Isocarboxazid is a monamine oxidase inhibitor (MAO inhibitor) used in therapy of severe depression. Isocarboxazid therapy is associated with rare instances of clinically apparent acute liver injury.
Isocarboxazid (eye" soe kar box' a zid) is a hydrazine antidepressant that acts through inhibition of monamine oxidase, an enzyme that inactivates several neurotransmitter amines such as norepinephrine and serotonin. By inhibition of catabolism of serotonin and norepinephrine, isocarboxazid increases brain levels of these neurotransmitters which probably underlie its antidepressant effects. Isocarboxazid was approved for use as therapy of depression in the United States in 1959, 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. Isocarboxazid is available in generic forms and under the brand name of Marplan as tablets of 10 mg. The usual initial adult dose of isocarboxazid is 10 mg twice daily, with increase in the dose based upon efficacy and tolerance to a maximum of 60 mg per day. Common side effects include drowsiness, dizziness, headache, insomnia, tremor, dry mouth, nausea, increased appetite, weight gain and sexual dysfunction. Isocarboxazid interacts with many medications as well as many foods and beverages, and patients require careful monitoring and education.
Isocarboxazid, 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. Isocarboxazid has also been associated with rare cases of acute, clinically apparent liver injury. The time to clinical onset of liver injury due to MAO inhibitors is typically 1 to 4 months after starting and the usual pattern of serum enzyme elevations is hepatocellular, 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 isocarboxazid 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 isocarboxazid therapy are usually self-limited and do not require dose modification or discontinuation of therapy. The acute liver injury caused by isocarboxazid 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 isocarboxazid 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.
REPRESENTATIVE TRADE NAMES
Isocarboxazid – Generic, Marplan®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 11 March 2014
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 of antidepressants 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 iproniazid and less commonly with phenelzine and isocarboxazid, and least commonly with the nonhydrazide MAO inhibitor, tranylcypromine).
Larrey D, Ripault M-P. 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 MAO inhibitors and liver injury which was most common with iproniazid, which has been withdrawn; isocarboxazid is not mentioned).
O'Donnell JM, Shelton RC. Drug therapy of depression and anxiety disorders. In, Brunton LL, Chabner KA, Knollman KC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 397-415. (Textbook of pharmacology and therapeutics; the MAO inhibitors were the first antidepressants in clinical medicine, but inhibit both MAO-A and MAO-B which results in major drug and food interactions; specific MAO-B inhibitors are used for Parkinson disease, specific MAO-A inhibitors have been developed but are not available in the United States).
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).
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  and peniprazine , with minor increases noted; no data on frequency of levels above normal).
Knight JA. Drug-induced hepatic injury. Marplan hepatitis. Am J Psychiatry 1961; 118: 73-4. PubMed Citation (23 year old woman developed jaundice 4 months after starting isocarboxazid [bilirubin 6.8 mg/dL, ALT 540 U/L, Alk P 3 time ULN], resolving within a few months of stopping).
Cook GC, Sherlock S. Jaundice and its relation to therapeutic agents. Lancet 1965; 1: 175-9. PubMed Citation (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 , phenoxypropazine , prochlorperazine  and halogenated anesthetics ; 20 cases of cholestatic hepatitis due to drugs, 18 due to chlorpromazine, 1 perphenazine and 1 nitrofurantoin).
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).
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 is in use, but has been associated with severe cases of hepatitis and development of cirrhosis).
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, antidepressants were implicated in 11 cases, but none were attributed to a MAO inhibitor).
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