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BACKGROUND: The introduction of esketamine into the field of psychiatry comes on the heels of excitement from studies on racemic ketamine. While the intranasal route has been the most studied to date, other modes of administration of esketamine may also be of interest in the management of depression.AIMS: To systematically review the literature on non-intranasal esketamine for depression in terms of its antidepressant effect and safety.METHODS: We searched PubMed, Embase, the Cochrane Library, and Google Scholar from inception up to February 2021. Search terms included a combination of Medical Subject Headings and text words indicative of esketamine and depression. We selected both controlled and uncontrolled studies examining non-intranasal esketamine for the treatment of depression.RESULTS: We identified four randomized controlled trials (RCTs) on intravenous esketamine and 15 open-label studies on intravenous (n = 80), subcutaneous (n = 73), and oral (n = 5) esketamine. We found intravenous, subcutaneous, and possibly oral administration of esketamine to be effective in reducing depressive symptoms in most patients with major depressive disorder, bipolar depression, and (severe) treatment-resistant depression. Clinical response to repeated administration of esketamine persisted over the course of treatment. Esketamine was well tolerated by most patients, but open-label data indicate marked psychotomimetic symptoms in exceptional cases. The overall quality of the controlled studies was considered high, the overall quality of the uncontrolled studies low to moderate.CONCLUSIONS: Intravenous, subcutaneous, and possibly oral esketamine may offer an effective and safe addition to the depression treatment armamentarium. However, as most included studies lacked a control group and had small sample sizes, the quality of our results is limited. Different types and formulations of ketamine remain to be compared directly.

Background: The introduction of esketamine into the field of psychiatry comes on the heels of excitement from studies on racemic ketamine. While the intranasal route has been the most studied to date, other modes of administration of esketamine may also be of interest in the management of depression. Aims: To systematically review the literature on non-intranasal esketamine for depression in terms of its antidepressant effect and safety. Methods: We searched PubMed, Embase, the Cochrane Library, and Google Scholar from inception up to February 2021. Search terms included a combination of Medical Subject Headings and text words indicative of esketamine and depression. We selected both controlled and uncontrolled studies examining non-intranasal esketamine for the treatment of depression. Results: We identified four randomized controlled trials (RCTs) on intravenous esketamine and 15 open-label studies on intravenous ( n = 80), subcutaneous ( n = 73), and oral ( n = 5) esketamine. We found intravenous, subcutaneous, and possibly oral administration of esketamine to be effective in reducing depressive symptoms in most patients with major depressive disorder, bipolar depression, and (severe) treatment-resistant depression. Clinical response to repeated administration of esketamine persisted over the course of treatment. Esketamine was well tolerated by most patients, but open-label data indicate marked psychotomimetic symptoms in exceptional cases. The overall quality of the controlled studies was considered high, the overall quality of the uncontrolled studies low to moderate. Conclusions: Intravenous, subcutaneous, and possibly oral esketamine may offer an effective and safe addition to the depression treatment armamentarium. However, as most included studies lacked a control group and had small sample sizes, the quality of our results is limited. Different types and formulations of ketamine remain to be compared directly.

IntroductionFor major depression, a one-size-fits-all treatment does not exist. Patients enter a ‘trial-and-change’ algorithm in which effective therapies are subsequently applied. Unfortunately, an empirically based order of treatments has not yet been determined. There is a magnitude of different treatment strategies while clinical trials only compare a small number of these. Network meta-analyses (NMA) might offer a solution, but so far have been limited in scope and did not account for possible differences in population characteristics that arise with increasing levels of treatment-resistance, potentially violating the transitivity assumption. We; therefore, present a protocol for a systematic review and NMA aiming at summarising and ranking treatments for treatment-resistant depression (TRD) while covering a broad range of therapeutic options and accounting for possible differences in population characteristics at increasing levels of treatment-resistance.Methods and analysisRandomised controlled trials will be included that compared next-step pharmacological, neuromodulation or psychological treatments for treatment-resistant depression (TRD; ie, failure to respond to ≥1 adequate antidepressant drug trial(s) in the current episode) to each other or to a control condition. Primary outcomes will be the proportion of patients who responded to (efficacy) and dropped out of (acceptability) the allocated treatment. A random effects NMA will be conducted, synthesising the evidence for each outcome and determining the differential efficacy of treatments. Heterogeneity in treatment nodes will be reduced by considering alternative geometries of the network structure and by conducting a meta-regression examining different levels of TRD. Local and global methods will be applied to evaluate consistency. The Cochrane Risk of Bias 2 tool, Confidence in Network Meta-Analysis and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework will be used to assess risk of bias and certainty.Ethics and disseminationThis review does not require ethical approval.

