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Théo Korchia: Improving The Treatment Of Schizophrenia

Théo Korchia: Improving The Treatment Of Schizophrenia

My name is Théo KORCHIA, and I am a French psychiatrist, particularly involved in the treatment of early-onset schizophrenic disorders. 

First of all, I'd like to thank the Schizophrenia International Research Society for honouring me with this prestigious award, as well as the Faculty of Medical and Paramedical Sciences at Aix-Marseille University (France) and the Assistance Publique des Hôpitaux de Marseille (APHM), which supported me and enabled me to spend a year at McGill University in Montreal. 

Schizophrenia is a pathology often shrouded in mystery and prejudice, which profoundly affects the lives not only of those who suffer from it, but also those around them. 

Management of the first psychotic episodes determines the outcome and prognosis of patients, and it is therefore necessary to improve it. Generally speaking, my work highlights the value of pharmacogenetics, adapting and personalizing the antipsychotic treatment to different genetic profiles for greater efficacy. Consequently, various side-effects of antipsychotic therapy, notably sexual dysfunction which is very disabling and leads to discontinuation of treatment, are drastically reduced. Patient motivation must also be strengthened by including them in therapeutic decisions to improve overall quality of life. 

A particularly innovative aspect of my work concerns the impact of sexual dysfunction in patients suffering from schizophrenia. This issue, which has long remained on the fringes of psychiatric research, is crucial to patients' quality of life. Sexual dysfunction can be both a symptom of the illness and a side-effect of treatment, making it a dual challenge to overcome. 

My perseverance on this issue has led to the publication of a meta-analysis of over 21,000 patients worldwide, in the journal JAMA Psychiatry. 

Our study reveals with edifying clarity the high frequency of sexual dysfunction in individuals with schizophrenia spectrum disorders, showing an overall prevalence of 56.4%, with great variation in the types of dysfunction. This underlines the urgency of no longer neglecting adverse sexual effects in the treatment of schizophrenia. In the same way that weight gain or somnolence are side-effects commonly considered in the evaluation of antipsychotic treatments, it is crucial to include sexual dysfunction in our benefit-risk analysis. Recognizing and addressing these adverse effects goes beyond improving patients' quality of life; it represents a significant step forward in establishing a solid therapeutic alliance. Open communication about these issues, which are often stigmatized or played down, fosters a relationship of trust between doctor and patient, which is essential for effective management of schizophrenia. By taking these undesirable effects into account, we are improving not only adherence to treatment, but also the overall management of the patient, by recognising the importance of sexual health as a fundamental component of the patient's well-being. 

This study therefore represents a significant advance, opening-up new prospects for treatments that are more respectful and tailored to patients' needs. 

What drives my research is the conviction that innovation in psychiatry is not limited to the discovery of new drugs. It also lies in our ability to rethink the way we treat patients, by integrating dimensions of their experience that have been underestimated until now. The aim is twofold: to improve the quality of life of people suffering from schizophrenia and to reduce the obstacles to effective treatment, particularly those associated with the side effects of medication. 

The implications of the studies I lead aim to have a direct impact on clinical practice by providing healthcare professionals with the tools they need to build a solid therapeutic alliance, thereby encouraging adherence to treatment and improving clinical outcomes. Considering sexual dysfunction, and more broadly the side effects of antipsychotics, is a concrete example of this influence. 

My vision is of a dynamic psychiatry that is constantly evolving, where care is tailored to the uniqueness of each individual, and where each scientific advance lights the way towards better mental health. 

I am therefore grateful to be able to share with you not only my research objectives, but also my vision of a future in which the management of schizophrenia is more enlightened, more effective and, above all, more humane. The road is long, the challenges many, but the passion that drives my quest is unshakeable. With determination and perseverance, we can provide meaningful answers to those struggling with mental suffering, and open up new horizons for the psychiatry of tomorrow. 

