Although atypical antipsychotics have lowered the prevalence and severity of extrapyramidal symptoms (EPS), they still contribute to the overall side-effect burden of approved antipsychotics. Drugs with novel mechanisms without D2 dopamine receptor blocking activity have shown promise in treating schizophrenia without the side effects of currently available treatments. KarXT (xanomeline–trospium chloride) represents a possible alternative that targets muscarinic receptors. KarXT demonstrated efficacy compared with placebo in 3 out of 3 short-term acute studies and has not been associated with many of the side effects of D2 dopamine receptor antagonists. Here, we further characterize EPS rates with KarXT in these trials.

EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) were 5-week, randomized, double-blind, placebo-controlled, inpatient trials in people with schizophrenia experiencing acute psychosis. Data from the safety populations, defined as all participants who received ³1 dose of trial medication, were pooled. For this analysis, we used a broader definition of EPS-related adverse events (AEs) to encompass any new onset of dystonia, dyskinesia, akathisia, or extrapyramidal disorder reported any time after the first dose of medication. Additionally, EPS were assessed by examining change from baseline to week 5 on the Simpson-Angus Scale (SAS), Barnes Akathisia Rating Scale (BARS), and Abnormal Involuntary Movement Scale (AIMS).

A total of 683 participants (KarXT, n=340; placebo, n=343) were included in the analyses. The rate of treatment-emergent AEs (TEAEs) associated with EPS was 3.2% in the KarXT group vs 0.9% in the placebo group. The most commonly reported TEAE was akathisia (KarXT, 2.4%; placebo 0.9%); half of possible akathisia cases in the KarXT group (4/8 TEAEs) were from a single US site, considered by the investigator to be unrelated to trial drug, and resolved without treatment. Overall rates of akathisia TEAEs deemed related to trial drug were low (KarXT, 0.6%; placebo 0.3%). Dystonia, dyskinesia, and extrapyramidal disorder TEAEs were reported by only a single subject each (0.3%) in the KarXT arm. All reported TEAEs were mild to moderate in severity. KarXT was associated with no clinically meaningful mean±SD changes from baseline to week 5 on the SAS (-0.1±0.6), BARS (-0.1±0.9), or AIMS (0.0±0.7).

The incidence of EPS-related TEAEs with KarXT was low in comparison to those observed in similar trials of antipsychotics (D2 dopamine receptor antagonists), although head-to-head studies have not been completed. Moreover, KarXT was not associated with increased scores on EPS scales (SAS, BARS, AIMS) across 5 weeks of treatment. These results, combined with the robust efficacy of KarXT in trials to date, suggest that KarXT’s novel mechanism of action may provide therapeutic benefit in the absence of EPS frequently associated with currently available antipsychotics.

Karuna Therapeutics

In prior studies, the dual M1/M4 preferring muscarinic receptor agonist xanomeline demonstrated antipsychotic activity in people with schizophrenia and Alzheimer’s disease, but its further clinical development was limited primarily by gastrointestinal side effects. KarXT combines xanomeline and the peripherally restricted muscarinic receptor antagonist trospium chloride. KarXT is designed to preserve xanomeline’s beneficial central nervous system effects while mitigating adverse events (AEs) due to peripheral muscarinic receptor activation. The efficacy and safety of KarXT in schizophrenia was demonstrated in the 5-week, randomized, double-blind, placebo-controlled EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) trials.

The EMERGENT trials enrolled people with a recent worsening of positive symptoms warranting hospitalization, Positive and Negative Syndrome Scale total score ≥80, and Clinical Global Impression–Severity score ≥4. Eligible participants were randomized 1:1 to KarXT or placebo. KarXT dosing (xanomeline/trospium) started at 50 mg/20 mg twice daily (BID) and increased to a maximum of 125 mg/30 mg BID. Safety was assessed by monitoring for spontaneous AEs after administration of the first dose of trial drug until the time of discharge on day 35. Data from the EMERGENT trials were pooled, and all safety analyses were conducted in the safety population, defined as all participants who received ≥1 dose of trial drug.

