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Imipramine (Tofranil)

TCA • Last reviewed 2025-09-27

General information

Imipramine is a tertiary amine TCA indicated for major depressive disorder and remains a second-line option when modern agents fail. It is also approved for nocturnal enuresis in children aged ≥6 years.

Combined imipramine + desipramine plasma levels correlate with efficacy (goal 150–300 ng/mL); concentrations above 350 ng/mL markedly increase anticholinergic and cardiac toxicity.

Imipramine exhibits strong anticholinergic, antihistamine, and alpha-adrenergic blockade, causing sedation, orthostasis, weight gain, and constipation.

Baseline ECG is recommended before initiating therapy in adults over 40 or those with cardiovascular disease due to QT prolongation and conduction delay risk.

Dosing & administration

Depression: start 25–50 mg at bedtime; increase by 25–50 mg every 3–7 days to 150–200 mg/day (divided or bedtime).

Nocturnal enuresis: 10–25 mg at bedtime; max 75 mg (age-dependent).

Adjust dose based on TDM and tolerability; reduce in hepatic impairment or CYP2D6 poor metabolizers.

Mechanism of action

Blocks serotonin and norepinephrine reuptake transporters; secondary effects include muscarinic, histamine H1, and alpha-1 receptor antagonism.

Metabolism & pharmacokinetics

Peak concentration 2–6 h post-dose. Metabolized hepatically (CYP2D6/CYP1A2) to desipramine. Elimination half-life ~19–24 h; elimination primarily renal as metabolites.

Drug interactions

Avoid MAOIs, cisapride, and serotonergic combinations (risk of serotonin syndrome/QT).

CYP2D6 inhibitors (fluoxetine, paroxetine, quinidine) raise levels; enzyme inducers (carbamazepine) reduce efficacy.

Alcohol and other CNS depressants enhance sedation; anticholinergics increase cognitive adverse effects.

Monitoring & safety checks

Discontinuation guidance

Taper gradually over ≥4 weeks to minimize cholinergic rebound, irritability, and insomnia.

References

  1. Imipramine Prescribing Information — DailyMed
  2. TDM of imipramine and desipramine — Ther Drug Monit (2022)
  3. Guideline on nocturnal enuresis management (2021)

Educational use only — verify details in current prescribing information and authoritative clinical guidelines before making prescribing decisions.