A recent systematic review examined studies of antidepressant discontinuation in children and adolescents. The researchers identified 528 published articles, of which 28 were included. In addition, 19 records were obtained through other methods, with 14 included. The corpus of records included 13 randomized, double-blind, placebo-controlled trials (3026 patients), Of the 13 studies, 10 examined serotonin reuptake inhibitors (SSRIs), four examined serotonin-norepinephrine reuptake inhibitors (SNRIs), and one examined a TCA (imipramine). Trials ranged in duration from 4 to 35 weeks.
Recommendations from this review focus on decisions around antidepressant pharmacotherapy, and the strategies for cross titration, stopping antidepressants and understanding the physiology and pharmacology of these medications. Additionally, researchers provide insights on the pharmacokinetic and pharmacodynamic factors influencing withdrawal-related symptoms, tapering, and cross-titration Regarding pharmacokinetics, withdrawal symptoms are more common with antidepressants with shorter half-lives (e.g., paroxetine) than antidepressants with longer half-lives (e.g., fluoxetine).
Acute antidepressant treatment is initially associated with a reduction in the firing frequency
of serotonergic neurons, which progressively increases over time (Figure 1). This is accompanied by a decrease in serotonin transporter (SERT) expression and 5-HT1A receptor expression. With chronic SSRI exposure, presynaptic 5-HT1A receptors become desensitized and downregulated. When an SSRI is withdrawn, the firing rates of serotonergic neurons rise, leading to an increase in synaptic serotonin (5-HT). During this period, 5-HT1A and postsynaptic 5-HT receptors may become supersensitive. The severity of withdrawal symptoms has been hypothesized to correlate with the extent of dose reduction.
When considering the discontinuation of antidepressant treatment, factors such as treatment response, comorbidities, and changes in the patient's environment must be carefully assessed. Withdrawal symptoms associated with antidepressants in youth vary by medication. Discontinuing SSRIs has been reported to produce palpitations, derealization, disinterest, tension, anxiety, nausea/ vomiting, changes in appetite, hypersomnia, and abnormal movements. However, the magnitude of withdrawal symptoms may be related to the pharmacokinetic and pharmacodynamic profile of the medication. Withdrawal symptoms and relapse have a very different temporal course Table
Table. Differentiating withdrawal symptoms from relapse in antidepressant-treated children and adolescents.
In deprescribing, clinicians often switch from one medication to another, either because of a lack of efficacy or side effects. This practice increasingly involves cross-titration—switching from one medication to another while overlapping the two medications. In the cross-titration of antidepressants in children and adolescents, careful consideration of specific receptor profiles and pharmacokinetics is paramount to mitigate the risk of relapse and discontinuation-emergent/withdrawal symptoms.
Reference:
Stimpfl JN et al. Journal of Child and Adolescent Psychopharmacology. 2025;35(1):3-22.Abstract
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