Previous studies have suggested that alterations in white matter (WM) microstructure are implicated in suicidal thoughts and behaviours (STBs). However, findings of diffusion tensor imaging (DTI) studies have been inconsistent. In this large-scale mega-analysis conducted by the ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium, we examined WM alterations associated with STBs.

Data processing was standardised across sites, and resulting WM microstructure measures (fractional anisotropy, axial diffusivity, mean diffusivity and radial diffusivity) for 25 WM tracts were pooled across 40 cohorts. We compared these measures among individuals with a psychiatric diagnosis and lifetime history of suicide attempt (n=652; mean age=35.4±14.7; female=71.8%), individuals with a psychiatric diagnosis but no STB (i.e., clinical controls; n=1871; mean age=34±14.8; female=59.8%), and individuals with no mental disorder diagnosis and no STB (i.e., healthy controls; n=642; mean age=29.6±13.1; female=62.9%). We also compared these measures among individuals with recent suicidal ideation (n=714; mean age=36.3±15.3; female=66.1%), clinical controls (n=1184; mean age=36.8±15.6; female=63.1%), and healthy controls (n=1240; mean age= 31.6±15.5; female=61.0%).

We found subtle but statistically significant effects, such as lower fractional anisotropy associated with a history of suicide attempt, over and above the effect of psychiatric diagnoses. These effects were strongest in the corona radiata, thalamic radiation, fornix/stria terminalis, corpus callosum and superior longitudinal fasciculus. Effect sizes were small (Cohen’s d < 0.25). Recent suicidal ideation was not associated with alterations in WM microstructure.

This large-scale coordinated mega-analysis revealed subtle regional and global alterations in WM microstructure in individuals with a history of suicide attempt. Longitudinal studies are needed to confirm whether these alterations are a risk factor for suicidal behaviour.

ALvH receives consultancy fees from the Augeo foundation. CAZ is a full-time US government employee. He is listed as a co-inventor on a patent for the use of ketamine and its metabolites in major depression and suicidal ideation. Dr. Zarate has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. HPB has consulted to the Milken Institute. MW is a member of the following advisory boards and gave presentations to the following companies: Bayer AG, Germany; Boehringer Ingelheim, Germany; and Biologische Heilmittel Heel GmbH, Germany. MW has further conducted studies with institutional research support from HEEL and Janssen Pharmaceutical Research for a clinical trial (IIT) on ketamine in patients with MDD, unrelated to this investigation. MW did not receive any financial compensation from the companies mentioned above. IA received speakers honorarium from Lundbeck. IBH is the Co-Director, Health and Policy at the Brain and Mind Centre (BMC) University of Sydney. The BMC operates an early-intervention youth services at Camperdown under contract to headspace. He is the Chief Scientific Advisor to, and a 3.2% equity shareholder in, InnoWell Pty Ltd which aims to transform mental health services through the use of innovative technologies. AC reports being currently an employee of the Regeneron Genetics Center, and may own Regeneron stock or stock options. JCS acknowledge to be related with the next companies ALKERMES (Advisory Board), BOEHRINGER Ingelheim (Consultant), COMPASS Pathways (Research Grant), JOHNSON & JOHNSON (Consultant), LIVANOVA (Consultant), RELMADA (Research Grant), SUNOVION (Research Grant),Mind Med (Research Grant). PMP received payment or honoraria for lectures and presentations in educational events for Sandoz, Daiichi Sankyo, Eurofarma, Abbot, Libbs, Instituto Israelita de Pesquisa e Ensino Albert Einstein, Instituto D Or de Pesquisa e Ensino. All other authors report no biomedical financial interests, disclosures or potential conflicts of interest.

