Alzheimer’s disease (AD) is a major health problem and a growing recognition exists that efforts to prevent it must be undertaken by both governmental and non-governmental organizations. In this context, the pineal product, melatonin, has a promising significance because of its chronobiotic/cytoprotective properties potentially useful for a number of aspects of AD. One of the features of advancing age is the gradual decrease in circulating melatonin levels. A limited number of therapeutic trials have indicated that melatonin has a therapeutic value as a neuroprotective drug in the treatment of AD and minimal cognitive impairment (which may evolve to AD). Both in vitro and in vivo, melatonin prevented the neurodegeneration seen in experimental models of AD. For these effects to occur, doses of melatonin about two orders of magnitude higher than those required to affect sleep and circadian rhythmicity are needed. More recently, attention has been focused on the development of potent melatonin analogs with prolonged effects, which were employed in clinical trials in sleep-disturbed or depressed patients in doses considerably higher than those employed for melatonin. In view that the relative potencies of the analogs are higher than that of the natural compound, clinical trials employing melatonin in the range of 50–100 mg/day are urgently needed to assess its therapeutic validity in neurodegenerative disorders such as AD.

A temporal relationship between the nocturnal rise in melatonin secretion and the increase in sleep propensity at the beginning of the night, coupled with the sleep-promoting effects of exogenous melatonin, indicate that melatonin is involved in the regulation of sleep. This action is attributed to the MT 1 and MT 2 melatonin receptors present in the hypothalamic suprachiasmatic nucleus and other brain areas. The sleep-promoting actions of melatonin, which are demonstrable in healthy humans, have been found to be useful in subjects suffering from circadian rhythm sleep disorders and in elderly patients, who had low nocturnal melatonin production and secretion. The effectiveness of melatonin in treating sleep disturbances in these patients is relevant because the sleep-promoting compounds that are usually prescribed, such as benzodiazepines and related drugs, have many adverse effects, such as next-day hangover, dependence, and impairment of memory. Melatonin has been used for improving sleep in patients with insomnia mainly because it does not cause any hangover or show any addictive potential. However, there is a lack of consistency concerning its therapeutic value (partly because of its short half-life and the small quantities of melatonin used). 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. A prolonged-release preparation of melatonin 2 mg (Circadin ® ) has been approved for the treatment of primary insomnia in patients aged $55 years in the European Union. This prolonged-release preparation of melatonin had no effect on psychomotor functions, memory recall, or driving skills during the night or the next morning relative to placebo, and was associated with significantly less impairment on many of these tasks relative to zolpidem alone or in combination with prolonged-release melatonin. In 3-week and 6-month randomized, double-blind, clinical trials in patients with primary insomnia aged $55 years, prolonged-release melatonin was associated with improvements relative to placebo in many sleep and daytime parameters, including sleep quality and latency, morning alertness, and quality of life. Prolonged-release melatonin was very well tolerated in clinical trials in older patients, with a tolerability profile similar to that of placebo. Short-term or longerterm treatment with prolonged-release melatonin was not associated with dependence, tolerance, rebound insomnia, or withdrawal symptoms.

Circadian rhythm abnormalities, as shown by sleep/wake cycle disturbances, constitute one the most prevalent signs of depressive illness; advances or delays in the circadian phase are documented in patients with major depressive disorder (MDD), bipolar disorder, and seasonal affective disorder (SAD). The disturbances in the amplitude and phase of rhythm in melatonin secretion that occur in patients with depression resemble those seen in chronobiological disorders, thus suggesting a link between disturbed melatonin secretion and depressed mood. Based on this, agomelatine, the first MT 1 /MT 2 melatonergic agonist displaying also 5-HT 2C serotonergic antagonism, has been introduced as an antidepressant. Agomelatine has been shown to be effective in several animal models of depression and anxiety and it has beneficial effects in patients with MDD, bipolar disorder, or SAD. Among agomelatine's characteristics are a rapid onset of action and a pronounced effectiveness for correcting circadian rhythm abnormalities and improving the sleep/wake cycle. Agomelatine also improves the 3 functional dimensions of depression-emotional, cognitive, and social-thus aiding in the full recovery of patients to a normal life.

The present study sought to determine whether autonomic activity is associated with dominance in verbal over spatial reasoning tasks. A group of 19 healthy adults who performed a verbal and spatial aptitude test was evaluated. Autonomic function was assessed by means of heart rate variability analysis, before and during the tasks. The results showed that a better relative performance in verbal over spatial reasoning tasks was associated with vagal prevalence in normal subjects.