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Heterogeneity in schizophrenia spectrum disorders is a major challenge to implementing personalized medicine and uncovering etiological pathways. Recent work identified subtypes of schizophrenia that exhibit unique patterns of clinical symptoms and features using a common clinical scale. The current study sought to: (1) replicate prior identification of subtypes using the Positive and Negative Syndrome Scale (PANSS) in a new cohort of people with schizophrenia; (2) further characterize differences between subtypes in symptoms, affect, cognition, functioning, and personality; and (3) determine if brain structure abnormalities vary across subtypes. Phenotypic data were obtained on 356 individuals with schizophrenia spectrum disorders. Structural brain magnetic resonance imaging data were acquired on a subset of 203 individuals with schizophrenia and 186 healthy people. A 2-step cluster analysis of PANSS data was used to identify subtypes of schizophrenia. Subtypes were compared on characteristics and brain volume. Clustering revealed 3 clusters aligning with previous subtypes: distress, negative, and low symptom. The distress subtype demonstrated higher levels of negative emotions, neuroticism, and schizotypal personality traits. The negative subtype exhibited more severe cognitive impairment, higher levels of disorganized and anhedonia symptoms, and worse functioning. Abnormalities in cortical volumes followed a gradient, the negative subtype demonstrated the largest number of cortical regions with smaller volume relative to healthy people, followed by the distress subtype, then the low symptom subtype. In contrast, smaller subcortical volumes were consistent across subtypes. Our findings support the presence of subtypes of schizophrenia spectrum disorders that differ in affect, cognition, functioning, personality, and brain structure.

Xanomeline and trospium chloride (formerly KarXT) is a muscarinic M1 and M4 receptor agonist recently approved for the treatment of schizophrenia in adults. Unlike all previously approved antipsychotics, it does not directly block dopamine D2 receptors. Given its novel mechanism of action, understanding patients' subjective treatment experiences, including perceived symptom changes, is clinically important. This is a qualitative study embedded within a larger 52-week open-label long-term safety study that investigated patient perspectives on xanomeline/trospium monotherapy in clinically stable outpatients transitioned from previous antipsychotic treatments. A subsample completed up to 2 semi-structured interviews to explore their experience-favorable or unfavorable-approximately 6 weeks (n = 70) and 6 months (n = 47) post-initiation. Thematic analysis was applied to interview transcripts. At study entry, most participants reported symptoms despite ongoing antipsychotic treatment, including positive (auditory hallucinations, >80%), negative (low motivation, >70%), and cognitive (trouble concentrating, >70%) symptoms. Over 60% reported meaningful improvement in one or more symptoms within 6 weeks of starting xanomeline/trospium, increasing to about 80% by 6 months. Less than 10% reported symptom worsening at either time point. Participants described these improvements as personally meaningful, with notable benefits in daily functioning. Participants entered this study with various persistent, burdensome schizophrenia symptoms despite ongoing treatment. Most experienced substantial and sustained symptom relief for up to 6 months after initiating xanomeline/trospium treatment. These qualitative findings highlight xanomeline/trospium's potential to provide meaningful relief across multiple symptom domains and support functional recovery. A companion report explores quality of life and medication satisfaction.

Long-acting injectable (LAI) antipsychotics improve adherence and reduce schizophrenia relapse rates vs oral antipsychotics (OAs) but remain underused. The ADVANCE study explored country-level differences in LAI use among healthcare professionals (HCPs), patients, and caregivers, to identify drivers of LAI use. ADVANCE included participants from Australia, Canada, China, Germany, Israel, South Korea, Spain, and the United States. Eligible HCPs spent ≥25% of their time in direct patient care, managed an adult population of whom ≥10% have schizophrenia, and treated patients prescribed LAIs. Patients aged ≥18 years and caregivers of adults living with schizophrenia who had tried/been offered an LAI were included. Participants completed a 30-minute survey. Systemic factors reported by HCPs (n = 791) associated with higher LAI use included being a physician vs nonphysician, having Hispanic/Latino/Spanish ethnicity, managing more adult patients with schizophrenia, and having more staff and nurse support. Nonadherence to OAs was the main HCP-reported reason for LAI recommendation. Patient characteristics, lack of available LAIs corresponding to OAs, and perceptions of patients' behavior were top reasons HCPs would not recommend an LAI. For patients (n = 470), symptom improvement and HCP recommendation, and for caregivers (n = 381), ease of injections, reduced hospitalizations, and fewer side effects were the main reasons for LAI acceptance. The top reason patients and caregivers declined LAIs was concern about side effects. Results from ADVANCE demonstrate that systemic and attitudinal factors influence LAI use by HCPs, and these factors vary by country. Enhancing HCP-patient communication may improve LAI acceptance.

