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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Mirtazapine

Last Update: February 16, 2014.

OVERVIEW

Introduction

Mirtazapine is a tetracyclic antidepressant with a somewhat unique mechanism of action. Mirtazapine therapy can be associated with transient asymptomatic elevations in serum aminotransferase levels and has been linked to rare instances of clinically apparent acute liver injury.

Background

Mirtazapine (mir taz' a peen) is a tetracyclic derivative with a somewhat unique antidepressant activity in comparison to the selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants. Its mechanism of action is not well defined, but it is a potent antagonist of serotonin 5-HT2 and 5-HT3 receptors and appears to enhance central noradrenergic and serotonergic (5-HT1A) activity with less activity against peripheral receptors. Mirtazapine was approved for use in moderate and severe depression in the United States in 1996 and remains in wide use, with more than 5 million prescriptions being filled yearly. The major indication for mirtazapine therapy is major depressive disorder. Mirtazapine is available as regular and oral disintegrating tablets of 15, 30 and 45 mg in multiple generic forms and under the brand name Remeron. The recommended dosage in adults is 15 mg once daily at bedtime, which can be increased to a maximum of 45 mg daily. Common side effects are drowsiness, fatigue, blurred vision, dry mouth, increased appetite and weight gain.

Hepatotoxicity

Liver test abnormalities have been reported to occur in up to 10% of patients on mirtazapine, but elevations are usually modest and rarely require dose modification or discontinuation. Rare instances of acute, clinically apparent episodes of liver injury with marked liver enzyme elevations with or without jaundice have been reported in patients on mirtazapine. The onset of injury has varied greatly from several months to several years. The pattern of serum enzyme elevations is usually hepatocellular, but mixed forms have also been described. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) are uncommon.

Mechanism of Injury

The mechanism by which mirtazapine causes liver injury is not known. Mirtazapine is extensively metabolized by the liver, mainly via the cytochrome P450 system, and hepatotoxicity may be mediated by toxic intermediates of its metabolism. In some instances, serum enzyme elevations may be due to nonalcoholic steatohepatitis triggered by weight gain caused by mirtazapine therapy.

Outcome and Management

The serum aminotransferase elevations that occur on mirtazapine therapy are usually self-limited and do not require dose modification or discontinuation of therapy. Rare instances of acute liver failure and chronic hepatitis have been attributed to mirtazapine therapy. Persons with intolerance to mirtazapine may have similar reactions to other antidepressants and careful monitoring is warranted if other such agents are used.

Drug Class: Antidepressant Agents

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Mirtazapine – Generic, Remeron®

DRUG CLASS

Antidepressant Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Mirtazapine61337-67-5C17-H19-N3
Image of Mirtazapine Chemical Structure

