Bipolar disorder (BD) is a chronic and complex affective disorder among top diseases that cause disability worldwide. Internalized stigmatization is a process including the awareness of negative stereotypes adopted by the society, participation in and internalization of these judgements, associated with impaired social functionality. Studies examining internalized stigma and related factors in BD is limited.

In this study, it is aimed to investigate the associations between internalized stigmatization and clinical characteristics, as well as sociodemographic and marital features of patients with BD.

This observational and cross-sectional study was conducted at a specialized affective disorders clinic in a university hospital between November 2020 and March 2021. During routine follow-up, each consecutive patient with BD was invited and a total of 118 were included in the study. Information about sociodemographic, marital and clinical characteristics of patients was collected through a prepared data form and follow-up documents. Internalized Stigma of Mental Illness Scale (ISMIS) was administered to assess internalized stigma. Statistical analysis of data was conducted by SPSS version 25 and a statistical significance level of p<0.05 was determined.

Mean ISMIS total score of the sample was 56.50 ±13.65. Multiple linear regression was used to test the predictors of higher ISMIS scores. Being currently unemployed (p=0.012, Β=0.208), shorter BD duration (p<0.001, Β=0.302) and presence of inter-episode residual symptoms (p=0.004, Β=0.248) predicted higher ISMIS total. Younger age (p=0.002, Β=0.264), being female (p=0.007, Β=0.226) and absence of mania dominance (p=0.019, Β=0.190) predicted higher alienation scores. Presence of inter-episode residual symptoms predicted both stereotype endorsement (p<0.001, Β=0.320) and perceived discrimination (p<0.001, Β=0.358). Younger age (p=0.001, Β=0.281) and total number of depressive episodes (p=0.015, Β=0.212) also predicted perceived discrimination. Shorter BD duration and absence of seasonality predicted higher ISMIS social withdrawal, while history of hospitalization predicted higher ISMIS stigma resistance.

Our study demonstrated similar mean ISMIS total scores to the findings previously reported in Türkiye, while roughly lower than results in the international literature. Considering that internalized stigmatization was increased in earlier stages of BD and in younger patients, as well as in patients with inter-episode residual symptoms, it might be important to implement psychosocial interventions for internalized stigmatization and appropriate psychoeducation programs in the earlier periods of BD. Therefore a multidimensional and holistic approach towards internalized stigmatization may positively contribute to the functionality of patients with BD.

None Declared

Persistent depressive episodes and subsyndromic depressive symptoms frequently characterize mood alterations in bipolar disorder (BD) and negatively influence quality of life and suicide risk. BD patients with predominant depressive episodes generally show significantly higher treatment resistance rates. Although not specifically approved in Italy for bipolar depression, recently published observational data suggest that the cariprazine add-on may be a potential effective short-term treatment for resistant bipolar depression. Nevertheless data on long-term cariprazine treatment are lacking.

This study evaluated the efficacy and safety of long-term cariprazine augmentation in patients suffering from treatment-resistant bipolar depression.

30 resistant bipolar depressed patients, whose resistance was defined according to The CINP Guidelines on the Definition and Evidence-Based Interventions for Treatment-Resistant Bipolar Disorder, were treated with cariprazine 1,5 -3 mg flexible dose for 4 weeks, added to previous mood stabilizing and/or antidepressant treatment. Psychopathology at time 0 and at 4, 8, 12, 16, 20, 24 weeks of treatment was evaluated using the Hamilton Depression Rating Scale (HDRS), the Hamilton Anxiety Rating Scale (HARS), the Young Mania Rating Scale (YMRS) and the Bipolar Depression Rating Scale (BDRS); safety and tolerability was measured by the UKU Side Effect Rating Scale. The drop-out rate was assessed throughout the study duration.

Cariprazine add-on was effective in the study sample but only during the first 4 weeks of treatment. Improvement in depression scores started from the first week, reaching about 40% mean HDRS score reduction at T4; a moderate ulterior decrease (-15%) was reached at T24 but was accompanied by a significant drop-out rate; anxiety symptoms improved (mean HARS score reduction 37% at T4) mainly during the first 4 weeks. The treatment was generally well tolerated. From week 4 to 24 we observed a near 70% drop-out rate (18 total drop-outs) with maximum drop-outs between weeks 4-8 (n=7) and 18-24 (n=7). Discontinuation causes were inefficacy (5/18); clinical worsening (10/18); side effects (3/18); hypomanic shift (2/18).

Despite the relatively small population examined and the observational design, our results suggest that cariprazine may represent an effective and safe short-term enhancement strategy in resistant bipolar depression. Long-term treatment, in this sample, did not lead to significant improvements and was burdened by a high drop-out rate, mainly due to inefficacy/clinical worsening. Further studies on larger samples are needed to confirm these preliminary findings, both in short-term and in longer observations.

None Declared

Bipolar disorder (BD) is a chronic and recurrent disease characterized by acute mood episodes alternated with periods of euthymia. The available literature postulates that a biphasic dysregulation of mitochondrial bioenergetics might be observed in BD.

We aimed to explore differences in in vivo mitochondrial respiration (1) intra-individually: longitudinally within patients during an acute mood episode of BD and after clinical remission, and (2) inter-individually: between patients with BD on depressive or manic episodes and healthy controls (HC).

Patients admitted to our acute psychiatric ward with a manic episode or bipolar depression were recruited. Different mitochondrial oxygen consumption rates (OCRs) were assessed during the acute episode (T0) and after clinical remission (T1) in one million of peripheral blood mononuclear cells (PBMC): Routine, Leak, ETC and Rox. They were measured as picomoles of oxygen per million cells (pmol O2/million). This experiment was also conducted in HC. High-resolution respirometry was performed at 37°C by polarographic oxygen sensors in a two-chamber Oxygraph-2k system. Manic and depressive symptoms were assessed using standardized psychometric scales. Oxygen consumption capacity was compared (1) intra-individually, during acute episodes and after clinical remission, and (2) inter-individually, during acute manic and depressive episodes, and in HC. Statistical analyses were performed with SPSS, GraphPad and R Statistics.

