Adverse Effects, Drug Interactions, and Special Populations

Module 7 — Chapter 17: Antidepressant Drugs

Discontinuation Syndrome — FINISH Mnemonic and Risk by Agent
FINISH Mnemonic
Discontinuation Syndrome Symptoms
  • F — Flu-like symptoms: myalgia, fatigue, sweating, chills
  • I — Insomnia: vivid dreams, nightmares, disrupted sleep
  • N — Nausea (and vomiting)
  • I — Imbalance: dizziness, gait unsteadiness
  • S — Sensory disturbances: "brain zaps" — electric-shock sensations from the head (pathognomonic)
  • H — Hyperarousal: anxiety, agitation, irritability
Risk Ranking by Agent
Highest to Lowest Risk
  • Highest: Paroxetine (shortest half-life, no active metabolite, anticholinergic rebound) and venlafaxine immediate-release (very short half-life)
  • Intermediate: Sertraline, citalopram, escitalopram, duloxetine
  • Lowest: Fluoxetine — norfluoxetine active metabolite provides inherent self-tapering over weeks
  • Brain zaps distinguish discontinuation syndrome from relapse; relapse does not produce sensory disturbances
High-Yield Cytochrome P450 Drug Interactions
Antidepressant Enzyme Inhibited High-Risk Victim Drug Clinical Consequence
Fluoxetine, Paroxetine Cytochrome P450 2D6 (potent) Tamoxifen Reduced endoxifen (active metabolite) → reduced breast cancer efficacy — use alternative selective serotonin reuptake inhibitor
Fluoxetine, Paroxetine Cytochrome P450 2D6 (potent) Tricyclic antidepressants, antipsychotics, codeine Elevated levels → toxicity risk (tricyclic antidepressants); reduced analgesia (codeine)
Fluvoxamine Cytochrome P450 1A2 (potent) Clozapine, olanzapine, theophylline 3-fold or more increase in clozapine levels → seizures, cardiotoxicity; theophylline toxicity
Fluvoxamine, Fluoxetine, Paroxetine Cytochrome P450 2C9 Warfarin (S-enantiomer) Elevated international normalized ratio — check within 2 weeks of starting or changing dose
St. John's Wort Cytochrome P450 3A4 inducer + weak serotonin reuptake transporter inhibition Prescription antidepressants Reduces antidepressant levels + additive serotonergic risk — avoid combination
Special Populations — Prescribing Principles
Pregnancy
Key Considerations
  • Untreated depression carries its own fetal risks — weigh against medication risk
  • Preferred: sertraline and escitalopram (most safety data, lowest placental transfer)
  • Avoid paroxetine when possible (cardiovascular malformation signal)
  • Neonatal adaptation syndrome in ~30% of third-trimester-exposed neonates — transient, resolves in 2 weeks
  • Black-box warning for suicidality applies regardless of pregnancy
Lactation
Relative Infant Dose
  • Key measure: relative infant dose (infant weight-adjusted dose as percent of maternal dose)
  • Sertraline: lowest relative infant dose — preferred first choice
  • Paroxetine: also low relative infant dose — acceptable
  • Fluoxetine: higher relative infant dose plus long neonatal half-life (norfluoxetine) — avoid when alternatives exist
  • Individualize based on maternal illness severity and infant age
Elderly (>65)
Modified Prescribing
  • Start at half adult dose; titrate slowly
  • Avoid tertiary tricyclic antidepressants (Beers Criteria) — anticholinergic burden, fall risk
  • Preferred: escitalopram or sertraline
  • Citalopram maximum 20 mg per day in patients over 60 (QTc risk)
  • Monitor sodium at baseline and 4 weeks (syndrome of inappropriate antidiuretic hormone secretion risk several-fold higher)
  • Check orthostatic blood pressure — alpha-1 blockade causes falls
Serotonin Syndrome versus Neuroleptic Malignant Syndrome

Serotonin syndrome: rapid onset (hours), clonus and hyperreflexia, serotonergic drug combination, treat with cyproheptadine and benzodiazepines. Neuroleptic malignant syndrome: slow onset (24 to 72 hours or more), lead-pipe rigidity and bradyreflexia, dopamine antagonist precipitant, treat with bromocriptine and dantrolene. Clonus is the key distinguishing finding.