Disability In Schizophrenia Research Articles

Efficacy of KarXT on negative symptoms in acute schizophrenia: A post hoc analysis of pooled data from 3 trials

BackgroundCurrently approved antipsychotics do not adequately treat negative symptoms (NS), which are a major determinant of functional disability in schizophrenia. KarXT, an M1 /M4 preferring muscarinic receptor agonist, has shown efficacy as a broad-spectrum monotherapy for the treatment of schizophrenia in participants with acute psychosis. Post hoc analyses evaluated the possibility that NS improve independently of positive symptoms with KarXT in a subgroup of participants with moderate-to-severe NS and no predominance of positive symptoms. MethodsData were pooled from the three pivotal trials of KarXT monotherapy in people with schizophrenia with an acute exacerbation of psychosis. All 3 studies used similar 5-week randomized, double-blind, placebo-controlled designs (modified intention-to-treat sample N = 640). PANSS criteria proposed in the literature identified a subset of study participants (n = 64) with prominent NS. ResultsKarXT was significantly better than placebo on PANSS Marder Negative Factor Scores in the full sample (p < .001; Cohen's d = 0.42) and more so in the prominent NS subgroup (p < .001; Cohen's d = 1.18). Further, the KarXT effect in the NS subgroup remained significant after accounting for changes in positive symptoms, depression/anxiety, disorganization, and hostility. ConclusionsParticipants with prominent NS revealed greater improvement of NS following KarXT therapy than the full sample that persisted after accounting for positive and other symptoms. While these findings must be interpreted with caution, they are consistent with the possibility that NS improvements associated with KarXT are not secondary to improvements in other symptom domains and support further investigation in larger, stable outpatient studies.

Theta-burst rTMS in schizophrenia to ameliorate negative and cognitive symptoms: a double-blind, sham-controlled, randomized clinical trial

IntroductionSchizophrenia is a major mental disorder that affects approximately 1% of the population worldwide. Social cognition impairments and negative symptoms such as blunted affect or emotional withdrawal strongly contribute to the psychosocial functioning deficits and long-term disability in schizophrenia. The state-like and trait-like components of social cognition are impaired in schizophreniaObjectivesTreatment effects of conventional approaches with antipsychotics or psychosocial interventions are limited when it comes to reducing negative and cognitive symptoms in schizophrenia. While there is emerging clinical evidence that new, augmented protocols based on theta-burst stimulation can increase rTMS efficacy dramatically in depression, data on similar augmented therapies are very limited in schizophrenia. The different patterns of network impairments in subjects may underlie that some but not all patients responded to given stimulation locations.MethodsTherefore, we propose an augmented theta-burst stimulation protocol in schizophrenia by stimulating both locations connected to negative symptoms, namely the vermis of the cerebellum and the left Dorsolateral Prefrontal Cortex (DLPFC). Ninety subjects with schizophrenia presenting negative symptoms and aging between 18-50 years will be randomized to active and sham stimulation in a 1:1 ratio. The TBS parameters we adopted follow the standard TBS protocols, with 3-pulse 50-Hz bursts given every 200 ms (at 5 Hz) and an intensity of 100% active motor threshold. We plan to deliver 1800 stimuli to the vermis and 1800 stimuli to the left DLPFC daily in two 9.5-minute blocks for four weeks.ResultsThe primary endpoint is the change in negative symptom severity measured by the Positive and Negative Syndrome Scale (PANSS). Secondary efficacy endpoints are the change in cognitive flexibility measured by the Wisconsin Card Sorting Test and the change in social cognition assessed by the ‘Reading the Mind in the Eyes’, facial emotion recognition, and the ‘Faux pas’ tests. The safety outcome is the number serious adverse events.ConclusionsIn conlucion the aim of our study is to proove the safety and efficacy of theta burst stimulation for treating negativ sympotoms of schizophrenia.Disclosure of InterestNone Declared

Correlation of health literacy, health management self-efficacy, and attitude in elderly patients with schizophrenia: A cross-sectional study.