20 patients with BD (15 manic, 5 depressed) and 10 HC were included. A significant increase in the maximal oxygen consumption capacity (ETC) was observed in clinical remission (27.4 ± 17.4) compared to the acute episodes (21.1 ± 11.7, p = 0.001), which remained significant after subtracting Rox from the other rates (p = 0.001). At T1, patients admitted with a manic episode tended to show higher mean ETC (31.2 ± 18.7) compared with T0 (24.1 ± 12.0, p = 0.074); the tendency persisted after Rox subtraction (p = 0.076). Patients admitted with a depressive episode also showed higher ETC means in T1 (16.3 ± 3.8) compared to T0 (12.1 ± 3.4), but there were not significant differences (p = 0.231). When HC, manic and depressive patients at T0 were compared between them, significant differences were observed in ETC (H =8.5; p =0.014) and Rox (H =13.8; p = 0.001). After Rox deduction, differences in ETC remained (H =11.7; p = 0.003). Individuals with bipolar depression showed lower ETC rates (12.1 ± 3.4) than those with a manic episode (24.1 ± 12.0; t = -3.5, p = 0.003), which was also found after Rox deduction (p = 0.001).

In both manic and depressive episodes in BD, mitochondrial respiration might be reduced and increase after clinical remission. Further studies with larger samples will allow to confirm these results and also to identify potential mitochondrial state-dependent biomarkers.

A. Giménez-Palomo Grant / Research support from: AGP is supported by a Rio Hortega 2021 grant (CM21/00094) from the Spanish Ministry of Health financed by ISCIII and cofinanced by Fondo Social Europeo Plus (FSE+)., M. Guitart-Mampel: None Declared, A. Meseguer: None Declared, M. Valentí: None Declared, L. Bracco: None Declared, H. Andreu: None Declared, E. Vieta: None Declared, G. Garrabou: None Declared, I. Pacchiarotti: None Declared

People with severe mental illness (SMI), including schizophrenia and bipolar disorder, experience significant health inequalities and are more likely to develop long-term physical health conditions (LTCs), such as type 2 diabetes and cardiovascular disease. Many people with SMI rely on informal caregivers, typically friends and family, to support their health and enable them to live in the community. Informal caregivers of people with SMI experience high levels of caregiver burden, social isolation, and poor health outcomes. However, it is unclear how co-existing LTCs contribute to the caregiving experience.

The aim of this study was to explore the lived experience of informal caregivers of people with co-existing SMI and LTCs.

We conducted a qualitative study with informal caregivers of people with co-existing SMI and LTCs in England. We recruited 12 informal caregivers and conducted five semi-structured interviews and two focus groups between December 2018 and April 2019. The interviews and focus groups were audio recorded, transcribed verbatim and thematically analysed.

SMI impacts profoundly on the health and well-being of both service users and their informal caregivers. Service users were described as too unwell with their SMI to engage in self-management of their mental and physical health, with the primary responsibility for these tasks falling to informal caregivers. There were significant barriers to adequate physical healthcare for service users, therefore informal caregivers needed to advocate extensively for their loved ones to ensure access to services. Informal caregivers felt significantly under-supported and struggled with the caregiver burden associated with SMI and LTCs. This burden included the constant monitoring of risk, anxiety around the vulnerability of their loved one, repeated hospitalisations, physical health concerns, lack of respite services, lack of recognition of their role, the guilt associated with paternalistic care, shame and stigma, and the difficulties managing the changeable nature of SMI.

Informal caregivers of people with SMI face an additional caregiver burden resulting from co-existing LTCS. This adds substantially to their caring role, yet they do not receive the necessary support, and therefore their own health and wellbeing are negatively impacted. Improved recognition of the role of informal caregivers and additional support, including improved provision of respite services, are needed to improve the well-being of informal caregivers.

C. Carswell: None Declared, J. Brown: None Declared, D. Shiers Consultant of: DS is an expert adviser to the National Institute for Health and Care Excellence Centre for Guidelines; the views expressed are those of the authors and not those of National Institute for Health and Care Excellence., P. Coventry: None Declared, N. Siddiqi: None Declared

People with personality disorder (PD) often experience suffering, suboptimal psychiatric treatment outcomes, and early mortality due to chronic physical illness (CPI) and multimorbidity (≥2 CPI)  (CPM). Increasing research underscores the elevated prevalence of CPI and CPM in those with PD.

To compare the prevalence of CPI/CPM between the general population and those with PD and to explore the relationship between CPI/CPM and various aspects of PD.

This cross-sectional study enrolled 126 PD patients (70.6% female, mean age 41.22 years) based on the ICD-10 criteria, and 126 socio-demographically matched individuals from the general population. The participants completed the following instruments: the ICD-11 Personality Disorder Severity Scale (PDS-ICD-11), the Personality Assessment Questionnaire for ICD-11 (PAQ-11), Subjective Emptiness Scale (SES), the Reflective Functioning Questionnaire-Revised-7 (RFQ-R-7), and self-reported chronic physical illnesses questionnaire.

