A cross ancestry genetic study of psychiatric disorders from India.

Genome-wide association studies across diverse populations may help validate and confirm genetic contributions to risk of disease. We estimated the extent of population stratification as well as the predictive accuracy of polygenic scores (PGS) derived from European samples to a data set from India. We analysed 2685 samples from two data sets, a population neurodevelopmental study (cVEDA) and a hospital-based sample of bipolar affective disorder (BD) and obsessive-compulsive disorder (OCD). Genotyping was conducted using Illumina's Global Screening Array. Population structure was examined with principal component analysis (PCA), uniform manifold approximation and projection (UMAP), support vector machine (SVM) ancestry predictions, and admixture analysis. PGS were calculated from the largest available European discovery GWAS summary statistics for BD, OCD, and externalizing traits using two Bayesian methods that incorporate local linkage disequilibrium structures (PGS-CS-auto) and functional genomic annotations (SBayesRC). Our analyses reveal global and continental PCA overlap with other South Asian populations. Admixture analysis revealed a north-south genetic axis within India (FST 1.6%). The UMAP partially reconstructed the contours of the Indian subcontinent. The Bayesian PGS analyses indicates moderate-to-high predictive power for BD. This was despite the cross-ancestry bias of the discovery GWAS dataset, with the currently available data. However, accuracy for OCD and externalizing traits was much lower. The predictive accuracy was perhaps influenced by the sample size of the discovery GWAS and phenotypic heterogeneity across the syndromes and traits studied. Our study results highlight the accuracy and generalizability of newer PGS models across ancestries. Further research, across diverse populations, would help understand causal mechanisms that contribute to psychiatric syndromes and traits.

Long-term impact of the COVID-19 pandemic on obsessive-compulsive disorder.

There is limited data on the long-term effect of the COVID-19 pandemic on obsessive-compulsive disorder (OCD). We report on the course of a cohort of individuals with OCD followed-up over a period of one year during the first wave of the COVID-19 pandemic in India. A cohort of 240 individuals registered at a specialty OCD clinic was regularly followed-up using standardized rating tools at three months, six months, and one year into the onset of the COVID-19 pandemic in India. These were compared with clinical ratings recorded in a comparable historical cohort of 207 individuals with OCD, followed up during a non-pandemic year. The pandemic and non-pandemic (historical control) cohorts did not differ in illness severity and rate of relapse. It was found that COVID-19-related anxiety declined over time. Among those patients who were treatment responders prior to the pandemic, COVID-19-related anxiety and non-adherence to medication predicted a relapse of symptoms. Contrary to our expectations, the rate of relapse and illness trajectory in the pandemic cohort did not differ from the non-pandemic cohort, suggesting that the pandemic did not impact our largely medication-adherent cohort. Adherence to treatment seemed to have a protective effect during the pandemic.

Prevalence and Correlates of Psychiatric Comorbidity and Multimorbidity in Parkinson's Disease and Atypical Parkinsonian Syndromes.

PURPOSE: Psychiatric comorbidity in Parkinson's disease (PD) and atypical parkinsonian syndromes (APS) has been consistently associated with poor outcomes. However, the co-occurrence of multiple psychiatric disorders has been sparsely studied. This study examines the prevalence, patterns, and correlates of psychiatric comorbidity and multimorbidity among in-patients hospitalised with PD/APS. METHODS: Patients (N-110 [PD-71, APS-39]) underwent a single cross-sectional assessment. Psychiatric comorbidity was examined using the Mini International Neuropsychiatric Interview. Other domains assessed include sleep disorders, quality of life, and caregiver burden. STATISTICAL ANALYSIS: In addition to descriptive statistics, multinomial logistic regression was used to examine the effect of sociodemographic and clinical factors on comorbidities. RESULTS: The prevalence of psychiatric comorbidity in patients with PD and APS was 77.00% and 71.79%, with approximately half of those having co-occurrence of multiple psychiatric disorders. In both disorders, depression was the most common, followed by anxiety disorder. The two commonest patterns of multimorbidity reported in PD were the combination of depression and anxiety disorder, followed by the combination of psychosis, depression, and anxiety, with the order being reversed in APS. When compared to those without, those with single psychiatric comorbidity had higher odds of having REM sleep behaviour disorder and caregiver stress. Those with multiple psychiatric comorbidities had higher odds of being female, higher UPDRS part-1 scores, REM sleep behaviour disorder, poor sleep quality, and caregiver stress. CONCLUSION: Psychiatric illness is highly comorbid among patients with PD/APS, with most having multiple co-occurring psychiatric illnesses. Clinicians must be aware to ensure early detection and intervention.

