Pathophysiology
Clinical meaning
Antidepressant discontinuation syndrome (ADS) occurs when SSRIs, SNRIs, or other serotonergic/noradrenergic antidepressants are abruptly stopped or rapidly tapered after sustained use (typically ≥4-6 weeks). The syndrome reflects neuroadaptive changes that developed during chronic antidepressant exposure. During sustained SSRI/SNRI therapy, the brain undergoes neuroplastic adaptations: (1) postsynaptic serotonin receptors (5-HT1A, 5-HT2A) are downregulated in response to chronically elevated synaptic serotonin; (2) presynaptic serotonin autoreceptors (5-HT1A, 5-HT1B/1D) are desensitized; (3) serotonin synthesis and reuptake transporter expression are altered. When the drug is abruptly removed, synaptic serotonin drops rapidly, but the downregulated postsynaptic receptors cannot compensate — resulting in a relative serotonergic deficit until receptor re-upregulation occurs (days to weeks). The risk and severity of discontinuation syndrome correlate with: (1) half-life of the drug — shorter half-life = higher risk (paroxetine t½ ~21 hours vs. fluoxetine t½ ~4-6 days including active metabolite norfluoxetine); (2) duration of therapy (longer use = more neuroadaptation); (3) dose (higher doses = more neuroadaptation); (4) individual variation in CYP2D6 metabolism. The FINISH mnemonic captures the symptom clusters: Flu-like symptoms (fatigue, myalgias, chills), Insomnia (sleep disturbance, vivid dreams), Nausea...