This month's brainbuzz™ features research demonstrating that there is a link between long repeated DNA sequences in the genome with psychiatric disorders like schizophrenia; scientist and patient & family advisor perspectives on a study about medical assistance in dying; and pharmacogenetic testing that shows promise in patients with depression. On behalf of CAMH, I wish everyone a safe and restful summer until our next newsletter in September.
Please reach out at any time if you have any questions or feedback.
Aristotle Voineskos VP Research, CAMH
Probe of DNA repeats reveals
genetic link to schizophrenia
A SickKids-CAMH study shows long repeated DNA sequences found in the genome may contribute to how the complex psychiatric disorder arises
Researchers at The Hospital for Sick Children (SickKids) and Centre for Addiction and Mental Health (CAMH) have found that repeated DNA sequences in the genome may contribute to an individual’s risk of developing schizophrenia.
Tandem repeats are a class of DNA sequence where two or more nucleotides, known as the building blocks of DNA, are repeated adjacent to one another. Sometimes these repeats can expand when they are passed from one generation to the next. As a repeat sequence expands, the likelihood that it may disrupt a gene’s function increases.
Tandem repeat expansions are known to contribute to more than 50 conditions, including Huntington’s Disease. Less is known about the role of these tandem repeats in a complex disorder like schizophrenia, which is
influenced by the effects of many variants in different genes.
Led by Dr. Ryan Yuen, Scientist in the Genetics & Genome Biology program at SickKids, and Dr. Anne Bassett, a Senior Scientist at CAMH and University Health Network, a study published May 12, 2022 in Molecular Psychiatry found that individuals with schizophrenia have a high number of rare tandem
repeat expansions that are not typically found in the general population. These tandem repeat expansions are located near genes, and often together with other genetic variants, that are known to be associated with schizophrenia.
As part of the study, the team found that the expansions were also present in the sequenced genomes of individuals with a family history of schizophrenia.
“This is the first time these rare repeat expansions have been assessed genome-wide in schizophrenia. Our findings suggest that the tandem repeat expansions are an important class of variants that contribute to schizophrenia risk,” says Yuen.
Tandem repeat expansions contribute to errors in how neurons in the brain communicate
Tandem repeats are generally found in non-coding DNA, which means their function is unclear and they can be difficult for researchers to study. The researchers applied a novel computational approach developed by Yuen and his team at SickKids to search and find rare long tandem repeat expansions across the entire genome of 257 adults with schizophrenia carefully assessed by Bassett’s team. They compared the data to genomes of 225 individuals with no psychiatric conditions as well as to a cohort of over 2,500 individuals from the 1000 Genomes Project, an international genome database.
The study found that tandem repeat expansions contribute to dysfunction at the synapse – where neurons connect and communicate with each other in the brain – likely by disrupting the regulatory process of their associated genes.
The research follows other recently published studies that describe other contributors to schizophrenia risk – one that identified common variant regions and the second that focused on rare protein-disrupting variants.
“We found that genes with tandem repeat expansions are overlapping with other discoveries we’re seeing in the field. Our study helps to fill some of the gaps in our knowledge and underlines the important function of the synaptic functions in schizophrenia as well as the complex way in which schizophrenia is affected by different types of genetic variants,” says Yuen, whose team previously used the same approach to link tandem repeat expansions to autism spectrum disorder.
Findings help expand understanding of the genetic underpinnings of schizophrenia
Bassett says the findings provide more evidence for the array of genetic risk underlying schizophrenia and related psychiatric disorders.
“Given the biological complexity of schizophrenia, we hope that our findings, in combination with other recent studies in the field, can be used to further advance understanding of this disorder as a brain disease to help destigmatize the illness,” says Bassett. “These findings are a major step forward for the future of schizophrenia research.”
Yuen notes future studies with a larger cohort size are required to further characterize the role of the rare
tandem repeats in the condition.
“As we unlock greater understanding of the genetic underpinnings of schizophrenia, we could one day move toward a future in which genetic risk factors can be used to individualize treatment approaches for patients.”
