Urbanicity and rates of untreated psychotic disorders in three diverse settings in the Global South.

BACKGROUND: Extensive evidence indicates that rates of psychotic disorder are elevated in more urban compared with less urban areas, but this evidence largely originates from Northern Europe. It is unclear whether the same association holds globally. This study examined the association between urban residence and rates of psychotic disorder in catchment areas in India (Kancheepuram, Tamil Nadu), Nigeria (Ibadan, Oyo), and Northern Trinidad. METHODS: Comprehensive case detection systems were developed based on extensive pilot work to identify individuals aged 18-64 with previously untreated psychotic disorders residing in each catchment area (May 2018-April/May/July 2020). Area of residence and basic demographic details were collected for eligible cases. We compared rates of psychotic disorder in the more v. less urban administrative areas within each catchment area, based on all cases detected, and repeated these analyses while restricting to recent onset cases (<2 years/<5 years). RESULTS: We found evidence of higher overall rates of psychosis in more urban areas within the Trinidadian catchment area (IRR: 3.24, 95% CI 2.68-3.91), an inverse association in the Nigerian catchment area (IRR: 0.68, 95% CI 0.51-0.91) and no association in the Indian catchment area (IRR: 1.18, 95% CI 0.93-1.52). When restricting to recent onset cases, we found a modest positive association in the Indian catchment area. CONCLUSIONS: This study suggests that urbanicity is associated with higher rates of psychotic disorder in some but not all contexts outside of Northern Europe. Future studies should test candidate mechanisms that may underlie the associations observed, such as exposure to violence.

Cannabis use and psychotic disorders in diverse settings in the Global South: findings from INTREPID II.

BACKGROUND: Cannabis use has been linked to psychotic disorders but this association has been primarily observed in the Global North. This study investigates patterns of cannabis use and associations with psychoses in three Global South (regions within Latin America, Asia, Africa and Oceania) settings. METHODS: Case-control study within the International Programme of Research on Psychotic Disorders (INTREPID) II conducted between May 2018 and September 2020. In each setting, we recruited over 200 individuals with an untreated psychosis and individually-matched controls (Kancheepuram India; Ibadan, Nigeria; northern Trinidad). Controls, with no past or current psychotic disorder, were individually-matched to cases by 5-year age group, sex and neighbourhood. Presence of psychotic disorder assessed using the Schedules for Clinical Assessment in Neuropsychiatry and cannabis exposure measured by the World Health Organisation Alcohol, Smoking and Substance Involvement Screening Test (ASSIST). RESULTS: Cases reported higher lifetime and frequent cannabis use than controls in each setting. In Trinidad, cannabis use was associated with increased odds of psychotic disorder: lifetime cannabis use (adj. OR 1.58, 95% CI 0.99-2.53); frequent cannabis use (adj. OR 1.99, 95% CI 1.10-3.60); cannabis dependency (as measured by high ASSIST score) (adj. OR 4.70, 95% CI 1.77-12.47), early age of first use (adj. OR 1.83, 95% CI 1.03-3.27). Cannabis use in the other two settings was too rare to examine associations. CONCLUSIONS: In line with previous studies, we found associations between cannabis use and the occurrence and age of onset of psychoses in Trinidad. These findings have implications for strategies for prevention of psychosis.

Concepts of madness in diverse settings: a qualitative study from the INTREPID project.

BACKGROUND: In order to facilitate case identification of incident (untreated and recent onset) cases of psychosis and controls in three sites in India, Nigeria and Trinidad, we sought to understand how psychoses (or madness) were conceptualized locally. The evidence we gathered also contributes to a long history of research on concepts of madness in diverse settings. METHODS: We conducted focus group discussions and individual interviews to collect information about how informants in each site make sense of and respond to madness. A coding framework was developed and analyses of transcripts from the FGDs and interviews were conducted. RESULTS: Analyses suggest the following: a) disturbed behaviors are the primary sign of madness; b) madness is attributed to a wide range of causes; and, c) responses to madness are dictated by cultural and pragmatic factors. These findings are congruent with similar research that has been conducted over the past 50 years. CONCLUSIONS: The INTREPID research suggests that concepts about madness share similar features across diverse settings: a) terms for madness are often derived from a common understanding that involves disruptions in mental processes and capacities; b) madness is recognized mostly by disruptive behaviours or marked declines in functioning; c) causal attributions are varied; and, d) help-seeking is a complex process.

