Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults: Réseau canadien pour les traitements de l'humeur et de l'anxiété (CANMAT) 2023 : Mise à jour des lignes directrices cliniques pour la prise en charge du trouble dépressif majeur chez les adultes.

BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) last published clinical guidelines for the management of major depressive disorder (MDD) in 2016. Owing to advances in the field, an update was needed to incorporate new evidence and provide new and revised recommendations for the assessment and management of MDD in adults. METHODS: CANMAT convened a guidelines editorial group comprised of academic clinicians and patient partners. A systematic literature review was conducted, focusing on systematic reviews and meta-analyses published since the 2016 guidelines. Recommendations were organized by lines of treatment, which were informed by CANMAT-defined levels of evidence and supplemented by clinical support (consisting of expert consensus on safety, tolerability, and feasibility). Drafts were revised based on review by patient partners, expert peer review, and a defined expert consensus process. RESULTS: The updated guidelines comprise eight primary topics, in a question-and-answer format, that map a patient care journey from assessment to selection of evidence-based treatments, prevention of recurrence, and strategies for inadequate response. The guidelines adopt a personalized care approach that emphasizes shared decision-making that reflects the values, preferences, and treatment history of the patient with MDD. Tables provide new and updated recommendations for psychological, pharmacological, lifestyle, complementary and alternative medicine, digital health, and neuromodulation treatments. Caveats and limitations of the evidence are highlighted. CONCLUSIONS: The CANMAT 2023 updated guidelines provide evidence-informed recommendations for the management of MDD, in a clinician-friendly format. These updated guidelines emphasize a collaborative, personalized, and systematic management approach that will help optimize outcomes for adults with MDD.

Patient-reported outcomes on sleep quality and circadian rhythm during treatment with intravenous ketamine for treatment-resistant depression.

Background: Intravenous (IV) ketamine is a rapid acting antidepressant used primarily for treatment-resistant depression (TRD). It has been suggested that IV ketamine's rapid antidepressant effects may be partially mediated via improved sleep and changes to the circadian rhythm. Objectives: This study explores IV ketamine's association with changes in patient-reported sleep quality and circadian rhythm in an adult population with TRD. Methods: Adult patients (18-64 years) with TRD scheduled for IV ketamine treatment were recruited to complete patient rated outcomes measures on sleep quality using the Pittsburgh Sleep Quality Index (PSQI) and circadian rhythm using the Morningness-Eveningness Questionnaire (MEQ). Over a 4-week course of eight ketamine infusions, reports were obtained at baseline (T0), prior to second treatment (T1), prior to fifth treatment (T2), and 1 week after eighth treatment (T3). Results: Forty participants with TRD (mean age = 42.8, 45% male) were enrolled. Twenty-nine (72.5%) had complete follow-up data. Paired t tests revealed statistically significant improvements at the end of treatment in sleep quality (PSQI) (p = 0.003) and depressive symptoms (Clinically Useful Depression Outcome Scale-Depression, p < 0.001) while circadian rhythm (MEQ) shifted earlier (p = 0.007). The PSQI subscale components of sleep duration (p = 0.008) and daytime dysfunction (p = 0.001) also improved. In an exploratory post hoc analysis, ketamine's impact on sleep quality was more prominent in patients with mixed features, while its chronobiotic effect was prominent in those without mixed features. Conclusion: IV ketamine may improve sleep quality and advance circadian rhythm in individuals with TRD. Effects may differ in individuals with mixed features of depression as compared to those without. Since this was a small uncontrolled study, future research is warranted.

Patient-reported changes in sleep during treatment with intravenous ketamine for depression Intravenous ketamine is a fast acting treatment for depression that does not respond to more conventional antidepressant medications. Almost all people with depression have problems with sleep as a symptom of their illness. This can include things like difficulties falling asleep, problems staying asleep, sleeping more or less than usual, and shifting the sleep schedule to stay up later than usual. It has been previously suggested that improving sleep in people with depression may be part of how ketamine exerts its antidepressant effect. This study surveyed patients with depression who received eight intravenous infusions of ketamine (two per week for 4 weeks) to ask them about their sleep quality and patterns before treatment, part way through their course of treatment and after the treatments were completed. Symptoms of depression were also measured. Data were collected on 29 people. People reported overall that sleep quality did improve with ketamine treatments, and that timing of sleep shifted earlier. Sleep duration increased and people had less problems with daytime functioning. There is a subtype of depression called depression with "mixed features," meaning that these people, in addition to being depressed, may have some activating symptoms like irritability, restlessness, and agitation. It is thought that this type of depression may be biologically different from depression without these symptoms. In this study, around half (15/29) had mixed features. Sleep quality improved only in the group without mixed features. On the other hand, the group with mixed features had their sleep schedule shift earlier, but the group without mixed features did not. This supports the idea that these two types of depression may be biologically different, and ketamine treatment may exert different effects on the sleep of each group. This was a small study, but suggests a need for future research.

