tranylcypromine

Tranylcypromine is used to treat major depressive disorder, including atypical depression, especially when there is an anxiety component, typically as a second-line treatment.{{cite web | work = UK Electronic medicines compendium. | url = https://www.medicines.org.uk/emc/medicine/25577 | title = Tranylcypromine | access-date = 28 October 2015 }} It is also used in depression that is not responsive to reuptake inhibitor antidepressants, such as the SSRIs, TCAs, or bupropion. In addition to being a recognized treatment for major depressive disorder, tranylcypromine has been demonstrated to be effective in treating

obsessive-compulsive disorder{{cite journal | vauthors = Jenike MA | title = Rapid response of severe obsessive-compulsive disorder to tranylcypromine | journal = The American Journal of Psychiatry | volume = 138 | issue = 9 | pages = 1249–1250 | date = September 1981 | pmid = 7270737 | doi = 10.1176/ajp.138.9.1249 }}{{cite journal | vauthors = Marques C, Nardi AE, Mendlowicz M, Figueira I, Andrade Y, Camisão C, Coscarelli P, Versiani M | title = A tranilcipromina no tratamento do transtorno obsessivoðcompulsivo: relato de seis casos. | trans-title = The tranylcypromine in the treatment of obsessive-compulsive disorder: Report of six cases | language = pt-BR | journal = Jornal Brasileiro de Psiquiatria | date = 1994 | pages = 400–403 | url = https://www.researchgate.net/publication/294754327 }}{{cite journal | vauthors = Joffe RT, Swinson RP | title=Tranylcypromine in primary obsessive-compulsive disorder | journal=Journal of Anxiety Disorders | volume=4 | issue=4 | date=1990 | doi=10.1016/0887-6185(90)90033-6 | pages=365–367 |url=https://psycnet.apa.org/record/1991-13396-001| url-access=subscription }} and panic disorder.{{cite journal | vauthors = Nardi AE, Lopes FL, Valença AM, Freire RC, Nascimento I, Veras AB, Mezzasalma MA, de-Melo-Neto VL, Soares-Filho GL, King AL, Grivet LO, Rassi A, Versiani M | title = Double-blind comparison of 30 and 60 mg tranylcypromine daily in patients with panic disorder comorbid with social anxiety disorder | journal = Psychiatry Research | volume = 175 | issue = 3 | pages = 260–265 | date = February 2010 | pmid = 20036427 | doi = 10.1016/j.psychres.2008.06.025 | s2cid = 45566164 }}{{cite journal | vauthors = Saeed SA, Bruce TJ | title = Panic disorder: effective treatment options | journal = American Family Physician | volume = 57 | issue = 10 | pages = 2405–2412 | date = May 1998 | pmid = 9614411 | url = https://www.aafp.org/pubs/afp/issues/1998/0515/p2405.html }}

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.{{cite journal | vauthors = Ricken R, Ulrich S, Schlattmann P, Adli M | title = Tranylcypromine in mind (Part II): Review of clinical pharmacology and meta-analysis of controlled studies in depression | journal = Eur Neuropsychopharmacol | volume = 27 | issue = 8 | pages = 714–731 | date = August 2017 | pmid = 28579071 | doi = 10.1016/j.euroneuro.2017.04.003 | s2cid = 30987747 | url = | doi-access = free }}{{cite journal | vauthors = Ulrich S, Ricken R, Buspavanich P, Schlattmann P, Adli M | title = Efficacy and Adverse Effects of Tranylcypromine and Tricyclic Antidepressants in the Treatment of Depression: A Systematic Review and Comprehensive Meta-analysis | journal = J Clin Psychopharmacol | volume = 40 | issue = 1 | pages = 63–74 | date = 2020 | pmid = 31834088 | doi = 10.1097/JCP.0000000000001153 | s2cid = 209343653 | url = }}

Contraindications include:{{cite journal | vauthors = Gillman PK | title = Advances pertaining to the pharmacology and interactions of irreversible nonselective monoamine oxidase inhibitors | journal = Journal of Clinical Psychopharmacology | volume = 31 | issue = 1 | pages = 66–74 | date = February 2011 | pmid = 21192146 | doi = 10.1097/JCP.0b013e31820469ea | s2cid = 10525989 }}

