In the first, of these companion trials, collectively termed the BOLDER (BipOLar DEpRession) studies, 360 patients with BP-I and 182 patients with BP-II were randomized to receive 8 weeks

of treatment with either quetiapine 600 mg/day, 300 mg/day, or placebo.33 A significant reduction in baseline-to-end point, MADRS total score was evidenced in both of the quetiapine arms over placebo. Similarly, rates of response and remission were also higher in quetiapine-treated subjects. A subgroup analysis, however, did not find subjects with BP-II to demonstrate a significant improvement, on the primary outcome measure at the 8-week end point. Unlike olanzapine monotherapy, an analysis of individual MADRS items showed quetiapine to not Inhibitors,research,lifescience,medical only reduce the core symptoms of depression, but to also lower suicidal thoughts to a greater extent than placebo. A confirmatory study, BOLDER II, replicated the initial findings in BOLDER I, providing additional support, for a specific antidepressant effect with quetiapine.34 Although the magnitude of the overall treatment effect, was smaller than observed in Inhibitors,research,lifescience,medical BOLDER I, both the quetiapine 600 mg/day and 300 mg/day doses were superior

to placebo at reducing depressive symptoms. This effect was maintained Inhibitors,research,lifescience,medical regardless of the bipolar subtype (type I or II) or the presence of rapid-cycling, a course specifier traditionally associated with poor treatment response. There was no indication that larger doses of quetiapine provided additional antidepressant, benefit, suggesting that, a total daily dose of 300 mg be the recommended target. In an attempt to explain quetiapine’s antidepressant activity, Goldstein and colleagues35 have recently reported that norquetiapine, the dealkylated active metabolite of Inhibitors,research,lifescience,medical quetiapine, possesses

very high affinity for serotonin (5-HT)2A receptors (Ki=3nM). Inhibitors,research,lifescience,medical Since (positron emission tomography (PET) Metabolism inhibitor studies indicate that, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and electroconvulsive therapy also downregulate the 5-HT2A receptor, this point of mechanistic commonality may provide explanation Phosphoprotein phosphatase for quetiapine’s relatively robust and broad spectrum effect, in mood disorders. In addition, Goldstein also reported that norquetiapine binds with high affinity to the 5-HT7C receptor (Ki=18.5 nM), acts as a potent, inhibitor of the noradrenergic transporter, and exerts partial agonist, activity at the 5-HT1A receptor. Partial agonist effects at 5-HT1A receptors may implicate frontal cortex dopamine release as an alternative explanation for the efficacy of quetiapine in depression. Aripiprazole As a class, the atypical antipsychotics have demonstrated clear superiority over placebo in the treatment of acute mania. Emerging evidence, however, urges restraint in assuming that, all atypicals share similar efficacy for the treatment of acute depressive episodes in bipolar disorder.