The study investigated the relationship between chronic diseases and health problems, emotional health status, health literacy, health self-management attitude, and health management self-efficacy in older patients with schizophrenia. It is expected to provide multiple health perspectives in the care of older patients with schizophrenia and improve their health literacy and self-management. A cross-sectional study. Data collection from 2020/09 to 2021/10, the study of older patients with schizophrenia who were diagnosed with schizophrenia and were over 50 years, live in residential mental rehabilitation institutions in eastern Taiwan as older people. Data were collected on demographic variables, chronic diseases, health problems, health literacy, healthy management self-efficacy, and attitudes. The study results show 61.49 years (SD = 6.57), the gender, health literacy, and health management self-efficacy can effectively explain the variance of health self-management state by 18.5% (F(3,116) = 10.01, p < 0.000), in which health literacy (β = 0.28, t = 3.07, p = 0.003) and health management self-efficacy (β = 0.19, t = 2.03, p = 0.04) that in the analysis of predictors, emotional health status, and health literacy not only have significant explanatory power on health management self-efficacy and the performance of physical functions but are also important factors affecting the quality of life among the elderly; the important influencing factor of health management self-efficacy and health self-management behaviour is health literacy. Therefore, health literacy is crucial to the health attitudes of older patients with schizophrenia. This study found that increased health literacy among older patients with schizophrenia can enhance their attitude and ability to manage their health. IMPLICATIONS FOR THE PROFESSION AND NO PATIENT OR PUBLIC CONTRIBUTION: Nursing can provide nursing measures related to individual health literacy to help patients improve their health literacy, maintain the health of chronic older patients with schizophrenia, reduce elderly schizophrenia disability, enhance patients' ability to manage their self-efficacy and health self-management attitude, and improving the health and quality of life of patients.

A Novel Psychosocial Intervention for Motivational Negative Symptoms in Schizophrenia: Combined Motivational Interviewing and CBT.

Negative symptoms are a primary cause of disability in schizophrenia for which there are no established pharmacotherapies. This study evaluated a novel psychosocial intervention that combined two evidence-based practices-motivational interviewing and cognitive-behavioral therapy (MI-CBT)-for the treatment of motivational negative symptoms. Seventy-nine participants with schizophrenia and moderate to severe negative symptoms were included in a randomized controlled trial comparing the 12-session MI-CBT treatment with a mindfulness control condition. Participants were assessed at three time points through the study period, which included 12 weeks of active treatment and 12 weeks of follow-up. The primary outcome measures were motivational negative symptoms and community functioning; the secondary outcomes included a posited biomarker of negative symptoms: pupillometric response to cognitive effort. Compared with the control group, participants in the MI-CBT group showed significantly greater improvements in motivational negative symptoms over the acute treatment period. Their gains relative to baseline were maintained at follow-up, although the differential benefit relative to control subjects was attenuated. There were nonsignificant effects toward improvements in community functioning and differential change in the pupillometric markers of cognitive effort. The results show that combining motivational interviewing with CBT yields improvements in negative symptoms, a feature of schizophrenia generally thought of as resistant to intervention. Motivational negative symptoms not only responded to the novel treatment, but the gains were maintained over the follow-up period. Implications for future studies and for improving the generalization of the negative symptom gains to daily functioning domains are discussed.

Disability and premorbid adjustment in schizophrenia: A retrospective analysis.

Schizophrenia is highly disabling. Though efforts at genetic mapping to identify those at risk of the illness have been promising but same cannot be said about predicting its associated disability before illness-onset (i.e., during premorbid phase). It is envisaged that Schizophrenia-related disability may be ameliorated if premorbid clinical markers are adequately predictive enough to identify those at risk and worked upon them. This study aimed to determine whether there is a relationship between schizophrenia-related disability and premorbid adjustment. This cross-sectional study was conducted at the out-patient clinic of the Neuropsychiatric Hospital, Aro, Abeokuta, Ogun State, Nigeria. Three hundred patients with the diagnosis of schizophrenia and within the age range of 18-64 years were eligible for the study. Mean age of the participants was 41.9 ± 10.05 years with a slight female dominance (50.7%). Spearman's correlation revealed a direct correlation between disability and premorbid adjustment, albeit rather weak (r s = 0.130, p = 0.025). Pre-diagnostic factors such as premorbid functioning may play a role in the subsequent functioning of an individual post-diagnosis. Other research efforts may focus on yet-to-be identified premorbid factors that may be targets of prevention to reduce disability in schizophrenia. This research serves as a pioneer work on disability and premorbid adjustment and has provided a template for the early identification of those at risk of schizophrenia by providing an intervention opportunity at the premorbid stage.

