Have hepatic side-effects been reported for sertraline and which antidepressant is the best alterna

Fråga: Have hepatic side-effects been reported for sertraline and which antidepressant is the best alternative in a patient with liver disease? A female patient with alcohol dependence developed a mixed liver toxicity (increased aminotransferase and alkaline phosphatase values) after treatment with sertraline for two weeks, ALAT 2.13; GT 9.6 and ALP 10. Pre-treatment laboratory values were: ALAT 0.29; GT 2.8 and ALP 5.9.

Sammanfattning: Hepatotoxicity seems to be associated with sertraline as with the other SSRIs. However, this adverse effect seems to be rather rare. Very few reports have associated moclobemide with hepatotoxicity and this is supported by the results from preclinical toxicity studies. However, lack of prospective comparative studies on the liver toxicity among various antidepressants makes it difficult to evaluate whether any of them is better than the others.

Svar: Increased aminotransferase values were reported in 0.5 per cent to 0.8 per cent of sertraline treated patients participating in clinical trials (1). Of the 244 adverse drug reactions reported to Swedish Adverse Drug Reactions Committee between 1995 and 1999 regarding sertraline, 5 cases of hepatic toxicity (one hepatitis and 4 with increased liver enzyme levels) have been reported (2). These findings are in accordance with preclinical toxicity studies suggesting that the liver is a target organ for sertraline toxicity (3). A slight elevation of aminotransferase values is not likely to affect the hepatic metabolism of sertraline, but patients with liver cirrhosis show decreased oral clearance with 1.7-fold increase in the maximum concentration (4). Thus liver toxicity seems to be a rather rare, but possible, problem with sertraline.

All antidepressant agents are metabolised by the liver. We have not been able to find any prospective or retrospective controlled studies comparing the liver toxicity of different antidepressants. It is known that tricyclic antidepressants can induce intrahepatic cholestasis. However, the incidence of this adverse effect seems to be low (5). Limited amount of information is available on the hepatotoxicity of the serotonin selective reuptake inhibitors (SSRIs). However, a Medline search revealed several case reports on SSRI-induced hepatotoxicity, mostly with fluoxetine, which is the most widely used SSRI (6). The liver toxicity with fluoxetine is reversible after discontinuation of the drug treatment (6). It should be noted that the incidence figure (0.5 per cent) of fluoxetine-induced hepatotoxicity during reported clinical trials seems to be similar to that reported for sertraline (6). The WHO International Programme for Drug monitoring has assembled 229 (149 with monotherapy) reports of fluoxetine-related acute hepatitis, 54 (22) cases for fluvoxamine, 80 (50) for paroxetine and 65 (51) for sertraline (6). Thus, although so far SSRIs have been considered safer than tricyclic antidepressants with regard to hepatotoxicity the accumulating evidence on the safety of the SSRIs may dispute this assumption (6).

As far as the other antidepressant drugs are concerned, moclobemide seems to possess low liability to induce hepatotoxicity (7). Only one case of hepatic adverse effect has been reported to SADRAC. Further, the preclinical toxicology data suggests low hepatotoxicity of moclobemide (8). However, the lack of prospective comparative studies with other antidepressants makes it very hard to evaluate whether moclobemide is truly safer than eg SSRIs or tricyclic antidepressants. Several reports of hepatotoxicity including death have been reported with nefazodone (2,9) and also with mirtazapine (2), although they have been marketed only for a short period of time. Thus, these two drugs are not suitable in a patient with earlier liver toxicity.