range temporal correlations, indicated by larger power law exponent (PLE), in the auditory cortex, robustly predicted narrower audio-tactile TBW, which was in turn associated with lower cognitive-perceptual schizotypy. Furthermore, PLE was highest and TBW narrowest for individuals with intermediate levels of E/I balance, with shifts towards either extreme resulting in reduced multisensory temporal precision and increased schizotypy, effectively forming a neural “tuning curve” for multisensory experience and schizophrenia risk. Our findings shed light on the neurobiological underpinnings of multisensory integration and its potentially clinically relevant inter-individual variability.



Reduced Thickness of the Anterior Cingulate Cortex in Individuals With an At-Risk Mental State Who Later Develop Psychosis

2017-01-30

Abstract
Background: Despite the fact that only a part of the individuals with at-risk mental state (ARMS) for psychosis do develop psychosis, biological markers of future transition to psychosis have not been well documented. Structural abnormality of the anterior cingulate gyrus (ACG), which probably exists prior to the onset of psychosis, could be such a risk marker. Methods: We conducted a multicenter magnetic resonance imaging (MRI) study of 3 scanning sites in Japan. 1.5-T 3D MRI scans were obtained from 73 ARMS subjects and 74 age- and gender-matched healthy controls. We measured thickness, volume, and surface area of the ACG using labeled cortical distance mapping and compared these measures among healthy controls, ARMS subjects who later converted to overt psychosis (ARMS-C), and those who did not (ARMS-NC). Results: Seventeen of 73 (23%) ARMS subjects developed overt psychosis within the follow-up period. The thickness of the left ACG was significantly reduced in ARMS-C relative to healthy subjects (P = .026) while both ARMS-C (P = .001) and ARMS-NC (P = .01) had larger surface areas of the left ACG compared with healthy controls. Conclusion: Further studies will be needed to identify potential markers of future transition to psychosis though cortical thinning of the ACG might be one of the candidates.



Postsynaptic Density-95 Isoform Abnormalities in Schizophrenia

2017-01-26

Abstract
Background:
Postsynaptic density-95 (PSD-95) protein expression is dysregulated in schizophrenia in a variety of brain regions. We have designed experiments to examine PSD-95 mRNA splice variant expression in the dorsolateral prefrontal cortex from subjects with schizophrenia.
Methods:
We performed quantitative PCR and western blot analysis to measure PSD-95 expression in schizophrenia vs control subjects, rodent haloperidol treatment studies, rodent postmortem interval studies, and GluN1 knockdown (KD) mice vs controls.
Results:
We found decreased mRNA expression of beta (t = 4.506, df = 383, P < .0001) and truncated (t = 3.378, df = 383, P = .0008) isoforms of PSD-95, whereas alpha was unchanged. Additionally, we found decreased PSD-95 protein expression in schizophrenia (t = 2.746, df = 71, P = .0076). We found no correlation between PSD-95 protein and alpha, beta, or truncated mRNA isoforms in schizophrenia. PSD-95 beta transcript was increased (t = 3.346, df = 14, P < .05) in the GluN1 KD mouse model of schizophrenia. There was an increase in PSD-95 alpha mRNA expression (t = 2.905, df = 16, P < .05) in rats following long-term haloperidol administration.
Conclusions:
Our findings describe a unique pathophysiology of specific PSD-95 isoform dysregulation in schizophrenia, chronic neuroleptic treatment, and a genetic lesion mouse model of drastically reduced N-methyl-d-aspartate receptor (NMDAR) complex expression. These data indicate that regulation of PSD-95 is multifaceted, may be isoform specific, and biologically relevant for synaptic signaling function. Specifically, NMDAR-mediated synaptic remodeling, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking and interaction may be impaired in schizophrenia by decreased PSD-95 beta and truncated expression (respectively). Further, increased PSD-95 beta transcript in the GluN1 KD mouse model poses a potential compensatory rescue of NMDAR-mediated function via increased postsynaptic throughput of the severely reduced GluN1 signal. Together, these data propose that disruption of excitatory signaling complexes through genetic (GluN1 KD), pharmacologic (antipsychotics), or disease (schizophrenia) mechanisms specifically dysregulates PSD-95 expression.