An Emergency Department Survey on Research Participation in the Patient With Suicidal Ideation or Suicide Attempt.

The patient expressing suicidal ideation is a common mental health presentation in the emergency department (ED) but a notion exists that this psychiatric crisis precludes them from research participation. In order to better understand the potential research participation of suicidal patients, this study surveyed patients in the ED with suicide attempt or ideation. This was an anonymized survey study interviewing 50 patients in a tertiary care ED with a chief complaint of suicide attempt or suicidal ideation. A script was read by the research assistant regarding a hypothetical research study using ketamine to treat suicidality in the ED and asked to rate their interest in participation in the study as well as their interest in a 1-week follow-up call. Most patients (84%) reported that they would be interested in participating in this research project while 96% of all 50 patients would be interested in a follow-up phone call at 1 week. The data from this study should help other emergency medicine and psychiatry researchers advance projects in this underserved ED patient population.

Diet and depression: A systematic review of whole dietary interventions as treatment in patients with depression.

BACKGROUND & RATIONALE: Depression is a common mental illness that afflicts over 300 million individuals worldwide. Despite a variety of therapeutic options available, a significant number of depressed patients fail to respond to treatment. Current guidelines for treating depression suggest that supplementation of essential nutrients may be an appropriate adjunctive to treatment, but research investigating full dietary interventions for depressed patients is scarce. STUDY OBJECTIVE: The primary aim of this study was to systematically review published scientific literature investigating full dietary interventions as treatment for individuals with a diagnosis of depression. In doing so, we assessed existing evidence for recommendation of a dietary intervention and reviewed theory of how diet may be important in this context. METHODS: A systematic search was conducted using OVID to search Medline, PsychINFO, and EMBASE, and PubMed for relevant publications. Only studies including full dietary interventions for patients with Major Depressive Episode, Major Depressive Disorder, Persistent Depressive Disorder, Seasonal Affective Disorder, or Dysthymia, as diagnosed using criteria defined in the chapter of "Depressive Disorders" in the DSM, were included. RESULTS: Only five studies met the inclusion criteria for this review. All five studies included in this review reported improvements in mood following dietary intervention as compared to the comparison group. However, heterogeneity in both the dietary intervention and the outcome(s) measured made it difficult to compare these studies against each other and to generalize them to larger populations. CONCLUSION: The findings of this review provide preliminary evidence for the positive impact of dietary interventions in the treatment of depressed patients. However, the mechanism by which particular diets induce positive changes in mood, be it through anti-inflammatory mechanisms or via weight loss in overweight patients, is unclear. Future research investigating the impact of dietary interventions on a large-scale is warranted and needed.

Use of ketamine for treatment resistant depression: updated review of literature and practical applications to a community ketamine program in Edmonton, Alberta, Canada.

Background: Though intravenous (IV) ketamine and intranasal (IN) esketamine are noted to be efficacious for treatment-resistant depression (TRD), access to each of these treatments within healthcare systems is limited due to cost, availability, and/or monitoring requirements. IV ketamine has been offered at two public hospital sites in Edmonton, Canada since 2015. Since then, demand for maintenance ketamine treatments has grown. This has required creative solutions for safe, accessible, evidence-based patient care. Objectives: Aims of this paper are twofold. First, we will provide a synthesis of current knowledge with regards to the clinical use of ketamine for TRD. Consideration will be given regarding; off-label racemic ketamine uses versus FDA-approved intranasal esketamine, populations treated, inclusion/exclusion criteria, dosing, assessing clinical response, concomitant medications, and tolerability/safety. Second, this paper will describe our experience as a community case study in applying evidence-based treatment. We will describe application of the literature review to our clinical programming, and in particular focus on cost-effective maintenance treatments, long-term safety concerns, routes of ketamine administration other than via intravenous, and cautious prescribing of ketamine outside of clinically monitored settings. Methodology: We conducted a literature review of the on the use of ketamine for TRD up to June 30, 2023. Key findings are reviewed, and we describe their application to our ketamine program. Conclusion: Evidence for the use of ketamine in resistant depression has grown in recent years, with evolving data to support and direct its clinical use. There is an increasing body of evidence to guide judicious use of ketamine in various clinical circumstances, for a population of patients with a high burden of suffering and morbidity. While large-scale, randomized controlled trials, comparative studies, and longer-term treatment outcomes is lacking, this community case study illustrates that currently available evidence can be applied to real-world clinical settings with complex patients. As cost is often a significant barrier to accessing initial and/or maintenance IV or esketamine treatments, public ketamine programs may incorporate SL or IN ketamine to support a sustainable and accessible treatment model. Three of such models are described.