Effectiveness of a community-based intervention for people with schizophrenia and their caregivers in India (COPSI): a randomised controlled trial.

BACKGROUND: Observational evidence suggests that community-based services for people with schizophrenia can be successfully provided by community health workers, when supervised by specialists, in low-income and middle-income countries. We did the COmmunity care for People with Schizophrenia in India (COPSI) trial to compare the effectiveness of a collaborative community-based care intervention with standard facility-based care. METHODS: We did a multicentre, parallel-group, randomised controlled trial at three sites in India between Jan 1, 2009 and Dec 31, 2010. Patients aged 16-60 years with a primary diagnosis of schizophrenia according to the tenth edition of the International Classification of Diseases, Diagnostic Criteria for Research (ICD-10-DCR) were randomly assigned (2:1), via a computer-generated randomisation list with block sizes of three, six, or nine, to receive either collaborative community-based care plus facility-based care or facility-based care alone. Randomisation was stratified by study site. Outcome assessors were masked to group allocation. The primary outcome was a change in symptoms and disabilities over 12 months, as measured by the positive and negative syndrome scale (PANSS) and the Indian disability evaluation and assessment scale (IDEAS). Analysis was by modified intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 56877013. FINDINGS: 187 participants were randomised to the collaborative community-based care plus facility-based care group and 95 were randomised to the facility-based care alone group; 253 (90%) participants completed follow-up to month 12. At 12 months, total PANSS and IDEAS scores were lower in patients in the intervention group than in those in the control group (PANSS adjusted mean difference -3.75, 95% CI -7.92 to 0.42; p=0.08; IDEAS -0.95, -1.68 to -0.23; p=0.01). However, no difference was shown in the proportion of participants who had a reduction of more than 20% in overall symptoms (PANSS 85 [51%] in the intervention group vs 44 [51%] in the control group; p=0.89; IDEAS 75 [48%] vs 28 [35%]). We noted a significant reduction in symptom and disability outcomes at the rural Tamil Nadu site (-9.29, -15.41 to -3.17; p=0.003). Two patients (one in each group) died by suicide during the study, and two patients died because of complications of a road traffic accident and pre-existing cardiac disease. 18 (73%) patients (17 in the intervention group) were admitted to hospital during the course of the trial, of whom seven were admitted because of physical health problems, such as acute gastritis and vomiting, road accident, high fever, or cardiovascular disease. INTERPRETATION: The collaborative community-based care plus facility-based care intervention is modestly more effective than facility-based care, especially for reducing disability and symptoms of psychosis. Our results show that the study intervention is best implemented as an initial service in settings where services are scarce, for example in rural areas. FUNDING: Wellcome Trust.

Searching for psychosis: INTREPID (1): systems for detecting untreated and first-episode cases of psychosis in diverse settings.

PURPOSE: Our understanding of psychotic disorders is largely based on studies conducted in North America, Europe and Australasia. Few methodologically robust and comparable studies have been carried out in other settings. INTREPID is a programme of research on psychoses in India, Nigeria, and Trinidad. As a platform for INTREPID, we sought to establish comprehensive systems for detecting representative samples of cases of psychosis by mapping and seeking to engage all professional and folk (traditional) providers and potential key informants in defined catchment areas. METHOD: We used a combination of official sources, local knowledge of principal investigators, and snowballing techniques. RESULTS: The structure of the mental health systems in each catchment area was similar, but the content (i.e., type, extent, and nature) differed. Tunapuna-Piarco (Trinidad), for example, has the most comprehensive and accessible professional services. By contrast, Ibadan (Nigeria) has the most extensive folk (traditional) sector. We identified and engaged in our detection system-(a) all professional mental health services in each site (in- and outpatient services-Chengalpet, 6; Ibadan, 3; Trinidad, 5); (b) a wide range of folk providers (Chengalpet, 3 major healing sites; Ibadan, 19 healers; Trinidad: 12 healers); and c) a number of key informants, depending on need (Chengalpet, 361; Ibadan, 54; Trinidad, 1). CONCLUSIONS: Marked differences in mental health systems in each catchment area illustrate the necessity of developing tailored systems for the detection of representative samples of cases with untreated and first-episode psychosis as a basis for robust, comparative epidemiological studies.

