Antidepressant-Induced Liver Injury: A Review for Clinicians
Abstract
Objective
Method
Results
Conclusions
Method
Results
Epidemiology
Risk Factors
Interaction | CYP450 Metabolism | CYP450 Inhibition | Potential Enzymatic Mechanism | Reported Liver Toxicity | References |
---|---|---|---|---|---|
Moclobemide-fluoxetine | Moclobemide: 2C19; fluoxetine: 2D6, 2C | Moclobemide: 2D6, 2C9, 1A2; fluoxetine: 2D6, 2C9/19, 3A4 | Inhibition | Death: 1 | 21, 22 |
Amitriptyline-diazepam | Amitriptyline: 2C19, 3A4, 1A2, 2C9, 2D6; diazepam: 2C19, 3A4 | Amitriptyline: none; diazepam: 3A4 | Competition and inhibition | Death: 1 | 23–25 |
Venlafaxine-trazodone | Venlafaxine: 2D6, 3A4; trazodone: 2D6 | Venlafaxine: 2D6; trazodone: 3A4, 1A2 | Competition and inhibition | Liver transplant: 1; spontaneous resolution: 1 | 21, 26–28 |
Duloxetine-mirtazapine | Duloxetine: 1A2, 2D6; mirtazapine: 1A2, 2D6 | Duloxetine: none; mirtazapine: none | Competition | Death: 1; spontaneous resolution: 1 | 21, 29, 30 |
Duloxetine-fluoxetine | Duloxetine: 1A2, 2D6; fluoxetine: 2D6, 2C | Duloxetine: none; fluoxetine: 2D6, 2C9/19, 3A4 | Competition and inhibition | Severe hepatocellular injury with spontaneous resolution: 1 | 21, 31 |
Duloxetine-clorazepate | Duloxetine: 1A2, 2D6; clorazepate: 3A4 | Duloxetine: none; clorazepate: none | Competition and inhibition | Severe hepatocellular injury with spontaneous resolution: 1 | 21, 31 |
Duloxetine-trazodone | Duloxetine: 1A2, 2D6; trazodone: 2D6 | Duloxetine: none; trazodone: 3A4, 1A2 | Competition and inhibition | Fulminant hepatic failure with spontaneous resolution: 1 | 21, 32 |
Sertraline-donepezil | Sertraline: 2D6, 3A4, 2C9/19; donepezil: 2D6, 3A4, 1A2 | Sertraline: 2D6, 3A4, 1A2; donepezil: none | Competition | Fulminant hepatic failure with spontaneous resolution: 1 | 21, 33, 34 |
Sertraline-diazepam | Sertraline: 2D6, 3A4, 2C9/19; diazepam: 2C19, 3A4 | Sertraline; 2D6, 3A4, 1A2; diazepam: 3A4 | Competition and inhibition | Death: 1 | 21, 24, 35 |
Paroxetine-trazodone | Paroxetine: 2D6; trazodone: 2D6 | Paroxetine: 2D6; trazodone: 3A4, 1A2 | Competition and inhibition | Spontaneous resolution: 1 | 21, 36 |
Nefazodone-clonazepam | Nefazodone: 3A4, 2D6; clonazepam: 3A4 | Nefazodone: 3A4; clonazepam: none | Competition | Spontaneous resolution: 1 | 37, 38 |
Trazodone-thioridazine | Trazodone: 2D6; thioridazine: none | Trazodone: 3A4, 1A2; thioridazine: 2D6 | Inhibition | Death: 1 | 21, 28, 39 |
Antidepressant Class and Agent | Epidemiology | Type of Lesion | Mechanism | Latency | Coprescriptions | Outcome | Other | Risk of Liver Injury |
---|---|---|---|---|---|---|---|---|
MAO inhibitors | ||||||||
Iproniazid | Abnormal LFT: 3% of treated patients (20) | Hepatocellular | Metabolic; immuno-allergic (autoantibodies: antimitochondrial type 6) (45) | 4 days–6 months | Fluoxetine | Death or LT in 20% of patients developing jaundice (45–48) | Hepatic focal necrosis in rats (100–400 mg/kg) (49); withdrawn in 1978 due to hepatotoxicity (available in France until 1999) | ++++ |
Phenelzine | Abnormal LFT: 3% of treated patients (20) | Cholestatic cirrhosis | Metabolic | 2–4 months | LT: 2; cirrhosis: 1 (50, 51) | +++ | ||
Moclobemide | Abnormal LFT: 3% of treated patients (20) | Cholestatic; hepatocellular | Immuno-allergic | 1–3 weeks | Fluoxetine | Death: 1; recovery: 1 (22, 52) | ++ | |
Tricyclic and tetracyclic drugs | ||||||||
Imipramine, desipramine | Cholestatic jaundice: 0.5%–1% of treated patients (53); no DILI in clinical trials (54, 55); DILI: 4/100,000 patient-years (5, 14) | Hepatocellular; cholestatic; VBDS | Immuno-allergic | 1 week–5 months | Death: 1; LT: 1; VBDS: 1; recovery: 4; (53, 56–60) | Cross-toxicity between tricyclic/tetracyclic drugs (6, 40, 41) | +++ | |
Amitriptyline | Abnormal LFT: 3% of treated patients (19) | Cholestatic; hepatocellular; VBDS | Immuno-allergic | 1–8 months | Deaths: 3; VBDS: 1; recovery: 4; (25, 61–65) | Cross-toxicity between tricyclic/tetracyclic drugs (6, 40, 41) | +++ | |
Maprotiline | Unknown | Hepatocellular; cholestatic | Metabolic | 25 days–4 years | Recovery: 5 (66–70) | + | ||
Clomipramine | Unknown | Hepatocellular | Immuno-allergic | ∼1 month | Recovery: 2 (40, 71) | Cross-toxicity between tricyclic/tetracyclic drugs (6, 40) | + | |