Association of intranasal esketamine, a novel 'standard of care' treatment and outcomes in the management of patients with treatment-resistant depression: protocol of a prospective cohort observational study of naturalistic clinical practice.

INTRODUCTION: Esketamine is the S-enantiomer of racemic ketamine and has been approved by the Food and Drug Administration for the management of treatment resistant depression, demonstrating effective and long-lasting benefits. The objective of this observational study is to elucidate the association of intranasal (IN) esketamine with beneficial and negative outcomes in the management of treatment resistant major depressive disorder. METHODS AND ANALYSIS: This is a multicentre prospective cohort observational study of naturalistic clinical practice. We expect to recruit 10 patients per research centre (6 centres, total 60 subjects). After approval to receive IN esketamine as part of their standard of care management of moderate to severe treatment resistant depression, patients will be invited to participate in this study. Association of esketamine treatment with outcomes in the management of depression will be assessed by measuring the severity of depression symptoms using the Montgomery-Åsberg Depression Rating Scale (MADRS), and tolerability by systematically tracking common side effects of ketamine treatment, dissociation using the simplified 6-Item Clinician Administered Dissociative Symptom Scale and potential for abuse using the Likeability and Craving Questionnaire (LCQ). Change in depressive symptoms (MADRS total scores) over time will be evaluated by within-subject repeated measures analysis of variance. We will calculate the relative risk associated with the beneficial (reduction in total scores for depression) outcomes, and the side effect and dropout rates (tolerability) of adding IN esketamine to patients' current pharmacological treatments. Covariate analysis will assess the impact of site and demographic variables on treatment outcomes. ETHICS AND DISSEMINATION: Approval to perform this study was obtained through the Health Sciences Research Ethics Board at Queen's University. Findings will be shared among collaborators, through departmental meetings, presented on different academic venues and publishing our manuscript.

A survey of drug liking and cravings in patients using sublingual or intranasal ketamine for treatment resistant depression: A preliminary evaluation of real world addictive potential.

Ketamine has gained rapid popularity as a treatment option for treatment resistant depression (TRD). Though seen only in limited contexts, ketamine is a potential drug of abuse, addiction and diversion. Clinical ketamine studies to date have not systematically evaluated factors relevant to addiction risk in patients with TRD, but in treating patients with ketamine, risks of potential harms related to addiction must be considered. As clinical access to intravenous ketamine programs is limited in much of Canada, these considerations become even more important for clinicians who elect to offer patients less supervised, non-parenteral forms of ketamine treatment. This study explores factors relevant to addiction risk in a real-world sample of 33 patients with TRD currently or previously treated with sublingual (SL) or intranasal (IN) ketamine in the community. First, patients were surveyed using a Drug Liking and Craving Questionnaire (DLCQ) to assess their level of drug liking and craving for ketamine, and to screen for symptoms of a ketamine use disorder. Second, the pharmacy records of these patients were reviewed for red flags for addiction such as dose escalation or early refills. Third, surveys were administered to the treating psychiatrists of patients who had discontinued ketamine to determine if abuse concerns contributed to reason for discontinuation. Though limited to a small sample, results indicate that ketamine is not a universally liked or craved substance in patients with TRD. Prescribers of non-parenteral ketamine should monitor patients and prescribe cautiously. Factors related to addiction (as in the DLCQ) should be explored for clinicians to consider individual risk/benefit for judicious use of ketamine in patients with TRD.

Intravenous ketamine for depression: A clinical discussion reconsidering best practices in acute hypertension management.