The mean number of CPI in patients with PD and matched controls was 2.69 (SD=2.371) and 1.02 (SD=1.702), respectively, and this difference was statistically significant. Patients with PD also suffered more often from CPM than none or one CPI, compared to matched controls. In the multivariate logistic regression analyses among the patients with PD, higher personality disorder severity, increased trait Negative Affectivity and poorer reflective functioning/mentalizing were predictive of having CPM. These relationships were independent of age, gender, education status, income level, length of psychiatric treatment, and smoking status. Subjective emptiness was not significantly predictive of having CPM.

This study highlights a higher prevalence of CPI and CPM in individuals with PD compared to the general population. Factors such as higher PD severity, increased Negative Affectivity, and poorer reflective functioning were identified as predictors of CPM. These findings underscore the necessity for integrated healthcare approaches to address the multifaceted needs of PD patients, emphasizing the importance of considering both mental and physical health in treatment strategies.

None Declared

In DSM-5 Section III, the Alternative Model for Personality disorders (AMPD), a dimensional approach for conceptualization and diagnosing complex character problems was introduced. Based on recent findings, AMPD aligns well with the theory of Young’s Schema Therapy (ST). ST seems to offer a valuable clinical framework that complements the empirically based AMPD, which is not built upon a certain theory of psychopathology.

The aim of the current study was to explore the association between early maladaptive schemas (EMSs), DSM-5 pathological personality traits and certain psychological symptoms to gain a better understanding of their relationship and highlight the connection points between AMPD and the theory of ST.

A total of 490 Hungarian participants, including 98 males, took part in the cross-sectional research, with an average age of 26.9 (SD = 9.34). All participants completed the short form of Young’s schema questionnaire (YSQ-S3), the brief form of PID-5 (PID-5 BF) and the revised version of the Derogatis Symptom Checklist (SCL-90 R).

Results of a series of hierarchical regression analyses found that all five schema domains were able to predict psychological symptoms and DSM-5 pathological personality traits at a statistically significant level. Moreover, in accordance with our data, specific EMS patterns are associated with different psychological symptoms and pathological personality traits. Ultimately, we identified two EMSs, namely Negativity/Pessimism and Insufficient Self-control, which predicted all of our dependent variables.

Our findings suggest that the relationship between EMSs and DSM-5 pathological personality traits goes beyond the established fact that EMSs, like any other indicators of personality problems are associated with psychopathological symptoms and traits. This is supported by the fact that we could link specific EMS patterns to the pathological personality traits and psychological symptoms that we investigated. We believe that our results contribute to the clinical utility of AMPD, by assisting the creation of schema profiles tailored to personality pathologies, thereby facilitate the diagnostic process and the development of schema - focused interventions. Furthermore, it seems that the identified EMSs, Negativity/Pessimism and Insufficient Self-control play a special role in relation to pathological personality traits and psychological symptoms and should be considered with particular emphasis in terms of risk group classification and vulnerability.

None Declared

Many COVID-19 survivors who were attacked and suffered severe symptoms of the virus have suffered from post-traumatic stress disorder (PTSD) which persists for long periods. These people need treatment to alleviate the severity of these disorders. Metacognitive therapy (MCT) is one of the modern therapeutic trends in psychological counseling, which focuses on the nature of the thought rather than on identifying and changing the thought as in other cognitive therapies. It is also concerned with whether people possess an aspect of reflective awareness and aims for a broader understanding of the way the mind works. Working on the process of metacognition, that is, the individual’s thinking about what he knows, being aware of his thoughts, and constantly monitoring and organizing them, helps reduce anxiety disorders and mood swings, and this will reduce psychotic disorders.

The current study aims to identify the effect of a virtual reality (VR) counseling program based on MCT in reducing the severity of PTSD among survivors of Covid-19. It also examines the continuity of the effectiveness of this program in reducing these disorders.

The quasi-experimental method (two group design) with experimental and control groups with a pre-posttest and a follow-up test was adopted. The sample for the current study consisted of 60 COVID-19 survivors suffering from PTSD. The PTSD scale was applied online to a group of people recovering from Covid-19 from the Arab Republic of Egypt. Then those who had high scores were selected, contacted and their consent was obtained to apply a virtual reality counseling program to them. The counseling program was implemented via virtual reality technology, and consisted of 20 counseling sessions, each session lasted between 60-90 minutes. The program continued for two months, with two sessions per week.

The results of the current research revealed a significant improvement in the experimental group through a significant reduction in their post-traumatic stress disorders. The results also showed the effectiveness of the counseling program based on metacognitive therapy in reducing the manifestations of post-traumatic stress disorders in those recovering from Covid-19. The results confirmed the continuing effect of the program after the follow-up period.

Using metacognitive therapy has an effective effect in reducing post-traumatic stress disorder, and it can be used with many psychologically disturbed people.

None Declared

Prolonged grief disorder has recently been added to the Diagnostic and Statistical Manual of Mental Disorders 5, Text Revision. To understand the health burden and then allocate economic and professional resources, it is necessary to provide epidemiological data for this new disorder. More information on the characteristics of people suffering from PGD is also beneficial to better identify individuals at risk.

This study, therefore, aimed to estimate the prevalence of the PGD criteria in a special period such as the Covid-19 pandemic and in a representative population-based sample, evaluate the sociodemographic, and loss-related correlates of PGD caseness and explore possible predictors.

The study included 126 people (97 females/29 males) who lost a relative for any reason during the Covid-19 pandemic period (March 2019-January 2022) in Turkey.We used self-reported data from articipants who all completed questions on socio-demographic and loss-related characteristics plus Hospital Anxiety and Depression Scale (HADS), Prolonged Grief Disorder Scale (PG-13), Multidimensional Scale of Perceived Social Support (MSPSS), Adult Separation Anxiety Questionnaire (ASA-27).

