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Individuals with intellectual and developmental disabilities (IDDs) are at increased risk for serious metabolic comorbidities, which is further exacerbated by the high rate of antipsychotic use in this population. There is currently a lack of literature on effective treatment options for antipsychotic-induced weight gain and metabolic abnormalities in IDD. This case series reports on the clinical use of metformin in patients with IDD on antipsychotics.We conducted a retrospective review of patients in a novel clinical service at the Centre for Addiction and Mental Health in Toronto, Ontario, Canada for adults with IDD experiencing antipsychotic-related weight gain and other metabolic aberrations. Charts were reviewed for weight and other metabolic outcome measures before and after commencing metformin treatment.In 11 patients referred to this clinic, the mean weight loss while on metformin treatment was 11.1 kg, with over 50% of the sample achieving clinically meaningful weight loss of7%. Additional adaptive changes were observed for fasting glucose, glycated hemoglobin, triglyceride, and high-density lipoprotein cholesterol levels.In line with its use in severe mental illness, metformin may be a safe, effective, and accessible treatment option for patients with IDD experiencing metabolic adverse effects of antipsychotic medication. Further research and randomized controlled trials are needed to examine the efficacy of metformin in this population.

Antipsychotic-induced weight gain is an extremely common problem in people with schizophrenia and is associated with increased morbidity and mortality. Adjunctive pharmacological interventions may be necessary to help manage antipsychotic-induced weight gain. This review splits and updates a previous Cochrane Review that focused on both pharmacological and behavioural approaches to this problem.To determine the effectiveness of pharmacological interventions for preventing antipsychotic-induced weight gain in people with schizophrenia.The Cochrane Schizophrenia Information Specialist searched Cochrane Schizophrenia's Register of Trials on 10 February 2021. There are no language, date, document type, or publication status limitations for inclusion of records in the register.We included all randomised controlled trials (RCTs) that examined any adjunctive pharmacological intervention for preventing weight gain in people with schizophrenia or schizophrenia-like illnesses who use antipsychotic medications.At least two review authors independently extracted data and assessed the quality of included studies. For continuous outcomes, we combined mean differences (MD) in endpoint and change data in the analysis. For dichotomous outcomes, we calculated risk ratios (RR). We assessed risk of bias for included studies and used GRADE to judge certainty of evidence and create summary of findings tables. The primary outcomes for this review were clinically important change in weight, clinically important change in body mass index (BMI), leaving the study early, compliance with treatment, and frequency of nausea. The included studies rarely reported these outcomes, so, post hoc, we added two new outcomes, average endpoint/change in weight and average endpoint/change in BMI.Seventeen RCTs, with a total of 1388 participants, met the inclusion criteria for the review. Five studies investigated metformin, three topiramate, three H2 antagonists, three monoamine modulators, and one each investigated monoamine modulators plus betahistine, melatonin and samidorphan. The comparator in all studies was placebo or no treatment (i.e. standard care alone). We synthesised all studies in a quantitative meta-analysis. Most studies inadequately reported their methods of allocation concealment and blinding of participants and personnel. The resulting risk of bias and often small sample sizes limited the overall certainty of the evidence. Only one reboxetine study reported the primary outcome, number of participants with clinically important change in weight. Fewer people in the treatment condition experienced weight gains of more than 5% and more than 7% of their bodyweight than those in the placebo group (5% weight gain RR 0.27, 95% confidence interval (CI) 0.11 to 0.65; 1 study, 43 participants;7% weight gain RR 0.24, 95% CI 0.07 to 0.83; 1 study, 43 participants; very low-certainty evidence). No studies reported the primary outcomes, 'clinically important change in BMI', or 'compliance with treatment'. However, several studies reported 'average endpoint/change in body weight' or 'average endpoint/change in BMI'. Metformin may be effective in preventing weight gain (MD -4.03 kg, 95% CI -5.78 to -2.28; 4 studies, 131 participants; low-certainty evidence); and BMI increase (MD -1.63 kg/m2, 95% CI -2.96 to -0.29; 5 studies, 227 participants; low-certainty evidence). Other agents that may be slightly effective in preventing weight gain include H2 antagonists such as nizatidine, famotidine and ranitidine (MD -1.32 kg, 95% CI -2.09 to -0.56; 3 studies, 248 participants; low-certainty evidence) and monoamine modulators such as reboxetine and fluoxetine (weight: MD -1.89 kg, 95% CI -3.31 to -0.47; 3 studies, 103 participants; low-certainty evidence; BMI: MD -0.66 kg/m2, 95% CI -1.05 to -0.26; 3 studies, 103 participants; low-certainty evidence). Topiramate did not appear effective in preventing weight gain (MD -4.82 kg, 95% CI -9.99 to 0.35; 3 studies, 168 participants; very low-certainty evidence). For all agents, there was no difference between groups in terms of individuals leaving the study or reports of nausea. However, the results of these outcomes are uncertain given the very low-certainty evidence.There is low-certainty evidence to suggest that metformin may be effective in preventing weight gain. Interpretation of this result and those for other agents, is limited by the small number of studies, small sample size, and short study duration. In future, we need studies that are adequately powered and with longer treatment durations to further evaluate the efficacy and safety of interventions for managing weight gain.

Individuals with intellectual and/or developmental disability (IDD) are often prescribed antipsychotics (APs). However, despite their known propensity to cause metabolic adverse effects, including weight gain, diabetes, and increased risk of cardiovascular events, there is currently a limited body of literature describing the metabolic consequences of AP use in this population.We searched MEDLINE, EMBASE, PsychINFO, CENTRAL, and CINAHL databases to identify all randomized trials that reported on the metabolic effects of APs in individuals with IDD. Random effects meta-analyses were used to examine weight gain as both a continuous and dichotomous outcome.Eighteen randomized trials met our inclusion criteria with a total of 1376 patients across a variety of IDDs. AP use was associated with significantly greater weight gain compared with placebo (Continuous: mean difference = 1.10 kg, [0.79, 1.40], p 0.00001, IThis review (PROSPERO # CRD42021255558) demonstrates that AP use is associated with significant weight gain among patients with IDD. Concerningly, most reported studies were in children and adolescents, which sets up an already vulnerable population for adverse medical sequalae at an early age. There was also a lack of long-term studies in adults with IDD. Further studies are required to better understand how AP use affects metabolic parameters in this group of individuals.