A total of 683 participants (KarXT, n=340; placebo, n=343) were included in the pooled safety analyses. Across the EMERGENT trials, 51.8% of people in the KarXT group compared with 29.4% in the placebo group reported ≥1 treatment-related AE. The most common treatment-relatedAEs occurring in ≥5% of participants receiving KarXT and at a rate at least twice that observed in the placebo group were nausea (17.1% vs 3.2%), constipation (15.0% vs 5.2%), dyspepsia (11.5% vs 2.3%), vomiting (10.9% vs 0.9%), and dry mouth (5.0% vs 1.5%). The most common treatment-related AEs in the KarXT group were all mild or moderate in severity.

In pooled analyses from the EMERGENT trials, KarXT was generally well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the efficacy results showing a clinically meaningful reduction in the symptoms of schizophrenia, support the potential of KarXT to be the first in a new class of antipsychotic medications based on muscarinic receptor agonism and a well-tolerated alternative to currently available antipsychotics.

Karuna Therapeutics

This study aimed to understand the current landscape of USA-based disaster medicine (DM) programs through the lens of alumni and program directors (PDs). The data obtained from this study will provide valuable information to future learners as they ponder careers in disaster medicine and allow PDs to refine curricular offerings.

Two separate surveys were sent to USA-based DM program directors and alumni. The surveys gathered information regarding current training characteristics, career trajectories, and the outlook of DM training.

The study had a 57% response rate among PDs, and 42% response rate from alumni. Most programs are 1-year and accept 1-2 fellows per class. More than 60% of the programs offer additional advanced degrees. Half of the respondents accept international medical graduates (IMGs). Only 25% accept non-MD/DO/MBBs trained applicants. Most of the alumni hold academic and governmental positions post-training. Furthermore, many alumni report that fellowship training offered an advantage in the job market and allowed them to expand their clinical practice.

The field of disaster medicine is continuously evolving owing to the increased recognition of the important roles DM specialists play in healthcare. The fellowship training programs are experiencing a similar evolution with an increasing trend toward standardization. Furthermore, graduates from these programs see their training as a worthwhile investment in career opportunities.

This study analyzes disparities in initial health care responses in Turkey and Syria following the 2023 earthquakes.

Using Humanitarian Data Exchange, Crude Mortality Rates (CMR) and injury rates in both countries were calculated, and temporal trends of death tolls and injuries in the first month post- catastrophe were compared. World Health Organization (WHO) Flash Appeal estimated funding requirements, and ratios of humanitarian aid personnel in Urban Search and Rescue (USAR) teams per population from ReliefWeb and MAPACTION data were used to gauge disparities.

56 051 096 individuals were exposed, with Turkey having 44 million vs 12 million in Syria. Turkey had higher CMR in affected areas (10.5 vs. 5.0 per 10,000), while Syria had higher CMR in intensely seismic regions (9.3 vs. 7.7 per 1,000). Turkey had higher injury rates (24.6 vs. 9.9 per 10 000). Death and injury rates plateaued in Syria after 3 days, but steadily rose in Turkey. Syria allocated more funding for all priorities per population except health care facilities’ rehabilitation. Turkey had 219 USAR teams compared to Syria’s 6, with significantly more humanitarian aid personnel (23 vs. 2/100,000).

Significant disparities in the initial health care response were observed between Turkey and Syria, highlighting the need for policymakers to enhance response capabilities in conflict-affected events to reduce the impact on affected populations.

The 2023 Turkish-Syrian earthquakes, the most devastating in the region since 1939, heightened challenges in Syria’s health care system amid ongoing conflict, disrupting Gaziantep’s humanitarian aid supply route. The initial health care responses post-earthquakes in Turkey and Syria were analyzed through a descriptive study, where Crude Mortality Rates (CMR) and injury rates during the first week were calculated. The World Health Organization’s funding priorities and the ratio of humanitarian aid personnel in Urban Search and Rescue teams per population were assessed. Turkey had 4-fold higher earthquake exposure and experienced higher CMR and injuries per population, while Syria had higher CMR in intensely seismic regions. Temporal trends showed plateaued death and injury rates in Syria within 3 days, while Turkey’s continued to increase. Syria required more funding across nearly all priorities while Turkey had more humanitarian aid personnel per population. Significant health care response disparities were observed, emphasizing the imperative for policymakers to enhance initial responses in conflict-affected events.

