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Irreversible non-selective MAO inhibitor and antidepressant drug

Pharmaceutical compound
Tranylcypromine
(1R,2S)-(+)-tranylcypromine (left),
(1S,2R)-(−)-tranylcypromine (right)
Clinical data
Trade namesParnate, many generics[1]
Other namestrans-2-Phenylcyclopropylamine
AHFS/Drugs.comMonograph
MedlinePlusa682088
License data
Pregnancy
category
  • AU: B2
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability50%[4]
MetabolismLiver[5][6]
Elimination half-life2.5 hours[4]
ExcretionUrine, Feces[4]
Identifiers
  • (±)-trans-2-phenylcyclopropan-1-amine
    or
    rel-(1R,2S)-2-phenylcyclopropan-1-amine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard100.005.312 Edit this at Wikidata
Chemical and physical data
FormulaC9H11N
Molar mass133.194 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  • c1cccc(c1)[C@@H]2C[C@H]2N
  • InChI=1S/C9H11N/c10-9-6-8(9)7-4-2-1-3-5-7/h1-5,8-9H,6,10H2/t8-,9+/m0/s1 checkY
  • Key:AELCINSCMGFISI-DTWKUNHWSA-N checkY
 X markNcheckY (what is this?)  (verify)

Tranylcypromine, sold under the brand name Parnate among others,[1] is a non-selective and irreversible monoamine oxidase inhibitor (MAOI).[4][7] It is used primarily as an antidepressant in the treatment of major depressive disorder, including treatment-resistant depression.[8] Along with phenelzine and isocarboxazid, tranylcypromine is one of the classic irreversible, non-selective MAOIs used in modern psychiatric practice.[8]

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

[edit]

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

[edit]

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]

Dietary restrictions

[edit]

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.[22][20][23][8]

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.[8][24] 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.[8]

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.[8]

[edit]

Incidence of adverse effects[18]

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

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

Other (unknown incidence) adverse effects include:

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]

Interactions

[edit]

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.

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

Pharmacology

[edit]

Pharmacodynamics

[edit]

Tranylcypromine acts as a nonselective and irreversible inhibitor of monoamine oxidase.[4] Regarding the isoforms of monoamine oxidase, it shows slight preference for the MAOB isoenzyme over MAOA.[22] This reduces the breakdown of monoamines, such as serotonin, norepinephrine, dopamine, and epinephrine, as well as trace amines such as tryptamine, octopamine, and phenethylamine.[22][20] 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.[8]

Tranylcypromine may also act as a norepinephrine reuptake inhibitor at higher therapeutic doses.[22] Compared to amphetamine, tranylcypromine shows low potency as a dopamine releasing agent, with even weaker potency for norepinephrine and serotonin release.[22][20] Contemporary MAOI guidance describes potential norepinephrine reuptake inhibition at 40–60 mg and potential dopamine-releasing activity at around 100 mg as working hypotheses requiring further confirmation.[8]

Tranylcypromine has also been shown to inhibit the histone demethylase, BHC110/LSD1. Tranylcypromine inhibits this enzyme with an IC50 < 2 μM, thus acting as a small molecule inhibitor of histone demethylation with an effect to derepress the transcriptional activity of BHC110/LSD1 target genes.[27] The clinical relevance of this effect is unknown.

Tranylcypromine has been found to inhibit CYP46A1 at nanomolar concentrations.[28] The clinical relevance of this effect is unknown.

Mechanism of tranylcypromine inhibition of MAO.[29]

Pharmacokinetics

[edit]

Tranylcypromine reaches its maximum concentration (tmax) within 1–2 hours.[22] After a 20 mg dose, plasma concentrations reach at most 50-200 ng/mL.[22] While its half-life is only about 2 hours, its pharmacodynamic effects last several days to weeks due to irreversible inhibition of MAO.[22]

Metabolites of tranylcypromine include 4-hydroxytranylcypromine, N-acetyltranylcypromine, and N-acetyl-4-hydroxytranylcypromine, which are less potent MAO inhibitors than tranylcypromine itself.[22] Amphetamine was once thought to be a metabolite of tranylcypromine, but has not been shown to be.[22][25][20]

Tranylcypromine inhibits CYP2A6 at therapeutic concentrations.[20]

Chemistry

[edit]

Synthesis

[edit]
Synthesis of tranylcypromine[30]

Analogues

[edit]

Tranylcypromine derivatives and analogues acting as serotonin 5-HT2 receptor modulators are known.[31]

History

[edit]

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]

Research

[edit]

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]

See also

[edit]

