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Background: The COVID-19 pandemic disrupted the delivery of diabetes care and worsened mental health among many patients with type 2 diabetes (T2D). This disruption puts patients with T2D at risk for poor diabetes outcomes, especially those who experience social disadvantage due to socioeconomic class, rurality, or ethnicity. The appropriate use of communication technology could reduce these gaps in diabetes care created by the pandemic and also provide support for psychological distress., Objective: The purpose of this study is to test the feasibility of an innovative co-designed Technology-Enabled Collaborative Care (TECC) model for diabetes management and mental health support among adults with T2D., Methods: We will recruit 30 adults with T2D residing in Ontario, Canada, to participate in our sequential explanatory mixed methods study. They will participate in 8 weekly web-based health coaching sessions with a registered nurse, who is a certified diabetes educator, who will be supported by a digital care team (ie, a peer mentor, an addictions specialist, a dietitian, a psychiatrist, and a psychotherapist). Assessments will be completed at baseline, 4 weeks, and 8 weeks, with a 12-week follow-up. Our primary outcome is the feasibility and acceptability of the intervention, as evident by the participant recruitment and retention rates. Key secondary outcomes include assessment completion and delivery of the intervention. Exploratory outcomes consist of changes in mental health, substance use, and physical health behaviors. Stakeholder experience and satisfaction will be explored through a qualitative descriptive study using one-on-one interviews., Results: This paper describes the protocol of the study. The recruitment commenced in June 2021. This study was registered on October 29, 2020, on ClinicalTrials.gov (Registry ID: NCT04607915). As of June 2022, all participants have been recruited. It is anticipated that data analysis will be complete by the end of 2022, with study findings available by the end of 2023., Conclusions: The development of an innovative, technology-enabled model will provide necessary support for individuals living with T2D and mental health challenges. This TECC program will determine the feasibility of TECC for patients with T2D and mental health issues., Trial Registration: ClinicalTrials.gov NCT04607915; https://clinicaltrials.gov/ct2/show/NCT04607915., International Registered Report Identifier (irrid): DERR1-10.2196/39724., (©Lenka Vojtila, Diana Sherifali, Rosa Dragonetti, Iqra Ashfaq, Scott Veldhuizen, Farooq Naeem, Sri Mahavir Agarwal, Osnat C Melamed, Allison Crawford, Philip Gerretsen, Margaret Hahn, Sean Hill, Sean Kidd, Benoit Mulsant, Eva Serhal, Leah Tackaberry-Giddens, Carly Whitmore, Jennifer Marttila, Frank Tang, Seeta Ramdass, Gloria Lourido, Sanjeev Sockalingam, Peter Selby. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 17.01.2023.)

Purpose/background: 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., Methods/procedures: 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., Findings/results: 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 of >7%. Additional adaptive changes were observed for fasting glucose, glycated hemoglobin, triglyceride, and high-density lipoprotein cholesterol levels., Implications/conclusions: 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., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Hypothalamic detection of elevated circulating glucose triggers suppression of endogenous glucose production (EGP) to maintain glucose homeostasis. Antipsychotics alleviate symptoms associated with schizophrenia but also increase the risk for impaired glucose metabolism. In the current study, we examined whether two acutely administered antipsychotics from different drug classes, haloperidol (first generation antipsychotic) and olanzapine (second generation antipsychotic), affect the ability of intracerebroventricular (ICV) glucose infusion approximating postprandial levels to suppress EGP. The experimental protocol consisted of a pancreatic euglycemic clamp, followed by kinomic and RNA-seq analyses of hypothalamic samples to determine changes in serine/threonine kinase activity and gene expression, respectively. Both antipsychotics inhibited ICV glucose-mediated increases in glucose infusion rate during the clamp, a measure of whole-body glucose metabolism. Similarly, olanzapine and haloperidol blocked central glucose-induced suppression of EGP. ICV glucose stimulated the vascular endothelial growth factor (VEGF) pathway, phosphatidylinositol 3-kinase (PI3K) pathway, and kinases capable of activating K ATP channels in the hypothalamus. These effects were inhibited by both antipsychotics. In conclusion, olanzapine and haloperidol impair central glucose sensing. Although results of hypothalamic analyses in our study do not prove causality, they are novel and provide the basis for a multitude of future studies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: While several pharmacological and behavioral treatments are available for alcohol use disorder (AUD), they may not be effective for all patients. The aim of this systematic review and meta-analysis was to evaluate the efficacy and safety of rTMS and tDCS for craving in AUD., Methods: EMBASE, Cochrane Library, PsycINFO, and PubMed databases were searched for original, peer-reviewed research articles in the English language published between January 2000 and January 2022. Randomized controlled trials (RCTs) reporting changes in alcohol craving among patients with AUD were selected. Random-effects meta-analysis was employed to pool data., Results: Changes in alcohol craving were extracted from 15 RCTs. Six studies assessed the efficacy of rTMS while nine studies examined tDCS. Results demonstrated that in comparison to sham stimulation, active rTMS to the DLPFC yields small but significant reductions in alcohol craving (standardized mean difference [SMD] = -0.27, p  = .03). However, DLPFC stimulation via tDCS was not superior to sham stimulation in producing changes in alcohol craving (SMD = -0.08, p  = .59)., Conclusions: Our meta-analysis suggests that rTMS may be superior to tDCS in reducing alcohol craving in patients with AUD. However, additional research is needed to identify optimal stimulation parameters for both non-invasive neuromodulatory techniques in AUD., Competing Interests: There are no conflicts of interest to report, (© 2022 The Author(s). Published by Elsevier B.V.)

