April 2022 This month's brainbuzz™ features a look into CAMH's TAY Cohort study which focuses on better understanding the onset of youth psychosis; an interview with Dr. Etay Hay who uses real human brain cells in computer models of the brain; and new clinical guidelines for mental health and the use of nutraceuticals and medicinal plants. Please reach out if you have any questions or feedback. Aristotle Voineskos 
Investigating the mystery of youth psychosisCAMH’s Toronto Adolescent & Youth (TAY) CAMH Cohort Study It is one of the most important and heart-breaking questions in all of health care: why do some young people with mental health challenges go on to develop life-threatening psychosis while others do not? We know from previous research that 75 per cent of youths who go on to develop psychosis had sought mental health treatment in the previous three years. But only 5 per cent of them showed any overt symptoms of psychosis before it emerged. Are there signs and symptoms that can be detected early enough, if we only knew what they were, that would make possible targeted treatments that might prevent psychosis from emerging? Those are some of the fundamental questions that CAMH’s Toronto Adolescent & Youth (TAY) Cohort Study, which will follow 3,000 youth between the ages of 11 and 24 who have sought mental health treatment at CAMH, is trying to answer. The study will follow these young patients over a five-year period in unprecedented detail, tracking not just their clinical care inside and outside of CAMH, but also their genetics, brain circuitry and key aspects of brain functioning like memory and cognition. “The brain changes rapidly as it is developing in adolescence and there are specific periods of time during spurts of growth and circuit formation when, if the brain is not developing normally, symptoms of mental illness can emerge,” says principle Investigator Dr. Aristotle Voineskos, Vice President, Research at CAMH and Director of the Campbell Family Mental Health Research Institute. “It’s not going to be possible to prevent psychosis in everyone, but if we can identify who the kids at higher risk are, we can design a system for them that is much more monitoring-intensive that may be able to prevent psychosis from emerging in some patients.” Psychosis typically emerges in the late teens or early 20s and is the number one cause of disability for young people from 15 to 19. “This is around the age of onset for most mental health and substance use difficulties so it’s a critical priority for research,” says Dr. Lena Quilty, Senior Scientist and Director of Research Training at CAMH, Senior Scientist at the Campbell Family Mental Health Research Institute and co-lead of the cognition and memory part of the study. “We have the capacity at CAMH now to do something of this size that isn’t being done anywhere else in Canada. The way it brings together experts from across the fields of mental health research is really exciting.” As a world-class research facility embedded in a world-class hospital, CAMH was already uniquely positioned to take on a project of this size and it has been carefully thought out in a way that is perfectly aligned with CAMH’s core values and strategic vision, including making patients and families an integral part of all aspects of the process, and always staying focused on the direct impact CAMH research can have on patient care. “This is not research that will go on for ten years and then we’ll sit down and think about how it can inform clinical practice.” says Senior Scientist Kristin Cleverley, who is the co-lead of the signs and symptoms section of the study. “Every time we make a decision about the study, we take it back to the clinical team and say ‘How exactly will you use this? Can we make a dashboard that you can immediately use to inform patient care?” Three key factors that made this study possible According to Dr. Voineskos, the vast ambition of the CAMH TAY Cohort study was made possible by the confluence of three
factors: money from the Discovery Fund created by an anonymous philanthropic donation in 2018, the creation of the Krembil Centre for Neuroinformatics in 2017, which aspires to become an “atlas of brain health”, and the creation of three major child and youth-focused centres in the past decade that he calls the “engines of innovation” at CAMH. (The Margaret and Wallace McCain Centre for Children, Youth, and Family Mental Health established in 2012, The Slaight Family Centre for Youth in Transition established in 2014 and The Cundill Centre for Child and Youth Depression established in
2015). “We don’t take a diagnosis of this kind lightly. We have important frameworks for identifying people who are at high-risk for psychosis, but we are missing a huge proportion of the population that actually goes on to develop it,” says Dr. George Foussias, Chief of the Schizophrenia Division at CAMH and Director of the Slaight Family Centre for Youth in Transition. “We know from previous research that there is an increased risk for psychosis in the future for young people who present early with mental health issues. But up until now we have not had a mechanism to predict who is at particularly high risk and needs more comprehensive services wrapped around them that are focused not just on their struggles in the moment, but also preventative interventions to try and minimize the risk that they will develop psychosis in the future. That is one of the big aims of the TAY cohort study.” 
Four reasons why this study is truly unique There are a number of factors that make the TAY Cohort study truly unique.