Correlation of BDNF, VEGF, TNF‐α, and S100B with cognitive impairments in chronic, medicated schizophrenia patients

Cognitive impairment is a prominent cause of disability in schizophrenia. Although antipsychotic drugs can rescue the psychotic symptoms, the cognitive impairments persist, with no treatment available. Alterations of BDNF, VEGF, TNF‐α, and S100B have been linked to cognitive impairment in several neurological disorders. However, it remains unclear whether their levels are correlated with the cognitive functions of schizophrenia patients. Forty‐one chronic, medicated schizophrenia patients were included in this study. Enzyme‐linked, immunosorbent assays were used to measure the serum concentrations of BDNF, VEGF, TNF‐α, and S100B. Associations between serum protein levels and various domains of the cognitive functions of the schizophrenia patients were observed. We found significant, positive correlations between serum BDNF and the processing speed and attention levels of the patients. Serum VEGF was also positively correlated with their memory and learning functions. In contrast, serum S100B and TNF‐α were negatively correlated with the processing speed and attention of the schizophrenia patients. The findings warrant further investigation of these molecules as potential prognostic markers or treatment targets for cognitive impairment in schizophrenia patients.

Transforming Discoveries About Cortical Microcircuits and Gamma Oscillations Into New Treatments for Cognitive Deficits in Schizophrenia.

The major cause of disability in schizophrenia is cognitive impairment, which remains largely refractory to existing treatments. This reflects the fact that antipsychotics and other therapies have not been designed to address specific brain abnormalities that cause cognitive impairment. This overview proposes that understanding how specific cellular and synaptic loci within cortical microcircuits contribute to cortical gamma oscillations may reveal treatments for cognitive impairment. Gamma oscillations are rhythmic patterns of high frequency (∼30-100 Hz) neuronal activity that are synchronized within and across brain regions, generated by a class of inhibitory interneurons that express parvalbumin, and recruited during a variety of cognitive tasks. In schizophrenia, both parvalbumin interneuron function and task-evoked gamma oscillations are deficient. While it has long been controversial whether gamma oscillations are merely a biomarker of circuit function or actually contribute to information processing by neuronal networks, recent neurobiological studies in mice have shown that disrupting or enhancing synchronized gamma oscillations can reproduce or ameliorate cognitive deficits resembling those seen in schizophrenia. In fact, transiently enhancing the synchrony of parvalbumin interneuron-generated gamma oscillations can lead to long-lasting improvements in cognition in mice that model aspects of schizophrenia. Gamma oscillations emerge from specific patterns of connections between a variety of cell types within cortical microcircuits. Thus, a critical next step is to understand how specific cell types and synapses generate gamma oscillations, mediate the effects of gamma oscillations on information processing, and/or undergo plasticity following the induction of gamma oscillations. Modulating these circuit loci, potentially in combination with other approaches such as cognitive training and brain stimulation, may yield potent and selective interventions for enhancing cognition in schizophrenia.

Effect of mGluR2 positive allosteric modulation on frontostriatal working memory activation in schizophrenia.