Objective Electroconvulsive therapy (ECT) is a well-established therapeutic intervention for major depressive disorder. Recent literature has shown that the anesthetic agent ketamine has some antidepressant properties at low doses and may be an alternative therapy for treatment-resistant major depressive disorder. We hypothesized that the use of low-dose ketamine as an anesthetic adjunct in ECT would more rapidly improve depression while maintaining hemodynamic stability than ECT with propofol alone. Methods Institutional ethics approval was obtained, and the use of ketamine in this study was approved by Health Canada. This is a randomized, double-blinded, placebo-controlled trial that involved ketamine administration at 0.5 mg/kg IV in addition to propofol anesthesia for ECT. The primary outcome was the number of ECT treatments required to achieve a 50% reduction in the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes included the number of ECT treatments required to achieve a 25% reduction in MADRS score, as well as any differences in the Clinical Global Impression Scale for Severity, hemodynamic variables, and seizure duration. Adverse events were recorded for safety assessment. Results A total of 45 patients completed the study. No difference was found between groups with respect to the primary or secondary outcomes. The ketamine group showed a trend towards a decreased dose of propofol required to achieve adequate anesthesia. No adverse events were reported. Conclusion Low-dose ketamine does not improve psychiatric outcomes in the setting of propofol-based anesthesia for ECT. Specifically, ketamine did not reduce the number of ECT sessions necessary to achieve a 50 or 25% reduction in MADRS scores. Reassuringly, the fact that no differences in hemodynamic variables or unexpected adverse events occurred suggests that low-dose ketamine may be safely used in this setting should clinical indications warrant its use. Clinical trial registration ClinicalTrials.gov, NCT02579642.

INTRODUCTION: For major depression, a one-size-fits-all treatment does not exist. Patients enter a 'trial-and-change' algorithm in which effective therapies are subsequently applied. Unfortunately, an empirically based order of treatments has not yet been determined. There is a magnitude of different treatment strategies while clinical trials only compare a small number of these. Network meta-analyses (NMA) might offer a solution, but so far have been limited in scope and did not account for possible differences in population characteristics that arise with increasing levels of treatment-resistance, potentially violating the transitivity assumption. We; therefore, present a protocol for a systematic review and NMA aiming at summarising and ranking treatments for treatment-resistant depression (TRD) while covering a broad range of therapeutic options and accounting for possible differences in population characteristics at increasing levels of treatment-resistance.METHODS AND ANALYSIS: Randomised controlled trials will be included that compared next-step pharmacological, neuromodulation or psychological treatments for treatment-resistant depression (TRD; ie, failure to respond to ≥1 adequate antidepressant drug trial(s) in the current episode) to each other or to a control condition. Primary outcomes will be the proportion of patients who responded to (efficacy) and dropped out of (acceptability) the allocated treatment. A random effects NMA will be conducted, synthesising the evidence for each outcome and determining the differential efficacy of treatments. Heterogeneity in treatment nodes will be reduced by considering alternative geometries of the network structure and by conducting a meta-regression examining different levels of TRD. Local and global methods will be applied to evaluate consistency. The Cochrane Risk of Bias 2 tool, Confidence in Network Meta-Analysis and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework will be used to assess risk of bias and certainty.ETHICS AND DISSEMINATION: This review does not require ethical approval.

