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Bridget King

Transcript:

My name is Bridget King, and I will have a poster at SIRS 2025 which is presenting a mega-analysis looking at neurometabolite levels in antipsychotic responsive versus non-responsive psychosis. It is estimated that up to 30% of patients with schizophrenia will not respond to antipsychotic medication. Research using a brain imaging method called magnetic resonance spectroscopy or MRS has linked elevations in glutamate in the medial frontal cortex to non-response to antipsychotics. However, not all studies in this field have found elevations in glutamate in antipsychotic non-responders, and some studies have linked additional neurometabolites in this process, such as choline and myo-inositol. Patients with schizophrenia that don't respond to their antipsychotic medication have a higher illness burden because they have persistent symptoms of the disorder. Understanding the neurobiological mechanisms as to why some individuals with schizophrenia don't respond to antipsychotics could help pave the way to develop new and more effective treatments for schizophrenia. For example, if non-response to psychosis is associated with elevations in glutamate, these individuals may benefit from glutamatergic acting therapeutics.

My poster at SIRS 2025 presents a large-scale collaborative mega-analysis, which combines MRS data from 19 studies and over 1,000 participants from around the globe. This research aims to answer critical questions in the field, such as whether elevations in neurometabolites such as glutamate are linked to non-response in schizophrenia. If you would like to find out more about this research and our findings, please come along and visit my SIRS poster on April 1st at the Riverside Exhibit Hall West. It's poster number 102, and it's happening from 12 until 2 p.m.

Anne Felsenheimer

Transcript:

Hi, I’m Anne Felsenheimer — a medical doctor and PhD at the Institute of Cognitive Neuroscience at UCL and the Max Planck Institute of Cognitive and Behavioural Brain Sciences. 

At this year’s Congress of the Schizophrenia International Research Society, I’m presenting my work on interoception and the feeling of presence, conducted in collaboration with Sohee Park’s Lab during my time as an International Fulbright Scholar.  

Sometimes we're just sitting in a room, maybe working on the next presentation... 

... and suddenly we get this strange feeling that there is someone else in the room with us.  

We might even turn around and realise that no, actually we are still alone. This feeling of someone being there when they are not called felt presence. Why do we have this feeling?  

One idea is, that we indeed sense something that is there - such as our heartbeat. 

But instead of attributing it to our own body, we think this sensation is coming from someone else.  

Although there is a lot of stigma attached to it, the feeling of presence is actually quite common. It's not always unsettling - sometimes it can feel like a comforting presence, even like a guardian angel. But it is also associated with a higher risk of psychosis, where the felt presence is often more distressing. One might ask: are there different mechanisms at work?  

By studying felt presence, we can gain new insights of how perception and consciousness works on a general level. 

But this research also helps us distinguish between harmless and potentially high-risk experiences, develop targeted interventions and reduce the stigma surrounding these mysterious sensations. 

Huiquan Zhou

Slide 1 

Hi, everyone. Thank you for being here today. I am excited to present our study on the association between clozapine use and the risk of hospitalization among people with schizophrenia, using a self-controlled case series study design. 

Slide 2 

Schizophrenia is a chronic and severe mental disorder that often leads to recurrent hospitalizations, placing a significant burden on patients, families, and healthcare systems. Clozapine, the gold-standard treatment for TRS, has been shown to reduce symptoms and improve outcomes. However, critical gaps remain in our understanding of its real-world impact on hospitalization risk. 

First, there is limited evidence of clozapine’s impact on specific types of hospitalizations, such as psychiatric versus non-psychiatric admissions. Second, the comparative effectiveness of clozapine versus depot in preventing hospitalizations remains controversial, with conflicting findings in the literature. Third, real-world evidence is limited, and previous cohort studies often fail to address confounding due to between-person comparisons. 

