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Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithiums possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P

Abstract Background Clinical practice guidelines are crucial for enhancing healthcare quality and patient outcomes. Yet, their implementation remains inconsistent across various professions and disciplines. Previous findings on the implementation of the German guideline for schizophrenia (2019) revealed low adherence rates among healthcare professionals. Barriers to guideline adherence are multifaceted, influenced by individual, contextual, and guideline-related factors. This study aims to investigate the effectiveness of a digital guideline version compared to print/PDF formats in enhancing guideline adherence. Methods A multicenter, cluster-randomized controlled trial was conducted in South Bavaria, Germany, involving psychologists and physicians. Participants were divided into two groups: implementation of the guideline using a digital online version via the MAGICapp platform and the other using the traditional print/PDF version. The study included a baseline assessment and a post-intervention assessment following a 6-month intervention phase. The primary outcome was guideline knowledge, which was assessed using a guideline knowledge questionnaire. Results The study included 217 participants at baseline and 120 at post-intervention. Both groups showed significant improvements in guideline knowledge; however, no notable difference was found between both study groups regarding guideline knowledge at either time points. At baseline, 43.6% in the control group (CG) and 52.5% of the interventional group (IG) met the criterion. There was no significant difference in the primary outcome between the two groups at either time point (T0: Chi2 (1) = 1.65, p = 0.199, T1: Chi2 (1) = 0.34, p = 0.561). At post-intervention, both groups improved, with 58.2% in the CG and 63.5% in the IG meeting this criterion. Conclusions While the study did not include a control group without any implementation strategy, the overall improvement in guideline knowledge following an implementation strategy, independent of the format, was confirmed. The digital guideline version, while not superior in enhancing knowledge, showed potential benefits in shared decision-making skills. However, familiarity with traditional formats and various barriers to digital application may have influenced these results. The study highlights the importance of tailored implementation strategies, especially for younger healthcare providers. Trial registration https://drks.de/search/de/trial/DRKS00028895

Abstract Stratified medicine holds great promise to tailor treatment to the needs of individual patients. While genetics holds great potential to aid patient stratification, it remains a major challenge to operationalize complex genetic risk factor profiles to deconstruct clinical heterogeneity. Contemporary approaches to this problem rely on polygenic risk scores (PRS), which provide only limited clinical utility and lack a clear biological foundation. To overcome these limitations, we develop the CASTom-iGEx approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue specific gene expression levels. The paradigmatic application of this approach to coronary artery disease or schizophrenia patient cohorts identified diverse strata or biotypes. These biotypes are characterized by distinct endophenotype profiles as well as clinical parameters and are fundamentally distinct from PRS based groupings. In stark contrast to the latter, the CASTom-iGEx strategy discovers biologically meaningful and clinically actionable patient subgroups, where complex genetic liabilities are not randomly distributed across individuals but rather converge onto distinct disease relevant biological processes. These results support the notion of different patient biotypes characterized by partially distinct pathomechanisms. Thus, the universally applicable approach presented here has the potential to constitute an important component of future personalized medicine paradigms.

Abstract Background Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

IntroductionThe current study aimed to investigate the rates of anxiety, clinical depression, and suicidality and their changes in health professionals during the COVID-19 outbreak.Materials and methodsThe data came from the larger COMET-G study. The study sample includes 12,792 health professionals from 40 countries (62.40% women aged 39.76 ± 11.70; 36.81% men aged 35.91 ± 11.00 and 0.78% non-binary gender aged 35.15 ± 13.03). Distress and clinical depression were identified with the use of a previously developed cut-off and algorithm, respectively.Statistical analysisDescriptive statistics were calculated. Chi-square tests, multiple forward stepwise linear regression analyses, and Factorial Analysis of Variance (ANOVA) tested relations among variables.ResultsClinical depression was detected in 13.16% with male doctors and 'non-binary genders' having the lowest rates (7.89 and 5.88% respectively) and 'non-binary gender' nurses and administrative staff had the highest (37.50%); distress was present in 15.19%. A significant percentage reported a deterioration in mental state, family dynamics, and everyday lifestyle. Persons with a history of mental disorders had higher rates of current depression (24.64% vs. 9.62%; p

