imipramine

General Information

Imipramine is a tertiary amine tricyclic antidepressant used in treatment-resistant depression and pediatric nocturnal enuresis; its active metabolite desipramine adds potent noradrenergic activity.

Therapeutic benefit correlates with combined imipramine + desipramine concentrations (goal 150–300 ng/mL) guided by TDM; higher levels markedly increase anticholinergic and cardiac toxicity.

Substantial anticholinergic, antihistamine, and α-adrenergic blockade drive sedation, orthostasis, weight gain, constipation, and urinary retention; baseline ECG is advisable before initiating therapy in adults >40 years or those with cardiovascular disease.

The compare tool, the evidence library, and the Bipolar hub support side-by-side TCA counseling and augmentation planning.

Because of overdose lethality and cardiovascular risks, prescribers often restrict quantities and reserve imipramine for patients who fail SSRIs/SNRIs.

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Inhibits serotonin and norepinephrine reuptake transporters; desipramine metabolite enhances noradrenergic tone at steady state.

Antagonizes muscarinic, histamine H1, and α1-adrenergic receptors, explaining anticholinergic effects, sedation, weight gain, and orthostasis.

• SERT and NET inhibition.
• Strong M1, H1, and α1 antagonism.
• Sodium channel blockade contributes to arrhythmogenicity in overdose.

Metabolism and Pharmacokinetics

• Oral bioavailability ~40–60%; peak concentrations occur 2–6 hours post-dose.
• Hepatic metabolism via CYP2D6 (major) and CYP1A2/CYP3A4 to desipramine; half-life 12–24 hours (imipramine) and 12–30 hours (desipramine).
• Protein binding ~80%; elimination primarily renal as metabolites with <5% unchanged drug.
• Half-life extends in CYP2D6 poor metabolizers, elderly patients, and hepatic impairment, warranting lower dosing and TDM.

Dosing and Administration

• Depression (adult): typical starting doses are 25–50 mg at bedtime, with increases of 25–50 mg every 3–7 days to 150–200 mg/day (single bedtime dose or divided). Maximum 300 mg/day is typically reserved for inpatient settings with monitoring.
• Nocturnal enuresis (children ≥6 years): typical starting doses are 10–25 mg at bedtime, titrated by 10 mg weekly to 50 mg (ages 6–12) or 75 mg (≥12 years); tapers after 2–3 months are often used to reassess need.
• Starting and target doses are often reduced in older adults, hepatic impairment, or when co-administered with strong CYP2D6 inhibitors; slower titrations are common when tolerability issues arise.
• Tapers are typically gradual (≥4 weeks) to reduce cholinergic rebound, anxiety, and insomnia.

Monitoring & Labs

• Baseline ECG and electrolytes when cardiac risk is present or when higher doses are used; recheck ECG when symptoms (palpitations, syncope) occur or when QT-active drugs are added.
• Anticholinergic adverse effects (constipation, urinary retention, delirium), especially in older adults; dose reduction is often safer than adding more anticholinergics.
• TDM for suspected toxicity, nonadherence, or poor response, particularly when CYP2D6 inhibitors are co-prescribed.

TCAs have high overdose lethality; monitoring is as much about safety planning and dispensing quantities as it is about symptom response.

Adverse Effects

Interactions

• Contraindicated with MAOIs or within 14 days of MAOI therapy (hypertensive crisis/serotonin syndrome).
• Strong CYP2D6 inhibitors (fluoxetine, paroxetine, quinidine, bupropion) elevate imipramine/desipramine levels—dose reductions may be needed, and TDM can help guide dosing.
• CYP3A4 inducers (carbamazepine, rifampin) and smoking can lower exposure; dose may need adjustment based on response.
• Serotonergic agents increase serotonin syndrome risk; closer follow-up is often used when combinations occur.
• Additive QTc prolongation with antiarrhythmics, certain antipsychotics, or macrolide antibiotics—ECG monitoring is often considered when combining.
• Alcohol and CNS depressants exaggerate sedation; anticholinergics amplify cognitive impairment and urinary retention.

Other Useful Information

• Baseline ECG/electrolytes and periodic monitoring are often considered, particularly when doses exceed 150 mg/day.
• Therapeutic drug monitoring is valuable for poor response, suspected nonadherence, or signs of toxicity.
• Counseling often covers overdose risks and safe storage; limited dispensing with close follow-up is sometimes used.

References

1. Imipramine prescribing information — DailyMed (2025)
2. AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology — Pharmacopsychiatry (2018)
3. NICE clinical guideline: nocturnal enuresis in children and young people
4. APA Clinical Practice Guideline for the Treatment of Depression — American Psychiatric Association (2023)Guidelinedepressionclinical