Ketamine is a versatile medication with an emerging role for the treatment of numerous psychiatric conditions, including treatment resistant depression. Current psychiatry guidelines for its intravenous administration to treat depression recommend regular blood pressure monitoring and an aggressive approach to potential transient hypertensive episodes induced by ketamine infusions. While this approach is aimed at ensuring patient safety, it should be updated to align with best practice guidelines in the management of hypertension. This review defines and summarizes the currently recommended approach to the hypertensive emergency, the asymptomatic hypertensive urgency, and discusses their relevance to intravenous ketamine therapy. With an updated protocol informed by these best practice guidelines, ketamine treatment for depression may be more accessible to facilitate psychiatric treatment.

Efficacy and Tolerability of Two Novel "Standard of Care" Treatments-Intranasal Esketamine Versus Intravenous Ketamine-for Treatment-Resistant Depression in Naturalistic Clinical Practice: Protocol for a Pilot Observational Study.

BACKGROUND: Intravenous (IV) ketamine and intranasal (IN) esketamine have been studied as novel alternatives to manage treatment-resistant depression (TRD). The objective of this observational pilot study is to compare the real-world effectiveness and tolerability of IV ketamine and IN esketamine in the management of unipolar TRD. OBJECTIVE: To compare the effectiveness (primary outcome measure) and tolerability (secondary outcome measure) of racemic ketamine and esketamine in the management of TRD in adults and provide an expert qualitative commentary on the application of IV ketamine and IN esketamine in clinical practice (exploratory objective), focusing on the recruitment process, patient retention, effectiveness, and tolerability of the treatments. METHODS: This is a multicenter prospective observational study of naturalistic clinical practice. We expect to recruit 10 patients per treatment arm-IV ketamine or IN esketamine per center (2 centers, total 40 subjects). Patients experiencing moderate to severe TRD and who are candidates for receiving low-dose IV ketamine treatments or IN esketamine as part of their standard-of-care treatments will be recruited. We will measure the effectiveness of each treatment arm by measuring the severity of depression symptoms using the Montgomery and Åsberg Depression Rating Scale; tolerability, side effects, and the appearance of dissociation symptoms using the simplified 6-item version of the Clinician Administered Dissociative Symptom Scale (CADSS-6); and potential for abuse using a Likeability and Craving Questionnaire. Logistic regression will examine odds ratios, number needed to treat for response and remission, number needed to harm, and likelihood to be helped or harmed of each treatment. Covariate analysis will assess the impact of site and demographic variables on treatment efficacy. RESULTS: This observational trial was approved by the Queen's University Health Science and Affiliated Teaching Hospital's Research Ethics Board in February 2021. The two research centers involved have started patient recruitment. Our research center (Providence Care Hospital, Kingston, Ontario) has recruited 9 patients so far. We expect to finalize data gathering by August 2022. The manuscript is expected to be published by December 2022. CONCLUSIONS: We hypothesize that both treatments will have comparable rapid and robust antidepressant effects and similar tolerability profiles in a real-world setting for the management of TRD. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/34711.

The abuse liability of ketamine: A scoping review of preclinical and clinical studies.

While ketamine has been used clinically over the past decades, it has only been recently shown to be a promising therapy for treatment-resistant depression (TRD). However, ketamine and related dissociative agents may also be misused recreationally, creating significant concerns for abuse liability when prescribed for depression. Although the abuse potential of ketamine is widely recognized, there is limited evidence on the differential abuse liability of ketamine enantiomers, (S)-ketamine and (R)-ketamine. The current scoping review aims to summarize the extant literature on the abuse liability of (R,S)-ketamine and the enantiomers. A systematic search was conducted on the Embase, Medline, and APA PsycInfo databases from 1947 to July 29, 2021. Clinical and preclinical studies that assessed the abuse potential of (R,S)-ketamine, (S)-ketamine, and (R)-ketamine were screened and assessed for eligibility by two independent reviewers. A total of 65 eligible studies were identified; 55 were preclinical studies and 10 were clinical studies. Only 4 preclinical studies evaluated the abuse liability of ketamine enantiomers. Available preclinical evidence suggests that (R,S)-ketamine and (S)-ketamine have greater risk for abuse compared to (R)-ketamine. (R)-ketamine, at the antidepressant-relevant doses in rodents, appears to be safe with minimal liability for abuse. Although the abuse potential of (R,S)-ketamine is well-established in animals, limited clinical studies indicate that single or repeated ketamine administrations in professionally controlled settings did not result in misuse, dependence, diversion and/or gateway activity in patients with TRD. However, most clinical studies were retrospective and did not systematically evaluate the abuse liability of ketamine via validated psychological scales/questionnaires. Future randomized controlled trials are warranted to ascertain the abuse liability of racemic, (S)- and (R)-ketamine in TRD population, especially among patients with comorbid substance use disorders.

