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

Prior studies demonstrated the antipsychotic activity of the dual M1/M4 preferring muscarinic receptor agonist xanomeline 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 side effects due to peripheral muscarinic receptor activation. The efficacy and safety of KarXT in schizophrenia were demonstrated in the 5-week, randomized, double-blind, placebo-controlled EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) trials.

The EMERGENT trials randomized people with a recent worsening of positive symptoms warranting hospitalization, Positive and Negative Syndrome Scale (PANSS) total score ≥80, and Clinical Global Impression–Severity (CGI-S) score ≥4. KarXT dosing (xanomeline/trospium) started at 50 mg/20 mg twice daily (BID) and increased to a maximum of 125 mg/30 mg BID. In each trial, the primary efficacy endpoint was change from baseline to week 5 in PANSS total score. Other efficacy measures included change from baseline to week 5 in PANSS positive subscale, PANSS negative subscale, PANSS Marder negative factor, and CGI-S scores. Data from the EMERGENT trials were pooled, and efficacy analyses were conducted in the modified intent-to-treat population, defined as all randomized participants who received ≥1 trial drug dose and had a baseline and ≥1 postbaseline PANSS assessment.

The pooled analyses included 640 participants (KarXT, n=314; placebo, n=326). Across trials, KarXT was associated with a significantly greater reduction in PANSS total score at week 5 compared with placebo (KarXT, -19.4; placebo, -9.6 [least squares mean (LSM) difference, -9.9; 95% CI, -12.4 to -7.3; P<0.0001; Cohen’s d, 0.65]). At week 5, KarXT was also associated with a significantly greater reduction than placebo in PANSS positive subscale (KarXT, -6.3; placebo, -3.1 [LSM difference, -3.2; 95% CI, -4.1 to -2.4; P<0.0001; Cohen’s d, 0.67]), PANSS negative subscale (KarXT, -3.0; placebo, -1.3 [LSM difference, -1.7; 95% CI, -2.4 to -1.0; P<0.0001; Cohen’s d, 0.40]), PANSS Marder negative factor (KarXT, -3.8; placebo, -1.8 [LSM difference, -2.0; 95% CI, -2.8 to -1.2; P<0.0001; Cohen’s d, 0.42]), and CGI-S scores (KarXT, -1.1; placebo, -0.5 [LSM difference, -0.6; 95% CI, -0.8 to -0.4; P<0.0001; Cohen’s d, 0.63]).

In pooled analyses from the EMERGENT trials, KarXT demonstrated statistically significant improvements across efficacy measures with consistent and robust effect sizes. These findings support the potential of KarXT to be first in a new class of medications to treat schizophrenia based on muscarinic receptor agonism and without any direct dopamine D2 receptor blocking activity.

Karuna Therapeutics

Knowledge of sex differences in risk factors for posttraumatic stress disorder (PTSD) can contribute to the development of refined preventive interventions. Therefore, the aim of this study was to examine if women and men differ in their vulnerability to risk factors for PTSD.

As part of the longitudinal AURORA study, 2924 patients seeking emergency department (ED) treatment in the acute aftermath of trauma provided self-report assessments of pre- peri- and post-traumatic risk factors, as well as 3-month PTSD severity. We systematically examined sex-dependent effects of 16 risk factors that have previously been hypothesized to show different associations with PTSD severity in women and men.

Women reported higher PTSD severity at 3-months post-trauma. Z-score comparisons indicated that for five of the 16 examined risk factors the association with 3-month PTSD severity was stronger in men than in women. In multivariable models, interaction effects with sex were observed for pre-traumatic anxiety symptoms, and acute dissociative symptoms; both showed stronger associations with PTSD in men than in women. Subgroup analyses suggested trauma type-conditional effects.

Our findings indicate mechanisms to which men might be particularly vulnerable, demonstrating that known PTSD risk factors might behave differently in women and men. Analyses did not identify any risk factors to which women were more vulnerable than men, pointing toward further mechanisms to explain women's higher PTSD risk. Our study illustrates the need for a more systematic examination of sex differences in contributors to PTSD severity after trauma, which may inform refined preventive interventions.