Affective disturbances are a core feature of schizophrenia, yet patients' capacity to experience momentary affective shifts in real-world settings remains underexplored. Although consummatory pleasure appears preserved, studies suggest low levels of positive affect and high levels of negative affect in daily life. Physical exercise provides an ecologically valid context for probing short-term affective reactivity. This study examined whether high-intensity interval training (HIIT) elicited greater affective change than an active control condition (ACC), whether baseline symptom levels were associated with affective state, and whether baseline symptoms moderated affective reactivity. In a randomized controlled trial, 69 outpatients with schizophrenia were randomized to a 12-week intervention involving either supervised HIIT or an ACC involving low-intensity, interactive video gaming. Affective state was assessed immediately before and after the 12th session using the Positive and Negative Affect Schedule (PANAS). Depressive (CDSS), negative symptoms (PANSS-N), and apathy (AES) were measured at baseline. Linear mixed-effects models tested Group × Time effects. HIIT did not produce significantly greater changes in positive or negative affect than the active control. Across interventions, participants showed increases in positive affect and decreases in negative affect. Higher baseline symptom levels were associated with lower pre-session positive affect. Exploratory analyses indicated that participants with more severe negative symptoms showed greater positive affective gains following HIIT. A single session of structured activity, regardless of intensity, was associated with small but measurable affective improvements. These findings highlight the value of accessible activity-based interventions for enhancing affective well-being in schizophrenia.

Extrapyramidal symptoms (EPS) are common side effects of antipsychotic medications and can contribute to medication non-adherence and subsequent relapse in schizophrenia. Recent research suggests that inflammatory markers, such as the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), and systemic immune-inflammation index (SII), may serve as biomarkers for treatment response in schizophrenia. This exploratory study is a first look at the relationship between these inflammatory markers and EPS in patients with schizophrenia. Fifty patients with schizophrenia spectrum disorders were recruited, with 28 completing bloodwork. EPS was assessed using the Extrapyramidal Symptom Rating Scale (ESRS), and overall side effects were evaluated using the Glasgow Antipsychotic Side-Effect Scale (GASS). Blood samples were analyzed to calculate NLR, PLR, MLR, and SII. Monocyte count was negatively correlated with the ESRS akathisia subscale. Higher SII scores were significantly associated with self-reported parkinsonism and hyperkinesia. Patients on clozapine had significantly higher PLR and MLR compared to those on other antipsychotics. No significant association was found between total GASS scores and inflammatory markers. These findings suggest that certain inflammatory markers may be associated with specific EPS subscales. Further research with larger samples is needed to validate these results.

Schizophrenia spectrum disorders are known to affect the patient's functional performance. The functioning of those who are at familial risk for these disorders is less well understood. In this study, we compared the real-world functioning of adoptees with a genetic high-risk (HR) for schizophrenia spectrum disorders with adoptees without this risk (low-risk, LR). We hypothesized that the HR-group would have more difficulties in real-world functioning compared to the LR-group. The data were based on the Finnish Adoptive Family Study of Schizophrenia project. The study sample included 127 HR- and 130 LR-adoptees. An interview-based method, Strauss-Carpenter Level of Function (SCLF)-scale, was used to measure functional performance in a setup of adoptees living in comparable adoptive families. The SCLF-scale comprises domains for function, symptoms, social contacts, and work. The Structured Interview of Schizotypy was utilized in assessments of possible schizotypal traits of the HR- and LR-adoptees. No significant differences in the real-world functioning in total scores or scores of any SCLF domains were observed between HR- and LR-adoptees. Of single SCLF items, the HR-adoptees were characterized as being less likely to have achieved formal education and the LR-adoptees needed more help with their own basic needs. No differences were found in the real-world functioning between HR- and LR-populations. This indicates that the real-world functioning does not express one's genetic risk for schizophrenia spectrum disorders. Our findings highlight the importance of considering environmental factors when comparing genetically different groups.

