JAMA Netw Open. 2026 Mar 2;9(3):e260222. doi: 10.1001/jamanetworkopen.2026.0222.
ABSTRACT
IMPORTANCE: Adverse childhood experiences (ACEs) are key risk factors for major depressive disorder (MDD), but their associations with treatment-resistant depression (TRD) remain unclear, particularly after accounting for unmeasured confounding, such as shared genetic and familial environmental factors.
OBJECTIVE: To examine the association between ACEs and TRD while accounting for unmeasured confounding within families.
DESIGN, SETTING, AND PARTICIPANTS: This cohort study used a co-twin control design and was based on 2 Swedish Twin Registry cohorts: the Study of Twin Adults: Genes and Environment (STAGE) and the Young Adult Twins in Sweden Study (YATSS). The sample included twins born from 1959 to 1992 who completed surveys in 2005 to 2006 (for the STAGE cohort) or in 2013 to 2014 (for the YATSS cohort). Both cohorts were linked to Sweden’s National Patient Register and Prescribed Drug Register for follow-up until the end of 2016. Data analysis was conducted from September to November 2024.
EXPOSURE: ACEs, which were assessed using 7 yes or no items adapted from the Life Stressor Checklist-Revised: emotional neglect or abuse, physical neglect, physical abuse, sexual abuse, rape, hate crime, and witnessing family violence before age 19 years.
MAIN OUTCOMES AND MEASURES: TRD, which was defined as MDD diagnosed clinically or meeting the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria based on self-reported symptoms and having had at least 2 antidepressant switches of adequate duration (≥6 weeks) with no more than 14 weeks between consecutive prescriptions.
RESULTS: The full cohort included 21 192 twins, among whom 17 814 (10 205 females [57.3%]; mean [SD] age, 32.10 [7.82] years) were included in the main analysis. A total of 5558 individuals (31.2%) reported exposure to at least 1 ACE, and 996 (5.6%) reported 3 or more ACEs. The prevalence of TRD was 1.3% (n = 230) overall. Each additional ACE exposure was associated with increased odds of TRD (odds ratio [OR], 1.69; 95% CI, 1.56-1.84). In co-twin control analyses, the association remained within monozygotic and dizygotic twins (OR, 2.23; 95% CI, 1.30-3.83). Among ACE types, physical neglect (OR, 5.73; 95% CI, 3.75-8.75) and sexual abuse (OR, 5.01; 95% CI, 3.47-7.23) showed the greatest magnitude of associations with TRD.
CONCLUSIONS AND RELEVANCE: In this cohort study, ACE exposure was associated with an increased risk of TRD even after accounting for unmeasured familial confounding. The findings highlight the importance of preventing ACEs and incorporating ACE history into clinical assessment to identify individuals with MDD who may be at elevated risk for treatment resistance.
PMID:41817529 | DOI:10.1001/jamanetworkopen.2026.0222
