Predicting relapse after antidepressant withdrawal – a systematic review

Abstract

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.

A prognostic index for long-term outcome after successful acute phase cognitive therapy and interpersonal psychotherapy for major depressive disorder

“…In this study, we identified three post‐treatment predictors for long‐term depression severity: post‐treatment depression severity, negative beliefs about the future (hopelessness), and lower self‐esteem (self‐liking and self‐competence), all of which have been associated with an unfavorable course. Post‐treatment depression severity, or residual depression, has been found to have a strong prognostic value for an unfavorable course of depression (Berwian et al., ; Fava, Ruini, & Belaise, ; Hardeveld et al., ; Nierenberg et al., ; ten Doesschate, Bockting, Koeter, & Schene, ). Hopelessness as a predictor of long‐term depression severity is in line with the hopelessness theory of depression (Abramson, Metalsky, & Alloy, ; Liu, Kleiman, Nestor, & Cheek, ).…”

“…Based on previous research, we expected the number of previous episodes and childhood maltreatment to be identified as predictors as well (Berwian et al., ; Hardeveld et al., ; Kovacs et al., ; Nanni et al., ). However, our selection methods did not identify these variables.…”

“…First of all, evidence is inconclusive for several predictors, including stressful life events, a family history of MDD, severity of the depressive episode, and comorbidity (e.g., dysthymia and personality pathology, Burcusa & Iacono, ; Hardeveld et al., ; Hardeveld, Spijker, De Graaf, Nolen, & Beekman, ). Only a few predictors have been repeatedly found to relate to an unfavorable long‐term course of MDD, namely the number of previous episodes, residual symptoms, and childhood maltreatment (Berwian, Walter, Seifritz, & Huys, ; Hardeveld, Spijker, De Graaf, Nolen, & Beekman, ; Kovacs, Obrosky, & George, ; Nanni, Uher, & Danese, ). Second, several studies have shown that the risk of recurrence of MDD depends on the combination of multiple predictors each having a small prognostic effect (van Loo et al., ; Wang et al., ).…”

Low predictive power of clinical features for relapse prediction after antidepressant discontinuation in a naturalistic setting

“…These recommendations are based on evidence derived from the natural course of depression and overall relapse risk (Frank et al, 1991;Kessler et al, 2003;Nierenberg et al, 2010). However, the importance of these markers has been disputed (Berwian et al, 2017): two meta-analyses came to diametrically opposed conclusions about the relevance of the number of prior episodes (Viguera et al, 1998;Kaymaz et al, 2008), and five separate meta-analyses have failed to find an effect of length of ADM treatment on relapse risk after discontinuation (Viguera et al, 1998;Geddes et al, 2003;Kaymaz et al, 2008;Glue et al, 2010;Andrews et al, 2011).…”

Relapse prevention with levomilnacipran ER in adults with major depressive disorder: A multicenter, randomized, double-blind, placebo-controlled study

“…The majority of patients with major depressive disorder (MDD) have more than one major depressive episode, and at least 50% of patients who experience one episode are likely to experience another (APA, ; Kessler & Walters, ; Kessler, Zhao, Blazer, & Swartz, ). A higher number of previous episodes (Berwian, Walter, Seifritz, & Huys, ; Kendler, Thornton, & Gardner, ), more residual symptoms (Berwian et al., ; Nierenberg et al., ), and failure to reach remission after acute antidepressant treatment (APA, ; Rush et al., ) are associated with a greater risk of relapse, defined as the return of depression symptoms during an index episode. In addition, the STAR*D trial showed that the more acute treatment regimens a patient requires, the higher the risk of relapse (Rush et al., ).…”