Non-parenteral Ketamine for Depression: A Practical Discussion on Addiction Potential and Recommendations for Judicious Prescribing.

Intravenous (IV) ketamine is increasingly used off-label at subanesthetic doses for its rapid antidepressant effect, and intranasal (IN) esketamine has been recently approved in several countries for treating depression. The clinical utility of these treatments is limited by a paucity of publicly funded IV ketamine and IN esketamine programs and cost barriers to private treatment programs, as well as the drug cost for IN esketamine itself, which makes generic ketamine alternatives an attractive option. Though evidence is limited, use of non-parenteral racemic ketamine formulations (oral, sublingual, and IN) may offer more realistic access in less rigidly supervised settings, both for acute and maintenance treatment in select cases. However, the psychiatric literature has repeatedly cautioned on the addictive potential of ketamine and raised caution for both less supervised and longer-term use of ketamine. To date, these concerns have not been discussed in view of available evidence, nor have they been discussed within a broader clinical context. This paper examines the available relevant literature and suggests that ketamine misuse risks appear not dissimilar to those of other well-established and commonly prescribed agents with abuse potential, such as stimulants or benzodiazepines. As such, ketamine prescribing should be considered in a similar risk/benefit context to balance patient access and need for treatment with concern for potential substance misuse. Our consortium of mood disorder specialists with significant ketamine prescribing experience considers prescribing of non-parenteral ketamine a reasonable clinical treatment option in select cases of treatment-resistant depression. This paper outlines where this may be appropriate and makes practical recommendations for clinicians in judicious prescribing of non-parenteral ketamine.

Prevention and Management of Common Adverse Effects of Ketamine and Esketamine in Patients with Mood Disorders.

The emerging roles of ketamine and esketamine as effective rapid-acting antidepressants hold promise for patients suffering from treatment-resistant depression and/or major depressive disorder with suicidality. Practitioner familiarity with common tolerability/safety concerns along with pragmatic prevention and management strategies are needed to reduce patient burden and improve the acceptability and accessibility of these treatments. The most common treatment-emergent adverse events associated with ketamine/esketamine are dissociation, anxiety, nausea, increased blood pressure, and headache. The majority of side effects are mild, transient, dose dependent, and attenuate with subsequent treatments. Patient selection, baseline physical and psychiatric assessments, and an appropriate setting are critical first steps in the prevention and mitigation of adverse events. Patient education and supportive interventions play central roles in the prevention and management of select adverse events. Severe and/or clinically significant adverse effects may necessitate the judicious use of adjunctive medications. Moreover, practitioners must remain vigilant to the potential for abuse liability and long-term adverse events, for which there are insufficient data. This article succinctly reviews common treatment-emergent adverse events of ketamine and esketamine within the context of mood disorders, and provides practical suggestions for prevention and management at point-of-care.

Impact of Pandemics/Epidemics on Emergency Department Utilization for Mental Health and Substance Use: A Rapid Review.

Background: A prolonged COVID-19 pandemic has the potential to trigger a global mental health crisis increasing demand for mental health emergency services. We undertook a rapid review of the impact of pandemics and epidemics on emergency department utilization for mental health (MH) and substance use (SU). Objective: To rapidly synthesize available data on emergency department utilization for psychiatric concerns during COVID-19. Methods: An information specialist searched Medline, Embase, Psycinfo, CINAHL, and Scopus on June 16, 2020 and updated the search on July 24, 2020. Our search identified 803 abstracts, 7 of which were included in the review. Six articles reported on the COVID-19 pandemic and one on the SARS epidemic. Results: All studies reported a decrease in overall and MH related ED utilization during the early pandemic/epidemic. Two studies found an increase in SU related visits during the same period. No data were available for mid and late stage pandemics and the definitions for MH and SU related visits were inconsistent across studies. Conclusions: Our results suggest that COVID-19 has resulted in an initial decrease in ED visits for MH and an increase in visits for SU. Given the relative paucity of data on the subject and inconsistent analytic methods used in existing studies, there is an urgent need for investigation of pandemic-related changes in ED case-mix to inform system-level change as the pandemic continues.

