Tricyclic Antidepressants

Tricyclic antidepressants (amitriptyline, nortriptyline, imipramine, clomipramine, doxepin, dosulepin, lofepramine) are effective in depression but are third-line because of anticholinergic effects and toxicity in overdose. They remain widely used at lower doses for neuropathic pain, migraine prophylaxis and enuresis, and clomipramine for obsessive-compulsive disorder.

Mechanism. They block serotonin and noradrenaline reuptake, and also antagonise histamine H1, muscarinic and alpha-1 receptors and block cardiac sodium channels. These secondary effects cause most adverse effects and the toxicity.

Pharmacokinetics. Well absorbed, highly protein bound, with half-lives of 15 to 40 hours, and metabolised by CYP2D6 and CYP2C19. Plasma levels vary 10-fold between people. Nortriptyline levels can guide dosing (50 to 150 ng/mL).

Differences. Amitriptyline is the most sedating and anticholinergic. Nortriptyline and lofepramine are better tolerated. Clomipramine is strongly serotonergic and the most effective for obsessive-compulsive disorder.

• Depression: after SSRIs and SNRIs have failed, or in severe or melancholic depression.
• Neuropathic pain, including HIV and diabetic neuropathy, and tension headache and migraine prophylaxis: amitriptyline 10 to 25 mg at night, increased every 1 to 2 weeks.
• Obsessive-compulsive disorder: clomipramine after an SSRI has failed.
• Enuresis (children over 6 years): imipramine 25 mg at bedtime, specialist use.
• Starting dose: 10 to 25 mg in older adults and with cardiac disease, with a baseline ECG over 40 years or with cardiac risk.
• Supply: limit quantity (up to 1 to 2 weeks) in patients at risk of self-harm.

Special groups. Pregnancy: use if needed, with the lowest dose; neonatal withdrawal is possible. Breastfeeding: nortriptyline and amitriptyline give small infant exposure. Children: enuresis and obsessive-compulsive disorder only. Older adults: avoid where possible because of delirium, falls and cardiac effects. Kidney impairment: start low. Liver impairment: reduce the dose by 50%. Regional: amitriptyline is cheap and widely available, but intentional overdose is dangerous, so limit supplies.

Adverse effects. Dry mouth, constipation, urinary retention, blurred vision, sedation, confusion, postural hypotension, weight gain, sweating, tachycardia, QRS and QT prolongation, seizures, and mania.

Overdose. Toxic ingestion is over 10 mg/kg; features are coma, seizures, hypotension and wide-complex arrhythmia. ECG QRS over 100 ms is treated with sodium bicarbonate 1 to 2 mmol/kg intravenously (target pH 7.45 to 7.55). Seizures need benzodiazepines.

Contraindications. Recent myocardial infarction, arrhythmia or heart block, mania, narrow-angle glaucoma, urinary retention, and monoamine oxidase inhibitors within 14 days.

Interactions. Fluoxetine, paroxetine, bupropion and terbinafine raise levels through CYP2D6 inhibition. Antimuscarinics, alcohol and sedatives add effect. Clonidine effect is opposed. Adrenaline in local anaesthetic raises blood pressure and arrhythmia risk.

Monitoring. Lying and standing blood pressure, ECG at baseline and after dose increases in at-risk patients, weight, bowel and bladder function, and nortriptyline plasma levels if needed.

Referral and escalation. Overdose, arrhythmia, delirium, or an urgent need to stop.