Prescription rates of second-generation antipsychotics (SGAs) are rapidly increasing for non-indicated (i.e., off-label) usage. SGAs used for approved indications are associated with significant metabolic adverse effects, including weight gain. The objective of this systematic review and meta-analysis is to evaluate the metabolic adverse effects of SGA use for off-label management of psychiatric illnesses in the adult population. We performed a systematic database search to identify randomized controlled trials (RCTs) that reported on weight and other metabolic outcomes with off-label use of SGAs among adults. Thirty-eight RCTs met inclusion criteria for this review; 35 of these studies, with a total of 4930 patients, were included in the quantitative meta-analysis. Patients treated with olanzapine, risperidone, and quetiapine were more likely to report weight gain as a side effect and experience clinically significant (≥7%) weight gain compared to those treated with a placebo. Among studies that reported weight as a continuous outcome, olanzapine was associated with significantly greater weight gain across all disorders (mean difference (MD) = 3.24 kg, 95% CI: 2.57-3.90 p = 0.001, N = 12 studies). Similar trends were noted with quetiapine and risperidone. A meta-regression analysis revealed a positive dose-response association between olanzapine dose and weight gain (regression coefficient: 0.36, p = 0.001). This review demonstrates that off-label use of SGAs, and particularly olanzapine, is associated with significant weight gain among adult patients. Our findings are concerning given the widespread off-label use of SGAs. Further studies are required to better understand the effects of off-label SGA use on other metabolic parameters. The study was registered with the PROSPERO international database of prospectively registered systematic reviews (PROSPERO #143186)., (© 2021. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Schizophrenia (SCZ) is a psychiatric disorder characterized by a wide range of positive, negative and cognitive symptoms, along with an increased risk of metabolic syndrome and cardiovascular disease that contribute to a 15-20-year reduced life expectancy. Autonomic dysfunction, in the form of increased sympathetic activity and decreased parasympathetic activity, is postulated to be implicated in SCZ and its treatment. The aim of this narrative review is to view SCZ through an autonomic lens and synthesize the evidence relating autonomic dysfunction to different domains of SCZ. Using various methods of assessing autonomic activity, autonomic dysfunction was found to be associated with multiple aspects of SCZ pathophysiology, including symptom severity, cognitive impairment, and the development of cardiometabolic comorbidities, such as metabolic syndrome and high BMI. The strongest association of low heart rate variability was noted among patients on antipsychotic treatment with high-affinity muscarinic antagonism (i.e., clozapine, olanzapine and quetiapine). The review will also suggest ways in which studying autonomic dysfunction can help reduce morbidity and mortality associated with SCZ and its treatment.

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).

Objective: 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., Method: 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., Results: The antisaccade error percentage was significantly greater in OCD patients than HC (p < 0.001). In addition, OCD patients had less accurate final eye position compared to HC (p < 0.001). There were no significant correlation between antisaccade parameters and OCD severity measures., Conclusion: 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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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&#95;T bc RC and DA&#95;T bc RC. 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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: 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., Method: 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., Result: A statistically significant difference between groups [t = 5.22, P < 0.001] 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, P < 0.001, η2 = 0.09]., Conclusion: 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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest There are no potential conflicts of interest to report for any of the authors, (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: 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 (HC)., Methods: OCD patients (medication naïve)[N = 16], their unaffected siblings(FDR)[N = 16] and HC [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., Results: Both in O minus N contrast and O minus E contrast, the groups demonstrated significant differential activation of right insula (BA 13). 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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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<0.01; η p 2 =0.14) and self-stigma scores (F=14.47; p<0.001; η p 2 =0.21), wherein the brief psychoeducation group showed a significant increase in knowledge and reduction in self-stigma with medium effect size through baseline to the third month follow-up as compared to the treatment as usual group. We also observed a significant main effect of time; irrespective of the group allocation, there was a significant increase in the knowledge through baseline to third month follow-up (F=5.69; p=0.02; η p 2 =0.09). No main or interaction effects of group and time were observed on burden. The findings suggest that brief need based psychoeducation may increase knowledge about the illness and reduce self-stigma. Further systematic studies are warranted to test this intervention for long-term effects., (Copyright © 2017 Elsevier B.V. All rights reserved.)