Early-Life Adversity Strongly Associated With Antidepressant Resistance in Major Depression
Key Clinical Summary
- Adverse childhood experiences (ACEs) were significantly associated with higher odds of treatment-resistant depression (TRD), with each additional ACE increasing risk (OR 1.69; 95% CI, 1.56–1.84) in a Swedish cohort study.
- Associations persisted after controlling for shared genetic and familial environmental factors using a co-twin design (OR 2.23; 95% CI, 1.30–3.83).
- Physical neglect and sexual abuse showed the strongest associations with TRD (OR 5.73 and 5.01, respectively).
A cohort study published in JAMA Network Open found that adverse childhood experiences (ACEs) are strongly associated with treatment-resistant depression (TRD), even after accounting for familial and genetic confounding. Using Swedish Twin Registry data, investigators applied a co-twin control design to clarify whether early-life adversity independently contributes to antidepressant treatment resistance in major depressive disorder (MDD).
Study Findings
The study analyzed 17,814 twins (57.3% female; mean age, 32.1 years) drawn from 2 Swedish cohorts: the Study of Twin Adults: Genes and Environment (STAGE) and the Young Adult Twins in Sweden Study (YATSS). Participants were followed through national health registers until 2016.
Overall, 31.2% of individuals reported at least 1 ACE, and 5.6% reported 3 or more. The prevalence of TRD was 1.3% (n=230), defined as MDD with at least 2 antidepressant switches of adequate duration (≥6 weeks).
The risk of TRD increased with each additional ACE (OR 1.69; 95% CI, 1.56–1.84). Co-twin analyses accounting for shared familial and genetic factors confirmed the association (OR 2.23; 95% CI, 1.30–3.83), supporting a potentially causal relationship.
Among specific ACEs, physical neglect (OR 5.73; 95% CI, 3.75–8.75) and sexual abuse (OR 5.01; 95% CI, 3.47–7.23) demonstrated the strongest associations with TRD. Other exposures assessed included emotional abuse, physical abuse, rape, hate crime, and witnessing family violence before age 19.
Clinical Implications
These findings suggest that ACEs may play a clinically meaningful role in identifying patients at higher risk of treatment resistance in MDD. The persistence of associations after controlling for familial confounding strengthens the argument that early-life adversity contributes independently to poorer treatment outcomes.
For clinicians, incorporating ACE screening into psychiatric assessment may improve risk stratification and inform treatment planning. Patients with a history of multiple ACEs may benefit from closer monitoring, earlier consideration of alternative or adjunctive therapies, and trauma-informed care approaches.
Expert Commentary
First author Ying Xiong, PhD, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden, and coauthors noted that the findings may be limited by the small sample of discordant twin pairs for ACEs and TRD, self-reported ACE assessment, and potential residual bias.
The researchers emphasized that additional studies “with larger samples and more detailed measures of ACE severity, frequency, and duration are essential” to better define the association between ACEs and TRD.