Adolescent stress has been linked to an increased risk of developing psychiatric disorders, including schizophrenia. Previous findings from our group suggest that adolescent stress causes redox imbalance and functional impairments in parvalbumin (PV) interneurons and their associated perineuronal nets (PNNs) in the ventral hippocampus (vHip). These changes are associated with behavioral abnormalities, vHip hyperactivity, and dopamine system overdrive, mirroring observations in people with schizophrenia. Thus, we hypothesized that the antioxidant N-acetylcysteine (NAC) could mitigate schizophrenia-related alterations induced by adolescent stress in adult rats. Male Sprague-Dawley rats were subjected to a combination of daily footshock and restraint stress during adolescence [postnatal days (PD) 31-40]. NAC (900 mg/L) was administered through the drinking water either during (PD31-40) or after the adolescent stress (PD51-60). In adulthood (PD63), rats underwent behavioral tests to assess anxiety-like behaviors, social interaction, and cognition. From PD70, in vivo recordings of dopamine neurons in the ventral tegmental area (VTA) and immunostaining of PV, PNNs, and the oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-Oxo-dG) in the vHip were performed. Adolescent stress causes, in adulthood, anxiety-like responses, deficits in sociability and cognitive function, increased VTA dopamine neuron population activity, reduced PV+ cells in the vHip, including those surrounded by PNNs, and enhanced expression of 8-Oxo-dG, particularly in PV+ cells. NAC treatment, whether administered during or after adolescent stress, significantly attenuated these alterations. NAC effectively mitigates schizophrenia-related changes induced by adolescent stress and may serve as a pharmacological intervention for prevention and treatment strategies.

This post hoc analysis examined the efficacy of aripiprazole lauroxil (AL) by baseline severity of illness in the double-blind Aripiprazole Lauroxil and Paliperidone palmitate: INitiation Effectiveness study (NCT03345979) in patients with schizophrenia treated with AL every 2 months. Adults with acute schizophrenia were randomized to AL 1064 mg every 2 months or active control (paliperidone palmitate [PP] 156 mg monthly). Based on Clinical Global Impression-Severity scores, baseline severity of illness was categorized as moderate, marked, or severe. Changes from baseline in Positive and Negative Syndrome Scale (PANSS) Total score were assessed at week 25, along with PANSS items related to hostility/excitement. Numbers of patients with activation adverse events (AEs; anxiety, agitation, and insomnia) were also evaluated. Of 99 patients assigned to AL, 31 (31%) were moderately ill at baseline, 54 (55%) were markedly ill, and 14 (14%) were severely ill. With AL treatment, mean ± SE changes from baseline in PANSS Total score at week 25 were -21.1 ± 2.5 (moderately ill; baseline, 87.1), -24.1 ± 1.8 (markedly ill; baseline, 95.3), and -25.6 ± 6.4 (severely ill, baseline, 106.1). Improvements from baseline in PANSS scores related to hostility/excitement items were comparable among severity subgroups. No clear pattern of occurrence of the AEs anxiety, agitation, and insomnia was observed across baseline severity groups. In this post hoc analysis, safety related to activation and efficacy with AL treatment were comparable across baseline severity-of-illness subgroups of patients with schizophrenia.

Long-acting injectable antipsychotics (LAIs) improve adherence and reduce schizophrenia relapse rates. Data on which LAI attributes drive clinician preference are limited. In the DECIDE survey, 380 psychiatric clinicians (psychiatrists, psychiatric nurse practitioners, and physician assistants) were surveyed regarding preferences when selecting and initiating LAIs for patients with schizophrenia. Responses were analyzed by clinician use of LAIs (high [&#x2265;&#x2005;31% of their patients using LAIs] or low [&#x2264;&#x2005;14% of their patients using LAIs]) and mindset toward LAI use (early, severity reserved, adherence reserved, and LAI hesitant). Overall and across subgroups, side effects were the most important consideration when selecting a particular LAI, with 33% of clinicians ranking this as most important (26%-46% across subgroups). Clinician preference for the molecule was most often ranked least important (47% overall; 39%-59% across subgroups). A significantly higher proportion of clinicians with high vs low LAI use ranked product attributes as the most important consideration (26% vs 13%; P&#x2005;<&#x2005;.01). Across subgroups, multiple injection site options, small/on par needle, and price made at least two-thirds of clinicians somewhat/much more likely to use a particular LAI, and 63%-82% of clinicians reported being somewhat/much more likely to select an LAI dosed once monthly or less often vs 6%-11% being somewhat/much more likely to select an LAI dosed once every 2 weeks. Overall, results from DECIDE provide insight into the decision-making process of psychiatric clinicians when selecting an LAI and highlight opportunities to help clinicians deliver optimal care for patients with schizophrenia.

