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

Abstract

The risk of relapse after antidepressant medication (ADM) discontinuation is high. Predictors of relapse could guide clinical decision-making, but are yet to be established. We assessed demographic and clinical variables in a longitudinal observational study before antidepressant discontinuation. State-dependent variables were re-assessed either after discontinuation or before discontinuation after a waiting period. Relapse was assessed during 6 months after discontinuation. We applied logistic general linear models in combination with least absolute shrinkage and selection operator and elastic nets to avoid overfitting in order to identify predictors of relapse and estimated their generalisability using cross-validation. The final sample included 104 patients (age: 34.86 (11.1), 77% female) and 57 healthy controls (age: 34.12 (10.6), 70% female). 36% of the patients experienced a relapse. Treatment by a general practitioner increased the risk of relapse. Although within-sample statistical analyses suggested reasonable sensitivity and specificity, out-of-sample prediction of relapse was at chance level. Residual symptoms increased with discontinuation, but did not relate to relapse. Demographic and standard clinical variables appear to carry little predictive power and therefore are of limited use for patients and clinicians in guiding clinical decision-making.

Figure 1

Study design: we recruited remitted, medicated patients on antidepressant medication (ADM) and matched healthy controls (HC). They were assessed and compared at main assessment 1 (MA1) to identify traits characterising the remitted, medicated state. Next, patients were randomised to either discontinue their medication before MA2 (bottom arm, “discontinuation group” or enter a waiting period while continuing their ADM matched to the length of discontinuation time (top arm, “waiting group”). Differences in changes between MA1 and MA2 in the two separate groups were investigated to gain an understanding of the effects underlying discontinuation. Patients in the waiting group discontinued their ADM after MA2. After discontinuation, all patients entered the follow-up (FU) period of 6 months, whereas some patients had a relapse during this period and some patients finished this period without relapse. Differences in characteristics at MA1 of patients who relapsed and patients who did not relapse during FU provide information on which variables relates to relapse risk and can be used to identify predictors of relapse after ADM discontinuation.

Figure 2

(A) Survival curves for time until relapse during follow-up period for patients who were only treated by a general practitioner (GP) or additionally by a psychiatrist or psychologist. (B) Prediction: Receiver operating curves for a standard general linear model (blue) and a regularised general linear model using least absolute shrinkage and selection operator and elastic net (red) using the full sample (solid lines) and for subjects left out of the fit using leave-one-out (LOO) cross-validation (dashed lines).

Figure 3

(A–D) Discontinuation effects: changes in symptoms from main assessment one (MA1) to main assessment two (MA2) for depression (A), anxiety (B), somatic pain (C) and general impairment (D) in patients who discontinued between the two assessments and patients who did not discontinue. (E–H) Discontinuation relapse interaction effects: Changes in symptoms from MA1 to MA2 for depression (E), anxiety (F), somatic pain (G) and general impairment (H) in patients who discontinued and either relapsed or remained well during the follow-up period. (I–L) Test–retest reliability for symptom measures: Changes in symptoms from MA1 to MA2 for depression (I), anxiety (J), somatic pain (K) and general impairment (L) in patients who did not discontinue and either relapsed or remained well during the follow-up period. Asterisks indicate a significant difference at p < 0.05 for FDR-corrected p values. Asterisks on top of a line relate to a within-subjects difference between MA1 and MA2 for the group indicated by the line. Asterisks between two lines relate to a between-subjects difference at the indicated time point.