Anhedonia, the reduced capacity to experience pleasure, has long been considered a prominent feature of schizophrenia spectrum disorders. Many domain-specific conceptualizations of anhedonia and pleasure capacity have been developed, and there currently exist a variety of self-report assessment tools that purport to assess these various domains. The current systematic review and meta-analysis (PROSPERO: CRD42020156169) aimed to quantify overall and domain-specific self-reported anhedonia in people with schizophrenia compared to nonpsychiatric controls. We performed a literature search of PsycINFO, MEDLINE, and Embase databases for dissertations and peer-reviewed articles published in English prior to June 2021. Studies employing a psychometrically validated self-report measure of anhedonia, pleasure experience or affect in people with schizophrenia, schizoaffective, or schizophreniform disorders; studies utilizing at least one clearly defined healthy or community control group for comparison; and studies providing sufficient data to calculate effect sizes were included in this review. Random and mixed effects meta-analyses, meta-regressions, and subgroup comparisons were run across domains of anhedonia to explore weighted mean effect sizes and their associated moderators. In total, 146 studies met inclusion criteria, yielding 390 Hedges’ g effect sizes from the included comparisons. People with schizophrenia reported moderate-to-large elevations in overall and domain-specific anhedonia. A sensitivity analysis accounting for high risk of bias studies did not significantly impact results. Lastly, patient sex, education, negative symptom severity, antipsychotic class, and trait negative affect differentially moderated effect sizes across domains of anhedonia. Despite the heterogeneity inherent in schizophrenia spectrum disorders, self-reported anhedonia is ubiquitously reported across self-report measures in this population.

To evaluate the efficacy of peer-facilitated interventions for improving the physical health of people with schizophrenia spectrum disorders.Systematic review and random effects meta-analysis of peer-facilitated interventions for people with serious mental illness, including schizophrenia spectrum disorders, in which physical health outcomes were assessed.MEDLINE, PsycINFO, EMBASE, CINAHL, Web of Science, Scopus, CENTRAL, and PubMed. In addition, reference lists of reviews were examined for further relevant studies published to 10 November 2021.We included fourteen publications (thirteen randomised controlled trials of ten peer-facilitated interventions, and one secondary analysis; total of 2099 participants) that assessed physical health outcomes for people with mental health conditions, including schizophrenia spectrum disorders. Intervention duration ranged from three to eighteen months; peers were involved as sole or co-leaders of the programs in group or individual sessions. Meta-analysis identified a statistically significant pooled effect on physical activity and capacity (various measures; six studies; 468 intervention, 461 control participants; standardised mean difference, +0.19 standard deviation [SD]; 95% CI, +0.06-0.32 SD; IPeer-facilitated interventions for improving physical outcomes are feasible for people with schizophrenia spectrum disorders, a group at particular risk of certain physical health conditions. Further research is required to assess the effects of such interventions on other health-related parameters.CRD42021283578 (retrospective).

Clozapine is presently the sole antipsychotic with an indication for treatment-resistant Schizophrenia, but is associated with significant weight gain and other metabolic aberrations. This retrospective chart review aimed to evaluate the effectiveness of adjunctive metformin in preventing clozapine-induced weight gain.We conducted a retrospective chart review of patients newly initiated on clozapine at the Centre for Addiction and Mental Health in Canada, from November 2014 to April 2021. Our primary outcome was body weight at 6 and 12 months after clozapine initiation. Other metabolic parameters served as secondary outcomes.Among 396 patients (males: 71.5%, mean age: 42.8 years) initiated on clozapine, 69 were on metformin or prescribed it ≤3 months after clozapine initiation. The clozapine+metformin group demonstrated less weight gain compared with the clozapine-only group at 6 months (clozapine+metformin: -0.15 kg [SE = 1.08] vs. clozapine-only: 2.99 kg, SE = 0.54) and 12 months after clozapine initiation (clozapine+metformin: -0.67 kg, SE = 1.22 vs. clozapine-only: 4.72 kg, SE = 0.67). Adaptive changes were also observed for fasting glucose (F = 3.10, p = 0.046) and triglycerides (F = 8.56, p 0.001) in the clozapine+metformin group compared with clozapine only.In this large retrospective naturalistic cohort study, co-prescription of clozapine and metformin was associated with less weight gain and related metabolic dysfunction at 6 and 12 months after initiation versus clozapine alone. These findings provide evidence for the effectiveness of metformin in preventing clozapine-induced weight gain; larger randomized controlled trials are needed to confirm these results.

Clozapine (CLZ), the sole antipsychotic with superior efficacy for ultra-treatment resistant schizophrenia (TRS), is limited by adverse effects, including metabolic dysregulation. Clozapine’s main metabolite, N-desmethylclozapine (NDMC), has potent 5-HT2C antagonist properties which may explain this metabolic dysfunction, thus the CLZ:NDMC ratio is of particular interest. High insulin resistance states could be associated with CYP1A2 induction and lower CLZ:NDMC ratios. Additionally, lower CLZ:NDMC ratios have been associated with better cognitive, but worse metabolic functioning. This study investigated associations between metabolic and cognitive parameters with the CLZ/NDMC ratio. Primary outcomes included relationships between the CLZ:NDMC ratio to the homeostatic model assessment for insulin resistance (HOMA-IR) and Brief Assessment of Cognition in Schizophrenia (BACS) composite z-scores. Secondary outcomes assessed relationships between CLZ:NDMC ratios to fasting insulin, BMI, weight, fasting glucose, and BACS digit sequencing z-scores. 38 patients who were overweight or obese with schizophrenia or schizoaffective disorder completed fasting bloodwork, anthropometric, psychopathological, and cognitive assessments. Multivariate regressions found a statistically significant inverse association between the CLZ/NDMC ratio and HOMA-IR (B = − 1.028, SE B = .473, β = − 0.348 p = 0.037), which may have been driven by fasting insulin levels (B = − 27.124, SE B = 12.081, β = − 0.351 p = 0.031). The CLZ/NDMC ratio may predict insulin resistance/metabolic comorbidity among patients with TRS receiving clozapine.

Antipsychotics (APs) are the cornerstone of treatment for schizophrenia (SCZ) but are unfortunately associated with serious metabolic adverse effects including weight gain and type 2 diabetes. The pathophysiology of AP-induced metabolic dysfunction is largely undetermined. Brain insulin resistance has been posited to be at the cross-roads of many cognitive and metabolic disorders, and disruption of central insulin action has emerged as a possible explanatory mechanism underlying AP induced metabolic dysfunction. Previous studies suggest that change in neuroimaging-based parameters with intranasal insulin administration can be leveraged to investigate brain insulin resistance. In this proof-of-concept study, we will utilize neural signatures of insulin action in the brain to examine if APs disrupt brain insulin signaling. It is hypothesized that: 1) intranasal insulin (INI), but not intranasal placebo (INP), will change cerebral blood flow and resting state connectivity, as well as increase glutamate levels in the striatum and dorsolateral prefrontal cortex; 2) oral olanzapine (OLA), but not oral placebo (PL), will inhibit the effect of INI on these parameters. Thirty-two healthy volunteers will undergo a single blind, cross-over design, wherein all participants receive the following four treatment combinations, 2–6 weeks apart, in a random sequence: INP + PL, INP + OLA, INI + PL, and INI + OLA. Participants will undergo an MRI-based assay of brain insulin resistance 15 minutes after administering 160 IU INI or INP. The scanning protocol includes resting and task-based functional MRI, arterial spin labelling, and proton magnetic resonance spectroscopy. Demonstrating that OLA can acutely induce brain insulin resistance is clinically relevant to metabolic health in SCZ. Evidence of brain insulin resistance induced by acute AP dosing can inform the early use of adjunctive insulin sensitizers for the treatment of metabolic comorbidities associated with AP treatment in severe mental illness. Trial registration ClinicalTrials.gov Registration: NCT03741478.