Dysfunction of the dopamine system is the leading neurobiological hypothesis of schizophrenia. In this study, we tested this hypothesis in the context of aberrance salience theory of delusions using catecholamine depletion. We hypothesized that acute dopamine depletion improves both positive symptoms and salience attribution in individuals with schizophrenia. Catecholamine depletion was achieved by oral administration of alpha-methyl-para-tyrosine (AMPT) in 15 individuals with schizophrenia and 15 healthy volunteers. The study design consisted of a randomized, double-blind, placebo-controlled crossover, single-site experimental trial. The main outcome measures were the Scale for the Assessment of Positive Symptoms and the Salience Attribution Test. Catecholamine depletion transiently reduced specific psychotic symptoms in symptomatic individuals with schizophrenia, namely delusions and positive formal thought disorder (interaction treatment-by-timepoint, P = .013 and P = .010, respectively). We also found trends for catecholamine depletion to increase relevant bias and adaptive salience in participants with schizophrenia while decreasing them in healthy controls (interaction group-by-treatment, P = .060 and P = .089, respectively). Exploratory analyses revealed that in participants with schizophrenia, higher relevant bias at 3 hours after the end of AMPT treatment corresponded to lower delusional symptoms (Spearman's rho = -0.761, P = .001). This study suggests that the relationship between dopamine hyperactivity and delusional symptoms in schizophrenia is mediated by impaired attribution of salience to reward-predicting stimuli.

Some but not other studies on oxytocin for schizophrenia, particularly those using a higher dose, indicate that oxytocin improves negative symptoms of schizophrenia. We performed an add-on randomized controlled trial to examine the effect of high-dose oxytocin, social skills training, and their combination in the treatment of negative symptoms and social dysfunction in schizophrenia. Fifty-one subjects with schizophrenia were randomized, employing a two-by-two design: intranasal oxytocin (24 IU X3/day) or placebo, and social skills training or supportive psychotherapy, for 3 weeks. The primary outcome was the difference in the total score from baseline to end-of-study of a semi-structured interview which assessed patients' social interactions in 3 scenarios: sharing a positive experience, sharing a conflict, and giving support when the experimenter shared a conflict. The interactions were scored using the Coding Interactive Behavior Manual (CIB), clinical symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). No significant difference was found between groups in the total CIB or PANSS scores. The majority of comparisons in the different social interactions between oxytocin and placebo, and between social skills training vs supportive psychotherapy, were also nonsignificant. Social skills training reduced blunted affect and gaze. In post-hoc analyses of the support interaction, oxytocin improved synchrony and decreased tension, while in the positive interaction it improved positive affect and avoidance. None of these findings remained significant when controlling for multiple comparisons. In conclusion, oxytocin did not influence participants' social behavior, and was not effective in improving the symptoms of schizophrenia. Clinicaltrials.gov Identifier: NCT01598623.

The distressing nature of delusional beliefs is considered key to their persistence. One potential mechanism underlying delusional distress is global emotion dysregulation. Global emotion dysregulation is associated with general psychotic symptom severity, but its specific relationship to delusional distress has yet to be closely examined. People with (n&#x2005;=&#x2005;100) and without (n&#x2005;=&#x2005;52) schizophrenia-spectrum disorders completed measures of delusional ideation (Peters Delusion Inventory; PDI-21) and global emotion dysregulation (Difficulties in Emotion Regulation Scale; DERS-16). Participants with schizophrenia also completed a measure of delusion severity (Psychotic Symptom Rating Scales; PSYRATS). Relationships between delusion severity and global emotion dysregulation were assessed with linear regression, controlling for age, sex, and group. Associations between delusional distress and aspects of emotion dysregulation were determined using stepwise linear regression. Global emotion dysregulation was significantly elevated in those with schizophrenia compared to non-clinical controls, across all subscales (P&#x2005;<&#x2005;.001). Emotion dysregulation was significantly associated with delusional distress on both the PDI-21 (P&#x2005;<&#x2005;.001) and PSYRATS (P&#x2005;<&#x2005;.001). Stepwise regressions revealed a specific association between limited access to emotion regulation strategies and delusional distress on both scales (P's&#x2005;<&#x2005;.001). Delusional distress remained associated with emotion dysregulation when controlling for delusional preoccupation, and emotion dysregulation was not significantly associated with delusional conviction on either scale. Emotion dysregulation, particularly the sense that there is little one can do to regulate themselves when upset, relates to delusional distress. Interventions that increase access to more emotion regulation strategies may help decrease distress associated with delusional thinking.