The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Recommendations for the Use of Racemic Ketamine in Adults with Major Depressive Disorder: Recommandations Du Groupe De Travail Du Réseau Canadien Pour Les Traitements De L'humeur Et De L'anxiété (Canmat) Concernant L'utilisation De La Kétamine Racémique Chez Les Adultes Souffrant De Trouble Dépressif Majeur.

OBJECTIVE: Patients with major depressive disorder often have limited response to first-line and second-line medications; hence, novel pharmacological treatments are needed for treatment-resistant depression (TRD). Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has demonstrated rapid antidepressant effects in patients with TRD. The Canadian Network for Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence for efficacy and safety of racemic ketamine and to provide recommendations for its use in clinical practice. METHODS: A systematic review was conducted with computerized search of electronic databases up to January 31, 2020 using combinations of search terms, inspection of bibliographies, and review of other ketamine guidelines and consensus statements. The level of evidence and lines of treatment were assigned according to CANMAT criteria. Recommendations were given in question-answer format. RESULTS: Intravenous (IV) racemic ketamine given as a single infusion has Level 1 evidence for efficacy in adults with TRD. The evidence for multiple infusions, given as an acute series or as ongoing maintenance treatment, is limited to Level 3. Adverse events associated with ketamine infusions include behavioral (e.g., dissociative symptoms) and physiological (e.g., hypertension) events. There is only Level 3 or 4 evidence for non-IV formulations of racemic ketamine. Consensus recommendations are given for clinical administration of IV ketamine including patient selection, facility and personnel issues, monitoring, and maintaining response. CONCLUSIONS: Single-dose IV racemic ketamine is a third-line recommendation for adults with TRD. The need for repeated and maintenance ketamine infusions should be carefully assessed on a case-by-case basis with consideration of potential risks and benefits. Because of limited evidence for efficacy and risk for misuse and diversion, the use of oral and other formulations of racemic ketamine should be limited to specialists with ketamine-prescribing expertise and affiliations with tertiary or specialized centers.

Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers.

Ketamine, a drug introduced in the 1960s as an anesthetic agent and still used for that purpose, has garnered marked interest over the past two decades as an emerging treatment for major depressive disorder. With increasing evidence of its efficacy in treatment-resistant depression and its potential anti-suicidal action, a great deal of investigation has been conducted on elucidating ketamine's effects on the brain. Of particular interest and therapeutic potential is the ability of ketamine to exert rapid antidepressant properties as early as several hours after administration. This is in stark contrast to the delayed effects observed with traditional antidepressants, often requiring several weeks of therapy for a clinical response. Furthermore, ketamine appears to have a unique mechanism of action involving glutamate modulation via actions at the N-methyl-D-aspartate (NMDA) and α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as well as downstream activation of brain-derived neurotrophic factor (BDNF) and mechanistic target of rapamycin (mTOR) signaling pathways to potentiate synaptic plasticity. This paper provides a brief overview of ketamine with regard to pharmacology/pharmacokinetics, toxicology, the current state of clinical trials on depression, postulated antidepressant mechanisms and potential biomarkers (biochemical, inflammatory, metabolic, neuroimaging sleep-related and cognitive) for predicting response to and/or monitoring of therapeutic outcome with ketamine.

Correction.

This corrects the article DOI: 10.4088/JCP.20lcx13316.

Esketamine for treatment resistant depression.

Introduction: Treatment Resistant Depression (TRD) is a common and burdensome condition with poor outcomes and few treatment options. Esketamine is the S-enantiomer of ketamine and has recently been FDA approved in the United States for treating depression that has failed to respond to trials of two or more antidepressants. Areas covered: This review will briefly discuss current treatment options for TRD, then review esketamine. Relevant literature was identified through online database searches, and clinical trial data were provided by Janssen Pharmaceuticals. Pharmacology, including kinetics and dynamics, is discussed, then clinical data regarding efficacy and safety for esketamine from Phase 2-3 trials are reviewed. Expert opinion: In the expert opinion, the authors discuss multiple factors including patient, physician, and social factors that will influence the use of esketamine. While the efficacy of esketamine compared to off-label use of racemic ketamine remains unclear, both esketamine's approval for use in TRD and longer-term safety data may position it preferentially above racemic ketamine, although factors such as cost and monitoring requirements may limit its use. While questions remain regarding duration and frequency of treatment, as well as addictive potential, esketamine is a novel treatment option offering new hope for TRD.