Median age was 34 years, range (18-63); 12 participants were diagnosed with PGD (9.5%). No difference was detected between deaths due to COVID-19 and its complications and deaths due to other causes in terms of PGD diagnosis and PGD symptom severity. When we divide the participants into two groups according to PGD diagnosis (PGD and nonPGD):The average age of the PGD group was higher (Z=-2.068; p=0,31) and they had more additional medical conditions (χ²=7.21; p=0,007). Thoughts of guilt were more common in the PGD group (χ²=7.92; p=0,005). Additionally, HADS-total, HADS -depression, HADS -anxiety and ASA-27 were higher in the PGD group (respectively: Z=-4.047; P=0,00, Z=-4.209; P=0,00, Z=-3.437; P=0,001, Z=-1.975; P=0,048). PGD occurred most frequently after first-degree losses (χ²=13.67; p=0,00) and was inversely proportional to the age of the loss (Z=-1.979; P=0,04). In the nonPGD group, the rate of believing in any religion (χ²=5.807; p=0,016). and the level of fulfilling the requirements of the religion were higher ( χ²=10.584; p=0,05). In the linear regression analysis examining the predictors associated with the severity of prolonged grief; the deceased person was a first-degree relative (t= 6.23; p<0,001) and younger in age (t=-3.71; p<0,001), the presence of guilt (t= 3.28; p=0,001), and increased separation anxiety (t= 4.13; p<0,001) and depression scores (t= 4.29; p<0,001) were significant boost of prolonged grief severity.

Although higher PGD rates were expected in deaths due to Covid-19 compared to deaths due to other causes, we did not detect any significant difference in this study. However, this study identified some possible predictors associated with PGD.

None Declared

Patients suffering from mental disorders tend to be less adherent to the recommended therapies. Moreover, the COVID-19 pandemic had a global impact on physical and social well-being, which turned out stronger in the most fragile patients, like those with a mental condition.

To assess whether the COVID-19 pandemic influenced the physical healthcare gap between patients with and without severe mental illness (SMI) treated for chronic conditions.

Data were retrieved from Healthcare Utilization Databases of Lombardy region (Italy). Prevalent users of antihypertensive drugs, statins or antidiabetic drugs, receiving healthcare in Lombardy during 2020, were identified. Among them, those with a previous diagnosis of schizophrenic or bipolar disorder were selected and matched with up to 3 patients without any sign of mental disorder by sex, age and number of contacts with the NHS during the previous year. 3 cohorts (not necessarily independent) were formed.

High adherence to specific recommended drug therapies and discontinuation during 2020 were evaluated.

Association between presence of SMI and high adherence was evaluated by using a log-binomial model (risk ratios, RR with 95% CI); a Cox model (hazard ratios, HR) was used for discontinuation.

As comparison, same analyses were performed to the cohorts of prevalent users in 2019, to evaluate the impact of the COVID-19 pandemic. Results were stratified according to the type of mental disorder.

36'436, 14'136 and 12'597 prevalent users of antihypertensives, statins or antidiabetics respectively were identified, of which 25% with SMI (9'109, 3'536 and 3'152 respectively).

During the pandemic period, for all the three cohorts, patients with mental illness had 10% lower probability of being adherent to the recommended drug therapies.

The association between SMI and discontinuation was significant and varied among the three cohorts, with HR (95% CI): 1.27 (1.21; 1.33) for antihypertensives users, 1.16 (1.07; 1.26) for antidiabetics users and 1.08 (1.01; 1.16) for statins users.

Compared with 2019 the gap remained similar, except for discontinuation of antidiabetics, where the gap diminished from 34% in 2019 to 16% in 2020.

No differences between the two mental disorders were found.

Results show that suffering from a mental disorder in people with chronic physical conditions affects their adherence to recommended drug therapies. During the pandemic period, the restrictive measures adopted may have led to a better care by family members, counteracting any increase in the gap.

The healthcare gap in patients suffering from mental illness remains an unsolved problem of primary importance for public health.

None Declared

High-fat diet (HFD) consumption during pregnancy can shape fetal brain development, increasing susceptibility to mental disorders. Nevertheless, the mechanisms underlying these negative outcomes remain unclear.

We hypothesize that mHFD induces inflammation and oxidative stress (OS) in the fetal brain, disrupting excitatory/inhibitory (E/I) balance in the adult brain. This results in altered hypothalamic-pituitary-adrenal (HPA) axis reactivity, emotional regulation, and cognitive function. We tested the ability of N-acetyl-cysteine (NAC) - a powerful anti-oxidant and anti-inflammatory compound - to counteract mHFD effects.

Our mHFD model consists of female C57BL/6N mice fed either HFD (fat 58%, carbohydrate 25.5%, and protein 16.4%) or control diet (CD, fat 10.5%, carbohydrate 73.1% and protein 16.4%) before and during pregnancy (13 weeks). After 5 weeks on diets, half of them received NAC (1g/kg) for 8 weeks, until delivery.

Gene expression of Il-1b, Cd68, Tmem119, iNOS, and Arg1 was measured in fetal brains. Cognitive function and emotional phenotype were assessed in adult male and female offspring through the Morris Water Maze (MWM) and the Emergence test, respectively. HPA axis functionality was assessed by measuring plasma corticosterone levels by ELISA following acute stress. Gene expression of vesicular glutamate transporter 1 (Vglut1) and vesicular GABA transporter (Vgat) were assessed as markers of E/I balance.

Exposure to mHFD induced inflammation and OS in the fetal brain of both sexes, by increasing Il-1b and iNOS/Arg1. Additionally, Cd68 and Tmem119 were specifically increased in females. In adulthood, mHFD reduced latency to emerge from the shelter in the Emergence test in both sexes. In females, mHFD impaired cognitive function, reducing time spent in the MWM target zone, and increased HPA reactivity in response to acute stress. Furthermore, mHFD decreased Vgat expression in both sexes, resulting in an imbalanced Vglut1/Vgat ratio towards excessive excitatory input. Maternal NAC supplementation rescued this imbalance.