Patients with schizophrenia have exceedingly high rates of metabolic comorbidity including type 2 diabetes and lose 15–20 years of life due to cardiovascular diseases, with early accrual of cardiometabolic disease. In this study, thirty overweight or obese (Body Mass Index (BMI) > 25) participants under 40 years old with schizophrenia spectrum disorders and early comorbid prediabetes or type 2 diabetes receiving antipsychotic medications were randomized, in a double-blind fashion, to metformin 1500 mg/day or placebo (2:1 ratio; n = 21 metformin and n = 9 placebo) for 4 months. The primary outcome measures were improvements in glucose homeostasis (HbA1c, fasting glucose) and insulin resistance (Matsuda index—derived from oral glucose tolerance tests and homeostatic model of insulin resistance (HOMA-IR)). Secondary outcome measures included changes in weight, MRI measures of fat mass and distribution, symptom severity, cognition, and hippocampal volume. Twenty-two patients (n = 14 metformin; n = 8 placebo) completed the trial. The metformin group had a significant decrease over time in the HOMA-IR (p = 0.043) and fasting blood glucose (p = 0.007) vs. placebo. There were no differences between treatment groups in the Matsuda index, HbA1c, which could suggest liver-specific effects of metformin. There were no between group differences in other secondary outcome measures, while weight loss in the metformin arm correlated significantly with decreases in subcutaneous, but not visceral or hepatic adipose tissue. Our results show that metformin improved dysglycemia and insulin sensitivity, independent of weight loss, in a young population with prediabetes/diabetes and psychosis spectrum illness, that is at extremely high risk of early cardiovascular mortality. Trial Registration: This protocol was registered with clinicaltrials.gov (NCT02167620).

The introduction of chlorpromazine and the work that ensued provided the foundation to reposition schizophrenia as a biological illness. The present paper follows the evolution of antipsychotics and their shift from 'typical' to 'atypical'. Atypicality is reviewed in reference to its original definition, clozapine's role, and developments that now leave the concept's utility in question. In a similar fashion, drug development is reviewed in the context of the illness' multiple symptom domains, as well as differences captured by clinical staging and phenotyping. Collectively, the evidence argues for a more nuanced approach to drug development that aligns with the illness' heterogeneity and complexity. Just as 'atypical' as a descriptor for antipsychotics may be outdated, it may be time to set aside the notion of developing drugs that treat 'schizophrenia'.

Schizophrenia is a debilitating psychiatric illness that remains poorly understood. While the bulk of symptomatology has classically been associated with disrupted brain functioning, accumulating evidence demonstrates that schizophrenia is characterized by systemic inflammation and disturbances in metabolism. Indeed, metabolic disease is a major determinant of the high mortality rate associated with schizophrenia. Antipsychotic drugs (APDs) have revolutionized management of psychosis, making it possible to rapidly control psychotic symptoms. This has ultimately reduced relapse rates of psychotic episodes and improved overall quality of life for people with schizophrenia. However, long-term APD use has also been associated with significant metabolic disturbances including weight gain, dysglycemia, and worsening of the underlying cardiometabolic disease intrinsic to schizophrenia. While the mechanisms for these intrinsic and medication-induced metabolic effects remain unclear, inflammation appears to play a key role. Here, we review the evidence for roles of inflammatory mechanisms in the disease features of schizophrenia and how these mechanisms interact with APD treatment. We also discuss the effects of common inflammatory mediators on metabolic disease. Then, we review the evidence of intrinsic and APD-mediated effects on systemic inflammation in schizophrenia. Finally, we speculate about possible treatment strategies. Developing an improved understanding of inflammatory processes in schizophrenia may therefore introduce new, more effective options for treating not only schizophrenia but also primary metabolic disorders.

COVID-19 can worsen the physical health of individuals with serious mental illness, a vulnerable group already facing physical health disparities. COVID-19 is further reducing access to physical health care due to shutdown of services deemed "non-urgent" and overcrowding of emergency services. Management of chronic diseases, highly prevalent in this group, is undermined due to exacerbation of psychiatric disorders, reduction in availability of social support, and worsening of negative social determinants of health. In this commentary, we discuss the challenges experienced by this group and offer mitigation strategies to reduce: (1) inequalities in access to physical health care; and (2) disruptions to the management of chronic physical conditions in the face of COVID-19. Recommendations include coordinated efforts by health authorities, primary and mental health care organizations, researchers, policymakers, and other stakeholders. These efforts should ensure equitable access to physical health care and implementation of innovative programs to protect the physical health of people with serious mental illness during and following the pandemic.

Background Patients with obsessive compulsive disorder (OCD) have bias toward threat-related information as evidenced through emotional interference tasks, for which fronto-striatal and fronto-limbic regions have been proposed as substrates. In this study, we sought to examine the endophenotype pattern of neuro-hemodynamic substrates of emotion counting stroop (ecStroop) paradigm in patients with OCD, their unaffected siblings [first degree relatives-FDR] and healthy controls. Methods OCD patients (medication naive)[N=16], their unaffected siblings(FDR)[N=16] and healthy controls [N=24] were compared using an established ecStroop paradigm in a 3-Tesla fMRI. The relative BOLD signals corresponding to the three types of conditions (neural words-N, words with negative emotional salience-E and words with salience for OCD-O) were examined in the apriori hypothesized brain regions with age, sex and years of education as covariates. The regions with uncorrected p Results Both in O minus N contrast (F=10.9) and O minus E contrast (F=10.5), the groups demonstrated significant differential activation of right insula (BA 13,p=0.02). The post-hoc analyses showed in patients and FDRs relative to HC the following: significant hyperactivation of insula in O minus E contrast; significant hyperactivation of right insula and right DLPFC (BA 9) in O minus N contrast. Conclusions The neuro-hemodynamic responses corresponding to the obsessive words in insula and DLPFC could be potential endophenotypes. “Threat relatedness” might thus have a vulnerability meaning in the pathogenesis and neurobiological basis of OCD.

Objective Spatial normalization of brain MR images is highly dependent on the choice of target brain template. Morphological differences caused by factors like genetic and environmental exposures, generates a necessity to construct population specific brain templates. Brain image analysis performed using brain templates from Caucasian population may not be appropriate for non-Caucasian population. In this study, our objective was to construct an Indian brain template from a large population (N = 157 subjects) and compare the morphometric parameters of this template with that of Chinese-56 and MNI-152 templates. In addition, using an independent MRI data of 15 Indian subjects, we also evaluated the potential registration accuracy differences using these three templates. Methods Indian brain template was constructed using iterative routines as per established procedures. We compared our Indian template with standard MNI-152 template and Chinese template by measuring global brain features. We also examined accuracy of registration by aligning 15 new Indian brains to Indian, Chinese and MNI templates. Furthermore, we supported our measurement protocol with inter-rater and intra-rater reliability analysis. Results Our results showed that there were significant differences in global brain features of Indian template in comparison with Chinese and MNI brain templates. The results of registration accuracy analysis revealed that fewer deformations are required when Indian brains are registered to Indian template as compared to Chinese and MNI templates. Conclusion This study concludes that population specific Indian template is likely to be more appropriate for structural and functional image analysis of Indian population.

