Agomelatine-induced gynaecomastia

To the Editor

Psychoactive drugs such as tricyclic antidepressants, atypical antipsychotics, haloperidol, phenothiazines and diazepam are known to cause gynaecomastia (Johnson and Murad, 2009). To the best of my knowledge, this is a first case report of gynaecomastia induced by agomelatine.

A 19-year-old male presented to the general medicine clinic with 2 months of progressive bilateral breast swelling and tenderness. Further history revealed he was started on agomelatine 25 mg once a day by his psychiatrist for depression about 2 months before the breast symptoms developed. He denied alcohol, illicit drug, anabolic steroid or other medication use. History also did not suggest thyroid, liver or renal disease.

Physical examination revealed a normal-built young man with bilateral tender gynaecomastia, without galactorrhoea. Laboratory tests showed a mildly increased serum prolactin of 443 mIU/L (normal range 86–324 mIU/L). Testosterone, luteinizing hormone, oestradiol and human chorionic gonadotropin (hCG) levels were normal.

Agomelatine was discontinued and, on review 2 months later, the patient reported significant improvement with reduced breast swelling and no tenderness. At 4 months after stopping agomelatine, there was complete resolution of gynaecomastia, and prolactin improved to a normal level (263 mIU/L).

This appears to be a first case report of agomelatine-induced gynaecomastia. The pathophysiology of agomelatine-inducing gynaecomastia is not clear. Agomelatine is a melatonin (MT1/MT2) agonist and serotonin (5-HT_2C) receptor antagonist, and has been marketed for the treatment of major depression since the late 2000s (Servier, 2009). It does not affect extracellular serotonin levels, but facilitates dopamine and noradrenaline release in the prefrontal cortex. Endocrinological side effects, such as gynaecomastia, galactorrhoea and hyperprolactinaemia have not been reported before (Carney and Shelton, 2011; Howland, 2011; Servier, 2009). However, gynaecomastia due to melatonin consumption has been reported (De Bleecker et al., 1999). Possible explanations include oestrogen–androgen ratio imbalance and hyperprolactinaemia, but this patient had normal sex hormones and the prolactin was only mildly raised. Nonetheless, the temporal relationship of agomelatine use with subsequent development of gynaecomastia and discontinuation of the drug with resolution of symptoms and signs in the absence of other risk factors, strongly suggests that agomelatine is the cause of gynaecomastia in this patient.

This case highlights the importance of being aware of the potential side effects of relatively new drugs in patient care.