The Processing-Speed Impairment in Psychosis Is More Than Just Accelerated Aging

2017-01-06

Abstract
Processing speed is impaired in patients with psychosis, and deteriorates as a function of normal aging. These observations, in combination with other lines of research, suggest that psychosis may be a syndrome of accelerated aging. But do patients with psychosis perform poorly on tasks of processing speed for the same reasons as older adults? Fifty-one patients with psychotic illnesses and 90 controls with similar mean IQ (aged 19–69 years, all African American) completed a computerized processing-speed task, reminiscent of the classic digit–symbol coding task. The data were analyzed using the drift-diffusion model (DDM), and Bayesian inference was used to determine whether psychosis and aging had similar or divergent effects on the DDM parameters. Psychosis and aging were both associated with poor performance, but had divergent effects on the DDM parameters. Patients had lower information-processing efficiency (“drift rate”) and longer nondecision time than controls, and psychosis per se did not influence response caution. By contrast, the primary effect of aging was to increase response caution, and had inconsistent effects on drift rate and nondecision time across patients and controls. The results reveal that psychosis and aging influenced performance in different ways, suggesting that the processing-speed impairment in psychosis is more than just accelerated aging. This study also demonstrates the potential utility of computational models and Bayesian inference for finely mapping the contributions of cognitive functions on simple neurocognitive tests.



A Study of TNF Pathway Activation in Schizophrenia and Bipolar Disorder in Plasma and Brain Tissue

2017-01-03

Abstract
Objective:
A proinflammatory imbalance in the tumor necrosis factor (TNF) system may contribute to the pathogenesis of schizophrenia (SCZ) and bipolar disorders (BDs) and related comorbidities. We investigated the relative distribution of TNF-related molecules in blood and dorsolateral prefrontal cortex (DLPFC) in these disorders.
Method:
We measured plasma levels of TNF, soluble TNF receptor 1 (sTNFR1), soluble TNF receptor 2 (sTNFR2), and a disintegrin and metalloprotease-17 (ADAM17) using enzyme immunoassays and calculated the TNF/sTNFRs ratio (TNF/sTNFR1+sTNFR2) in a sample of 816 SCZ and BD spectrum patients and 624 healthy controls (HCs). TNF, TNFRSF1A (TNFR1), TNFRSF1B (TNFR2), and ADAM17 mRNA levels were determined in whole blood, and postmortem DLPFC obtained from an independent cohort (n = 80 SCZ, n = 44 BD, and n = 86 HC).
Results:
In peripheral blood, we show increased TNF-related measures in patients compared to HC, with an increased TNF/sTNFRs ratio (p = 6.00 × 10−5), but decreased TNF mRNA expression (p = 1 × 10−4), with no differences between SCZ and BD. Whole blood ADAM17 mRNA expression was markedly higher in BD vs SCZ patients (p = 1.40 × 10−14) and vs HC (p = 1.22 × 10−8). In postmortem DLPFC, we found no significant differences in mRNA expression of TNF pathway genes between any groups.
Conclusions:
SCZ and BD patients have increased plasma TNF pathway markers without corresponding increase in blood cell gene expression. ADAM17 expression in leukocytes is markedly different between the two disorders, while alterations in TNF-related gene expression in DLPFC are uncertain. Further studies are necessary to elucidate the aberrant regulation of the TNF pathway in severe mental disorders.