Overall, these data show that mHFD increases inflammation and OS in fetal brains, with greater effects in female offspring, inducing alterations in the E/I neuronal balance with concomitant disruptions of the neuroendocrine system and the emotional and cognitive profiles during adulthood. The supplementation with NAC was effective in rescuing the E/I imbalance as well as the behavioral phenotype.

None Declared

With increasing urbanization, more people are exposed to mental health risk factors stemming from the urban social or physical environment. However, research on urbanization and depression is not clear.

This study aimed to explore environmental and social factors with depression symptoms in view of a network theory of mental health disorders.

The study was conducted among a representative sample of 3,296 habitants of Metropolis GZM (63% of women)– the most urbanized region in Poland. The measurements used were PHQ-9, UCLA, Neighbourhood Cohesion (Neighbourhood Belonging and Social Cohesion), REAT 2.0 (Quality of architecture in neighborhood area), distance and frequency use of green public areas, Self-Rated Health, Physical Activity, size of place of residence per person.

The prevalence of depression risk in villages (N=713), towns under 20,000 (N=219), towns (under 99,000; N=823), and cities (under 300,000; N=1541) was 44.2%, 44.7%, 39.2%, and 34.9% respectively.

The depression nodes with the highest centrality degree and expected influence were PHQ9 (suicidal thoughts), PHQ2 (feeling depressed), and neighborhood belonging. Living in a more urbanized area (UA) had a smaller centrality degree in the network. Edges between PHQ9 and environmental factors were mediated by loneliness (UCLA). Poor architectural conditions (REAT) were linked positively with neighborhood belonging and adversely with social cohesion. Living in UA was negatively related to PHQ9, PHQ5 (eating control), and PHQ2, social cohesion, and green area distance, while positively to PHQ7 (problems with being focused), poor physical health, REAT, and neighborhood belonging (Figure 1).

Living in a city is negatively related to the most central depression symptoms. Even though social cohesion is negatively linked to UA, neighborhood belonging is higher in more urbanized areas.

The balance between detrimental environmental factors and those that protect mental health requires a better understanding of the interaction between urban living and depression.

None Declared

Major depressive disorder (MDD) is a prevalent and disabling condition. Approximately 30-50% of patients do not respond to first-line medication or psychotherapy. Therefore, several studies have investigated the predictive potential of pretreatment severity rating or neuroimaging features to guide clinical approaches that can speed optimal treatment selection.

To evaluate the performance of 1) severity ratings (scores of Hamilton Depression/Anxiety Scale, illness duration, and sleep quality, etc.) and demographic characteristic and 2) brain magnetic resonance imaging (MRI) features in predicting treatment outcomes for MDD. Second, to assess performance variations among varied modalities and interventions in MRI studies.

We searched studies in PubMed, Embase, Web of Science, and Science Direct databases before March 22, 2023. We extracted a confusion matrix for prediction in each study. Separate meta-analyses were performed for clinical and MRI studies. The logarithm of diagnostic odds ratio [log(DOR)], sensitivity, and specificity were conducted using Reitsma’s random effect model. The area under curve (AUC) of summary receiver operating characteristic (SROC) curve was calculated.

Subgroup analyses were conducted in MRI studies based on modalities: resting-state functional MRI (rsfMRI), task-based fMRI (tbfMRI), and structural MRI (sMRI), and interventions: antidepressant (including selective serotonin reuptake inhibitors [SSRI]) and electroconvulsive therapy (ECT). Meta-regression was conducted 1) between clinical and MRI studies and 2) among modality or intervention subgroups in MRI studies.

We included ten studies used clinical features covering 6494 patients, yielded a log(DOR) of 1.42, AUC of 0.71, sensitivity of 0.61, and specificity of 0.74. In terms of MRI, 44 studies with 2623 patients were included, revealing an overall log(DOR) of 2.53. The AUC, sensitivity, and specificity were 0.89, 0.78, and 0.75.

Studies using MRI features had a higher sensitivity (0.89 vs. 0.61) in predicting treatment outcomes than clinical features (P < 0.001). RsfMRI had higher specificity (0.79 vs. 0.69) than tbfMRI subgroup (P = 0.01). No significant differences were found between sMRI and other modalities, nor between antidepressants (SSRIs and others) and ECT. Antidepressant studies primarily identified predictive imaging features in limbic and default mode networks, while ECT mainly focused on limbic network.

Our findings suggest a robust promise for pretreatment brain MRI features in predicting treatment outcomes in MDD, offering higher accuracy than clinical studies. While tasks in tbfMRI studies differed, those studies overall had less predictive utility than rsfMRI data. For MRI studies, overlapping but distinct network level measures predicted outcomes for antidepressants and ECT.

None Declared

Current ketamine-based therapies for treatment-resistant depression (TRD) often induce dissociative effects. A novel oral PR ketamine formulation (KET01) results in a low and delayed peak concentration of ketamine, high hydroxynorketamine concentration, and is associated with limited dissociative properties.

To investigate efficacy, safety, and pharmacokinetics of KET01 in TRD.

KET01-02 was a randomized, double-blind phase 2 trial in outpatients with TRD comparing adjunct 120 mg (n=42) or 240 mg (n=40) oral KET01 once-daily for 3 weeks to placebo (PBO, n=40). The primary endpoint was change from baseline in the MADRS mean score on Day 21. KET01-03 was a randomized, double-blind, cross-over phase I trial in 26 healthy volunteers comparing single doses of 240 mg oral KET01 and 84 mg an approved intranasal formulation of eketamine. The primary endpoint was maximum change of Clinician-Administered Dissociative States Scale (CADSS) score from baseline.