“Until now there hasn’t been a lot of attention paid to the evolution of psychosis and how it crosses boundaries longitudinally,” says Dr. Voineskos. “Different disorders develop at different times. A three-year-old doesn’t get psychosis, they get autism. A six-year-old gets ADHD or facial ticks. We know from studying adults that psychosis and depression overlap, but that’s a snapshot in time after the brain has fully developed. What if you could prevent that ADHD from turning into depression when they become a teenager? What if you could prevent psychosis by treating a totally different disorder earlier on?” “The hope is that this study will help us support early intervention before the impact of these illnesses multiply,” says Quilty. “In terms of our ability to identify predictors it’s not just about psychosis. You can say the same thing about suicide risk. We know suicidal thoughts are not always linked to suicidal actions, so being able to identify those that are will help us intervene there as well. There are so many critical care outcomes that this study is going to inform, nor just psychosis.” How this study will impact all future research at CAMH Because all of this patient data will be entered into the CAMH BrainHealth Databank, it will benefit all future research at CAMH. For example, CAMH is on theleading-edge of research into the interaction between cannabis and the brain at a genetic and molecular level in regards to psychosis risk. While the science is still in its infancy, there are emerging concerns that cannabis-use among youth already at-risk for psychosis might increase that risk. If the mountain of patient data from at-risk youth in the TAY study finds more direct evidence of a link between cannabis and psychosis, it could have major implications for treatment and even public policy. The current national guidelines for lower risk cannabis use, developed by CAMH when cannabis was legalized, do recommend that teenagers avoid cannabis use and that anyone with a family history of psychosis abstain, but there are a growing number of scientists who believe that cannabis should not be used by anyone until the age of 25 when the brain has fully developed. Another virtue of the study is that it is being used as a real-world training, education and mentoring exercise for dozens of post-grad students and early-career researchers and clinicians who have been recruited to assist in the massive logistics of the study. “In addition to allowing so many patients to benefit from this
research, It is also an unprecedented opportunity to build CAMH’s international impact by helping to train the next generation of leaders in child and youth mental health,” says Dr. Quilty. 
Conversation with CAMH scientist Etay Hay on brain cell networks and mental illnessTo understand how much humility is required to work in neuroscience, consider this: there are about 86 billion neurons in the human brain and we still don’t know exactly what goes on in any one of them, or how they interact with each other. The rise of neuroinformatics has allowed us to build the most sophisticated simulations ever of human neurons and the networks of the brain, but we have not been able to study experimentally how the neurons interact in a living brain. Therefore, the leading theories about depression in the brain have been essentially based on generalized observation and educated guesses about how the living human brain actually works and responds to medication. Until now. Thanks to a unique partnership between the Krembil Centre for Neuroinformatics at CAMH and the Krembil Brain Institute at Toronto Western University, CAMH scientists have created the world’s first model of human brain microcircuitry that incorporates the properties of live human brain cells. The living brain cells come from patients with epilepsy who underwent a rare form of brain surgery that involved removing a tiny portion of the brain to reduce certain types of seizures. Among the first results from that partnership is a CAMH-led study entitled, “Reduced inhibition in depression impairs stimulus processing in human cortical microcircuits,” recently published in the journal Cell Reports. In the paper, the authors have demonstrated how a type of treatment-resistant depression manifests itself in the brain, specifically linking the role of a particular type of neuron known as a Somatostatin (SST)to impaired cognitive function. The authors believe this new simulation of the human brain integrating data from living brain cells may have enormous implications for future research at CAMH and around the world, and could pave the way for a new generation of drugs for treatment-resistant depression. We caught up with lead author Dr. Etay Hay, Independent Scientist at the Krembil Centre for Neuroinformatics at CAMH to discuss his groundbreaking research. What was the main purpose of this particular research study? Is the main significance of this study that with live human cells and computational models you have validating one of the leading theories of depression in the brain? Our goal was to use computer models based on live human brain tissue to confirm a hypothesis about how depression looks in the brain. The result was that, yes, we were able to confirm our hypothesis, and provide even more information about what happens in our brains during depression. What is the value of incorporating real human brain cells into your computer model? This paper is part of a project that is producing a very realistic model of human brain cell networks that enables us to study accurately and ethically what happens inside the human brain. Using this model, we’re able to study human disorders, especially mental health conditions, with much more accuracy than we ever have before. How does your new human brain model address one of the biggest challenges in neuroscience in terms of being able to study living brain cells rather than post-mortem brain tissue? Incorporating what we’ve learned from living brain tissue, our new model allows us to better predict how different types of conditions will affect real functioning brain cell networks. This is brand new and the potential for what we can learn using this model is very exciting. Do you agree with the premise that we still don’t really know what really goes on in a single brain cell? To an extent, yes. Rodent brain cells have been studied for decades now and there are similarities to the human brain cell, so we are not in uncharted waters. But there are some key differences and they make it important to develop models for human cells and simulate human microcircuits to study them. So I would say we know quite a bit about the single neuron, but there is still more to learn, especially in the human neurons, and also how they function within a network, which is how our whole brain functions. How important is it to understand what happens in our physical brains during depression, rather than just looking to help the symptoms? In order to develop drugs to treat mental health conditions, we need to really understand how these conditions physically affect the brain. This new model of our brain connections enables us to test our theories about depression in a realistic environment which can help play an important role in the development of future drugs. Do you believe this research has fairly large implications for practical research as well as patient care? Absolutely. For example, we are already using this model to study how to better diagnose depression using clinically-relevant brain signals. In one study we are using our computer model to simulate the effect of the SST neuron on EEG brain signals, so that we can eventually diagnose this in patients. Another one is testing new compounds like the ones Senior Scientist and Campbell Family Chair in Clinical Neuroscience Dr. Etienne Sibille has developed (in his work on reversing memory loss), to demonstrate their real-world impact on the brain. Testing these treatments on our realistic computer model is the next step towards eventual human trials. Why did you decide to come to Canada from your native Israel? I really like the country. I like the mentality here. I like that people respect each other. I love nature, and Canada is really beautiful so it really suits me. When I came here to do my undergrad I didn’t know much about it but very soon I fell in love with Canada and I knew that eventually I want to settle here. Why CAMH? I do like the neuroscientific community in the GTA, especially with Toronto becoming a greater hub for different kinds of neuroscientific research, including artificial intelligence. So it’s a pretty exciting place to be. It is also really attractive to have applications to our research, where our
computational simulation results can actually affect the diagnosis and care of patients. I’ve done many years of theoretical and basic science research that serve the research community. My previous models have been used in labs across the world, but it’s very satisfying to actually know that my research has some more real-world relevance. 
