Person:

Chaaya Salloum, Naji

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: To review existing staging models and definitions of Treatment Resistant Depression (TRD), and offer future directions within the context of up-to-date evidence. Data Sources: A PubMed search was conducted on 25 February 2018 for articles in English on TRD staging or definition using the following key terms: depressive disorder, treatment-resistant OR treatment resistant depression cross-referenced with staging OR degree OR level OR definition. Relevant cross-references from identified articles were also included. Study Selection: We identified 18 articles that included either a proposed TRD staging model, a proposed TRD definition, empirical work to support a model and/or definition, or any combination of the above. Data Extraction: Included articles were discussed in chronological order in terms of the date the TRD staging model (and accompanying TRD definition if applicable) was first proposed. This was followed by a synthesis of findings from validation studies pertaining to staging and/or definition. Results: Five staging models were identified. Strengths identified across staging models include rigorous assessment of adequacy of treatment, differentiation of resistance versus symptom return, assignment of equal weights to different pharmacotherapies, and accounting for augmentation. Future considerations should include differential weighting to specific augmentation agents based on available evidence, added weight to ECT and ketamine treatments, and the addition of evidence-based psychotherapies. In terms of TRD diagnosis, dichotomous versus continuous approaches were considered, with the latter (beginning with one failed trial) best explaining available data from large trials. Conclusion: The most up-to-date evidence in the literature should guide future research in the definition and staging of TRD.