RESUMO
Background: Intranasal esketamine has received regulatory approvals for the treatment of depression. Recently a large trial of repeated dose racemic ketamine also demonstrated efficacy in severe depression. However, uncertainties remain regarding comparative efficacy, dosage, and the time course of response. Methods: In this systematic review and meta-analysis, we searched Embase, Medline, Pubmed, PsycINFO, and CENTRAL up to April 13, 2023, for randomised controlled trials (RCTs) investigating ketamine for depression. Two investigators independently assessed study eligibility and risk of bias and extracted the data on depression severity scores, response and remission rates, and all-cause dropouts. Multivariable mixed-effects meta-regressions incorporated drug formulation (racemic (Rac) or esketamine (Esket)) and dose (Low or High) as covariates. Treatment effects were assessed: immediately following the first dose, during further repeated dosing, and follow-up after the final dose of a treatment course. This study is registered with PROSPERO (CRD42021221157). Findings: The systematic review identified 687 articles, of which 49 RCTs were eligible for analysis, comprising 3299 participants. Standardised mean differences (95% confidence intervals) immediately following the first/single treatment were moderate-high for all conditions (Rac-High: -0.73, -0.91 to -0.56; Esket-High: -0.48, -0.75 to -0.20; Rac-Low: -0.33, -0.54 to -0.12; Esket-Low: -0.55, -0.87 to -0.24). Ongoing effects during repeated dosing were significantly greater than the control for Rac-High (-0.61; -1.02 to -0.20) and Rac-Low (-0.55, -1.09 to -0.00), but not Esket-Low (-0.15, -0.49 to 0.19) or Esket-High (-0.22, -0.54 to 0.10). At follow-up effects remained significant for racemic ketamine (-0.65; -1.23 to -0.07) but not esketamine (-0.33; -0.96 to 0.31). All-cause dropout was similar between experiment and control conditions for both formulations combined (Odds Ratio = 1.18, 0.85-1.64). Overall heterogeneity varied from 5.7% to 87.6. Interpretation: Our findings suggested that effect sizes for depression severity, as well as response and remission rates, were numerically greater for racemic ketamine than esketamine. Higher doses were more effective than low doses. Differences were evident in initial effects, ongoing treatment, and lasting effects after the final dose. Funding: None.
RESUMO
BACKGROUND: Depression is associated with cognitive deficits across multiple domains, including working memory. The n-back task, a convenient psychometric tool capable of computerised delivery and concurrent use with neuroimaging, can provide enhanced insight into working memory dysfunction in depression. This meta-analysis sought to investigate the n-back task under varying cognitive load conditions (i.e. different levels of 'n') to clarify the pattern of working memory deficits in depression. METHODS: We conducted a systematic review and meta-analysis of studies involving unipolar depressed participants and matched controls utilising the n-back task. Meta-analyses were performed for accuracy and response times at four levels of cognitive load (0-, 1-, 2-, and 3-back). RESULTS: 31 studies (total 1,666 participants) met inclusion criteria and were included for quantitative analyses. Depressed individuals had significantly reduced accuracy compared to controls for 1-, 2-, and 3-back tasks, but not the attentional 0-back task. Likewise, response latencies were prolonged for all task levels (0-, 1-, 2-, and 3-back). Additional meta-regression analyses indicated that participant age and clinical status (i.e. inpatient/outpatient) may exacerbate working memory deficits associated with depression. LIMITATIONS: Our results indicate high levels of heterogeneity between studies, particularly for response times. CONCLUSIONS: Accuracy impairments were worse at higher levels of n, with the largest effect size obtained on the 2-back task, suggesting deficits to higher executive functions. Response times were consistently prolonged at all cognitive loads in agreement with a pattern of generalised psychomotor retardation.
