The BOLDER Study Group Objective: There is a major unmet need for effective options in the treatment of bipolar depression. Method: Five hundred forty-two outpatients with bipolar I (N=360) or 11 (N=182) disorder experiencing a major depressive episode (DSM-IV) were randomly assigned to 8 weeks of quetiapine (600 or 300 mgl day) or placebo. The prima ry efficacy measure was mean change from base))ne to week 8 in the Montgomery-Asberg Depression Rating Scale total score. Additional efficacy assessments included the Hamilton Depression Rating Scale, Clinical Global Impression of severity and improvement, Hamilton Anxiety Rating Sea Ie, Pittsburgh Sleep Quality Index, and Quality of life Enjoyment and Satisfaction Questionnaire. Results: Quetiapine at either dose demonstrated statistically significant improvement in Montgomery-Asberg Depression Rating Scale total scores compared with placebo from week 1 onward. The proportions of patients meeting response criteria (250% Montgomery-Asberg Depression Rating Scale score improvement) at the final assessment in the groups taking 600 and 300 mglday of quetiapine were 58.2% and 57.6%, respectively, versus 36.1 % for placebo. The proportions of patients meeting remission criteria (Montgomery-Asberg Depression Rating Scale :5::12) were 52.9% in the groups taking 600 and 300 mg/day of quetiapine versus 28.4% for placebo. Quetiapine at 600 and 300 mglday significantly improved 9 of 10 and B of 10 Montgomery-Asberg Depression Rating Scale items, respectively, compa red to placebo, including the core sym ptoms of depression_ Treatmentemergent mania rates were low and similar for the quetiapine and placebo groups (3.2% and 3.9%, respectively). Conclusions: Quetiapine monotherapy is effkacious and well tolerated for the treatment of bipolar depression.

Impaired mitochondrial function, oxidative stress and formation of excessive levels of reactive oxygen species play a key role in neurodegeneration in Parkinson's disease. Myeloperoxidase is a reactive oxygen generating enzyme and is expressed by microglia. The novel compound AZD3241 is a selective and irreversible inhibitor of myeloperoxidase. The hypothesized mechanism of action of AZD3241 involves reduction of oxidative stress leading to reduction of sustained neuroinflammation. The purpose of this phase 2a randomized placebo controlled multicentre positron emission tomography study was to examine the effect of 8 weeks treatment with AZD3241 on microglia in patients with Parkinson's disease. Parkinson patients received either AZD3241 600 mg orally twice a day or placebo (in 3:1 ratio) for 8 weeks. The binding of (11)C-PBR28 to the microglia marker 18 kDa translocator protein, was examined using positron emission tomography at baseline, 4 weeks and 8 weeks. The outcome measure was the total distribution volume, estimated with the invasive Logan graphical analysis. The primary statistical analysis examined changes in total distribution volume after treatment with AZD3241 compared to baseline. Assessments of safety and tolerability of AZD3241 included records of adverse events, vital signs, electrocardiogram, and laboratory tests. The patients had a mean age of 62 (standard deviation = 6) years; 21 were male, three female and mean Unified Parkinson's Disease Rating Scale III score (motor examination) ranged between 6 and 29. In the AD3241 treatment group (n = 18) the total distribution volume of (11)C-PBR28 binding to translocator protein was significantly reduced compared to baseline both at 4 and 8 weeks (P < 0.05). The distribution volume reduction across nigrostriatal regions at 8 weeks ranged from 13-16%, with an effect size equal to 0.5-0.6. There was no overall change in total distribution volume in the placebo group (n = 6). AZD3241 was safe and well tolerated. The reduction of (11)C-PBR28 binding to translocator protein in the brain of patients with Parkinson's disease after treatment with AZD3241 supports the hypothesis that inhibition of myeloperoxidase has an effect on microglia. The results of the present study provide support for proof of mechanism of AZD3241 and warrant extended studies on the efficacy of AZD3241 in neurodegenerative disorders.

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In this 10-week, double-blind, fixed-dose study, elderly institutionalized patients with dementia and agitation were randomized (3:3:2) to quetiapine 200mg/day, 100mg/day, or placebo. The primary endpoint was change in Positive and Negative Syndrome Scale (PANSS)-Excitement Component (EC) scores at endpoint, analysed using last observation carried forward (LOCF) and observed cases (OC) approaches. Other efficacy measures were the Clinical Global Impression of Change (CGI-C), and response rates (percentage with > or =40% reduction [PANSS-EC]; "much" or "very much improved" [CGI-C]), Neuropsychiatric Inventory-Nursing Home version (NPI-NH), and Cohen-Mansfield Agitation Inventory (CMAI). The key safety measure was incidence of adverse events; change in Mini-Mental State Examination (MMSE) was also assessed. Baseline characteristics of 333 participants (quetiapine 200mg/day, n=117; quetiapine 100mg/day, n=124; placebo, n=92) and completion rates (63-65%) were comparable among groups. Compared with placebo, quetiapine 200mg/day was associated with clinically greater improvements in PANSS-EC (LOCF, p=0.065; OC, p=0.014 [ANCOVA]), CGI-C (LOCF, p=0.017; OC, p=0.002 [ANOVA]), and CGI-C response rates (LOCF, p=0.002; OC, p<0.001 [Chi-square test]). Quetiapine 100mg/day did not differentiate from placebo on these measures. There were no between-group differences in NPI-NH or CMAI. Incidences of cerebrovascular adverse events, postural hypotension, and falls were similar among groups. MMSE did not change in any group. Mortality was numerically higher in the quetiapine groups; rates were not statistically different from placebo. The results of this study suggest that quetiapine 200mg/day was effective and well-tolerated for treating agitation associated with dementia. However, caution should be exercised given the concerns regarding increased mortality with atypical antipsychotics in this vulnerable patient population.

The efficacy and safety of single oral doses of the leukotriene D4-receptor antagonist, ICI 204,219, were tested in subjects with acute seasonal allergic rhinitis. Subjects who were enrolled in the double-blind, placebo-controlled trial spent 8 h/d for two consecutive days in a park at the peak of ragweed season (counts > 1,000 grains/m3). Subjects (n = 164) who had sufficient symptoms during a 3-h baseline period on Day 1 were randomized to treatment with 10 (n = 33), 20 (n = 33), 40 (n = 33), or 100 mg (n = 32) of ICI 204,219 or placebo (n = 33). Rhinitis symptoms (nasal congestion, sneezing, rhinorrhea, itchy nose, throat and palate, and eye symptoms) were recorded hourly in the park and three times each evening at home. Blood samples were collected twice daily to determine plasma levels of ICI 204,219. Nasal congestion improved (p < 0.01) most consistently from the evening of Day 1 through Day 2 after treatment with 20- and 40-mg doses of ICI 204,219 versus placebo. Sneezing and rhinorrhea (p < or = 0.05) also improved on Day 2 for subjects who received 20- and 40-mg doses of ICI 204,219 compared with placebo. Mean symptoms scores for the entire day showed that 20 mg of ICI 204,219 was the minimally effective dose in this trial. The onset of action for all treatment groups, including placebo, was within the first 2 h of dosing. No serious adverse events were reported during the trial. ICI 204,219 was well tolerated and relieved symptoms of acute seasonal allergic rhinitis.