The work was supported by SickKids Catalyst Scholar in Genetics, Brain Canada, The Azrieli Foundation, the University of Toronto McLaughlin Centre, Nancy E.T. Fahrner Award, Dr. Bassett’s Dalglish Chair in 22q11.2 Deletion Syndrome at the University Health Network and University of Toronto and former Tier 1 Canada Research Chair in Schizophrenia Genetics and Genomic Disorders, grants from the Canadian Institutes of Health Research (CIHR), and SickKids Foundation.
Engagement Excellence: MAiD Study
The MAiD study is a critically important CAMH research study about the implementation of medical assistance in dying (MAiD) for mental illness, which is set to become legal in Canada in March 2023. This qualitative study examines patient and family member perspectives of MAiD for people whose sole underlying condition is mental illness. This project amplifies patient and family perspectives to help guide future decision-making on this important topic for Canadians.
Dr. Lisa Hawke is an Independent Scientist in the Centre for Complex Interventions at CAMH.
Why did you decide to partner with patients and family members on this MAiD study?
Dr. Lisa Hawke: Partnering with patients and family members is really important to the research I do. Since this study aims to understand the perspectives of patients and family members on the very important topic of MAiD, it was clear that our team needed to work with them to make sure we do this work right, in ways that are relevant to their real-world experiences.
What impact did engagement have on this project?
Dr. Lisa Hawke: We’re early in the project, but advisors have already had a significant impact. For example, the patient and family group helped us realize that the draft interview guide we had started to develop was focusing too much on diagnostic issues and not enough on the real-world experience of people who might consider MAiD. This led to a major shift in the questions we are asking our participants, which will help ensure the research results are relevant to patients and families. Advisors will continue to be involved throughout the project, and I look forward to seeing how they continue to shape this work.
What advice do you have for other CAMH staff who are starting to do engagement
work?
Dr. Lisa Hawke: Take some time to plan how you’re going to engage patients and families and think through your goals together with your team. This will help you get the most out of your engagement work. Reach out to other research teams who are doing engagement work to learn best practices and how those practices might work for you. Connect with CAMH’s patient, family, or youth research engagement teams; they’re great resources to help get you started.
Why do you think engagement is important?
Dr. Lisa Hawke: No matter how well-intentioned we may be as researchers, it’s so easy for us to see things through an academic lens and ultimately miss the point as far as
real-world experiences go. Engagement keeps us connected to the people and topics we are researching.
Mary Rose van Kesteren is a patient representative and has been an advisor on this project since the launch of this group.
Why did you start partnering on this project?
Mary Rose van Kesteren: I believe in the investigation of the truth and that the whole person must be considered in this investigation. Additionally, I found the topic intriguing, especially since my views shifted based on varying scenarios of when MAiD might be applied. It is critically important that support needs are taken into account when making decisions about MAiD and that someone represents patients throughout the
process. I felt that collaborating on this project would enable me to do a thorough deep dive and help clarify my views both at a conceptual and philosophical level, based on various scenarios, as well as based on how MAiD is currently applied to physical health.
Why do you think engagement is important?
Mary Rose van Kesteren: Engagement is critical, since to come closer to the truth one must hear all voices, especially the voices of those most involved. People with lived experience, as either patients or family members, allow researchers and policy-makers to see the big picture and understand their experience at the level of the heart. During engagement, we are reflecting what is in our hearts, and this
is where it starts. MAiD is a very complex topic and it becomes even more complex when it’s about mental health. We need all the voices at the table— everything we do has limits, and this is true in science too.
Michael Dawthorneis a family representative and has been an advisor on this project since the launch of this group.
What did you enjoy most about engaging on this study?
Michael Dawthorne: It provided me with a new experience, being part of formal research and I’ve learned so much about that aspect of the mental health system. By participating in a study with such a variety of perspectives; professionals, researchers, caregivers and those with lived experience, I saw people’s thoughts and opinions challenged and evolve. Open discussion and dialogue are the only way we can move forward.