Siblings of persons with schizophrenia are important in providing long-term social support to the patients. Interventions addressing their needs are very sparse. Hence, this study aimed at testing the short-term effects of brief need based psychoeducation on knowledge, self-stigma, and burden among siblings of persons with schizophrenia. In this prospective controlled open label trial, 80 siblings of persons with schizophrenia were allocated in equal numbers to the brief need based psychoeducation group and the treatment-as-usual group. The outcomes were measured at baseline, and after the first and third month post-intervention. RM-ANCOVA was conducted to test the effect of the brief psychoeducation on outcome scores. The groups were similar with respect to socio-demographic, clinical, and outcome scores at the baseline. There was a significant group×time interaction effect on knowledge (F=8.71; p

Earlier studies have implicated CHRNA7, coding α-7 nicotinic acetylcholine receptor (α7 nAChR), and its partially duplicated chimeric gene CHRFAM7A in schizophrenia. However, the relationship between the alterations in peripheral gene expression of CHRFAM7A and severity of clinical symptoms has not been examined. Furthermore, potential influence of the antipsychotic medication on CHRFAM7A expression in drug-naive or drug-free schizophrenia is an unexplored area. CHRFAM7A gene expression in lymphocytes was analyzed in 90 antipsychotic-naïve or free schizophrenia patients using TaqMan-based quantitative RT-PCR. Psychotic symptoms were assessed using Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms (SANS). The relationship between psychopathology and CHRFAM7A expression was examined. In addition, measurement of CHRFAM7A gene expression was repeated during follow-up after short-term antipsychotic treatment in 38 patients. There was significant inverse correlation between CHRFAM7A expression and total negative psychopathology score-SANS, and this relationship persisted after accounting for possible confounders such as age, sex and smoking. On exploration of the factor structure of psychopathology using principal component analysis, all the negative symptoms-affective flattening, alogia, apathy, anhedonia and inattention were found to be inversely associated with CHRFAM7A expression. Furthermore, analysis of repeated measures revealed a significant increase in CHRFAM7A expression in patients after short-term administration of antipsychotic medication. Our study observations support the role for CHRFAM7A gene in schizophrenia pathogenesis and suggest a potential novel link between deficient CHRFAM7A expression and negative psychopathology. Furthermore, up-regulation of CHRFAM7A gene expression by antipsychotics suggests that it could be a potential state marker for clinical severity.

Some aspects of saccadic performance have been found to be abnormal in chronic schizophrenia. The majority of this research has, however, been performed on patients treated with long-term antipsychotic medication. Very few studies have examined saccadic performance in antipsychotic-naïve/free patients. There are also very few studies describing the relationship between saccadic performance and clinical symptoms, particularly in antipsychotic free patients. In this study, we compared pro and antisaccade performance in a large sample of antipsychotic-naïve/free schizophrenia patients (N = 45) with healthy controls (N = 57). Clinical symptoms were assessed using Scale for Assessment of Positive Symptoms (SAPS) and Negative Symptoms (SANS). In the antisaccade task, patients made significantly more errors, and their correct antisaccades had smaller amplitudes in comparison to healthy controls. Higher error rates were associated with increased severity of hallucinations. In the prosaccade task, patients had less accurate final eye positions, and made saccades with slower latency and reduced amplitude compared to the healthy controls. These observations in schizophrenia patients without the potential confounds of antipsychotic treatment suggest intrinsic link between saccadic deficits and schizophrenia pathogenesis. The relationship between antisaccade errors and hallucination severity supports the potential link between hallucinations and deficits in inhibitory control.

Introduction: Clozapine remains the most effective antipsychotic for treatment-refractory schizophrenia. However, ~40% of the patients respond insufficiently to clozapine. Clozapine's effects, both beneficial and adverse, have been proposed to be partially attributable to its main metabolite, N-desmethylclozapine (NDMC). However, the relation of the clozapine to norclozapine ratio (CLZ:NDMC; optimally defined as ~2) to clinical response and metabolic outcomes is not clear.Areas covered: This narrative review comprehensively examines the clinical utility of the CLZ:NDMC ratio to reduce metabolic risk and increase treatment efficacy. The association of the CLZ:NDMC ratio with changes in psychopathology, cognitive functioning, and cardiometabolic burden will be explored, as well as adjunctive treatments and their effects.Expert opinion: The literature suggests a positive association between the CLZ:NDMC ratio and better cardiometabolic outcomes. Conversely, the CLZ:NDMC ratio appears inversely associated with better cognitive functioning but less consistently with other psychiatric domains. The CLZ:NDMC ratio may be useful for predicting and monitoring cardiometabolic adverse effects and optimizing potential cognitive benefits of clozapine. Future studies are required to replicate these findings, which if substantiated, would encourage examination of adjunctive treatments aiming to alter the CLZ:NDMC ratio to best meet the needs of the individual patient, thereby broadening clozapine's clinical utility.

Obsessive-Compulsive Disorder (OCD) is characterized by abnormalities in the cortico-striato-thalamo-cortical (CSTC) circuitry of the brain. Antisaccade eye movement tasks measure aspects of the voluntary control of behaviour that are sensitive to CSTC circuitry dysfunction.In this study, we examined antisaccade eye movement parameters of OCD patients in comparison with healthy controls (HC). In addition, we also examined the relationship between the antisaccade eye movement parameters and the severity of OCD. Antisaccade performance among right handed OCD patients (N = 65) was compared to matched right handed HC (N = 57). Eye tracking data during the task performance were collected using an Eye-Link eye-tracker at 1000-Hz sampling rate. OCD symptom severity was evaluated using Yale-Brown obsessive compulsive scale.The antisaccade error percentage was significantly greater in OCD patients than HC (p0.001). In addition, OCD patients had less accurate final eye position compared to HC (p0.001). There were no significant correlation between antisaccade parameters and OCD severity measures.Deficient performance in antisaccade task supports CSTC abnormality in OCD and this appears to be independent of the illness severity. Examining this in remitted participants with OCD and in unaffected first degree relatives could help ascertaining their endophenotype validity.