Customising informed consent procedures for people with schizophrenia in India.

BACKGROUND: There is little information on how the ethical and procedural challenges involved in the informed participation of people with schizophrenia in clinical trials are addressed in low- and middle-income countries (LMICs). The informed consent procedure used in the collaborative community care for people with schizophrenia in India (COPSI) RCT was developed keeping these challenges in mind. We describe the feasibility of conducting the procedure from the trial, researcher and participants perspectives and describe the reasons for people consenting to participate in the trial or refusing to do so. METHODS: Three sources of information were used to describe the feasibility of the COPSI consent procedure: key process indicators for the trial perspective, data from a specially designed post-interview form for participant's observations and focus group discussion (FGD) with the research interviewers. Categorical data were analysed by calculating frequencies and proportions, while the qualitative data from the FGD, and the reasons for participation or refusal were analysed using a thematic content analysis approach. FINDINGS: 434 people with schizophrenia and their primary caregiver(s) were approached for participation in the trial. Consent interviews were conducted with 332, of whom 303 (91%) agreed to participate in the trial. Expectation of improvement was the most common reason for agreeing to participate in the trial, while concerns related to the potential disclosure of the illness, especially for women, were an important reason for refusing consent. CONCLUSIONS: The COPSI consent procedure demonstrates preliminary, observational information about the feasibility of customising informed consent procedures for people with schizophrenia LMIC contexts. This and other similar innovations need to be refined and rigorously tested to develop evidence-based guidelines for informed consent procedures in such settings.

DSM-IV "criterion A" schizophrenia symptoms across ethnically different populations: evidence for differing psychotic symptom content or structural organization?

There is significant variation in the expression of schizophrenia across ethnically different populations, and the optimal structural and diagnostic representation of schizophrenia are contested. We contrasted both lifetime frequencies of DSM-IV criterion A (the core symptom criterion of the internationally recognized DSM classification system) symptoms and types/content of delusions and hallucinations in transethnic schizophrenia populations from Australia (n = 776), India (n = 504) and Sarawak, Malaysia (n = 259), to elucidate clinical heterogeneity. Differences in both criterion A symptom composition and symptom content were apparent. Indian individuals with schizophrenia reported negative symptoms more frequently than other sites, whereas individuals from Sarawak reported disorganized symptoms more frequently. Delusions of control and thought broadcast, insertion, or withdrawal were less frequent in Sarawak than Australia. Curiously, a subgroup of 20 Indian individuals with schizophrenia reported no lifetime delusions or hallucinations. These findings potentially challenge the long-held view in psychiatry that schizophrenia is fundamentally similar across cultural groups, with differences in only the content of psychotic symptoms, but equivalence in structural form.

Qualitative study to explore the perspectives and mental health experiences of first episode psychosis patients and their caregivers in North India.

BACKGROUND: The onset of psychosis brings unfamiliar experiences that can be disturbing for patients and their caregivers. Few studies from India (only one from North India) have examined these experiences from the perspective of the patient and caregiver. We explored experiences of first episode psychosis (FEP) patients and their caregivers within a North Indian context. METHOD: Semi-structured interviews were conducted in 2019 with ten FEP patients and their caregivers (total n=20) receiving out-patient care in a tertiary care centre. Topic guides focused on concerns/complaints, symptoms, help-seeking, and barriers and facilitators to treatment. Interviews were audio recorded, transcribed, and analysed using qualitative content analysis. RESULTS: Main categories of responses from patients and caregivers included: initial complaints for seeking help, initial emotional response, barriers to seeking treatment, perceived dysfunction and improvement, experienced stigma, understanding about illness, early follow-up, preventive measures and awareness programs. Caregivers undergo myriad of emotional reactions including anger, anxiety, guilt, and confusion. Symptoms other than psychotic symptoms were the primary complaint upon seeking help, and there was lack of understanding about the psychosocial model of care (role of medications acknowledged with little awareness regarding psychosocial interventions in recovery). Persisting occupational dysfunction despite perceived symptomatic improvement was described by both patients and caregivers. CONCLUSION: North Indian patients with FEP lack awareness of symptoms. Therefore, onus for seeking help often falls on their caregivers. Psychoeducation from first contact with services and increasing awareness about psychotic illness within the community might help address lack of awareness about symptoms, mental health services, early signs of relapse, and importance of psychosocial interventions in achieving functional recovery.