Global commission: new clinical guidelines for mental health and the use of nutraceuticals and medicinal plantsNew findings from a major international review examining the ‘best of the best’ available scientific evidence reveals which nutraceuticals(nutrient-based natural products) and phytoceuticals (plant-based natural products) are beneficial in the management of a range of mental health disorders. The review and new clinical guidelines focused on studies involving common and severe mental disorders: mood disorders such as major depressive disorder and bipolar disorder; anxiety disorders such as generalised anxiety disorder, obsessive compulsive disorder and trichotillomania (hair-pulling disorder); psychotic disorders such as schizophrenia; and attention deficit hyperactivity disorder (ADHD). Commissioned by The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) and published today in World Journal of Biological Psychiatry, the latest clinical guidelines are the evidence-based recommendations of an expert taskforce involving 30 leading academics and clinicians from 15 countries, including Western Sydney University, University of British Columbia, Harvard University, University of Arizona College, Deakin University, University of Melbourne, The University of Tokyo, University of Toronto/the Centre for Addiction and Mental Health (CAMH), Federal University of Rio de Janeiro, China Medical University, and University of Canterbury. The chair of the taskforce, Jerome Sarris, Professor of Integrative Mental Health at NICM Health Research Institute, Western Sydney University, said the review and new clinical guidelines are a significant piece of work that help address the current guideline gaps and assist clinicians in an evidence-informed approach to decision-making around the growing interest and use of supplements for major psychiatric disorders. “Clinicians and the public often aren’t sure of what is effective and isn’t. Our research and guidelines provide much more assurance based on the evidence, giving firmer guidance on effectiveness, dosage, population base for use, conditions, and special considerations,” said Professor Sarris. “Despite what some people may say or believe, there is actually a lot of high-quality evidence out there, and the purpose of these guidelines were to provide a synthesis of this evidence as well as clinician input to provide definitive practice guidelines. “In this most recent research, we have included our initial meta-reviews from 2019 and 2020, supplemented with a current additional literature search – it is the world’s largest meta-synthesis in this field analysing top-tier evidence, from clinical trials and data worldwide, in over 10,000 individuals treated for psychiatric disorders,” Professor Sarris said. Patients often ask clinicians about the utility of various nutrient or plant based natural products in the treatment of various psychiatric illnesses says Dr. Lakshmi Yatham, President of the World Federation of Societies of Biological Psychiatry. “The WFSBP/CANMAT guidelines provide evidence-based recommendations for use of these products and thus are extremely helpful for clinicians in advising patients about the role of these agents and in choosing the most appropriate agents for managing various psychiatric illnesses,” he said. Several key findings from the review: Mood Disorders:
Anxiety disorders:
Schizophrenia:
ADHD:
The review also provides detail on safety and tolerability issues, and clinical advice regarding prescription and consideration for use in specialised populations. Senior leadership team member of the taskforce and co-author Dr. Arun Ravindran, Professor of Psychiatry at the University of Toronto and Clinician Scientist at CAMH added: “The use of alternative and complementary therapies by the public has grown exponentially in recent years. Patients often expect physicians to prescribe them appropriately and safely. These guidelines from a global panel of opinion leaders will serve as a user-friendly resource for both physicians and consumers.” Harvard Medical School Professor of Psychiatry, Director of Depression Clinical Research Program at Massachusetts General Hospital and co-author Dr. David Mischoulon further added: “I prescribe several of these therapies in my practice, which includes many people who have not obtained benefit from approved treatments. But I always make sure to have a careful discussion with the patient about the known and potentially unknown risks and benefits. I also advise that individuals with more serious psychiatric conditions who are interested in using these natural remedies preferably do so under the supervision of a qualified clinician.” The review and clinical guidelines can be accessed online at https://www.tandfonline.com/doi/full/10.1080/15622975.2021.2013041 
Buzz-worthy News
 |