01. Which Antidepressants Have the Highest Risk of Discontinuation Symptoms?

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Antidepressant Discontinuation Symptoms: More Common Than We Thought?

Have you ever had patients tell you that coming off of their antidepressants feels awful? They may describe bad GI symptoms like nausea, diarrhea or constipation. Some mention headaches like the kind you get when you try to stop using caffeine.

Others might even describe more unusual sensations like zaps of electricity running down their spine.

New Study Suggests 1 in 7 Patients Experience Discontinuation Symptoms

According to a new systematic review and meta-analysis published in Lancet Psychiatry, about one in seven patients may experience symptoms associated with antidepressant discontinuation. The article analyzed 79 studies involving more than 21,000 participants, about 16,500 of whom had discontinued an antidepressant.

• About 17% of patients had symptoms that were attributable to their own expectations about stopping medications.
• Even after accounting for this phenomenon, about 14% of all patients reported symptoms.
• About 3% of patients, or 1 in 35, had symptoms that were considered severe.

Tapering May Not Reduce Discontinuation Symptoms

Interestingly, the frequency of symptoms did not seem to have any relationship to whether the medication was abruptly stopped or slowly tapered. This is notable as most guidelines recommend tapering as a means to reduce discontinuation symptoms.

However, the meta-analysis found no difference in discontinuation rates between studies that involved abrupt discontinuation and those involving slow tapering. There was no head-to-head comparison of the two approaches in most individual studies.

Certain Antidepressants Associated with Higher Rates of Discontinuation Symptoms

Among antidepressants, imipramine, desvenlafaxine, venlafaxine and escitalopram were associated with higher rates of discontinuation symptoms. A similar group of antidepressants, imipramine, desvenlafaxine, venlafaxine and paroxetine were associated with more severe symptoms.

• Paroxetine is perhaps the most notoriously associated with this phenomenon, probably due to its very short half-life.
• Immediate-release venlafaxine is similar in this regard.

On the opposite end of the spectrum, sertraline and fluoxetine were among the antidepressants with the lowest rates of discontinuation symptoms in the study.

Strategies for Managing Antidepressant Discontinuation Symptoms

If your patients report experiencing symptoms that could be attributed to antidepressant discontinuation, here are some strategies:

1. Try to better understand the symptoms and make sure they seem consistent with this phenomenon and don’t have a better explanation.
2. If they seem legit, employ hyperbolic tapering by restoring to the original or approximate dose of the antidepressant and then beginning a very slow taper usually over several weeks and sometimes over months.
3. Another strategy, particularly with SSRI discontinuation symptoms, is to switch to a different SSRI. For example, if you have a patient on paroxetine, you might make a direct switch to something like fluoxetine which has a much longer half-life, maintain that for a week or two and then either do a quick taper or just discontinue it and let it auto-taper.
4. If you are transitioning antidepressants rather than stopping antidepressants completely, you may be able to do a cross-taper to the new agent in a way that mitigates a lot of discontinuation symptoms.

Abstract

Incidence of antidepressant discontinuation symptoms: a systematic review and meta-analysis

Jonathan Henssler, M.D., Yannick Schmidt, M.D., Urszula Schmidt, M.D., Guido Schwarzer, Ph.D., Prof. Tom Bschor, M.D., Prof. Christopher Baethge, M.D.

Background

Antidepressant discontinuation symptoms are becoming an increasingly important part of clinical practice, but the incidence of antidepressant discontinuation symptoms has not been quantified. An estimate of antidepressant discontinuation symptoms incidence could inform patients and clinicians in the discontinuation of treatment, and provide useful information to researchers in antidepressant treatments. We aimed to assess the incidence of antidepressant discontinuation symptoms in patients discontinuing both antidepressants and placebo in the published literature.

Methods

We systematically searched Medline, EMBASE, and CENTRAL from database inception until Oct 13, 2022 for randomised controlled trials (RCTs), other controlled trials, and observational studies assessing the incidence of antidepressant discontinuation symptoms. To be included, studies must have investigated cessation or tapering of an established antidepressant drug (excluding antipsychotics, lithium, or thyroxine) or placebo in participants with any mental, behavioural, or neurodevelopmental disorder. We excluded studies in neonates, and those using antidepressants for physical conditions such as pain syndromes due to organic disease. After study selection, summary data extraction, and risk of bias evaluation, data were pooled in random-effects meta-analyses. The main outcome was the incidence of antidepressant discontinuation symptoms after discontinuation of antidepressants or placebo. We also analysed the incidence of severe discontinuation symptoms. Sensitivity and meta-regression analyses tested a selection of methodological variables.

Findings

From 6095 articles screened, 79 studies (44 RCTs and 35 observational studies) covering 21 002 patients were selected (72% female, 28% male, mean age 45 years [range 19·6–64·5]). Data on ethnicity were not consistently reported. 16 532 patients discontinued from an antidepressant, and 4470 patients discontinued from placebo. Incidence of at least one antidepressant discontinuation symptom was 0·31 (95% CI 0·27–0·35) in 62 study groups after discontinuation of antidepressants, and 0·17 (0·14–0·21) in 22 study groups after discontinuation of placebo. Between antidepressant and placebo groups of included RCTs, the summary difference in incidence was 0·08 [0·04–0·12]. The incidence of severe antidepressant discontinuation symptoms after discontinuation of an antidepressant was 0·028 (0·014–0·057) compared with 0·006 (0·002–0·013) after discontinuation of placebo. Desvenlafaxine, venlafaxine, imipramine, and escitalopram were associated with higher frequencies of discontinuation symptoms, and imipramine, paroxetine, and either desvenlafaxine or venlafaxine were associated with a higher severity of symptoms. Heterogeneity of results was substantial.

Interpretation

Considering non-specific effects, as evidenced in placebo groups, the incidence of antidepressant discontinuation symptoms is approximately 15%, affecting one in six to seven patients who discontinue their medication. Subgroup analyses and heterogeneity figures point to factors not accounted for by diagnosis, medication, or trial-related characteristics, and might indicate subjective factors on the part of investigators, patients, or both. Residual or re-emerging psychopathology needs to be considered when interpreting the results, but our findings can inform clinicians and patients about the probable extent of antidepressant discontinuation symptoms without causing undue alarm.

Reference

Henssler, J. M.D., Schmidt, Y M.D., Schmidt, U M.D., Schwarzer, G. Ph.D., Bschor, T. M.D., Baethge, C. M.D. (2024). Incidence of antidepressant discontinuation symptoms: a systematic review and meta-analysis. Lancet Psychiatry 2024; 11: 526–35