To address these gaps, we conducted a self-controlled case series study, a robust method where each individual serves as their own control. This design divides the observation period for each individual into different exposure types, eliminating the influence of fixed confounders such as genetics or chronic comorbidities. Our study leverages a regional representative cohort of new clozapine users in Hong Kong, providing a unique opportunity to examine clozapine’s real-world effectiveness under the Chinese context. 

Slide 3 

We first compare the effectiveness of clozapine with other antipsychotics in general. We divided the observation periods into the pre-exposure period, the first clozapine exposure period, the washout period, the subsequent clozapine exposure period, and the period using other antipsychotics. We found that, compared to the use of other antipsychotics, both the first clozapine use and subsequent clozapine use showed significant lower risk associated with all-cause, psychiatric and non-psychiatric hospitalization.    

Slide 4 

We then compare the effectiveness of depot and combination use of depot and clozapine against the use of clozapine only. Similarly, we divided the whole observation period by different exposure types. The results showed that compare to clozapine use only, both combination use and depot use were associated with higher risk of all-cause, psychiatric and non-psychiatric hospitalization. We welcome and invite constructive comments and ideas from you.  

P2 Visual Event-Related Potential Response Predicts Clinical Outcomes in Patients at Clinical High Risk for Psychosis - Transcript for SIRS 2025 Early Career Award 

Jennifer Lepock  

80%-90% of schizophrenia (SCZ) patients experience a period of less intense symptoms preceding psychosis with changes in mood, behavior, interests and thoughts (Addington & Heinssen, 2012) For example, whereas an individual with SCZ may have a fixed belief the FBI are spying on them, a Clinical High Risk (CHR) individual may have fleeting thoughts that they are being watched or followed by unknown persons, and still have insight that this may not be true. Our ability to predict SCZ based on CHR symptoms is still limited. A majority of CHR individuals will not go on to develop SCZ, but their psychiatric follow-up requires substantial time and cost for them and the health-care system, and carries risks of side effects and stigmatization. To avoid unnecessary treatment and target interventions to those most at risk, new tests are needed to predict which CHR patients are most likely to develop SCZ. Although only a minority of CHR patients develop psychosis, approximately half of those who do not do so continue to experience persistent symptoms. Moreover, approximately half of CHR patients who do not develop a psychotic disorder have poor social and/or occupational functioning at follow-up. 

Neurophysiological indices are a potential tool for enhancing our ability to predict outcomes in CHR patients. These indices offer the advantage of being objective and rater-independent . Cognitive event-related brain potentials (ERPs) are a type of neurophysiological index that uses electroencephalography to non-invasively record voltage changes at the scalp associated with cognitive events such as stimuli or responses. A number of ERP waveforms have been found to be reliably reduced in schizophrenia, contributing to our knowledge about its underlying neurocognitive pathophysiology.  

Some of these ERP waveforms have demonstrated promising predictive results in CHR patients. 

ERP measure that could plausibly contribute to prognostic algorithms in CHR populations is the N400 waveform.  

400 amplitudes are normally smaller (less negative) to meaningful stimuli that are more related to preceding context. This “N400 semantic priming effect” is attenuated in patients with schizophrenia, compared with control individuals. We have found CHR individuals to also have attenuated N400 semantic priming effects compared to controls, and these deficiencies predicted functioning at one and two year follow up. 

There is evidence that prediction effects can be seen even earlier when a stimulus fits what is predicted, during the stage of early visual processing of word form reflected by the P2, during the 175-300 ms time window after stimulus onset. 

In the present study, we aimed to examine whether the P2 amplitudes are abnormal in patients at clinical high risk (CHR). In CHR patients, P2 is an early indicator of using context to predict what comes next with regard to the orthographic form of predicted words, and deficits in this prediction may reflect increased risk for functional impairment. 

Hsi Wei

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Understand what happens in the brains of individuals experiencing psychosis related language difficulties down to a millisecond precision. 

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Hi, I am Hsi Tiana Wei, a postdoctoral researcher at McGill University and Douglas Mental Health Institute, and I'm excited to share with you what we found. 

