Tranylcypromine

Overview

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.[1–4] WP

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. WP

Drug class

Monoamine oxidase inhibitor antidepressant WP

From the Wikipedia article's infobox.

Uses, dosage and effects

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.[4][5][6] WP

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.[4] WP

In addition to major depressive disorder, tranylcypromine has been studied or used in other psychiatric conditions, including obsessive–compulsive disorder, panic disorder, and ADHD.[7–13] WP

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.[14][15] WP

Risks and side effects

Adverse effects

Incidence of adverse effects[14] WP

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

• Dizziness secondary to orthostatic hypotension (17%) WP

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

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

Other (unknown incidence) adverse effects include: WP

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

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.[4] WP

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.[4][16][17] WP

Of note, there has not been found to be a correlation between sex and age below 65 regarding incidence of adverse effects.[14] WP

Tranylcypromine is not associated with weight gain and has a low risk for hepatotoxicity compared to the hydrazine MAOIs.[6][14] WP

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.[5][14][18] WP

Cases of suicidal ideation and suicidal behaviours have been reported during tranylcypromine therapy or early after treatment discontinuation.[5] WP

Symptoms of tranylcypromine overdose are generally more intense manifestations of its usual effects.[5] WP

Interactions

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.[4][19] WP

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.[4] WP

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:[4][19] WP

• Dexmedetomidine[4][19] WP
• nicotine[4][19] WP
• TSNAs (found in cured tobacco products, including cigarettes)[4][19] WP
• Valproate[4][19] WP

Norepinephrine reuptake inhibitors prevent neuronal uptake of tyramine and may reduce its pressor effects.[19] WP

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.[2][16][19] WP

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.[4] WP

Tranylcypromine 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. 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.[4][16][19] WP

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. The clinical relevance of this effect is unknown.[20] WP

Tranylcypromine has been found to inhibit CYP46A1 at nanomolar concentrations. The clinical relevance of this effect is unknown.[21] WP

Pharmacokinetics

Tranylcypromine reaches its maximum concentration (tₘₐₓ) within 1–2 hours. 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.[16] WP

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.[16][17][19] WP

Tranylcypromine inhibits CYP2A6 at therapeutic concentrations.[19] WP

Research

Research

Tranylcypromine is known to inhibit LSD1, an enzyme that selectively demethylates two lysines found on histone H3. 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.[16][20][22][23] WP

Tranylcypromine may have neuroprotective properties applicable to the treatment of Parkinson's disease, similar to the MAO-B inhibitors selegiline and rasagiline. 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.[6][24] WP

History

History

Tranylcypromine was originally developed as an analog of amphetamine. Although it was first synthesized in 1948, 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.[2][16][25][26] WP

The drug was introduced by Smith, Kline and French in the United Kingdom in 1960, and approved in the United States in 1961. 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.[16][19][27][28] WP

Chemistry

Formula

C9H11N PC

Molar mass (g/mol)

133.19 PC

IUPAC name (computed by PubChem)

trans-(1R,2S)-2-phenylcyclopropan-1-amine PC

SMILES

C1[C@H]([C@@H]1N)C2=CC=CC=C2 PC

InChIKey

AELCINSCMGFISI-DTWKUNHWSA-N PC

PubChem CID

19493

IUPAC name

(±)-trans-2-phenylcyclopropan-1-amineorrel-(1R,2S)-2-phenylcyclopropan-1-amine WP

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Other International brands for Tranylcypromine
2. Other Williams DA. Foye's Principles of Medicinal Chemistry. 2007
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5. Other Tranylcypromine
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