by Nikou Kelardashti
Graphic design by Anne McGrath
In the realm of psychiatry and mental health, the search for innovative approaches to improve the lives of individuals grappling with mood disorders has been an ongoing quest. Currently in Canada, 1 in 5 individuals experience a mental illness each year.1 While there are treatments available for individuals afflicted by these disorders, a significant proportion of patients do not respond well to conventional medications, or they experience adverse side-effects.2 For instance, conventional antidepressants often have delayed onset of response and low rates of remission.2 Therefore, there is an urgent need for new, fast-acting, efficient, and enduring medications for psychiatric disorders.
Dr. Ishrat Husain—Associate Professor of Psychiatry at the University of Toronto, Lead of the Mood Disorders Service, and Head of the Clinical Trials Unit at the Centre for Addiction and Mental Health (CAMH)—is a pioneering Clinician-Scientist at the forefront of research in the field. Dr. Husain is dedicated to discovering innovative treatments for mood disorders, with the overall aim of improving outcomes across diverse populations and settings.
Photo provided by Niki Akbarian.
“During my clinical training as a resident, I was astounded by the number of patients that weren’t getting better with the treatments that we had currently to offer—particularly for patients with depressive illness, whether that’s a bipolar or unipolar depression,” Dr. Husain shared. This observation ignited Dr. Husain’s passion for exploring innovative approaches to treat these disorders, initiating the development of novel clinical trials.
Early in his career, Dr. Husain embarked on an investigation of inflammation as a potential treatment target for mood disorders. This decision was informed by evidence that a subgroup of individuals with depressive illness have an overactive inflammatory response system. Therefore, repurposing anti-inflammatory agents seemed to be a promising avenue for individuals with persistent depressive symptoms. For his doctoral research, Dr. Husain led one of the largest trials to date on repurposed anti-inflammatory agents and mood disorders. In this study, they assessed the use of minocycline and celecoxib, two anti-inflammatory drugs, as adjunct treatments for bipolar depression.3 Although their research did not show significant effects of the drugs, it did provide Dr. Husain with valuable experience in designing and leading clinical trials.
While Dr. Husain and his team were completing this trial, researchers at Imperial College London published preliminary evidence in 2016 for the safety and efficacy of psilocybin.2 Psilocybin is a serotonin receptor agonist that occurs naturally in psilocybe mushroom species, and this paper showed its promise in the treatment of treatment-resistant depression (TRD). “I was blown away by the large and sustained anti-depressant effect sizes that psilocybin therapy appeared to show,” Dr. Husain exclaimed. “I was fascinated by the potential of psilocybin therapy for mood disorders.”
In a Phase II international trial of psilocybin, CAMH served as the Canadian research site, with Dr. Husain leading the research team. The study assessed three psilocybin doses—25 mg, 10 mg, 1 mg (control)—which were administered alongside psychological support. The findings indicated that the 25 mg dose was significantly more effective than the lower doses in alleviating symptoms of depression, with participants in the 25 mg group achieving higher rates of response and remission.4
Through this clinical trial, Dr. Husain gained insight into the intricacies of conducting clinical trials involving psychedelic drugs. This experience provided him with a first-hand view of the positive aspects of this treatment approach. That being said, Dr. Husain also emphasizes that mental illnesses, particularly depression, show case-by-case variation in their causes. Therefore, a more nuanced approach is needed to explore various methods of treating these conditions. “I think that if we are focused on one singular therapy that is going to help all people with treatment-resistant depression, we are setting ourselves up for failure, so we need to look at different approaches,” Dr. Husain explains. “Psychedelic therapy is interesting as it combines biological with psychological, as the drug is given alongside psychological support.”
Recognizing the importance of incorporating diverse approaches in the treatment of depressive illnesses, Dr. Husain’s research aims to address the issue more comprehensively. This includes assessing the efficacy of repurposed drugs and exploring scalable psychological interventions that can be applied across different populations. For example, a substantial segment of his research program is being conducted in low- and middle-income countries, where his team is examining the effectiveness of psychological interventions delivered by non-specialists for treatment of bipolar and depressive disorders.
Another complexity associated with depressive mental disorders is their frequent co-occurrence with other conditions. Consequently, Dr. Husain’s team is engaged in various clinical trials exploring the effectiveness of psilocybin in the context of comorbid conditions, such as TRD in autism, TRD in obsessive-compulsive disorder, and TRD in chronic pain. Moreover, continuing investigations aim to uncover the mechanism of action of psilocybin and understand the nuances involved in psilocybin therapy. Dr. Husain has pursued this goal by using Positron Emission Tomography (PET) imaging before and after psilocybin therapy to investigate synaptic density as a potential pathophysiological model. Nevertheless, the mechanism of action of psilocybin remains the subject of ongoing investigation.
As a leading expert in clinical trials, Dr. Husain points out that despite clear advancements in the design of clinical trials, there remain certain limitations that need to be addressed. These include ensuring effective blinding and conducting comprehensive assessments of blinding. Additionally, researchers should consider pre-treatment expectancy as a potential moderator of outcome that should be monitored. Moreover, it is crucial for researchers to ensure that their study samples are heterogeneous with respect to gender, sex, and ethnicity to enhance the generalizability of results to the broader population.
As for raising awareness among the general population, Dr. Husain emphasizes, “[psychedelic therapy] is still very experimental, and although it is a promising area of research, the public should be made aware that a lot of the findings that they are reading about are from studies involving highly selected groups of people in a very controlled setting, with a lot of support and oversight.” He further notes that “self-medication is unsafe and can lead to serious safety issues.”
Lastly, Clinician-Scientists like Dr. Husain, committed to improving their patient’s well-being, provide a more optimistic perspective for the field of psychiatry. Dr. Husain elucidates, “my research is always clinically informed. It should be a bilateral relation between clinicians and researchers. Without any sort of clinical context, how are we going to know what is important to our patients and what outcomes they are looking for?” By nurturing this collaboration between clinicians and researchers, the field of psychiatry can continue to evolve and take innovative, meaningful strides toward improving the lives of individuals grappling with mental health challenges.
References
- Centre for addiction and Mental Health. Mental Illness and Addiction: Facts and Statistics. CAMH. 2020. https://www.camh.ca/en/driving-change/the-crisis-is-real/mental-health-statistics
- Carhart-Harris, RL, Bolstridge M, Rucker J, et al. Psilocybin with Psychological Support for Treatment-Resistant Depression: An Open-Label Feasibility Study. The Lancet Psychiatry, 2016;3(7):619-27.
- Husain, MI, Chaudhry IB, Khoso AB, et al. Minocycline and Celecoxib as Adjunctive Treatments for Bipolar Depression: A Multicentre, Factorial Design Randomised Controlled Trial. The Lancet Psychiatry, 2020;7(6):515-27.
- Goodwin, GM, Aaronson ST, Alvarez O., et al. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine, 2022;387(18):1637-48.
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