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Making a Difference

Rohail Kahn

Written by:

Rohail Kahn

Growing up, my brother was my idol.

His determination, unrelenting drive in life made me realize how important he was to others around him. His life, ever unpredictable, spiraled into a shadow over his brilliance. His battle with schizophrenia has become a part of our family’s story, one of pain, perseverance, and progress.

I watched him go from a boy with goals, a social life, and connection with family and friends, to a young adult who destroyed everything he worked for.

In 2016, my brother began his college journey at the University of California, Santa Cruz

(UCSC). As a Division 3 NCAA runner, he had the discipline, talent, and will to speak of a bright future.

But as running seasons changed, so did his path in life. College, intoxicated by the allure of independence, became candy for a child. My brother found himself in a crowd that led him into the drugs that made hell seem like a second layer of heaven. His experimentation morphed into dependency, and sooner than later, he dropped out. The cannabis, methamphetamine, and LSD that once promised escape turned into handcuffs from life.

Addiction stole him.

He dropped out in his freshman year and began living in our house. Then he left for three months. Some of the hardest three months for my family. And with his diagnosis, came the symptoms.

“Stop stalking me.”

These words erupted throughout the house every hour.

The delusions that live in his head, only hurt him. He complains about how alone he is, but how he is never alone. His sleep and hygiene deteriorated, to the point where I couldn’t even sit next to him. His hair and beard grew into a nest. His scribbles on the wall showed nothing but his captivity. After the walls were pure graphite grey, the numerous 51/50 calls for his aggression, and his countless visits to the mental health hospitals, he decided to rent his own apartment in San Francisco.

At the time, my mental health was depreciating. With my fuming hormones as a teenager, I began to have thoughts that I was schizophrenic. It was scary to think about. Sleepless nights thinking about how schizophrenia is going to affect me. It wasn’t until I started reading about mental health that I learned how common these feelings can be for teens, and that they are often temporary and treatable with the right support. Looking back now, I realize how important it is to seek help and to share your struggles. Those feelings taught me to value mental health and empathy in a way I never had before.

My brother never took mental health seriously. He created conspiracies about companies threatening to attack him, and blocked any company logos in his room. He put tape on other people’s rooms. He threatened to hurt people if they continued stalking him. One report led to another, and he officially got evicted. I still recall the landlord telling my family about how thick the number of reports were. It was sad to see that he could go nowhere.

My brother decided to seek treatment - a flicker of hope we saw.

While on medicine, my brother aspired to go to college, to pursue a degree in art, and one day, become an artist. Each step forward, no matter how tentative, is a success.

My brother has shown me the true meaning of perseverance. Not only with diagnosis, but with his dreams.

Enhancing Informed Consent in Schizophrenia Research by harnessing the power of lived experience perspectives.

Rebecca Soole1, 2, 3, Urska Arnautovska1, 2, 3, Nicole Korman1,2, Andrea Baker3, Dan Siskind1, 2, 3

1Faculty of Medicine, University of Queensland, Brisbane, Australia

2Metro South Addiction and Mental Health Services, Brisbane, Australia

3Queensland Centre for Mental Health Research, Brisbane, Australia

Informed consent is a cornerstone of self-determination of consumers receiving health and mental health services. Ensuring that potential participants understand the research study they are entering and voluntarily agree to participate is imperative to uphold ethical and regulatory standards of research activities. Patient Information and Consent Forms (PICFs) have faced criticism as potential barriers to valid consent due to their length and complexity. These barriers can be especially challenging for individuals with schizophrenia, who may face cognitive and motivational difficulties such as shorter attention and difficulties in executive functioning.

It is crucial that the very documents designed to facilitate informed consent are tailored to the unique needs of the population to ensure both ethical compliance and meaningful informed consent.  To address these challenges, we conducted two participatory co-design sessions at a Brisbane psychosocial rehabilitation facility with individuals living with schizophrenia. The goal was to gather consumer insights on various aspects of our research teams current PICF—specifically its length, the use of visual prompts, and alternative ways to present content. This approach allowed us to gain invaluable insights from those who have firsthand experience with the challenges of navigating consent materials.

