Approximately 1 in 6 patients experience antidepressant withdrawal symptoms, systematic review finds

In a recent study published in Lancet Psychiatry, researchers performed a meta-analysis to determine the prevalence of antidepressant discontinuation symptoms.

Background

Adverse symptoms associated with antidepressant cessation are a rising issue in psychiatry, clinical practice, patients, and the public. Antidepressant discontinuation syndromes (ADS) are a collection of symptoms classified in various ways.

Clinical practice guidelines now urge educating patients about the hazards of sudden withdrawal and decreasing antidepressants. The most common symptoms are dizziness, headaches, nausea, sleeplessness, and irritability.

The prevalence and severity of ADS are debated, with some authors suggesting that 56% of patients suffer from discontinuation symptoms, with over half categorized as severe. Medical specialists share opposing views on the severity of ADS.

About the study

In the present meta-analysis, researchers examined the frequency of antidepressant stoppage symptomatology in individuals stopping antidepressants or using a placebo.

The team systematically searched the PubMed, CENTRAL, and EMBASE databases through 13 October 2022 for randomized clinical trials (RCTs), observational studies, and other trials evaluating the incidence rates of antidepressant usage termination-related symptoms. Included studies investigated the tapering or cessation of antidepressant drugs (excluding lithium, thyroxine, and antipsychotics) or placebo among individuals with behavioral, neurodevelopmental, or mental disorders.

The researchers excluded studies conducted among newborns and those including individuals prescribed antidepressant medications for conditions like pain syndromes resulting from organic diseases. They extracted data, evaluated bias risks using the Newcastle-Ottawa scale (NOS), and pooled the results using random-effects models.

The primary endpoint was antidepressant cessation symptom incidence after discontinuing antidepressants vs. placebo. The researchers also analyzed the incidence rates of severe symptoms related to antidepressant use termination. They determined heterogeneity between the included studies using I2 and τ2 statistics. Sensitivity analyses and meta-regressions tested several methodological variables, re-calculating the meta-analyses using the arcsine transformation.

The researchers also performed pre-specified subgroup analyses to evaluate the effects of specific antidepressants, the presence of tapering regimens, the length and dosing of antidepressant treatment, the duration of observation periods, whether the researchers used structured instruments to assess symptoms, and diagnosis as an indication for antidepressant treatment on the incidence of antidepressant discontinuation symptoms. They evaluated the risk difference of antidepressant discontinuation symptoms between groups who ended antidepressants and the comparable groups who discontinued placebo, using one risk difference from each RCT.

Results

From 6,095 articles screened, the team performed full-text screening for 366 records and selected 79 studies (35 observational-type studies and 44 RCTs), including 21,002 individuals (mean age of 45 years, 28% males, and 72% females). Most patients were diagnosed with mood disorders (64%) and anxiety disorders (28%). Other diagnoses included fibromyalgia, psychotic disorders, anorexia nervosa, sleep-wake disorders, impulse-control disorders, and obsessive-compulsive disorder.

In total, 16,532 individuals discontinued antidepressants, and 4,470 discontinued placebo drugs. Among the studies, 41% (n=32) had NOS scores ≥7.0 and low bias risks, and 50% (n=38) of studies applied tapering. The mean length of antidepressant treatment before quitting ranged from seven days to 156 weeks. The monitoring of discontinuation symptoms lasted from 1.5 to 196 days. The prevalence of one or more antidepressant discontinuation symptoms was 0.3 in 62 participants and 0.2 in 22 groups following placebo cessation. The overall difference in incidence between the antidepressant medication and placebo drug groups in the included RCTs was 0.1.

The rate of severe-intensity antidepressant usage termination symptoms after discontinuing antidepressants was 0.03 versus 0.01 after discontinuing placebos. Venlafaxine, desvenlafaxine, escitalopram, and imipramine were linked to higher rates of discontinuation-related symptoms, whereas paroxetine, imipramine, and either venlafaxine or desvenlafaxine were related to higher levels of symptoms. The results showed significant heterogeneity. Subgroup and sensitivity analyses enabled the partial attribution of heterogeneity to moderating variables.

Conclusions

The study found that one among every six or seven individuals who stop taking their drugs has antidepressant discontinuation symptoms, with a frequency of around 15%. The finding might be due to factors unaccounted for by medical diagnosis, medications, trial-related traits, or subjective variables. Even in placebo-controlled research, the study revealed that one-third of individuals who stop taking antidepressants experience discontinuation symptoms.

Approximately one in every 30 patients who stopped using antidepressants experienced severe discontinuation symptoms. Specific antidepressants influence the prevalence of discontinuation symptoms, the use of symptom detection devices, and study rigor, although significant statistical variability persists.

The results indicate that paroxetine, imipramine, venlafaxine, and desvenlafaxine are associated with a higher likelihood of severe antidepressant cessation symptoms than other antidepressants. However, the researchers discovered minor discrepancies across different antidepressants, which might be due to meaningful nonpharmacological effects.