This work was supported by the MQ Brighter Futures Award MQBFC/2 (LS, LC, MD, LvV, ALvH, HB) and the National Institute of Mental Health of the National Institutes of Health under Award Number R01MH117601 (LS, LvV, NJ). ALvH was funded by a MQ Brighter Futures Award MQBFC/2, a Royal Society Dorothy Hodgkin Fellowship (DH15017), an MRC MRF emerging leaders award, the Leiden University Social Resilience and Security fund, and an NWO VIDI award. HPB was supported by the MQ Brighter Futures Award MQBFC/2, the National Center for Advancing Translational Science (Grant Number: UL1TR000142), the National Institute of Mental Health (Grant Numbers: RC1MH088366, R01MH69747), Brain and Behavior Research Foundation, International Bipolar Disorders Foundation, American Foundation for Suicide Prevention SRG-1-10-119, and the John and Hope Furth Endowment. EDB is supported by the National Institute of Mental Health Intramural Research Program (ZIA MH002857). NB is supported by the Italian Ministry of Health, grant Ricerca Corrente RC 23. The University of Minnesota adolescent MDD study is supported by the National Institute of Mental Health (K23MH090421), the National Alliance for Research on Schizophrenia and Depression, the University of Minnesota Graduate School, the Minnesota Medical Foundation, and the Biotechnology Research Center (P41 RR008079 to the Center for Magnetic Resonance Research), University of Minnesota, and the Deborah E. Powell Center for Womens Health Seed Grant, University of Minnesota. FB is supported by the Italian Ministry of Health, grant PNRR-MAD-2022-12375859. BiDirect was funded by grants from the German Federal Ministry of Education and Research (BMBF; Grants FKZ-01ER0816 and FKZ-01ER1506) to KB. BB and LC are supported by the Interdisciplinary Center of Clinical Research of the Medical Faculty Jena. M.C.-R. acknowledges funding support from the Consejeria de Salud y Familias (Junta de Andalucia) 2020 grant, which covers his salary (RH-0081-2020). Funding for the DEPARRESTCLIN cohort was provided by a national grant (ANR SAMENTA 2012) of the Agence Nationale de la Recherche (ANR). BCD is funded by a NHMRC CJ Martin fellowship (1161356). BCF acknowledges this work was supported by the Instituto de Salud Carlos III (PI14/00639 and PI14/00918) and Fundacion Instituto de Investigacion Marques de Valdecilla (NCT0235832 and NCT02534363). UD acknowledges this work was funded by the German Research Foundation (DFG), Udo Dannlowski (co-speaker FOR2107, DA 1151/5-1, DA 1151/5-2, grant DA1151/9-1, DA1151/10-1 and DA1151/11-1) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Muenster (grant Dan3/022/22 to UD). MuensterNeuroimagingCohort: This work was funded by the German Research Foundation (SFB-TRR58, Project C09 to UD). JWE is supported by the National Institute of Mental Health Intramural Research Program (ZIA MH002857). NPF acknowledges the LTS Colorado data acquisition was supported by grants from the National Institutes of Health (NIH) in the United States (AG046938 and MH063207). NPF was supported by NIH grants AG046938,, MH117131, MH124846, DA042742, DA046413, DA046064, and DA051018. IHG is supported by the National Institute of Mental Health Grant R37MH101495. TH acknowledges this study was supported by funding from the Canadian Institutes of Health Research (103703, 106469 and 142255, 180449, 186254), Nova Scotia Health Research Foundation, Dalhousie Clinical Research Scholarship to T. Hajek, Brain & Behavior Research Foundation (formerly NARSAD); 2007 Young Investigator and 2015 Independent Investigator Awards to T. Hajek. This work was also supported by the AMED Brain/MINDS Beyond Program (JP18dm0307002) and JSPS KAKENHI (JP19K03309 and JP22H01090). TCH is supported in part by the National Institutes of Health (K01MH117442, R21MH130817, R01MH127176). YI was supported by JSPS KAKENHI (JP23K07004). FI was supported by an NHMRC EL1 Investigator Grant (GNT2018157) and the Bill and Patricia Richie Foundation Fellowship. YI was supported by JSPS KAKENHI (JP23K02956). FJ acknowledges this study was supported by an operating grant from the Canadian Institutes for Health Research (CIHR #119288). TK acknowledges this work was funded by the German Research Foundation (DFG grants FOR2107 KI588/14-1, and KI588/14-2, and KI588/20-1, KI588/22-1 to Tilo Kircher, Marburg, Germany). Biosamples and corresponding data were sampled, processed and stored in the Marburg Biobank CBBMR. This work was funded by the German Research Foundation (DFG grants KR 3822/5-1, KR 3822/7-2 to Axel Krug). ETCL is funded in part by the American Foundation for Suicide Prevention SRG-0-112-20. CLJ is supported by PRISMA U.T. AMM