What we learned from consumers

The feedback from these sessions was clear: consumer representatives expressed preference for a shorter PICF, one that incorporated visual prompts as anchors to guide reading and facilitate initial discussions about the study. This approach was deemed more user-friendly, less overwhelming, and more motivating for individuals first learning about the research.

However, consumer representatives also recognised the need for a longer, more detailed text-based PICF for those who wanted or valued more in-depth information. To cater to this, our final design included both a short, icon-based PICF for initial conversations and a more detailed, text-based version for deeper engagement. To bridge these two versions, consumer representatives suggested the use of consistent visual icons to help readers navigate between the short and long PICFs.

To further enhance readability, a question-and-answer format was adopted for each paragraph in both versions. This format allows readers to quickly find the information that is most relevant to them. Additionally, consumer representatives provided valuable feedback on improving the overall aesthetics of the PICF, identifying jargon that could be simplified to improve accessibility, as well as language modifications to better emphasise autonomy.

Integrating consumer feedback into our practice

The insights gained from our co-design sessions have already begun to shape our research practices. The newly designed short and long-form PICFs received ethical clearance for use in our established schizophrenia platform trial. By incorporating lived experience into the design process, we are making strides toward more inclusive and accessible research practices.

Conclusion: Towards More Ethical and Effective Research

Traditional PICFs can inadvertently act as barriers to valid consent, particularly in populations with cognitive challenges. Our research underscores the importance of customising consent forms to meet the diverse needs of potential participants who may be interested in participating in research. By integrating the perspectives of those with lived experience, we made these materials more accessible and effective, promoting informed decision-making and enhancing the ethical conduct of schizophrenia research.

Impact and Future Directions

These adaptations are a critical step towards promoting informed decision-making in health-related research participation and meaningful and equitable engagement with individuals affected by schizophrenia. By tailoring PICFs to better serve individuals with schizophrenia, we empower this often-marginalised group to make informed choices, thus supporting their autonomy and reducing the stigma associated with schizophrenia. Our approach intends to not only facilitate greater access to research but also hopes to foster a more inclusive and respectful environment for participants of research studies and lived experience colleagues.

If you are interested in learning more about our co-designed PICFs or considering them for your research, please reach out to us at r.soole@uq.edu.au. Our dedicated team at the Physical and Mental Health Stream, University of Queensland, is committed to enhancing research accessibility for individuals living with schizophrenia, both in Australia and worldwide.

 Elaine Elisabetsky, Ph. D.

Written by:

Elaine Elisabetsky, Ph.D.

After finishing my PhD in the memory field, I was troubled with the prospect of my career. Although memory neuroscience is a fascinating topic from a scientific perspective, for the young demographic of 1980s Brazil, memory issues were not a high priority in public health, and I aspired for my studies to have practical implications. As a pharmacologist, though I knew that teaching and mentoring could be very gratifying, part of me envied the professional activities that, though perhaps less intellectually challenging, result in more immediate and concrete outcomes. Two pieces of information helped me respect the desire to change course: (i) I became aware that Brazil imported 78% of the medication it needed, and (ii) I learned that during the Falkland War between Argentina and the UK, the UK and allied countries ceased the export of antibiotics to Argentina. It dawned on me how the dependency in medical resources could undermine a country’s sovereignty in different ways.

During my weekly time with Current Contents (if you are old enough to be anywhere near science at that time you know what I am talking about) I came across the Journal of Ethnopharmacology. If you are not acquainted with the discipline, it focusses on investigating traditional systems of medicine. It can be used for anything from an anthropological view of an ethic group concepts of health and disease, to adapt public health info in a culturally appropriate way to ameliorate outcomes (hygiene practices, vaccines, etc), to the search for new drugs from natural resources used with medical purposes. I decided to become an ethnopharmacologist, let go of a post doc grant from the French Government to work at the Hôpital Sainte-Anne (where chlorpromazine was discovered) and Gif Sur Ivette, and move to the Brazilian Amazon with a research grant from the Brazilian CNPq (National Council of Scientific and Technological Development). At the time there was a governmental effort to take young (and unemployed) PhDs to the Amazon region. My naïve idealistic idea was that a country with one of the planet’s highest rates of biodiversity and rich in traditional peoples who know the value of the flora, that is rich in sociobiodiversity, a sound scientific effort based upon these resources had the potential to help create a national pharmaceutical industry.

