Tranylcypromine

Indications

• FDA-approved for the treatment of major depressive disorder without melancholia in adults who have not responded to other therapy.
• The label restricts use to patients in whom other antidepressant treatments have failed, reflecting the required dietary vigilance.
• Off-label for treatment-resistant bipolar depression, where its activating profile can help anergic and hypersomnic presentations.
• Off-label for social anxiety disorder and panic disorder after first-line and second-line pharmacotherapy have proved inadequate.
• Often chosen over phenelzine when sedation and weight gain would be unacceptable, since it is stimulating rather than sedating.
• Not approved for pediatric use; safety and effectiveness in patients under 18 years have not been established.

Mechanism of action

• Irreversibly inhibits both MAO-A and MAO-B, so monoamine oxidase activity recovers only through new enzyme synthesis over roughly 2 weeks.
• Structurally a cyclopropylamine analogue of amphetamine, which gives it mild releasing and reuptake-inhibiting properties beyond enzyme blockade.
• These amphetamine-like actions explain the activating profile, the potential for insomnia, and occasional reports of misuse at high doses.
• Gut and hepatic MAO-A inhibition abolishes first-pass metabolism of dietary tyramine, allowing pressor amines into the systemic circulation.
• Elevated synaptic serotonin, norepinephrine, and dopamine account for both antidepressant efficacy and the risk of serotonin syndrome.

Pharmacokinetics

• Rapidly absorbed with peak plasma concentrations at about 1 to 2 hours; divided daily dosing is used despite the irreversible effect.
• Plasma half-life is only about 1.5 to 3.2 hours, which bears no relation to the duration of pharmacologic action.
• Cleared largely by oxidative metabolism with subsequent renal excretion of metabolites; ring hydroxylation and N-acetylation both occur.
• Enzyme activity returns over approximately 1 to 2 weeks after the last dose, which defines the mandatory washout interval.
• It is a weak inhibitor of CYP2A6 and CYP2C19, though the clinically dominant interactions are pharmacodynamic rather than metabolic.

Dosing

• Start 30 mg/day PO in divided doses, typically 20 mg in the morning and 10 mg in the afternoon to limit insomnia.
• If there is no response after 2 weeks, increase by 10 mg/day at intervals of 1 to 3 weeks up to the maximum of 60 mg/day.
• Avoid dosing after mid-afternoon because the activating effect commonly produces initial insomnia and agitation.
• Supplied only as 10 mg tablets; the tyramine-restricted diet begins with the first dose and continues 2 weeks past the last dose.
• Some experts exceed 60 mg/day in refractory cases, but this is off-label and requires intensive blood pressure monitoring.
• Taper gradually when stopping and observe a 14-day washout before any serotonergic or sympathomimetic agent is started.

Adverse effects

• Insomnia and overstimulation are the most characteristic effects and often require the last dose to be moved earlier in the day.
• Orthostatic hypotension is common and dose limiting despite the stimulant profile, and it contributes to falls in older adults.
• Hypertensive crisis presents with severe occipital headache, palpitations, neck stiffness, nausea, sweating, and photophobia.
• Serotonin syndrome with hyperthermia, clonus, rigidity, and autonomic instability can be fatal when serotonergic drugs are combined.
• Weight gain is less than with phenelzine, but sexual dysfunction, dry mouth, and edema remain frequent complaints.
• Rare hepatocellular injury, and abuse or dependence at supratherapeutic doses, have both been described with this agent.

Monitoring

• Measure supine and standing blood pressure at every visit and instruct the patient in home monitoring during titration.
• Provide written tyramine dietary instructions before the first dose and reinforce that they continue 2 weeks after stopping.
• Teach the patient to seek emergency care for sudden severe headache, chest pain, or palpitations rather than self-treating.
• Review every prescription, over-the-counter product, and supplement at each visit, since new agents drive most serious events.
• Obtain baseline liver enzymes and recheck if malaise, anorexia, or jaundice develops during long-term treatment.

Interactions

• Contraindicated with SSRIs, SNRIs, tricyclics, triptans, tramadol, meperidine, linezolid, methylene blue, and St. John's wort.
• Contraindicated with all sympathomimetics including pseudoephedrine, phenylephrine, amphetamines, and with dextromethorphan and buspirone.
• Requires a 14-day washout in both directions for most antidepressants, and a 5-week washout after stopping fluoxetine.
• Contraindicated in pheochromocytoma, cerebrovascular disease, cardiovascular disease, and significant hepatic impairment.
• Avoid meperidine absolutely; morphine, fentanyl, and hydromorphone are the preferred opioids when analgesia is unavoidable.

Special populations

• Human pregnancy data are very limited and the drug crosses the placenta; alternatives are preferred unless the depression is refractory.
• Lactation data are essentially absent, so breastfeeding is generally discouraged during treatment with this agent.
• Safety and effectiveness in patients under 18 years have not been established, and pediatric use is not recommended.
• Older adults are at higher risk of orthostatic hypotension and falls; start at 10 mg daily and increase very gradually.
• Contraindicated in hepatic disease; use cautiously with renal impairment because metabolites are renally eliminated.

Clinical pearls

• The most activating MAOI; keep the last dose before mid-afternoon to protect sleep.
• Less weight gain and sedation than phenelzine, but the same absolute diet and drug restrictions.
• Hypertensive crisis is a boxed warning here, not just a precaution.