Skip Navigation

DRUG RECORD

 

TRANYLCYPROMINE

OVERVIEW
Tranylcypromine

 

Introduction

Tranylcypromine is a nonhydrazine monamine oxidase inhibitor (MAO inhibitor) used in therapy of severe depression.  Tranylcypromine therapy is associated with rare instances of clinically apparent acute liver injury.

 

Background

Tranylcypromine (tran" il sip' roe meen) is an antidepressant that acts through inhibition of monoamine oxidase, an enzyme that inactivates several neurotransmitter amines such as norepinephrine and serotonin.  By inhibition of catabolism of serotonin and norepinephrine, tranylcypromine increases brain levels of these neurotransmitters, actions which probably underlie its antidepressant effects.  Tranylcypromine was approved for use as therapy of major depression in the United States in 1961, but it is now rarely used because of the availability of more potent and better tolerated antidepressants such as the tricyclic antidepressants and the selective serotonin reuptake inhibitors.  Tranylcypromine is available in generic forms and under the brand name of Parnate as tablets of 10 mg.  The usual adult dose of tranylcypromine is 30 to 60 mg daily in divided doses.  Common side effects include drowsiness, dizziness, headache, insomnia, tremor, dry mouth, nausea, increased appetite, weight gain and sexual dysfunction.  Tranylcypromine interacts with many medications as well as many foods and beverages, and patients require careful monitoring and education.

 

Hepatotoxicity

Tranylcypromine, like most monamine oxidase inhibitors, can cause transient serum aminotransferase elevations in a proportion of patients.  These elevations are usually mild, asymptomatic and self-limited and do not require dose modification.  Tranylcypromine has also been associated with rare cases of acute, clinically apparent liver injury.  The few cases described have resembled those caused by other MAO inhibitors.  The time to clinical onset is typically 1 to 4 months and the usual pattern of serum enzyme elevations is hepatocellular (Case 1), although cholestatic injury has also been described.  Immunoallergic features (rash, fever, eosinophilia) are uncommon as is autoantibody formation.

 

Mechanism of Injury

The mechanism by which tranylcypromine causes serum aminotransferase elevation is not known.  It undergoes extensive hepatic metabolism and a possible cause of liver injury is production of a toxic intermediate of metabolism.

 

Outcome and Management

The serum aminotransferase elevations that occur on tranylcypromine therapy are usually transient and mild and do not require dose modification or discontinuation of therapy.  The acute liver injury caused by tranylcypromine is typically self-limited, but progressive and fatal instances of acute hepatitis have been reported.  Rechallenge usually causes a prompt recurrence of the liver injury and should be avoided.  Patients with tranylcypromine induced liver injury are likely to have cross sensitivity to other monamine oxidase inhibitors, but should be able to tolerate tricyclic antidepressants or selective serotonin reuptake inhibitors.

Drug Class:  Antidepressant Agents

 

Other drugs in the Subclass, MAO Inhibitors:  Isocarboxazid, Phenelzine

 

Top of page


CASE REPORT
Tranylcypromine

 

Case 1.  Acute self-limited hepatitis due to tranylcypromine.
[Modified from:  Bandt C, Hofbauer FW. Liver injury associated with tranylcypromine therapy. JAMA 1964 188: 752-3. PubMed Citation]

 

A 49 year old woman with recurrent depression was treated with tranylcypromine (20 mg per day) and developed fatigue after 6 and jaundice after 7 weeks of therapy.  She had no history of liver disease, nor exposure to or risk factors for viral hepatitis, and drank minimal amounts of alcohol.  She was not taking other medications.  Physical examination showed jaundice and hepatomegaly, but no rash or fever.  Blood tests showed elevations in serum enzymes and bilirubin levels of 14.9 mg/dL (Table).  All medications were stopped and she began to improve with clearance of jaundice within a week.  A liver biopsy showed inflammation, hepatocellular injury and intrahepatic cholestasis thought to be compatible with drug-induced liver injury.  At 21 days after presentation, she was rechallenged with tranylcypromine for two days, developing nausea and vomiting with rise in AST levels from 19 U/L to 540 U/L without recurrence of jaundice (but a slight rise in direct bilirubin).  A cholecystogram done after recovery was normal.

 

Key Points

Medication: Tranylcypromine (20-30 mg daily)
Pattern: Hepatocellular (R=9)
Severity: 3+ (jaundice, hospitalization)
Latency: 6 weeks initially, within 24 hours on rechallenge
Recovery: ~1 Month
Other medications:None mentioned

 

Laboratory Values

Time After Starting Time After Stopping

AST

(U/L)

Alk P (U/L) Bilirubin (mg/dL) Other
Tranylcypromine taken for 7 weeks
7 weeks 0 670 26.5 14.9
8 weeks 5 days 410 5.0
9 weeks 10 days 340 3.2
10 weeks 17 days 36 6.5 0.9
Tranylcypromine restarted for 2 days
10 weeks (0) 21 days 19 0.6 Rechallenge
  22 (0) days 540 1.1
  23 (1) day 420
  24 (2) days 200 0.5
  25 (3) days 67
  27 (4) days 31 0.4
Normal Values <35 <13 <1.2

Dates and values estimated from Figure 1. Numbers in parentheses are days after starting and stopping rechallenge doses.