Please believe me, as someone born and raised in the cosmopolitan metropolis of São Paulo — which makes me feel comfortable in NYC — an Amazonian town in the early '80s felt as foreign to me as it would to most people reading this. My strategy was to talk to as many people as possible about diseases and cures in hope to identify local treatments to mental disorders. As maintaining the health of the family members is traditionally a women’s role, I visited as many different villages as possible and baked farina, assisted in the fields, drunk midafternoon coffee, washed clothing and did whatsoever activities women do to discuss disease and treatments. Many of these activities are communal at the very small villages by the rivers or entrenched in the jungle. With my training on psychopharmacology and behavioral animal models, whenever I thought I had a decent working hypothesis, “does the species X have psychopharmacology property Y?”, I could format the experiments and test it in the lab. The other common strategy was to go to the Ver-o-Peso market, where a whole section was and is dedicated to medicinal plants commerce and learn from the vendors and their exchange with their clients.

Aa a more universal academic characteristic, you may identify when I say I needed to generate results, present posters at meeting and publish papers as any other young scientist do to hopefully establish a research group. You can then understand I could not opt/specialize in a given disorder: if what I heard led me to anxiety, or pain, or epilepsy, or depression, so be it. During the following years we were able to characterize the psychopharmacology profile and mechanisms of action of anticonvulsants (https://pubmed.ncbi.nlm.nih.gov/?term=Elisabetsky+and+Linalool&sort=date), analgesics (https://pubmed.ncbi.nlm.nih.gov/?term=Elisabetsky+and++psychotria&sort=date), a nootropic neuroprotector
(https://pubmed.ncbi.nlm.nih.gov/?term=Elisabetsky+and+Ptychopetalum&sort=date) and an antipsychotic
(https://pubmed.ncbi.nlm.nih.gov/?term=Elisabetsky+and+alstonine&sort=date) drug.

It was this last piece of research that got me into the sad and fascinating schizophrenia field. The study of alstonine as an innovative antipsychotic came from an ethnopharmacology expedition among the Igbo in Nigeria. In the early 90s, the Igbos comprised an over 10 million people tribe, organized as dozens of small kingdoms. I was part of an ethnopharmacology expedition sponsored by an American pharmaceutical company interested in antiviral drugs. During the expedition in rural Nigeria (Enugo State), we came across a group of people extracting palm oil; one in this group happened to be the King of that kingdom. After understanding what we were doing, he insisted we should visit Dr. Chidi Osondu, according to him a famous healer with clients coming from all over Nigeria. So we did and it turned out that Dr. Osondu was a traditional psychiatrist. Part of his clinic was a very dramatic sector where voodoo dolls, remains of hanged animals, a portrait of the holy supper, another from Shiva, and several other quite weird components, to say the least, were present. But in the middle of this film-like setting, his description of the treatment given to patients made every sense to me: he did X when they arrive too agitated or aggressive, or Y if not, the way he titrated the dose over the course of treatment, etc. Of note, the patients headquarter was adequate, and internees quickly rose from the floor straw mattresses (no impaired blood pressure as you would expect from a Rauwolfia extract) and politely interacted with us visitors (unlike what you would expect from patients treated with older antipsychotics). Mind you that this is 1993 and clozapine was quite new, expensive and certainly not available at rural Nigeria clinics. I was given some of the medicinal plant powder by Dr. Osondu, and with the help of chemists and my students proceeded to characterize the alkaloid alstonine as an atypical antipsychotic with an innovative mechanism of action (at the time the only that had no direct interactions with dopamine D2 receptors).
We know the prevalence statistics for schizophrenia. We also know of the difficulties in diagnosing and categorizing a disorder with such diverse presentations and courses. I have no means to know if Dr. Osondu’s patients were affected with schizophrenia, but they were certainly mentally ill enough to be admitted to the clinic for a certain amount of time. Now we are also certain that these patients were treated with an atypical antipsychotic. Our ongoing efforts aim to bring alstonine to clinical application, offering hope for improved therapeutic options and a better quality of life for individuals battling schizophrenia, as so many are underserved by current treatments. The history of alstonine makes one wonder how many useful drugs are overlooked due to Western science's inability to view other medical systems as legitimate systems rather than mere folklore. If we surpass the prejudice, a new path to discovering drugs useful for managing schizophrenia might open up.

