A transdiagnostic evaluation of adult temperamental profiles and their interactions with childhood adversities across major psychiatric disorders

Background Temperamental profiles and adverse childhood experiences (ACEs) have been reported in most major psychiatric disorders. However, the nature of this relationship is complex and under-studied.

A total of 1162 individuals (N=532 affected; N=457 unaffected first-degree relatives (FDRs) and N=173 healthy controls) were included. Affected individuals and their FDRs were from 393 multiplex families of schizophrenia, bipolar disorder, obsessive-compulsive disorder, or alcohol use disorder. They were assessed using the self-reported Adult Temperament Questionnaire (ATQ), and the ACEs International Questionnaire. We performed frequentist and Bayesian mixed-effects regression models, to look for associations between the ATQ domains, ACEs score and their interaction with each diagnosis/familial risk. External validity of our final model was tested to predict diagnosis in an independent cohort. Receiver operator characteristic plots and the area under the curve (AUC) were used to evaluate its prediction accuracy.

All temperamental domains: negative affectivity (NA), extraversion (EV), effortful control (EC) and orienting sensitivity (OS) had significant associations in a unique configuration within each of the four diagnoses and their familial risk. ACEs, and its interactions were significantly associated with alcohol use disorder only. In the external validation dataset, the final model was found to successfully predict AUD (AUC=0.82), BD (AUC=0.75) and OCD (AUC=0.74), but not SCZ (AUC=0.53).

These findings provide unique insights into the complexities of temperament in major psychiatric disorders, and emphasize the importance of evaluating temperament in conjunction with childhood adversity to characterize risk. Competing Interest Statement The authors have declared no competing interest. Funding Statement This research is funded by the Accelerator program for Discovery in Brain disorders using Stem cells (ADBS) (jointly funded by the Department of Biotechnology, Government of India, and the Pratiksha trust; Grant BT/PR17316/MED/31/326/2015) and), and the Centre for Brain and Mind (CBM) grant of the Rohini Nilekani Philanthropies. BV is funded by the Intermediate (Clinical and Public Health) Fellowship (IA/CPHI/20/1/505266) of the DBT/Wellcome Trust India Alliance. The validation dataset was derived from the Consortium for Vulnerability to Externalizing Disorders and Addictions (c-VEDA), which is jointly funded by the Indian Council for Medical Research (ICMR/MRC/3/M/2015-NCD-I) and the Newton Grant from the Medical Research Council (MR/N000390/1), United Kingdom Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The project was reviewed and approved by the Institutional Ethics Review Board of the National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka, India I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes ↵## ADBS-CBM Consortium: Biju Viswanath, Venkatasubramanian Ganesan, John P John, Meera Purushottam, Reeteka Sud, Bharath Holla, Jayant Mahadevan, Srinivas Balachander, Sreeraj VS, Vijay Kumar K G, Suhas Ganesh, Suhas Satish, Preethi V Reddy, Vijaykumar S Harbishettar, Lekhansh Shukla, Pradip Paul, Bhagyalakshmi M.S, Palanimuthu T Sivakumar, Arun Kandasamy, Muralidharan Kesavan, Urvakhsh Meherwan Mehta, Ashitha S.N.M, Bhupesh Mehta, Thennarasu Kandavel, B Binu Kumar, Jitender Saini, A Shyamsundar, Gautam Arunachal Udipi, Himani Kashyap, Anish V Cherian, K S Meena, Latha K, Jagadisha Thirthalli, Prabha S Chandra, Pratima Murthy, Upinder S Bhalla, Mathew Varghese, Sanjeev Jain, Vivek Benegal, Padinjat Raghu, Janardhan Y C Reddy Department of Psychiatry, NIMHANS, Bangalore; Department of Biostatistics, NIMHANS, Bangalore; Department of Neuroimaging and Interventional Radiology, NIMHANS, Bangalore; Department of Biophysics, NIMHANS, Bangalore; National Centre for Biological Sciences (NCBS), Bangalore; Institute of Stem Cell and Regenerative Medicine (InStem), Bangalore ↵# cVEDA Consortium: Eesha Sharma, Nilakshi Vaidya, Sunita Simon Kurpad, Rebecca Kuriyan-Raj, Debasish Basu, Subodh Bhagyalakshmi Nanjayya, Kalyanaraman Kumaran, Ghattu Krishnaveni, Amit Chakrabarti, Rajkumar Lenin Singh, Roshan Lourembam Singh, Kartik Kalayaram, Rose Dawn Bharath, Dimitri Papadopoulos Orfanos, Mathew Hickman, Mireille Toledano, Yuning Zhang, Gunter Schumann Department of Child and Adolescent Psychiatry, NIMHANS, Bangalore; Centre for Population Neuroscience and Precision Medicine (PONS), Institute of Psychiatry, Psychology & Neuroscience, SGDP Centre, King’s College London, London, UK; Department of Psychiatry, St John’s Medical College and Research Institute; Department of Psychiatry, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh; Epidemiology Research Unit, CSI Holdsworth Memorial Hospital, Mysore; Foundation for Research and Advocacy in Mental Health, Mysore; ICMR-Centre for Ageing and Mental Health (I-CAM), Division of Non-Communicable Diseases (NCD), Indian Council of Medical Research (ICMR), Kolkata; Regional Institute of Medical Sciences, Imphal; Rishi Valley School, Madanapalle; Department of Neuroimaging and Interventional Radiology, NIMHANS, Bangalore; NeuroSpin, CEA, Université Paris-Saclay, Gif-sur-Yvette, France; Centre for Population Neuroscience and Precision Medicine, MRC Social, Genetic, Developmental Psychiatry Centre, Institute of Psychology, Psychiatry & Neuroscience, King’s College London, London, UK; MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK; Centre for Population Neuroscience and Precision Medicine, Charité Mental Health, Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin, Berlin, Germany The ADBS-CBM consortium is updated to: Biju Viswanath, Venkatasubramanian Ganesan, John P John, Meera Purushottam, Reeteka Sud, Bharath Holla, Jayant Mahadevan, Srinivas Balachander, Sreeraj VS, Vijay Kumar K G, Suhas Ganesh, Suhas Satish, Preethi V Reddy, Vijaykumar S Harbishettar, Lekhansh Shukla, Pradip Paul, Bhagyalakshmi M.S, Palanimuthu T Sivakumar, Arun Kandasamy, Muralidharan Kesavan, Urvakhsh Meherwan Mehta, Ashitha S.N.M, Bhupesh Mehta, Thennarasu Kandavel, B Binu Kumar, Jitender Saini, A Shyamsundar, Gautam Arunachal Udipi, Himani Kashyap, Anish V Cherian, K S Meena, Latha K, Jagadisha Thirthalli, Prabha S Chandra, Pratima Murthy, Upinder S Bhalla, Mathew Varghese, Sanjeev Jain, Vivek Benegal, Padinjat Raghu, Janardhan Y C Reddy Data availability statement The study datasets will be made available upon request to the Principal Investigators of the ongoing ADBS (adbsnimhans.org) and c-VEDA (cveda-project.org) studies. The R codes used for statistical analysis can be provided upon request to the corresponding author (SB).