Pilot study to test the feasibility and clinical efficacy of a psychosocial care programme for patients with psychosis in low-resource settings.

BACKGROUND: Home-based psychosocial care has the potential to improving outcomes in patients with schizophrenia and related disorders (SCZ). There is lack of India data for such care in early psychosis. We developed the "Saksham" programme, a bespoke self-managed home-based psychosocial care model, available in two formats: manual-based and mobile-application based. With the anticipated success of recruitment of early psychosis cases in our setting, we plan to test the such intervention in this population in future trials. AIM: To assess the feasibility of the Saksham programme intervention in people with SCZ and its clinical efficacy as an adjunct to treatment as usual. METHODS: Seventy-five patient-caregiver pairs (total n=150) were recruited. Patients received either: treatment-as-usual (TAU) (n=25), manual-based Saksham intervention+TAU (n=25), or app-based Saksham intervention+TAU (n=25). Feasibility (i.e. acceptability, practicality, demand, implementation and integration) was assessed at three-months. Participants were assessed for psychopathology, illness-severity, cognition, functioning, disability, and caregiver-coping at baseline, one-month, and three-month. The percentage changes over time were compared across three groups. RESULTS: More found the mobile application-based intervention acceptable and easy-to-use than the manual-based intervention (92 % vs 68 %, and 76 % vs 68 %, respectively). Psychopathology and caregiver-burden improved significantly in all three groups (p<0.05). Cognition, disability, functioning, and caregiver burden improved significantly in the two Saksham intervention groups, with greater improvement in the Saksham app group (p<0.05). CONCLUSION: Home-based intervention is feasible and acceptable in a low-resource setting, with preliminary evidence for effectiveness. These findings need corroboration with randomised controlled trials in early psychosis to ameliorate course of illness.

Protocol-based assessment and management of first episode psychosis: Comparison of short and medium-term outcomes in psychopathology, quality of life, functioning and family burden across two sites in India.

BACKGROUND: Standard assessment and management protocols exist for first episode psychosis (FEP) in high income countries. Due to cultural and resource differences, these need to be modified for application in low-and middle-income countries. AIMS: To assess the applicability of standard assessment and management protocols across two cohorts of FEP patients in North and South India by examining trajectories of psychopathology, functioning, quality of life and family burden in both. METHOD: FEP patients at two sites (108 at AIIMS, North India, and 115 at SCARF, South India) were assessed using structured instruments at baseline, 3, 6 and 12 months. Standard management protocols consisted of treatment with antipsychotics and psychoeducation for patients and their families. Generalised estimating equation (GEE) modelling was carried out to test for changes in outcomes both across and between sites at follow-up. RESULTS: There was an overall significant improvement in both cohorts for psychopathology and other outcome measures. The trajectories of improvement differed between the two sites with steeper improvement in non-affective psychosis in the first three months at SCARF, and affective symptoms in the first three months at AIIMS. The reduction in family burden and improvement in quality of life were greater at AIIMS than at SCARF during the first three months. CONCLUSIONS: Despite variations in cultural contexts and norms, it is possible to implement FEP standard assessment and management protocols in North and South India. Preliminary findings indicate that FEP services lead to significant improvements in psychopathology, functioning, quality of life, and family burden within these contexts.

Genetic interactions of schizophrenia using gene-based statistical epistasis exclusively identify nervous system-related pathways and key hub genes.