Even though conventional neurobiological models of obsessive compulsive disorder (OCD) commonly demonstrate abnormalities involving fronto-striatal circuits, there is emerging evidence regarding the role of posterior brain structures such as cerebellum. In this study, we examined the cerebellar regional volume in a large sample of medication-naïve OCD patients compared to matched healthy controls (HC). In 49 medication naïve right handed OCD patients and 39 age and sex matched HC, sub-region wise volume of cerebellum was extracted from the T1 weighted images using Spatially Unbiased Infra tentorial Template (SUIT) toolbox and compared using hypothesis driven, region of interest approach after clinical assessment with standard scales. After controlling for age, sex and ICV, the subjects with OCD had significantly smaller cerebellum compared to HC, especially in the posterior lobe sub-regions - lobule VI and left crus 1. This study gives preliminary evidence for region specific cerebellar volumetric deficits in the pathophysiological of OCD. Regional cerebellar volume deficits conform to the abnormal connectivity of cerebellum to specific cortical regions and it is indicative of involvement of regions outside the conventional fronto-striatal circuitry. This might be important in the context of cognitive deficits seen in OCD.

Disturbed eating behaviours have been widely reported in psychotic disorders since the early 19th century. There is also evidence that antipsychotic (AP) treatment may induce binge eating or other related compulsive eating behaviours. It is therefore possible that abnormal eating patterns may contribute to the significant weight gain and other metabolic disturbances observed in patients with psychosis. In this scoping review, we aimed to explore the underlying psychopathological and neurobiological mechanisms of disrupted eating behaviours in psychosis spectrum disorders and the role of APs in this relationship. A systematic search identified 35 studies that met our eligibility criteria and were included in our qualitative synthesis. Synthesizing evidence from self-report questionnaires and food surveys, we found that patients with psychosis exhibit increased appetite and craving for fatty food, as well as increased caloric intake and snacking, which may be associated with increased disinhibition. Limited evidence from neuroimaging studies suggested that AP-naïve first episode patients exhibit similar neural processing of food to healthy controls, while chronic AP exposure may lead to decreased activity in satiety areas and increased activity in areas associated with reward anticipation. Overall, this review supports the notion that AP use can lead to disturbed eating patterns in patients, which may contribute to AP-induced weight gain. However, intrinsic illness-related effects on eating behaviors remain less well elucidated, and many confounding factors as well as variability in study designs limits interpretation of existing literature in this field and precludes firm conclusions from being made.

Multiple lines of evidence have suggested a potential role of Neuregulin-1 (NRG1) in the neurodevelopmental pathogenesis of schizophrenia. Interaction between genetic risk variants present within NRG1 locus and non-specific gestational putative insults can significantly impair crucial processes of brain development. Such genetic effects can be analyzed through the assessment of digit ratio and dermatoglyphic patterns. We examined the role of two well-replicated polymorphisms of NRG1 (SNP8NRG221533 and SNP8NRG243177) on schizophrenia risk and its probable impact on the digit ratio and dermatoglyphic measures in patients (N = 221) and healthy controls (N = 200). In schizophrenia patients, but not in healthy controls, a significant association between NRG1 SNP8NRG221533 C/C genotype with lower left 2D:4D ratio, as well as with higher FA_TbcRC and DA_TbcRC. The substantial effect of SNP8NRG221533 on both digit ratio and dermatoglyphic measures suggest a potential role for NRG1 gene variants on neurodevelopmental pathogenesis of schizophrenia.

Schizophrenia is a complex neuropsychiatric disorder with significant genetic predisposition. In a subset of schizophrenia patients, mitochondrial dysfunction could be explained by the genomic defects like mitochondrial DNA Copy Number Variations, which are considered as a sensitive index of cellular oxidative stress. Given the high energy demands for neuronal functions, altered Mitochondrial DNA copy number (mtDNAcn) and consequent impaired mitochondrial physiology would significantly influence schizophrenia pathogenesis. In this context, we have made an attempt to study mitochondrial dysfunction in schizophrenia by assessing mtDNAcn in antipsychotic-naïve/free schizophrenia patients.mtDNAcn was measured in 90 antipsychotic-naïve / free schizophrenia (SCZ) patients and 147 Healthy Controls (HC). The relative mtDNAcn was determined by quantitative real-time polymerase chain reaction (qPCR) using TaqMan® multiplex assay method.A statistically significant difference between groups [t = 5.22, P0.001] was observed, with significantly lower mtDNAcn in SCZ compared to HC. The group differences persisted even after controlling for age and sex [F (4, 232) = 22.68, P0.001, η2 = 0.09].Lower mtDNAcn in SCZ compared to HC suggests that mtDNAcn may hold potential to serve as an important proxy marker of mitochondrial function in antipsychotic-naïve/free SCZ patients.

Insulin action in the central nervous system is a major regulator of energy balance and cognitive processes. The development of central insulin resistance is associated with alterations in dopaminergic reward systems and homeostatic signals affecting food intake, glucose metabolism, body weight and cognitive performance. Emerging evidence has highlighted a role for antipsychotics (APs) to modulate central insulin-mediated pathways. Although APs remain the cornerstone treatment for schizophrenia they are associated with severe metabolic complications and fail to address premorbid cognitive deficits, which characterize the disorder of schizophrenia. In this review, we first explore how the hypothesized association between schizophrenia and CNS insulin dysregulation aligns with the use of APs. We then investigate the proposed relationship between CNS insulin action and AP-mediated effects on metabolic homeostasis, and different domains of psychopathology, including cognition. We briefly discuss a potential role of CNS insulin signaling to explain the hypothesized, but somewhat controversial association between therapeutic efficacy and metabolic side effects of APs. Finally, we propose how this knowledge might inform novel treatment strategies to target difficult to treat domains of schizophrenia. This article is part of the issue entitled 'Special Issue on Antipsychotics'.

Combining cognitive retraining with transcranial direct current stimulation (tDCS) has been hypothesized to improve cognitive deficits in schizophrenia. The effect of combining a neuropsychological/psychophysiological task with tDCS, called "online-tDCS" for cognitive enhancement in schizophrenia is not rigorously assessed. In this proof-of-concept study, we aimed at evaluating the effect of a single session online-tDCS on working memory(WM) and its transferability to other cognitive functions. Numerical n-back(NNB), digit symbol substitution test(DSST), emotional matching and labelling test(E-MALT), and anti-saccade eye movement beeforefore and after 20 min tDCS (anode: left dorsolateral prefrontal cortex and cathode: left temporoparietal junction) applied during Sternberg's task(WM-task) were assessed. Twenty-three schizophrenia patients with cognitive deficits were randomized to receive either online-tDCS or offline-tDCS (without simultaneous Sternberg's task) sessions. All patients received one session each of active and sham tDCS in a randomized counterbalanced double-blind cross-over design. RMANOVA revealed a significant interaction effect between tDCS type (Online/Offline) x activeness (active/sham) of tDCS; the reaction time during 2-back performance in the NNB test improved in online-sham (F = 5.23, p < 0.038) but not online-active tDCS session. No significant changes were noted in DSST, E-MALT, and anti-saccade performance. Improved performance after online-sham tDCS suggests that performing the Sternberg's task enhanced 2-back performance. The counterintuitive observation was noted with respect to the non-enhancement of WM performance on combining the task to tDCS. Aberrant plasticity in schizophrenia might attain a transitional ceiling that would have resulted in restriction of enhancement on combining the two plasticity modulators. The transferability of improvement to other cognitive domains could not be ascertained.

