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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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Trazodone

Last Update: February 26, 2020.

OVERVIEW

Introduction

Trazodone is a serotoninergic modulating antidepressant that is used in therapy of depression, aggressive behavior and panic disorder. Trazodone therapy can be associated with transient, usually asymptomatic elevations in serum aminotransferase levels and has been linked to rare instances of clinically apparent acute liver injury.

Background

Trazodone (traz' oh done) is a triazolopyridine derivative whose mechanism of action is believed to be inhibition of serotonin reuptake and modulation of serotonin receptor activity, which results in increased levels and activity of serotonin. Trazodone was approved for use in major depressive disorder in the United States in 1981 and remains in wide use, with more than 22 million prescriptions being filled yearly. Trazodone is also used off-label for control of aggressive behavior, panic disorder, anxiety, insomnia, substance abuse, bulimia, schizophrenia and dementia. Trazodone has anxiolytic activity and normalizes sleep patterns, effects that have made trazodone one of the most frequently prescribed drugs for insomnia. Trazodone is available in tablets of 50, 75, 100, 150 and 300 mg in several generic forms and formerly under the brand name Desyrel. The recommended dosage for depression in adults is 150 mg in divided doses that can be increased in 50 mg amounts to a maximum of 600 mg daily. An extended release formulation is also available in 150 mg tablets (Oleptro) which is given once daily. It is typically given in single, bedtime lower doses for insomnia. Common side effects of trazodone are drowsiness, fatigue, dizziness, headache, dry mouth, blurred vision, nausea, decreased libido, increased appetite and weight gain. Uncommon but potentially severe adverse events include suicidal thoughts and behaviors, activation of mania, serotonin syndrome, cardiac arrhythmias, orthostatic hypotension, priapism and angle-closure glaucoma.

Hepatotoxicity

Liver test abnormalities occur in a proportion of patients on trazodone, but elevations are usually modest and usually do not require dose modification or discontinuation. At least a dozen instances of acute, clinically apparent episodes of liver injury with marked liver enzyme elevations with or without jaundice have been reported in patients on trazodone. The onset of injury varies from a few days to 6 months and the pattern of serum enzyme elevations is usually hepatocellular, but mixed and cholestatic forms have also been described. Several cases have had immunoallergic features (rash, fever, eosinophilia), but these were not prominent. Autoimmune (autoantibodies) features are uncommon. Rare instances of acute liver failure and death from trazodone have been reported. Nefazodone, an antidepressant similar in structure and mechanism of action to trazodone, was approved for use in 1998, but is currently not commonly used because of multiple reports of acute hepatocellular injury, with a high mortality rate arising 2 weeks to 6 months after starting therapy.

Likelihood score: B (likely but rare cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which trazodone causes liver injury is not known. Trazodone is extensively metabolized by the liver, mainly via the cytochrome P450 system (CYP3A4), and hepatotoxicity may be mediated by toxic intermediates of its metabolism. Trazodone is susceptible to multiple drug-drug interactions.

Outcome and Management

The serum aminotransferase elevations that occur on trazodone 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 trazodone therapy. Persons with intolerance to trazodone may have similar reactions to other antidepressants, and careful monitoring is warranted if other such agents are used.

Drug Class: Antidepressant Agents

Other Drugs in the Subclass: Nefazodone

CASE REPORT

Case 1. Acute hepatitis due to trazodone.(1)

A 38 year old woman with rheumatoid arthritis developed itching followed by jaundice approximately 18 months after starting trazodone. She was also receiving prednisone (10 mg daily), methotrexate, hydroxychloroquine, nabumetone, propoxyphene, folate, birth control pills and alendronate, but had been on this regimen for many years. She had no history of liver disease or known risk behaviors for acquiring hepatitis and did not drink alcohol. On examination, she was jaundiced but had no rash, fever or signs of chronic liver disease. Laboratory results showed a bilirubin of 11.0 mg/dL with marked elevations in serum aminotransferase levels (Table). Her liver tests had been normal on routine testing several months previously. Tests for hepatitis A, B and C were negative as were autoantibodies. An abdominal ultrasound showed no evidence of biliary obstruction. A liver biopsy showed intrahepatic cholestasis, modest inflammation, and ballooning degeneration but no fat or fibrosis. Trazodone was stopped, and she began to improve rapidly. She was discharged from the hospital, but one week later restarted trazodone. After two days she had a return of her symptoms and jaundice. Within two weeks of stopping trazodone for the second time, she had no symptoms of liver disease and her liver tests were near-normal.

Key Points

Medication:Trazodone
Pattern:Hepatocellular (R=5.8)
Severity:3+ (jaundice, hospitalization)
Latency:Initially 18 months, with rechallenge 3 days
Recovery:Within 1 month
Other medications:Prednisone, methotrexate, hydroxychloroquine, nabumetone, propoxyphene, folate, birth control pills, alendrolate.