• Porphyria
• Cardiovascular or cerebrovascular disease
• Pheochromocytoma
• Tyramine, found in several foods, is metabolized by MAO. Ingestion and absorption of tyramine causes extensive release of norepinephrine, which can rapidly increase blood pressure to the point of causing hypertensive crisis.
• Concomitant use of serotonin-enhancing drugs, including SSRIs, serotonergic TCAs, dextromethorphan, and meperidine may cause serotonin syndrome.
• Concomitant use of MRAs, including fenfluramine, amphetamine, and pseudoephedrine may cause toxicity via serotonin syndrome or hypertensive crisis.
• L-DOPA given without carbidopa may cause hypertensive crisis.

{{Main|Foods containing tyramine}}

Tyramine is a biogenic amine produced as a (generally undesirable) byproduct during the fermentation of certain tyrosine-rich foods. It is rapidly metabolized by MAO-A in those not taking MAO-inhibiting drugs. Individuals sensitive to tyramine-induced hypertension may experience an uncomfortable, yet fleeting, increase in blood pressure after ingesting relatively small amounts of tyramine. {{cite journal | doi=10.1016/j.lwt.2013.11.001 | title=Tyramine production among lactic acid bacteria and other species isolated from kimchi | year=2014 | vauthors = Kim MJ, Kim KS | journal=LWT - Food Science and Technology | volume=56 | issue=2 | pages=406–413 | doi-access=free }}

Advances in food safety standards in most nations, as well as the widespread use of starter-cultures shown to result in undetectable to low levels of tyramine in fermented products has rendered concerns of serious hypertensive crises rare in those consuming a modern diet.{{cite journal | vauthors = Gillman PK | title = Monoamine oxidase inhibitors: a review concerning dietary tyramine and drug interactions. | journal = PsychoTropical Commentaries | date = 2016 | volume = 1 | pages = 1–90 | url = https://www.psychotropical.com/wp-content/uploads/4.20-MAOI_diet_long.pdf }} Those treated with MAOIs should still exercise caution, particularly at home, if it is unclear whether food has been properly refrigerated. Since tyramine-producing microbes also produce compounds to which humans have a natural aversion, disposal of any questionable food—particularly meats—should be sufficient to avoid hypertensive crises.

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%)
• Hypertension (1–2 hours after ingestion) (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

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.

It is generally recommended that MAOIs be discontinued prior to anesthesia; however, this creates a risk of recurrent depression. In a retrospective observational cohort study, patients on tranylcypromine undergoing general anesthesia had a lower incidence of intraoperative hypotension, while there was no difference between patients not taking an MAOI regarding intraoperative incidence of bradycardia, tachycardia, or hypertension.{{cite journal | vauthors = van Haelst IM, van Klei WA, Doodeman HJ, Kalkman CJ, Egberts TC | title = Antidepressive treatment with monoamine oxidase inhibitors and the occurrence of intraoperative hemodynamic events: a retrospective observational cohort study | journal = The Journal of Clinical Psychiatry | volume = 73 | issue = 8 | pages = 1103–9 | date = August 2012 | pmid = 22938842 | doi = 10.4088/JCP.11m07607 }} The use of indirect sympathomimetic drugs or drugs affecting serotonin reuptake, such as meperidine or dextromethorphan poses a risk for hypertension and serotonin syndrome respectively; alternative agents are recommended.{{cite journal | vauthors = Smith MS, Muir H, Hall R | title = Perioperative management of drug therapy, clinical considerations | journal = Drugs | volume = 51 | issue = 2 | pages = 238–59 | date = February 1996 | pmid = 8808166 | doi = 10.2165/00003495-199651020-00005 | s2cid = 46972638 }}{{cite journal | vauthors = Blom-Peters L, Lamy M | title = Monoamine oxidase inhibitors and anesthesia: an updated literature review | journal = Acta Anaesthesiologica Belgica | volume = 44 | issue = 2 | pages = 57–60 | date = 1993 | pmid = 8237297 }} Other studies have come to similar conclusions. Pharmacokinetic interactions with anesthetics are unlikely, given that tranylcypromine is a high-affinity substrate for CYP2A6 and does not inhibit CYP enzymes at therapeutic concentrations.