Transcranial direct current stimulation (tDCS), a non-invasive, neuromodulatory technique, is being increasingly applied to several psychiatric disorders. In this study, we describe the side-effect profile of repeated tDCS sessions (N = 2005) that were administered to 171 patients (156 adults and 15 adolescents) with different psychiatric disorders [schizophrenia [N = 109], obsessive-compulsive disorder [N = 28], alcohol dependence syndrome [N = 13], mild cognitive impairment [N = 10], depression [N = 6], dementia [N = 2] and other disorders [N = 3]]. tDCS was administered at a constant current strength of 2 mA with additional ramp-up and ramp-down phase of 20 s each at the beginning and end of the session, respectively. Other tDCS protocol parameters were: schizophrenia and obsessive-compulsive disorder: 5-days of twice-daily 20-min sessions with an inter-session interval of 3-h; Mild cognitive impairment/dementia and alcohol dependence syndrome: at least 5-days of once-daily 20-min session; Depression: 10-days of once-daily 30 min session. At the end of each tDCS session, any adverse event observed by the administrator and/or reported by the patient was systematically assessed using a comprehensive questionnaire. The commonly reported adverse events during tDCS included burning sensations (16.2%), skin redness (12.3%), scalp pain (10.1%), itching (6.7%), and tingling (6.3%). Most of the adverse events were noted to be mild, transient and well-tolerated. In summary, our observations suggest that tDCS is a safe mode for therapeutic non-invasive neuromodulation in psychiatric disorders in adults as well as the adolescent population.

Insulin signaling in the central nervous system is at the intersection of brain and body interactions, and represents a fundamental link between metabolic and cognitive disorders. Abnormalities in brain insulin action could underlie the development of comorbid schizophrenia and type 2 diabetes. Among its functions, central nervous system insulin is involved in regulation of striatal dopamine levels, peripheral glucose homeostasis, and feeding regulation. In this review, we discuss the role and importance of central nervous system insulin in schizophrenia and diabetes pathogenesis from a historical and mechanistic perspective. We describe central nervous system insulin sites and pathways of action, with special emphasis on glucose metabolism, cognitive functioning, inflammation, and food preferences. Finally, we suggest possible mechanisms that may explain the actions of central nervous system insulin in relation to schizophrenia and diabetes, focusing on glutamate and dopamine signaling, intracellular signal transduction pathways, and brain energetics. Understanding the interplay between central nervous system insulin and schizophrenia is essential to disentangling this comorbid relationship and may provide novel treatment approaches for both neuropsychiatric and metabolic dysfunction. This article is part of the issue entitled 'Special Issue on Antipsychotics'.

Background: Emerging evidence suggests an important role of the human gut microbiome in psychiatry and neurodevelopmental disorders. An increasing body of literature based on animal studies has reported that the gut microbiome influences brain development and behavior by interacting with the gut-brain axis. Furthermore, as the gut microbiome has an important role in metabolism and is known to interact with pharmaceuticals, recent evidence suggests a role for the microbiome in antipsychotic-induced metabolic side effects in animals and humans. Purpose: Here we present the protocol for a two-phase study investigating the gut microbiome in healthy controls and in patients with schizophrenia treated with antipsychotics. Methods: Phase I of our study involves humans exclusively. We recruit 25 patients who are chronically treated with clozapine and compare them with 25 healthy controls matched for age, sex, BMI, and smoking status. A second cohort consists of 25 patients newly starting on clozapine, and a third cohort includes 25 antipsychotic-naive patients. The patients in the second cohort and third cohort are prospectively assessed for up to 6 and 12 weeks, respectively. Phase II of this study will incorporate microbiota humanized mouse models to examine the influence of human fecal transplant on metabolic parameters and the gut-brain axis. Progress and Future Directions: We are underway with the first participants enrolled in all phase I treatment cohorts. This study will contribute to elucidating the role of the gut microbiome in schizophrenia and metabolic side effects. In addition, its results may help to explore potential therapeutic targets for antipsychotic-induced metabolic side effects.

ObjectiveRecent observations demonstrate a significant ameliorative effect of add-on transcranial direct current stimulation (tDCS) on auditory verbal hallucinations (AVHs) in schizophrenia. Of the many SNPs, NRG1 rs35753505 and catechol-o-methyl transferase (COMT) rs4680 polymorphisms have shown to have a strong association with neuroplasticity effect in schizophrenia.MethodsSchizophrenia patients (n=32) with treatment resistant auditory hallucinations were administered with an add-on tDCS. The COMT (rs4680) and NRG1 (rs35753505) genotypes were determined. The COMT genotypes were categorised into Val group (GG; n=15) and Met group (GG/AG; n=17) and NRG1 genotypes were categorised into AA group (n=12) and AG/GG group (n=20).ResultsThe reduction in auditory hallucination sub-scale score was significantly affected by COMT-GG genotype [Time×COMT interaction: F(1,28)=10.55, p=0.003, ɳ2=0.27]. Further, COMT-GG effect was epistatically influenced by the co-occurrence of NRG1-AA genotype [Time×COMT×NRG1 interaction: F(1,28)=8.09, p=0.008, ɳ2=0.22]. Irrespective of genotype, females showed better tDCS response than males [Time×Sex interaction: F(1,21)=4.67, p=0.04, ɳ2=0.18].ConclusionCOMT-GG and NRG1-AA genotypes aid the tDCS-induced improvement in AVHs in schizophrenia patients. Our preliminary observations need replication and further systematic research to understand the neuroplastic gene determinants that modulate the effect of tDCS.

Transcranial direct current stimulation (tDCS) has generated interest as a treatment modality for schizophrenia. Dopamine, a critical pathogenetic link in schizophrenia, is also known to influence tDCS effects. We evaluated the influence of antipsychotic drug type (as defined by dopamine D 2 receptor affinity) on the impact of tDCS in schizophrenia. DSM-IV-TR-diagnosed schizophrenia patients [ N =36] with persistent auditory hallucinations despite adequate antipsychotic treatment were administered add-on tDCS. Patients were divided into three groups based on the antipsychotic's affinity to D 2 receptors. An auditory hallucinations score (AHS) was measured using the auditory hallucinations subscale of the Psychotic Symptom Rating Scales (PSYRATS). Add-on tDCS resulted in a significant reduction inAHS. Antipsychotic drug type had a significant effect on AHS reduction. Patients treated with high affinity antipsychotics showed significantly lesser improvement compared to patients on low affinity antipsychotics or a mixture of the two. Furthermore, a significant sex-by-group interaction occurred; type of medication had an impact on tDCS effects only in women. Improvement differences could be due to the larger availability of the dopamine receptor system in patients taking antipsychotics with low D 2 affinity. Sex-specific differences suggest potential estrogen-mediated effects. This study reports a first-time observation on the clinical utility of antipsychotic drug type in predicting tDCS effects in schizophrenia.

