Tranylcypromine

Tranylcypromine is used to treat major depressive disorder, especially when depression has not responded sufficiently to other antidepressant treatments.^[9][10] Modern guidance on classic MAOIs recommends considering tranylcypromine, phenelzine, or isocarboxazid after insufficient response to other antidepressant treatments and before electroconvulsive therapy when a rapid treatment response is not required.^[8]

Tranylcypromine may be particularly considered when psychomotor retardation is prominent or when depression has predominantly melancholic or endogenous features, although modern expert guidance cautions that a strict division between tranylcypromine for melancholic depression and phenelzine for anxious depression is not always clinically reliable.^[8] The typical effective dose range is 30–60 mg/day, and expert clinicians may use doses up to 80–100 mg/day when clinically indicated, with greater side-effect burden at higher doses. Some improvement may occur within days or weeks, but the full antidepressant effect of a given dose may take 4–6 weeks.^[8]

In addition to major depressive disorder, tranylcypromine has been studied or used in other psychiatric conditions, including obsessive–compulsive disorder,^[11][12][13] panic disorder,^[14][15] and ADHD.^[16][17]

Systematic reviews and meta-analyses have reported that tranylcypromine is significantly more effective in the treatment of depression than placebo and has efficacy over placebo similar to that of other antidepressants such as tricyclic antidepressants.^[18][19]

Contraindications and precautions include:^{[9][10][20][8]}

• Inability or unwillingness to follow the required dietary tyramine restrictions and medication precautions.
• Pheochromocytoma, because of the risk of severe hypertensive reactions.
• Porphyria.
• Serious or unstable cardiovascular or cerebrovascular disease, depending on individual risk assessment. Stable hypertension is not itself a contraindication to classic MAOI treatment, because MAOIs commonly lower blood pressure and may cause orthostatic hypotension. Hypertensive reactions during MAOI treatment are mainly associated with tyramine ingestion or interacting sympathomimetic drugs rather than ordinary baseline hypertension itself.^[8]
• Foods containing substantial amounts of tyramine, especially spoiled, aged, cured, fermented, or matured foods. This is a dietary restriction rather than a contraindication to treatment itself.^[8]
• Drugs with significant serotonin reuptake inhibition or serotonin-releasing activity, because of the risk of serotonin toxicity. Examples include selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, clomipramine, imipramine, tramadol, tapentadol, methadone, meperidine, dextromethorphan, dextropropoxyphene, pentazocine, levorphanol, and MDMA.^[8]
• Use with another classic irreversible MAOI is generally avoided outside a planned specialist-supervised switch, because full MAO-A and MAO-B inhibition is already expected and evidence for routine long-term dual-MAOI treatment is limited. This is distinct from medically supervised switching between phenelzine, tranylcypromine, and isocarboxazid, where modified washouts or cautious transitions have been used by some expert clinicians under close monitoring.^[8][21]
• Stimulant and sympathomimetic drugs vary in risk depending on mechanism, dose, and route. Medium- or high-dose amphetamines and MDMA are generally avoided because of monoamine-releasing activity, including serotonergic activity. Cocaine is also avoided because of potent monoamine reuptake inhibition and sympathomimetic cardiovascular effects. Low-dose amphetamines, ephedrine, and pseudoephedrine are relative rather than absolute contraindications; if used, reduced dosing, slow titration, and blood pressure monitoring are advised. Other stimulants or wakefulness-promoting agents, such as methylphenidate, modafinil, and bupropion, are not automatically contraindicated but require low starting doses, slow titration, and monitoring when combined with MAOIs.^[8]
• L-DOPA given without carbidopa may cause hypertensive reactions.^[20]
• Some specific antihypertensive drugs, such as methyldopa and reserpine, are generally avoided with MAOIs. Antihypertensive drugs as a class are not contraindicated.^[8]
• Certain anesthetic-related drugs require avoidance or special caution, especially serotonergic opioid analgesics such as meperidine (pethidine) and tramadol, as well as pancuronium, a muscle relaxant sometimes used with general anesthetics. Other opioids listed as serotonergic or uncertain-risk include methadone, tapentadol, dextromethorphan, dextropropoxyphene, pentazocine, and levorphanol. Up-to-date MAOI literature does not support routine discontinuation of MAOI treatment before surgery or general anesthesia. In most cases, potentially serious interactions can be avoided through careful selection or dose adjustment of anesthetic, analgesic, and vasopressor agents before, during, and after surgery; the MAOI should not be discontinued without consultation with the prescribing clinician.^[8]

Incidence of adverse effects^[18]

Very common (>10% incidence) adverse effects include:

• Dizziness secondary to orthostatic hypotension (17%)

Common (1-10% incidence) adverse effects include:

