Tranylcypromine, sold under the brand name Parnate among others, is a non-selective and irreversible monoamine oxidase inhibitor (MAOI). It is used primarily as an antidepressant in the treatment of major depressive disorder, including treatment-resistant depression. Along with phenelzine and isocarboxazid, tranylcypromine is one of the classic irreversible, non-selective MAOIs used in modern psychiatric practice.
Tranylcypromine is also known as trans-2-phenylcyclopropyl-1-amine and is formed pro forma from the cyclization of amphetamine's isopropylamine side chain. As a result, it is classified structurally as a substituted phenethylamine and amphetamine, or more specifically as a phenylcyclopropylamine.
Medical uses Tranylcypromine is used to treat major depressive disorder, especially when depression has not responded sufficiently to other antidepressant treatments. 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.
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. 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.
In addition to major depressive disorder, tranylcypromine has been studied or used in other psychiatric conditions, including obsessive–compulsive disorder, panic disorder, and ADHD.Zametkin A, Rapoport JL, Murphy DL, Linnoila M, Ismond D. Treatment of hyperactive children with monoamine oxidase inhibitors. I. Clinical efficacy. Arch Gen Psychiatry. 1985 Oct;42(10):962-6. doi: 10.1001/archpsyc.1985.01790330042005. PMID: 3899047.Levin GM. Attention-deficit hyperactivity disorder: the pharmacist's role. Am Pharm. 1995 Nov;NS35(11):10-20. PMID: 8533716.
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.
Contraindications and precautions Contraindications and precautions include:
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. 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. 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. 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. 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. L-DOPA given without carbidopa may cause hypertensive reactions. Some specific antihypertensive drugs, such as methyldopa and reserpine, are generally avoided with MAOIs. Antihypertensive drugs as a class are not contraindicated. 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.
Dietary restrictions
Tyramine is a biogenic amine produced by microbial decarboxylation of tyrosine and may be present in high amounts in some foods that are fermented, matured, aged, or spoiled. Because inhibition of MAO-A reduces the breakdown of dietary tyramine in the gastrointestinal tract and liver, excessive tyramine intake can raise blood pressure through peripheral norepinephrine release and may cause hypertensive urgency or emergency.
Modern food standards and starter-culture methods have substantially reduced tyramine levels in many foods compared with the 1950s and 1960s, making severe tyramine-related hypertensive reactions uncommon when dietary and medication precautions are followed, although the risk is not eliminated. Higher-risk foods include some aged cheeses, some artisan beers, some fermented meats, and fermented products such as soy sauce, miso, tempeh, sauerkraut, Marmite, and kimchi.
If excessive tyramine intake 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.
Adverse effects Incidence of adverse effects
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. 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.
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. 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.
Of note, there has not been found to be a correlation between sex and age below 65 regarding incidence of adverse effects.
Tranylcypromine is not associated with weight gain and has a low risk for hepatotoxicity compared to the hydrazine MAOIs.
Tranylcypromine abuse has been reported at doses ranging from 120 to 600 mg per day. 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.
Cases of suicidal ideation and suicidal behaviours have been reported during tranylcypromine therapy or early after treatment discontinuation.
Symptoms of tranylcypromine overdose are generally more intense manifestations of its usual effects.
Interactions 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.
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.
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. CYP2A6 substrates or related compounds include: 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.
Pharmacology
Pharmacodynamics Tranylcypromine acts as a nonselective and irreversible inhibitor of monoamine oxidase. Regarding the isoforms of monoamine oxidase, it shows slight preference for the MAOB isoenzyme over MAOA. This reduces the breakdown of monoamines, such as serotonin, norepinephrine, dopamine, and epinephrine, as well as trace amines such as tryptamine, octopamine, and phenethylamine. The clinical relevance of increased trace amine availability is unclear.
Classic MAOIs increase the absolute amount of monoamine neurotransmitters within as well as outside neurons, unlike reuptake inhibitors, which mainly produce relative extracellular increases by blocking transporter-mediated reuptake.