Educational attainment (EduA) is correlated with life outcomes, and EduA itself is influenced by both cognitive and non-cognitive factors. A recent study performed a ‘genome-wide association study (GWAS) by subtraction,’ subtracting genetic effects for cognitive performance from an educational attainment GWAS to create orthogonal ‘cognitive’ and ‘non-cognitive’ factors. These cognitive and non-cognitive factors showed associations with behavioral health outcomes in adults; however, whether these correlations are present during childhood is unclear.

Using data from up to 5517 youth (ages 9–11) of European ancestry from the ongoing Adolescent Brain Cognitive DevelopmentSM Study, we examined associations between polygenic scores (PGS) for cognitive and non-cognitive factors and cognition, risk tolerance, decision-making & personality, substance initiation, psychopathology, and brain structure (e.g. volume, fractional anisotropy [FA]). Within-sibling analyses estimated whether observed genetic associations may be consistent with direct genetic effects.

Both PGSs were associated with greater cognition and lower impulsivity, drive, and severity of psychotic-like experiences. The cognitive PGS was also associated with greater risk tolerance, increased odds of choosing delayed reward, and decreased likelihood of ADHD and bipolar disorder; the non-cognitive PGS was associated with lack of perseverance and reward responsiveness. Cognitive PGS were more strongly associated with larger regional cortical volumes; non-cognitive PGS were more strongly associated with higher FA. All associations were characterized by small effects.

While the small sizes of these associations suggest that they are not effective for prediction within individuals, cognitive and non-cognitive PGS show unique associations with phenotypes in childhood at the population level.

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

Panic disorder (PD) and agoraphobia (AG) are highly comorbid anxiety disorders with an increasing prevalence that have a significant clinical and public health impact but are not adequately recognized and treated. Although the current functional neuroimaging literature has documented a range of neural abnormalities in these disorders, primary studies are often not sufficiently powered and their findings have been inconsistent.

This meta-analysis aims to advance our understanding of the neural underpinnings of PD and AG by identifying the most robust patterns of differential neural activation that differentiate individuals diagnosed with one of or both these disorders from age-matched healthy controls.

We conducted a comprehensive literature search in the PubMed database for all peer-reviewed, whole-brain, task-based functional magnetic resonance imaging (fMRI) activation studies that compared adults diagnosed with PD and/or AG with age-matched healthy controls. Each of these articles was screened by two independent coding teams using formal inclusion criteria and according to current PRISMA guidelines. We then performed a voxelwise, whole-brain, meta-analytic comparison of PD/AG participants with age-matched healthy controls using multilevel kernel density analysis (MKDA) with ensemble thresholding (p<0.05-0.0001) to minimize cluster size detection bias and 10,000 Monte Carlo simulations to correct for multiple comparisons.

With data from 34 primary studies and a substantial sample size (N=2138), PD/AG participants, relative to age-matched healthy controls, exhibited a reliable pattern of statistically significant, (p<.05-0.0001; FWE-corrected) abnormal neural activation in multiple brain regions of the cerebral cortex and basal ganglia across a variety of experimental tasks.

In this meta-analysis we found robust patterns of differential neural activation in participants diagnosed with PD/AG relative to age-matched healthy controls. These findings advance our understanding of the neural underpinnings of PD and AG and inform the development of brain-based clinical interventions such as non-invasive brain stimulation (NIBS) and treatment prediction and matching algorithms. Future studies should also investigate the neural similarities and differences between PD and AG to increase our understanding of possible differences in their etiology, diagnosis, and treatment.