Immediate vs Gradual Discontinuation in Antipsychotic Switching: A Systematic Review and Meta-analysis

2017-01-02

Abstract
Background:
Antipsychotic switching is routine in clinical practice, although it remains unclear which is the preferable switching method: immediate discontinuation of the current antipsychotic or a gradual tapering approach. The first strategy has been implicated in rebound/withdrawal symptoms and emergence/exacerbation of symptoms, whereas the gradual approach is thought to pose a risk of additive or synergistic side effects if employed in the context of a crossover approach.
Methods:
MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were systematically searched. Randomized controlled trials examining immediate vs gradual antipsychotic discontinuation in antipsychotic switching in patients with schizophrenia and/or schizoaffective disorder were selected. Data on clinical outcomes, including study discontinuation, psychopathology, extrapyramidal symptoms, and treatment-emergent adverse events, were extracted.
Results:
A total of 9 studies involving 1416 patients that met eligibility criteria were included in the meta-analysis. No significant differences in any clinical outcomes were found between the 2 approaches (all Ps > .05). Sensitivity analyses revealed that the findings remained unchanged in the studies where switching to aripiprazole was performed or where immediate initiation of the next antipsychotic was adopted, while some significant differences were observed in switching to olanzapine or ziprasidone.
Conclusions:
These findings indicate that either immediate or gradual discontinuation of the current antipsychotic medication represents a viable treatment option. Clinicians are advised to choose an antipsychotic switching strategy according to individual patient needs. This said, immediate discontinuation may be advantageous both for simplicity and because a stalled cross-titration process in antipsychotic switching could end up in antipsychotic polypharmacy.



What Is an Attenuated Psychotic Symptom? On the Importance of the Context

2016-12-30

Abstract
Attenuated psychotic symptoms (APS) are the key criteria to identify the individuals at enhanced risk of developing psychotic disorders. Competing clinicians-rated or self-rated psychometric instruments can also be used to detect APS, which makes it difficult to interpret their actual clinical significance. This article summarizes the empirical differences between the clinicians-rated and self-rated interviews and explores the impact of the context (referral pathways, settings, and assessment procedures) on the clinical significance of the APS.



Distinct Patterns of Cerebral Cortical Thinning in Schizophrenia: A Neuroimaging Data-Driven Approach

2016-12-22

Abstract
Schizophrenia is an etiologically and clinically heterogeneous disorder. Although neuroimaging studies have revealed brain alterations in schizophrenia, most studies have assumed that the disorder is a single entity, neglecting the diversity of alterations observed in the disorder. The current study sought to explore the distinct patterns of altered cortical thickness in patients with schizophrenia and healthy individuals using a data-driven approach. Unsupervised clustering using self-organizing maps followed by a K-means algorithm was applied to regional cortical thickness data in 108 schizophrenia patients and 121 healthy controls. After clustering, the clinical characteristics and cortical thickness patterns of each cluster were assessed. Unsupervised clustering revealed that a 6-cluster solution was the most appropriate in this sample. There was substantial overlap between the patterns of cortical thickness in schizophrenia patients and healthy controls, although the distributions of the patients and controls differed across the clusters. The patterns of altered cortical thickness in schizophrenia exhibited cluster-specific features; patients within a cluster exhibited the most extensive cortical thinning, particularly in the medial prefrontal and temporal regions, while those in other clusters exhibited reduced cortical thickness in the medial frontal region or temporal lobe. Furthermore, in the schizophrenia group, extensive cortical thinning was correlated with a higher dosage of antipsychotic medication, while preserved cortical thickness appeared to be linked to less negative symptoms. This data-driven neuroimaging approach revealed distinct patterns of cortical thinning in schizophrenia, possibly reflecting the etiological heterogeneity of the disorder.



