Pharmacology  ·  CNS

Antidepressant Adverse Effects, Interactions, and Special Populations

Module 7 — Chapter 17: Antidepressant Drugs

Abbreviations: SSRI = selective serotonin reuptake inhibitor  ·  SNRI = serotonin-norepinephrine reuptake inhibitor  ·  TCA = tricyclic antidepressant  ·  MAOI = monoamine oxidase inhibitor  ·  QTc = corrected QT interval  ·  NSAID = non-steroidal anti-inflammatory drug  ·  GI = gastrointestinal  ·  SIADH = syndrome of inappropriate antidiuretic hormone  ·  PPI = proton pump inhibitor  ·  PPHN = persistent pulmonary hypertension of the newborn

Adverse Effect Profile by Class
Class Sexual Dysfunction Weight Gain Sedation QTc Risk Discontinuation Syndrome
SSRIs (most) High Moderate Low Low (citalopram: high) High (paroxetine highest)
SNRIs High Low Low Low High (venlafaxine)
TCAs Moderate High High High Moderate
MAOIs High High Moderate Low Moderate
Bupropion None None/loss None Low Low
Mirtazapine None High High (especially 15 mg) Low Low
High-Yield Drug Interactions
Bleeding Risk
SSRI + NSAID Interaction
  • SSRIs deplete platelet serotonin → impaired platelet aggregation
  • NSAIDs inhibit prostaglandins → loss of gastric mucosal protection
  • Combined: ~15-fold increase in upper GI bleeding risk
  • Mitigation: add proton pump inhibitor when combination unavoidable
  • Anticoagulants further increase risk — monitor closely
Oncology Interaction
Paroxetine/Fluoxetine + Tamoxifen
  • Tamoxifen requires CYP2D6 conversion to active endoxifen
  • Paroxetine and fluoxetine potently inhibit CYP2D6
  • Endoxifen levels reduced by 65–75% with paroxetine
  • Increased breast cancer recurrence risk documented
  • Solution: use sertraline or venlafaxine (low CYP2D6 inhibition) instead
Discontinuation Syndrome and Special Populations
FINISH Mnemonic
Discontinuation Syndrome
  • Flu-like symptoms (myalgia, chills)
  • Insomnia and vivid dreams
  • Nausea and vomiting
  • Imbalance and dizziness
  • Sensory disturbances ("brain zaps," paresthesias)
  • Hyperarousal and anxiety
  • Highest risk: paroxetine, venlafaxine. Lowest: fluoxetine
  • Management: gradual taper over weeks; restart + taper if severe
Pregnancy, Lactation, Elderly
Special Population Rules
  • Pregnancy: sertraline preferred (best safety data); avoid paroxetine (cardiac malformation signal); third-trimester SSRI → neonatal adaptation syndrome and small PPHN risk
  • Lactation: sertraline and paroxetine lowest milk transfer; compatible with breastfeeding
  • Elderly: SSRIs → SIADH/hyponatremia (monitor sodium first 4 weeks); TCAs on Beers Criteria (anticholinergic, falls, QTc); prefer sertraline, escitalopram, or venlafaxine
  • Pediatric black box: all antidepressants carry warning for increased suicidal ideation in under-25 population; monitor closely in first weeks
Antidepressant Selection Guide

Sexual dysfunction intolerable: bupropion or mirtazapine. Weight gain intolerable: bupropion or venlafaxine. Insomnia dominant: mirtazapine or trazodone (low dose). Cardiac patient: sertraline (SADHART evidence) or escitalopram (STABILITY); avoid TCAs. Pregnancy: sertraline. Elderly: sertraline or escitalopram (low interaction, tolerable). On tamoxifen: sertraline or venlafaxine. Neuropathic pain: duloxetine or TCA.

Suggested References

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