Negative symptoms and cognitive deficits contribute strongly to disability in schizophrenia, and are resistant to existing medications. Recent drug development has targeted enhanced NMDA function by increasing mGluR2/3 signaling. However, the clinical utility of such agents remains uncertain, and markers of brain circuit function are critical for clarifying mechanisms and understanding individual differences in efficacy. We conducted a double-blind, placebo-controlled, randomized cross-over (14 day washout) pilot study evaluating adjunctive use of the mGluR2 positive allosteric modulator AZD8529 (80mg daily for 3 days), in chronic stable patients with schizophrenia (n=26 analyzed). We focused on 3T fMRI response in frontostriatal regions during an n-back working memory task, testing the hypothesis that AZD8529 produces fMRI changes that correlate with improvement in negative symptoms and cognition. We found that AZD8529 did not produce significant group-average effects on symptoms or cognitive accuracy. However, AZD8529 did increase n-back fMRI activation in striatum (p<0.0001) and anterior cingulate/paracingulate (p=0.002). Greater drug-versus-placebo effects on caudate activation significantly correlated with greater reductions in PANSS negative symptom scores (r=−0.42, p=0.031), and exploratory correlations suggested broader effects across multiple symptom domains and regions of interest. These findings demonstrate that fMRI responses to mGluR2 positive modulation relate to individual differences in symptom reduction, and could be pursued for future biomarker development. Negative clinical results at the group level should not lead to premature termination of investigation of this mechanism which may benefit an important subset of individuals with schizophrenia. Imaging biomarkers may reveal therapeutic mechanisms, and help guide treatment towards specific populations.

No association between cortical dopamine D2 receptor availability and cognition in antipsychotic-naive first-episode psychosis

Cognitive impairment is an important predictor of disability in schizophrenia. Dopamine neurotransmission in cortical brain regions has been suggested to be of importance for higher-order cognitive processes. The aim of this study was to examine the relationship between extrastriatal dopamine D2-R availability and cognitive function, using positron emission tomography and the high-affinity D2-R radioligand [11C]FLB 457, in an antipsychotic-naive sample of 18 first-episode psychosis patients and 16 control subjects. We observed no significant associations between D2-R binding in the dorsolateral prefrontal cortex or hippocampus (β = 0.013–0.074, partial r = −0.037–0.273, p = 0.131–0.841). Instead, using Bayesian statistics, we found moderate support for the null hypothesis of no relationship (BFH0:H1 = 3.3–8.2). Theoretically, our findings may suggest a lack of detrimental effects of D2-R antagonist drugs on cognition in schizophrenia patients, in line with clinical observations.

The Cognitive Model of Negative Symptoms in Schizophrenia: A Hierarchical Component Model With PLS-SEM.

The cognitive model of negative symptoms suggests that some dysfunctional beliefs mediate the relationship between neurocognitive deficits and negative symptoms and disability. This study tested the hypothesis that dysfunctional performance beliefs mediate neurocognitive deficits, negative symptoms, and disability. We used a hierarchal component model with 85 men patients diagnosed with chronic schizophrenia. Results showed a moderate to strong correlation between dysfunctional performance beliefs, neurocognitive deficits, negative symptoms, and disability. These results support the Hierarchal component model (HCM) of the cognitive model of negative symptoms. Our results indicated that the disability in schizophrenia is mediated through dysfunctional performance beliefs, neurocognitive deficits, and negative symptoms pathway. Further, dysfunctional performance beliefs have a crucial role in this pathway. Therefore, targeting this vicious cycle of dysfunctional beliefs can improve disability in patients with schizophrenia.