Hyeon-Seung Lee: The Research Of An Early-Career Scientist On Schizophrenia & Self-Disturbance

Hyeon-Seung Lee: The Research Of An Early-Career Scientist On Schizophrenia & Self-Disturbance

Hyeon-Seung Lee

Individuals with depression often report their core belief of "I am worthless and unlovable." Individuals with anxiety disorders and OCD often report “what if” statement as a sign of excessive worry that leads to the thoughts of the worst-case scenario. Then, what would be a representative sign of schizophrenia? It is difficult to pick just one phenomenon given the multifaceted nature of the disorder, but I would pick "as if" statements related to the sense of self. Past research points out that self-disturbances are intertwined with the emergence of schizophrenia symptoms such as delusions and hallucinations. People at-risk often describe their experiences like this: “It feels 'as if' I am untuned to my body.” The anomalous feeling of altered self (agency, body ownership, self-boundary, and the experience of sensation, perception, and emotion) is a salient feature in the lives of those with schizophrenia. Bleuler’s original conceptualization of schizophrenia as that of the splitting of the mind and Kraepelin’s analogy of “an orchestra without a conductor” that indicates “a loss of inner unity”, both emphasize aberrations in the basic sense of self.  These self-disturbances have been shown to be important for predicting functional outcomes.  

Although the Research Domain Criteria (RDoC) of the National Institute of Mental Health (NIMH) and the International Classification of Diseases (ICD-11) include self-related features, self-disorder is not a prominent feature in either approach. Moreover, the sense of self has been ignored in the diagnosis, research, and treatment of schizophrenia due to lack of reliable and valid measures. With new methodological advances, it is now possible to empirically investigate the etiology and nature of self-disorders. As an early career researcher working with Dr. Sohee Park and multidisciplinary collaborators, I have developed and implemented novel experimental paradigms to elucidate and measure aspects of self-disturbances in schizophrenia. For instance, I have used virtual reality (VR) based measures to assess the neurocognitive representation of bodily space (i.e., peripersonal space) and how it is linked to schizophrenia symptoms. I also utilized VR-based social skills training to provide simulation and rehearsal of interpersonal interactions in realistic settings rather than explicitly teaching social cognitive skills to individuals with schizophrenia. In addition, I use computerized tools to visualize embodied emotions, manipulate cortical activities with brain stimulation, and assess the integrity of frontoparietal networks with neuroimaging to fully investigate the self-disturbances, symptoms, and social dysfunctions in schizophrenia. 

Specifically, my master’s thesis focused on the abnormal spatial self-consciousness in schizophrenia formed through multisensory processing. As objects or people approach one’s personal space, multisensory neurons in the frontoparietal brain facilitate appropriate reactions. I used VR-based multisensory integration tasks to identify the inflection point where multisensory reaction time is facilitated, which estimates the size and slope of personal space. I found that individuals with schizophrenia generate small but unclearly-defined personal space boundaries relative to controls in the social context. The size or shape of personal space was associated with the severity of negative symptoms and hallucinations. In an ongoing review study, I further demonstrated how personal space is altered in various mental disorders (e.g., anxiety, post-traumatic stress disorder, autism spectrum disorders, etc.). The personal space size is enlarged in various disorders; however, the self-space is more solidly formed in individuals with anxiety and autism spectrum disorders, while the boundary is unclearly generated in those with schizophrenia. My dissertation research further examines the altered representation of personal space, investigating the effect of threat, social distress, and socioemotional factors. 

Another line of research is investigating cross-cultural differences in the manifestation of psychosocial dysfunction. Previously, I examined the impact of the COVID-19 pandemic on the mental health of the general population from various cultures. Given the pandemic and social distancing were increasing feelings of social disconnection and loneliness, I expected that social disconnection and loneliness play a major role in poor physical and mental health. Delving into how cultural differences in public health strategies and compliance of the general population yield variances in reported stress, mood, anxiety, and psychotic experiences provided me with either a microscopic or a macroscopic view of psychosocial dysfunction. Moreover, I investigated culture-general and specific aspects of mental health symptoms and abnormal self-related experiences in schizophrenia. Previous cross-cultural works highlighted that though symptoms and self-disturbances are salient and prevalent in both Western and non-western cultures, there were culture-specific aspects such as relatively high tolerance for anomalous self-experiences and less attenuated embodied emotion in Koreans. I would like to continue to investigate cultural effects on psychosocial functions. 