What advice do you have for other partners who are starting to do engagement work?
Michael Dawthorne: I see engagement work as an opportunity to share my experience with others and to support the development of a better mental health system. For others starting, I’d encourage them to speak up and have their voices heard. Your personal experiences, both positive and negative, can benefit so many others. The next family or individual may not have the strength, skill, or will to persevere and the small improvements we make can help make a positive difference for them.
Pharmacogenetic testing shows promise improving symptoms in patients with treatment-resistant depression
CAMH-led clinical trial provides further evidence for widespread use of pharmacogenetic testing in prescribing anti-depressants
Pharmacogenetic testing was associated with nearly a two-fold (89 per cent) increase in remission rates compared to treatment as usual in a Centre for Addiction and Mental Health- (CAMH-)led clinical study just published in the journal Translational Psychiatry.
The 52-week double-blind study, comparing pharmacogenetic testing guided treatment to treatment as usual, is the first of its kind in Canada and involved 276 patients who
had been previously diagnosed with treatment-resistant depression, meaning that their condition had not improved after trying at least two antidepressant medications.
“Remission, or full recovery from symptoms, is one of the most challenging endpoints to achieve when treating major depressive disorder,” said senior author Dr. James Kennedy, Head of the Tanenbaum Centre for
Pharmacogenetics at the Campbell Family Mental Health Research Institute at CAMH. “The findings from this study contribute the first randomized, controlled data in Canada to the growing body of evidence of the clinical value of combined multi-gene pharmacogenetic testing.”
Pharmacogenetics is based on the premise that each person may metabolize or respond to medications in different ways based on their own individual genetic profile. That can mean that patients given the same dosage of an anti-depressant medication may have very different levels of it in their bodies, or that some
patients may be able to tolerate higher doses of a drug without debilitating side effects based on their genetics. Through customized genetic testing via a cheek swab, pharmacogenetics can help select appropriate drugs and dosages for each patient with the fewest side effects in the shortest period of time.
“Myriad Genetics is proud to support this important study that advances our knowledge of the utility of pharmacogenetic testing in Canadian patients suffering from treatment-resistant major depressive disorder,” said Jay Elliott, Vice President of Medical Affairs at Myriad Genetics. “Although the CAMH trial was underpowered, it is encouraging that the results largely replicate prior studies in American patients, reinforcing the generalizability of pharmacogenetic testing for depression across health care
settings.”
“Using pharmacogenetics for treatment-resistant depression we can be much more precise about exactly which drug will suit each person’s unique blueprints for the bodily systems that usher the drug into the brain and enable it to fight depression,” said Dr. Kennedy. “It’s very personalized to each individual.”
At the recommendation of her doctor, Toronto lawyer Cara Sweeny turned to pharmacogenetics at CAMH after not responding to a variety of medications for depression and anxiety. After genetic testing determined her body could tolerate—and in fact needed—three times the standard dose of one anti-depressant drug, she was given the higher dose and within two months her mood improved dramatically.
“I have this very specific memory of one day just opening up my back door to let my dog out, just an ordinary thing, and I felt that feeling of happiness that starts in your gut for the first time in a really long time,” says Sweeny, 52.
While the findings of this Canadian study are considered preliminary because of the sample size, they mirror the results of a much larger American pharmacogenetics clinical trial that reported a 51 per cent increase in remission rates for major depression compared to treatment as usual.
“Pharmacogenetic tests are currently not covered by public health plans in Canada,” added Dr. Kennedy. “The average healthcare savings following pharmacogenetic testing, per depression patient, are over $3,000. If half of the 1.6 million Canadians with depression could get the test, savings could total $2.4 billion per year. Patient suffering during trial-and-error prescribing would be reduced. These study findings should be considered by health policy decision makers, as they provide further impetus for implementation of reimbursement by public payers.”
Funding for the study was provided by Assurex Health Ltd. (now affiliated with Myriad Genetics), CAMH, Ontario Genomics and Genome Canada.
