Phenelzine

Phenelzine is primarily used in the treatment of major depressive disorder, including treatment-resistant depression. Modern guidance on classic MAOIs recommends considering phenelzine, tranylcypromine, or isocarboxazid after insufficient response to other antidepressant treatments and before electroconvulsive therapy when a rapid treatment response is not required.^[6]

Patients with atypical depression may respond particularly well to phenelzine,^[7] but evidence also supports the use of classic MAOIs in melancholic depression.^[8] Phenelzine may be especially useful when depression is accompanied by premorbid anxiety, comorbid panic disorder, or other treatment-resistant anxiety symptoms, reflecting its additional effects on GABA metabolism.^[6]

Phenelzine has also been studied or used in anxiety-related and other psychiatric conditions including panic disorder,^[9] social anxiety disorder,^[10] post-traumatic stress disorder (PTSD),^[11] obsessive–compulsive disorder (OCD),^[12][13] dysthymia,^[14] bipolar depression,^[15] and bulimia nervosa.^[16]

Common or clinically important adverse effects of phenelzine include orthostatic hypotension, dizziness, dry mouth, constipation, urinary retention, sedation or somnolence, insomnia, weight gain, edema, sweating, sexual dysfunction, and reduced vitamin B₆ levels or pyridoxine deficiency. Hypoglycemia and clinically relevant cytochrome P450 interactions may also occur, particularly with hydrazine MAOIs such as phenelzine.^[6]

Rare adverse effects reported with phenelzine include hypomania or mania, psychosis, hepatotoxicity, and acute liver failure, the last of which has been reported mainly in susceptible individuals, including people with pre-existing liver damage, old age, long-term effects of alcohol consumption, or viral infection.^[17]

Phenelzine is contraindicated in patients who are unable or unwilling to follow the required dietary tyramine restrictions and medication precautions, and in patients with pheochromocytoma because of the risk of hypertensive emergency. This contraindication reflects a preventable risk: tyramine-related hypertensive emergencies are uncommon when dietary and medication precautions are followed, and modern food standards have substantially reduced excessive tyramine exposure compared with the period when MAOIs were first introduced.^[6] It is also contraindicated with drugs, supplements, or recreational drugs that have significant serotonin reuptake inhibition or significant serotonin-releasing activity, because of the risk of serotonin toxicity. Examples include selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), clomipramine, imipramine, MDMA, and certain analgesics such as meperidine, tramadol, methadone, tapentadol, dextromethorphan, dextropropoxyphene, pentazocine, and levorphanol.^[6]

Concomitant use of multiple MAO-inhibiting agents is generally listed as contraindicated or avoided in prescribing guidance. For combinations of classic MAOIs with one another, the caution is based mainly on limited safety data and the fact that routine long-term coadministration usually has little therapeutic rationale, since classic MAOIs already inhibit both MAO-A and MAO-B irreversibly. This concern is not the same as the serotonin-toxicity risk seen when MAOIs are combined with drugs that significantly inhibit serotonin reuptake or release serotonin. A classic MAOI-to-classic MAOI overlap is not expected to cause serotonin toxicity unless another serotonergic drug with clinically significant serotonin reuptake inhibition or serotonin-releasing activity is also involved.^[6]

This should be distinguished from medically supervised switching between classic MAOIs, where shorter washouts, direct switches, or cautious cross-tapering have been used by some expert clinicians under close monitoring. In that context, temporary MAOI-to-MAOI overlap may have practical utility, such as reducing relapse risk or avoiding a prolonged untreated interval when changing from one MAOI to another because of adverse effects or inadequate response.^[6][18]

Drugs described as "stimulants" are not a uniform pharmacological category and are not uniformly contraindicated with phenelzine. Modern MAOI guidance distinguishes amphetamines by dose: medium or high doses are avoided because of serotonin-releasing activity, while low-dose amphetamines are listed as a strong relative contraindication rather than an absolute contraindication. When used by experienced clinicians, they require specialist caution, reduced starting doses, slow titration, and blood-pressure monitoring. Lisdexamfetamine may be lower risk than some other amphetamine preparations because of its lower peak plasma concentration and longer time to peak concentration.^[6]

Ephedrine and pseudoephedrine are also relative, not absolute, contraindications. They are generally avoided or used only cautiously at reduced doses with monitoring because they may raise blood pressure. Pseudoephedrine is less potent than ephedrine, and ephedrine is less potent than amphetamine.^[6]

Phenelzine generally does not need to be stopped before surgery solely because anesthesia is planned. Modern guidance states that MAOI treatment should not be discontinued without conferring with the prescribing psychiatrist, because depressive relapse risk may outweigh perioperative interaction risk when anesthetic and analgesic agents are chosen carefully.^[6] In perioperative care, the main drugs to avoid are those with significant serotonin reuptake inhibition or serotonin-releasing activity, especially serotonergic opioid analgesics such as meperidine (pethidine) and tramadol. Other opioids listed as serotonergic or uncertain-risk include methadone, tapentadol, dextromethorphan, dextropropoxyphene, pentazocine, and levorphanol.^[6]

