SD showed synergistic interactions with drugs that increase the activity of brain 5-HT,42,43,85 NA,118 and DA46 systems; conversely, DA antagonists block the behavioral119 and antidepressant120 effects of SD. Similar synergistic effects have been described for light therapy, which significantly potentiates serotonergic antidepressants,59,66 is influenced by genotypes influencing the density of the 5-HT transporter,112

and can prevent the mood-lowering A-769662 solubility dmso effect of acute tryptophan depletion, which reduces brain 5-HT.121 Finally, an increasing interest on glutamatergic neurotransmission in depression stemmed from trials reporting antidepressant effects of the NMDA antagonists ketamine122 Inhibitors,research,lifescience,medical and the glutamatergic Inhibitors,research,lifescience,medical modulator riluzole.123 Glutamatergic neurotransmission follows a strict circadian rhythm, and in animal models

it is first enhanced and then markedly depressed during SD.124 In vivo single proton magnetic resonance spectroscopy (1H-MRS) indicated that glutamatergic transmission is altered by SD, as shown Inhibitors,research,lifescience,medical by reduced glutamate concentrations, the changes being proportional to both perceived and observed mood amelioration in bipolar depression.125 Remarkably, these effects were observed in the anterior cingulate cortex, a brain area which has been widely implicated in providing a neural basis for mood-congruent cognitive biases in depression,126 and where chronotherapeutics was shown to profoundly change metabolism127,128 and neural reactivity to stimulus words48 in responders to treatment. Biological clock and long-lasting effects on biological rhythms Inhibitors,research,lifescience,medical The hypothesis that several psychiatric conditions may involve primary or secondary changes in biological Inhibitors,research,lifescience,medical clocks,129 and the observations that biological rhythms show a range of abnormalities in mood disorders,130 make the biological clock a primary candidate to explain the mechanism of action of chronotherapeutic techniques. The molecular

machinery which constitutes the biological master clock in the suprachiasmatic nuclei (SCN) is being elucidated,131 but the systematic study of the relationship between clock and therapeutic Unoprostone interventions in psychiatry is just beginning.132 Growing evidence supports the hypothesis that changes in brain monoaminergic functioning influence the function of the biological clock molecular machinery, and the clock and the control of biological rhythms are emerging targets for antidepressant drug treatment.133,134 New animal models have been used to test the interactions between circadian genes and mood-related neurotransmitter systems, and, conversely, to explore the effects of light on brain circuitries and of antidepressant and mood-stabilizing drugs on the clock.