Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial

Biol Psychiatry. 1998 Jul 15;44(2):77-87. doi: 10.1016/s0006-3223(98)00126-7.


Background: Recent reports describe discontinuation-emergent adverse events upon cessation of selective serotonin reuptake inhibitors including dizziness, insomnia, nervousness, nausea, and agitation. We hypothesized that interruption of fluoxetine treatment would be associated with fewer discontinuation-emergent adverse events than interruption of sertraline or paroxetine treatment, based on fluoxetine's longer half-life.

Methods: In this 4-week study, 242 patients with remitted depression receiving maintenance therapy with open-label fluoxetine, sertraline, or paroxetine for 4-24 months had their maintenance therapy interrupted with double-blind placebo substitution for 5-8 days. The Symptom Questionnaire (SQ), the Discontinuation-Emergent Signs and Symptoms checklist, the 28-item Hamilton Depression Rating Scale, and the Montgomery-Asberg Depression Rating Scale were used to assess somatic distress and stability of antidepressant response.

Results: Two hundred twenty patients (91%) completed the study. Following interruption of therapy, fluoxetine-treated patients experienced fewer discontinuation-emergent events than either sertraline-treated or paroxetine-treated patients (p < .001). The mean SQ somatic symptom scale score in fluoxetine-treated patients was significantly lower than that in sertraline-treated and paroxetine-treated patients (p < .001). Fluoxetine-treated patients also experienced less reemergence of depressive symptoms than sertraline-treated or paroxetine-treated patients (p < .001).

Conclusions: Abrupt interruption of antidepressant therapy for 5-8 days was associated with the emergence of new somatic and psychological symptoms in patients treated with paroxetine and to a lesser degree sertraline, with few symptoms seen with fluoxetine.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial

MeSH terms

  • 1-Naphthylamine / adverse effects
  • 1-Naphthylamine / analogs & derivatives*
  • 1-Naphthylamine / pharmacokinetics
  • 1-Naphthylamine / therapeutic use
  • Adult
  • Depressive Disorder / diagnosis
  • Depressive Disorder / prevention & control
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Fluoxetine / adverse effects*
  • Fluoxetine / pharmacokinetics
  • Fluoxetine / therapeutic use
  • Half-Life
  • Health Status
  • Humans
  • Male
  • Middle Aged
  • Paroxetine / adverse effects*
  • Paroxetine / pharmacokinetics
  • Paroxetine / therapeutic use
  • Placebos
  • Prospective Studies
  • Psychiatric Status Rating Scales
  • Selective Serotonin Reuptake Inhibitors / adverse effects*
  • Selective Serotonin Reuptake Inhibitors / pharmacokinetics
  • Selective Serotonin Reuptake Inhibitors / therapeutic use
  • Serotonin / pharmacokinetics
  • Serotonin / physiology
  • Sertraline
  • Substance Withdrawal Syndrome / diagnosis
  • Substance Withdrawal Syndrome / epidemiology
  • Substance Withdrawal Syndrome / etiology*
  • Surveys and Questionnaires


  • Placebos
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Serotonin
  • Paroxetine
  • 1-Naphthylamine
  • Sertraline