Original Title: Kétamine parentérale pour la dépression réfractaire aux traitements chez l’adulte : pertinence clinique, enjeux et encadrement

Authors' objectives: Difficult-to-treat depression, better known as “treatment-resistant depression”, is a multifactorial condition with significant functional impacts on the daily life of those affected. For the past few years, ketamine has been available to certain persons with this condition as an adjunct to the usual treatments, although this is an off-label use. Because of an increase in the number of requests to institutional pharmacology committees, the National Director of Mental Health and Forensic Psychiatry Services and the Direction of pharmaceuticals affairs and drugs of the Ministère de la Santé et des Services sociaux (MSSS) asked the Institut national d’excellence en santé et en services sociaux (INESSS) to assess the relevance of using parenteral ketamine in this context and, if applicable, to make recommendations to guide its use in Quebec. This work of clinical relevance is in line with the 2022-2026 interministerial mental health action plan - S’unir pour un mieux-être collectif.

Authors' results and conclusions: RESULTS (#1 TREATMENT-RESISTANT DEPRESSION: A MEDICAL CONDITION WITH MAJOR CONSEQUENCES): Approximately 21.7% of Canadians with a major depressive disorder are resistant to treatment, the prevalence in Québec being 13%. Over a 12- month period, major depressive disorders affect 7.6% of Canadians and 7.9% of Quebecers aged 18 to 64 years. There are people with this condition across the province. They are not just in the main urban centres, where second- and third-line treatments, such as neuromodulation, are available. (#2 AN ADDITIONAL TREATMENT OPTION FOR HIGHLY VULNERABLE INDIVIDUALS): The pathophysiology of major depressive disorder is multifactorial and includes hereditary and psychosocial factors and neuroendocrine alterations. • The treatment options include non-pharmacological (including self-care) and pharmacological interventions. • It is generally accepted that, in major depressive disorder, the likelihood of responding to therapy decreases with each treatment failure.(#3 PARENTERAL KETAMINE: A FAVOURABLE RISK-BENEFIT RATIO, ALTHOUGH SOME UNCERTAINTIES REMAIN): Regardless of the duration of treatment (single dose or acute-treatment phase with multiple doses for 2 to 4 weeks), parenteral ketamine seems to be efficacious in the short term, especially in reducing the severity of depressive symptoms (level of scientific evidence low to moderate). • The evaluation of the scientific data from primary studies is based on randomized clinical trials, but most are phase II studies with fewer than 100 participants and a limited duration of follow up. Considering the early stage in our evolving knowledge concerning the use of ketamine in treatment-resistant depression, it is possible that practices will change in light of future scientific data. (#4 CONDITIONS TO BE MET FOR PROPERLY SELECTING INDIVIDUALS WHO WILL BE ABLE TO BENEFIT FROM PARENTERAL KETAMINE WITHOUT COMPROMISING THEIR SAFETY OR WELL-BEING): Establishing clinical guidelines for deciding whether to use ketamine is essential but complex. The first key step consists in making an accurate diagnosis of treatment-resistant depression, which is defined in the literature and on the basis of the experience of the psychiatrists who were consulted, as that after the failure of several pharmacological trials and of psychotherapy, if it was possible to initiate such therapy. Other factors to consider include symptom severity, the presence of comorbidities and access to psychotherapy or neuromodulation. Carefully selecting patients is necessary for maximizing the benefits of the treatment and reducing the risks, but the wide range of clinical profiles makes this a challenging task. (#5 QUALIFIED RESOURCES AND PROPER INFRASTRUCTURE FOR OPTIMIZING THE TREATMENT EXPERIENCE AND ACHIEVING THE DESIRED BENEFITS WITHOUT HARM TO THE PERSON): The psychedelic model, a more recent practice for which the level of scientific evidence is still very low, considers ketamine’s dissociative effects beneficial and incorporates psychotherapeutic support to help the person accept and benefit from the experience. • The hybrid model speeds up a psychological process supported by psychotherapy, but it does not lead to biological healing. For a rapid and lasting response, it is essential to improve sleep, physical activity and social contact. Psychotherapy is crucial for a lasting remission. It is provided during treatment. (#6 A RELATIVELY AFFORDABLE AND MORE EASILY ACCESSIBLE TREATMENT, BUT WITH CERTAIN ORGANIZATIONAL AND PROFESSIONAL CHALLENGES): Although the use of ketamine for treatment-resistant depression is on the rise, this is still an infrequently used therapeutic approach. For all of Québec, for the 2023- 2024 fiscal year, just over 100 people used ketamine during psychiatric care. (#7 EQUITY OF ACCESS AND INFORMED CONSENT CHALLENGES IN THE CONTEXT OF EVOLVING KNOWLEDGE): Those with treatment-resistant depression, who are often in highly vulnerable situations and have unmet health needs, may not be fully aware of the risks and benefits of this treatment, which can compromise their free and informed consent. In addition to this complex situation are the uncertainties regarding the mediumand long-term effects and the risk of misuse. It is important to check that the person understands that ketamine is administered as an adjunct to other treatments and that its use requires close monitoring.