Samara Walpole, Ph.D.

Written by:

Samara Walpole, Ph.D.

Associate Research Fellow

University of Wollongong

I have always been fascinated by understanding how the brain works and exploring how the brain can change on a molecular level in the context of neuropsychiatric and neurological disorders. I first became interested in schizophrenia research during my undergraduate degree at the University of Wollongong, Australia, where I was fortunate to work with Professor Kelly Newell. Under her guidance, I explored molecular changes in the brain associated with schizophrenia using postmortem human brain tissue. This early exposure to research sparked my passion for understanding the biological foundations of psychiatric disorders and their complexity.
Building on this interest, I pursued a PhD with Professor Newell, focusing on the molecular changes in the brains of individuals with major depressive disorder. While my PhD work centred on depression, I explored mechanisms that are relevant across multiple psychiatric conditions, giving me a broader perspective on brain signalling and dysfunction. Now, in my postdoctoral research, I am returning to schizophrenia, applying the skills and knowledge I developed during my training to better understand the molecular and cellular changes that contribute to this disorder.

My research addresses several key questions that I believe are critical to advancing our understanding of schizophrenia. Specifically, I am to understand how several of the key biological pathways, such as inflammation and neurotransmitter signalling, contribute to the development and pathophysiology of schizophrenia as well as how these pathways could underpin the significant heterogeneity observed in schizophrenia.

At the 2024 SIRS congress, I was fortunate to be awarded the opportunity to present my latest findings on sex-specific alterations in glutamatergic receptors in schizophrenia. In this study, we explored the gene and protein levels of several receptors responsible for controlling the level of excitatory signalling that can occur in the nucleus accumbens, a brain region associated with reward processing, motivation and emotional regulation. We found that females with schizophrenia have increased levels of these receptors whilst males showed significantly decreased levels. Our findings reiterate the importance of investigating sex-specific differences in psychiatric disorders. Furthermore, addressing these changes would likely require distinct approaches for males and females with schizophrenia, highlighting the need for the development of sex-specific treatments.

As an emerging researcher in biological psychiatry, receiving an Early Career Award provided me with pivotal opportunities essential for my professional advancement in schizophrenia research. Attendance at the SIRS Congress in 2024 allowed me to meet researchers from around the world where I was able to have stimulating discussions around different techniques and approaches for best practice in my research. This award offered me the opportunity to connect with a mentor, Dr Sabina Berretta from Harvard Medical School. As an esteemed expert in postmortem research, Dr Berretta provided me invaluable guidance in refining my research direction and how to navigate the complex academic career path.

Currently, I am working as a postdoctoral researcher in the School of Medical, Indigenous and Health Sciences at the University of Wollongong, Australia. My research focus is now on exploring the impact of immune dysfunction as well as the impact of biological sex on changes to the molecular underpinnings of schizophrenia. Moving forward, I hope my research can provide a better understanding of subgroup-specific differences in schizophrenia to facilitate the better design and implementation of more targeted treatment options.

Felisa Maria Herrero, Dr. sc. nat.

Written by:

Felisa Herrero, M.Sc.

Ph.D. Student

University of Zurich

My journey into psychosis research began during my doctoral studies at the University of Zurich, Switzerland. Driven by a deep curiosity about the brain, I had the opportunity to work with Prof. Dr. Urs Meyer, whose research on the impact of maternal immune activation during pregnancy, and its implications for neuropsychiatric disorders, fascinated me. Through my work, I discovered the intriguing potential of endogenous retroviruses to explain patterns seen in psychiatric conditions.

Endogenous retroviruses (ERVs) are genetic elements in our DNA that come from viral infections that occurred throughout evolution. These viral remnants have shaped our biology, but growing evidence suggests they may also contribute to neuropsychiatric disorders. Specifically, I’m studying a family of these retroviruses called HERV-W, which may play a role in conditions like psychosis and other developmental disorders. For my research, I use a mouse model that expresses a human version of the HERV-W gene, particularly one that produces a viral protein involved in the infection process.

Our findings suggest that just expressing this gene causes significant changes in behavior and cognition in the mice, such as difficulties with memory, social interactions, and repetitive behaviors. These findings point to a potential link between this endogenous retrovirus and psychiatric conditions like schizophrenia.

