Phenelzine

Indications

• FDA-approved for adult patients with depression characterized as atypical, nonendogenous, or neurotic who have failed other therapy.
• The label positions it as a treatment for patients who have not responded to a trial of other antidepressant drug therapy.
• Off-label but well supported for treatment-resistant major depression, particularly with hypersomnia, hyperphagia, and rejection sensitivity.
• Off-label for social anxiety disorder, where controlled trials showed effect sizes larger than those achieved by SSRIs.
• Off-label for panic disorder and for posttraumatic stress disorder when first-line and second-line agents have failed.
• Not approved for pediatric use, and safety and efficacy in children and adolescents have never been established.

Mechanism of action

• Forms an irreversible covalent bond with both MAO-A and MAO-B, so activity returns only as new enzyme is synthesized over about 2 weeks.
• MAO-A inhibition raises synaptic serotonin, norepinephrine, and dopamine, producing broad monoaminergic enhancement not achievable with reuptake blockers.
• MAO-A inhibition in gut wall and liver removes first-pass degradation of dietary tyramine, which is the basis of the hypertensive crisis risk.
• Absorbed tyramine displaces norepinephrine from sympathetic nerve terminals, causing an abrupt pressor surge minutes to hours after ingestion.
• A hydrazine derivative that also inhibits several other enzymes and can deplete pyridoxine, explaining the paresthesias seen in some patients.

Pharmacokinetics

• Rapidly absorbed orally with peak plasma concentrations within 2 to 4 hours of an oral dose, and food does not meaningfully interfere.
• Plasma half-life is only about 11.6 hours, but this number is clinically irrelevant because enzyme inhibition is irreversible.
• Metabolized largely by acetylation and by oxidation, with phenylacetic acid and parahydroxyphenylacetic acid as principal metabolites.
• Slow acetylators may reach higher concentrations and experience more adverse effects at any given dose than rapid acetylators.
• Functional recovery of monoamine oxidase requires roughly 2 weeks after the last dose, which sets every washout interval for this drug.

Dosing

• Start 15 mg PO three times daily, then increase to at least 60 mg/day fairly rapidly because lower doses often fail.
• Doses of 60-90 mg/day are usually required for response; 90 mg/day is the maximum recommended in the label.
• Allow up to 4 weeks at the target dose before declaring the trial a failure, and do not stop prematurely for early jitteriness alone.
• Once a sustained response is achieved, the dose may be reduced slowly to a maintenance level as low as 15 mg daily or every other day.
• Supplied only as 15 mg tablets; the tyramine-restricted diet must start with the first dose and continue for 2 weeks after the last dose.
• Taper gradually when discontinuing, and observe a full 14-day washout before starting any serotonergic or sympathomimetic agent.

Adverse effects

• Orthostatic hypotension is the most common dose-limiting effect and often appears paradoxically several weeks into treatment.
• Weight gain, peripheral edema, and daytime sedation are frequent, while insomnia and afternoon somnolence are also commonly reported.
• Sexual dysfunction including anorgasmia occurs in a large minority of patients and is a leading reason for discontinuation.
• Hypertensive crisis with occipital headache, stiff neck, palpitations, and photophobia follows dietary tyramine or sympathomimetic exposure.
• Serotonin syndrome with hyperthermia, rigidity, clonus, and autonomic instability can be fatal when serotonergic drugs are combined.
• Pyridoxine deficiency causing paresthesias, and rare hepatocellular injury characteristic of hydrazine drugs, are both described.

Monitoring

• Check supine and standing blood pressure at every visit, and teach the patient to monitor at home during the titration period.
• Give written tyramine diet instructions and confirm understanding before the first dose; the diet continues 2 weeks after stopping.
• Obtain baseline liver enzymes and repeat if malaise, jaundice, or anorexia develops, given the hydrazine hepatotoxicity signal.
• Ask about paresthesias at each visit and consider pyridoxine 50-100 mg daily if they appear during long-term treatment.
• Review the complete medication list including over-the-counter cold remedies at every encounter, since new agents are the usual source of harm.

Interactions

• Absolutely contraindicated with SSRIs, SNRIs, tricyclics, triptans, tramadol, meperidine, linezolid, methylene blue, and St. John's wort.
• Contraindicated with sympathomimetics including pseudoephedrine, phenylephrine, amphetamines, and with dextromethorphan and buspirone.
• Requires a 14-day washout in both directions with most antidepressants, and a 5-week washout after stopping fluoxetine.
• Contraindicated in pheochromocytoma, congestive heart failure, hepatic disease, and with a history of frequent severe headache.
• Avoid meperidine entirely; morphine, fentanyl, and hydromorphone are safer opioid choices when analgesia cannot be avoided.

Special populations

• Pregnancy data are sparse and animal studies suggest possible fetal harm; the tyramine and drug restrictions further complicate obstetric care.
• Lactation data are essentially absent, so an alternative antidepressant is preferred for a woman who intends to breastfeed.
• Not approved and not recommended in patients under 16 years of age, and dietary adherence is difficult to guarantee in adolescents.
• Older adults are especially vulnerable to orthostatic hypotension and falls; start at 15 mg daily and titrate very cautiously.
• Contraindicated in significant hepatic impairment; use with caution and reduced doses in severe renal impairment.

Clinical pearls

• Underdosing is the usual cause of failure; most responders need 60-90 mg/day.
• Diet and drug restrictions persist 2 weeks after the last dose because MAO must be resynthesized.
• Fluoxetine needs a 5-week washout before starting an MAOI; 14 days is not enough.