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Minocycline and aspirin in the treatment of bipolar depression: a protocol for a proof-of-concept, randomised, double-blind, placebo-controlled, 2x2 clinical trial.

ABSTRACT: New medication classes are needed to improve treatment effectiveness in the depressed phase of bipolar disorder (BD). Extant evidence suggests that BD is characterised by neural changes such as dendritic remodelling and glial and neuronal cell loss. These changes have been hypothesised to result from chronic inflammation. The principal aims of the proposed research is to evaluate the antidepressant efficacy in bipolar depression of minocycline, a drug with neuroprotective and immune-modulating properties, and of aspirin, at doses expected to selectively inhibit cyclooxygenase 1 (COX-1).120 outpatients between 18 and 55 years of age, who meet DSM-IV-TR criteria for BD (type I or II) and for a current major depressive episode will be recruited to take part in a randomised, double-blind, placebo-controlled, parallel-group, proof-of-concept clinical trial following a 2×2 design. As adjuncts to existing treatment, subjects will be randomised to receive one of the four treatment combinations: placebo-minocycline plus placebo-aspirin, active-minocycline plus placebo-aspirin, placebo-minocycline plus active-aspirin or active-minocycline plus active-aspirin. The dose of minocycline and aspirin is 100 mg twice daily and 81 mg twice daily, respectively. Antidepressant response will be evaluated by assessing changes in the Montgomery-Asberg Depression Rating Scale scores between baseline and the end of the 6-week trial. As secondary outcome measures, the anti-inflammatory effects of minocycline and aspirin will be tested by measuring pre-treatment and post-treatment levels of C reactive protein and inflammatory cytokines.Minocycline has been widely used as an antibiotic in doses up to 400 mg/day. Low-dose aspirin has been safely used on a worldwide scale for its role as an antithrombotic and thrombolytic. The study progress will be overseen by a Data, Safety and Monitoring Board, which will meet once every 6 months. Results of the study will be published in peer-reviewed publications.Clinical Trials.gov: NCT01429272.

SUBMITTER: Savitz J

PROVIDER: S-EPMC3289990 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Minocycline and aspirin in the treatment of bipolar depression: a protocol for a proof-of-concept, randomised, double-blind, placebo-controlled, 2x2 clinical trial.

Savitz Jonathan J Preskorn Sheldon S Teague T Kent TK Drevets Douglas D Yates William W Drevets Wayne W

BMJ open 20120222 1

<h4>Introduction</h4>New medication classes are needed to improve treatment effectiveness in the depressed phase of bipolar disorder (BD). Extant evidence suggests that BD is characterised by neural changes such as dendritic remodelling and glial and neuronal cell loss. These changes have been hypothesised to result from chronic inflammation. The principal aims of the proposed research is to evaluate the antidepressant efficacy in bipolar depression of minocycline, a drug with neuroprotective an ...[more]

PMID: 22357572

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Project description:Depressive episodes are a major cause of morbidity and dysfunction in individuals suffering from bipolar disorder. Currently available treatments for this condition have limited efficacy and new therapeutic options are needed. Extensive research in the pathophysiology of bipolar disorder points to the existence of mitochondrial and bioenergetic dysfunction. We hypothesized that creatine monohydrate, a nutraceutical that works as a mitochondrial modulator, would be effective as an adjunctive therapy for bipolar depression. We conducted a double-blind trial in which 35 patients with bipolar disorder type I or II in a depressive episode by DSM-IV criteria and in use of regular medication for the treatment of this phase of the disease were randomly allocated into two adjunctive treatment groups for 6 weeks: creatine monohydrate 6 g daily (N = 17) or placebo (N = 18). Primary efficacy was assessed by the change in the Montgomery-Åsberg Depression Rating Scale (MADRS). We did not find a statistically significant difference in the comparison between groups for the change in score on the MADRS after 6 weeks in an intention-to-treat (ITT) analysis (p = 0.560; Cohen's d = 0.231). However, we found significant superiority of creatine add-on vs. placebo when we considered the remission criterion of a MADRS score ? 12 at week 6 analyzing the outcome of the 35 randomized patients on ITT (52.9% remission in the creatine group vs. 11.1% remission in the placebo group) and of the 23 completers (66.7% remission in the creatine group vs. 18.2% remission in the placebo group) (p = 0.012; OR = 9.0 and p = 0.036; OR = 9.0, respectively). Two patients who received creatine switched to hypomania/mania early in the trial. No clinically relevant physical side-effects were reported or observed. This proof-of-concept study, aiming to restore brain bioenergetics using an adjunctive mitochondrial modulator, is not conclusive on the efficacy of creatine add-on for bipolar depression, but suggests that this compound may have a role in the adjunctive treatment of this phase of the illness. Further investigation through randomized controlled trials with larger samples should be conducted to verify the efficacy of creatine supplementation for bipolar depression and also for subsyndromal depressive symptoms.