Tranylcypromine abuse has been reported at doses ranging from 120 to 600 mg per day.{{cite journal| vauthors = Le Gassicke J, Ashcroft GW, Eccleston D, Evans JI, Oswald I, Ritson EB |title=The Clinical State, Sleep and Amine Metabolism of a Tranylcypromine ('Parnate') Addict|journal=The British Journal of Psychiatry|date=1 April 1965|volume=111|issue=473|pages=357–364|doi=10.1192/bjp.111.473.357|s2cid=145562899 }} 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.

In addition to contraindicated concomitant medications, tranylcypromine inhibits CYP2A6, which may reduce the metabolism and increase the toxicity of substrates of this enzyme, such as:

• 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.

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 leads to an increase in the availability of monoamines, such as serotonin, norepinephrine, and dopamine, epinephrine as well as a marked increase in the availability of trace amines, such as tryptamine, octopamine, and phenethylamine. The clinical relevance of increased trace amine availability is unclear.

It may also act as a norepinephrine reuptake inhibitor at higher therapeutic doses. Compared to amphetamine, tranylcypromine shows low potency as a dopamine releasing agent, with even weaker potency for norepinephrine and serotonin release.

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.{{cite journal | vauthors = Lee MG, Wynder C, Schmidt DM, McCafferty DG, Shiekhattar R | title = Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications | journal = Chemistry & Biology | volume = 13 | issue = 6 | pages = 563–7 | date = June 2006 | pmid = 16793513 | doi = 10.1016/j.chembiol.2006.05.004 | doi-access = }} The clinical relevance of this effect is unknown.

Tranylcypromine has been found to inhibit CYP46A1 at nanomolar concentrations.{{cite journal | vauthors = Mast N, Charvet C, Pikuleva IA, Stout CD | title = Structural basis of drug binding to CYP46A1, an enzyme that controls cholesterol turnover in the brain | journal = The Journal of Biological Chemistry | volume = 285 | issue = 41 | pages = 31783–95 | date = October 2010 | pmid = 20667828 | pmc = 2951250 | doi = 10.1074/jbc.M110.143313 | doi-access = free }} The clinical relevance of this effect is unknown.

File:Tranylcypromine-MAO-inhibiton.png

Tranylcypromine reaches its maximum concentration (t_max) within 1–2 hours.{{cite journal | vauthors = Ulrich S, Ricken R, Adli M | title = Tranylcypromine in mind (Part I): Review of pharmacology | journal = European Neuropsychopharmacology | volume = 27 | issue = 8 | pages = 697–713 | date = August 2017 | pmid = 28655495 | doi = 10.1016/j.euroneuro.2017.05.007 | s2cid = 4913721 | doi-access = free }} After a 20 mg dose, plasma concentrations reach at most 50-200 ng/mL. While its half-life is only about 2 hours, its pharmacodynamic effects last several days to weeks due to irreversible inhibition of MAO.

Metabolites of tranylcypromine include 4-hydroxytranylcypromine, N-acetyltranylcypromine, and N-acetyl-4-hydroxytranylcypromine, which are less potent MAO inhibitors than tranylcypromine itself. Amphetamine was once thought to be a metabolite of tranylcypromine, but has not been shown to be.{{cite journal | vauthors = Sherry RL, Rauw G, McKenna KF, Paetsch PR, Coutts RT, Baker GB | title = Failure to detect amphetamine or 1-amino-3-phenylpropane in humans or rats receiving the MAO inhibitor tranylcypromine | journal = Journal of Affective Disorders | volume = 61 | issue = 1–2 | pages = 23–9 | date = December 2000 | pmid = 11099737 | doi = 10.1016/s0165-0327(99)00188-3 }}

Tranylcypromine inhibits CYP2A6 at therapeutic concentrations.

