Psychotropic drugs and liver disease: A critical review of pharmacokinetics and liver toxicity

Table 1 Psychotropic drugs with extensive first-pass metabolism[10-16]

Tricyclic antidepressants - first-pass metabolism greater than 50% after oral administration

SNRI antidepressants - venlafaxine

SSRI antidepressants - sertraline

NRI antidepressants - bupropion

Typical antipsychotics - chloropromazine

Atypical antipsychotics - olanzapine (40%), quetiapine

SSRI: Selective serotonin reuptake inhibitors; SNRI: Serotonin and norepinephrine reuptake inhibitors; NRI: Norepinephrine reuptake inhibitors.

Table 2 Antidepressants and liver toxicity

	Epidemiology	Type of lesion	Mechanism
Tricyclic antidepressants
Imipramine	ALT transient elevation-20%[45] Cholestatic jaundice: 0.5%-1%[2] DILI: 4/100000 patient-years[2,46] Fatal/Trxp DILI: 1[47]	Hepatocellular, cholestatic	Immuno-allergic
Amitriptiline	ALT transient elevation-10%[45] Abnormal LFT: 3%[48] Fatal/Trxp DILI: 1[39]	Hepatocellular, cholestatic	Immuno-allergic
Clomipramine	Severe DILI: 2 reports[42,49]	Hepatocellular	Immuno-allergic
MAO inibitors
Moclobemide	Abnormal LFT: 3%[50] Fatal DILI: 1[51]	Hepatocellular, cholestatic	Immuno-allergic
Serotonin-norepinephrine reuptake inhibitors
Venlafaxine	ALT > 3ULN: 0.4%[52] Severe DILI: 6[53-56] Fatal DILI/Trxp: 1[57]	Hepatocellular, cholestatic	Immuno-allergic, metabolic
Duloxetine	ALT > 3ULN: 1.1%[58] ALT > 5ULN: 0.6%[59] DILI: 26.2/100000 patient-years[60,61] Severe DILI-7[5] Fatal/Trxp DILI: 13[60]	Hepatocellular, cholestatic, mixed	Immuno-allergic, metabolic
Serotonin-reuptake inhibitors
Sertraline	ALT > 3ULN: 0.5%-1.3%[46] DILI: 1.28/100000 patient-years[46] Severe DILI: 4[62-65] Fatal/Trxp DILI: 2[66,67]	Hepatocellular, cholestatic, mixed	Immuno-allergic, metabolic
Paroxetine	ALT > 3ULN: 1%[46] Severe DILI: 4[68-71]	Hepatocellular, cholestatic, chronic hepatitis	Metabolic
Fluoxetine	ALT > 3ULN: 0.5%[46] Severe DILI: 6[72-77]	Hepatocellular, cholestatic, chronic hepatitis	Metabolic
Fluvoxamine	Unknown[38] DILI: 3[78-80]	Hepatocellular	Metabolic
Citalopram, escitalopram	No difference in LFT vs placebo[81,82]	?	?
Other antidepressants
Nefazodone	DILI: 28.96/10000 patient-years[38] Severe DILI-35[83] Fatal-20[83]	Hepatocellular, cholestatic, mixed	Metabolic
Trazodone	ALT > 3 unknown[38] Severe DILI-7[84] Fatal/Trxp DILI-2[57,85]	Hepatocellular, cholestatic	Immuno-allergic
Bupropion	ALT > 3ULN: 0.1%-1%[86] Severe DILI: 3[86-88] Fatal/Trxp DILI: 2[89,90]	?	?
Agomelatine	ALT > 3ULN: 1.4% (25 mg/d) ALT > 3ULN: 2.5% (50 mg/d)[6,91] Severe DILI: 6 reports[92,93] Fatal/Trxp DILI: 1[94]	Hepatocellular
Mirtazapine	ALT > 3ULN: 2%[95] Severe DILI 2: reports[96]

DILI: Drug-induced liver injury; ALT: Alanine aminotransferase; LFT: Liver function tests; ULN: Upper normal limit.

Table 3 Antipsychotics and liver toxicity

	Epidemiology	Type of lesion	Mechanism
Typical
Cloropromazine	Jaundice: 0.16%-0.3%[99] Severe DILI: > 350[100,101,115-124] Fatal Injury: 8[102-109]	Cholestatic	Immuno-allergic
Haloperidol	ALT > 3ULN: 2%[110] Severe DILI: 1[111]	Cholestatic	Immuno-allergic
Atypical
Clozapine	ALT > 3ULN: 15%[125] Severe DILI: 16[126-140] Fatal Injury: 2[141,142]	Hepatocellular Cholestatic Chronic esteatosis	Immuno-allergic Chronic estatosis
Olanzapine	ALT > 3ULN: 6%[143] Severe DILI: 7[139,144-149]	Hepatocellular Cholestatic Chronic esteatosis	Immuno-allergic, Chronic estatosis
Risperidone	ALT > 3ULN: 3%[150] Severe DILI: 13[150-162]	Hepatocellular Cholestatic Chronic esteatosis	Immuno-allergic Chronic estatosis
Quetiapine	ALT > 3ULN: 0%[143] Severe DILI: 3[151,163,164] Fatal injury: 2[165,166]	?	?
Ziprasidone	Not reported Severe DILI: 1[167]	?	?
Aripiprazole	Not reported
Amissulpride	Not reported

DILI: Drug-induced liver injury; ALT: Alanine aminotransferase; ULN: Upper normal limit.

Table 4 Mood stabilizers and benzodiazepines and liver toxicity

	Epidemiology	Type of lesion	Mechanism
Antiepileptics
Carbamazepine	Transient ALT, AST, GGT elevations: 61% patients 1%-22%[3] DILI: 1%[170]	Hepatocellular, cholestatic	++Hypersensitivity -- Metabolic
Valproate	Transient ALT, AST elevations: 10%-15% patients[170] Hyperrubillirubinemia-44%[170] DILI: 3%-44%[173] Fatal DILI: 0.02% (0.2% children < 2a)[1]	Hepatocellular	Metabolic (Toxic metabolites through w-oxidation) Statosis
Lamotrigine	Transient ALT, AST elevations < 1% Rare hepatotoxicity[170] (4 severe DILI)[174]	Hepatocellular	Metabolic
Topiramate	Transient ALT, AST elevations < 1%[1] Rare hepatotoxicity (2 severe DILI)[174]	Hepatocellular	Metabolic
Gabapentine; pregabaline	Rare hepatotoxicity[1]	?	?
Benzodiazepines
Chlordiazepoxide, diazepam, flurazepam	Rare hepatotoxicity[171,172]	Cholestatic	Hypersensitivity
Litium
	Very rare hepatotoxicity[1]	?	?

DILI: Drug-induced liver injury; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transferase.

Table 5 Pharmacokinetic changes caused by end-stage liver disease: Psychotropic drugs that require special attention

Avoid drugs with extensive first-pass metabolism	Avoid Tricyclic Antidepressants (first-pass metabolism 50%), venlafaxine, sertraline, bupropion, chlorpromazine, quetiapine
Avoid highly protein bound drugs	Avoid most psychotropic drugs (specially fluoxetine, aripiprazole and benzodiazepines). Except: Venlafaxine, lithium, topiramate, a gabapentin, a pregabalin, memantine
Avoid drugs depending on phase I hepatic metabolic reactions	Preferable: Lithium, gabapentin, topiramate, amisulpride (depending mainly on renal excretion) and some benzodiazepines (oxazepam, temazepam, lorazepam) that depend on phase II reaction or glucuronidation, which is preserved in cirrhosis