Bipolar At-Risk Criteria: An Examination of Which Clinical Features Have Optimal Utility for Identifying Youth at Risk of Early Transition From Depression to Bipolar Disorders

2016-11-21

Abstract
Background:
A clinical and research challenge is to identify which depressed youth are at risk of “early transition to bipolar disorders (ET-BD).” This 2-part study (1) examines the clinical utility of previously reported BD at-risk (BAR) criteria in differentiating ET-BD cases from unipolar depression (UP) controls; and (2) estimates the Number Needed to Screen (NNS) for research and general psychiatry settings.
Methods:
Fifty cases with reliably ascertained, ET-BD I and II cases were matched for gender and birth year with 50 UP controls who did not develop BD over 2 years. We estimated the clinical utility for finding true cases and screening out non-cases for selected risk factors and their NNS. Using a convenience sample (N = 80), we estimated the NNS when adjustments were made to account for data missing from clinical case notes.
Results:
Sub-threshold mania, cyclothymia, family history of BD, atypical depression symptoms and probable antidepressant-emergent elation, occurred significantly more frequently in ET-BD youth. Each of these “BAR-Depression” criteria demonstrated clinical utility for screening out non-cases. Only cyclothymia demonstrated good utility for case finding in research settings; sub-threshold mania showed moderate utility. In the convenience sample, the NNS for each criterion ranged from ~4 to 7.
Conclusions:
Cyclothymia showed the optimum profile for case finding, screening and NNS in research settings. However, its presence or absence was only reported in 50% of case notes. Future studies of ET-BD instruments should distinguish which criteria have clinical utility for case finding vs screening.



Behavioral Biomarkers of Schizophrenia in High Drinker Rats: A Potential Endophenotype of Compulsive Neuropsychiatric Disorders

2016-11-21

Abstract
Psychogenic polydipsia, which is compulsive, non-regulatory fluid consumption, is present in 6%–20% of chronic psychiatric patients and frequently associated with the schizophrenia diagnosis. In the present study, we investigated the relation between schizophrenia-like symptoms and biomarkers with a compulsive drinking behavior phenotype in rats. Rats that were selected for low drinking vs high drinking behavior following schedule-induced polydipsia (SIP) were assessed in a latent inhibition (LI) paradigm using tone and electrical foot shock and in a spatial reversal learning task to evaluate behavioral inflexibility. We also analyzed the myelin basic protein in different brain areas of high drinker (HD) and low drinker (LD) rats. The HD rats, which were characterized by a compulsive drinking behavior on SIP, had a reduced level of LI effect and increased behavioral inflexibility in the spatial reversal learning task in comparison to the LD group. Moreover, HD rats showed less myelination in the center of the corpus callosum, striatum, and amygdala in comparison to LD rats. These findings strengthen the validity of HD rats that were selected by SIP as a possible phenotype of compulsive neuropsychiatric disorders, as evidenced by the existence of behaviors and biological markers that are related to schizophrenia and obsessive-compulsive disorder, including a reduced LI effect, behavioral inflexibility and reduced brain myelination. Future studies could contribute to the elucidation of the mechanisms underlying the compulsive phenotype of HD rats and its relation to vulnerability to schizophrenia.



Heritability of Neuropsychological Measures in Schizophrenia and Nonpsychiatric Populations: A Systematic Review and Meta-analysis

2016-11-21

Abstract
Schizophrenia is characterized by neuropsychological deficits across many cognitive domains. Cognitive phenotypes with high heritability and genetic overlap with schizophrenia liability can help elucidate the mechanisms leading from genes to psychopathology. We performed a meta-analysis of 170 published twin and family heritability studies of >800 000 nonpsychiatric and schizophrenia subjects to accurately estimate heritability across many neuropsychological tests and cognitive domains. The proportion of total variance of each phenotype due to additive genetic effects (A), shared environment (C), and unshared environment and error (E), was calculated by averaging A, C, and E estimates across studies and weighting by sample size. Heritability ranged across phenotypes, likely due to differences in genetic and environmental effects, with the highest heritability for General Cognitive Ability (32%–67%), Verbal Ability (43%–72%), Visuospatial Ability (20%–80%), and Attention/Processing Speed (28%–74%), while the lowest heritability was observed for Executive Function (20%–40%). These results confirm that many cognitive phenotypes are under strong genetic influences. Heritability estimates were comparable in nonpsychiatric and schizophrenia samples, suggesting that environmental factors and illness-related moderators (eg, medication) do not substantially decrease heritability in schizophrenia samples, and that genetic studies in schizophrenia samples are informative for elucidating the genetic basis of cognitive deficits. Substantial genetic overlap between cognitive phenotypes and schizophrenia liability (average rg = −.58) in twin studies supports partially shared genetic etiology. It will be important to conduct comparative studies in well-powered samples to determine whether the same or different genes and genetic variants influence cognition in schizophrenia patients and the general population.



