Amygdala reactivity, antidepressant discontinuation and relapse: a longitudinal, observational study with a randomized component

Importance: Antidepressant discontinuation substantially increases the risk of a depression relapse. The neurobiological mechanisms through which this happens are not known. Amygdala reactivity to negative information is a marker of negative affective processes in depression that is reduced by antidepressant medication. However, it is unknown whether amygdala reactivity is sensitive to antidepressant discontinuation, and whether any change is related to the risk of relapse after antidepressant discontinuation. Objective: To investigate whether amygdala reactivity to negative facial emotions changes with antidepressant discontinuation and relates to subsequent relapse. Design: The AIDA study was a longitudinal, observational AIDA study, where patients were randomized to task-based fMRI measurement of amygdala reactivity either twice before, or after discontinuing antidepressants. Relapse was monitored over a six month follow-up period. Study recruitment took place until January 2018. Data were collected between July 1, 2015, to January 31, 2019 and statistical analyses were conducted between June 2021 and December 2023. Setting: University setting in Zurich, Switzerland, and Berlin, Germany.Participants:Patients with remitted major depressive disorder (rMDD) on antidepressants. Of 123 recruited patients, 80 (mean (SD) age 35.5 (11.4) years; 60 women (75%) were included in analyses. Of 66 recruited healthy controls matched for age, sex, and education, 53 were included in analyses (mean (SD) age 34.9 (10.7) years); 37 women (70%)).Exposure:Discontinuation of antidepressant medication.Outcomes:Task-based fMRI measurement of amygdala reactivity and MDD relapse within 6 months after discontinuation. Results: Amygdala reactivity of rMDD patients on medication did not differ from controls (left: t=0.77, p=0.44, right: t=0.88, p=0.37). An increase in amygdala reactivity after antidepressant discontinuation was associated with depression relapse (three-way interaction between group (continuation vs discontinuation), time point and relapse; beta=25.1, 95%-CI (4.4,45.8), p=0.018). Amygdala reactivity change was associated with shorter times to relapse (hazard ratio 1.05, 95%-CI (1.016,1.085)), and predictive of relapse (LOOCV balanced accuracy 71%, 95%-PPI (57%,84%)).Conclusions and Relevance:An increase in amygdala reactivity is associated with risk of relapse after antidepressant discontinuation and may represent a functional neuroimaging marker that could inform clinical decisions around antidepressant discontinuation.