Project description:Given evidence of chronic inflammation in bipolar disorder (BD), we tested the efficacy of aspirin and minocycline as augmentation therapy for bipolar depression. Ninety-nine depressed outpatients with BD were enrolled in a 6 week, double-blind, placebo-controlled trial, and randomized to one of four groups: active minocycline (100 mg b.i.d.) + active aspirin (81 mg b.i.d.) (M + A); active minocycline + placebo aspirin (M + P); placebo-minocycline + active aspirin (A + P); and placebo-minocycline + placebo aspirin (P + P). A blinded interim analysis mid-way through the study led to the dropping of the M + P and A + P arms from further enrollment giving numbers per group who were included in the final analysis of: 30 (M + A), 18 (M + P), 19 (A + P), and 28 (P + P). When the study started, there were three primary outcome measures. Based on the results of the interim analysis, the primary outcome variable, response to treatment as defined by >50% decrease in Montgomery-Äsberg Depression Rating Scale (MADRS) score was maintained. The other two (i.e., the change in mean MADRS score from baseline to end of study and the remission rate, with remission being defined as a score of <11 on the MADRS) were reduced to exploratory outcome measures because the interim analysis indicated that the study was adequately powered to test differences in response rate but not the mean change in MADRS scores or remission rates. CRP and IL-6 were assayed to measure inflammation. Urinary thromboxane B2 (11-D-TXB2) concentrations, which were significantly increased at baseline in the combined BD sample (n = 90) vs. a healthy control group (n = 27), served as an indirect marker of cyclooxygenase (COX) activity. In a two-group analysis, the M + A group showed a greater response rate than the P + P group (p(one-tailed) = 0.034, OR = 2.93, NNT = 4.7). When all four arms were included in the analysis, there was a main effect of aspirin on treatment response that was driven by both the M + A and the A + P groups (p(two-tailed) = 0.019, OR = 3.67, NNT = 4.0). Additionally, there was a significant 3-way interaction between aspirin, minocycline, and IL-6, indicating that response to minocycline was significantly greater in participants in the M + P group with higher IL-6 concentrations. Further, participants in the M + P group who responded to treatment had significantly greater decreases in IL-6 levels between baseline and visit 7 vs. non-responders. Regarding the exploratory outcomes, there was a main effect for aspirin on the remission rate (χ12 = 4.14, p(2t) = 0.04, OR = 2.52, NNT = 8.0). There was no significant main effect of aspirin or minocycline on the mean change in MADRS score across visits. Aspirin and minocycline may be efficacious adjunctive treatments for bipolar depression. Given their potential import, additional studies to confirm and extend these findings are warranted.

Project description:Oxygen enriched air may increase oxygen pressure in brain tissue and have biochemical effects even in subjects without lung disease. Consistently, several studies demonstrated that normobaric oxygen treatment has clinical benefits in some neurological conditions. This study examined the efficacy of normobaric oxygen treatment in subjects with depression. In a randomized, double-blind trial, 55 participants aged 18-65 years with mild to moderate depression (had a Hamilton Rating Scale for Depression [HRSD] score of ≥ 8) were recruited to the study from the Southern district in Israel. Participants underwent a psychiatric inclusion assessment at baseline and then were randomly assigned to either normobaric oxygen treatment of 35% fraction of inspired oxygen or 21% fraction of inspired oxygen (room air) through a nasal tube, for 4 weeks, during the night. Evaluations were performed at baseline, 2 and 4 weeks after commencement of study interventions, using the following tools: HRSD; Clinical Global Impression (CGI) questionnaire; World Health Organization-5 questionnaire for the estimation of Quality of Life (WHO-5-QOL); Sense of Coherence (SOC) 13-item questionnaire; and, Sheehan Disability Scale (SDS). A multivariate regression analysis showed that the mean ± standard deviation [SD] changes in the HRSD scores from baseline to week four were - 4.2 ± 0.3 points in the oxygen-treated group and - 0.7 ± 0.6 in the control group, for a between-group difference of 3.5 points (95% confidence interval [CI] - 5.95 to - 1.0; P = 0.007). Similarly, at week four there was a between-group difference of 0.71 points in the CGI score (95% CI - 1.00 to - 0.29; P = 0.001). On the other hand, the analysis revealed that there were no significant differences in WHO-5-QOL, SOC-13 or SDS scores between the groups. This study showed a significant beneficial effect of oxygen treatment on some symptoms of depression.Trial registration: NCT02149563 (29/05/2014).

Dataset Information

Minocycline and aspirin in the treatment of bipolar depression: a protocol for a proof-of-concept, randomised, double-blind, placebo-controlled, 2x2 clinical trial.

Publications

Minocycline and aspirin in the treatment of bipolar depression: a protocol for a proof-of-concept, randomised, double-blind, placebo-controlled, 2x2 clinical trial.

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