Reference: N Engl J Med. 2021 Sep 30;385(14):1257-1267
Many patients on antidepressants eventually feel better and wonder if they can come off of their meds. It’s hard to know whether patients feel better because of the medication or because of the episodic nature of depression itself, so sometimes the decision is made to discontinue medication and see what happens. What happens for many is that they end up back on meds. To that point, a recent study evaluated rates of relapse after discontinuation of antidepressants. Some might find the results a little depressing.
Researchers enrolled 478 adults from primary care practices in the UK (mean age 54 years, 73% women) with depression who had been taking an antidepressant (citalopram, sertraline, fluoxetine, or mirtazapine) for at least 2 years or who had had at least two episodes of depression, and who felt well enough to consider discontinuing their antidepressant. Patients were randomized 1:1 to either continue their medication (maintenance group) or to replace their medication with placebo after a 1-2 month taper (discontinuation group). Survey data were collected at four time points over 52 weeks and included a modified version of the Clinical Interview Schedule-Revised (rCIS-R) score. The primary outcome was first relapse of depression over the 52 week follow-up as evaluated by time-to-event analysis (Kaplan-Meier curve).
Relapse was reported in 135 of 240 (56%) in the discontinuation group and 92 of 238 patients (39%) in the maintenance group (hazard ratio, 2.06; 95% CI 1.56-2.70; P<0.001). Loss to follow up or study withdrawal was reported in 10% of the maintenance group and 23% of the discontinuation group by 52 weeks, but authors state that 98% of all patients provided primary outcome data, and that 100% were included in the primary analysis. Of the 56% in the discontinuation group who relapsed, 37% stayed on the trial medication (placebo), 53% restarted antidepressants prescribed outside of trial protocol (but during the data collection period), and 10% stopped their meds altogether. Discontinuation was high in the maintenance group as well, with 30% of patients discontinuing the trial (active) medication, many of whom also restarted an antidepressant outside the study protocol. A number of secondary outcomes generally indicated that the discontinuation group had more symptoms related to anxiety, depression, medication withdrawal, and had more sleep and quality of life issues, although at 52 weeks (when 39% of the discontinuation group were back on antidepressants) there were no between-group differences in these secondary outcomes.
Following the breadcrumbs of the actual primary outcome data through this article and appendix is challenging. Data for secondary and sensitivity analyses are presented with much more transparency and are easier to follow. Even though the authors report having primary endpoint data for 98% of participants, it seems likely that relies on imputed data (last observation carried forward) for drop-outs, which is not without problems, especially in this population at higher risk of relapse due to having been on meds for a long time or having relapsed already. The relapse rates of 56% and 39% for the discontinuation and maintenance groups, respectively, seem high (although maybe not surprising) considering that 39% and 89%, respectively, were taking an antidepressant one way or another at trial completion. Not a great case for antidepressant efficacy in general. But yes, it does seem like this mostly white, mostly female group at higher risk of relapse usually did better when they stayed on their meds. These data validate the idea that major depression sometimes requires long-term use of medications like many other chronic diseases. Between the results themselves and the way the authors report them, the bottom line is that we all need therapy after reading this study.
For more information, see the topic Antidepressant Medication Overview in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Katharine DeGeorge, MD, MS, Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia. Edited by, Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Dan Randall, MD, Deputy Editor at DynaMed; Carina Brown, MD, Assistant Professor at Cone Health Family Medicine Residency; Nicole Jensen, MD, family physician at WholeHealth Medical; Vincent Lemaitre, PhD, Medical Writer at DynaMed; and Christine Fessenden, Editorial Operations Assistant at DynaMed.