Laboratory Values

Time After
Starting
Time After
Stopping
ALT
(U/L)
Alk P
(U/L)
Bilirubin
(mg/dL)
Other
12 months13640.8Routine testing
Onset of pruritus and jaundice 18 months after starting trazodone
18 months0109220611.0
3 days7861918.7
Discharged from hospital and restarted trazodone shortly thereafter
10 (0) days147625910.3
15 (5) days4662023.3
19 (9) days1461542.4
23 (13) days551081.6
30 (20) days43931.4
51 (41) days17710.9
Normal Values<48<125<1.2
*

Numbers in parentheses indicate the days after stopping the second time.

Comment

Trazodone has been linked to rare cases of hepatic injury. The onset of injury is generally after several months and is typically hepatocellular, although cases with a shorter latency and with a cholestatic pattern of serum enzyme elevations have been described. In this case, the long latency period was atypical of trazodone and not characteristic of drug induced liver disease in general. Furthermore, the patient was taking other potentially hepatotoxic drugs (methotrexate, nabumetone). What makes the likelihood of trazodone being the cause of the injury was the inadvertent rechallenge that led to a rapid worsening of the injury. Furthermore, the liver biopsy showed no evidence of methotrexate injury and had changes that were considered typical of drug induced liver injury. The hepatic injury rapidly resolved with stopping therapy.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Trazodone – Generic, Desyrel®

DRUG CLASS

Antidepressant Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Trazodone19794-93-5C19-H22-Cl-N5-Oimage 134992960 in the ncbi pubchem database

CITED REFERENCES

1.
Fernandes NF, Martin RR, Schenker S. Trazodone-induced hepatotoxicity: a case report with comments on drug-induced hepatotoxicity. Am J Gastroenterol. 2000;95:532–5. [PubMed: 10685763]