Consistent Functional Connectivity Alterations in Schizophrenia Spectrum Disorder: A Multisite Study

2016-11-21

Abstract
Schizophrenia (SZ) is a severe mental illness with high heritability and complex etiology. Mounting evidence from neuroimaging has implicated disrupted brain network connectivity in the pathophysiology. However, previous findings are inconsistent, likely due to a combination of methodological and clinical variability and relatively small sample sizes. Few studies have used a data-driven approach for characterizing pathological interactions between regions in the whole brain and evaluated the generalizability across independent samples. To overcome this issue, we collected resting-state functional magnetic resonance imaging data from 3 independent samples (1 from Norway and 2 from Sweden) consisting of 182 persons with a SZ spectrum diagnosis and 348 healthy controls. We used a whole-brain data-driven definition of network nodes and regularized partial correlations to evaluate and compare putatively direct brain network node interactions between groups. The clinical utility of the functional connectivity features and the generalizability of effects across samples were evaluated by training and testing multivariate classifiers in the independent samples using machine learning. Univariate analyses revealed 14 network edges with consistent reductions in functional connectivity encompassing frontal, somatomotor, visual, auditory, and subcortical brain nodes in patients with SZ. We found a high overall accuracy in classifying patients and controls (up to 80%) using independent training and test samples, strongly supporting the generalizability of connectivity alterations across different scanners and heterogeneous samples. Overall, our findings demonstrate robust reductions in functional connectivity in SZ spectrum disorders, indicating disrupted information flow in sensory, subcortical, and frontal brain regions.



Predicting Cognition and Psychosis in Young Adults With 22q11.2 Deletion Syndrome

2016-10-26

Abstract
Objective: To assess the extent to which the trajectories of intellectual, academic achievement, executive functioning, attention, working memory, and emotion recognition tests will be predictive of psychosis in young adults with 22q11.2 deletion syndrome (22q11DS). Methods: Eighty-two participants with 22q11DS were assessed for psychiatric disorders and neuropsychological functioning with validated instruments. Siblings and community controls were employed as comparison groups. Results: Individuals with 22q11DS differed significantly from siblings and controls in longitudinal trajectories of visual and auditory working memory as well as academic achievement. Longitudinal trajectories of cognitive set shifting, reading decoding, and emotion recognition predicted the presence of positive symptoms of psychosis in early adulthood. Cognitive set shifting improved at a slower rate for individuals with 22q11DS + psychosis than those without psychosis. Emotion recognition increased steadily in individuals without psychosis, whereas for those with psychosis, scores increased until approximately 15 years of age, at which point they began to decrease rapidly. A similar, but more subtle effect, was seen for reading decoding. Conclusions: Our data are the first to go beyond IQ assessments in assessing longitudinal neuropsychological outcomes and risk for psychosis in 22q11DS. Individuals with 22q11DS who developed psychotic symptoms improved less appreciably and continued to demonstrate difficulties with cognitive flexibility relative to individuals with 22q11DS who did not have psychotic symptoms. Individuals with 22q11DS who developed psychosis had weaker reading skills in childhood and, after an initial improvement into adolescence, these individuals with psychosis had a decline in reading skills. In 22q11DS, cognitive deficits are both (a) traits that are preexisting and raise the risk for psychosis and (b) associated with the onset of psychotic symptoms. Future research should consider the extent to which cognitive set shifting and reading decoding are related to the Verbal IQ declines observed in the 22q11DS population.