Tranylcypromine-10mg-Quarter.jpg|Tranylcypromine 10-mg tablet

Tranylcypromine India.jpg|A box of tranylcypromine manufactured in India

File:Tranylcypromine-synth.png

Tranylcypromine was originally developed as an analog of amphetamine. Although it was first synthesized in 1948,{{cite journal| vauthors = Burger A, Yost WL |title=Arylcycloalkylamines. I. 2-Phenylcyclopropylamine|journal=Journal of the American Chemical Society|volume=70|issue=6|pages=2198–2201|doi=10.1021/ja01186a062|year=1948|bibcode=1948JAChS..70.2198B }} 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.{{cite journal | vauthors = López-Muñoz F, Alamo C | title = Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today | journal = Current Pharmaceutical Design | volume = 15 | issue = 14 | pages = 1563–86 | date = 2009 | pmid = 19442174 | doi = 10.2174/138161209788168001 }}

The drug was introduced by Smith, Kline and French in the United Kingdom in 1960, and approved in the United States in 1961.{{cite book | vauthors = Shorter E | title = Before Prozac: the troubled history of mood disorders in psychiatry | publisher = Oxford University Press | location = Oxford [Oxfordshire] | year = 2009 | isbn = 978-0-19-536874-1 | url = https://books.google.com/books?id=8VaYF8pIPxgC&pg=PR13}} 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.{{cite journal | vauthors = Atchley DW | title = Reevaluation of Tranylcypromine Sulfate(Parnate Sulfate) | journal = JAMA | volume = 189 | issue = 10 | pages = 763–4 | date = September 1964 | pmid = 14174054 | doi = 10.1001/jama.1964.03070100057011 }}

Tranylcypromine is known to inhibit LSD1, an enzyme that selectively demethylates two lysines found on histone H3.{{cite journal | vauthors = Zheng YC, Yu B, Jiang GZ, Feng XJ, He PX, Chu XY, Zhao W, Liu HM | title = Irreversible LSD1 Inhibitors: Application of Tranylcypromine and Its Derivatives in Cancer Treatment | journal = Current Topics in Medicinal Chemistry | volume = 16 | issue = 19 | pages = 2179–88 | date = 2016 | pmid = 26881714 | doi = 10.2174/1568026616666160216154042 }} Genes promoted downstream of LSD1 are involved in cancer cell growth and metastasis, and several tumor cells express high levels of LSD1. Tranylcypromine analogues with more potent and selective LSD1 inhibitory activity are being researched in the potential treatment of cancers.{{cite journal | vauthors = Przespolewski A, Wang ES | title = Inhibitors of LSD1 as a potential therapy for acute myeloid leukemia | journal = Expert Opinion on Investigational Drugs | volume = 25 | issue = 7 | pages = 771–80 | date = July 2016 | pmid = 27077938 | doi = 10.1080/13543784.2016.1175432 | s2cid = 20858344 }}

Tranylcypromine may have neuroprotective properties applicable to the treatment of Parkinson's disease, similar to the MAO-B inhibitors selegiline and rasagiline.{{cite journal | vauthors = Al-Nuaimi SK, Mackenzie EM, Baker GB | title = Monoamine oxidase inhibitors and neuroprotection: a review | journal = American Journal of Therapeutics | volume = 19 | issue = 6 | pages = 436–48 | date = November 2012 | pmid = 22960850 | doi = 10.1097/MJT.0b013e31825b9eb5 }}{{cite journal | vauthors = Riederer P, Laux G | title = MAO-inhibitors in Parkinson's Disease | journal = Experimental Neurobiology | volume = 20 | issue = 1 | pages = 1–17 | date = March 2011 | pmid = 22110357 | pmc = 3213739 | doi = 10.5607/en.2011.20.1.1 }} 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.

• Tranylcypromine/trifluoperazine

{{Reflist}}

{{Antidepressants}}

{{Monoamine metabolism modulators}}

{{Prostanoid signaling modulators}}

{{Phenethylamines}}

{{GlaxoSmithKline}}

Category:CYP2D6 inhibitors

Category:Monoamine oxidase inhibitors

Category:Norepinephrine-dopamine releasing agents

Category:Phenylcyclopropylamines

Category:Substituted amphetamines

Category:Substances discovered in the 1940s