KET01-03 trial; the mean (±SD) maximum change of CADSS score within 24 hours after dosing was 29.6±12.5 for intranasal eketamine and 0.7±1.7 for KET01 (p<0.00000000001). KET01-02 trial; no differences in CADSS score (range: 0.2 to 1.3), and heart rate and blood pressure were observed between the groups on Day 1 and beyond. 10%, 12%, and 15% of patients in the PBO, 120 mg/day, and 240 mg/day KET01 groups, respectively had CADSS score >4 and increase from baseline. At 7 hours post first KET01 dose (240 mg), plasma concentration of ketamine (38.7±27.0 ng/ml) was lower than its metabolites norketamine (267.5±81.6 ng/ml) and hydroxynorketamine (190.2±85.5 ng/ml). 240 mg/day KET01 induced clinically relevant reduction from baseline in MADRS score already within the first 7 hours of treatment (-7.65; Δ vs PBO: -2.22, n.s.), with a statistically significant separation on Day 4 (-10.02; Δ vs PBO: -3.66, p=0.020) and Day 7 (-12.21; Δ vs PBO: -3.95, p=0.042). MADRS score decrease was sustained throughout Day 21 (-13.15; Δ vs PBO: -1.82, n.s.), and during 4-week follow-up (-12.51; Δ vs PBO: -3.35, n.s.). Treatment-emergent adverse events occurred in 47.5%, 50.0%, and 62.5% of patients in the PBO, 120 mg/day, and 240 mg/day KET01 group, respectively.

Oral 240 mg/day KET01 induces a rapid, and clinically relevant reduction of depressive symptoms with only minimal signs of dissociation, potentially due to lower ketamine levels and increased norketamine and hydroxynorketamine levels compared to intravenous administration. Our results suggest that KET01 may be an efficacious and safe take-at-home adjunct treatment for TRD.

C. zu Eulenburg Employee of: HMNC Brain Health, E. Papanastasiou Employee of: HMNC Brain Health, K. Schmid Employee of: Develco Pharma, A. Damyanova Employee of: HMNC Brain Health, A. Glas Employee of: HMNC Brain Health, C. Strote Employee of: HMNC Brain Health, L. Arvastson Employee of: HMNC Brain Health, H. Eriksson Employee of: HMNC Brain Health

Cognitive Behavioral Therapy (CBT) and Acceptance and Commitment Therapy (ACT) seem be similarly effective for the treatment of major depressive disorder (MDD). However, much remains unknown about the differences in underlying psychological mechanisms of change. Assessing dynamic change of depressive symptoms and treatment-specific psychological constructs over time may yield important insights.

The current study will be the first to compare dynamic symptom networks in randomized groups of two psychotherapies by using dynamic time-warp (DTW) analyses.

We reanalyzed data from a randomized controlled trail of 82 patients suffering from MDD. Three depressive symptom subscales (mood, sleep, appetite/weight) and three treatment-related constructs (dysfunctional attitudes, decentering, and experiential avoidance) were collected at 7 time-points before, during, after treatment, and at up to 12 months follow-up. The DTW-analysis modeled the temporal dynamics of depressive symptoms and treatment-related constructs within each individual after which the findings were aggregated on the group-level. Undirected and directed networks were constructed, of which the latter yielded in- and out-strength for each node, that were compared between treatment arms.

Networks based on symptom and construct dynamics markedly differed between treatment arms. Within the CBT-arm a decrease of experiential avoidance was related to a decrease in dysfunctional attitudes (d = 0.059, p = 0.008). Within the ACT-arm a decrease of mood symptoms was related to a decrease of experiential avoidance (d = 0.051, p = 0.04) and an increase of decentering was related to a decrease in sleep symptoms (d = 0.038, p = 0.02) and appetite/weight symptoms (d = 0.049, p = 0.03).

DTW offers a promising alternative approach to study and compare working mechanisms of different treatment interventions. Comparing CBT and ACT revealed a decrease in experiential avoidance within CBT and an increase in the ability to decenter within ACT. However, within both treatments a change in other constructs, suggesting that a first alleviation of mood symptoms is important to activate underlying psychological change.

None Declared

Major depressive disorder (MDD) is a tremendous global disease burden and the leading cause of disability worldwide. Unfortunately, individuals diagnosed with MDD typically experience a delayed response to traditional antidepressants and many do not adequately respond to pharmacotherapy, even after multiple trials. The critical need for novel antidepressant treatments has led to a recent resurgence in the clinical application of psychedelics, and intravenous ketamine, which has been investigated as a rapid-acting treatment for treatment resistant depression (TRD) as well acute suicidal ideation and behavior. However, variations in the type and quality of experimental design as well as a range of treatment outcomes in clinical trials of ketamine make interpretation of this large body of literature challenging.

This umbrella review aims to advance our understanding of the effectiveness of intravenous ketamine as a pharmacotherapy for TRD by providing a systematic, quantitative, large-scale synthesis of the empirical literature.

We performed a comprehensive PubMed search for peer-reviewed meta-analyses of primary studies of intravenous ketamine used in the treatment of TRD. Meta-analysis and primary studies were then screened by two independent coding teams according to pre-established inclusion criteria as well as PRISMA and METRICS guidelines. We then employed metaumbrella, a statistical package developed in R, to perform effect size calculations and conversions as well as statistical tests.

In a large-scale analysis of 1,182 participants across 51 primary studies, repeated-dose administration of intravenous ketamine demonstrated statistically significant effects (p<0.05) compared to placebo-controlled as well as other experimental conditions in patients with TRD, as measured by standardized clinician-administered and self-report depression symptom severity scales.

