Both the APA and NICE guidelines suggest that patients continue using antidepressants, even after they no longer meet the criteria for depression, in order to prevent relapse (the return of previous depression symptoms). But the evidence for this approach is confounded by withdrawal symptoms.
The existing research on relapse consists of suddenly stopping the active drug and seeing what happens. But, according to researchers, relapse that happens just after a “cold turkey” discontinuation of antidepressants is likely to be a withdrawal effect. Researchers have also identified this issue in antipsychotic trials.
Researchers Michael P. Hengartner and Martin Plöderl wanted to investigate this further, so they examined all of the antidepressant relapse prevention trials submitted to the FDA between 1987 and 2012. These studies begin by stabilizing patients on an antidepressant. Then, one group is abruptly switched to a placebo, while the other group continues the active drug. If fewer people in the antidepressant group relapse, the researchers conclude that the drug is preventing relapse.
But, according to researchers, this ignores withdrawal effects, which can often look much like depressive symptoms. So Hengartner and Plöderl looked at when people in the placebo group began to relapse.
Previous research has concluded that the risk of relapse is relatively linear—increasing over time. So, they write, “if continued antidepressant treatment truly has prophylactic effects then, in patients randomized to antidepressants, the linear risk increase over time should be lower than in patients randomized to placebo.”
But instead, they found that there was an early peak in relapses in the placebo group—which then evened out. Eventually, the antidepressants were no better than placebo at reducing relapse.
They write, “The placebo–antidepressant separation was disproportionally large between weeks 3 and 6 of the randomized maintenance phase. The benefits of continuing antidepressants relative to abrupt/rapid discontinuation declined sharply after week 6.”
This unusual peak in relapse events was early in the drug discontinuation process—just when withdrawal effects would be expected. By the sixth week, this peak disappeared, and by 24 weeks, the antidepressant was no better than a placebo at preventing relapse.
“These findings indicate that the benefits of continuing antidepressant treatment relative to abrupt/rapid discontinuation decline sharply after a few weeks,” write Hengartner and Plöderl.
“Given that severe withdrawal reactions frequently meet common depression relapse criteria,” they add, “plausible explanation for the disproportionally large placebo–antidepressant separation during the first few weeks of the maintenance phase are thus withdrawal reactions that eventually fulfill relapse criteria in patients randomized to placebo. Withdrawal symptoms can develop acutely within a few days after discontinuation, but, worthy of note, slow progression of symptoms and delayed onset are also possible. Therefore, it is not unusual that withdrawal syndromes fulfill relapse criteria only after a few weeks, especially when a drug taper was applied and after discontinuation of antidepressants with a long half-life.”
The study was published in Therapeutic Advances in Psychopharmacology.
Hengartner, M. P., & Plöderl, M. (2021). Prophylactic effects or withdrawal reactions? An analysis of time-to-event data from antidepressant relapse prevention trials submitted to the FDA. Ther Adv Psychopharmacol, 11, 1–12. DOI: 10.1177/20451253211032051 (Link)