We also observed that the expression of this viral gene altered the activity of many brain genes. Particularly, it affected genes related to cognition and brain development. For example, we found that genes linked to schizophrenia, such as Setd1a and Shank3, were turned down, along with genes that are crucial for the brain's synaptic development. This suggests that HERV-W may influence brain function in ways that contribute to these disorders.

One of the most interesting aspects of our findings was how the gene expression changes also affected the brain’s "epigenetic" profile. Epigenetics refers to the way environmental factors can turn genes on or off without changing the underlying DNA sequence of our genomes. We saw that in these mice, the altered expression of certain genes affected the way their brain cells were able to "read" other genes, which partially explain the cognitive and behavioral issues.

Nevertheless, we found promising results by using a drug that targeted the epigenetic changes in these mice, we were able to reverse some of the cognitive and behavioral deficits caused by the viral gene expression. This drug is currently being tested as a potential treatment for psychiatric disorders.

At the SIRS 2024 conference, I had the chance to share these findings and receive valuable feedback, which has inspired new directions for my research.
Although much remains to be discovered, I hope the field of endogenous retroviruses gains more attention. Understanding the role of these genes could improve our knowledge of psychosis development and individual differences. This research may pave the way for more personalized medical approaches, recognizing what we all already know: one-size-fits-all treatments are not effective for everyone.

As I move forward in my postdoctoral research, I am eager to deepen our understanding of how endogenous retroviruses contribute to schizophrenia. I hope to uncover new insights that not only enhance our scientific knowledge but also bring us closer to developing personalized treatments. By continuing to collaborate with fellow researchers and engaging with the wider scientific community, I am optimistic that we can make meaningful strides in improving the lives of individuals affected by psychosis.

Giulia Cattarinussi, M.D.’s SIRS Journey

Giulia Cattarinussi, M.D.

PhD Student, Research Assistant

Department of Neuroscience, University of Padova, Padova, Italy

 

I have always been interested in how the brain controls our thoughts and behaviors. When I started Medical School, from the very beginning I focused my target to become a psychiatrist, and I developed a deep interest in the brain mechanisms underlying psychosis. During my training in Psychiatry, alongside my clinical work with adolescents and young adults, I started exploring the brain abnormalities associated with the risk for psychosis. To do so, I employed functional magnetic resonance imaging, a non-invasive neuroimaging technique that allows to measure brain activity and connectivity. During my PhD in Neuroscience, I developed a deep interest in how changes in brain function correlate with clinical symptoms and cognitive functions in individuals with psychosis at different stages of the disorder. Understanding the neurobiology underlying symptoms and cognitive functioning in psychosis is crucial, as it could help facilitate earlier and personalized treatments, leading to better prognosis.

In 2024 I had the honor to win the SIRS Early Career Award and to attend the SIRS Congress. On that occasion, I was able to present the results of my latest study on the functional connectivity of the cerebellum, a region of the brain that helps coordinate a wide range of functions in the brain and the body. This study showed that altered connectivity of the cerebellum with rest of the brain was associated with more severe symptoms and greater cognitive impairments in individuals with psychosis. These results highlight the role of the cerebellum in the pathophysiology of psychosis and speak to the fact that therapeutic strategies targeting the cerebellum might represent promising interventions to reduce psychotic symptoms and to improve cognitive performance. The study has recently been published in Schizophrenia Research.

For a young researcher like me, attending the SIRS Congress gave me the opportunity to present my work to such a wide and highly specialized audience, to meet researchers from all around the world and to learn and discover the most updated notions in the field of schizophrenia research. I also had the chance to discuss my research with people with lived experience of psychosis, receiving invaluable feedback that substantially improved my work.

Currently, I am working as a post-doctoral researcher at the Department of Psychological Medicine at the Institute of Psychiatry, Psychology and Neuroscience at King’s College London. My research focuses on the brain changes associated with inflammation in psychosis, and how these correlate with symptoms and cognitive functioning. I am also involved in a multicentric study that aims to identify cognitive markers able to predict functioning in psychosis at the individual level.