Quantfying the disorganization and the core deficit in classical schizophrenia

AimsTo derive scores for mental disorganization and impoverishment from commonly used rating scales, and test the hypothesis that disorganization and impoverishment, along with impaired cognition and role-function reflect a latent variable that is a plausible candidate for the putative core deficit.BackgroundFor more than 100 years, disorganization and impoverishment of mental activity have been recognised as fundamental symptoms of schizophrenia. These symptoms may reflect a core brain process underlying persisting disability. Delusions and hallucinations have been regarded as accessory features. The psychopathological processes predisposing to persisting disability in schizophrenia are poorly understood. The delineation of a core deficit underlying persisting disability would be potentially of great value in predicting outcome and developing improved treatment.MethodPatients aged 18–55 years were included if: they satisfied DSM IV criteria for schizophrenia or schizoaffective disorder. Healthy controls were recruited by public advertisement and selected to match the patient group in age and sex. Study sample included 39 participants with schizophrenia, 1 with schizoaffective disorder and 44 matched healthy controls. We derived disorganization and impoverishment scores from three symptom scales: PANSS, SSPI and CASH. We computed composite scores for disorganization and for impoverishment and employed Confirmatory Factor Analysis to test the hypothesis that a single factor accounts for the relationships between disorganization, impoverishment, cognitive impairment and impaired role function. We assessed the relationship between this latent “core deficit” and diminished Post Movement Beta Rebound (PMBR), an electrophysiological measure from Magnetoencephalography (MEG), associated with persisting brain disorders.ResultFit indices for the single factor model from CFA indicated a good fit: χ2(2) = 1.817, p = .403; RMSEA &lt;.001 GFI = .979. PMBR was significantly reduced in the schizophrenia group compared to healthy controls, t (68) = 3.55, p &lt; .001. Within the patient group, PMBR was significantly and negatively correlated with the CFA factor scores representing the Core Deficit score, r=−.543, p &lt; .01, indicating that high core deficit scores were associated with reduced PMBR. PMBR was significantly correlated with the composite Disorganization score, r=−.521, p &lt; .001.ConclusionOur findings demonstrate that the shared variance between impoverishment (psychomotor poverty); disorganization; cognitive impairment; and impaired role function can be accounted for by a latent variable that can reasonably be described as the core deficit of classical schizophrenia. The demonstration that the severity of the putative core deficit is correlated with the reduction in PMBR provides evidence that the core deficit is associated with an identifiable abnormality of brain dysfunction.

Cortical Pathways or Mechanism in the Face Inversion Effect in Patients with First-Episode Schizophrenia.

ObjectiveImpaired face perception is considered as a hallmark of social disability in schizophrenia. It is widely believed that inverted faces and upright faces are processed by distinct mechanisms. Previous studies have identified that individuals with schizophrenia display poorer face processing than controls. However, the mechanisms underlying the face inversion effect (FIE) in patients with first-episode schizophrenia (FSZ) remain unclear.MethodsWe designed an fMRI task to investigate the FIE mechanism in patients with schizophrenia. Thirty-four patients with FSZ and thirty-five healthy controls (CON) underwent task-related fMRI scanning, clinical assessment, anhedonia experience examination, and social function and cognitive function evaluation.ResultsThe patients with FSZ exhibited distinct functional activity regarding upright and inverted face processing within the cortical face and non-face network. These results suggest that the differences in quantitative processing might mediate the FIE in schizophrenia. Compared with controls, affected patients showed impairments in processing both upright and inverted faces; and for these patients with FSZ, upright face processing was associated with more severe and broader impairment than inverted face processing. Reduced response in the left middle occipital gyrus for upright face processing was related to poorer performance of social function outcomes evaluated using the Personal and Social Performance Scale.ConclusionOur data suggested that patients with FSZ exhibited similar performance in processing inverted faces and upright faces, but were less efficient than controls; and for these patients, inverted faces are processed less efficiently than upright faces. We also provided a clue that the mechanism under abnormal FIE might be related to an aberrant activation of non-face-selective areas instead of abnormal activation of face-specific areas in patients with schizophrenia. Finally, our study indicated that the neural pathway for upright recognition might be relevant in determining the functional outcomes of this devastating disorder.

Network Structures of Social Functioning Domains in Schizophrenia and Bipolar Disorder: A Preliminary Study.

ObjectiveThis study used network analyses to examine network structures reflecting interactions between specific domains of social functioning in schizophrenia (SZ) and bipolar disorder (BD).MethodsWe used the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) to assess six domains of social functioning (‘cognition’, ‘mobility’, ‘self-care’, ‘getting along’, ‘life activities’, and ‘participation’) in 143 patients with SZ, 81 patients with BD, and 106 healthy subjects. We constructed regularized partial correlation networks, estimated network centrality and edge strength, tested network stability, and compared SZ and BD network structures.ResultsPatients with SZ showed a significantly higher level of functional disability than patients with BD. In the networks we constructed, ‘cognition’ was the most central domain of social functioning in both SZ and BD. The ‘cognition’ domain was primarily associated with the ‘getting along’ domain in the SZ network and the ‘life activities’ domain in the BD network. We found no significant group-level differences in network structures for SZ vs. BD.ConclusionOur results suggest that cognition may play a pivotal role in social functioning in both SZ and BD. In addition, domains of social functioning in SZ and BD have similar network structures despite the higher level of disability in SZ compared to BD.