Background: The relationship between genotype and phenotype is governed by numerous genetic interactions (GIs), and the mapping of GI networks is of interest for two main reasons: 1) By modelling biological robustness, GIs provide a powerful opportunity to infer compensatory biological mechanisms via the identification of functional relationships between genes, which is of interest for biological discovery and translational research. Biological systems have evolved to compensate for genetic (i.e., variations and mutations) and environmental (i.e., drug efficacy) perturbations by exploiting compensatory relationships between genes, pathways and biological processes; 2) GI facilitates the identification of the direction (alleviating or aggravating interactions) and magnitude of epistatic interactions that influence the phenotypic outcome. The generation of GIs for human diseases is impossible using experimental biology approaches such as systematic deletion analysis. Moreover, the generation of disease-specific GIs has never been undertaken in humans. Methods: We used our Indian schizophrenia case-control (case-816, controls-900) genetic dataset to implement the workflow. Standard GWAS sample quality control procedure was followed. We used the imputed genetic data to increase the SNP coverage to analyse epistatic interactions across the genome comprehensively. Using the odds ratio (OR), we identified the GIs that increase or decrease the risk of a disease phenotype. The SNP-based epistatic results were transformed into gene-based epistatic results. Results: We have developed a novel approach by conducting gene-based statistical epistatic analysis using an Indian schizophrenia case-control genetic dataset and transforming these results to infer GIs that increase the risk of schizophrenia. There were ∼9.5 million GIs with a p-value ≤ 1 × 10-5. Approximately 4.8 million GIs showed an increased risk (OR > 1.0), while ∼4.75 million GIs had a decreased risk (OR <1.0) for schizophrenia. Conclusion: Unlike model organisms, this approach is specifically viable in humans due to the availability of abundant disease-specific genome-wide genotype datasets. The study exclusively identified brain/nervous system-related processes, affirming the findings. This computational approach fills a critical gap by generating practically non-existent heritable disease-specific human GIs from human genetic data. These novel datasets can train innovative deep-learning models, potentially surpassing the limitations of conventional GWAS.

Refining clinical phenotypes by contrasting ethnically different populations with schizophrenia from Australia, India and Sarawak.

We contrasted demographic and clinical characteristics in transethnic schizophrenia populations from Australia (n=821), India (n=520) and Sarawak, Malaysia (n=298) and proposed cultural explanations for identified site differences. From these we aimed to identify candidate variables free from significant cultural confounding that are hence suitable for inclusion in genetic analyses. We observed five phenomena: (1) more individuals were living alone in Australia than India or Sarawak; (2) drug use was lower in India than Australia or Sarawak; (3) duration of untreated psychosis (DUP) was longer in India than Australia or Sarawak; (4) the rate of schizoaffective disorder was lower in India than Australia or Sarawak; and (5) age at psychosis onset (AAO) was older in Sarawak than Australia or India. We suggest that site differences for living arrangements, drug use and DUP are culturally confounded. The schizoaffective site difference likely results from measurement bias. The AAO site difference, however, has no obvious cultural or measurement bias explanation. Therefore, this may be an ideal candidate for use in genetic studies, given that genetic variants affecting AAO have already been proposed.

Understanding needs of stakeholders and outcomes desired from a home-based intervention program for "difficult to treat" schizophrenia and related disorders: A qualitative study.

Background: We aimed to understand the needs of service users - families and patients with schizophrenia and related disorders, and mental health professionals (MHPs) and expectations from a home-based psychosocial intervention program in Indian setting. Materials and Methods: We conducted four focus group discussions (FGDs) with families, patients with schizophrenia and related disorders and MHPs. Two FGDs were conducted with families and one each with the patients and MHPs. Participants in families and MHP group were asked about their primary concerns in caring for the patients, perceived needs of patients and the areas that can be targeted through a home-based psychosocial intervention program. All FGDs were audio-recorded and verbatim transcribed. Content analysis of the data was done to obtain a final list of needs and expected outcomes from a psychosocial intervention supported by families. Results: Six key priority needs were identified for intervention: medication adherence, activities of daily living, promoting physical health, engagement in meaningful work, building of social and support networks and information about all aspects of illness. Priority outcomes identified by MHPs were mostly clinical like symptom reduction, fewer rehospitalisation while families and patients focused more on psychosocial outcomes, such as improvement of wellbeing, having relationships, engagement in meaningful activities, better organization of the day, increased self-respect, reduced stress, lesser interference, and critical comments. All groups suggested that book or mobile app or video could be used. Conclusion: This qualitative study shows that while both clinicians and service users consider recovery from schizophrenia and related disorders to be important, they differ on what they prioritise.

