Clomipramine

Clomipramine is a tertiary-amine tricyclic antidepressant with the strongest serotonin reuptake inhibition of its class. It is used for obsessive-compulsive disorder, depression, phobic and panic disorders and, as an adjunct, cataplexy in narcolepsy. It is typically used when SSRIs have failed in obsessive-compulsive disorder.

Classification. Tricyclic antidepressant, chlorinated tertiary amine.

Mechanism. Potent serotonin reuptake inhibition; its active metabolite desmethylclomipramine inhibits noradrenaline reuptake. It also has antimuscarinic, antihistamine and alpha-1 blocking effects and lowers the seizure threshold.

Pharmacokinetics. Well absorbed; extensive first-pass metabolism by CYP2C19, CYP2D6, CYP1A2 and CYP3A4 to desmethylclomipramine. Half-life about 20 to 40 hours (metabolite 54 to 77 hours).

All regimens are oral with no loading dose.

Obsessive-compulsive disorder, adults.

• Start 25 mg daily, taken with meals.
• Titration: increase over the first 2 weeks to 100 mg daily in divided doses with meals, then by 25 mg at weekly intervals as needed.
• Usual 100 to 200 mg daily; maximum 250 mg daily. After titration, the dose may be given once at bedtime.
• Judge response after 8 to 12 weeks at an adequate dose.

Depression, phobic and panic disorders. Start 10 mg daily and increase gradually to 30 to 150 mg daily, in divided doses or as a single bedtime dose. Maximum 150 mg daily (250 mg in hospital under specialist care).

Cataplexy with narcolepsy (specialist use). 10 mg daily, increased to a usual 10 to 75 mg daily.

Children and adolescents aged 10 to 17 years with obsessive-compulsive disorder. Start 25 mg daily, increase over 2 weeks to 3 mg/kg or 100 mg daily, whichever is smaller. Maximum 3 mg/kg or 200 mg daily, whichever is smaller.

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. Seizures (dose-related, rising sharply over 250 mg daily), arrhythmia, QT and QRS prolongation, postural hypotension, serotonin syndrome, hyponatraemia, mania, hepatic dysfunction. In overdose: coma, seizures, QRS over 100 ms and ventricular arrhythmia.

Common adverse effects. Dry mouth, constipation, sweating, tremor, sedation, dizziness, weight gain, sexual dysfunction (delayed ejaculation, anorgasmia).

Interactions. Fluvoxamine, fluoxetine, paroxetine, bupropion, terbinafine and ritonavir raise levels. Rifampicin and carbamazepine lower levels. Serotonin syndrome risk rises with tramadol, triptans, linezolid and other serotonergic drugs. QT-prolonging drugs and sedatives add to toxicity.

Common prescribing errors. Exceeding 250 mg daily; dispensing large quantities to patients at risk of self-harm; combining with an SSRI without level or ECG checks.

Special groups.

• Pregnancy: use only if benefit outweighs risk; neonatal withdrawal symptoms possible.
• Breastfeeding: moderate transfer; monitor the infant for sedation.
• Children: used for obsessive-compulsive disorder from 10 years only.
• Older adults: avoid where possible; start 10 mg.
• Kidney impairment: no adjustment; start low.
• Liver impairment: lower dose and monitor liver tests; avoid in severe disease.

Formulations. Capsules 10 mg, 25 mg, 50 mg and 75 mg; modified-release tablets in some regions. Take with food in divided doses during titration.

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

Monitoring. Review within 1 to 2 weeks and after each dose change for suicidality. Repeat the ECG at doses over 150 mg daily or when an interacting drug is added. Repeat liver tests if symptoms arise. 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.

Stopping. Taper over at least 4 weeks; discontinuation symptoms are common.

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