Psychiatric research is still mostly driven by researchers from Europe and North America. As a Korean scientist, I believe we have valuable contributions to make to this field and I hope to increase the representation of Korean and other Asian scientists in the field of schizophrenia research. Increased diversity of ideas and approaches will surely positively impact the future of the Schizophrenia International Research Society (SIRS). 

Bobana Samardžija, mag. pharm. inv.: Our Research Holds Implications for the Future Diagnostics & Therapeutics

Bobana Samardžija, mag. pharm. inv. Our Research Holds Implications for the Future Diagnostics & Therapeutics
Bobana Samardžija, mag. pharm. inv.
Chronic mental illnesses, such as schizophrenia and major depressive disorder, are widespread and serious conditions that profoundly affect the lives of millions worldwide. Despite their prevalence, our comprehension of these disorders remains incomplete, and current therapeutic strategies often merely alleviate symptoms rather than target root causes. While extensive research has identified numerous genes associated with schizophrenia and major depressive disorder, their individual impacts tend to be marginal or specific to particular groups, underscoring the substantial influence of environmental factors alongside genetic predispositions.
Innovative approaches to unravel the complexities of these disorders are emerging, with a particular focus on disruptions in protein balance within the brain. This novel perspective draws inspiration from the realm of neurodegenerative diseases, where the accumulation of toxic protein aggregates significantly contributes to pathology.
At the University of Rijeka in Croatia, we examine post-mortem brain samples from individuals diagnosed with depression, Alzheimer's disease, those who have tragically died by suicide, as well as control subjects. We aim to elucidate the patterns of protein aggregation across diverse brain regions. Furthermore, we are investigating the possibility of multiple proteins aggregating together within the same individual and assess protein aggregation in cell cultures, all in hope to shed light on the intricate mechanisms underlying chronic mental illnesses.
Complementing these endeavors, we are also pioneering efforts to analyze aggregating proteins in blood samples obtained from living patients diagnosed with these challenging conditions, aiming to establish a non-invasive diagnostic tool that could revolutionize clinical practice.
By venturing beyond the genetic determinants, our research holds implications for the future of diagnostic methodologies and therapeutic interventions targeting chronic mental illnesses. This perspective empowers us to chart new paths towards understanding and addressing the multifaceted nature of these disorders, ultimately fostering hope for enhanced outcomes and improved quality of life for patients and their families.

Kirsten Borup Bojesen, MD, PhD: A Clinician-Scientist Studying Schizophrenia

Kirsten Borup Bojesen, MD, PhD 

Residency trainee in psychiatry, postdoctoral researcher 

Copenhagen University Hospital, Center for Neuropsychiatric Schizophrenia Research (CNSR), Mental Health Center Glostrup, Nordstjernevej 41, 2600 Glostrup 

As a clinician-scientist, I have been struck by the large proportion of patients with schizophrenia insufficiently treated with antipsychotics and by the negative impact of cognitive deficits on everyday life. This has inspired me to explore the neurotransmitter aberrations underlying insufficient treatment response and cognitive deficits in patients with psychosis with a key focus on glutamate and GABA. My hope is that research on the impact of glutamatergic and GABAergic neurotransmitter disturbances on insufficient treatment outcome and cognition can pave the way for development of novel therapeutics.  