Abstract The response variability to repetitive transcranial magnetic stimulation (rTMS) challenges the effective use of this treatment option in patients with schizophrenia. This variability may be deciphered by leveraging predictive information in structural MRI, clinical, sociodemographic, and genetic data using artificial intelligence. We developed and cross-validated rTMS response prediction models in patients with schizophrenia drawn from the multisite RESIS trial. The models incorporated pre-treatment sMRI, clinical, sociodemographic, and polygenic risk score (PRS) data. Patients were randomly assigned to receive active (N = 45) or sham (N = 47) rTMS treatment. The prediction target was individual response, defined as ≥20% reduction in pre-treatment negative symptom sum scores of the Positive and Negative Syndrome Scale. Our multimodal sequential prediction workflow achieved a balanced accuracy (BAC) of 94% (non-responders: 92%, responders: 95%) in the active-treated group and 50% in the sham-treated group. The clinical, clinical + PRS, and sMRI-based classifiers yielded BACs of 65%, 76%, and 80%, respectively. Apparent sadness, inability to feel, educational attainment PRS, and unemployment were most predictive of non-response in the clinical + PRS model, while grey matter density reductions in the default mode, limbic networks, and the cerebellum were most predictive in the sMRI model. Our sequential modelling approach provided superior predictive performance while minimising the diagnostic burden in the clinical setting. Predictive patterns suggest that rTMS responders may have higher levels of brain grey matter in the default mode and salience networks which increases their likelihood of profiting from plasticity-inducing brain stimulation methods, such as rTMS. The future clinical implementation of our models requires findings to be replicated at the international scale using stratified clinical trial designs.

Aims Glutamatergic signalling deficits contribute to the neuropathology of cognitive symptoms in schizophrenia. Iclepertin (BI 425809), a glycine transporter-1 inhibitor, enhances N-methyl-D-aspartate receptor signalling in the brain by increasing synaptic levels of its co-agonist glycine. The Phase III CONNEX programme aims to assess the efficacy, safety and tolerability of iclepertin in improving cognition and functioning in schizophrenia. Methods CONNEX includes 3 randomised, double-blind, placebo-controlled parallel group trials in patients with schizophrenia from multiple centres across 41 countries in Asia, North and South America, Europe, and Asia Pacific Region (NCT04846868, NCT04846881, NCT04860830) receiving stable antipsychotic treatment. Each trial aims to recruit ~586 patients, 18–50 years old, treated with 1–2 antipsychotic medications (≥12 weeks on current drug; ≥35 days on current dose before treatment), who have functional impairment in day-to-day activities and interact ≥1 hour/week with a designated study partner. Patients with cognitive impairment due to developmental, neurological or other disorders, or receiving cognitive remediation therapy ≤12 weeks before screening will be excluded. Patients will be randomised 1:1 to once-daily oral iclepertin 10 mg (n = 293) or placebo (n = 293) for 26 weeks. Primary endpoint: change from baseline (CfB) in Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) overall composite T-score. Key secondary endpoints: CfB in Schizophrenia Cognition Rating Scale (SCoRS) total score and adjusted total time T-score in the Virtual Reality Functional Capacity Assessment Tool (VRFCAT). Results Trial completion is expected in Q1 2025. By 31/01/2024, there have been 811, 699 and 655 patients screened, 533, 474 and 458 randomised, and 320, 299 and 281 who have completed the trial medication for CONNEX-1, -2 and -3, respectively. Most patients are male (CONNEX-1: 69.3%, CONNEX-2: 69.0%, CONNEX-3: 63.3%) with similar age (mean [standard deviation; SD]) (CONNEX-1: 34.0 [8.9], CONNEX-2: 35.9 [8.4], CONNEX-3: 34.0 [8.8] years). For CONNEX-1, -2 and -3, mean (SD) duration of illness is 10.6 (8.3), 12.2 (7.9) and 9.6 (7.6) years and duration of previous schizophrenia treatment is 3.9 (4.6), 4.5 (4.9) and 3.3 (4.4) years. Baseline mean (SD) MCCB overall composite T-score (1: 28.4 [13.7], 2: 27.3 [13.8], 3: 29.7 [13.7]), SCoRS total score (1: 40.5 [11.1], 2: 39.9 [9.7], 3: 38.0 [10.0]) and VRFCAT adjusted total time T-score (1: 29.6 [22.3], 2: 30.7 [20.8], 3: 33.6 [18.1]) were similar across trials. Conclusion If successful, CONNEX will provide evidence for iclepertin as the first efficacious medication addressing cognitive impairments in schizophrenia. Studies funded by Boehringer Ingelheim.

