In the most, severe form of affective disorder, ie, bipolar disorder, patients experience cycling of moods that usually swing from being overly elated or irritable to sad and hopeless and then back again, with periods of normal mood in between. Unequivocally validated

biomarkers for affective disorder are sparse; there are, however, studies suggesting that measurement of stress hormone regulation processes, of rapid eye movement. (REM) sleep or of functional magnetic resonance imaging (fMRI) activation of limbic areas could represent valuable surrogate outcome of pharmacological antidepressant activity. Stress-related dysfunctional neuroendocrine regulation implicating the corticotropin-releasing Inhibitors,research,lifescience,medical hormone (CRH) system has been consistently demonstrated Inhibitors,research,lifescience,medical in major depression,28,29 and it has been proposed that neurodocrine dynamic challenge tests such as the combined dex/CRH test, serve as a screening tool to demonstrate the antidepressive effects of new compounds in clinical drug Inhibitors,research,lifescience,medical trials.30,31 Indices of REM sleep disinhibition, such as shortened BGJ398 clinical trial latency to REM sleep and increased density of ocular movement

during REM sleep, have been proposed as a familial sleep biomarker for increased risk of developing depression.32 Indeed, many studies, recently reviewed,33 suggest, that REM sleep disinhibition could reflect, a dysfunction of the monoaminergic system involved in the

Inhibitors,research,lifescience,medical pathophysiology of affective disorder. Drugs increasing noradrenergic or serotonin ergic functions inhibit, REM sleep, a property shared by most, antidepressant drugs. Consequently, REM sleep inhibition has been proposed as a potential biomarker of the antidepressant activity of a compound.34,35 Dysfunction of the prefrontal cortex, including the ventral anterior cingulate gyrus, has been implicated in anhedonia, exaggerated Inhibitors,research,lifescience,medical response to stress, abnormal response after presentation of mood-lowering stimuli, serotonin ergic challenges (such as tryptophan depletion paradigms), or selective serotonin reuptake inhibitor (SSRI) administration (reviewed by Hassler et al36). Changes in anterior cingulate function during affective Metalloexopeptidase facial processing associated with symptomatic improvement, indicate that such an fMRI activation paradigm may be a. useful surrogate outcome of antidepressant treatment response.37 Another area of interest, whose dysfunctional activation could serve as a surrogate outcome of antidepressant activity is the amygdala. Affective disorders have been characterized by an increased basal metabolism of the amygdala38 that, seems to relate to hypercortisolism and REM sleep abnormalities.37 Increased amygdala, reactivity in response to fearful stimuli has been observed in healthy individuals with a susceptibility to affective disorders.39,41 Moreover, a.