Serotonin-norepinephrine reuptake inhibitors | ||||||||
Venlafaxine | ALT >3×ULN: 0.4% of treated patients (17) | Hepatocellular; cholestatic | Metabolic; immuno-allergic | 10 days–6 months | Trazodone | LT: 1; recovery: 9 (26, 27, 72–78) | Non-dose-dependent abnormal LFT in clinical trials (17); 1 case of DILI following venlafaxine dosage escalation (75) | ++ |
Duloxetine | ALT >3×ULN: 1.1% of treated patients (placebo: 0.3%) (18); ALT >5×ULN: 0.6% of treated patients (placebo: 0%) (79); ALT increase leading to discontinuation in 0.4% of treated patients (80); Hy’s law: 0 (79); DILI: 26.2/100,000 patient-years (80, 81) | Hepatocellular; cholestatic; mixed | Metabolic; immuno-allergic | 2 weeks–3 months | Mirtazapine and fluoxetine | Death: 1; recovery: 12 (29–32, 80–82) | Dose-dependent abnormal LFT in clinical trials (80); 1 case of DILI following duloxetine dosage escalation (32); risk factor for DILI: preexisting chronic liver disease (18, 81–83) (cautious use in the U.S. [84] and contraindication in Europe [85]) | +++ |
Selective serotonin reuptake inhibitors | ||||||||
Sertraline | ALT >3×ULN: 0.5%–1.3% of treated patients (14); DILI: 1.28/100,000 patient-years (14); no DILI in clinical trials (86, 87) | Hepatocellular; cholestatic; mixed | Immuno-allergic; metabolic | 2 weeks–6 months | Death: 1; recovery: 10 (34, 35, 44, 88–92) | ++ | ||
Paroxetine | ALT >3×ULN: 1% of treated patients (16); no DILI in clinical trials (93, 94) | Hepatocellular; cholestatic; chronic hepatitis | Metabolic | 1 day–10 months | Complete recovery: 12 (36, 95–99) | + | ||
Fluoxetine | ALT >3×ULN: 0.5% of treated patients (15); no DILI in clinical trials (100, 101) | Hepatocellular; mixed; cholestatic; chronic hepatitis | Metabolic | 2.5 months–1 year | Chronic hepatitis: 1; recovery: 5; (102–106) | + | ||
Citalopram, escitalopram | No difference in LFT versus placebo (107, 108) | Hepatocellular | Metabolic | 4 days–8 weeks | Recovery: 4 (109–112) | + | ||
Fluvoxamine | Unknown | Hepatocellular | Metabolic | 9 days | Recovery: 1 (42) | + | ||
Other antidepressants | ||||||||
Nefazodone | DILI: 28.96/100,000 patient-years (14); severe DILI: 81.3% of cases (113); death or LT: 1/250,000–300,000 patient-years (6); no DILI in clinical trials (114) | Hepatocellular | Metabolic | 4 weeks–8 months | Deaths: 2; LT: 3; severe liver dysfunction: 2; recovery: 2 (14, 38, 115–119) | Discontinuation of branded formulation in 2003, but generic formulations available; FDA black box warning regarding hepatotoxicity | ++++ | |
Trazodone | Unknown | Hepatocellular; cholestatic | Immuno-allergic | 4 days–18 months | Thioridazine | Death: 1; chronic hepatitis: 1; recovery: 5 (39, 120–126) | ++ | |
Bupropion | ALT >3×ULN: 0.1%–1% of treated patients (127); no DILI in clinical trials (128) | Hepatocellular; cholestatic | Immuno-allergic | 20 days–6 months | Paroxetine | Deaths: 2; recovery: 5 (127, 129–133) | DILI possible after bupropion discontinuation (134) | +++ |
Mianserin | Unknown | Cholestatic; mixed; hepatocellular | Immuno-allergic | 12–28 days | Recovery: 4 (43, 135) | 1 case of DILI following mianserin dosage escalation (43); positive drug rechallenge (43) | ++ | |
Mirtazapine | ALT >3×ULN: 2% of treated patients (136); no DILI in clinical trials (136) | Cholestatic; mixed; hepatocellular | Metabolic | 2 weeks–3 years | Duloxetine | Recovery: 4(137–139) | ++ | |
Tianeptine | No difference in LFT versus placebo (140); no DILI in clinical trials (140) | Cholestatic; hepatocellular | Immuno-allergic | 6 days–2 months | Recovery: 4 (141–145) | Major metabolic: beta oxidation; microvesicular steatosis in mice (146) | ++ | |
Agomelatine | ALT >3×ULN: 1.4% with 25 mg/day and 2.5% with 50 mg/day (placebo: 0.6%) (147, 151) | Hepatocellular | Unknown | First months of treatment | LT: 1; recovery: 1; (148–150) | Assessment of LFT recommended before treatment and then after 3, 6, 12, and 24 weeks of treatment (151); dose-dependent abnormal LFT in clinical trials (147); postmarketing settings: normalization of LFT in most cases (148) | +++ |
Clinical Presentation and Diagnosis
Outcome
Discussion
Recommendations for Clinical Practice
Conclusions
References
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