Schizophrenia with and without obsessive-compulsive symptoms: a comparative analysis of performance on trail making test and disability on WHODAS

BackgroundPresence of obsessive-compulsive symptoms (OCS) affects performance on tests of some cognitive functions, such as the trail making test (TMT), and may affect the level of disability in schizophrenia (SZ).AimsThe...

M101. PREVELANCE USE OF TECHNOLOGICAL DEVICES AND INTERNET AMONG PATIENTS DIAGNOSED WITH SCHIZOPHRENIA AND SCHIZOAFFECTIVE DISORDER

BackgroundEffective use of technology makes human life much easier nowadays. This use has become widespread in health and has gained functionality in many areas. Using technology-based interventions, it is possible to minimize the loss of psychosocial functionality and cognitive disability in schizophrenia, in which social cognitive disability is one of the most basic symptom clusters. The aim of this study is to determine the prevalence of technological devices and internet usage in patients with schizophrenia and schizoaffective disorder, to determine the attitude of patients towards technological devices and internet usage and the relation between technology, internet usage with clinical variables such as psychosocial functioning, positive and negative symptoms.MethodsData were collected from the patients who applied to Dokuz Eylül University Medicine Faculty Schizophrenia Outpatient Clinic. Eighty-three schizophrenia patients and 13 schizoaffective disorder patients who meet the schizophrenia and schizoaffective disorder diagnostic criteria of DSM-5 were included in the study. The sociodemographic data registration form was completed. A questionnaire was developed for the purposes of the research to evaluate the use of technology. The level of psychosocial functioning was assessed using the Personal and Social Performance Scale (PSP), and the positive and negative symptom severity was evaluated using the Positive and Negative Syndrome Scale (PANSS).ResultsThe study found that 86% of patients owned mobile phone, 67% of patients used internet access, 67% of patients owned computer. 61% patients were using any kind of mobile application and 47% patients were using social media application. The most prevelant mobile applications among patients were facebook and whatsapp (48%). Younger patiens were using internet more than elders in a day (r=-0,395, p<0,001). Negative syptom scores were statistically lower among patients who were using mobile phones (M= 16,05, t=-2,50, p=0,014), internet connection in mobile phone (M=15,26, t=-2,93, p=0,004), using mobile application (M=15,47, t=-2,93, p=0,008), facebook (M=15,31, t=-2,32, p=0,022), whatsapp (M=14,77, t=-3,40, p=0,001), messenger (M=14,94, t=-2,33, p=0,022), messaging applications (M=14,96, t=-3,36, p=0,001), social media applications (M=15,04, t=-2,78, p=0,006) and who make video conversation (M=15,52, t=-2,21, p=0,029) than patients who were not using. PSP score of patients who were using mobile phone (M=50,62, t=2,34, p=0,021), internet access in mobile phone (M=57, t=3,07, p=0,003), mobile application (M=51,90, t=2,16, p=0,033), facebook (M=53,47, t=2,63, p=0,010), whatsapp (M=54,68, t=2,43, p=0,001), messenger (M=54,69, t=2,62, p=0,010), messaging applications (M=54,24, t=3,50, p=0,001), social media applications (M=54,29, t=3,10, p=0,003), and making video conversation (M=53,05, t=2,74, p=0,007) were statistically higher than the patients who were not using. There is also statistically significant relation between application usage and sub-items of PANSS.DiscussionThis study indicated that younger schizophrenia patients having less negative symptoms and increased psychosocial functionality was likely to use technological devices and mobile applications more. Patients may use applications more if they have been developed to facilitate their daily lives. Mobile applications and social media may affect the daily life activities of patients more intensively. In addition, using mobile applications may help patients to cope with their symptoms and improve psychosocial functioning.