IntroductionDuring the COVID-19 pandemic various degrees of lockdown were applied by countries around the world. It is considered that such measures have an adverse effect on mental health but the relationship of measure intensity with the mental health effect has not been thoroughly studied. Here we report data from the larger COMET-G study pertaining to this question.Material and methodsDuring the COVID-19 pandemic, data were gathered with an online questionnaire from 55,589 participants from 40 countries (64.85% females aged 35.80 ± 13.61; 34.05% males aged 34.90±13.29 and 1.10% other aged 31.64±13.15). Anxiety was measured with the STAI, depression with the CES-D and suicidality with the RASS. Distress and probable depression were identified with the use of a previously developed cut-off and algorithm respectively.Statistical analysisIt included the calculation of Relative Risk (RR), Factorial ANOVA and Multiple backwards stepwise linear regression analysis RESULTS: Approximately two-thirds were currently living under significant restrictions due to lockdown. For both males and females the risk to develop clinical depression correlated significantly with each and every level of increasing lockdown degree (RR 1.72 and 1.90 respectively). The combined lockdown and psychiatric history increased RR to 6.88 The overall relationship of lockdown with severity of depression, though significant was small.ConclusionsThe current study is the first which reports an almost linear relationship between lockdown degree and effect in mental health. Our findings, support previous suggestions concerning the need for a proactive targeted intervention to protect mental health more specifically in vulnerable groups.

Abstract Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Abstract Introduction Previous studies described various adaptive neuroplastic brain changes associated with physical activity (PA). EEG studies focused mostly on effects during or shortly after short bouts of exercise. This is the first study to investigate the capability of EEG to display PA‐induced long‐lasting plasticity in runners compared to a sedentary control group. Methods Thirty trained runners and 30 age‐ and sex‐matched sedentary controls (SC) were included as a subpopulation of the ReCaP (Running effects on Cognition and Plasticity) study. PA was measured with the International Physical Activity Questionnaire (IPAQ). Resting‐state EEG of the runners was recorded in the tapering phase of the training for the Munich marathon 2017. Power spectrum analyses were conducted using standardized low‐resolution electromagnetic tomography (sLORETA) and included the following frequency bands: delta: 1.5–6 Hz, theta: 6.5–8.0 Hz, alpha1: 8.5–10 Hz, alpha2: 10.5–12.0 Hz, beta1: 12.5–18.0 Hz, beta2: 18.5–21.0 Hz, beta3: 21.5–30.0 Hz, and total power (1.5–30 Hz). Results PA (IPAQ) and BMI differed significantly between the groups. The other included demographic parameters were comparable. Statistical nonparametric mapping showed no significant power differences in EEG between the groups. Discussion Heterogeneity in study protocols, especially in time intervals between exercise cessation and EEG recordings and juxtaposition of acute exercise‐induced effects on EEG in previous studies, could be possible reasons for the differences in results. Future studies should record EEG at different time points after exercise cessation and in a broader spectrum of exercise intensities and forms to further explore the capability of EEG in displaying long‐term exercise‐induced plasticity.

Abstract Several changes to the classification of mental disorders have been made during the past half century to increase the reliability, clinical use and validity of the diagnostic classification. Despite the high expansion of knowledge about mental disorders, understanding of their components and processes still requires fine-tuning. This symposium identifies key issues on different classification systems with different purposes relevant to understanding and classifying mental disorders. We discuss how key issues such as ICD-11, RDoC or Biomarkers correspond or diverge because of their different purposes, and constituencies. Although these approaches have varying degrees of overlap and distinguishing features, they share the goal of reducing the burden of suffering due to mental disorder. Disclosure of Interest None Declared

