Melatonin and its analogs in insomnia and depression

Abstract

: 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 MT1 and MT2 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 MT1 and MT2 melatonergic agonism and relatively weak serotonin 5HT2C 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 3 mg/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 50–100 mg/day are warranted before the relative merits of the melatonin analogs versus melatonin can be settled.

Melatonin-Induced Oncostasis, Mechanisms and Clinical Relevance

“…It must be noted that as shown by the binding affinities, half-life and relative potencies of the different melatonin agonists it is clear that studies using 2-5 mg melatonin/day are unsuitable to give appropriate comparison with the effect of the above mentioned compounds, which in addition to being generally more potent than the native molecule are employed in considerably higher amounts [180].…”

“…Its potentiality in treating sleep disturbances is relevant because the sleep-promoting compounds that are usually prescribed in cancer patients, like benzodiazepines and related Z drugs, have many adverse effects, such as next-day hangover, dependence and impairment of cognition. Indeed, a number of studies point out to a beneficial effect of melatonin in a wide variety of sleep disorders [180] and melatonin is increasingly recognized as an effective medication to stop benzodiazepine/Z drug abuse in patients [181]. Melatonin has been used for improving sleep in patients with insomnia mainly because it does not cause hangover or show any addictive potential.…”

“…Agomelatine has a unique pharmacological profile as it is both a MT 1 /MT 2 melatonin receptor agonist and an antagonist of 5-HT 2C receptors. As the first melatonergic antidepressant, agomelatine displays a non-monoaminergic mechanism of action [180]. MT 1 and MT 2 receptors also appear to be involved in sedating and anxiolytic effects of melatonergic drugs which have been linked to a facilitatory role of melatonin on γ-aminobutyric acid transmission [194].…”

“…Since melatonin is involved in the regulation of both circadian rhythms and sleep, any antidepressant drug with effects on melatonin receptors could be an advantage in treatment. Melatonin treatment has been found effective to treat circadian rhythm disorders [180,190]. As far as its antidepressant activity, melatonin (10 mg/day) was inactive to affect bipolar affective disorder [191] and improved sleep with no effect on symptoms of depression in major depressive disorder [192,193].…”

A Double-Blind, Placebo-Controlled Trial Related to the Effects of Melatonin on Oxidative Stress and Inflammatory Parameters of Obese Women

“…Melatonin (N-acetyl-5-methoxytryptamine) in mammals is synthesized in several cells, tissues, and organs mainly for local utilization (autocrine and paracrine actions) and the circulating melatonin is mostly provided by the pineal gland [11,12]. It is known that melatonin is responsible for regulation of circadian rhythms, immune responses and mood, and reduces oxidative stress [13][14][15][16]. The roles of melatonin in obesity management have been studied in animal models of diet-induced obesity.…”