by Sipan Haikazian

Graphic design by Jo Choi

Major depressive disorder (MDD) and bipolar disorder (BD) are mood disorders that affect around 5% and 1% of the Canadian population, respectively.¹ Individuals with both illnesses endure low mood, lack of interest in previously enjoyed activities, poor concentration, changes in essential functioning including sleep and appetite, and sometimes, suicidal thoughts. These symptoms must occur for at least two weeks at a time, although it is very common for these symptoms to persist for months.¹ Individuals with BD also experience bouts of mania or hypomania: increased energy, greatly increased interest in activities, and a higher propensity to engage in risky behaviours.² 

Dr. Joshua Rosenblat, a psychiatrist and researcher working for the Mood Disorder Psychopharmacology Unit (MDPU) at Toronto Western Hospital, sees and treats patients with these bouts of mental illness every day. In his practice, he often treats patients with particularly severe cases. While a wide variety of treatments exist for treating the depressive episodes, around 33% of patients diagnosed with either MDD or BD fail two full courses of antidepressant treatments, subsequently resulting in a classification of treatment-resistant depression.⁴

Dr. Rosenblat’s passion for patient mental health was founded during his rotations as a medical student at the University of Western Ontario. He participated in a rotation at the MDPU under the mentorship of Dr. Roger McIntyre, a world-renowned clinician-scientist specializing in mood disorders. Fast forward 10 years, he now finds himself practicing in the same department where his clinical interests were first sparked. Dr. Rosenblat reflected on his career trajectory, stating: “I think what really drew me into psychiatry and field of mood disorders were that the biggest breakthroughs are still yet to come. Combining this notion with my passion for research pushed me towards the career choice”.

Indeed, many alternative treatments exist for treatment-resistant depression, including a multi-purpose drug called ketamine. Originally used as an anesthetic during the Vietnam War, ketamine was re-purposed in the 21^st century as an antidepressant agent. While many antidepressant drugs target the monoamine neurotransmitter system in the brain (serotonin, dopamine, and norepinephrine), ketamine is unique for targeting the glutamate system.⁴ Multiple clinical trials have demonstrated that ketamine can rapidly reduce depressive symptoms in patients with treatment-resistant variants of both disorders, the fast-acting trait being unique among traditional treatment for depression.⁵ The drug is also well-tolerated: while ketamine does often increase blood pressure, heart rate, and feelings of dissociation, these effects are transient, with symptoms resolving within hours.⁵ Importantly, documented cases of patients transitioning from a depressed to manic state are exceedingly rare.⁵ In recent years, both the Food and Drug Administration (FDA) and Health Canada have approved intranasal esketamine (a form of ketamine) for use in treatment-resistant MDD (TRD).

As a medical student working in the MDPU, Dr. Rosenblat started investigating the role of inflammation in mood disorders. He describes his motivation to eventually start studying alternative treatments to MDD and BD: “After a few years of research, I found that I wanted to be on the frontier of novel treatments in mood disorders, studying and becoming an expert in the efficacy of high-impact therapy”. His graduate thesis, completed while he was in residency, focused on the efficacy of intranasal ketamine for treating depression in patients with cancer receiving end-of-life care. Since establishing his research lab at the MDPU, he has led and co-led a number of clinical trials using ketamine as an intervention, as outlined below: 

1. Repeated Ketamine Infusions for Treatment-Resistant BD (KET-BD): A randomized, double-blind, placebo-controlled clinical trial where participants with Treatment-Resistant BD are randomized to receive four infusions over two weeks of either intravenous ketamine or a placebo known as midazolam. The primary outcome is the change in depressive ratings after the four infusions.

2. Maintenance Ketamine Infusions for Treatment-Resistant BD (KET-BD-SUSTAIN): An open-label, 12-week, follow-up clinical trial where participants who showed significantly decreased depressive ratings in the KET-BD trial receive up to 6 booster infusions of ketamine on a bi-weekly basis. The primary outcome is the change in depressive ratings over the 12-week time period.

3. Ketamine and Internet-based Cognitive Behavioural Therapy for Treatment-Resistant Depression (KET-CBT): A 13-week randomized controlled clinical trial investigating the effects of internet-based cognitive behavioural therapy (CBT) in conjunction with six sub-anesthetic doses of intravenously administered ketamine on suicidality in TRD.

4. Ketamine Versus Electroconvulsive Therapy in Depression (KET-ECT): A multi-site clinical trial where patients with TRD are randomized to receive either electroconvulsive therapy or ketamine infusions. A plethora of clinical, neuroimaging, molecular, and cognitive assessments is conducted throughout the study.

Each project has a critical knowledge gap that Dr. Rosenblat is looking to address. KET-BD and KET-BD-SUSTAIN aim to determine the short and long-term efficacy, respectively, of ketamine in treatment-resistant BD. The third trial, KET-ECT, aims to determine whether CBT could concurrently extend the antidepressant and anti-suicidal effects observed post-ketamine infusion. Dr. Rosenblat is especially interested in the investigation on the anti-suicidal effects of the trial, as patients participating in the trial will be actively suicidal and are thus in most urgent need for treatment. Finally, KET-ECT aims to determine the comparative efficacy of two alternative treatments (ketamine vs ECT) used in moderate-severe TRD.

These clinical trials will prove useful in answering specific questions about ketamine’s antidepressant efficacy. “I think the most important question about our field is how best to optimize the use of ketamine in routine clinical practice”, Dr. Roesnblat explains. “Currently, ketamine is used as a last line of defence against depression, but the data is showing improvements with large effect sizes, so we need to determine what role ketamine plays in the treatment algorithm. What dosing and scheduling is optimal for this drug, and which patients would find the most efficacy in using this drug?”

Dr. Rosenblat is also beginning to roll out clinical trials focused on the efficacy of psilocybin in mood disorders, a novel intervention that holds much promise in the treatment of depression. With several large grants and an ever-growing research lab, Dr. Rosenblat strives to continue improving the treatment that patients with mood disorders receive through his rigorous research program and thoughtfully planned portfolio of studies.

References

1. Spijker J, De Graaf R, Bijl RV, et al. Duration of major depressive episodes in the general population: Results from the Netherlands Mental Health Survey and Incidence Study (NEMESIS). Br J Psychiatry. 2002 Sep;181(3):208–13. 

2. McIntyre RS, Berk M, Brietzke E, et al. Bipolar disorders. Lancet. 2020 Dec 5;396(10265):1841–56. 

3. Hidalgo-Mazzei D, Berk M, Cipriani A, et al. Treatment-resistant and multi-therapy-resistant criteria for bipolar depression: consensus definition. Br J Psychiatry. 2019 Jan;214(1):27–35. 

4. Li L, Vlisides PE. Ketamine: 50 Years of Modulating the Mind. Front Hum Neurosci [Internet]. 2016 Nov 29 [cited 2023 Oct 31];10. Available from: http://journal.frontiersin.org/article/10.3389/fnhum.2016.00612/full

5. Fancy F, Haikazian S, Johnson DE, et al. Ketamine for bipolar depression: an updated systematic review. Therapeutic Advances in Psychopharmacology. 2023 Jan;13:20451253231202724.