S173. GENOME-WIDE ASSOCIATION STUDIES OF SCHIZOPHRENIA AND BIPOLAR DISORDER IN A DIVERSE COHORT OF US VETERANS

BackgroundSchizophrenia and bipolar disorder are debilitating neuropsychiatric illnesses collectively affecting 2% of the world’s population, and which cause tremendous human suffering that impacts patients, their families and their communities. Recognizing the major impact of these disorders on the psychosocial function of more than 200,000 US Veterans, the Department of Veterans Affairs (VA) recently genotyping of nearly 9,000 veterans with schizophrenia or bipolar I disorder in Cooperative Studies Program (CSP) #572: “Genetics of Functional Disability in Schizophrenia and Bipolar Illness”, all of whom were extensively assessed for neurocognitive function and disability, and genotyped using a custom Affymetrix Axiom Biobank array.MethodsPrimary genome-wide association studies (GWAS) of schizophrenia and bipolar disorder were performed across and within ancestry goups, with attempted replication in matched subjects from the PGC and Genomic Psychiatry Cohort (GPC). We combined results for CSP#572 with available summary statistics from the PGC, Indonesia Schizophrenia Consortium and Genetic REsearch on schizophreniA neTwork-China and Netherland (GREAT-CN) study, and multi-ethnic GPC cohorts, achieving among the largest and most diverse studies of these disorders to date.ResultsPolygenic risk scores based on published PGC summary statistics for schizophrenia or bipolar disorder were significantly associated with case status among EA (P<10–30) and AA (P<0.0005) participants in CSP#572. Our primary analyses of schizophrenia yielded a single genome-wide significant association with variants in CHD7 at 8q12.2 for European-American (EA) participants, which remained significant in a joint analysis of EA and African-American (AA) subjects (P=4.62e-08). While no genome-wide significant associations were detected by our within-ancestry analyses of bipolar disorder, a cross-ancestry meta-analysis of CSP#572 participants yielded a significant finding at 10q25 with variants in SORCS3 (P=2.62e-08). Among loci attaining P<0.0001 in our within-ancestry analyses, 4 and 8 subsequently achieved genome-wide significance, respectively, when jointly analyzed with matched subjects from the PGC and GPC. Combining our results with published summary statistics, we performed a cross-ancestry GWAS meta-analysis of 69,280 schizophrenia cases and 138,379 controls, identifying 200 genome-wide significant loci of which 76 are newly reported here. Cross-ancestry analysis of 28,326 bipolar cases and 90,570 controls identified 24 genome-wide significant loci, including novel associations with common variants in PAX5, DOCK2, MACROD2, BRE, KCNG1, and LINC01378.DiscussionWe newly describe genome-wide analyses in a diverse cohort of US Veterans with schizophrenia or bipolar disorder, benchmarking the predictive value of polygenic risk scores based on published GWAS findings. Leveraging available summary statistics from studies of global populations, we add to burgeoning lists of genomic loci implicated in the etiologies of these disorders.

Optogenetics: illuminating the role of PV interneuron dysfunction in the cognitive symptoms of schizophrenia

Our understanding of the neural substrates underlying the cognitive symptoms of schizophrenia remains limited, contributing to a lack of pharmaceuticals effective in treating these deficits. Cognitive impairment is the main source of disability in schizophrenia. Thus, research endeavours involving the identification of therapeutic targets can vastly improve the lives of affected individuals. Compared to previously employed techniques, optogenetics has accelerated such endeavours by allowing for manipulations of neuronal activity to occur with an unprecedented combination of cellular and temporal specificity. Research using this technique has united multiple, once tangentially-related, streams of evidence suggesting dysfunctional fast-spiking parvalbumin (PV) containing interneurons are a common substrate underlying the cognitive aberrations documented in schizophrenia. This review summarizes relevant optogenetic studies and identifies areas for future research, using this emerging technique.

Social Cognition and Schizophrenia: Unresolved Issues and New Challenges in a Maturing Field of Research.