Familial risk of psychosis in obsessive-compulsive disorder: Impact on clinical characteristics, comorbidity and treatment response.

BACKGROUND: Family studies in obsessive-compulsive disorder (OCD) indicate higher rates of psychosis among their first-degree relatives (FDRs). However, the etiological and clinical relationships between the two disorders remain unclear. We compared the clinical characteristics and pharmacological treatment response in patients diagnosed with OCD with a family history of psychosis (OCD-FHP), with a family history of OCD (OCD-FHO) and those with sporadic OCD (OCD-S). METHODS: A total of 226 patients who met DSM-IV criteria for OCD (OCD-FHP = 59, OCD-FHO = 112, OCD-S = 55) were included for analysis. All patients were evaluated using the Mini International Neuropsychiatric Interview (MINI 6.0.0), Yale-Brown Obsessive-Compulsive Scale (YBOCS), and the Family Interview for Genetic Studies (FIGS). Treatment response was characterized over naturalistic follow-up. RESULTS: The three groups did not differ across any demographic or clinical variables other than treatment response. Patients in the OCD-FHP group were found to have received a greater number of trials with serotonin reuptake inhibitors (SRI) [F (2,223) = 7.99, p < 0.001], were more likely to have failed ≥2 trials of SRIs (χ2 = 8.45, p = 0.014), and less likely to have attained remission (χ2 = 6.57, p = 0.037) CONCLUSIONS: We observed that having a relative with psychosis may predispose to treatment resistance in OCD. Further research on the influence of genetic liability to psychosis on treatment response in OCD may offer novel translational leads.

Association of SAPAP3 allelic variants with symptom dimensions and pharmacological treatment response in obsessive-compulsive disorder.

Though several SAPAP3 gene knockout studies in mice have implicated its role in compulsivity, human studies have failed to demonstrate its association with obsessive-compulsive disorder (OCD). We examined the association between allelic variants of a single nucleotide polymorphism in the SAPAP3 gene (rs6662980) with specific aspects of the OCD phenotype. A total of 200 individuals with OCD were genotyped using the TaqMan assay. All participants were assessed using the Mini International Neuropsychiatric Interview and the Yale-Brown Obsessive-Compulsive Scale, and their response to serotonin reuptake inhibitors (SRIs) was evaluated over naturalistic treatment and follow-up. After correcting for multiple comparisons, the G allele at rs6662980 was found to be associated with contamination and washing symptoms (p = .003). Logistic regression analysis also showed that presence of the G allele predicted poor response to SRIs (odds ratio [OR] = 2.473, 95% confidence interval [1.157, 5.407], p = .021). Interaction between presence of the G allele and the Contamination and Washing factor score predicted greater SRI resistance (OR = 3.654, [2.761, 4.547], p = .004). We conclude that specific phenotypic manifestations of OCD, which include contamination and washing-related symptoms along with resistance to SRIs, may be affected by variations in the SAPAP3 gene. Limitations of the study are the lack of a dimensional measure for assessing OCD symptoms, the evaluation of treatment response over naturalistic follow-up, and that only a single locus in the SAPAP3 gene was examined. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Cross-diagnostic evaluation of minor physical anomalies in psychiatric disorders.

BACKGROUND: Minor physical anomalies (MPA) are markers of impaired neurodevelopment during the prenatal stage. Assessing MPA across psychiatric disorders may help understand their shared nature. In addition, MPA in family members would indicate a shared liability and endophenotype potential. We examined familial aggregation of MPA and their role as transdiagnostic and disorder-specific markers of 5 major psychiatric/neuropsychiatric conditions (schizophrenia, bipolar disorder, substance dependence, obsessive-compulsive disorder, and Alzheimer's dementia). METHODS: Modified Waldrop's MPA scale was applied on 1321 individuals from 439 transdiagnostic multiplex families and 125 healthy population controls (HC). Stage of fetal development (morphogenetic/phenogenetic)- and anatomical location (craniofacial/peripheral)-based sub-scores were calculated. Familiality and endophenotypic potential of MPA were analyzed with serial negative binomial mixed-effect regression. Cross-diagnostic differences and the effect of family history density (FHD) of each diagnosis on MPA were assessed. Mixed-effects Cox models estimated the influence of MPA on age-at-onset of illness (AAO). RESULTS: MPA were found to be heritable in families with psychiatric disorders, with a familiality of 0.52. MPA were higher in psychotic disorders after controlling for effects of sex and intrafamilial correlation. Morphogenetic variant MPA was noted to be lower in dementia in comparison to HC. FHD of schizophrenia and bipolar disorder predicted higher, and that of dementia and substance dependence predicted lower MPA. MPA brought forward the AAO [HR:1.07 (1.03-1.11)], and this was more apparent in psychotic disorders. CONCLUSION: MPA are transmissible in families, are specifically related to the risk of developing psychoses, and predict an earlier age at onset. Neurodevelopmentally informed classification of MPA has the potential to enhance the etiopathogenic and translational understanding of psychiatric disorders.