Amphetamine Enhances Gains in Auditory Discrimination Training in Adult Schizophrenia Patients

2016-10-26

Abstract
Targeted cognitive training (TCT) of auditory processing enhances higher-order cognition in schizophrenia patients. TCT performance gains can be detected after 1 training session. As a prelude to a potential clinical trial, we assessed a pharmacological augmentation of cognitive therapy (PACT) strategy by testing if the psychostimulant, amphetamine, augments TCT gains in auditory processing speed (APS) in schizophrenia patients and healthy subjects (HS). HS and schizophrenia patients were tested in a screening session (test 1), followed by a double-blind crossover design (tests 2–3), comparing placebo vs amphetamine (10 mg; 7 d between tests). On each test day, 1 hour of Posit Science “Sound Sweeps” training was bracketed by 2- to 4-minute pre- and post-training assessments of APS. Training consisted of a speeded auditory time-order judgment task of successive frequency modulation sweeps. Auditory system “learning” (APS post- vs pre-training) was enhanced by amphetamine (main effect of drug: P < .002; patients: d = 0.56, P < .02; HS: d = 0.39, nonsignificant), and this learning was sustained for at least 1 week. Exploratory analyses assessed potential biomarker predictors of sensitivity to these effects of amphetamine. Amphetamine enhances auditory discrimination learning in schizophrenia patients. We do not know whether gains in APS observed in patients after 1 hour of TCT predict clinical benefits after a full course of TCT. If amphetamine can enhance the therapeutic effects of TCT, this would provide strong support for a “PACT” treatment paradigm for schizophrenia.



Sex-Dependent Association of Perigenual Anterior Cingulate Cortex Volume and Migration Background, an Environmental Risk Factor for Schizophrenia

2016-10-09

Abstract
Migration status is one of the best-established risk factors for schizophrenia. An increase in risk is observed in both first- and second-generation immigrants, with a varying magnitude depending on the ethnic background of the individuals. The underlying mechanisms for the increased risk are only recently coming into focus. A causal role for social stress has been widely proposed, and recent work indicated altered neural stress processing in the perigenual anterior cingulate cortex (pACC) in migrants. Since previous work shows that social stress may lead to enduring changes in the gray matter volume of vulnerable brain regions, we investigated the impact of migration background on brain structure. We studied healthy young adults (N = 124), native Germans and second-generation migrants, using whole-brain structural magnetic resonance imaging. Groups were matched for a broad range of sociodemographic characteristics including age, gender, urban exposure, and education. We found a significant group by sex interaction effect in pACC gray matter volume, which was reduced in males with migration background only. This mirrors previous findings in urban upbringing, another risk factor for schizophrenia. Our results provide convergent evidence for an impact of environmental risk factors linked to schizophrenia on gray matter volume and extend prior data by highlighting the possibility that the pACC structure may be particularly sensitive to the convergent risk factors linked to schizophrenia.



Housing First Improves Adherence to Antipsychotic Medication Among Formerly Homeless Adults With Schizophrenia: Results of a Randomized Controlled Trial

2016-09-24

Abstract
Adherence to antipsychotic medication is a significant challenge among homeless patients. No experimental trials have investigated the impact of Housing First on adherence among patients with schizophrenia. We investigated whether Housing First in congregate and scattered-site configurations resulted in superior adherence compared to usual care. Adult participants (n = 165) met criteria for homelessness, schizophrenia, and initiation of antipsychotic pharmacotherapy prior to recruitment to an unblinded, 3-arm randomized controlled trial in Vancouver, Canada. Randomization arms were: congregate Housing First (CHF) with on-site supports (including physician and pharmacy services); scattered-site Housing First (SHF) with Assertive Community Treatment; or treatment as usual (TAU) consisting of existing services. Participants were followed for an average of 2.6 years. Adherence to antipsychotic medication was measured using the medication possession ratio (MPR), and 1-way ANOVA was used to compare outcomes between the 3 conditions. Data were drawn from comprehensive pharmacy records. Prior to randomization, mean MPR among participants was very low (0.44–0.48). Mean MPR in the follow-up period was significantly different between study arms (P < .001) and approached the guideline threshold of 0.80 in SHF. Compared to TAU, antipsychotic adherence was significantly higher in SHF but not in CHF. The results demonstrate that further implementation of SHF is indicated among homeless people with schizophrenia, and that urgent action is needed to address very low levels of antipsychotic adherence in this population (trial registration: ISRCTN57595077).



