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.

The Influence of Research Follow-Up during COVID-19 Pandemic on Mental Distress and Resilience: A Multicenter Cohort Study of Treatment-Resistant Depression.

BACKGROUND: During the COVID-19 outbreak, patients with mental disorders have faced more negative psychological consequences than the public. For people with treatment-resistant depression (TRD), it is unclear whether research engagement would protect them from the deterioration of their symptoms. The study aimed to examine if chronic depressive patients would have improved resilience and mental distress levels after follow-up interviews during an observation period under COVID-19. METHODS: The study was nested within a three-year prospective cohort study. A two-group comparison design was conducted, i.e., the follow-up group with regular research interviews every three months after baseline assessment and the control group with one assessment-only interview. The two groups were compared with demographics, psychosocial, and suicide information. RESULTS: Baseline assessments were not significantly different in sociodemographic variables, suicide risks, mental distress, and resilience between groups. Significant differences were detected in resilient coping and mental distress levels (p < 0.05). The follow-up group (n = 46) experienced a higher level of resilient coping (37% vs. 25%) and lower level of mental distress (47.8% vs. 64.7%) than the control group (n = 68). CONCLUSIONS: Findings highlight under universal government strategy against COVID-19, TRD patients receiving regular research follow-ups exhibited better resilience and less mental distress than those without regular support from healthcare providers.

The Effect of Repetitive Transcranial Magnetic Stimulation on Suicidal Ideation in Treatment-Resistant Depression: A Meta-Analysis.

Objective: To quantitatively synthesize the literature on the effects of repetitive transcranial magnetic stimulation (rTMS) on suicidal ideation (SI) in patients with treatment-resistant depression.Data Sources: A literature search was conducted using PubMed, SCOPUS, Ovid, MEDLINE, Embase, and Web of Science from inception to January 11, 2021, for the keywords repetitive transcranial magnetic stimulation, suicidal ideation, suicidality, treatment-resistant depression, refractory depression, transcranial magnetic stimulation, and brain stimulation.Study Selection: A total of 16 publications were eligible for inclusion. Studies were included that investigated the effects of rTMS in adolescents and/or adults 16 years or older diagnosed with unipolar or bipolar depression with suicidal ideation data before and after rTMS intervention.Data Extraction: Data were extracted and managed using Covidence. Extracted data included authors, publication year, country of origin, study design, patient demographics, primary diagnosis, comorbidities, mean age, outcome assessment instruments, detailed stimulation parameters, sham control procedures, and any serious adverse events related to SI.Results: A quantitative analysis of effect size using Hedges g was calculated for both randomized controlled trials and all other uncontrolled trials. We found a decrease in SI scores in randomized controlled trials (g = 0.158, 95% confidence interval [CI] = -0.078 to 0.393, P = .191), although the effect was not significant. There was a significant decrease in suicidal ideation scores for uncontrolled trials (g = 0.692, 95% CI = 0.463 to 0.922, P < .001).Conclusions: Our findings suggest that rTMS may be an effective treatment for SI in individuals with treatment-resistant depression, although further investigation is warranted.

The Use of Electroconvulsive Therapy in Neuropsychiatric Complications of Coronavirus Disease 2019: A Systematic Literature Review and Case Report.

BACKGROUND: There is a significant prevalence of new onset neuropsychiatric symptoms (NPS), some severe and persistent, in patients with coronavirus disease 2019 (COVID-19). OBJECTIVE: This study reports on the use of electroconvulsive therapy (ECT) to treat NPS associated with COVID-19. METHODS: A review of the literature pertaining to the use of ECT in patients with COVID-19 and NPS was performed through PubMed, PsycINFO, and MEDLINE. Search terms included "Electroconvulsive Therapy" and "ECT," combined with "COVID-19" and "Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2)." In addition, we present a case in which ECT was used to achieve complete remission in a patient who developed new onset, treatment-resistant depression, psychosis, and catatonia, associated with COVID-19. RESULTS: A total of 67 articles were reviewed with 3 selected for inclusion. These articles detailed 3 case reports of patients with new onset NPS (mania, psychosis and suicidality, and catatonia) that developed in the context of active COVID-19 and were treated successfully with ECT. CONCLUSIONS: ECT, a broad-spectrum treatment that has been found to be effective in various NPS (independent of etiology), is shown in our case report and others, to be safe and effective for NPS associated with COVID-19. Although we identified only 3 other cases in the literature, we believe that the probable antiinflammatory mechanism of ECT, its safety and tolerability, and the faster time to symptom remission support the need for more research and increased clinician awareness about this life-saving procedure.

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.

Challenges and pitfalls in anesthesia for electroconvulsive therapy.

Electroconvulsive therapy (ECT) refers to the application of electricity to the patients' scalp to treat psychiatric disorders, most notably, treatment-resistant depression. It is a safe, effective, and evidence-based therapy that is performed with general anesthesia. Muscle relaxation is used to prevent injuries related to the tonic-clonic seizure caused by ECT. Hypnotics are administered to induce amnesia and unconsciousness, so that, patients do not experience the period of muscle relaxation, while the generalized seizure is left unnoticed. For the anesthesiologist, ECT is associated with the challenges and pitfalls that are related to informed consent, social acceptance of ECT, airway management (especially in COVID-19 patients), and the interaction between ventilation and anesthetics from one viewpoint, and seizure induction and maintenance from another. The exact mode of action of the therapy is as unknown as the optimal choice or combination of anesthetics used.