Social cognition has become a topic of widespread interest in experimental and treatment research in schizophrenia over the past 15 years. This explosion of interest largely reflects the robust evidence that social cognition is among the strongest known correlates of poor community functioning throughout the course of schizophrenia. While progress has been impressive, we consider several fundamental questions about the scope, structure, and optimal measurement of social cognition that remain unanswered and point to the need for continued method development. We also consider more recently emerging questions about individual differences, ecological and cross-cultural validity, and intervention approaches, as well as broader technological changes that impact how we understand and use social cognition at a societal level. Continued efforts to creatively grapple with the complexities and challenges the field now faces hold great promise for helping us understand and more effectively treat a major source of functional disability in schizophrenia.

Quantifying the Core Deficit in Classical Schizophrenia.

In the classical descriptions of schizophrenia, Kraepelin and Bleuler recognized disorganization and impoverishment of mental activity as fundamental symptoms. Their classical descriptions also included a tendency to persisting disability. The psychopathological processes underlying persisting disability in schizophrenia remain poorly understood. The delineation of a core deficit underlying persisting disability would be of value in predicting outcome and enhancing treatment. We tested the hypothesis that mental disorganization and impoverishment are associated with persisting impairments of cognition and role function, and together reflect a latent core deficit that is discernible in cases diagnosed by modern criteria. We used Confirmatory Factor Analysis to determine whether measures of disorganization, mental impoverishment, impaired cognition, and role functioning in 40 patients with schizophrenia represent a single latent variable. Disorganization scores were computed from the variance shared between disorganization measures from 3 commonly used symptom scales. Mental impoverishment scores were computed similarly. A single factor model exhibited a good fit, supporting the hypothesis that these measures reflect a core deficit. Persisting brain disorders are associated with a reduction in post-movement beta rebound (PMBR), the characteristic increase in electrophysiological beta amplitude that follows a motor response. Patients had significantly reduced PMBR compared with healthy controls. PMBR was negatively correlated with core deficit score. While the symptoms constituting impoverished and disorganized mental activity are dissociable in schizophrenia, nonetheless, the variance that these 2 symptom domains share with impaired cognition and role function, appears to reflect a pathophysiological process that might be described as the core deficit of classical schizophrenia.

Positive Coping and Resilience as Mediators Between Negative Symptoms and Disability Among Patients With Schizophrenia.

Objective: This study proposes a schizophrenia disability model to describe the associations between negative symptoms and disability to test the possible mediating roles of positive coping and resilience and to compare the relative weights of the indirect effects of these two mediators in an integrated whole. Methods: A total of 407 hospitalized Han Chinese patients diagnosed with stable schizophrenia or schizoaffective disorder were included. Patients were evaluated using the following scales: the Simplified Coping Style Questionnaire (SCQ) for positive coping, the Connor-Davidson Resilience Scale (CD-RISC) for resilience, the Positive and Negative Syndrome Scale (PANSS) for negative symptoms, and the World Health Organization Disability Assessment Schedule, Version II (WHO-DAS II) for the severity of disability. The schizophrenia disability distal mediation model was constructed using the structural modeling (SEM) approach. Bootstrapping procedures and the PRODCLIN program were used to examine the mediating roles of positive coping and resilience. Results: The schizophrenia disability model was well-fitted to the observed data. Positive coping and resilience together with negative symptoms explained 66% of the variance in disability. Positive coping and resilience partly mediated the negative symptoms–disability relationship. The bootstrapped unstandardized indirect effect was 0.319, and the direct effect was 0.224. Positive coping also has a significant positive effect on resilience. In addition, the ratio of the specific indirect effect of positive coping to the total indirect effect (48%) is higher than that of resilience (30%). Conclusion: Positive coping and resilience are two key causal mediators of the negative symptoms–disability relationship. Positive coping and resilience are important personal resources for patients with schizophrenia. We found that the indirect effect of positive coping was relatively more important than that of resilience. This result suggests that personalized treatments aimed at resilience and positive coping can effectively buffer the impact of negative symptoms for patients with schizophrenia and promote rehabilitation.