Disparate lines of evidence including epidemiological and case-control studies have increasingly implicated vitamin D in the pathogenesis of schizophrenia. Vitamin D deficiency can lead to dysfunction of the hippocampus--a brain region hypothesized to be critically involved in schizophrenia. In this study, we examined for potential association between serum vitamin D level and hippocampal gray matter volume in antipsychotic-naïve or antipsychotic-free schizophrenia patients (n = 35). Serum vitamin D level was estimated using 25-OH vitamin D immunoassay. Optimized voxel-based morphometry was used to analyze 3-Tesla magnetic resonance imaging (MRI) (1-mm slice thickness). Ninety-seven percent of the schizophrenia patients (n = 34) had sub-optimal levels of serum vitamin D (83%, deficiency; 14%, insufficiency). A significant positive correlation was seen between vitamin D and regional gray matter volume in the right hippocampus after controlling for age, years of education and total intracranial volume (Montreal Neurological Institute (MNI) coordinates: x = 35, y = -18, z = -8; t = 4.34 pFWE(Corrected) = 0.018). These observations support a potential role of vitamin D deficiency in mediating hippocampal volume deficits, possibly through neurotrophic, neuroimmunomodulatory and glutamatergic effects.

Background and AimTranscranial direct current stimulation (tDCS) is a non-invasive and well-tolerated brain stimulation technique with promising efficacy as an add-on treatment for schizophrenia and for several other psychiatric disorders. tDCS modulates neuroplasticity; psychiatric disorders are established to be associated with neuroplasticity abnormalities. This review presents the summary of research on potential genetic basis of neuroplasticity-modulation mechanism underlying tDCS and its implications for treating various psychiatric disorders.MethodA systematic review highlighting the genes involved in neuroplasticity and their role in psychiatric disorders was carried out. The focus was on the established genetic findings of tDCS response relationship with BDNF and COMT gene polymorphisms.ResultSynthesis of these preliminary observations suggests the potential influence of neuroplastic genes on tDCS treatment response. These include several animal models, pharmacological studies, mentally ill and healthy human subject trials.ConclusionTaking into account the rapidly unfolding understanding of tDCS and the role of synaptic plasticity disturbances in neuropsychiatric disorders, in-depth evaluation of the mechanism of action pertinent to neuroplasticity modulation with tDCS needs further systematic research. Genes such as NRG1, DISC1, as well as those linked with the glutamatergic receptor in the context of their direct role in the modulation of neuronal signalling related to neuroplasticity aberrations, are leading candidates for future research in this area. Such research studies might potentially unravel observations that might have potential translational implications in psychiatry.

Emerging evidence demonstrates widespread abnormalities involving white matter (WM) tracts connecting different cortical regions in obsessive-compulsive disorder (OCD). The corpus callosum (CC), the largest inter-hemispheric tract connecting the association cortices, has been shown to be affected in OCD. This study examines CC abnormalities in a large sample of medication-naive OCD patients in comparison to matched healthy controls (HCs). We examined the mid-sagittal area of the CC in medication-naive OCD patients ( n =49) in comparison with age-, sex-, and handedness-matched HCs ( n =38). Witelson׳s method was used to measure the sub-regions of the CC – namely, the genu, body, isthmus and splenium – with good inter-rater reliability. The area of the body of the CC and total CC area were significantly larger in OCD patients than in HCs after controlling for age, sex and intracranial area. The Yale–Brown Obsessive-Compulsive Scale (Y–BOCS) compulsion score had a significant negative correlation with the areas of the isthmus and splenium of the CC in addition to the total CC area. The region-specific differences in the body of the CC and the region-specific association of severity score with posterior regions of the CC might be indicative of the involvement of additional areas like the dorsolateral prefrontal cortex, posterior parietal areas, occipital and association cortices in OCD that extend beyond the conventional orbito-fronto-striatal circuitry that is often posited to be involved in OCD.

Immunopathogenesis of schizophrenia has emerged as one of the predominant research paradigms in recent times. Based on the altered serum levels as well as gene expression, IL-6 has been considered as a peripheral biomarker of schizophrenia. However, the precise mechanism underlying the altered expression of IL6 in schizophrenia is inadequately known. Given the profound influence of environmental factors on schizophrenia risk, it is important to understand the effect of epigenetic changes on schizophrenia risk. Further, it is not known whether epigenetic changes modulate the expression of IL6 and its subsequent effects on the risk and progression of schizophrenia. In this study, we analysed and compared the methylation status of IL6 promoter sequence from −1200bp to +27bp in antipsychotic-naive/free schizophrenia patients (N = 47) and matched healthy controls (N = 47) using bisulfite sequencing method. In addition, we also examined the methylation status in these patients at least after 3-months of treatment with antipsychotics (N = 40). At baseline, a state of hypomethylation was observed in the IL6 promoter of schizophrenia subjects in comparison to healthy controls. This state of hypomethylation was shown to be reversed by the administration of antipsychotics. In summary, our observations emphasize a significant role for IL-6 promoter methylation in schizophrenia pathogenesis as well as treatment with antipsychotic medications.

Levels of striatal dopamine (DA) may be positively correlated with levels of striatal glutamate (Glu). While reduced insulin sensitivity (%S) has been associated with reduced striatal DA levels in healthy non-obese persons, whether reduced %S is also associated with reduced striatal Glu levels has not yet been established. Using

Persistent auditory verbal hallucinations (AVH) that are refractory to antipsychotic medications are reported in about 20-30% of schizophrenia patients. Transcranial Direct Current Stimulation (tDCS), a non-invasive and safe neuromodulatory technique, has attracted significant interest as an add-on treatment for refractory AVH in schizophrenia. Studies examining the efficacy of tDCS for refractory AVH in schizophrenia have reported inconsistent findings. In this study, using a randomized, double-blind, sham-controlled design (RCT), we sought to examine the effect of add-on tDCS [anode corresponding to left dorsolateral prefrontal cortex and cathode to left temporo-parietal junction; 2-mA, twice-daily sessions for 5-days] to treat refractory AVH in schizophrenia patients (N=25); following this RCT phase, patients that had30% reduction in AVH severity were offered an open-label extension (OLE) active stimulation to evaluate the effect of cross-over to verum tDCS. In the RCT phase, repeated measures ANOVA with tDCS type [verum (N=12) vs. sham (N=13)] as between subjects factor demonstrated a significant tDCS-type X time-point interaction [F=21.5, p0.001, partial-η2=0.48] with significantly greater reduction of AVH score in verum tDCS group as compared to sham group. In the OLE phase, sham-to-verum crossed over patients (N=13) showed significantly greater reduction in AVH severity than their corresponding change during RCT phase (t=2.9; p=0.01). Together, these observations add further support to the beneficial effects of add-on tDCS to treat refractory AVH schizophrenia.

