Clinical experiences with intranasal esketamine for major depressive disorder resistant to treatment and with a psychiatric emergency: case presentations.

Recently, esketamine became availableas an intranasal formulation, proposed for treatment-resistant depression (TRD). Three cases of TRD are presented, two with features of a psychiatric emergency. The first case is a 35-year-old man with MDD onset at the age of 27 years, with five previous failed therapies. The second patient is a middle-aged man with a 21-year MDD onset and six previous antidepressant treatments discontinued for poor therapeutic effects and tolerability. He also presented suicidal ideation with intent and a history of a failed suicide attempt by self-cutting his forearms. The third case is a 28-year-old female with a first MDD episode in 2020, treated first with amitriptyline and then with intravenous clomipramine. She had a history of a previous suicide attempt by self-cutting and, by her admission, showed active suicidal ideation with intent. In all three cases, a rapid reduction of depressive symptoms was observed with a subsequent complete resolution of suicidal ideation and intent in the two patients with such risk. Intranasal esketamine treatment was carried out with concomitant oral antidepressant therapy. The third patient reported the only recorded side effect: dissociation 20 min after every esketamine administration. Our preliminary experience proved esketamine's effectiveness on TRD symptoms and successful outcomes in psychiatric emergencies such as suicide risk.

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.

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.

Real-world effectiveness of repeated ketamine infusions for treatment resistant depression during the COVID-19 pandemic.

Herein we evaluate the impact of COVID-19 restrictions on antidepressant effectiveness of intravenous (IV) ketamine in adults with treatment-resistant depression (TRD). We conducted a case series analysis of adults with TRD (n = 267) who received four ketamine infusions at an outpatient clinic in Ontario, Canada, during COVID-19 restrictions (from March 2020 - February 2021; n = 107), compared to patients who received treatment in the previous year (March 2019 - February 2020; n = 160). Both groups experienced significant and comparable improvements in depressive symptoms, suicidal ideation, and anxiety with repeated ketamine infusions. Effectiveness of IV ketamine was not attenuated during the COVID-19 period.

Ketamine's rapid antisuicidal effects are not attenuated by Buprenorphine.

Ketamine's rapid antisuicidal action has gathered significant clinical interest in treatment of depression though concerns exist that its actions occur through the Opioid pathway. A recent study additionally reported that Naltrexone blocks antisuicidal effects of Ketamine suggesting that its antisuicidal effects are also due to opioid mechanisms. We present a case of treatment refractory depression with recent suicide attempt and active suicidal ideations who was on an Opioid partial agonist, Buprenorphine, for management of pain. Patient responded to a trial of IV ketamine treatment with rapid improvement in suicidal thoughts. Patient's suicidal ideations decreased after first Ketamine treatment and resolved after second treatment while maintained on Buprenorphine. Our finding shows that Buprenorphine does not block Ketamine's effects on suicidal ideations and therefore Ketamine treatment could be provided safely in controlled environment to those with substance use disorders or with chronic pain while being maintained on Buprenorphine. Additionally, our case suggests that non-Opioid mechanisms may be involved in Ketamine's antidepressant effects and its response to suicidal ideations in those on Opioid partial agonists.

Repeated ketamine injections in synergy with antidepressants for treating refractory depression: A case showing 6-month improvement.

WHAT IS KNOWN AND OBJECTIVE: Some patients with refractory depression who fail to respond to rapid injection of standard-dose ketamine are injected with high doses, but the safety and efficacy of this practice are unclear. CASE DESCRIPTION: A 57-year-old woman with refractory depression whose symptoms did not improve after 20-seconds intravenous injection of 0.5 mg/kg ketamine went into remission following eight, 1-minute intravenous injections of 1 mg/kg ketamine delivered over a 4-week period. By 6-month follow-up, no significant adverse events had occurred and cognitive function had improved. WHAT IS NEW AND CONCLUSION: High-dose intravenous injections of ketamine may stably improve depressive symptoms and cognitive function in patients with refractory depression who do not respond to rapid intravenous injection of standard-dose ketamine. The high-dose treatment appears to be associated with only mild side effects.