This study provides large-scale, quantitative support for the effectiveness of intravenous, repeated-dose ketamine as a therapy for TRD and a report of the relative effectiveness of several treatment parameters across a large and rapidly growing literature. Future investigations should use similar analytic tools to examine evidence-stratified conditions and the comparative effectiveness of other routes of administration and treatment schedules as well as the moderating influence of other clinical and demographic variables on the effectiveness of ketamine on TRD and suicidal ideation and behavior.

None Declared

Despite its apparent efficacy in the treatment of a range of psychiatric disorders, electroconvulsive therapy (ECT) is viewed by some as a contentious treatment. Although most clinicians and researchers consider ECT a safe and effective treatment, there are ongoing and significantly publicised concerns about potential side effects.

To explore use of ECT across Scotland in a large naturalistic clinical sample across an 11-year period from 2009 to 2019. To consider the efficacy and side effects of ECT for a range of common psychiatric disorders including, depression, bipolar depression, schizophrenia, and mania.

Using data from the Scottish Electroconvulsive Therapy (ECT) Accreditation Network (SEAN), information was collected for all adults who had received ECT. Variables included age, sex, Scottish Index of Multiple Deprivation (SIMD) quintile, International Classification of Diseases, Tenth Edition (ICD-10) diagnosis, indication for ECT, Mental Health Act status, consent status, entry and exit Montgomery-Asberg Depression Rating Scores (MADRS), entry and exit Clinical Global Index Severity CGI-S) scores and reported side effects. Side effects were recorded as present if the side effect was reported at any point during the episode of treatment.

4826 ECT episodes were recorded. The majority of episodes were in women (68.4%, n=3,301). Average age at treatment onset was 58.52 years. Males were slightly younger (m=58.24 years vs f= 58.65 years, p= 0.20). Mean number of treatments/episode was 9.59 (95% CI 9.32 – 9.85). Mean treatment dose delivered was 277.75mC (95%CI 272.88 – 282.63mC).

2920 episodes of treatment had CGI-S entry and exit recorded. At entry, mean CGI-S indicated marked illness (5.03 95% CI 4.99-5.07). Recipients with schizophrenia had the highest CGI-S score (5.45 95% CI 5.21-5.60), followed by those with post-partum disorders (5.38, 95% CI 4.61-6.14). At exit, mean CGI scores indicated borderline illness (2.07, 95% CI 2.03-2.11), recipients diagnosed with mixed affective state had the lowest CGI-S score (1.72, 95% CI 0.99-2.47) followed by those with schizoaffective disorder (2.01, 95% CI 1.76-2.42).

Anaesthetic complications (n=34) and prolonged seizures (n=38) were rare, occurring in <1% of treatment episodes. Cardiovascular complications were reported in 2.2% (n= 102). Nausea was reported in 7.2% (n= 334) and muscle aches in 12% (n=560). Confusion was reported in 19% (n=879) and cognitive side effects were reported in 26.2% (n=1212). One third of treatment episodes reported confusion or cognitive side effects (33.1%, n=1545).

From this large naturalistic clinical sample, ECT appears to be effective in improving illness severity as measured by CGI-S score. While some side effects (such as prolonged seizures and cardiovascular complications) were rare, others (such as confusion or cognitive side effects) were relatively common.

None Declared

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.

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.

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.

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

Iclepertin may represent the first efficacious medication for cognitive impairment associated with schizophrenia.

Boehringer Ingelheim

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

Evidence from observational and genetic studies suggests a bidirectional relationship between loneliness and psychosis. To our knowledge, no previous study has assessed the association between loneliness in childhood and first-episode psychosis (FEP).

We aimed to assess the association between loneliness in childhood and the odds of FEP and clinical variables of interest (i.e., diagnosis and clinical and functional severity) in FEP and to explore gender differences in this association.

This was an observational, case-control study, based on the AGES-CM cohort, a longitudinal prospective study including patients with FEP ages 7-40, their first-degree relatives, and an age- and sex-matched sample of controls in seven university hospitals in the region of Madrid. We assessed loneliness in childhood with the question “Have you ever felt lonely for more than 6 months before the age of 12” and objetive social isolation with the peer relationships item from the childhood subscale of the Premorbid Adjustment Scale. We conducted logistic and linear regression analyses to assess the association between childhood loneliness and i) the odds of presenting a FEP and ii) clinical variables of interest (diagnosis and scores on positive, negative, general, depressive, and manic symptoms and functioning), while adjusting for demographic variables.

The study sample comprised 285 patients with FEP (32.6% female, age 24.50 ± 6.2 years) and 546 controls (48.7% female, age 25.93 ± 5.5 years). Loneliness in childhood was associated with increased odds of FEP (adjusted odds ratio; aOR: 2.17, 95% CI [1.40-3.51], p=.002). This association remained significant after controlling for objective social isolation in childhood (aOR:2.70, IC 95% [1.58-4.62], p<.001).

The effect of the association was stronger in females (aOR:4.74, 95% CI [2.23-10.05], p<.001) than in males (aOR:1.17, IC 95% [0.63-2.19], p=.623). In females with FEP, loneliness in childhood was significantly associated with increased odds of receiving a diagnosis of other psychosis (aOR:0.155, 95% CI [0.048-0.506], p=.002) relative to an SSD diagnosis. In the FEP sample, loneliness in childhood was associated with greater severity of positive and affective symptoms and worse functioning.

Loneliness in childhood is associated with increased odds of FEP and clinical variables of interest. This suggests the potential role of this phenotype as an early risk marker for psychosis that could help guide targeted interventions.