None Declared

There has been rapidly growing interest in understanding the pharmaceutical and clinical properties of psychedelic and dissociative drugs, with a particular focus on ketamine. This compound, long known for its anesthetic and dissociative properties, has garnered attention due to its potential to rapidly alleviate symptoms of depression, especially in individuals with treatment-resistant depression (TRD) or acute suicidal ideation or behavior. However, while ketamine’s psychopharmacological effects are increasingly well-documented, the specific patterns of its neural impact remain a subject of exploration and basic questions remain about its effects on functional activation in both clinical and healthy populations.

This meta-analysis seeks to contribute to the evolving landscape of neuroscience research on dissociative drugs such as ketamine by comprehensively examining the effects of acute ketamine administration on neural activation, as measured by functional magnetic resonance imaging (fMRI), in healthy participants.

We conducted a meta-analysis of existing fMRI activation studies of ketamine using multilevel kernel density analysis (MKDA). Following a comprehensive PubMed search, we quantitatively synthesized all published primary fMRI whole-brain activation studies of the effects of ketamine in healthy subjects with no overlapping samples (N=18). This approach also incorporated ensemble thresholding (α=0.05-0.0001) to minimize cluster-size detection bias and Monte Carlo simulations to correct for multiple comparisons.

Our meta-analysis revealed statistically significant (p<0.05-0.0001; FWE-corrected) alterations in neural activation in multiple cortical and subcortical regions following the administration of ketamine to healthy participants (N=306).

These results offer valuable insights into the functional neuroanatomical effects caused by acute ketamine administration. These findings may also inform development of therapeutic applications of ketamine for various psychiatric and neurological conditions. Future studies should investigate the neural effects of ketamine administration, including both short-term and long-term effects, in clinical populations and their relation to clinical and functional improvements.

None Declared

Psychotic disorders are serious mental illnesses that require long-term antipsychotic treatment that provides sufficient efficacy, safety and therapeutic adherence. The latter is an essential factor that must be emphasized in clinical practice in order to avoid relapses. On this occasion, we have the need to know the long-term impact on our clinical practice and on the evolution of patients after the change in formulation of paliperidone palmitate 1 (PP1M) and 3 Month long-acting injectable antipsychotic (PP3M) to paliperidone palmitate 6 Month (PP6M).

The present study describes a sample of patients with severe mental disorders (n= 100) treated with six-monthly paliperidone palmitate (PP6M) studying the diagnoses, socio-demographic characteristics, number of relapses, tolerability and treatment adherence of patients.

Prospective descriptive study with a sample selected by non-probabilistic consecutive sampling, retrospective type, in a time interval of 15 month (n= 100 outpatients). The patients selected were all those who received 6 monthly paliperidone palmitate treatment from May 2022 to September 2023. A descriptive analysis was performed. Mean and standard deviation were calculated for quantitative variables and N and percentage for categorical variables.

Prospective study with consecutive sampling of 100 outpatients (62% men, 38% women; mean age 48 years) diagnosed with psychosis (76 % Schizophrenia, 21 % Unspecified psychosis, 3 % Delusional disorder) those who are administered PP6M long-acting injectable antipsychotic previously treated with PP1M (35%) and PP3M (65%).

After 15 months of the study, 4 patients (4%) have suffered a relapse, one of them (1%) requiring hospitalization. 5 patients (4%) declined to continue PP6M and have returned to their previous injectable. 1 patient (1%) has died of unknown causes outside the treatment. 90 patients continue treatment with PP6M (90% retention rate). 54 patients maintain antipsychotic monotherapy (54%). No additional adverse effects were reported after switching to PP6M. The subjective perception of satisfaction after the switch to PP6M by patients and caregivers was very high.

The present real clinical practice study shows that PP6M could be an effective and well tolerated treatment in patients with severe mental disorder, for patients diagnosed with psychosis, with a high rate of relapse prevention and high rates of compliance. Changing treatment from PP1M or PP3M to PP6M could help patients with severe mental disorder to normalize their lives and functionality.

None Declared