Antidepressant therapy: To continue or not?

In individuals who had been on antidepressant therapy for at least 9 months but felt well enough to consider discontinuing, the risk of relapse of depression was greater among those who stopped vs those who carried on with their current regimen, the ANTLER* trial has shown.

“Patients in the group assigned to discontinue their antidepressant medication in our trial had a higher frequency of relapse of depression than those who were assigned to keep taking their medication through 52 weeks of follow-up,” said the researchers.

At week 52, more than half (56 percent) of participants in the discontinuation arm relapsed, as opposed to 39 percent of those in the maintenance arm (hazard ratio, 2.06; p<0.001). [N Engl J Med 2021;385:1257-1267]

In terms of secondary outcomes, mean scores at 12 weeks were generally in the same direction as the primary outcome. Patients who discontinued their regimen had more symptoms of depression (PHQ-9**, 6.3 vs 4.1), anxiety (GAD-7**, 5.3 vs 3.1), and withdrawal (modified DESS**, 3.1 vs 1.3) vs with those who maintained their therapy.

Furthermore, there were twice as many patients in the discontinuation vs the maintenance arm who reported feeling worse at week 12 than they did 6 weeks prior (44 percent vs 21 percent; odds ratio, 2.88).

Treatment adherence rate was lower in the discontinuation vs the maintenance arm (52 percent vs 70 percent). By trial end, 39 percent of those who discontinued had resumed antidepressant therapy. According to the researchers, this might have factored in the lack of between-group differences for the secondary outcomes at 52 weeks.

The incidence of serious adverse events were similarly low in both maintenance and discontinuation arms (n=9 and 8, respectively). No deaths or suicide attempts were reported.

After screening adults who were being treated in general practices in the UK, 478 participants were enrolled (mean age 54 years, 73 percent female). Patients had a history of at least two prior depressive episodes or had been taking antidepressants for ≥2 years. Participants were randomized 1:1 to either maintain or taper and discontinue their current antidepressant*** regimen.

“An important limitation [of our study] is that our findings pertain only to patients who felt that they were ready to discontinue medication,” said the researchers. Other limitations to take note of are the lack of racial diversity and the inclusion of patients from one health system only. The findings may also not be generalizable to other classes of antidepressants, as the study was limited to the most common antidepressants prescribed in the UK.

Important, but disappointing news

“[The findings] confirm what most primary care physicians already knew or intuited. The frequency of relapse after discontinuation of treatment is high, particularly among patients with several previous depressive episodes,” said Dr Jeffrey Jackson from the Zablocki VA Medical Center, Milwaukee, Wisconsin, US, in a separate editorial. [N Engl J Med 2021;385:1327-1328] “[Based on] the Kaplan-Meier curves, relapse occurred sooner in the discontinuation than in the maintenance arm.”

“Not surprisingly, withdrawal symptoms were more common among those who tapered and discontinued their treatment than among those who continued to receive their typical regimen, and such symptoms were worse in the discontinuation than in the maintenance arm at 12, 26, and 39 weeks after discontinuation,” he added.

“These findings overall represent important but disappointing news, but just as disappointing were the relapse rates in both trial groups,” added Jackson.

As relapse remains common even among those who are continuing their pharmacologic regimen, Jackson underlined the need for close follow-up. “It is useful to educate patients to monitor their depressive symptoms and alert their provider if they sense they are having a relapse. The results of this and many other trials highlight the fact that current treatment options for depressed patients are not ideal.”