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Schizophrenic patients struggle with daily communication in the form of flattened affect. 

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Reduced and disorganized speech. To study speech, which is such a dynamic behavioral symptom. 

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MEG is an excellent neuroimaging tool that allows us to record high precision of spatial temporal, spectral. 

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And network level connectivity information. And these are all neuronal aspects that have shown deviations in schizophrenic patients. 

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And importantly, without understanding the associations between these deviated neural dynamics with communicative symptoms and clinical symptoms in schizophrenic patients. 

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The development of treatments focusing on neurochemical alterations using drugs or neural oscillatory modulations using non-invasive brain stimulations would be considerably limited. 

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So to improve the understanding of these associations, the current study that we ran, recruiting We are recruiting 25 schizophrenic patients and 25 healthy controls. 

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For three main domains of data. Including one session of MEG recording during a sensorimotor task so that we can characterize their neural dynamic. 

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And a natural speech task where we will extract the linguistic and acoustic features using large language models. 

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And a battery of clinical assessments. This is a rich data set that allowed us to look into the associations and interactions between neural dynamics, speech, and clinical symptoms in our patients and control groups. 

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So we're not only looking at factors and features that differentiate patients from control. 

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We're also looking into individual differences within each population group. So come to my presentation on April 1st at 5 p.m. In Regency Ballroom C. 

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To hear more about what we found and discuss how this study can inform the development of neuromodulatory treatments for psychosis. Looking forward to seeing you there. 

Deepa Purushothaman

Hello everyone, 

My name is Deepa, and I am excited to introduce to you our team’s research. We are poster number M73: Atypical neural activation during live face gaze in First Episode Psychosis predicts Bureau of Labor Statistics classification. I am a post doc at Yale, and we are a collaborative project by the Hirsch lab and STEP program at Yale. So, let me take you to the first slide. 

So, have you ever wondered how we instinctively look at people’s face, especially eyes, when you are talking to them? So, eye gaze and facial expressions tell us a lot of things about people’s emotions, even when they are not talking. So that’s why eye gaze and facial expression processing is considered the core of social cognition. And we know that in Schizophrenia, these core social cognitive processes are impaired. But how do we test them? So, imagine I need to test the motor circuits necessary for riding a bike. So, these will not be completely engaged, the circuits will not be completely engaged unless I sit on a bike and start riding. Similarly, the social cognitive circuits will not be completely engaged unless I see another human being face to face and start communicating with him or her. So, seeing movie clips or seeing static images may help us in understanding the neurology but it will not completely engage the social cognitive circuit. So, this is a challenge we all face. This was our research question: How do we bring a real world social dynamic interaction into the lab? And this is something I am excited to discuss with you at SIRS. 

At Hirsch lab, we came across , we put forward or we discovered a unique paradigm which includes two people, natural facial expressions and live eye gaze. It’s essentially two-person neuroscience, and what we did was, we compared people with First Episode Psychosis from the STEP clinic with typically developing individuals who do not have any neurodevelopmental, neurologic or psychiatric conditions. And while they are doing the task, we did FNIRS. And we had some amazing findings , interesting findings. I am excited to talk to you about all those things at SIRS. But I can only say that these findings could have immense ecological validity, treatment implications and it could even be a biological marker. So, let’s meet at SIRS. 

Deema Ali

Slide 1 

Hi everyone, I’m Deema, a PhD student at the University of Galway. My research focuses on studying the role of FOXP1 transcription factor in schizophrenia risk and cognitive function across development.  

Slide 2 

Transcription factors are proteins that regulate gene expression by binding to specific regions of DNA.  

They are crucial for controlling when, where, and how genes are turned on or off, influencing important processes including brain development. 

One of the transcription factors we are interested in is Forkhead Box Protein P1, or FOXP1.
Which is expressed in both the developing and adult brain and is considered one of the key regulatory genes during neural development. 