Moving forward, I would like to establish my own research program dedicated to the study of brain abnormalities in individuals with psychosis and to the translation of these findings to clinical practice. I hope that my line of research will provide a clearer picture of the brain mechanisms underlying psychosis, ultimately helping the development of better diagnostic tools and therapeutic strategies.

Time to Make Schizophrenia Research More Efficient:

After a two-and-a-half-hour flight which left Brisbane on a sunny Saturday morning mid-October, I was smiling ear to ear being able to roam freely around the streets of the vibrant city of Melbourne and looking forward to attending the Australian Trials Methodology (AusTriM) conference with my colleagues from the University of Queensland, including our team leader Professor Dan Siskind, my post-doc fellow Dr Rebecca Soole, and our amazing clinical trial manager, Andrea Baker. After having spent over 25 hours on the plane alone with a 3- and a 6-year-old just a week prior, returning to Australia from my home country Slovenia, this short trip was a dream flight and I almost felt lost at the Melbourne airport, without needing to keep check if both kids are next to me. The adventurous and nerdy child in me was no doubt doing flips out of excitement as I booked in my hotel with views over the Yarra River and grey Melbourne skies.

Our team had a presentation on Day 2 of the conference. This was on the Adaptive Platform Trial of semaglutide versus metformin versus combination (semagltuide/metformin) versus placebo among people living with schizophrenia. But before I get to the details of our SWiMS trial (Schizophrenia, Weight, Metformin and Semaglutide), the term Adaptive Platform Trial (APT) deserves some explanation.

Platform trial design presents a transformative methodologic approach that involves studying one or more treatments in one or more diseases or disease subgroups using the same overarching trial design. In other words, APT streamlines evidence generation by addressing multiple questions simultaneously and efficiently, typically with a common control group. By using one standardised control arm, against which multiple treatment arms can be compared, platform trials offer a highly efficient approach by saving on patient resources, plus recruited participants having a greater chance of being allocated to more promising novel and more effective treatments. This optimised use of control data reduces the overall sample size required, minimising recruitment time and resource expenditure compared to traditional individual randomised control trials (RCTs). Platform trials use sophisticated modelling and Response Adaptive Randomisation (RAR) techniques to evaluate multiple treatments across different areas of patient management. Moreover, by integrating multiple interventions simultaneously, the platform trial enables direct comparisons and enhances the comparability of observed treatment effects.

Sounds rather abstract, right? Wait until I delve into the statistical requirements to run an adaptive platform trial. To make a trial adaptive, which essentially means, that at any interim analysis throughout the trial, you can drop poorly performing treatment arm(s) and/or change the randomisation ratio to favour better performing treatment, you need a good statistician. Without a statistician who understands the APT design and the RAR technique, you will be left like a fish without water in the APT ocean. This is because the platform trials employ a Bayesian statistical framework, a powerful form of analysis that incorporates prior knowledge together with collected data to produce a combined estimate. This prior knowledge is gathered from an understanding of previous clinical trials, possible endpoints and an understanding about disease progression, to form a comprehensive and accurate assessment of treatment efficacy, superior to traditional analytical approaches. As such,  extensive statistical simulations are conducted to determine a range of decision rules including early stopping of treatment arms if meeting pre-defined criteria for superiority or inferiority, leading to greater trial efficiencies and a minimum statistical error. Simulations leverage prior knowledge of participant characteristics and hypothesised treatment trajectories to yield highly accurate predictions of future outcomes. These measures not only enhance efficiency but also have ethical benefits by minimising patient assignment to ineffective treatment arms and enhancing equitable access to better clinical care.

Such innovative trial designs have to date being applied in areas of breast cancer treatment (I-SPY2), severe community-acquired pneumonia (REMAP-CAP), and management of glioblastoma (GBM-AGILE), and are also being rapidly developed for other diseases. I strongly encourage interested readers to satisfy your curiosity and appetite for more information about this transformative clinical trial design by publications on this topic by Professor Steve Webb, the “godfather” of REMAP-CAP, the biggest global platform trial which generated, and is still generating at fast speed, mountains of empirical evidence on potential treatments to prevent mortality from COVID-19, Berry Statisticians, and other clinical academics who are working with APTs. Nevertheless, I will below attempt to provide a summary of the workshop on Platform Trials preceding the AusTriM Conference, led by esteemed biostatisticians, Professor Thomas Jaki and Professor James Wason, and the dense scientific program of the conference program.

