Half of people who stopped long term antidepressants relapsed within a year, study finds

Dear Editor,

Dr. Horowitz offers a valid critique of this discontinuation trial—that is, the confounding of illness relapse with antidepressant withdrawal symptoms.

Of the four antidepressants involved in the study by Lewis and Colleagues, fluoxetine and mirtazapine carry a lower risk of withdrawal symptoms upon abrupt discontinuation than sertraline and citalopram.[1] Risk of antidepressant withdrawal is highest with the serotonin reuptake inhibitors (SRIs), and generally inversely proportional elimination half-life of the SRI.[1] Among SRIs, fluoxetine has an unusually long elimination half-life, while Mirtazapine is not an SRI and has questionable serotonergic activity.[1,2]

Lewis and colleagues may help clarify the issue with existing data by stratifying patients into two groups: (1) fluoxetine and mirtazapine and (2) sertraline and citalopram, constituting low-and-high risk groups for antidepressant withdrawal, respectively. It should be noted that in the present study fluoxetine was tapered more quickly than other antidepressants (over 4 weeks versus 8 weeks), which should increase the risk of withdrawal symptoms in these fluoxetine-treated patients. Also, the SRIs in the present study were not prescribed at equivalent doses. As compared to fluoxetine and citalopram, sertraline was prescribed at a moderate (but not minimum) therapeutic dose. Sertraline-treated patients received a 50 milligram dose prior to discontinuation, whereas citalopram-treated individuals received a subtherapeutic 10 milligram daily dose. This reduction strategy for sertraline patients may have predisposed withdrawal symptoms based on the hyperbolic relationship between dose and serotonin transporter occupancy. [3,4]

Dr. Horowitz astutely notes that the taper strategy employed in this study, for all antidepressants, is insufficiently gradual based because of taper duration and terminal drug dose prior to discontinuation. A third limitation of this taper strategy is that alternating doses for SRIs with short half-lives such as sertraline and citalopram is likely to incur inter-dose withdrawal symptoms. These withdrawal symptoms would have occurred as early as week 5 of the taper protocol when the drug was alternated with placebo. This appears to align with the apparently steep increase in illness relapse between weeks 4 to 6 of the trial. That patients may have already experienced withdrawal symptoms as early as week 5 may have resulted in withdrawal symptom improvement or resolution by week 12, potentially reducing subsequent DESS scores and risk of illness relapse thereafter.

1. Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB (1998) Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry 44(2):77–87
2. Gillman PK. A systematic review of the serotonergic effects of mirtazapine in humans: implications for its dual action status. Human Psychopharmacology: Clinical and Experimental. 2006 Mar;21(2):117-25.
3. Shapiro BB. Subtherapeutic doses of SSRI antidepressants demonstrate considerable serotonin transporter occupancy: implications for tapering SSRIs. Psychopharmacology. 2018 Sep;235(9):2779-81.
4. Horowitz MA, Taylor D. Tapering of SSRI treatment to mitigate withdrawal symptoms. The Lancet Psychiatry. 2019 Jun 1;6(6):538-46.