Rare mutations in this gene are associated with an autosomal dominant neurodevelopmental disorder known as FOXP1 syndrome, which is characterized by intellectual disability, developmental delay, and speech and language delays. 

On the other hand, the recent schizophrenia-GWAS reported a number of genome-wide significant common variants within the FOXP1 gene. 

In this study, we aimed to investigate whether FOXP1-regulated genes contribute to schizophrenia risk, and if this contribution varies across different developmental stages. 

Slide 3 

To investigate this, we analyzed transcriptomic data generated from mouse and human models of FOXP1 loss-of-function across different developmental stages, including prenatal and postnatal periods.  

We used LD score regression analysis to determine whether FOXP1-regulated genes are enriched for schizophrenia heritability and we performed gene-set enrichment analysis to explore their overlap with schizophrenia-associated genes identified by single nuclei RNA-seq studies.  We also studied the role of FOXP1-regulated genes in synaptic functions and how FOXP1-SNPs affect the expression of its downstream genes.  

Slide 4 

Our main findings show that FOXP1-regulated genes are enriched for SCZ heritability, and this enrichment is stage-dependent. 

As we can see here that FOXP1-regulated genes show the highest enrichment for SCZ-associated genes during childhood and adolescence, while genes from the embryonic stage and newborn period show lower enrichment.  

We’ve also found that the enrichment for genes associated with cognitive functions is similar to that seen in schizophrenia.  

This highlights the importance of developmental timing in understanding genetic contributions to SCZ.  

Thanks for your attention and I would be happy to discuss more details at my poster number 82 

Early Career Award Elevator Pitch 

Joseph Ghanem

Intro: Hi everyone, my name is Joseph, and my research looks at the way the brains of individuals with a first episode of psychosis change over time and how these changes relate to domains of cognition such as memory. 

Background: There are different ways to look at brain changes, but in my research we do so through a measure called Fractional Anisotropy (FA) which looks at how water is moving through the brain’s white matter. White matter being a network of nerve fibers that sends information between different brain regions. High FA indicates healthy, well-organized white matter pathways, Low FA is indicative of a potential problem, such as damage to white matter.  

People with a longstanding psychotic disorder do have lower FA relative to healthy populations but there has been debate about how FA changes over time early, right after a first episode of psychosis, with some studies finding changes and others showing that it remains unchanged. The link between FA and verbal memory--the ability to remember words or sentences and recall them--is also unclear.  Previous studies are also confounded by small sample sizes and short-term follow-up periods, antipsychotic medication use, and chronicity. 

Studying the early stages, over a longer period and with a larger sample, is a promising avenue of better understanding changes in white matter in this population. 

Methods:  What is unique and exciting about my work is that we are looking at these changes over 18 months at different points in time, which is something that has not been done before using this measure in this population. We are doing so in a sample of 80 people with a first episode of psychosis, which is also larger than most previous studies. As these are individuals recently diagnosed with a first episode of psychosis, it allows us to initially scan their brains before their brains change due to medication.  

The way to measure FA is to first scan the brains of participants using Diffusion Magnetic Resonance Imaging, a technique that allows researchers to look directly at white matter. We then preprocess the scans, which is an essential step that removes small errors in the images and improves their quality—think of it as polishing an image. 

We then conduct statistical models that compare FA in different regions of the brain between patients and controls  

Results:  what we found was that FA did not differ between those with a first episode of psychosis and healthy controls, there was also no meaningful association between FA and verbal memory. 

Meaning:  Our findings suggest that differences in FA are small early on after a first episode of psychosis, which can be taken as an indication that this period is critical for intervening before changes start to occur. It is also possible that longer time periods are needed to begin seeing changes in FA.  

Ju-Chi Yu, Centre for Addiction and Mental Health 

Individuals with Autism Spectrum Disorder (ASD) and individuals with Schizophrenia Spectrum Disorder (SSD) both experience difficulties in social cognition (such as understanding social context and emotion), which influence their every-day functioning.  