 

Comment

The monamine oxidase (MAO) inhibitors are not commonly used and most reported cases of hepatotoxicity were published before 1970.  The described case is convincing because of the timing of onset and the response to rechallenge.  The case report predates the availability of tests for hepatitis A, B and C and modern imaging methods that have made rechallenge less necessary in confirming the diagnosis.  Several case reports have documented cross sensitivity to hepatic injury among the different MAO inhibitors.

 

Top of page


PRODUCT INFORMATION
Tranylcypromine

 

REPRESENTATIVE TRADE NAMES
Tranylcypromine Parnate®

 

DRUG CLASS
Antidepressant Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

Top of page


DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Tranylcypromine 95-62-5 C9-H11-N Image of Tranylcypromine Chemical Structure

Top of page


ANNOTATED BIBLIOGRAPHY
Tranylcypromine

 

References updated: 15 December 2013

  1. Zimmerman HJ. Antidepressants. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 493-8.  (Expert review of hepatotoxicity published in 1999; hepatic injury caused by monamine oxidase [MAO] inhibitors is similar to that of isoniazid with which they share structural similarity as hydrazines; the pattern of injury is typically hepatocellular and arises within 1-6 months of starting therapy; cases of fatal acute liver failure have been described most commonly with the initial MAO inhibitor, iproniazid, and less commonly with phenelzine and isocarboxazid, and least commonly with the nonhydrazide MAO inhibitor, tranylcypromine).

  2. Larrey D, Ripault MP. Hepatotoxicity of psychotropic drugs and drugs of abuse. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 443-62.  (Review of hepatotoxicity of antidepressants mentions that among MAO inhibitors iproniazid most commonly caused liver injury and phenelzine rarely; tranylcypromine is not discussed).

  3. O'Donnell JM, Shelton RC. Drug therapy of depression and anxiety disorders. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 396-415.  (Textbook of pharmacology and therapeutics).

  4. Rosenblum LE, Korn LJ, Zimmerman HJ. Hepatocellular jaundice as a complication of iproniazid therapy. Arch Intern Med 1960; 105: 115-25. PubMed Citation  (Classic paper on iproniazid hepatotoxicity; review of 90 patients; more common in women, ages 25-75 years, onset in 1-4 months [~95%], usually hepatocellular pattern similar to viral hepatitis, 22% mortality and demonstration that this is higher than in acute viral hepatitis).

  5. Bandt C, Hofbauer FW. Liver injury associated with tranylcypromine therapy. JAMA 1964 188: 752-3. PubMed Citation  (49 year old developed fatigue after 6 and jaundice after 7 weeks of tranylcypromine therapy [bilirubin 14.9 mg/dL, AST 670 U/L, Alk P 2x ULN], with rapid rise in AST [to ~600 U/L] with rechallenge: Case 1).

  6. Holdswoth CD, Atkinson M, Goldie W. Hepatitis caused by the newer amine-oxidase-inhibiting drugs. Lancet 1961; 2: 621-23. PubMed Citation  (Four cases of severe liver injury with cross sensitivity to several MAO inhibitors including iproniazid, pheniprazine and nialamide; case 4 was 56 year old woman who developed jaundice and itching after 5 months of phenelzine [bilirubin 2.8 mg/dL, ALT 150 U/L Alk P 3 times ULN], resolving rapidly upon stopping).

  7. Crisp AH, Hays P, Carter A. Three amine-oxidase inhibitor drugs in the treatment of depression. Relative value and toxic effects. Lancet 1961; 1: 17-8. PubMed Citation  (Prospective study of liver test abnormalities during courses of iproniazid [n=17], nialamide [18] and peniprazine [20] with minor enzyme increases noted; no data on frequency of levels above normal).

  8. Cook GC, Sherlock S. Jaundice and its relation to therapeutic agents. Lancet 1965; 1: 175-9. PubMed Citation  (Summary of cases of drug induced liver disease seen at Royal Free Hospital from 1959-65; 11 cases of acute liver failure due to drugs including iproniazid [n=3], phenelzine [2], phenoxypropazine [2], prochlorperazine [1], and halogenated anesthetics [3]; 20 cases of cholestatic hepatitis due to drugs, 18 due to chlorpromazine, 1 perphenazine and 1 nitrofurantoin).

  9. Steingart AB, Cotterchio M. Do antidepressants cause, promote, or inhibit cancers? J Clin Epidemiol 1995; 48: 1407-12. PubMed Citation  (Conflicting data from animal studies and epidemiological surveys have provided little evidence of a link between antidepressant use and breast, liver or other cancer after control for confounding variables).

  10. Lucena M, Carvajal A, Andrade R, Velasco A. Antidepressant-induced hepatotoxicity. Expert Opin Drug Saf 2003; 2: 249-62. PubMed Citation  (Review of hepatotoxicity of antidepressants; antidepressant use has increased markedly between 1992 and 2002, accounting for 5% of cases of hepatotoxicity; MAO inhibitors were first antidepressants developed; iproniazid caused a severe hepatitis and was withdrawn; phenelzine is still in use, but has been associated with severe cases of hepatitis and development of cirrhosis).

  11. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation  (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, none were attributed to tranylcypromine or other MAO inhibitors).

Top of page


OTHER REFERENCE LINKS
Tranylcypromine
  1. PubMed logoRecent References on Tranylcypromine

  2. Clinical Trials logoTrials on Tranylcypromine

Top of page