C. Díaz-Caneja Grant / Research support from: Instituto de Salud Carlos III (PI17/00481, PI20/00721, JR19/00024), European Union, Consultant of: Angelini, L. Donaire: None Declared, V. Cavone: None Declared, Á. Andreu-Bernabeu: None Declared, J. González-Peñas: None Declared, M. Díaz-Marsá: None Declared, R. Rodríguez-Jiménez: None Declared, Á. Ibáñez: None Declared, E. Baca-García: None Declared, J. C. Leza: None Declared, M. F. Bravo-Ortiz: None Declared, J. L. Ayuso-Mateos: None Declared, C. Arango Grant / Research support from: Madrid Regional Government (R&D activities in Biomedicine S2022/BMD-7216 AGES 3-CM), Instituto de Salud Carlos III, European Union, Consultant of: Acadia, Angelini, Biogen, Boehringer, Gedeon Richter, Janssen Cilag, Lundbeck, Medscape, Menarini, Minerva, Otsuka, Pfizer, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda

Verbal fluency, a cognitive function that reflects executive functions and the rapid retrieval of pertinent information from memory, has yielded inconsistent findings in previous research on autism spectrum disorder (ASD), however in schizophrenia (SCH) semantic fluency exhibits a more pronounced impairment compared to letter fluency.

In this study we aim to comprehensively investigate verbal fluency in ASD, SCH, and neurotypical healthy control individuals (NTP). The primary objective is to investigate disparities in novel response generation, specifically between the ASD, SCH and NTP groups, using phonemic and semantic fluency tasks. Three central inquiries guide our research: (1) whether differences between groups (ASD, SCH, and NTP) can be identified in word productivity, clustering, errors, and perseverations; (2) whether participants with ASD and SCH exhibit different word production with elevated imageability and concreteness values; and (3) if individuals with ASD and schizophrenia demonstrate reduced productivity during the earlier phases of fluency tasks.

Forty participants with ASD (12 female, 24 male, 4 other, mean age: 30.5), 39 with SCH (10 female, 28 male, 1 other, mean age: 34.7) and 41 NTP (13 female, 28 male, mean age: 31.0) were recruited from the outpatient units of the Department of Psychiatry and Psychotherapy, Semmelweis University. Participants were requested to list as many words as they could on two phonemic and two semantic category conditions. Audio recordings were later transcribed. To assess concreteness and imageability, we employed a seven-point scale and recruited independent external raters to evaluate a total of 1481 words.

Preliminary results indicate that the three study groups did not differ significantly in phonemic fluency (F(2, 119)= 0.983, p=0.377), during either time period. However, a significant difference was observed in semantic fluency (F(2, 119)= 6.531, p=0.002). Post-hoc tests (Tukey corrected) revealed that this difference stemmed from impaired performance in the SCH group. Participants with schizophrenia (SCH) exhibited reduced semantic word productivity compared to both neurotypical (NTP) individuals and participants with ASD (Figure 1). However, there were no significant differences between participants with ASD and NTP individuals.

Image:

In conclusion, our study investigated the characteristics of verbal fluency in a transdiagnostic approach. While phonemic fluency did not reveal significant differences among the three groups, our analysis of semantic fluency unveiled a distinction. Specifically, individuals with schizophrenia exhibited impaired semantic word productivity. Our study highlights the complex nature of verbal fluency impairments in different conditions and the importance of considering more nuanced methods when assessing cognitive functions.

None Declared

Schizophrenia is a major mental disorder with a high risk of suicide, which is one of the leading causes of early death in schizophrenia patients. It is known that suicidal behavior is 20-50 times higher in schizophrenia patients compared to the general population. Clinical features makes it difficult to determine the risk of suicide in this patient group. Since genetic studies on suicides of patients with schizophrenia are limited, this area was deemed worthy of research.

CircRNAs can potentially serve as minimally invasive biomarkers because they can freely cross the blood-brain barrier. It is aimed to define the effect of circRNA molecules on suicidal behavior in patients diagnosed with schizophrenia and other schizophrenia spectrum psychotic disorders, and to increase protective and preventive approaches by predicting possible consequences of suicidal behavior.

104 patients followed up with the diagnosis of schizophrenia and and other schizophrenia spectrum psychotic disorders were included in the study. RNA was isolated from the blood taken into a hemogram tube, and three cirRNA molecules were identified using a number of RNA sequencing techniques. In addition, sociodemographic characteristics of the participants, clinical features of the disease, suicidal behavior history, current treatment status were questioned in detail. Simultaneously, the current clinical status was evaluated with clinical evaluation scales as Positive and Negative Syndrome Scale (PANSS), Calgary depression scale for schizophrenia (CDSS), Suicide Probability Scale (SPS), Beck Suicidal Intend Scale (BSIS).

Three circRNA molecules were identified, chr3_196488683, chr5_69175537 and hsa_circ_0084021. No significant difference was found between these molecules and past suicide attempts. It was found that chr5_69175537 was negatively associated with the age of onset of psychotic disorder negative symptoms, and hsa_circ_0084021 was negatively associated with the age of onset of both negative and positive symptoms. When the relationship between the clinical assessment scales and suicidal behavior was evaluated, the PANSS general symptoms subscale score was significantly higher in the group with suicidal behavior (p<0.05). CDSS mean scores and BSIS scores were also found to be significantly higher in the group with previous suicide attempts (p<0.01).

Although our findings do not allow definitive conclusions due to the complex interaction between epidemiological and clinical factors and limited literature, it has shown that schizophrenia contains many risks that increase suicidal behavior. To predict suicide, circRNA molecules need to be supported by prospective studies with large sample groups and comparison with control groups.

None Declared