Person:

Fava, Maurizio

ABSTRACT Objective: This was an analysis of pimavanserin, a 5-hydroxytryptamine 2A antagonist/inverse receptor agonist, on dysregulated sleep in patients with major depressive disorder (MDD) by DSM-5 criteria and an inadequate antidepressant response.

Methods: For this analysis of CLARITY, a Phase 2 study of adjunctive pimavanserin, sleep/wakefulness disturbances were measured with the sum of Hamilton Depression Rating Scale (HAMD) insomnia items (Items 4, 5, and 6) and the Karolinska Sleepiness Scale (KSS). Outcomes included change from baseline for HAMD insomnia score >3, correlation between the HAMD insomnia score and KSS, and change from baseline for the Sheehan Disability Scale (SDS) and Unproductive Days subscore in patients with a baseline KSS >6.

Results: The study was conducted between December 2016 and October 2018. At baseline, HAMD insomnia factor score >3 occurred in 76% with placebo and 85% with pimavanserin. The overall LS mean (standard error) weighted difference was -0.5 (0.32) with a 95% confidence interval (CI) -1.2 to, 0.1 (p=0.088) at Week 5. Improvement was observed with pimavanserin vs. placebo at Weeks 2, 3, and 4, with effect sizes of 0.370 to 0.524 (p<0.05). For KSS, the LS mean difference at Week 5 was -1.1 (0.30), 95% CI -1.7 to, -0.5 (p=0.0003; effect size: 0.627) for pimavanserin vs. placebo. Among those with a KSS >6 at baseline (n=120 placebo and n=42 pimavanserin), the LS mean difference in the SDS mean score at Week 5 was -1.1 (0.46), 95% CI -2.0 to, -0.2 (p=0.019; effect size: 0.442) for pimavanserin vs. placebo.

Conclusions: Adjunctive pimavanserin significantly improved sleep/wakefulness sleep disturbance during treatment of MDD, which was associated with greater improvement in function. This study was registered at clinicaltrials.gov: NCT03018340.

Key Words: insomnia, major depressive disorder, pimavanserin, sleep

Objective: Esketamine, the s-enantiomer of ketamine, was recently approved as a rapid-acting intranasal therapy for depression and is currently under development for suicidality. The authors sought to determine the efficacy of adjunctive intranasal esketamine in major depressive disorder (MDD). Data Sources: A systematic search of Pubmed/Medline was conducted up to January 2019, in addition to abstracts of major psychiatric meetings held since 2010. Where necessary, authors and/or study sponsors were contacted in order to obtain a copy of the presentation as well as any pertinent study details. Study Selection: 241 study abstracts were initially identified and reviewed. Selected studies were randomized, double-blind clinical trials comparing adjunctive intranasal esketamine to adjunctive placebo for MDD. Data Extration: Data were extracted independently by two of the authors. A random effects model was used to calculate the standardized mean difference (SMD) between esketamine and placebo (intranasal saline) in the MADRS score change from baseline to endpoint, serving as the primary outcome of the study. Results: Five trials with 774 patients were pooled. Adjunctive esketamine was significantly more effective than placebo for MADRS score change, response, and remission (N=774, SMD = 0.36, 95% CI = 0.24 - 0.49, p < .0001; response: RR = 1.40, 95% CI: 1.22 - 1.61, p < .0001; remission: RR = 1.45, 95% CI: 1.20 - 1.75, p < .0001). Results remained statistically significant regardless of differences in the study sample, fixed vs. new/optimized baseline antidepressants, or duration of the study. Conclusions: Adjunctive intranasal esketamine for patients with MDD who are either treatment-resistant or acutely suicidal appears to be an effective treatment strategy.

Objective: A meta-analysis of studies of vortioxetine in adults with major depressive disorder (MDD). Data Sources: Abstracts were identified using PubMed by cross-referencing “vortioxetine” with “placebo” and “randomized.” No language or publication year restrictions were used. Study Selection: Randomized, double-blind, placebo-controlled clinical trials comparing oral vortioxetine monotherapy with placebo for acute treatment of MDD. Data Extraction: Data were extracted with a pre-coded form, as follows: number of patients randomized, treatment group, Montgomery-Asberg Depression Rating Scale (MADRS) response and remission rates, mean change in scores from baseline and standard errors for the MADRS, Hamilton Anxiety Rating Scale (HAM-A), and Digit Symbol Substitution Test (DSST). Results: 7,269 subjects randomized to vortioxetine (n=3,630) or placebo (n=3,639) from 17 studies were included. The probability of receiving placebo did not predict difference in change in MADRS scores between vortioxetine and placebo (estimate 4.1, p=0.54). The standardized mean difference (SMD) (95% CI) for change in MADRS versus placebo was 0.33 (0.24 - 0.41), and was 0.25 (0.08 - 0.39), 0.33 (0.19 - 0.47), 0.26 (-0.06 to 0.58), and 0.44 (0.27 - 0.62) for 5mg, 10 mg, 15 mg, and 20 mg doses respectively. Greater difference in efficacy between drug and placebo was observed in studies with a low than a high placebo response rate. Conclusion: Vortioxetine is more effective than placebo in improving depression, anxiety and cognition. Less informative or uninformative studies obscured the true treatment effect.