Identification of biomarkers that predict response to subthalamic nucleus deep brain stimulation in resistant obsessive-compulsive disorder: protocol for an open-label follow-up study.

INTRODUCTION: Deep brain stimulation (DBS) of bilateral anteromedial subthalamic nucleus (amSTN) has been found to be helpful in a subset of patients with severe, chronic and treatment-refractory obsessive-compulsive disorder (OCD). Biomarkers may aid in patient selection and optimisation of this invasive treatment. In this trial, we intend to evaluate neurocognitive function related to STN and related biosignatures as potential biomarkers for STN DBS in OCD. METHODS AND ANALYSIS: Twenty-four subjects with treatment-refractory OCD will undergo open-label STN DBS. Structural/functional imaging, electrophysiological recording and neurocognitive assessment would be performed at baseline. The subjects would undergo a structured clinical assessment for 12 months postsurgery. A group of 24 healthy volunteers and 24 subjects with treatment-refractory OCD who receive treatment as usual would be recruited for comparison of biomarkers and treatment response, respectively. Baseline biomarkers would be evaluated as predictors of clinical response. Neuroadaptive changes would be studied through a reassessment of neurocognitive functioning, imaging and electrophysiological activity post DBS. ETHICS AND DISSEMINATION: The protocol has been approved by the National Institute of Mental Health and Neurosciences Ethics Committee. The study findings will be disseminated through peer-reviewed scientific journals and scientific meetings.

Are There Familial Patterns of Symptom Dimensions in Obsessive-Compulsive Disorder?

Background: Obsessive-compulsive disorder (OCD) is a heterogeneous illness, and emerging evidence suggests that different symptom dimensions may have distinct underlying neurobiological mechanisms. We aimed to look for familial patterns in the occurrence of these symptom dimensions in a sample of families with at least two individuals affected with OCD. Methods: Data from 153 families (total number of individuals diagnosed with DSM-5 OCD = 330) recruited as part of the Accelerator Program for Discovery in Brain Disorders using Stem Cells (ADBS) was used for the current analysis. Multidimensional Item Response Theory (IRT) was used to extract dimensional scores from the Yale-Brown Obsessive-Compulsive Scale (YBOCS) checklist data. Using linear mixed-effects regression models, intra-class correlation coefficients (ICC), for each symptom dimension, and within each relationship type were estimated. Results: IRT yielded a four-factor solution with Factor 1 (Sexual/Religious/Aggressive), Factor 2 (Doubts/Checking), Factor 3 (Symmetry/Arranging), and Factor 4 (Contamination/Washing). All except for Factor 1 were found to have significant ICCs, highest for Factor 3 (0.41) followed by Factor 4 (0.29) and then Factor 2 (0.27). Sex-concordant dyads were found to have higher ICC values than discordant ones, for all the symptom dimensions. No major differences in the ICC values between parent-offspring and sib-pairs were seen. Conclusions: Our findings indicate that there is a high concordance of OCD symptom dimensions within multiplex families. Symptom dimensions of OCD might thus have significant heritability. In view of this, future genetic and neurobiological studies in OCD should include symptom dimensions as a key parameter in their analyses.

Dissimilar social cognition signatures in remitted schizophrenia and bipolar disorder.

In the light of shared genetic underpinnings of schizophrenia and bipolar disorder, their comparative profile of social cognition (SC) performance - an intermittent phenotype and determinant of functional outcome - is poorly understood. Using data from 160 individuals, we identify unique patterns of composite and domain-specific SC-abilities between these groups after controlling for their neurocognition. Individuals with schizophrenia and not bipolar disorder demonstrated deficits in composite SC-measures, which were not associated with their functional status. While patients with bipolar disorder had significantly lower scores on emotion recognition, they outperformed the healthy and schizophrenia groups on the second-order theory of mind.

