108 This study abated enthusiasm for examining the antidepressant effects of melatonin for some time, but a subsequent group of better designed studies have emerged. These are summarized in Table VII These studies continue to document the hypnotic effects of melatonin, but produce inconsistent findings as far as antidepressant effects are concerned. The studies do however, involve

small samples and limited follow-up, making it difficult to reach a definitive conclusion about the clinical efficacy of melatonin as an antidepressant. Further study is necessary to definitively assess the extent of the antidepressant effect Inhibitors,research,lifescience,medical of melatonin and its potential role relative to standard antidepressant treatments. Table Inhibitors,research,lifescience,medical VII. Melatonin treatment of depression In addition to the use of the actual hormone melatonin, agomelatine, acting at both the melatonin-1 and melatonin-2 receptor, is the first melatonergic agonist to have been developed as an antidepressant. This compound resynchronizes circadian rhythms which have been altered in animal

models, and also normalizes circadian rhythms in depressed subjects.115 It has been shown to have acute antidepressant effects superior to placebo and comparable to, or even more favorable than, standard antidepressants such as sertraline, fluoxetine, and venlafaxine in Inhibitors,research,lifescience,medical several controlled trials.115-118 It is also generally well

tolerated. Agomelatine may not only represent a new class of antidepressant with a different tolerability profile, but it may also provide indirect evidence that melatonin may be involved in the cascade of biological events associated Inhibitors,research,lifescience,medical with the etiology and treatment response of major Inhibitors,research,lifescience,medical depression. Adrenal axis hormones There is a well-described relationship between hypercortisolism and depressive symptoms in both psychiatric and endocrine patients.119 Approximately half of all severely depressed subjects have elevated levels of cortisol,119 and depression is a frequent complication of both Cushing’s syndrome as well as with longer-term and treatment with exogenous corticosteroids.119 These observations have led to the notion that interference with cortisol secretion may produce antidepressant effects. This approach to C646 cost hormonal treatment of depression involving the adrenal axis means reducing the levels and effects of adrenal hormones rather than enhancing hormone levels by exogenous administration as has been discussed with the other hormonal systems. Major depression may be associated with a defect at or above the level of the hypothalamus resulting in the hypersecretion of corticotrophin-releasing hormone (CRH) and, therefore, leading to hypercortisolism.119 Various strategies to reduce adrenal function have been undertaken starting with a variety of antiglucocorticoid agents.