Introduction Schizophrenia is a chronic neuropsychiatric disorder that often requires long-term pharmacotherapy to manage symptoms and prevent relapse. There are important clinical differences between early-stage versus late-stage schizophrenia, like the predominant symptomatology. In later stages, negative, cognitive, and anxiety/depressive symptoms dominate the clinical picture, with relapses further potentiating the emergence of positive symptoms. Therefore, it is crucial to establish the efficacy of an antipsychotic medication in the later stages of schizophrenia as well. Cariprazine is a novel dopamine D3-preferring D3/D2 receptor partial agonist that has shown efficacy in treating schizophrenia across the symptom spectrum. Objectives The aim of this poster is to present the findings of cariprazine’s efficacy in treating late-stage schizophrenia, especially in symptoms that are more commonly occurring in this phase of the disorder. Methods This poster reports the results of a post-hoc pooled analysis of three 6-week, double-blind, placebo-controlled trials (NCT01104766, NCT01104779, NCT00694707) that assessed the efficacy of cariprazine in schizophrenia. The primary outcome was the change in Positive and Negative Syndrome Scale (PANSS) Total Scores from baseline to endpoint. The analysis focused on patients with late-stage schizophrenia (defined as having an illness-duration of more than 15 years) who received cariprazine at doses between 1.5 mg/day to 6.0 mg/day. The changes in PANSS-derived Marder Factor Scores for Negative, Disorganised Thought (i.e., Cognitive) and Anxiety/Depression symptoms were further examined. The least square mean differences (LSMDs) between cariprazine and placebo groups were calculated using mixed-models for repeated measures (MMRM). Results Altogether, 128 placebo-, and 286 cariprazine-treated patients were identified as having schizophrenia for more than 15 years. The mean age of patients was about 45 years, while the mean illness-duration was about 24 years. The mean baseline PANSS scores were the same between the two groups. In the late-stage schizophrenia population, at Week 6, cariprazine yielded statistically significantly greater reductions on the PANSS Total Score (LSMD -6.7, p

Abstract The World Health Organization (WHO) has stated that in situations of armed conflict, “Around 10 percent of the people who experience traumatic events will have serious mental health problems, and another 10 percent will develop behavior that will hinder their ability to function effectively.” Problems include post-traumatic stress disorder, anxiety, depression, substance misuse, and possibly precipitation of psychosis. War has a catastrophic effect on the health and well being of nations. Studies have shown that conflict situations cause more mortality and disability than any major disease. Only through a greater understanding of conflicts and the myriad of mental health problems that arise from them, coherent and effective strategies for dealing with such problems can be developed. Disclosure of Interest None Declared

Introduction Cognitive impairment associated with schizophrenia (CIAS) is an important unmet need as there are no effective treatments available. Iclepertin (BI 425809), a glycine transporter-1 inhibitor, has been shown to improve CIAS in Phase II trials, and Phase III trials are underway. Objectives The ongoing CONNEX-X extension study aims to collect additional safety data relating to iclepertin treatment in patients with CIAS. Methods CONNEX-X (NCT05211947/1346-0014) is a multinational, multicentre, open-label, single-arm extension study in patients with CIAS who completed 26 weeks of treatment (iclepertin 10 mg or placebo) in one of 3 Phase III CONNEX parent trials (NCT04846868/1346-0011, NCT04846881/1346-0012, NCT04860830/1346-0013). An estimated 1400 clinically stable outpatients will be treated (iclepertin 10 mg daily) for 1 year, irrespective of previous treatment (iclepertin/placebo). Patients are excluded if any of the following circumstances occur during the parent study and up to Visit 1 of CONNEX-X: suicidal behaviour or ideation (type 5 on the Columbia-Suicide Severity Rating Scale), diagnosis with moderate/severe substance use disorder, diagnosis other than schizophrenia (according to Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition), development of any condition preventing participation, a haemoglobin level decrease (>25% or

Abstract Mortality from cardiovascular disease is increased in people with mental health disorders in general and schizophrenia in particular. The causes are multifactorial, but it is known that antipsychotic medication can cause cardiac side-effects beyond the traditional coronary risk factors. Schizophrenia itself is a contributor to an increased risk of cardiovascular mortality via cardiac autonomic dysfunction and a higher prevalence of metabolic syndrome, both contributing to a reduced life expectancy. Overall, management of cardiovascular risk within this population group must be multifaceted and nuanced to allow the most effective treatment of serious mental illness to be conducted within acceptable parameters of cardiovascular risk; some practical measures are presented for the clinical cardiologist. Disclosure of Interest None Declared

Abstract The burden of mental illness in Europe: High individual and societal burden, but only 2% spent on mental health. The tradition of European Psychiatry needs to be strengthened in care, research and teaching.Within the long-term Strategic Mental Health Plan of the EPA the improvement of clinical care research, the “mapping excellence” and “developing core treatment guidelines” require further action. Researching the influence of environmental stressors on the development and maintenance of mental illness and fostering stepped care approaches to improve resilience are none the less important. Furthermore, to improve the reliability and especially validity of diagnoses of mental disorders by introducing (bio)markers and defining dimensions of mental illnesses using big data and predictive sciences are just as important as an enforced research on reducing stigma and discrimination of mental disorders. Disclosure of Interest None Declared