Social connection is associated with better health, including reduced risk of dementia. Personality traits are also linked to cognitive outcomes; neuroticism is associated with increased risk of dementia. Personality traits and social connection are also associated with each other. Taken together, evidence suggests the potential impacts of neuroticism and social connection on cognitive outcomes may be linked. However, very few studies have simultaneously examined the relationships between personality, social connection and health.

We tested the association between neuroticism and cognitive measures while exploring the potential mediating roles of aspects of social connection (loneliness and social isolation).

We conducted a cross-sectional study with a secondary analysis of the Canadian Longitudinal Study on Aging (CLSA) Comprehensive Cohort, a sample of Canadians aged 45 to 85 years at baseline. We used only self-reported data collected at the first follow-up, between 2015 and 2018 (n= 27,765). We used structural equation modelling to assess the association between neuroticism (exposure) and six cognitive measures (Rey Auditory Verbal Learning Test immediate recall and delayed recall, Animal Fluency Test, Mental Alternation Test, Controlled Oral Word Association Test and Stroop Test interference ratio), with direct and indirect effects (through social isolation and loneliness). We included age, education and hearing in the models and stratified all analyses by sex, females (n= 14,133) and males (n=13,632).

We found positive, statistically significant associations between neuroticism and social isolation (p<0.05) and loneliness (p<0.05), for both males and females. We also found inverse, statistically significant associations between neuroticism and all cognitive measures (p<0.05), except the Stroop Test interference ratio. In these models, there was consistent evidence of indirect effects (through social isolation and loneliness) and, in some cases, evidence of direct effects. We found sex differences in the model results.

Our findings suggest that the association between neuroticism and cognitive outcomes may be mediated by aspects of social connection and differ by sex. Understanding if and how modifiable risk factors mediate the association between personality and cognitive outcomes would help develop and target intervention strategies that improve social connection and brain health.

Reading is an important skill, and becomes even more so beyond elementary years, when the focus shifts to comprehension as a means of learning and understanding academic material across subjects (Kamil et al., 2008; Shanahan et al., 2010; Snow, 2002). One construct receiving much recent interest in research, especially that related to academic achievement, is mind wandering (MW). MW has been defined as "a shift away from a primary task toward internal information" (Smallwood & Schooler, 2006). Though it is known to be ubiquitous among people (McVay & Kane, 2012), there are numerous theories about why MW occurs, in different contexts, and in relation to various other factors, and no one theory is currently dominant. MW and other factors such as working memory (WM) and decoding are all known to influence functional outcomes such as reading comprehension (RC), but there is little information on how all of these factors interact with one another with regard to RC. Most prior work focuses on adults and thus generalization to children is still needed. Therefore, the goals of this project were to examine the roles of WM, MW, decoding, and their interactions in relation to RC. It was hypothesized that each would demonstrate a significant relationship with the outcome of RC and that they would interact with one another beyond their individual main effects.

The sample included 214 6th and 7th grade students with a larger proportion of struggling readers. Participants were each administered the Kaufman Test of Educational Achievement -Third Edition (KTEA-3; Kaufman & Kaufman, 2014) Letter Word Recognition subtest (decoding), the Weschler Intelligence Scale for Children - Fifth Edition (WISC-5; Wechsler, 2014) Digit Span and Picture Span subtests(WM), and the Gates-MacGinitie Reading Tests - Fourth Edition (GMRT-4; MacGinitie, 1978) Comprehension subtest (RC). Four measures of MW were administered: the trait-based Mind Wandering Questionnaire (MWQ; Mrazek et al., 2013); two task-based (or state-dependent) retrospective reporting (TBRR) questionnaires (Matthews et al., 2002), and a researcher-generated single-item task-based retrospective report administered after four tasks. Correlations and regression were utilized to evaluate the relationships among predictor variables, and with regard to RC, including how predictors moderate one another.

