A substantial proportion of the burden of depression arises from its recurrent nature. The risk of relapse after antidepressant medication (ADM) discontinuation is high but not uniform. Predictors of individual relapse risk after antidepressant discontinuation could help to guide treatment and mitigate the long-term course of depression. We conducted a systematic literature search in PubMed to identify relapse predictors using the search terms ‘(depress* OR MDD*) AND (relapse* OR recurren*) AND (predict* OR risk) AND (discontinu* OR withdraw* OR maintenance OR maintain or continu*) AND (antidepress* OR medication OR drug)’ for published studies until November 2014. Studies investigating predictors of relapse in patients aged between 18 and 65 years with a main diagnosis of major depressive disorder (MDD), who remitted from a depressive episode while treated with ADM and were followed up for at least 6 months to assess relapse after part of the sample discontinued their ADM, were included in the review. Although relevant information is present in many studies, only 13 studies based on nine separate samples investigated predictors for relapse after ADM discontinuation. There are multiple promising predictors, including markers of true treatment response and the number of prior episodes. However, the existing evidence is weak and there are no established, validated markers of individual relapse risk after antidepressant cessation. There is little evidence to guide discontinuation decisions in an individualized manner beyond overall recurrence risk. Thus, there is a pressing need to investigate neurobiological markers of individual relapse risk, focusing on treatment discontinuation.

IMPORTANCE Nearly 1 in 3 patients with major depressive disorder who respond to antidepressants relapse within 6 months of treatment discontinuation. No predictors of relapse exist to guide clinical decision-making in this scenario.OBJECTIVES To establish whether the decision to invest effort for rewards represents a persistent depression process after remission, predicts relapse after remission, and is affected by antidepressant discontinuation. DESIGN, SETTING, AND PARTICIPANTSThis longitudinal randomized observational prognostic study in a Swiss and German university setting collected data from July 1, 2015, to January 31, 2019, from 66 healthy controls and 123 patients in remission from major depressive disorder in response to antidepressants prior to and after discontinuation. Study recruitment took place until January 2018. EXPOSURE Discontinuation of antidepressants. MAIN OUTCOMES AND MEASURESRelapse during the 6 months after discontinuation. Choice and decision times on a task requiring participants to choose how much effort to exert for various amounts of reward and the mechanisms identified through parameters of a computational model. RESULTS A total of 123 patients (mean [SD] age, 34.5 [11.2] years; 94 women [76%]) and 66 healthy controls (mean [SD] age, 34.6 [11.0] years; 49 women [74%]) were recruited. In the main subsample, mean (SD) decision times were slower for patients (n = 74) compared with controls (n = 34) (1.77 [0.38] seconds vs 1.61 [0.37] seconds; Cohen d = 0.52; P = .02), particularly for those who later relapsed after discontinuation of antidepressants (n = 21) compared with those who did not relapse (n = 39) (1.95 [0.40] seconds vs 1.67 [0.34] seconds; Cohen d = 0.77; P < .001). This slower decision time predicted relapse (accuracy = 0.66; P = .007). Patients invested less effort than healthy controls for rewards (F 1,98 = 33.970; P < .001). Computational modeling identified a mean (SD) deviation from standard drift-diffusion models that was more prominent for patients than controls (patients, 0.67 [1.56]; controls, -0.71 [1.93]; Cohen d = 0.82; P < .001). Patients also showed higher mean (SD) effort sensitivity than controls (patients, 0.31 [0.92]; controls, -0.08 [1.03]; Cohen d = 0.51; P = .05). Relapsers differed from nonrelapsers in terms of the evidence required to make a decision for the low-effort choice (mean [SD]: relapsers, 1.36 [0.35]; nonrelapsers, 1.17 [0.26]; Cohen d = 0.65; P = .02). Group differences generally did not reach significance in the smaller replication sample (27 patients and 21 controls), but decision time prediction models from the main sample generalized to the replication sample (validation accuracy = 0.71; P = .03).CONCLUSIONS AND RELEVANCE This study found that the decision to invest effort was associated with prospective relapse risk after antidepressant discontinuation and may represent a persistent disease process in asymptomatic remitted major depressive disorder. Markers based on effort-related decision-making could potentially inform clinical dec...