The AusTriM workshop and presentations delved deep into master protocols, a class of efficient clinical trial designs aiming to answer multiple research questions within a single trial protocol, as well as the different platform trials that are currently being developed or trialled across Australia. The conference also provided valuable knowledge about the intricate framework required for designing multi-arm multi-stage platform trials which are capable of adapting based on accumulating data, a methodology integral to the adaptive platform trial presented, information borrowing methods for basket and umbrella trials; methodologies for sharing information across different arms of the trial, optimizing resources, and enhancing overall efficiency, a concept seamlessly aligning with the APT’s goals, software tools available for implementing master protocols which can empower researchers to navigate the complexities of these trial designs and support them in the practical application of these theoretical concepts, and last, but not least, the different APTs designs. These designs include Group-sequential design where arms can be stopped at different stages for efficacy  and/or futility, Drop-the-losers design where you take forward a (pre-specified) fixed number of experimental treatments at each stage based on interventions performance, and the Adaptive randomisation design which is useful for trial with low number of likely effective treatments.

This low number of likely effective treatments brings us back to our SWiMS trial, which I presented on Day 2 of the conference (while Dan Siskind, who, as a lead Chief Investigator on this project, would be more deserving to deliver the presentation, was in his clinic seeing clients). This MRFF-funded trial, which was halted due to the global shortcake of the famous tik-tok drug, semaglutide (branded under the name Ozempic) in 2022, was designed to address the significant cardiometabolic burden faced by individuals experiencing schizophrenia, which is largely driven by the metabolic side effects of antipsychotic medications. This delay in the commencement of SWiMS trial made us pivot our efforts and writing of the clinical trial protocol into writing a Master protocol which would support a schizophrenia-focused platform trial. As such, the arm included in SWiMS (semaglutide, metformin, combination semagltuide/metformin, and placebo) would represent the first comparison embedded within the schizophrenia adaptive platform trial. While we are currently looking to obtain the funding to fund the setup of the platform, it is anticipated that by making SWiMS an adaptive trial, we will reduce the total number of participants needed to reliably assess the efficacy of the intervention arms for weight reduction in individuals with schizophrenia who are also grappling with antipsychotic-induced obesity. This marks a pioneering effort within the field, as it represents an opportunity for all future trial with people living with schizophrenia to generate evidence more efficiently on potential effective treatments and the effective treatments to be translated into clinical care more rapidly.

Overall, the AusTrim Conference 2023 transcended the traditional RCT research world, giving us a glimpse of in a new era of clinical trial design, and importantly, of new possibilities for patients of health services and specifically for schizophrenia research and treatment. No doubt, the idea of running a multi-site adaptive platform trial is an ambitious one. However – following my moto in life, where there is a will, there’s a way - with combined efforts of different stakeholders, including statisticians, psychiatrists, trialists, clinical trial managers, and last, but least important of consumers, these novel designs bring a promise to redefine how we approach and identify the optimal set of treatments to address the physical and mental health challenges of schizophrenia, offering hope and progress to those impacted by schizophrenia. Returning from a refreshing 10 degrees Celsius, with a head slightly overloaded from all the statistical terms and complexities of platform trial designs, to scorching 33 degrees in Brisbane, there was – unfortunately or fortunately - no time to dwell on thinking how are we going to create such a complex structure for trials in schizophrenia as we had a final, end-of-the-year Ethics Committee deadline to catch so we can bring SWiMS as an adaptive platform trial to life in 2024.

Although diving into the APTs world and their underlying statistical processes no doubt comes with a steep learning curve, this innovative trial design undoubtedly provides an opportunity: it fosters a collaboration among clinicians, researchers, and other stakeholders involved in the care of individuals with schizophrenia to streamline and standardises clinical trial processes so that evidence on the efficacy of promising treatments to address pressing issues related to the physical and mental health of this population is produced in a more effective and comprehensive manner, while facilitating the translation to clinical practice more rapidly.

Author

Urska Arnautovska

Senior Research Fellow, Faculty of Medicine, The University of Queensland

Senior Mental Health Clinician, Metro South Addiction and Mental Health Services, Queensland Health

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