Benzodiazepine sedative-
hypnotic drugs are widely used for the treatment of
insomnia. Nevertheless, their adverse effects, such as next-day hangover, dependence and impairment of memory, make them unsuitable for long-term treatment.
Melatonin has been used for improving sleep in patients with
insomnia mainly because it does not cause hangover or show any addictive potential. However, there is a lack of consistency on its therapeutic value (partly because of its short half-life and the small quantities of
melatonin employed). Thus, attention has been focused either on the development of more potent
melatonin analogs with prolonged effects or on the design of slow release
melatonin preparations. The MT(1) and MT(2) melatonergic receptor
ramelteon was effective in increasing total sleep time and sleep efficiency, as well as in reducing sleep latency, in
insomnia patients. The melatonergic
antidepressant agomelatine, displaying potent MT(1) and MT(2) melatonergic agonism and relatively weak
serotonin 5HT(2C) receptor antagonism, was found effective in the treatment of depressed patients. However, long-term safety studies are lacking for both
melatonin agonists, particularly considering the pharmacological activity of their metabolites. In view of the higher binding affinities, longest half-life and relative higher potencies of the different
melatonin agonists, studies using 2 or 3mg/day of
melatonin are probably unsuitable to give appropriate comparison of the effects of the natural compound. Hence, clinical trials employing
melatonin doses in the range of 50-100mg/day are warranted before the relative merits of the
melatonin analogs versus
melatonin can be settled.