Effectiveness of a healthy lifestyle promotion program as adjunctive teletherapy for treatment-resistant major depression during COVID 19 pandemic: A randomized clinical trial protocol.

INTRODUCTION: Treatment-resistant depression (TRD) has a high prevalence and can be exacerbated by poor physical health and economic hardships, which have become common stressors during the current COVID-19 pandemic. The therapeutic approaches used to treat these patients are not always available, may be not be accepted by some patients, and often require face-to-face interactions. OBJECTIVE: The main aim of this study will be to evaluate the effectiveness of an Internet-based adjuvant lifestyle-based intervention for patients with TRD. METHODS: This will be a parallel, randomized, and controlled clinical trial. A total of 180 patients with TRD will be randomly allocated (1:1:1) to 1 of 3 groups: treatment prescribed by the mental health team and written suggestions for lifestyle changes (placebo control group); treatment prescribed by the mental health team, written suggestions for lifestyle changes, and an 8-week mindfulness-based cognitive therapy program (active control group); or treatment prescribed by the mental health team, written suggestions for lifestyle changes, and an 8-week lifestyle change promotion program (intervention group). We will perform this study during the COVID-19 pandemic, and will administer interventions by teletherapy, and contact participants by telephone calls, text messages, and/or teleconferences. We will collect patient data using questionnaires administered at baseline, immediately after the intervention, and after 6 and 12 months. The primary outcome will be score on the Beck Depression Inventory-II. The secondary outcomes will be score on the Clinical Global Impressions Scale (used to quantify and track patient progress and treatment response over time) and health-related quality of life measured using the European Quality of Life-5 Dimensions Questionnaire. DISCUSSION: Patients with TRD are especially vulnerable when face-to-face psychotherapy is unavailable. The main strength of the proposed study is the novelty of the intervention to be used as an adjuvant therapy. Our results may provide guidance for treatment of patients with TRD in future situations that require lockdown measures. CLINICALTRIALS REGISTRATION NUMBER: NCT04428099.

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.

Connectivity guided theta burst transcranial magnetic stimulation versus repetitive transcranial magnetic stimulation for treatment-resistant moderate to severe depression: study protocol for a randomised double-blind controlled trial (BRIGhTMIND).

INTRODUCTION: The BRIGhTMIND study aims to determine the clinical effectiveness, cost-effectiveness and mechanism of action of connectivity guided intermittent theta burst stimulation (cgiTBS) versus standard repetitive transcranial magnetic stimulation (rTMS) in adults with moderate to severe treatment resistant depression. METHODS AND ANALYSIS: The study is a randomised double-blind controlled trial with 1:1 allocation to either 20 sessions of (1) cgiTBS or (2) neuronavigated rTMS not using connectivity guidance. A total of 368 eligible participants with a diagnosis of current unipolar major depressive disorder that is both treatment resistant (defined as scoring 2 or more on the Massachusetts General Hospital Staging Score) and moderate to severe (scoring >16 on the 17-item Hamilton Depression Rating Scale (HDRS-17)), will be recruited from primary and secondary care settings at four treatment centres in the UK. The primary outcome is depression response at 16 weeks (50% or greater reduction in HDRS-17 score from baseline). Secondary outcomes include assessments of self-rated depression, anxiety, psychosocial functioning, cognition and quality of life at 8, 16 and 26 weeks postrandomisation. Cost-effectiveness, patient acceptability, safety, mechanism of action and predictors of response will also be examined. ETHICS AND DISSEMINATION: Ethical approval was granted by East Midlands Leicester Central Research Ethics Committee (ref: 18/EM/0232) on 30 August 2018. The results of the study will be published in relevant peer-reviewed journals, and then through professional and public conferences and media. Further publications will explore patient experience, moderators and mediators of outcome and mechanism of action. TRIAL REGISTRATION NUMBER: ISRCTN19674644.

[The Impact of the COVID-19 Pandemic on the Health and Coping Behaviors of Patients With Treatment-Resistant Depression].

BACKGROUND: The COVID-19 pandemic has had a disastrous impact globally. For the general public and for people with mental illnesses, this pandemic may cause mental/physical stress and major life impacts. PURPOSE: This study was designed to explore the related changes in daily life and impacts on the well-being of a group of patients with chronic treatment-resistant depression (TRD) during the COVID-19 pandemic. METHODS: This study was a part of a long-term, follow-up study of a cohort of patients with TRD collected in 2018. All of the subjects who were diagnosed with major depression and fit the inclusion criteria were referred by the psychiatrists from two teaching hospitals. Structured interviews were used to collect data on physical and psychological changes during the pandemic period between January and May 2020. The researchers organized the key points by recording or note taking. Thematic analysis was used to summarize and classify themes and units. RESULTS: The 116 respondents revealed that the COVID-19 pandemic affected their health in the biological, psychological, and social dimensions. The three emerging themes included: The threatening of homogeneity in the whole person's health, the interaction between bio-psycho-social aspects, and positive growth of individuals with TRD. Although the participants had confidence in the prevention strategies of the government related to COVID-19, they expressed feelings of distress and restlessness with regard to COVID-19-related news reports. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: The COVID-19 pandemic has affected the health of patients with TRD in both positive and negative ways. As the goal of government preventive strategies is to protect and promote public health, regular attention should be paid to the negative effects of long-term exposure to pandemic-related news on this vulnerable population.