Psychiatric symptoms and syndromes transcending diagnostic boundaries in Indian multiplex families: The cohort of ADBS study.

Syndromes of schizophrenia, bipolar disorder, obsessive-compulsive disorder, substance use disorders and Alzheimer's dementia are highly heritable. About 10-20% of subjects have another affected first degree relative (FDR), and thus represent a 'greater' genetic susceptibility. We screened 3583 families to identify 481 families with multiple affected members, assessed 1406 individuals in person, and collected information systematically about other relatives. Within the selected families, a third of all FDRs were affected with serious mental illness. Although similar diagnoses aggregated within families, 62% of the families also had members with other syndromes. Moreover, 15% of affected individuals met criteria for co-occurrence of two or more syndromes, across their lifetime. Using dimensional assessments, we detected a range of symptom clusters in both affected and unaffected individuals, and across diagnostic categories. Our findings suggest that in multiplex families, there is considerable heterogeneity of clinical syndromes, as well as sub-threshold symptoms. These families would help provide an opportunity for further research using both genetic analyses and biomarkers.

A randomized controlled trial of mindfulness-based cognitive therapy vs stress management training for obsessive-compulsive disorder.

BACKGROUND: Recently, mindfulness-based therapies have emerged as a treatment modality for OCD, but there is sparse controlled data. We report the efficacy of mindfulness-based cognitive therapy (MBCT) in treating OCD in comparison with stress management training (SMT). METHODS: 60 outpatients with DSM-IV-TR OCD attending a specialty OCD clinic were randomly assigned in 1:1 ratio to either MBCT (n=30) or SMT (n= 30). Both the groups received 12 weekly sessions of assigned intervention. An independent blind rater assessed the primary outcome measure at baseline and at the end of 12 weeks. RESULTS: Significantly greater proportion of patients responded to MBCT than to SMT (80% vs. 27%, P <0.001). In the linear mixed-effects modelling for intent-to-treat analysis, there was a significant reduction in the illness severity measured using the Yale-Brown Obsessive-Compulsive Scale, obsessive beliefs of 'responsibility/threat estimation' and 'perfectionism/intolerance of uncertainty' measured using the Obsessive Beliefs Questionnaire and anxiety. LIMITATIONS: Small sample size with a relatively high attrition in the control group. Lack of a cognitive behaviour therapy (CBT) control group. CONCLUSIONS: Mindfulness-based cognitive therapy is efficacious in the treatment of OCD. Future studies should compare MBCT with CBT in larger representative samples and also examine the sustainability of change in longitudinal studies.

Case Report: Obsessive compulsive disorder in posterior cerebellar infarction - illustrating clinical and functional connectivity modulation using MRI-informed transcranial magnetic stimulation.

Objectives: We describe atypical and resistant neuropsychiatric clinical manifestations in a young male with posterior cerebellar gliosis. We also attempt to test the mediating role of the cerebellum in the clinical presentation by manipulating the frontal-cerebellar network using MRI-informed transcranial magnetic stimulation (TMS). Methods: A case report of a young adult male describing obsessive-compulsive symptoms, probably secondary to an infarct in the cerebellar right crus II, combined with an examination of behavioral and functional connectivity changes following TMS treatment. Results: Obsessions, compulsions, and pathological slowing were observed in the background of a posterior cerebellar infarct, along with impairments in vigilance, working memory, verbal fluency, visuospatial ability, and executive functions, in the absence of any motor coordination difficulties. These symptoms did not respond to escitalopram. MRI-informed intermittent theta-burst stimulation delivered to the pre-supplementary motor area identified based on its connectivity with the cerebellar lesion in the crus II resulted in partial improvement of symptoms with enhanced within and between-network modularity of the cerebellar network connectivity. Conclusion: We illustrate a case of OCD possibly secondary to a posterior cerebellar infarct, supporting the role of the cerebellum in the pathophysiology of OCD. Functional connectivity informed non-invasive neuromodulation demonstrated partial treatment response. A seriation technique showed extended connectivity of the cerebellar lesion regions following the neuromodulatory treatment.

Cutting-edge genetics in obsessive-compulsive disorder.