Authors' recommendations: INESSS considers that acute adjunctive therapy with parenteral ketamine may be relevant as part of the continuum of interdisciplinary mental health care and services in certain adults with depression that does not respond to optimized treatments (e.g., several failed pharmacological trials and failure of psychotherapy, if it was possible to initiate such therapy), as long as the decision is based on the following:  A psychiatric evaluation, a measurement of the severity of the depression using a validated scale, and a precise differential diagnosis for treatment-resistant depression;  A consideration of the absolute contraindications6 and the populations, conditions or situations for which caution should be exercised because of safety issues (e.g., pregnancy and breastfeeding) or limits in current scientific knowledge. If in doubt, a discussion with a specialist or an experienced colleague is required before prescribing this treatment;  A risk-benefit analysis of ketamine assessing: - The person’s clinical picture, their medical history and their medication history; - The prognosis for difficult-to-treat major depressive disorder and its impact on the person and their family;

Authors' methods: For the purpose of this work, the evaluation questions were drawn up to meet the objectives set out in this request. This was done in such a way as to cover the populational, clinical, organizational and economic dimensions in INESSS’s Statement of principles and ethical foundations. In addition to the questions were sociocultural, environmental and ethical considerations that contributed to the overall value assessment. In collaboration with a scientific information advisor (librarian), a systematic scientific literature search was conducted in the following databases: MEDLINE, Embase, PsycInfo, EBM Reviews (the Cochrane Database of Systematic Reviews and the NHS Economic Evaluation Database) and CINAHL Complete. A manual search of the grey literature was carried out as well. The lists of references in the selected publications were scanned for other relevant items. Two clinical-administrative databases were examined, namely, the insured persons registration file and the file of medical services provided by fee-for-service physicians, which were used to obtain an overview of the volume of feefor-service billing for the psychiatric use of ketamine, electroconvulsive therapy and repeated transcranial magnetic stimulation over the past 10 years. For the rapid reviews, identified items were selected by one professional, while full texts were selected by two professionals working independently. Methodological quality or scientific credibility was assessed independently by two scientific professionals. The risks of bias and levels of scientific evidence for different efficacy endpoints in randomized clinical trials were assessed using the RoB2 and GRADE tools, respectively. The extraction, analysis and synthesis of the data gathered to examine certain aspects of the clinical, sociocultural and economic dimensions were carried out by one professional and validated by another.

Project Status: Completed

URL for project: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/ketamine-pertinence-dans-la-depression-refractaire-aux-traitements-et-encadrement.html

Year Published: 2025

URL for published report: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/ketamine-pertinence-dans-la-depression-refractaire-aux-traitements-et-encadrement.html

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Canada

Province: Quebec

Organisation Name: Institut national d'excellence en sante et en services sociaux

Contact Address: L'Institut national d'excellence en sante et en services sociaux (INESSS) , 2021, avenue Union, bureau 10.083, Montreal, Quebec, Canada, H3A 2S9;Tel: 1+514-873-2563, Fax: 1+514-873-1369

Contact Name: demande@inesss.qc.ca

Contact Email: demande@inesss.qc.ca

Copyright: L'Institut national d'excellence en sante et en services sociaux (INESSS)