ANNOTATED BIBLIOGRAPHY

References updated: 26 February 2020

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  • O'Donnell JM, Bies RR, Shelton RC. Drug therapy of depression and anxiety disorders. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 267-78.
    (Textbook of pharmacology and therapeutics).
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    (63 year old man developed rash and asymptomatic liver test abnormalities 4 weeks after starting trazodone [bilirubin normal, ALT 55 rising to 211 U/L, Alk P 139 to 535 U/L], serum enzymes worsening for a week after stopping therapy before rapidly falling to normal).
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    (71 year old woman developed jaundice 2 weeks after starting trazodone [bilirubin 12 mg/dL, AST 780 U/L, Alk P 1310 U/L], bilirubin peaking 2 weeks later [29 mg/dL], but injury ultimately resolved within 8 weeks of stopping).
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    (71 year old woman developed fever and rash several months after starting trazodone [bilirubin normal, ALT 81 U/L, Alk P 177 U/L, eosinophils 7%, ANA negative], resolving within 2 weeks of stopping).
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    (75 year old woman developed jaundice 7 months after starting trazodone [bilirubin 17.9 mg/dL, ALT 933 U/L, Alk P 144 U/L], biopsy showing chronic hepatitis, rapid clinical improvement, but bilirubin was raised for 6 months after stopping).
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    (Three women, ages 54, 16 and 57 years, developed jaundice 8, 3 and 6 months after starting nefazodone [bilirubin 34.0, 22.5 and 11.8 mg/dL, ALT 2040, 1345 and 1625 U/L, Alk P 97, 206 and 273 U/L], biopsies showing massive and centrilobular necrosis; 1 died, 1 recovered and 1 was transplanted).
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  • Fernandes NF, Martin RR, Schenker S. Trazodone-induced hepatotoxicity: a case report with comments on drug-induced hepatotoxicity. Am J Gastroenterol. 2000;95:532–5. [PubMed: 10685763]
    (39 year old woman developed jaundice 18 months after starting trazodone [bilirubin 11.0 mg/dL, ALT 1092 U/L and Alk P 206 U/L], improving rapidly upon stopping, but recurring with inadvertent rechallenge: Case 1).
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    (46 year old man with HIV-HCV co-infection had onset of symptoms of hepatitis within 5 days of entering cocaine detoxification program and starting trazodone [bilirubin 2.1 mg/dL, ALT 2581 U/L, Alk P 342 U/L], resolving rapidly upon stopping).
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    (Among 27,542 reports of hepatic injury in WHO database, 786 were related to SSRIs [3%], including citalopram 42, fluoxetine 222, fluvoxamine 54, paroxetine 191, sertraline 112, nefazodone 91 and venlafaxine 74, only nefazodone has an excess of hepatic reports in relationship to total reports).
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    (60 year old was found to have abnormal liver tests without symptoms 6 months after starting trazodone [bilirubin 1.3 mg/dL, ALT 218 U/L, GGT 96 U/L], abnormalities resolving rapidly upon stopping).
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    (51 year old man developed jaundice and confusion 7 months after starting nefazodone and 1 week after a dose increase [bilirubin 1.7 mg/dL, ALT 1964 U/L, Alk P 96 U/L], resolving rapidly upon stopping).
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    (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, antidepressants accounted for 12 cases [4%]: duloxetine [6], bupropion [2], fluoxetine [2], amitriptyline [1], sertraline [1]; no mention of trazodone).
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    (Among adverse event reports attributed to antidepressants submitted to 4 European pharmacovigilance databases, 3300 [10%] were for hepatotoxicity, rates being highest for agomelatine [14.6%], but was not above average for trazodone, 1.0% to 4.9%]).
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  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A, Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America: an analysis of published reports. Ann Hepatol. 2014;13:231–9. [PubMed: 24552865]
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    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 20 [15%] were attributed to antidepressants, most frequently to duloxetine [n=7], bupropion [n=4], escitalopram [n=3], and 1 each for imipramine, fluoxetine, nefazodone and trazodone).
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    (Using data on adverse drug reaction reports from the Uppsala Monitoring Center of WHO, there were higher relative hepatotoxicity reports for nefazodone, agomelatine, many tricyclics and mirtazapine).
  • Friedrich ME, Akimova E, Huf W, Konstantinidis A, Papageorgiou K, Winkler D, Toto S, et al. Drug-induced liver injury during antidepressant treatment: results of AMSP, a drug surveillance program. Int J Neuropsychopharmacol. 2016;19:pyv126. pii. [PMC free article: PMC4851269] [PubMed: 26721950]
    (Among 184,234 psychiatric inpatients from 80 hospitals, 149 cases [0.08%] of drug induced liver injury were reported but only one of them was attributed to trazodone).
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    (Among almost 50,000 cases of hepatocellular carcinoma registered in the Taiwan National Health Insurance Research Database, the rate of antidepressant use was lower than in approximately 250,000 matched controls from the database).
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    (Review of hepatotoxicity of recently approved medications mentions that liver injury in recently approved agents and only rare instances have been linked to antidepressant use, highest rates associated with duloxetine).
  • Carvalhana S, Oliveira A, Ferreira P, Resende M, Perdigoto R, Barroso E. Acute liver failure due to trazodone and diazepam. GE Port J Gastroenterol. 2017;24:40–2. [PMC free article: PMC5553376] [PubMed: 28848778]
    (63 year old man developed acute liver failure 3 months after starting trazodone and diazepam [bilirubin 12.0 mg/dL, ALT 4638 U/L, Alk P 122 U/L, INR 1.84], with worsening liver failure and transplant two weeks later).
  • Ferrajolo C, Scavone C, Donati M, Bortolami O, Stoppa G, Motola D, Vannacci A, et al. DILI-IT Study Group. Antidepressant-induced acute liver injury: a case-control study in an Italian inpatient population. Drug Saf. 2018;41:95–102. [PubMed: 28770534]
    (Among 179 cases of hospitalizations for unexplained acute liver injury enrolled in an Italian prospective study between 2010 and 2014, 17 had been exposed to antidepressants including citalopram [n=4], sertraline [n=3], amitriptyline [n=3] and paroxetine [n=2], and trazodone [n=1], and another was exposed to both trazodone and mirtazapine).
  • Billioti de Gage S, Collin C, Le-Tri T, Pariente A, Bégaud B, Verdoux H, Dray-Spira R, et al. Antidepressants and hepatotoxicity: a cohort study among 5 million individuals registered in the French National Health Insurance Database. CNS Drugs. 2018;32:673–84. [PMC free article: PMC6061298] [PubMed: 29959758]
    (Using the French National Health Insurance Database, 382 serious liver injuries were found in approximately 5 million persons initiating antidepressant therapy, rates being 32.8 per 100,000 with mirtazapine, 22.2 with venlafaxine, 19.2 for SSRIs and 12.6 with duloxetine; trazadone is not specifically discussed).
  • Drugs for anxiety disorders. Med Lett Drugs Ther. 2019;61(1578):121–6. [PubMed: 31386647]
    (Concise review of drugs for anxiety including SSRIs, SNRIs and benzodiazepines including mechanism of action, clinical efficacy, safety and costs; does not mention ALT elevations or hepatotoxicity).
  • Pladevall-Vila M, Pottegård A, Schink T, Reutfors J, Morros R, Poblador-Plou B, Timmer A, et al. Risk of acute liver injury in agomelatine and other antidepressant users in four European countries: a cohort and nested case-control study using automated health data sources. CNS Drugs. 2019;33:383–95. [PMC free article: PMC6441103] [PubMed: 30830574]
    (Analysis of data sources from 4 European countries identified 3.2 million persons initiating antidepressant therapy among whom there was no increased risk for acute liver injury for agomelatine compared to citalopram, an SSRI with a low rate of hepatotoxicity).
  • Schwasinger-Schmidt TE, Macaluso M. Other antidepressants. Handb Exp Pharmacol. 2019;250:325–55. [PubMed: 30194544]
    (Review of the pharmacology of antidepressants mentions that the common side effects of trazodone are drowsiness, dizziness and dry mouth but does not mention hepatotoxicity or ALT elevations).
  • Drugs for depression. Med Lett Drugs Ther. 2020;62(1592):25–32. [PubMed: 32320387]
    (Concise review of the mechanism of action, clinical efficacy, safety and costs of drugs for depression; hepatotoxicity is mentioned only for nefazodone [now rarely used because of severe hepatotoxicity] and duloxetine [in heavy drinkers]).

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