ANNOTATED BIBLIOGRAPHY

References updated 16 February 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 published in 1999; no mention of mirtazapine).
  • Larrey D, Ripault MP. Mirtazapine. Hepatotoxicity of psychotropic drugs and drugs of abuse. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 452. (Review of hepatotoxicity of antidepressants mentions that.
    mirtazapine has been implicated in a small number of cases).
  • 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. 397-415.
    (Textbook of pharmacology and therapeutics).
  • Montgomery SA. Safety of mirtazapine: a review. Int Clin Psychopharmacol 1995; 10 Suppl 4: 37-45. [PubMed: 8930008]
    (Summary of safety results from prelicensure trials; common side effects were drowsiness, dry mouth, increased appetite and weight gain; annual rate of serum enzyme elevations was 10% with mirtazapine, 12% with amitriptyline and 7% with placebo).
  • Marttila M, Jaaskelainen J, Jarvi R, Romanov M, Miettinen E, Sorri P, Ahlfors U, et al. A double-blind study comparing the efficacy and tolerability of mirtazapine and doxepin in patients with major depression. Eur Neuropsychopharm 1995; 15: 441-6. [PubMed: 8998395]
    (In a controlled trial of doxepin vs mirtazapine in 163 patients with depression, there were no statistically significant changes in biochemical tests from baseline in either group and no instances of clinically apparent liver injury).
  • Fawcett J, Barkin RL. Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression. J Affect Disord 1998; 51: 267-85. [PubMed: 10333982]
    (Review of chemical structure, pharmacology, mechanism of action, efficacy and safety of mirtazapine; side effects more common than with placebo include drowsiness, dry mouth, increased appetite, and weight gain; liver injury and ALT elevations were not mentioned).
  • Hui CK, Yuen MF, Wong WM, Lam SK, Lai CL. Mirtazapine-induced hepatotoxicity. J Clin Gastroenterol. 2002; 35: 270-1. [PubMed: 12192206]
    (Two cases of mirtazapine hepatotoxicity; 54 year old woman developed jaundice 3 years after starting mirtazapine [bilirubin 28.7 mg/dL, ALT 316 U/L, Alk P 150 U/L, protime 27.8 sec], resolving slowly by 5 months after stopping; 49 year old woman developed jaundice 1 year after starting mirtazapine [bilirubin 8.2 mg/dL, ALT 550 U/L, Alk P 140 U/L, protime 18 sec], with worsening for 2 weeks [bilirubin 35.7 mg/dL], resolving slowly within 3 months of stopping).
  • Carvajal García-Pando A, García del Pozo J, Sánchez AS, Velasco MA, Rueda de Castro AM, Lucena MI.Hepatotoxicity associated with the new antidepressants. J Clin Psychiatry 2002; 63: 135-7. [PubMed: 11874214]
    (Analysis of cases of hepatotoxicity from antidepressants in Spanish Pharmacovigilance System from 1989-1999, identified 99 cases; among SSRIs, 26 were attributed to fluoxetine, 14 paroxetine, 6 fluvoxamine, 5 sertraline, 3 venlafaxine and 2 citalopram; among tricyclics, 16 clomipramine 7 amitriptyline, 6 imipramine; among miscellaneous, 3 nefazodone and 1 trazodone; but all similar in rate ~1-3 per 100,000 patient-years of exposure, except for nefazodone=29/100,000; mirtazapine not mentioned).
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  • Biswas PN, Wilton LV, Shakir SA. The pharmacovigilance of mirtazapine: results of a prescription event monitoring study on 13554 patients in England. J Psychopharmacol 2003; 17: 121-6. [PubMed: 12680749]
    (Analysis of prescription event monitoring in UK National Health Service between 1997-9 including 13,554 patients who received mirtazapine; 4.2% had adverse event, most common being drowsiness, malaise, dizziness, nausea, weight gain and headache; 12 reports of facial edema and 6 of allergy, but none of hepatitis or jaundice).
  • Degner D, Grohmann R, Kropp S, Rüther E, Bender S, Engel RR, Schmidt LG. Severe adverse drug reactions of antidepressants: results of the German multicenter drug surveillance program AMSP. Pharmacopsychiatry 2004; 37 Suppl 1: S39-45. [PubMed: 15052513]
    (Analysis of adverse drug reactions reported from 1993-2000 in 35 psychiatric hospitals; 0.7% of SSRI recipients had a severe adverse event; hepatic in 0.05%).
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    (Among ~50,000 liver transplants done in the United States between 1990 and 2002, 270 [0.5%] were done for drug induced acute liver failure, only four being due to antidepressants: nefazodone [2], bupropion [1], and paroxetine [1]).
  • Andrade RJ, Lucena MI, Fernández MC, Pelaez G, Pachkoria K, García-Ruiz E, García-Muñoz B, et al.; Spanish Group for the Study of Drug-Induced Liver Disease. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005; 129: 512-21. [PubMed: 16083708]
    (Reports to a Spanish network found 461 cases of drug induced liver disease, antidepressants accounted for 23 cases [5%], but mirtazapine was not specifically mentioned).
  • Björnsson E, Olsson R. Suspected drug-induced liver fatalities reported to the WHO database. Dig Liver Dis 2006; 38: 33-8. (Survey of drug induced liver fatalities reported to WHO database between 1968-2003 revealed 4690 reports; no antidepressant ranked among the top 21 agents that were linked to at least 50 cases each)
    .
  • Sabaté M, Ibáñez L, Pérez E, Vidal X, Buti M, Xiol X, Mas A, et al. Risk of acute liver injury associated with the use of drugs: a multicentre population survey. Aliment Pharmacol Ther 2007; 25: 1401-9. [PubMed: 17539979]
    (Among 126 cases of drug induced liver injury seen in Spain between 1993-2000, 3 were attributed to paroxetine and 3 to fluoxetine, with a relative risk of injury to rate of use in the population of 3.0 and 1.8 respectively; mirtazapine was not specifically mentioned).
  • DeSanty KP, Amabile CM. Antidepressant-induced liver injury. Ann Pharmacother 2007; 41: 1201-11. [PubMed: 17609231]
    (Review of drug induced liver injury and reports of injury from MAO inhibitors, SSRIs, tricyclics and atypical agents).
  • Adetunji B, Basil B, Mathews M, Osinowo T. Mirtazapine-associated dose-dependent and asymptomatic elevation of hepatic enzymes. Ann Pharmacother 2007; 41: 359. [PubMed: 17244643]
    (20 year old man developed asymptomatic rises in serum enzymes 3 months after starting mirtazapine [bilirubin 0.4 mg/dL, ALT 182 U/L, Alk P 131 U/L], resolving within 2 months of stopping).
  • 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. [PMC free article: PMC3654244] [PubMed: 18955056]
    (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, antidepressants accounted for 12 cases [4%]: duloxetine [6], buproprion [2], fluoxetine [2], amitryptiline [1], sertraline [1], but none were attributed to mirtazapine).
  • Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]
    (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, 3 of which were linked to antidepressants: one each for nefazodone, fluoxetine and venlafaxine).
  • Rodriguez-Pecci MS, Fuente-Aguado Jde L, Montero-Tinnirello J, Fernandez-Fernandez FJ. [Mirtazapine-associated hepatotoxicity]. Med Clin (Barc) 2010; 135: 625-6. Spanish. [PubMed: 19822332]
    (63 year old man developed fatigue within 6 months of starting miztazapine [bilirubin 0.4 mg/dL, ALT 96 U/L, Alk P 455 U/L, GGT 945 U/L], abnormalities resolving within 2 months of stopping).
  • Kang SG, Yoon BM, Park YM. Mirtazapine-induced hepatocellular-type liver injury. Ann Pharmacother 2011; 45: 825-6. [PubMed: 21666084]
    (19 year old man developed nausea and ALT elevations within 2 weeks of starting mirtazapine [bilirubin 0.7 mg/dL, peak ALT 358 U/L, Alk P 32 U/L], resolving within 2 weeks of stopping).
  • Park SH, Ishino R. Liver injury associated with antidepressants. Curr Drug Saf 2013; 8: 207-23. [PubMed: 23914755]
    (Review of antidepressant induced liver injury).
  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver iInjury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. [PubMed: 23419359]
    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, none of which were attributed to mirtazapine).

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