Social cognition consists of lower-level and higher-level components.  

We called the lower-level cognition the “simulation” component, which includes emotional recognition. 

For the higher-level social cognition, we called it the “mentalizing” component, which involves more complex processing of emotion, such as theory of mind and understanding the intent or attitudes of others (for example, when others are lying or being sarcastic). 

These two components of social cognition are related to different neural circuits. 

Simulation network involves connectivity in the mirror neuron system, including limbic system and right frontoparietal regions.  

Mentalizing network involves connectivity between the cortical midline structures and lateral temporoparietal regions. 

Despite the clinical relevance of atypical social cognition in autism and schizophrenia spectrum disorders, these deficits are rarely targeted for treatment, and their neurological basis is not well understood.  

In this study, we aim to identify transdiagnostic network features specifically related to social cognition, hoping to potentially inform future interventions targeting atypical social cognitive behaviors. 

To do so, we examine the functional connectivity from the empathic accuracy task, which involves both levels of social cognition. 

However, the observed functional connectivity can be affected by many factors, because these brain regions can be responsible for multiple functions aside from social cognition. 

Therefore, we performed advanced multivariate analysis and extracted the social component of functional network connectivity.  

Specifically, this component is a gradient of networks that differentiate simulation and mentalizing networks.  

Then, we examined how network configuration along this component associates with social cognitive behaviors, and how such association relates to clinical symptoms and functioning. 

If you would like to learn more about this study, please stop by my poster M116 on Monday at noon! 

Kara Dempster

Imagine you are hearing voices and experiencing paranoid delusions. Now imagine you were told that there was treatment for those symptoms. You anticipate relief finally. Now imagine that the treatment the experts offer you does not work. You wonder if they have gotten the diagnosis wrong. This is the plight of an individual with treatment resistant schizophrenia.  

My name is Kara Dempster and I am an early career clinician researcher at Dalhousie University in Halifax Nova Scotia with an interest in elucidating the underlying neurobiological correlates of treatment resistant schizophrenia.  

A third of individuals with schizophrenia do not respond to first line antipsychotic treatments and meet criteria for treatment resistant schizophrenia, the majority being poor responders from their first episode of psychosis. The evidence for clozapine is unequivocal in this group. Despite this, it is vastly underutilized. In an ideal world, individuals could be offered clozapine from the onset of their illness, or even after a single failed antipsychotic trial. 

The issue of determining clozapine eligibility is of particular importance in early phase psychosis as the response to clozapine is more robust. In addition, the onset of psychosis occurs during a crucial developmental period. It is simply harder to get back on track developmentally if one has missed out on normative functional experiences due to severe mental illness at this critical time. 

It has been hypothesized that there may be two subtypes of schizophrenia; one characterized by good response to dopamine blocking treatments, and the later being resistant to this pharmacology. Several studies have found that elevated glutamate in early psychosis is associated with poorer response to treatment at various discrete intervals. To date, no one has examined the association of elevated glutamate in early phase psychosis, and eligibility for clozapine.  

In breast cancer, for example, each individual is not offered the same treatment. Treatment choices are based off the type of cancer, and other factors like hormone receptor status. Offering someone a medication that does not at all address  the underlying cause of their symptoms seems grossly inadequate in comparison. The ability to use brain based measures to predict who would benefit from clozapine treatment would allow us to offer appropriate individuals this disease modifying treatment earlier in the course of illness.  

In conclusion, our current process of offering all individuals with schizophrenia the same medication without any consideration of underlying neurobiology is antiquated and contributes to prolonged suffering and disability. Elevated glutamate may be one marker of treatment resistant schizophrenia. I invite you to come see my poster on Tuesday April 1. I will be presenting my work on “The Association of Anterior Cingulate Cortex Glutamate and Clozapine Eligibility in an Early Psychosis Sample”.