Introduction In a 12-week, Phase II (NCT02832037) trial, iclepertin (BI 425809), an inhibitor of glycine transporter-1, was generally well tolerated and significantly improved cognition in 509 patients with schizophrenia. Objectives The Phase III CONNEX programme aims to confirm the efficacy, safety and tolerability of iclepertin in improving cognition and functioning across a larger cohort of patients with schizophrenia. Methods The CONNEX programme includes 3 randomised, double-blind, placebo-controlled parallel group trials in patients with schizophrenia (NCT04846868, NCT04846881, NCT04860830) receiving stable antipsychotic treatment. Each trial aims to recruit ˜586 patients, 18–50 years old, treated with 1–2 antipsychotic medications (≥12 weeks on current drug and ≥35 days on current dose before treatment) who have functional impairment in day-to-day activities and interact ≥1 hour per week with a designated study partner. Patients with cognitive impairment due to developmental, neurological or other disorders, with a current DSM-5 diagnosis other than schizophrenia or receiving cognitive remediation therapy within 12 weeks prior to screening, will be excluded. Patients will be recruited from multiple centres across 41 countries in Asia, North and South America, Europe and the Asia-Pacific Region, and randomised 1:1 to receive either iclepertin 10 mg (oral administration; n=293), or placebo (n=293) once daily for 26 weeks. The primary endpoint is change from baseline in overall composite T-score of the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery. The key secondary endpoints are change from baseline in total score on the Schizophrenia Cognition Rating Scale and change from baseline in the adjusted total time T-score in the Virtual Reality Functional Capacity Assessment Tool. Results The CONNEX programme is currently recruiting (Table); the first patients were enrolled in Aug–Sept 2021 and completion is expected in Q1 2025. The presentation will describe the current study status, information relating to screening failures, and the experience of collecting these data as part of a large multi-country, multicentre study. Table. The number of patients recruited by 31 August 2023 CONNEX 1 CONNEX 2 CONNEX 3 Screened 565 521 493 Randomised 409 360 350 Completed trial medication 202 184 191 Conclusions Iclepertin may represent the first efficacious medication for cognitive impairment associated with schizophrenia. Funding Boehringer Ingelheim Disclosure of Interest C. Reuteman-Fowler Employee of: Boehringer Ingelheim, Z. Blahova Employee of: Boehringer Ingelheim, S. Ikezawa Consultant of: Boehringer Ingelheim Pharma GmbH, Lundbeck, Takeda Pharma, Sumitomo Dainippon Pharma, Employee of: International University of Health and Welfare, Mita Hospital, Tokyo, Japan, S. Marder Consultant of: Boehringer Ingelheim Pharma GmbH, Merck, Biogen and Sunovion, P. Falkai Consultant of: Boehringer Ingelheim Pharma GmbH, Boehringer Ingelheim Pharma Advisory Board, J. H. Krystal Shareolder of: Freedom Biosciences, Inc., Biohaven Pharmaceuticals, Sage Pharmaceuticals, Spring Care, Biohaven Pharmaceuticals Medical Sciences, EpiVario, RBNC Therapeutics, Terran Biosciences and Tempero Bio, Consultant of: Aptinyx, Atai Life Sciences, AstraZeneca Pharmaceuticals, Biogen, Biomedisyn Corporation, Bionomics, Boehringer Ingelheim International, Cadent Therapeutics, Clexio Bioscience, COMPASS Pathways, Concert Pharmaceuticals, Epiodyne, EpiVario, Greenwich Biosciences, Heptares Therapeutics, Janssen, Jazz Pharmaceuticals, Otsuka America Pharmaceutical, Perception Neuroscience Holdings, Spring Care, Sunovion Pharmaceuticals, Takeda Industries, Taisho Pharmaceutical Co.; Biohaven Pharmaceuticals, BioXcel Therapeutics, Cadent Therapeutics, Cerevel Therapeutics, Delix Therapeutics, EpiVario, Eisai, Jazz Pharmaceuticals, Novartis, PsychoGenics, RBNC Therapeutics, Tempero Bio and Terran Biosciences Advisory Boards