All three key predictors demonstrated a significant relationship with RC both via zero-order correlations and main effects in the context of interactive relationships. WM and decoding demonstrated positive relationships with RC and MW demonstrated a negative relationship with RC, though only when one (MWQ) measure of MW was used, rather than the TBRR measure. There was a significant interaction of decoding and MW as measured by the TBRR questionnaires on the outcome of RC. Other interactions were not significant.

These results clarify the interactive relationships of these three key predictors on the important academic achievement outcome of RC, ultimately suggesting that intervention strategies for achievement problems in areas such as RC should consider MW in conjunction with decoding abilities in order to implement effective strategies that capitalize on individual children's strengths and build on their particular weaknesses.

COVID-19 misinformation proliferating online has led to adverse health and societal consequences. Older adults are a particularly vulnerable population due to increased risk for both COVID-19 related complications and susceptibility to, as well as sharing of, misinformation on social networking sites. The present study aimed to: 1) investigate differences in COVID-19 headline accuracy discernment and online sharing of COVID-19 misinformation in older and younger adults; and 2) examine individual differences in global cognition, health literacy and verbal IQ in online sharing of COVID-19 misinformation.

Fifty-two younger (age 18 to 35 years) and fifty older adults (age 50 and older) completed a telephone neurocognitive battery, health literacy and numeracy measures and self-report questionnaires. Participants also completed a social media headline-sharing experiment (Pennycook et al.,2020) in which they were presented true and false COVID-19 headlines and asked to indicate: 1) the likelihood that they would share the story on social media; and 2) the factual accuracy of the story.

A repeated measures multivariate analysis of variance controlling for gender and race/ethnicity showed no effects of age (p=.099), but a significant interaction between actual COVID-19 headline accuracy and likelihood of sharing (p<.001), such that accuracy is more strongly related to sharing false headlines (r=-.64) versus true headlines (r=-.43). Moreover, higher likelihood of sharing false COVID-19 headlines was associated with lower verbal IQ and numeracy skills in older adults (rs=-.51--.40; ps<.01) and with lower verbal IQ, numeracy, and global cognition in younger adults (rs=-.66--.60; ps<.01).

Findings indicate that headline accuracy judgements are an important predictor of sharing COVID-19 misinformation in both older and younger adults. Further, individual differences in cognition, IQ, and numeracy may predict the likelihood of misinformation sharing in younger adults, while IQ and numeracy skills may act as important antecedents of misinformation sharing in older adults. Future work might leverage modern, neuropsychologically-based psychoeducation approaches to improving health and science literacy related to COVID-19.

Several hypotheses may explain the association between substance use, posttraumatic stress disorder (PTSD), and depression. However, few studies have utilized a large multisite dataset to understand this complex relationship. Our study assessed the relationship between alcohol and cannabis use trajectories and PTSD and depression symptoms across 3 months in recently trauma-exposed civilians.

In total, 1618 (1037 female) participants provided self-report data on past 30-day alcohol and cannabis use and PTSD and depression symptoms during their emergency department (baseline) visit. We reassessed participant's substance use and clinical symptoms 2, 8, and 12 weeks posttrauma. Latent class mixture modeling determined alcohol and cannabis use trajectories in the sample. Changes in PTSD and depression symptoms were assessed across alcohol and cannabis use trajectories via a mixed-model repeated-measures analysis of variance.

Three trajectory classes (low, high, increasing use) provided the best model fit for alcohol and cannabis use. The low alcohol use class exhibited lower PTSD symptoms at baseline than the high use class; the low cannabis use class exhibited lower PTSD and depression symptoms at baseline than the high and increasing use classes; these symptoms greatly increased at week 8 and declined at week 12. Participants who already use alcohol and cannabis exhibited greater PTSD and depression symptoms at baseline that increased at week 8 with a decrease in symptoms at week 12.

Our findings suggest that alcohol and cannabis use trajectories are associated with the intensity of posttrauma psychopathology. These findings could potentially inform the timing of therapeutic strategies.