My research has focused on glutamatergic and GABAergic aberrations in initially antipsychotic-naïve patients with first-episode psychosis and the impact of these disturbances on short- and long-term treatment outcome as well as cognitive performance. Specifically, we have found that higher levels of glutamate in thalamus and lower levels of GABA in dorsal Anterior Cingulate Cortex (dACC) are present from illness onset in antipsychotic-naïve first-episode patients and related to poor short-term treatment outcome after 6 and 26 weeks. Moreover, low GABA levels in dACC at illness onset are associated with poor functional outcome after two years of illness, and lower levels of glutamate in the dACC are associated with impaired cognitive function. Going further into the neurobiological underpinnings of insufficient treatment response, we investigated if brain glutamate and GABA levels were related to striatal dopaminergic function that is the main target of antipsychotic compounds. We observed that lower GABA levels in dACC were associated with higher striatal perfusion during the first two years of illness, suggesting that prefrontal GABA levels have a downregulatory effect on striatal activity and may be a novel treatment target. Furthermore, an aberrant interrelation between dACC levels of GABA and dopamine synthesis capacity in nucleus accumbens assessed with positron emission tomography could identify antipsychotic-naïve patients from healthy controls, whereas individual neurotransmitters were unable to do so, suggesting that aberrant interactions between neurotransmitters are more crucial for development of schizophrenia than single neurotransmitter disturbances. Currently, we examine the trajectory of glutamate levels in dACC and thalamus during the first two years of illness and relate neurotransmitter levels to long-term treatment outcome and cognitive function. Moreover, we investigate if a glutamatergic compound developed for neurological disorders is effective in patients with first-episode psychosis.   

Our findings so far imply that treatment targeting glutamatergic and GABAergic disturbances can be beneficial in first-episode patients during the first two years of illness. As novel treatments are warranted not only during first-episode psychosis but also in the more chronic stage of the illness, we are currently preparing to re-examine brain levels of glutamate and GABA in the same cohort of patients and healthy controls after ten years.  

I am always thrilled to attend the SIRS conference and get inspirated by both junior and senior researchers dedicating their time to improve the treatment and everyday life for patients with schizophrenia and psychotic disorders. The SIRS early career award 2023 and mentor program was very helpful in expanding my international network, and I especially gained from guidance on funding, publishing strategies, and life-work balance in academia. The program has supported me in developing my research career trajectory. It makes me believe that our combined international effort into unravelling the neurobiological and environmental factors underlying schizophrenia will lead to development of novel treatment options during the next decades. 

Dr. Natalia Mansur Haddad’s Perspective & Experience as a Psychiatric Researcher

By: Dr. Natalia Mansur Haddad

I have enjoyed studying and understanding schizophrenia since the initial period of my first graduation, still in the field of psychology. Afterwards, I went to medical school to become a psychiatrist. Thereby, I have always been fascinated by psychosis in general as an area of ​​study and research. During the last 10 years of clinical practice, I delved deeper into the care of chemically dependent patients and substance use disorders. At the confluence of these subjects, I have the privilege of studying the endocannabinoid system in a population with psychosis and how the impact of cannabis can influence its regulation. 

In 2022 I had the great opportunity to win the SIRS Early Career Award. On that occasion, I was able to show the partial results of our study, which pointed to the use of cannabis as a factor that influences the reduction in endocannabinoid 2-AG values ​​in plasma. In the following years, we continued to study the ECS and found an increase in peripheral CB2 receptors associated with the use of non-clozapine antipsychotics. The data complement the current literature, which is ambiguous and should be further studied. 

 It was very important for a young investigator like me to attend to an international meeting and it was a unique opportunity to establish international collaboration with important researchers in the field. It was a great honor and an encouragement to proceed with my research. I recently published an article with the findings of my thesis on changes in the endocannabinoid system of patients with schizophrenia in the European Archives of Psychiatry and Clinical Neuroscience Journal. 

I have started my master's degree in February 2020, upgraded to doctorate degree and my thesis defense will take place next month.
All this development and career evolution in recent years gives me confidence to continue researching and sharing the results of my research with the international community. I believe that one of the main objectives is to align research results with clinical practice, thus contributing to the development of new screening methods for the disorder such as biomarkers, which can improve the diagnosis, treatment and prognosis of these individuals. 

My research group is very diverse, we work at a Public Hospital and University in São Paulo - Brazil, and adverse situations are very frequent in an underrepresented country. However, year after year we prove that we can carry out quality research and talk to researchers from around the world, contributing relevant data from a large and diverse population sample with a major impact on global health. We intend to continue building knowledge and strengthening ties with the international community. 

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.


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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