Phenelzine

Phenelzine is an irreversible, nonselective monoamine oxidase inhibitor (MAOI) hydrazine used for depression that has not responded to other antidepressants, especially atypical depression, and in specialist practice for panic and social anxiety disorders. Its dangers are hypertensive crisis with tyramine-rich foods and sympathomimetic drugs, and serotonin syndrome with serotonergic drugs.

Classification. Irreversible nonselective MAO-A and MAO-B inhibitor, hydrazine structure.

Mechanism. Permanently inactivates both MAO isoenzymes, raising stores of serotonin, noradrenaline and dopamine. Enzyme activity returns only as new enzyme is made, over about 2 weeks after the last dose.

Pharmacokinetics. Well absorbed orally. Metabolised mainly by oxidation and acetylation, with some inhibition of CYP2C and GABA transaminase. Plasma half-life about 12 hours, but the pharmacodynamic effect lasts about 2 weeks. Response may take 2 to 6 weeks.

All regimens are oral with no loading dose.

Treatment-resistant or atypical depression, adults (specialist use).

• Start 15 mg three times daily.
• Titration: increase to 60 mg daily in divided doses over the first 2 to 4 weeks based on response and blood pressure; further increase to a maximum of 90 mg daily under specialist care if needed.
• Maintenance after response: reduce gradually to the lowest effective dose, often 15 mg daily or on alternate days.
• Duration: at least 6 months after remission.

Older adults. Start 15 mg daily or on alternate days and increase slowly; usual maximum 45 mg daily.

Switching. Wait at least 14 days after stopping phenelzine before starting another antidepressant, and at least 14 days after stopping a non-MAOI antidepressant before starting phenelzine (5 weeks after fluoxetine).

Contraindications. Phaeochromocytoma, cerebrovascular disease, heart failure, severe cardiovascular disease, liver disease or abnormal liver tests, severe kidney impairment, use with other antidepressants, sympathomimetics, pethidine, tramadol, dextromethorphan, buspirone, triptans or levodopa, a planned general anaesthetic or major surgery within 10 days, children under 16 years.

Serious adverse effects. Boxed-warning-level risk of suicidal thinking and behaviour in under 25 years. Hypertensive crisis (severe occipital headache, palpitations, neck stiffness, sweating), serotonin syndrome, orthostatic hypotension, hepatotoxicity, peripheral neuropathy from pyridoxine depletion, mania, seizures, oedema.

Common adverse effects. Dizziness on standing, insomnia, weight gain, dry mouth, constipation, sexual dysfunction, sedation, oedema.

Interactions. Tyramine-rich foods (mature cheese, cured and fermented meats, fermented soya products, yeast extracts, broad beans, tap or unpasteurised beer, overripe fruit) can cause hypertensive crisis. Khat contains cathinone and must be avoided. Pseudoephedrine, ephedrine, phenylephrine, amphetamines and methylphenidate can cause crisis. SSRIs, SNRIs, tricyclics, tramadol, pethidine and dextromethorphan can cause serotonin syndrome. Insulin and oral hypoglycaemics are potentiated.

Common prescribing errors. Starting too soon after another antidepressant; omitting dietary and drug counselling; supplying over-the-counter cold remedies without warning; forgetting the 14 day washout after stopping.

Special groups.

• Pregnancy: avoid; limited data and risk of hypertensive effects.
• Breastfeeding: avoid; no safety data.
• Children: not advised in under 16 years.
• Older adults: start low; orthostatic hypotension and falls.
• Kidney impairment: caution; avoid in severe impairment.
• Liver impairment: contraindicated.

Formulations. Tablets 15 mg. Give in divided doses, the last no later than mid-afternoon to limit insomnia. Give the patient written warnings and a treatment card listing food and drug restrictions.

Baseline. Blood pressure lying and standing, liver tests, kidney function, mood history including past mania, suicide risk, medicines list including over-the-counter drugs, dietary and khat use.

Monitoring. Blood pressure at each review and with each dose increase; review within 1 to 2 weeks for suicidality. Repeat liver tests if symptoms of liver injury arise. Stop the drug if hypertension is sustained or liver injury develops.

Stopping. Taper over at least 4 weeks; keep dietary and drug restrictions for 14 days after the last dose.

Referral and escalation. Prescribing is restricted to psychiatry or under specialist advice. Severe headache with palpitations or blood pressure over 180/120 mmHg is a hypertensive emergency needing immediate hospital care and parenteral blood pressure control.