The identification of single-nucleotide polymorphisms (SNPs) in genes putatively related to pathophysiological processes in major depressive disorder (MDD) might improve both diagnosis and personalized treatment strategies eventually leading to more effective interventions. Considering the important role of the glucocorticoid receptor and the related FK506 binding protein 51 (FKBP51) in the pathophysiology of MDD, we aimed to investigate putative associations between variants of FKBP5, the coding gene of FKBP51, with antidepressant treatment resistance and MDD susceptibility.Nine common SNPs of the FKBP5 gene prioritized based on location and, putative or known functions were genotyped in Han Chinese population, including MDD patients with or without antidepressant-treatment resistance and healthy controls. Associations of FKBP5 SNPs with MDD susceptibility and treatment response were examined in the whole group of MDD patients, as well as in subgroups stratified by antidepressant treatment resistance, compared with healthy controls.In total, 181 Han Chinese patients with MDD and 80 healthy controls were recruited. No significant SNP or haplotype associations were observed in the whole patient group. There were nominal significant differences both for the haplotype block with SNPs in strong LD (r2 > 0.8, P = .040) and haplotype block with SNPs in moderate LD (r2 > 0.1, P = .017) between the haplotype distributions of patients with antidepressant treatment resistance (n = 81) and healthy controls, but both significances did not survive multiple testing correction. Furthermore, no specific haplotype could be observed causing a significant difference in any combination between all comparisons.No associations were observed of FKBP5 variants with MDD or antidepressant treatment response. The lack of associations might be due to the relatively small sample size of this study (power ranged from 0.100 to 0.752). A follow-up study will need larger, better phenotyped, and more homogeneous samples to draw a definitive conclusion regarding the involvement of this gene in MDD.

Nitrous oxide (N2O) is one of the oldest drugs still in use in medicine. Despite its superior pharmacokinetic properties, controversy remains over its continued use in clinical practice, reflecting in part significant improvements in the pharmacology of other anaesthetic agents and developing awareness of its shortcomings. This narrative review describes current knowledge regarding the clinical use of N2O based on a systematic and critical analysis of the available scientific literature. The pharmacological properties of N2O are reviewed in detail along with current evidence for the indications and contraindications of this drug in specific settings, both in perioperative care and in procedural sedation. Novel potential applications for N2O for the prevention or treatment of chronic pain and depression are also discussed. In view of the available evidence, we recommend that the supply of N2O in hospitals be maintained while encouraging its economic delivery using modern low flow delivery systems. Future research into its potential novel applications in prevention or treatment of chronic conditions should be pursued to better identify its role place in the developing era of precision medicine.

BACKGROUND: Major depression is probably best seen as a chronically recurrent disorder, with patients experiencing another depressive episode after remission. Therefore, attention to reduce the risk of relapse or recurrence after remission is warranted. The aim of this review is to meta-analytically examine the effectiveness of psychological interventions to reduce relapse or recurrence rates of depressive disorder.METHODS: We systematically reviewed the pertinent trial literature until May 2014. The random-effects model was used to compute the pooled relative risk of relapse or recurrence (RR). A distinction was made between two comparator conditions: (1) treatment-as-usual and (2) the use of antidepressants. Other sources of heterogeneity in the data were explored using meta-regression.RESULTS: Twenty-five randomised trials met inclusion criteria. Preventive psychological interventions were significantly better than treatment-as-usual in reducing the risk of relapse or recurrence (RR=0.64, 95% CI=0.53-0.76, z=4.89, pLIMITATIONS: Differences between the primary studies in methodological design, composition of the patient groups and type of intervention may have caused heterogeneity in the data, but could not be evaluated in a meta-regression owing to poor reporting.CONCLUSIONS: We conclude that there is supporting evidence that preventive psychological interventions reduce the risk of relapse or recurrence in major depression.