Metacognition as a Mediating Variable Between Neurocognition and Functional Outcome in First Episode Psychosis

2016-09-02

Abstract
Background:
Neurocognitive and functional outcome deficits have long been acknowledged in schizophrenia and neurocognition has been found to account for functional disability to a greater extent than psychopathology. Much of the variance in functional outcome however still remains unexplained and metacognition may mediate the relationship between neurocognition, functional capacity, and self-reported social and occupational function.
Method:
Eighty first episode psychosis participants were recruited and completed measures of neurocognition (memory, executive function, and intelligence quotient), metacognition (Beck Cognitive Insight Scale, Metacognitive Awareness Interview), psychopathology (PANSS), and both functional capacity (UPSA) and real-life social and occupational function (The Time Use Survey). Path analyses investigated the relationships between variables through structural equation modeling.
Results:
A series of path models demonstrated that metacognition partially mediates the relationship between neurocognition and functional capacity, and fully mediates the relationship between functional capacity and social and occupational function.
Conclusion:
The present study findings identify that metacognition may be critical to translating cognitive and functional skills into real-world contexts, and this relationship is found at early stages of illness. Understanding how individuals translate cognitive and functional skills into the real-world (the competence–performance gap) may offer valuable guidance to intervention programs. This finding is important to models of recovery as it suggests that intervention programs that focus on enhancing metacognition abilities may have a greater impact than traditional rehabilitation programs focusing on cognitive abilities, on social and occupational outcomes.



Senses or Schizophrenia

2015-02-26

My last appointment with my psychologist she showed me an article she found online. She seemed eager to see what my opinion was. I was able to read the first paragraph and then I tried to just skim what was on the page.



Understanding Referential Thinking

2015-02-13

I am currently twenty-eight years old and have had schizoaffective disorder since age nineteen. During episodes and after I developed referential thinking where I thought people were directly referencing me in conversation when they were only talking about the subject they mentioned. Someone could be saying, “I hate that, it’s really awful,” and I would think they were indirectly saying they hated me and that I was awful. While thinking someone was referencing me, I felt worried the person speaking disliked me which created stress and contributed towards my belief they were referencing me. My referential thinking usually occurred while I was feeling stressed and had poor self-esteem. I believed I was an unlikeable person which made me feel others would think the same thing and want to mention it. When people have used more pronouns and less descriptive language, I have made more referential connections between their message and myself. When I heard pronouns while perceiving information referentially I always substituted the pronoun for myself even if the person wasn’t talking about me. For example, a person would say “Someone took too many cookies.”. They could have been talking about my sister but I would perceive them as talking about me. When I knew exactly who or what the speaker was talking about, I substituted the pronoun with my own name far less. The people expressing negativity were simply disappointed about the subject they were discussing and the only reason it seemed as though they were talking about me was because I was assuming the subject of their statement was in some way intended to be me and the descriptions referencing the subject were intended to describe me. When I have reminded myself the speaker is only talking about the subject they actually stated and that subject is not a symbol which is intended to take my stead, I have been able to determine who or what the speaker is actually talking about and have realized their words have nothing to do with me.



How Do You Know If You Are in La La Land?

2014-06-09

Schizophrenia—It is like being in a crowd sometimes and everyone is making you turn turn turn around to listen to them but you are too busy driving the bus.