Commentary on the Canadian Network for Mood and Anxiety Treatments 2023 Clinical Guidelines for Management of Major Depressive Disorder in Adults – Capturing the State of the Art

The Canadian Network for Mood and Anxiety Treatments (CANMATs) Task Force have updated the clinical guidelines for the treatment of major depressive disorder (MDD) in adults. The last guidelines were produced in 2016 and since that time there have been significant advances in the field. The CANMAT task force conducted an extensive literature review, assessing all systematic and meta-analyses to date to provide a summary of the latest evidence for the assessment and treatment of MDD. This was a considerable undertaking considering the complexity of treatment options, difficulty balancing outcomes such as efficacy, tolerability, and feasibility and the limited evidence available for some treatments.

The Task Force has certainly risen to the challenge and synthesized evidence, clinician, and patient opinion to provide clear and accessible guidelines. The eight-topic format designed around important clinical questions makes it easy to navigate for clinicians and patients alike. The topics provide important and pragmatic advice on how to select treatments, monitor response, discontinue treatment, prevent recurrence, and suggest strategies for the management of inadequate treatment response. The last is particularly important given the poorer long-term outcomes associated with difficult-to-treat depression (DTD), ¹ and the burden of side effects that come with polypharmacy. The guidelines include the full range of treatments for MDD including psychological, psychoeducation, lifestyle, complementary and alternative medicine, pharmacological, and neuromodulation approaches. The use of clear flow charts and tables adds to its user-friendliness.

A whole section is dedicated to digital health interventions: widely available, scalable, and low cost. Whilst the digital divide is recognised, the advantage of mental health support via a smart phone or tablet is rightly acknowledged. The guidelines provide a clear summary of evidence-based digital interventions whilst highlighting the risks in terms of the platform's use of personal information and data security, the efficacy of untested commercially produced interventions, and hidden costs with subscription packages.

The importance of combining psychological approaches with pharmacotherapy for MDD is made clear, in keeping with other guidelines. ² The challenge of treatment evaluation is acknowledged, notably the lack of blinding and options for comparison conditions. The top recommendation based on evidence from controlled studies, is in-person Cognitive Behavioural Therapy to be initiated after treatment with an antidepressant. Interpersonal therapy and behavioural activation are also the first line. The type (e.g., treatment and acceptability) and level of evidence are both clearly presented, essential in such a guideline.

There is a wide range of guidelines for MDD published by local, national and international bodies, giving rise to significant variations in advice on treatment strategies. ³ In terms of pharmacological augmentation for people with DTD, the CANMAT recommendation of aripiprazole as a first line adjunct-treatment after two failed antidepressant trials is consistent with the majority of guidelines which acknowledge the relatively robust evidence base for this treatment strategy.^3,4 However, like the 2016 CANMAT guidelines, lithium remains a second-line option for adjunct-treatment in 2023 guidance. This is at odds with other guidelines which advocate the use of lithium as a first-line treatment in augmentation strategies in DTD ³ and patient accounts which mostly suggest lithium is acceptable and helpful. ⁵ The reason behind this is given as poor-quality trials of lithium therapy prior to 2003, which are often included in meta-analyses, and the added burden of blood monitoring with lithium therapy. Ketamine (both intranasal esketamine and intravenous racemic ketamine) sits alongside lithium as a second-line option, in a much more established position than in 2016 guidance, where it was an experimental treatment, reflecting the mounting body of evidence in support of ketamine for DTD in recent years.^3,4,6 This is in keeping with guidelines published more recently ³ but will likely differ from much of the guidance that will emerge from Europe as opposed to the US, which has fewer financial restrictions on recommendations. This includes National Institute for Health and Clinical Excellence (NICE) guidance ⁷ which does not recommend s/Ketamine in either form due in part to ongoing concerns about its cost effectiveness. This is an important focus for NICE guidelines, given that the recommendations are primarily for the publicly funded National Health Service (NHS). ⁷

NICE guidance is framed by health economic considerations and its format echoes this. It is relatively unhelpful to the clinician, with limited treatment options. In contrast, CANMAT guidance includes a wide range of treatments, some of which are not available in Canada. It is far less prescriptive, more nuanced and aligned to a personalised approach to managing DTD. A strength of CANMAT guidelines is the strong emphasis on treating symptom domains as opposed to specific diagnoses, unlike some counterparts.

In years to come, greater acknowledgement and understanding of the heterogeneity within MDD will likely revolutionise both treatment and related future guidance. This has already occurred in disorders such as oncology where there are now many therapeutic interventions tailored to the individual molecular features of the patient and/or their disease. Most commonly this is based on genomic biomarkers for various tumour types. This approach far surpasses the current approach in treating depression which at best relies on phenotypic biomarkers to guide treatment decisions. In future times MDD guidelines may look very different. They might discuss treatment options for glutamate, microbiome ⁸ or immune/inflammatory mediated depression, rather than generic MDD. In support of this, emerging evidence indicates there may be a subtype of immunometabolic depression. Studies show associations between patients with atypical profiles of depression (hyperphagia, weight gain, hypersomnia, fatigue and leaden paralysis) with aspects of immunometabolic dysregulation including abdominal obesity, circulating levels of glucose, insulin, proinflammatory cytokines, genetic liability for high body mass index, triglycerides and leptin when compared with healthy controls. ⁹ This association is weaker or statistically non-significant when other symptom profiles are examined or when more heterogenous MDD samples are used. This evidence suggests that these biological processes are potentially more closely related to the symptoms of atypical depression. There is also some preliminary evidence that these biological factors may moderate the effects of current antidepressants. ⁹ Characterisation and identification of the biological distinctions between subgroups will have even greater significance as antidepressants with more varied mechanisms are developed.

Future clinical guidelines may also have input from artificial intelligence, which should enable the quicker integration of the latest evidence. As we envision the integration of artificial intelligence in the development of clinical guidelines however, we must tread carefully, ensuring that while we embrace technological progress, we do not lose the benefit of the human wisdom exemplified in current CANMAT guidelines and their summary of the current state of the art of treatment of depression.