S02 -​​ 
Novel Treatments and Clinical Considerations for Treatment-Resistant Psychiatric Illness​​ 

Friday, 23 October​​ 
13:30 – 16:45 (3 hrs plus 15 min break
Martin Katzman*, MD, FRCPC; Irvin Epstein, MD; Jerzy Hubert, MD; Tia Sternat, MSc, MSci​​ 


CanMEDS Roles:​​ 

  • Medical Expert​​ 

  • Scholar​​ 

  • Collaborator​​ 

At the end of this session, participants will be able to:​​ 1) Determine the neurobiology of treatment-resistant psychopathology; 2) Evaluate the risks and benefits of novel psychopharmacological agents targeting treatment-resistant disorders; and 3) Consider the role of reward processing deficits in substance use and abuse.​​ 

The growing percentage of psychiatric patients failing to respond to one or multiple lines of treatment over the past two decades has not changed despite new research and novel treatments for mental disorders. With the legalization of cannabis in Canada, research regarding the medical use has oriented towards a better understanding the role of the endocannabinoid system, especially in mental disorders. Studies have examined the role of a hyperactive glutamatergic system in complex mood and anxiety disorders and the clinical effects of substances considered as drugs of abuse that may directly reduce glutamatergic excitotoxicity. Determining which novel treatments are appropriate for an individual patient can be difficult; thus, it is important to consider the patients’ underlying psychobiology to better help guide physicians’ decisions. For example, we know that patients with treatment-resistant disorders often exhibit higher rates of substance abuse, making pharmacological management more complex. Understanding why a patient may prefer one illicit substance to another can provide insight into their underlying neurobiological deficits. Exploring substance use patterns may better inform our understanding of processes like reward processing and hedonic tone, which may bear positive implications on treatment outcomes. The aim of this symposium is to synthesize the latest clinical research on novel approaches to manage treatment-resistant psychiatric illness, in light of the psychobiological characteristics and risk factors that may be associated with failure to improve or true treatment resistance. As well, the presenters will examine the neurobiology and complex psychopharmacology in terms of novel treatments for complex disorders.

S02a - The Role of Alternate Treatment Modalities in Major Depressive Disorder
Irvin Epstein*, MD​​ 

At the end of this session, participants will be able to:​​ 1) Better understand the clinical rationale for the use of ketamine in treatment-resistant depressive individuals; 2) Appreciate the biological actions and mechanisms at an intracellular and regional level that account for​​ ketamine’s rapid relief of MDD symptoms; and 3) Evaluate the potential for risk associated with ketamine administration.​​ 

Depression is a chronic condition with great variability in severity and clinical trajectory, which impacts an individual’s psychosocial wellbeing and functioning. The rates of both symptom persistence and likelihood of relapse are high while remission rates are low. There has been an increased body of literature in support of ketamine, an anesthetic agent, having robust and rapid antidepressant effects in individuals diagnosed with treatment-resistant depression. This has led to increasing research into its potential clinical utility as an adjunctive agent in the pharmacological management of acute depressive episodes and in refractory patients. This presentation will discuss new research regarding the clinical use of ketamine and other analogue glutaminergic antagonists. As well, the discussant will review the research with respect to the use of novel psychedelic agents including PCP and NMDA, which may also have potential antidepressant and anti-suicidal activities in individuals with MDD.

The focus will be on the biology and role associated with the rapid administration of ketamine for alleviating acute depressive symptoms and for chronic-lapsing depressive episodes. Typical depressive symptoms ameliorated include: melancholia, anhedonia, anergia, dysphoria, and acute-onset suicidal ruminations and ideation. As well, we propose a model for understanding the co-administration of traditional monoamine antidepressants as well as adjunctive use of ketamine in a comprehensive multimodal treatment approach for major depressive disorder. We will conclude by discussing how these dissociative agents may have the potential to alleviate the disabling symptoms and psychopathology associated across depressive disorders.


  • Domany Y, Bleich-Cohen M, Tarrasch R, et al. Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study. Br J Psychiatry 2019;214(1):20–26.

  • Lally N, Nugent AC, Luckenbaugh DA, et al. Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Transl Psychiatry 2014;4(10):e469.

S02b - Exploring the Clinical Utility of Psychedelics in the Treatment of PTSD and Complex Disorders
Jerzy Hubert*, MD​​ 

At the end of this session, participants will be able to:​​ 1) Understand the neurobiological underpinnings of psychedelics in the treatment of PTSD; 2) Identify potential therapeutic areas for use of psychedelics and novel treatments in clinical practice; and 3) Consider the differences in mechanisms of action between psychedelics and other psychiatric agents for mood and anxiety disorders.​​ 

It has been established that up to 40% of patients treated with adequate psychopharmacological dosing may fail to respond to first line treatments. Furthermore, of individuals that respond to treatment, less than 30% achieve full remission. While these figures have been widely recognized in the depression literature, cases of complex trauma, such as repeated childhood sexual abuse, have also been shown to have poorer prognoses and treatment outcomes. As such, there is a need for novel and improved treatments that may target the underlying neurobiological similarities among complex disorders.​​ 

N,N-Dimethyltryptamine, psilocybin and LSD are serotonin 5-HT1A/2A/2C receptor agonists and have been shown to increase positive mood in preliminary studies. Furthermore, 5-HT2A/2C receptor agonists have been shown to reduce anxiety and depressive behaviours in animal models. Another possibly shared mechanism of action may be in the modulation of glutamatergic neurotransmission induced by 5-HT2A-receptor agonism. Given that depression is associated with lower levels of BDNF, deficient neurogenesis and neurotrophic activity, treatments that increase neurogenesis may prove to have positive effects, especially when dosed appropriately and administered with concurrent psychotherapy. The presenter will review the neurobiology and potential mechanisms of action of psychedelics including psilocybin, LSD and MDMA, especially in the context of PTSD treatment. Future directions for the treatment of both complex and treatment-resistant PTSD will be discussed.