Introduction Psychiatric drugs, including antipsychotics and antidepressants, are widely prescribed, even in young and adolescent populations at early or subthreshold disease stages. However, their impact on brain structure remains elusive. Elucidating the relationship between psychotropic medication and structural brain changes could enhance the understanding of the potential benefits and risks associated with such treatment. Objectives Investigation of the associations between psychiatric drug intake and longitudinal grey matter volume (GMV) changes in a transdiagnostic sample of young individuals at early stages of psychosis or depression using an unbiased data-driven approach. Methods The study sample comprised 247 participants (mean [SD] age = 25.06 [6.13] years, 50.61% male), consisting of young, minimally medicated individuals at clinical high-risk states for psychosis, individuals with recent-onset depression or psychosis, and healthy control individuals. Structural magnetic resonance imaging was used to obtain whole-brain voxel-wise GMV for all participants at two timepoints (mean [SD] time between scans = 11.15 [4.93] months). The multivariate sparse partial least squares (SPLS) algorithm (Monteiro et al. JNMEDT 2016; 271:182-194) was embedded in a nested cross-validation framework to identify parsimonious associations between the cumulative intake of psychiatric drugs, including commonly prescribed antipsychotics and antidepressants, and change in GMV between both timepoints, while additionally factoring in age, sex, and diagnosis. Furthermore, we correlated the retrieved SPLS results to personality domains (NEO-FFI) and childhood trauma (CTQ). Results SPLS analysis revealed significant associations between the antipsychotic classes of benzamides, butyrophenones and thioxanthenes and longitudinal GMV decreases in cortical regions including the insula, posterior superior temporal sulcus as well as cingulate, postcentral, precentral, orbital and frontal gyri (Figure 1A-C). These brain regions corresponded most closely to the dorsal and ventral attention, somatomotor, salience and default network (Figure 1D). Furthermore, the medication signature was negatively associated with the personality domains extraversion, agreeableness and conscientiousness and positively associated with the CTQ domains emotional and physical neglect. Image: Conclusions Psychiatric drug intake over a period of one year was linked to distinct GMV reductions in key cortical hubs. These patterns were already visible in young individuals at early or subthreshold stages of mental illness and were further linked to childhood neglect and personality traits. Hence, a better and more in-depth understanding of the structural brain implications of medicating young and adolescent individuals might lead to more cautious, sustainable and targeted treatment strategies. Disclosure of Interest None Declared

Introduction The clinical high-risk state for psychosis (CHR) is associated with alterations in grey matter volume (GMV) in various regions such as the hippocampus (Vissink et al. BP:GOS 2022; 2(2) 147-152). Within the scope of the North American Prodrome Longitudinal Study (NAPLS-2; Cannon et al. AM J Psychiatry 2016; 173(10), 980-988), a publicly available risk calculator based on clinical variables was developed to assess the likelihood of individuals to transition to psychosis within a 2-year period. Objectives In the current study, we aim to examine the association between GMV and NAPLS-2 risk scores calculated for individuals with CHR and recent-onset depression (ROD), taking a transdiagnostic approach on the transition to psychosis. Methods The sample consisted of 315 CHR (M = 23.85, SD = ± 5.64; female: 164) and 295 ROD (M = 25.11, SD = ± 6.21; female: 144) patients from the multi-site Personalised Prognostic Tools for Early Psychosis Management (PRONIA) Study (Koutsouleris et al. JAMA Psychiatry 2018; 57(11), 1156-1172). Risk scores were calculated using the six clinical and neurocognitive variables included in the NAPLS-2 risk calculator that were significant for predicting psychosis. Further, we derived smoothed GMV maps from T1-weighted structural magnetic resonance imaging using a full width at half maximum kernel size of 8 mm. We employed a multiple regression design in SPM12 to examine associations between risk scores and GMV. On the whole-brain level, we calculated permutation-based threshold-free cluster enhancement (TFCE) contrasts using the TFCE toolbox. Additionally, we calculated t-contrasts within a region-of-interest (ROI) analysis encompassing the hippocampus. All results were thresholded at p < 0.05 with family wise error correction to address multiple comparisons. Results Our analysis revealed that linear GMV increases in the right middle and superior frontal gyrus (kE= 2726 voxels) were significantly associated with higher risk for psychosis transition within two years (see figure 1, highlighted in blue). In the ROI analysis, we found a significant negative linear association between GMV decreases in the left hippocampus (kE = 353 voxels) and higher risk for psychosis transition (see figure 1, highlighted in red). Image: Conclusions GMV reductions in the hippocampus have frequently been observed in CHR and psychosis patients (Vissink et al. BP:GOS 2022; 2(2) 147-152), therefore our results further highlight the crucial role of this region in the progression of the disease. There is limited evidence on GMV increases in CHR patients. However, the GMV increase we found in the frontal pole may reflect compensatory mechanisms of the brain in the development of psychosis. In addition, we were able to provide biological validation of the NAPLS-2 risk calculator and its assessment of risk for transition to psychosis. Disclosure of Interest None Declared