Several melatonin receptors agonists (ramelteon, prolonged-release melatonin, 
agomelatine and tasimelteon) have recently become available for the treatment of 
insomnia, depression and circadian rhythms sleep-wake disorders. The efficacy 
and safety profiles of these compounds in the treatment of the indicated 
disorders are reviewed. Accumulating evidence indicates that sleep-wake 
disorders and co-existing medical conditions are mutually exacerbating. This 
understanding has now been incorporated into the new Diagnostic and Statistical 
Manual of Mental Disorders, 5th Edition (DSM-5). Therefore, when evaluating the 
risk/benefit ratio of sleep drugs, it is pertinent to also evaluate their 
effects on wake and comorbid condition. Beneficial effects of melatonin receptor 
agonists on comorbid neurological, psychiatric, cardiovascular and metabolic 
symptomatology beyond sleep regulation are also described. The review underlines 
the beneficial value of enhancing physiological sleep in comorbid conditions.