Life events and psychosis: case-control study from India, Nigeria, and Trinidad and Tobago.

BACKGROUND: There is evidence of an association between life events and psychosis in Europe, North America and Australasia, but few studies have examined this association in the rest of the world. AIMS: To test the association between exposure to life events and psychosis in catchment areas in India, Nigeria, and Trinidad and Tobago. METHOD: We conducted a population-based, matched case-control study of 194 participants in India, Nigeria, and Trinidad and Tobago. Cases were recruited through comprehensive population-based, case-finding strategies. The Harvard Trauma Questionnaire was used to measure life events. The Screening Schedule for Psychosis was used to screen for psychotic symptoms. The association between psychosis and having experienced life events (experienced or witnessed) was estimated by conditional logistic regression. RESULTS: There was no overall evidence of an association between psychosis and having experienced or witnessed life events (adjusted odds ratio 1.19, 95% CI 0.62-2.28). We found evidence of effect modification by site (P = 0.002), with stronger evidence of an association in India (adjusted odds ratio 1.56, 95% CI 1.03-2.34), inconclusive evidence in Nigeria (adjusted odds ratio 1.17, 95% CI 0.95-1.45) and evidence of an inverse association in Trinidad and Tobago (adjusted odds ratio 0.66, 95% CI 0.44-0.97). CONCLUSIONS: This study found no overall evidence of an association between witnessing or experiencing life events and psychotic disorder across three culturally and economically diverse countries. There was preliminary evidence that the association varies between settings.

Evolution of Community Telepsychiatry in India Showcasing the SCARF Model.

This review chronicles the origin of telepsychiatry services started by the Schizophrenia Research Foundation (SCARF) in the community and traces the birth of the Scarf Telepsychiatry in Pudukkottai (STEP) program at Pudukkottai in Tamil Nadu. This paper also examines the trajectory of STEP and highlights other relevant models existing in the country in the last decade.

INTREPID II: protocol for a multistudy programme of research on untreated psychosis in India, Nigeria and Trinidad.

INTRODUCTION: There are few robust and directly comparable studies of the epidemiology of psychotic disorders in the Global South. INTREPID II is designed to investigate variations in untreated psychotic disorders in the Global South in (1) incidence and presentation (2) 2-year course and outcome, (3) help-seeking and impact, and (4) physical health. METHODS: INTREPID II is a programme of research incorporating incidence, case-control and cohort studies of psychoses in contiguous urban and rural areas in India, Nigeria and Trinidad. In each country, the target samples are 240 untreated cases with a psychotic disorder, 240 age-matched, sex-matched and neighbourhood-matched controls, and 240 relatives or caregivers. Participants will be followed, in the first instance, for 2 years. In each setting, we have developed and are employing comprehensive case-finding methods to ensure cohorts are representative of the target populations. Using methods developed during pilot work, extensive data are being collected at baseline and 2-year follow-up across several domains: clinical, social, help-seeking and impact, and biological. ETHICS AND DISSEMINATION: Informed consent is sought, and participants are free to withdraw from the study at any time. Participants are referred to mental health services if not already in contact with these and emergency treatment arranged where necessary. All data collected are confidential, except when a participant presents a serious risk to either themselves or others. This programme has been approved by ethical review boards at all participating centres. Findings will be disseminated through international conferences, publications in international journals, and through local events for key stakeholders.

Design and clinical characteristics of a homogeneous schizophrenia pedigree sample from Tamil Nadu, India.