References

[edit]
  1. 1 2 "International brands for Tranylcypromine". Drugs.com. Retrieved 17 April 2016.
  2. ↑ "TRANYLCYPROMINE ASP (MedTAS Pty Ltd)". Tga.gov.au. Retrieved 12 June 2026.
  3. ↑ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  4. 1 2 3 4 5 6 Williams DA (2007). "Antidepressants". In Foye WO, Lemke TL, Williams DA (eds.). Foye's Principles of Medicinal Chemistry. Hagerstwon, USA: Lippincott Williams & Wilkins. pp. 590–1. ISBN 978-0-7817-6879-5.
  5. ↑ "Tranylcypromine". Drugbank.ca. Retrieved 6 December 2019.
  6. ↑ Baker GB, Urichuk LJ, McKenna KF, Kennedy SH (June 1999). "Metabolism of monoamine oxidase inhibitors". Cellular and Molecular Neurobiology. 19 (3): 411–26. doi:10.1023/a:1006901900106. PMC 11545467. PMID 10319194. S2CID 21380176.
  7. ↑ Baldessarini RJ (2005). "17. Drug therapy of depression and anxiety disorders". In Brunton LL, Lazo JS, Parker KL (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics. New York: McGraw-Hill. ISBN 978-0-07-142280-2.
  8. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Van den Eynde V, Abdelmoemin WR, Abraham MM, Amsterdam JD, Anderson IM, Andrade C, et al. (August 2023). "The prescriber's guide to classic MAO inhibitors: phenelzine, tranylcypromine, isocarboxazid for treatment-resistant depression". CNS Spectrums. 28 (4): 427–440. doi:10.1017/S1092852922000906. hdl:2066/313910. PMID 35837681.
  9. 1 2 3 4 5 "Tranylcypromine". UK Electronic medicines compendium. Retrieved 28 October 2015.
  10. 1 2 3 4 5 Riederer P, Laux G (March 2011). "MAO-inhibitors in Parkinson's Disease". Experimental Neurobiology. 20 (1): 1–17. doi:10.5607/en.2011.20.1.1. PMC 3213739. PMID 22110357.
  11. ↑ Jenike MA (September 1981). "Rapid response of severe obsessive-compulsive disorder to tranylcypromine". The American Journal of Psychiatry. 138 (9): 1249–1250. doi:10.1176/ajp.138.9.1249. PMID 7270737.
  12. ↑ Marques C, Nardi AE, Mendlowicz M, Figueira I, Andrade Y, Camisão C, et al. (1994). "A tranilcipromina no tratamento do transtorno obsessivoðcompulsivo: relato de seis casos" [The tranylcypromine in the treatment of obsessive-compulsive disorder: Report of six cases]. Jornal Brasileiro de Psiquiatria (in Brazilian Portuguese): 400–403.
  13. ↑ Joffe RT, Swinson RP (1990). "Tranylcypromine in primary obsessive-compulsive disorder". Journal of Anxiety Disorders. 4 (4): 365–367. doi:10.1016/0887-6185(90)90033-6.
  14. ↑ Nardi AE, Lopes FL, Valença AM, Freire RC, Nascimento I, Veras AB, et al. (February 2010). "Double-blind comparison of 30 and 60 mg tranylcypromine daily in patients with panic disorder comorbid with social anxiety disorder". Psychiatry Research. 175 (3): 260–265. doi:10.1016/j.psychres.2008.06.025. PMID 20036427. S2CID 45566164.
  15. ↑ Saeed SA, Bruce TJ (May 1998). "Panic disorder: effective treatment options". American Family Physician. 57 (10): 2405–2412. PMID 9614411.
  16. ↑ 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.
  17. ↑ Levin GM. Attention-deficit hyperactivity disorder: the pharmacist's role. Am Pharm. 1995 Nov;NS35(11):10-20. PMID: 8533716.
  18. 1 2 3 4 5 6
  19. ↑ Ulrich S, Ricken R, Buspavanich P, Schlattmann P, Adli M (2020). "Efficacy and Adverse Effects of Tranylcypromine and Tricyclic Antidepressants in the Treatment of Depression: A Systematic Review and Comprehensive Meta-analysis". J Clin Psychopharmacol. 40 (1): 63–74. doi:10.1097/JCP.0000000000001153. PMID 31834088. S2CID 209343653.
