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  string(2098) "Background: Rapid-acting treatment options are needed for MDD (Major Depressive Disorder). Significant progress has been made in understanding the potential of ketamine and its s-enantiomer, esketamine, as rapid-acting antidepressants.

Objective: The objective of this study was to estimate the magnitude of the treatment effect for intranasal (IN) esketamine over placebo at 24 hours post first dose and at study endpoint.

Study design: This was a systematic review and meta-analysis of randomized double-blind controlled trials comparing adjunctive treatment of standard antidepressants with IN esketamine versus placebo in subjects with MDD.

Participants: This analysis included participants from randomized, double-blind clinical trials comparing adjunctive treatment of standard antidepressants with IN esketamine for MDD. Studies of the following were excluded: patients with bipolar disorder, dysthymic disorder, psychotic MDD, minor depressive disorder, seasonal affective disorder, depressed patients with a specific medical condition, or active alcohol or substance abuse disorders.

Main outcome measures: Standardized mean difference (SMD) in change in Montgomery-Asberg Depression Rating Scale (MADRS) score from baseline to study endpoint.

Statistical analysis: Estimates of the SMD in MADRS score changes were pooled after examining for homogeneity. A random effects model was used for this meta-analysis.

Data Sources: PubMed, abstracts of major psychiatric meetings, and ClinicalTrials.gov were searched up to November 2020 with no language constraints, cross-referencing ?intranasal? with: ?esketamine? and ?randomized?. Study Selection: Of 27 studies reviewed, eight articles, with a total of 1437 patients with MDD, met study criteria and were included in the meta-analysis.

Results: Augmentation of standard antidepressants with IN esketamine resulted in greater Montgomery-Asberg Depression Rating Scale (MADRS) score reduction than adjunctive intranasal placebo at 24 hours. Across the trials, the SMD was 0.34 (95% CI (0.11, 0.46), p"
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  string(1172) "Data Sources: PubMed, abstracts of major psychiatric meetings, clinicaltrials.gov.

Inclusion/exclusion criteria:

We selected randomized, double-blind clinical trials comparing adjunctive treatment of standard antidepressants with IN esketamine for MDD. Further, we selected studies that used IN placebo augmentation as a comparator. We then selected studies that also met the following inclusion criteria:

1)	Studies that used either the HDRS (Hamilton Depression Rating Scale)(14), or the MADRS (Montgomery Asberg Depression Rating Scale)(15) as their primary outcome measure;

2)	Studies that exclusively focused on patients with MDD.

Reports were excluded if they exclusively focused on the treatment of patients with bipolar disorder, dysthymic disorder, psychotic MDD, minor depressive disorder, seasonal affective disorder, depressed patients with a specific medical condition, or active alcohol or substance abuse disorders. Reports not describing original data (i.e. containing data published elsewhere) and those that were not focused on the acute phase of treatment (i.e. continuation, maintenance, relapse prevention) were excluded."
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Main outcome measure for this meta-analysis: standardized mean difference for intranasal esketamine versus control at 24 hours post first dose."
  ["project_main_predictor_indep"]=>
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  ["project_other_variables_interest"]=>
  string(682) "One reviewer suggesting reporting Hazard Ratios for remission versus non-remission at 24 hours and endpoint. This reviewer also suggested a meta-regression analysis for baseline severity. In order to run these additional analyses, we are seeking the following specific data points:

NCT02417064: remission at 24 hours (N, %) for placebo, 56mg esketamine and 84mg esketamine groups.

NCT02418585: remission at 24 hours (N, %) for placebo and flexibly dose esketamine.

NCT02918318: baseline MADRS (mean and standard deviation), remission at 24 hours (N, %), remission at study endpoint (N, %) for all groups- placebo, 28mg esketamine, 56mg esketamine, 84mg esketamine."
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  string(866) "The primary outcome of the meta-analysis was to compare the standardized mean difference in change in primary outcome scores between adjunctive esketamine and placebo. To accomplish this, we pooled the estimates of standardized mean difference (SMD) in change scores after examining for homogeneity using the test statistic proposed by DerSimonian and Laird. We presented as our final estimate the findings of the random effects model; this model is more conservative than the fixed-effects model and incorporates both within-study and between-study variance. Exploratory analyses included evaluating TRD and SI studies separately and evaluating studies by dose separately. All exploratory analyses were conducted in an identical fashion as the primary and secondary analyses. All analyses utilized the meta package of meta-analytic tools as implemented in Stata 15."
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  string(298) "A manuscript describing this meta-analysis has already been reviewed by the Journal of Clinical Psychiatry and accepted pending revisions. The peer reviewers have suggested some additional analyses. We hope to re-submit to the JCP within a month once we have gathered the additional data suggested."
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  string(194) "
1. Papakostas GI, Salloum NC, Hock RS, Jha MK, Murrough JW, Mathew SJ, et al. Efficacy of Esketamine Augmentation in Major Depressive Disorder: A Meta-Analysis. J Clin Psychiatry 2020;81
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