letter to the editor

Agomelatine-induced hepatotoxicity 2251 3

Dear Sir,

Agomelatine (AG) is a melatonin analogue which repre-sents a novel class of antidepressants. It acts as an agonist at melatonin MT(1) and MT(2) receptors and as a specific antagonist at 5-HT(2C) receptors. It is rapidly absorbed orally and mainly metabolised via CYP1A2 hepatic isoen-zymes, has no active metabolites and has an elimination half-life of 1–2 h. Although, AG is generally well-tolerated with low adverse event discontinuation rates, it currently requires monitoring of liver function because a small number of patients had raised liver enzyme activities in the trial program [1]. Controlled studies in humans have shown that AG is as effective as the selective serotonin reuptake inhibitor (SSRI) antidepressants paroxetine and sertraline in the treatment of major depression [2]. A review of the research studies conducted to April 2011 concludes that AG should only be considered as an alter-native drug for patients who do not respond to or cannot tolerate other antidepressant drugs [3]. Many medica-tions are associated with hepatic toxicity as well. Drug–drug and drug–phytochemical interaction may lead to hepatic injury. The severity of drug-induced hepatic injury can range from transient asymptomatic liver enzyme elevation to fulminant hepatic failure (FHF). The exact incidence of FHF remains uncertain, but stud-ies suggest that leading causes in North America are drug overdose and idiosyncratic drug reactions [4]. Lit-tle is reported in literature regarding acute AG-induced hepatotoxicity.

The present article describes a case of organic mood affective disorders with insomnia treated with AG with drug-induced hepatotoxicity. Upon discontinuation of AG, levels of serum aspartate aminotransferase (S-AST)

and serum alanine aminotransferase (S-ALT) declined progressively.

A 44-year-old Slovenian female patient was admitted in August 2012 to a Psychiatric Department because of insomnia. In her medical history, she denied alcohol, herbal products and/or other drug use. She was diag-nosed with organic mood affective disorders. Her medica-tion previous to hospitalisation included zolpidem 5 mg daily. She had no known history of liver disease. Base-line laboratory results collected on admission included a normal platelet count, normal liver enzymes and liver function tests. Laboratory tests results before introduc-ing AG were as follows: S-ALT: 0.38  µkat/L (normal < 0.74 µkat/L), S-AST: 0.49 µkat/L (normal < 0.58 µkat/L) and serum gamma glutamyl transpeptidase (S-GGT): 0.17 µkat/L (normal < 0.92 µkat/L). Alkaline phosphatase (ALP), bilirubin, albumin and prothrombin time were within the normal range. Autoimmune hepatitis mark-ers, thyroid tests, ferritin and ceruloplasmin were within the normal range. Treatment with AG titrated from 25 to 50 mg daily in 1 week was introduced by her psychiatrist in the hospital. After 14 days of treatment, laboratory tests results were as follows: S-ALT 0.72 µkat/L, S-AST 0.63  µkat/L, S-GGT 0.33  µkat/L, the De-Ritis quotient (S-AST/S-ALT) was 0.88. After 3 weeks of treatment, lab-oratory tests results were as follows: S-ALT 1.76 µkat/L, S-AST 0.97 µkat/L, S-GGT 0.42 µkat/L, the De-Ritis quo-tient was 0.55. Therefore, AG was discontinued abruptly and escitalopram 10  mg daily and olanzapine 10  mg daily were introduced. ALP, bilirubin and albumin were within the normal range. These findings were attributed to hepatocellular-type liver damage associated with AG use. After a 1 week withdrawal of AG, S-ALT and S-AST levels returned to normal range: S-ALT 0.98  µkat/L, S-AST 0.6 µkat/L and S-GGT 0.36 µkat/L. The patient did not undergo percutaneous liver biopsy as serum enzyme levels, S-ALT and S-AST returned to normal range, and she did not consent to the biopsy procedure. S-AST, S-ALT and S-GGT were assessed in blood. According to the recommendations of the International Federation of Clinical Chemistry (IFCC), S-AST, S-ALT and S-GGT

Wiener klinische WochenschriftThe Central European Journal of Medicine

Wien Klin Wochenschr (2013) 125:225–226DOI 10.1007/s00508-013-0344-0

Agomelatine-induced hepatotoxicityMatej Štuhec

M. Štuhec, PharmD () Psychiatric Hospital Ormoz, Ptujska Cesta 33, Ormoz, Sloveniae-mail: matejstuhec@gmail.com

Received: 29 January 2013 / Accepted: 25 February 2013 / Published online: 22 March 2013© Springer-Verlag Wien 2013

226 Agomelatine-induced hepatotoxicity 1 3

letter to the editor

were ascertained by means of reference procedures at 37 °C [5, 6].

There are few reports of hepatotoxic adverse effects of AG. However, clinically notable transient aminotransfer-ase elevations were observed in 4.5 % of the patients in the group treated with 50 mg of AG daily. Study was 8-week double-blind multicenter trial and was reported in 2010 [7]. The patient described in this case developed severe hepatic enzyme disturbances during AG treatment. S-AST and S-ALT levels were higher than normal. Treat-ment with AG was stopped abruptly. No other medication was changed regarding dosage regime in this time. The patient recovered in 1 week after discontinuation of AG. Hepatic enzymes S-ALT and S-AST normalised rapidly after discontinuation of AG. From the ratio S-AST/S-ALT (ratio close 1), it is possible to conclude that hepatocytes damage already occurred and recovered soon after AG discontinuation. AG seems to be the cause of hepatic injury. The laboratory test abnormalities appeared after its introduction. Therefore, caution is advised for patients with elevated liver enzymes who are receiving AG as ele-vated S-AST and S-ALT transaminases may be the earliest manifestation of hepatotoxicity. Unfortunately, it is not possible to reliably predict which patients will progress to hepatic failure. We also recommend routine liver func-tion tests during AG therapy as well as the avoidance of AG by patients with the elevated liver enzymes and liver failure.

In addition, experience with AG across a range of clinical studies suggests that this compound offers a novel approach to the treatment of depression combin-ing efficacy, even in severe depression, with an extremely favourable side-effect profile and sleep regulation [8]. AG may be useful as augmentation in escitalopram therapy in the resistant obsessive-compulsive disorder [9]. A pos-sible area of use for the AG in the treatment of benzodi-azepine withdrawal and addiction was also reported [10]. More research is needed on these effects of AG for more frequent clinical use.

In conclusion, although AG is generally known to be a well-tolerated and safe drug, physicians and clinical pharmacists should be aware of the risk of hepatotoxic-ity associated with AG use. Nevertheless, carefully moni-toring biochemical liver tests in patients receiving AG is indispensable to early evidence of the development of hepatotoxicity and possibly liver failure.

Conflict of interestThe authors have no personal affiliations, financial rela-tionship or any commercial interest to disclose relative to this article. The submitted report or any essential part of it is not published or simultaneously submitted to other publications prior to its appearance in this Journal.

References

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