is supported by the Wellcome Trust Grants (220857/Z/20/Z, 226770/Z/22/Z, 104036/Z/14/Z, 216767/Z/19/Z), and the European Union Horizon 2020 Grant (Grant Agreement 847776). KAM acknowledges this study was funded by the National Institute of Mental Health (R01-MH103291). PBM acknowledges this study was funded by the Australian National Medical and Health Research Council (Program Grant 1037196 (PBM and MB); Investigator Grant 1177991 (PBM)), the Lansdowne Foundation, Good Talk, and the Keith Pettigrew Family Bequest (PBM). IN work is funded by the Deutsche Forschungsgemeinschaft (DFG) grants NE2254/1-2, NE2254/2-1, NE2254/3-1, NE2254/4-1. PMP acknowledges BHRCS was supported with grants from the National Institute of Development Psychiatric for Children and Adolescent (INPD) and the Grant Fapesp 2014/50917-0 - 2021/05332-8 CNPq 465550/2014-2. FP acknowledges support for the team in Nimes, CINES grants access to HPC facilities (A0100311413). FaP is supported by the Italian Ministry of Health, grant RF-2019-12370182. FeP is supported by the Italian Ministry of Health, grant Ricerca Corrente RC 23. SP is supported by the Italian Ministry of Health, grant PNRR-MAD-2022-12375716, RF-2018-12367249. GR acknowledges this study was funded by the Australian National Medical and Health Research Council (Program Grant 1037196 (PBM and MB); Investigator Grant 1177991 (PBM)), the Lansdowne Foundation, Good Talk, and the Keith Pettigrew Family Bequest (PBM). RRG was supported by EMERGIA Junta de Andalucia program (EMERGIA20_00139), the VII Plan Propio of the University of Seville, the Plan de Consolidacion (CNS2023-143647) and the Proyectos de Generacion de Conocimiento (PID2021-122853OA-I00) from the Spanish Ministry of Science and Innovation. MDS is supported by the National Institute of Mental Health (Project Number R01MH125850); Brain and Behavior Research Foundation (Grant Number 28972). HRS was supported by a grant from the National Institutes of Health in the United States (DA051018). JCS acknowledges this work was partially supported by NIMH (1R01MH085667-01A1), John S. Dunn Foundation (Houston, Texas), and Pat Rutherford Chair in Psychiatry (UTHealth Houston). GS is supported by the Italian Ministry of Health, grant Ricerca Corrente RC 23. JDS is supported by the grants MRC (MR/S010351/1, MR/W002388/1, MR/W002566/1) and EPSRC (EP/Y017544/1). The DCHS cohort is funded by the Bill & Melinda Gates Foundation [INV-006732]. DJS is funded by the South African Medical Research Council. BS acknowledges this work was funded by the German Research Foundation (DFG grant as part of FOR2107: STR1146/18-1 to Benjamin Straube, Marburg, Germany). MW is supported by German Center for Mental Health (DZPG); FKZ: 01EE2103; and NeuroMarKet: Neuroimaging and Blood Markers as Indicators of Ketamine Efficacy in Treatment Resistant Depression; BMBF-EU-EraNet-Neuron, FKZ: 01EW2010A. HCW acknowledges this work is supported by the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6], Scottish Funding Council [HR03006], Wellcome Trust [216767/Z/19/Z] & Wellcome Trust (Wellcome Trust Strategic Award STratifying Resilience and Depression Longitudinally (STRADL) Reference 104036/Z/14/Z). CAZ is supported by the National Institute of Mental Health Intramural Research Program (ZIA MH002857). TTY is supported by the National Center for Complementary and Integrative Health (NCCIH) R21AT009173, R61AT009864, and R33AT009864 to TTY; by the National Center for Advancing Translational Sciences (CTSI), National Institutes of Health, through UCSF-CTSI UL1TR001872 to TTY; by the American Foundation for Suicide Prevention (AFSP) SRG-1-141-18 to TTY; by UCSF Weill Institute for Neurosciences to TTY; by UCSF Research Evaluation and Allocation Committee (REAC) and J. Jacobson Fund to TTY; by the National Institute of Mental Health (NIMH) R01MH085734 and the Brain and Behavior Research Foundation (formerly NARSAD) to TTY. PMT is supported by NIH grants R01AG058854, R01MH116147 and R01MH129742. NJ is supported by R01MH134004. MER receives Fellowship support from the Rebecca L Cooper Medical Research Foundation (F20231230).

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 University of Melbourne human research ethics committee, where the database is hosted, gave ethical approval for this work.

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).

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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

All data produced in the present study could be made available upon reasonable request to the authors, but access to raw data is limited, as approval from each participating cohort is required for this.