  20. 1 2 3 4 5 6 7 8 9 10 11 Gillman PK (February 2011). "Advances pertaining to the pharmacology and interactions of irreversible nonselective monoamine oxidase inhibitors". Journal of Clinical Psychopharmacology. 31 (1): 66–74. doi:10.1097/JCP.0b013e31820469ea. PMID 21192146. S2CID 10525989.
  21. ↑ Gillman PK. "Swapping from one MAOI to another MAOI". PsychoTropical Research.
  22. 1 2 3 4 5 6 7 8 9 10 11 12 13 14
  23. ↑ Kim MJ, Kim KS (2014). "Tyramine production among lactic acid bacteria and other species isolated from kimchi". LWT - Food Science and Technology. 56 (2): 406–413. doi:10.1016/j.lwt.2013.11.001.
  24. ↑ Gillman PK (November 2018). "A reassessment of the safety profile of monoamine oxidase inhibitors: elucidating tired old tyramine myths". Journal of Neural Transmission. 125 (11): 1707–1717. doi:10.1007/s00702-018-1932-y.
  25. 1 2 Sherry RL, Rauw G, McKenna KF, Paetsch PR, Coutts RT, Baker GB (December 2000). "Failure to detect amphetamine or 1-amino-3-phenylpropane in humans or rats receiving the MAO inhibitor tranylcypromine". Journal of Affective Disorders. 61 (1–2): 23–9. doi:10.1016/s0165-0327(99)00188-3. PMID 11099737.
  26. ↑ Le Gassicke J, Ashcroft GW, Eccleston D, Evans JI, Oswald I, Ritson EB (1 April 1965). "The Clinical State, Sleep and Amine Metabolism of a Tranylcypromine ('Parnate') Addict". The British Journal of Psychiatry. 111 (473): 357–364. doi:10.1192/bjp.111.473.357. S2CID 145562899.
  27. 1 2 Lee MG, Wynder C, Schmidt DM, McCafferty DG, Shiekhattar R (June 2006). "Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications". Chemistry & Biology. 13 (6): 563–7. doi:10.1016/j.chembiol.2006.05.004. PMID 16793513.
  28. ↑ Mast N, Charvet C, Pikuleva IA, Stout CD (October 2010). "Structural basis of drug binding to CYP46A1, an enzyme that controls cholesterol turnover in the brain". The Journal of Biological Chemistry. 285 (41): 31783–95. doi:10.1074/jbc.M110.143313. PMC 2951250. PMID 20667828.
  29. ↑ Gaweska H, Fitzpatrick PF (October 2011). "Structures and Mechanism of the Monoamine Oxidase Family". Biomolecular Concepts. 2 (5): 365–377. doi:10.1515/BMC.2011.030. PMC 3197729. PMID 22022344.
  30. ↑  
  31. ↑
  32. ↑ Burger A, Yost WL (1948). "Arylcycloalkylamines. I. 2-Phenylcyclopropylamine". Journal of the American Chemical Society. 70 (6): 2198–2201. Bibcode:1948JAChS..70.2198B. doi:10.1021/ja01186a062.
  33. ↑ López-Muñoz F, Alamo C (2009). "Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today". Current Pharmaceutical Design. 15 (14): 1563–86. doi:10.2174/138161209788168001. PMID 19442174.
  34. ↑ Shorter E (2009). Before Prozac: the troubled history of mood disorders in psychiatry. Oxford [Oxfordshire]: Oxford University Press. ISBN 978-0-19-536874-1.
  35. ↑ Atchley DW (September 1964). "Reevaluation of Tranylcypromine Sulfate(Parnate Sulfate)". JAMA. 189 (10): 763–4. doi:10.1001/jama.1964.03070100057011. PMID 14174054.
  36. 1 2 3 Zheng YC, Yu B, Jiang GZ, Feng XJ, He PX, Chu XY, et al. (2016). "Irreversible LSD1 Inhibitors: Application of Tranylcypromine and Its Derivatives in Cancer Treatment". Current Topics in Medicinal Chemistry. 16 (19): 2179–88. doi:10.2174/1568026616666160216154042. PMID 26881714.
  37. ↑ Przespolewski A, Wang ES (July 2016). "Inhibitors of LSD1 as a potential therapy for acute myeloid leukemia". Expert Opinion on Investigational Drugs. 25 (7): 771–80. doi:10.1080/13543784.2016.1175432. PMID 27077938. S2CID 20858344.
  38. ↑ Al-Nuaimi SK, Mackenzie EM, Baker GB (November 2012). "Monoamine oxidase inhibitors and neuroprotection: a review". American Journal of Therapeutics. 19 (6): 436–48. doi:10.1097/MJT.0b013e31825b9eb5. PMID 22960850.
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