This article reviews recent advances in the genetics of obsessive-compulsive disorder (OCD). We cover work on the following: genome-wide association studies, whole-exome sequencing studies, copy number variation studies, gene expression, polygenic risk scores, gene-environment interaction, experimental animal systems, human cell models, imaging genetics, pharmacogenetics, and studies of endophenotypes. Findings from this work underscore the notion that the genetic architecture of OCD is highly complex and shared with other neuropsychiatric disorders. Also, the latest evidence points to the participation of gene networks involved in synaptic transmission, neurodevelopment, and the immune and inflammatory systems in this disorder. We conclude by highlighting that further study of the genetic architecture of OCD, a great part of which remains to be elucidated, could benefit the development of diagnostic and therapeutic approaches based on the biological basis of the disorder. Studies to date revealed that OCD is not a simple homogeneous entity, but rather that the underlying biological pathways are variable and heterogenous. We can expect that translation from bench to bedside, through continuous effort and collaborative work, will ultimately transform our understanding of what causes OCD and thus how best to treat it.

Prescribing practices of Indian psychiatrists in the treatment of bipolar disorder.

OBJECTIVE: The treatment of bipolar disorder is challenging because of its clinical complexity and availability of multiple treatment options, none of which are ideal mood stabilizers. This survey studies prescription practices of psychiatrists in India and their adherence to guidelines. METHOD: In total, 500 psychiatrists randomly selected from the Indian Psychiatric Society membership directory were administered a face-to-face 22-item questionnaire pertaining to the management of bipolar disorder. RESULTS: For acute mania, most practitioners preferred a combination of a mood stabilizer and an atypical antipsychotic to monotherapy. For acute depression, there was a preference for a combination of an antidepressant and a mood stabilizer over other alternatives. Electroconvulsive therapy was preferred in the treatment of severe episodes and to hasten the process of recovery. Approximately, 50% of psychiatrists prescribe maintenance treatment after the first bipolar episode, but maintenance therapy was rarely offered lifelong. While the majority (85%) of psychiatrists acknowledged referring to various clinical guidelines, their ultimate choice of treatment was also significantly determined by personal experience and reference to textbooks. LIMITATIONS: The study did not study actual prescriptions. Hence, the responses to queries in the survey are indirect measures from which we have tried to understand the actual practices, and of course, these are susceptible to self-report and social-desirability biases. This was a cross-sectional study; therefore, temporal changes in responses could not be considered. CONCLUSION: Overall, Indian psychiatrists seemed to broadly adhere to recommendations of clinical practice guidelines, but with some notable exceptions. The preference for antidepressants in treating depression is contrary to general restraint recommended by most guidelines. Therefore, the efficacy of antidepressants in treating bipolar depression in the context of Indian psychiatrists' practice needs to be studied systematically. Not initiating maintenance treatment early in the course of illness may have serious implications on the long-term outcome of bipolar disorder.

Course and naturalistic treatment seeking among persons with first episode mania in India: A retrospective chart review with up to five years follow-up.

BACKGROUND: An understanding of the early course of Bipolar Disorder (BD) can contribute towards developing timely interventions. First episode mania (FEM) determines a diagnosis of bipolarity, and therefore, onset of BD-I. We investigated the course of BD-I over a five-year period after FEM by retrospective chart review. METHODS: Charts of patients diagnosed with FEM in 2008 (n = 108) were reviewed. Data was extracted about FEM and subsequent course up to 5 years, for those who came for follow-up during this period. The factors influencing course were evaluated with statistical analyses including logistic regression and survival analysis. RESULTS: The mean age at onset of BD was 26 ±â€¯9.2 years and mean age at FEM was 27.1 ±â€¯9 years. 41 (38%) patients had previous depression. Patients who returned for at least one follow-up were 60/108 (55.6%), with 54 (90%) of them experiencing another mood episode following FEM. Most recurrences occurred between 6 months to 1 year after FEM, with manic episodes occurring two-three times as frequently as depressive episodes. Good adherence to treatment was a predictor of fewer hospitalizations [B = -0.61; t = -3.1; p = 0.004]. LIMITATIONS: The study was limited by its retrospective design and high number of dropouts. CONCLUSION: The five-year course after FEM showed twice the number of manic compared to depressive recurrences, irrespective of when the recurrence occurred. Consistent with earlier reports from India, BD-I appears to be mania-predominant, even early in the course. This has significant implications in planning maintenance treatments.