• Tachycardia (5–10%)
• Hypomania (7%)
• Paresthesia (5%)
• Weight loss (2%)
• Confusion (2%)
• Dry mouth (2%)
• Sexual function disorders (2%)
• Transient hypertension after dosing (2%)
• Rash (2%)
• Urinary retention (2%)

Other (unknown incidence) adverse effects include:

• Increased/decreased appetite
• Blood dyscrasias
• Chest pain
• Diarrhea
• Edema
• Hallucinations
• Hyperreflexia
• Insomnia
• Jaundice
• Leg cramps
• Myalgia
• Palpitations
• Sensation of cold
• Suicidal ideation
• Tremor

Significant orthostatic hypotension is a predictable, dose-dependent adverse effect of classic MAOI treatment, particularly during treatment initiation and after dose increases. It often improves with continued treatment and only rarely requires discontinuation.^[8] Tranylcypromine can also cause transient blood-pressure increases shortly after dosing, usually lasting 1–3 hours. These increases are often asymptomatic but may be accompanied by palpitations or headache; treatment cessation is rarely necessary.^[8]

Despite its amphetamine-like structure, tranylcypromine can cause both activating and sedating adverse effects. Sedation can occur, especially early in treatment, while insomnia is also a prominent adverse effect. Amphetamine was once proposed as a metabolite of tranylcypromine, but this has not been demonstrated in humans or animals receiving the drug.^[8][22][25] Significant hypoglycemia was reported in older literature, but modern guidance considers it unlikely at therapeutic tranylcypromine doses, in contrast to hydrazine MAOIs such as phenelzine and isocarboxazid.^[8]

Of note, there has not been found to be a correlation between sex and age below 65 regarding incidence of adverse effects.^[18]

Tranylcypromine is not associated with weight gain and has a low risk for hepatotoxicity compared to the hydrazine MAOIs.^[18][10]

Tranylcypromine abuse has been reported at doses ranging from 120 to 600 mg per day.^[9][26][18] It is thought that higher doses have more amphetamine-like effects and abuse is promoted by the fast onset and short half-life of tranylcypromine.^[18]

Cases of suicidal ideation and suicidal behaviours have been reported during tranylcypromine therapy or early after treatment discontinuation.^[9]

Symptoms of tranylcypromine overdose are generally more intense manifestations of its usual effects.^[9]

The major interaction risks of tranylcypromine and other classic MAOIs are mechanistically distinct. Drugs with significant serotonin reuptake inhibition or significant serotonin-releasing activity can precipitate serotonin toxicity, while tyramine-rich foods and some indirectly acting sympathomimetics can cause blood-pressure elevation.^[8][20]

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.^[8]

Tranylcypromine has been reported to inhibit several cytochrome P450 enzymes, including CYP2A6, CYP2C19, CYP2C9, CYP2D6, CYP3A4, and CYP2B6. Clinically significant pharmacokinetic interactions are considered unlikely at typical therapeutic doses, with possible exceptions such as CYP2A6 substrates.^[8] CYP2A6 substrates or related compounds include:^[20]

• Dexmedetomidine
• nicotine
• TSNAs (found in cured tobacco products, including cigarettes)
• Valproate

Norepinephrine reuptake inhibitors prevent neuronal uptake of tyramine and may reduce its pressor effects.^[20]

• 
  Tranylcypromine 10-mg tablet
• 
  A box of tranylcypromine manufactured in India

Synthesis

Tranylcypromine was originally developed as an analog of amphetamine.^[4][22] Although it was first synthesized in 1948,^[32] its MAOI action was not discovered until 1959. Precisely because tranylcypromine was not, like isoniazid and iproniazid, a hydrazine derivative, its clinical interest increased enormously, as it was thought it might have a more acceptable therapeutic index than previous MAOIs.^[33]

The drug was introduced by Smith, Kline and French in the United Kingdom in 1960, and approved in the United States in 1961.^[34] It was withdrawn from the market in February 1964 due to a number of patient deaths involving hypertensive crises with intracranial bleeding. However, it was reintroduced later that year with more limited indications and specific warnings of the risks.^[35][22][20]

Tranylcypromine is known to inhibit LSD1, an enzyme that selectively demethylates two lysines found on histone H3.^[27][22][36] Genes promoted downstream of LSD1 are involved in cancer cell growth and metastasis, and several tumor cells express high levels of LSD1.^[36] Tranylcypromine analogues with more potent and selective LSD1 inhibitory activity are being researched in the potential treatment of cancers.^[36][37]

Tranylcypromine may have neuroprotective properties applicable to the treatment of Parkinson's disease, similar to the MAO-B inhibitors selegiline and rasagiline.^[38][10] As of 2017, only one clinical trial in Parkinsonian patients has been conducted, which found some improvement initially and only slight worsening of symptoms after a 1.5 year followup.^[10]

• Phenylcyclopropylamine
• Tranylcypromine/trifluoperazine
• Cyprolidol