  • dos Santos RG, Osorio FL, Crippa JAS, et al. Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): a systematic review of clinical trials published in the last 25 years. Ther Adv Psychopharmacol 2016;6:193–213.

  • Mithoefer MC, Grob CS, Brewerton TD. Novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA. The Lancet Psychiatry 2016;3:481–8.

S02c - Hedonic Tone: A Behavioural Marker for Substance Use Across Psychiatric Illnesses
Tia Sternat*, MSc, MSci​​ 

At the end of this session, participants will be able to:​​ 1) Explore underlying processes that may explain to substance use; 2) Synthesize neurobiological and behavioural information from patients into personalized treatment plans; and 3) Evaluate the clinical utility of hedonic tone in comorbid psychiatric presentations.​​ 

Exposure to trauma may lead to substance abuse as a method of coping and mood regulation. In cases where patients respond poorly to initial treatment lines, rates of comorbid substance abuse are increased. Understanding how and why a patient is more likely to use a certain illicit substance can offer insight into what processes these patients are attempting to regulate, and thus improve personalized treatment approaches.​​ 

Hedonic tone, or an individual’s baseline capacity to experience pleasure, may explain why patients gravitate towards certain substances. Low hedonic tone has been detected in mood and anxiety disorders, attention-deficit hyperactivity disorder, and substance use disorder. Individuals with low hedonic tone require increased levels of stimulation to reach neutral or euthymic states, which can lead to substance abuse.​​ 

Studies show that dopaminergic circuits are highly implicated in hedonic tone. Stimulants such as cocaine may be the drug of choice in populations with dopaminergic deficits. Glutamate signalling is also involved in reward processing. Cannabis abuse may be explained by the inhibition of glutamate and GABA release, which is influenced by the endocannabinoid system.

Understanding why individuals cope using specific substances can inform clinicians of what neurobiological processes are being compensated. Substance use, seen through the lens of hedonic tone, may explain high rates of comorbidity between substance abuse and psychiatric illness and why certain treatments are less effective than others. Recognizing these deficits can help determine the most appropriate intervention for individuals that are attempting to self-medicate or respond poorly to medication.


  • Sternat T, Fotinos K, Fine A, et al. Low hedonic tone and attention-deficit hyperactivity disorder: risk factors for treatment resistance in depressed adults. Neuropsychiatr Dis Treat 2018;14:2379–87.

  • Katzman M, Sternat T. Neurobiology of hedonic tone: the relationship between treatment-resistant depression, attention-deficit hyperactivity disorder, and substance abuse. Neuropsychiatr Dis Treat 2016;12:2149–64.​​ 

S02d - The Neurobiology of Complex Disorders and Novel Treatments
Martin Katzman*, MD, FRCPC

At the end of this session, participants will be able to:​​ 1) Identify overlapping neurobiological features of treatment-resistant depression, PTSD and other comorbidities; 2) Synthesize information on the endocannabinoid system in relation to the treatment of inflammatory disorders, including depression and anxiety; and 3) Discuss the changing landscape on interventions for treatment-resistant psychiatric illness.​​ 

Our understanding of the endogenous endocannabinoid system has led physicians to consider the utilization of cannabis and cannabis-related products for a broad range of psychiatric conditions. Similarly, other illicit substances including psychedelics such as N, N –Dimethyltryptamine, Psilocybin, MDMA, and LSD have also been implicated in recent psychiatric literature. While results from preliminary studies appear to be promising, it is imperative that we comprehend the complexities of the neurobiological underpinnings of these medications in order to better recognize their therapeutic potential in clinical practice.​​ 

This presentation will review the current literature regarding the neurobiology and mechanism of action of cannabinoids in relation to healthy central nervous system functioning, executive functioning, and its utility in mood and anxiety disorders. Specifically, it will discuss the endocannabinoid system as it has been implicated in the regulation of individual’s stress responses, as seen in two endocannabinoids: anandamide (AEA) which increases, and 2-arachidonoyl glycerol (2-AG) which decreases, in response to stress. Furthermore, it will review the neurobiology underlying the propensity for self-medication, especially in terms of the glutamatergic system implicated in treatment-resistant depression. The presenter will seek to elucidate the relationship between these complex interrelated neurobiological systems in terms of treatment of non-remitting mood and anxiety disorders in clinical practice.


  • Morena M, Patel S, Bains JS, et al. Neurobiological interactions between stress and the endocannabinoid system. Neuropsychopharmacology 2016;41(1):80.

  • dos Santos RG, Osorio FL, Crippa JAS, et al. Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): a systematic review of clinical trials published in the last 25 years. Ther Adv Psychopharmacol 2016;6:193–213.


/ Virtual Conference 2020