Other perioperative agents requiring avoidance or special caution include pancuronium, a muscle relaxant sometimes used with general anesthetics, and methylene blue, which has clinically relevant MAOI activity itself. These are not avoided because they are serotonin reuptake inhibitors. Direct-acting vasopressors such as epinephrine, norepinephrine, and phenylephrine are not absolute contraindications, but lower initial doses and careful titration are advised because their pressor effects may be potentiated. Indirect sympathomimetics such as ephedrine are generally avoided or used only cautiously because they may raise blood pressure.^[6]

Methylphenidate should be distinguished from amphetamines because it is primarily a dopamine reuptake inhibitor rather than a monoamine releaser. Modern guidance lists methylphenidate, modafinil, and bupropion among augmenting agents that can be combined with MAOIs using a low test dose, slow dose increases, and monitoring.^[6] A review of stimulant–MAOI combinations found no documented reports of hypertensive crises or fatalities when stimulants were cautiously added to an MAOI.^[19]

Other relative contraindications or situations requiring special caution include uncontrolled hypertension or hypotension, diabetes mellitus, pregnancy, breastfeeding, bipolar disorder without mood-stabilizing treatment, and lack of recent health assessment.^[6]

Phenelzine requires attention to dietary tyramine and clinically important drug interactions, but severe tyramine-related hypertensive reactions are uncommon when dietary and medication precautions are followed. Modern food standards have substantially reduced tyramine levels in many foods compared with the 1950s and 1960s, making excessive tyramine ingestion less likely than in earlier decades. The highest-risk foods are generally those that are fermented, matured, or spoiled, including some aged cheeses, some artisan beers, fermented meats, and fermented products such as soy sauce, miso, tempeh, sauerkraut, Marmite, and kimchi.^[6]

Because inhibition of monoamine oxidase reduces the breakdown of dietary tyramine in the gastrointestinal tract and liver, excessive tyramine intake can raise blood pressure through peripheral norepinephrine release. If this causes a marked blood-pressure rise, the reaction is usually self-limiting and typically reaches its maximum within about 2 hours. Modern guidance advises against rapid blood-pressure reduction outside appropriate medical supervision, because overtreatment can cause hypotensive overshoot; sublingual nifedipine is specifically discouraged. The Cambridge Prescriber's Guide recommends benzodiazepine administration with blood-pressure monitoring, with emergency clinicians using clinical judgment in severe cases and considering short-acting agents such as phentolamine when additional treatment is needed.^[6] A safety review reported that deaths from tyramine/MAOI-induced hypertension are extremely rare and that no deaths from MAOI-induced hypertension had been reported in the medical literature for several decades.^[20]

Phenelzine should not be combined with drugs that have significant serotonin reuptake inhibition or significant serotonin-releasing activity, because of the risk of serotonin toxicity. Examples include selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), clomipramine, imipramine, MDMA, and certain analgesics such as meperidine, tramadol, methadone, tapentadol, dextromethorphan, dextropropoxyphene, pentazocine, and levorphanol. This serotonin-toxicity mechanism is distinct from the usual caution about overlapping MAO-inhibiting agents. Classic MAOI-to-classic MAOI overlap is not expected to cause serotonin toxicity by itself, although routine long-term coadministration is generally avoided because of limited safety data and lack of usual therapeutic rationale.^[6]

Indirect monoamine-releasing sympathomimetics without significant serotonergic activity, such as ephedrine and pseudoephedrine, are not absolute contraindications, but may increase blood pressure and are generally avoided or used only cautiously at reduced doses with monitoring. Pseudoephedrine is considered less potent than ephedrine, and ephedrine less potent than amphetamine.^[6]

Direct adrenergic agents such as epinephrine, norepinephrine, phenylephrine, isoproterenol, and dobutamine may be used when clinically necessary, but reduced initial doses and careful monitoring are advised because of possible potentiation.^[6]

Phenelzine has also been linked to reduced vitamin B₆ levels and pyridoxine deficiency.^[21] Modern guidance considers pyridoxine hydrochloride supplementation advisable with phenelzine, either from the start of treatment or if related adverse effects appear, according to clinician preference, and specifically recommends it when paresthesia or peripheral neuropathy occurs.^[6] Transaminases such as GABA-transaminase have been shown to be dependent upon vitamin B₆^[22] and may be involved in a potentially related process, since the phenelzine metabolite phenylethylidenehydrazine (PEH) is a GABA-transaminase inhibitor. Both phenelzine and vitamin B₆ are rendered inactive upon these reactions occurring. The pyridoxine form of B₆ is generally preferred for supplementation in this context, since this form has been shown to reduce hydrazine toxicity from phenelzine and, in contrast, the pyridoxal form has been shown to increase the toxicity of hydrazines.^[23]

Phenelzine, also known as 2-phenylethylhydrazine or phenylethylamine hydrazide, is a phenethylamine and hydrazine derivative.^[37][38] It is the hydrazide of β-phenethylamine and can also be referred to as N-aminophenethylamine.^[37][38]

Synthesis of phenelzine was first described by Emil Votoček and Otakar Leminger in 1932.^[47][48]

Phenelzine showed promise in a phase II clinical trial from March 2020 in treating prostate cancer.^[49] Phenelzine has also been shown to have neuroprotective effects in animal models.^[50][51][52]