Imipramine

Imipramine is the first tricyclic antidepressant, a tertiary amine converted to the active secondary amine desipramine. It is used for depression, nocturnal enuresis in children and, in specialist practice, panic disorder. It carries the full tricyclic burden of anticholinergic, orthostatic and cardiac effects.

Classification. Tricyclic antidepressant, tertiary amine.

Mechanism. Inhibits serotonin and noradrenaline reuptake (noradrenaline more through desipramine), with antimuscarinic, antihistamine and alpha-1 blocking effects and sodium channel blockade.

Pharmacokinetics. Well absorbed; extensive first-pass metabolism. CYP2C19 and CYP1A2 demethylate it to desipramine; CYP2D6 hydroxylates both. Half-life about 11 to 25 hours for imipramine and 12 to 24 hours for desipramine. Combined concentration of about 150 to 300 ng/mL is the usual range when measured.

All regimens are oral with no loading dose.

Major depression, adults.

• Start 25 mg at night, or 25 mg three times daily.
• Titration: increase by 25 mg every 3 to 7 days to 100 to 150 mg daily.
• Maximum 200 mg daily as an outpatient; up to 300 mg daily in hospital under specialist care.
• Duration: at least 6 months after remission.

Older adults. Start 10 mg; usual 30 to 50 mg daily; do not exceed 100 mg daily without specialist advice.

Nocturnal enuresis, children aged 6 years and over. 25 mg one hour before bedtime. If response is inadequate after 1 week, increase to 50 mg (under 12 years) or 75 mg (12 years and over). Maximum 2.5 mg/kg daily. Treat for up to 3 months and stop gradually.

Panic disorder (specialist use). Start 10 mg at night, increase slowly to 50 to 150 mg daily.

Contraindications. Recent myocardial infarction, arrhythmias, heart block, mania, MAOI use now or within 14 days of stopping it, hypersensitivity. Caution in epilepsy, narrow-angle glaucoma, urinary retention and prostatic hypertrophy.

Serious adverse effects. Boxed-warning-level risk of suicidal thinking and behaviour in under 25 years. Arrhythmia, QT and QRS prolongation, postural hypotension, seizures (dose-related), serotonin syndrome, urinary retention, delirium, hyponatraemia, mania, rare blood dyscrasias. In overdose: coma, seizures, QRS over 100 ms and ventricular arrhythmia.

Common adverse effects. Dry mouth, constipation, blurred vision, sweating, tachycardia, tremor, sedation, weight gain, sexual dysfunction.

Interactions. CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, terbinafine), fluvoxamine and ritonavir raise levels. Rifampicin and carbamazepine lower levels. QT-prolonging drugs, anticholinergics and sedatives add to toxicity. Adrenaline and noradrenaline given parenterally can cause marked hypertension.

Common prescribing errors. Using doses over 2.5 mg/kg daily in children; giving to patients with recent myocardial infarction; large dispensed quantities in patients at risk of self-harm.

Special groups.

• Pregnancy: use only if benefit outweighs risk; neonatal withdrawal symptoms possible.
• Breastfeeding: low infant levels; acceptable with monitoring.
• Children: enuresis use only, with an ECG if there is a family history of sudden cardiac death.
• Older adults: avoid where possible; start 10 mg.
• Kidney impairment: no adjustment; start low.
• Liver impairment: lower dose; avoid in severe disease.

Formulations. Tablets 10 mg, 25 mg and 50 mg in most regions. Give at night in a single dose once settled. No infusion form in most regions.

Baseline. ECG in patients over 40 years or with cardiac disease, lying and standing blood pressure, mood history including past mania, suicide risk, sodium in older adults, bladder symptoms, medicines list.

Monitoring. Review within 1 to 2 weeks and after each dose change for suicidality. Repeat the ECG if the dose exceeds 100 mg daily or an interacting drug is added. Check sodium 2 to 4 weeks after starting in high-risk patients; review the need for the drug if sodium falls under 130 mmol/L and stop it if under 125 mmol/L or if symptomatic. Measure a trough level if response is poor or adherence uncertain.

Stopping. Taper over at least 4 weeks.

Referral and escalation. Refer to psychiatry for suicidal intent, psychosis, mania or failure of two adequate courses. Overdose, QRS over 100 ms, seizures or syncope needs emergency care.