OBJECTIVE: The genetic complexity of schizophrenia may be compounded by the diagnostic imprecision inherent in distinguishing schizophrenia from closely related mood and substance use disorders. Further complexity may arise from studying genetically and/or environmentally diverse ethnic groups. Reported here are the ascertainment, demographic features and clinical characteristics, of a diagnostically and ethnically homogeneous schizophrenia pedigree sample from Tamil Nadu, India. Also reported is the theoretical power to detect genetic linkage in the subset of affected sibling pairs. METHOD: Affected sibling pair and trio pedigrees were identified by caste/ethnicity. Affected probands and siblings fulfilled DSM-IV criteria for schizophrenia or schizoaffective disorder. RESULTS: The present sample consisted of 159 affected sibling pairs and 187 parent-offspring trios originating primarily from the Tamil Brahmin caste, but also incorporating pedigrees from genetically similar, geographically proximal caste groups. Consistent with previous studies in Tamil Nadu, a very low prevalence of affective psychoses such as schizoaffective disorder, was observed, with most affected individuals having schizophrenia (499/504). Also observed were extremely low rates of nicotine (12.4%), alcohol (1.1%) and illicit drug use (0%). Most affected individuals exhibited negative symptoms (>90%) and a severe, chronic course. All participants lived in the same geographic and climatic region and most affected individuals resided with close family members, increasing uniformity of the sociocultural environment. In affected sibling pairs, power to detect linkage to small-effect risk loci was modest, but this homogeneous sample may be enriched for loci of larger effect. CONCLUSIONS: This Indian schizophrenia sample exhibits diagnostic and ethnic homogeneity with high consistency of sociocultural environmental features. These characteristics should assist efforts to identify risk genes for schizophrenia.

Association of Schizophrenia Risk With Disordered Niacin Metabolism in an Indian Genome-wide Association Study.

Importance: Genome-wide association studies (GWASs) in European populations have identified more than 100 schizophrenia-associated loci. A schizophrenia GWAS in a unique Indian population offers novel findings. Objective: To discover and functionally evaluate genetic loci for schizophrenia in a GWAS of a unique Indian population. Design, Setting, and Participants: This GWAS included a sample of affected individuals, family members, and unrelated cases and controls. Three thousand ninety-two individuals were recruited and diagnostically ascertained via medical records, hospitals, clinics, and clinical networks in Chennai and surrounding regions. Affected participants fulfilled DSM-IV diagnostic criteria for schizophrenia. Unrelated control participants had no personal or family history of psychotic disorder. Recruitment, genotyping, and analysis occurred in consecutive phases beginning January 1, 2001. Recruitment was completed on February 28, 2018, and genotyping and analysis are ongoing. Main Outcomes and Measures: Associations of single-nucleotide polymorphisms and gene expression with schizophrenia. Results: The study population included 1321 participants with schizophrenia, 885 family controls, and 886 unrelated controls. Among participants with schizophrenia, mean (SD) age was 39.1 (11.4) years, and 52.7% were male. This sample demonstrated uniform ethnicity, a degree of inbreeding, and negligible rates of substance abuse. A novel genome-wide significant association was observed between schizophrenia and a chromosome 8q24.3 locus (rs10866912, allele A; odds ratio [OR], 1.27 [95% CI, 1.17-1.38]; P = 4.35 × 10-8) that attracted support in the schizophrenia Psychiatric Genomics Consortium 2 data (rs10866912, allele A; OR, 1.04 [95% CI, 1.02-1.06]; P = 7.56 × 10-4). This locus has undergone natural selection, with the risk allele A declining in frequency from India (approximately 72%) to Europe (approximately 43%). rs10866912 directly modifies the abundance of the nicotinate phosphoribosyltransferase gene (NAPRT1) transcript in brain cortex (normalized effect size, 0.79; 95% CI, 0.6-1.0; P = 5.8 × 10-13). NAPRT1 encodes a key enzyme for niacin metabolism. In Indian lymphoblastoid cell lines, (risk) allele A of rs10866912 was associated with NAPRT1 downregulation (AA: 0.74, n = 21; CC: 1.56, n = 17; P = .004). Preliminary zebrafish data further suggest that partial loss of function of NAPRT1 leads to abnormal brain development. Conclusions and Relevance: Bioinformatic analyses and cellular and zebrafish gene expression studies implicate NAPRT1 as a novel susceptibility gene. Given this gene's role in niacin metabolism and the evidence for niacin deficiency provoking schizophrenialike symptoms in neuropsychiatric diseases such as pellagra and Hartnup disease, these results suggest that the rs10866912 genotype and niacin status may have implications for schizophrenia susceptibility and treatment.