Processing speed deficit, ascertained by digit-symbol substitution test (DSST), is considered as a fundamental impairment in schizophrenia. Clinical correlates of processing speed abnormalities, especially using the parametric version of DSST is yet to be evaluated comprehensively. In this study, we examined schizophrenia patients (N = 66) and demographically matched healthy controls (N = 72) using computer-administered parametric DSST (pDSST) with fixed (pDSSTF) as well as random (pDSSTR) conditions and analysed the relationship between pDSST performance and clinical symptoms. Psychopathology was assessed using Scale for Assessment of Positive Symptoms (SAPS)/Negative Symptoms (SANS) with good inter-rater reliability. In comparison with healthy controls, patients demonstrated significantly lesser number of correct responses (CN) in pDSSTF (t = 8.0; p

The Geschwind-Behan-Galaburda (GBG) hypothesis links cerebral lateralisation with prenatal testosterone exposure. Digit ratio measures in adults have been established as potential markers of foetal sex hormonal milieu. The aim of the study was to evaluate the sex-dependent interaction of digit ratio measures and cerebral lateralization as well as their neurohemodynamic correlates using functional MRI (fMRI). Digit ratio measures-ratio of index finger (2D) length to ring finger (4D) length (2D:4D) and difference between 2D:4D of two hands, i.e., right minus left (DR-L)-were calculated using high resolution digital images in 70 right-handed participants (42 men) based on reliable and valid method. fMRI was acquired during the performance of a spatial working memory task in a subset of 25 individuals (14 men), and analysed using Statistical Parametric Mapping 8 (SPM8) and the Laterality Index toolbox for SPM8. Men had significantly less bilateral 2D:4D than women. There was a significant negative correlation between right 2D:4D and 2-Back task accuracy (2BACC) in women. A significant sex-by-right 2D:4D interaction was observed in left parahippocampal gyrus activation. Additionally, sex-by-DR-L interaction was observed in left IPL activation. DR-L showed a significant positive correlation with the whole brain Laterality Index (LI), and LI, in turn, demonstrated a significant negative correlation with 2BACC. Our study observations suggest several novel sex-differential relationships between 2D:4D measures and fMRI activation during spatial working memory task performance. Given the pre-existing background data supporting digit ratio measures as putative indicator of prenatal sex hormonal milieu, our study findings add support to the Geschwind-Behan-Galaburda (GBG) hypothesis.

Error monitoring and response inhibition is a key cognitive deficit in obsessive-compulsive disorder (OCD). Frontal midline regions such as the cingulate cortex and pre-supplementary motor area are considered critical brain substrates of this deficit. Electrophysiological equivalent of the above dysfunction is a fronto-central event related potential (ERP) which occurs after an error called the error related negativity (ERN). In this study, we sought to compare the ERN parameters between medication-naive, comorbidity-free subjects with OCD and healthy controls (HC). Age, sex and handedness matched subjects with medication-naive, comorbidity-free OCD (N = 16) and Healthy Controls (N = 17) performed a modified version of the flanker task while EEG was acquired for ERN. EEG signals were recorded from the electrodes FCz and Cz. Clinical severity of OCD was assessed using the Yale Brown Obsessive Compulsive Scale. The subjects with OCD had significantly greater ERN amplitude at Cz and FCz. There were no significant correlations between ERN measures and illness severity measures. Overactive performance monitoring as evidenced by enhanced ERN amplitude could be considered as a biomarker for OCD.

There is a lack of studies on siblings of persons with schizophrenia (SOPS) in Asia. This study aims to explore the needs of SOPS in India. 15 SOPS participated in this qualitative explorative study. All the interviews were audio recorded and later transcribed. Data analysis was carried out using General Inductive Approach. Five themes emerged from the data: managing illness or socio-occupational functioning; follow up services; informational needs; personal needs; and miscellaneous needs. SOPS in India have some distinctive needs. Identifying these needs might help in developing and designing specific psychosocial interventions for better management.

The ‘cognitive mapping' component of spatial cognition, namely – the allocentric/egocentric function and its relation to symptoms in schizophrenia is relatively unexplored. In this study, we compared schizophrenia patients ( N =44) to demographically-matched healthy controls ( N =43) using computer-administered visuospatial transformation tasks with egocentric and allocentric components and analyzed their correlation with symptoms. Significant diagnosis X task-type interaction effect was seen on task accuracy. Patients performed significantly worse than controls in the allocentric letter rotation task (LRT) but not in the egocentric people rotation task (PRT). Accuracy in the LRT was significantly lesser than in PRT among patients but not among controls. Patients were significantly slower as compared to controls in both tasks. Both groups took longer to perform PRT as compared to LRT. LRT accuracy showed significant negative correlation with total positive symptoms as well as negative symptoms scores. Angle of rotation, perspective (front-facing/back-facing), orientation (mirrored/normal), and stimulus type (letter/number) were found to significantly influence performance in both groups of subjects. The present data support the finding that there is a differential impairment of allocentric abilities in schizophrenia patients. Further systematic research in this area may facilitate better understanding of schizophrenia pathogenesis.

Impaired insight in schizophrenia patients has been linked with prefrontal deficits. In this open-label study, we examined for potential insight facilitation effects of add-on tDCS (with anodal stimulation of left DLPFC and cathodal stimulation over left temporo-parietal junction) in schizophrenia patients (N=21) with persistent auditory hallucinations despite adequate antipsychotic treatment. Following tDCS, there was a significant improvement in insight with concurrent significant reduction in auditory hallucination severity. Improvement in insight correlated significantly with improvement in severity of auditory hallucinations. These findings suggest improvement of insight with add-on tDCS in schizophrenia with persistent auditory hallucinations.

Treatment of nonresponsive auditory hallucinations in schizophrenia have been reported to improve with transcranial direct-current stimulation. This case description illustrates the use of add-on transcranial direct-current stimulation for rapid amelioration of auditory hallucinations in schizophrenia during the acute phase. Because transcranial direct-current stimulation is safe, largely well tolerated, and relatively inexpensive, this add-on treatment option is worth exploring through further rigorous studies.

Background & objectives: Hyponatremia is a common problem encountered in patients presenting with nonspecific symptoms. We undertook this study to investigate the clinical profile of patients with hyponatremia, the precipitating factors, the response to therapy and to compare, using these parameters, hyponatremia at presentation to that developing in the hospital. Methods: Seventy consecutive patients with serum sodium less than or equal to 125 mmol/l at presentation or at any time during hospital admission were identified and studied using a proforma. The severity of hyponatremia, therapy given and time taken for recovery were analysed. Results: The mean age of patients was 48.1 ± 16.1 yr. The mean serum sodium was 117.8 ± 6.4 mmol/l. Confusion, headache and malaise were the most common symptoms, two patients had seizures, and 20.0 per cent patients showed no clinical manifestations. Nausea was significantly (P