Cognitive impairment is a core feature of schizophrenia and a key determinant of functional outcome. Although conventional paper-and-pencil based cognitive assessments used in schizophrenia remained relatively static during most of the 20th century, this century has witnessed the emergence of innovative digital technologies that aim to enhance the ecological validity of performance-based assessments. This narrative review provides an overview of new technologies that show promise for enhancing the ecological validity of cognitive and functional assessments. We focus on 2 approaches that are particularly relevant for schizophrenia research: (1) digital functional capacity tasks, which use simulations to measure performance of important daily life activities (e.g., virtual shopping tasks), delivered both in-person and remotely, and (2) remote device-based assessments, which include self-administered cognitive tasks (e.g., processing speed test) or functionally-focused surveys regarding momentary activities and experiences (e.g., location, social context), as well as passive sensor-based metrics (e.g., actigraphy measures of activity), during daily life. For each approach, we describe the potential for enhancing ecological validity, provide examples of select measures that have been used in schizophrenia research, summarize available data on their feasibility and validity, and consider remaining challenges. Rapidly growing evidence indicates that digital technologies have the potential to enhance the ecological validity of cognitive and functional outcome assessments, and thereby advance research into the causes of, and treatments for, functional disability in schizophrenia.

The relationship between Klotho and cognitive dysfunction in schizophrenia has been scarcely explored, with a few paradoxical findings. Hence, we aimed to enhance our understanding by testing associations between the functional KL-VS gene variant and circulating protein levels. This case-control study included 239 healthy controls and 241 patients with schizophrenia, who were comprehensively characterized by neurocognitive tests and further subtyped into cognitive clusters; cognitively deficient (CD) and cognitively spared (CS), using K-means cluster analysis. Linear regression models were run to assess the main and iinteraction effects of the KL-VS heterozygosity (KL-VSHet+)/KL levels with confounding variables (disease status and age) on cognitive scores. There was no main effect of KL-VSHet+ on the cognitive domains, but the CD cluster exhibited strong negative interactions between disease status and Klotho for executive function at the gene level, KL-VSHet+ &#xd7; disease status, &#x3b2; = -.61, P&#x2005;=&#x2005;.043, with comparatively higher effect observed for KL levels, KL levels&#x2005;&#xd7;&#x2005;disease status, &#x3b2; = -.91, P&#x2005;=&#x2005;.028. There was an opposing positive interaction for response inhibition, KL-VSHet+ &#xd7; disease status, limited again to the CD cluster, &#x3b2; = .35, P&#x2005;=&#x2005;.046, with a higher effect at protein levels, KL levels&#x2005;&#xd7;&#x2005;disease status, &#x3b2; = .72, <.004, though without CD cluster effect. Overall, these dissociable patterns of association across cognitive domains indicate the need to exert caution over accepting any generalised direction of effect of Klotho at gene or protein level on cognition in schizophrenia.

Negative symptoms of schizophrenia are highly predictive of poor functional outcomes, and current treatment approaches have been minimally efficacious for these symptoms. CT-155/BI 3972080 (CT-155) is being developed as a smartphone-based digital therapeutic (DTx) rooted in evidence-based psychosocial interventions. Patient feedback on the usability, facilitators, and barriers to app use are of critical importance for long-term effectiveness of CT-155. This qualitative analysis explored user experiences with a beta version of CT-155 (CT-155 beta) following participation in an exploratory clinical study. Semistructured interviews were conducted with 42 participants at the end of a multicenter, 7-week, single-arm, open-label, study of CT-155 beta (NCT05486312). Thematic analysis was used to identify key patterns in participant experiences, focusing on usability, perceived benefits, and challenges. Participant feedback revealed insights regarding: (1) usability of the app, (2) benefits of use, and (3) considerations for implementation. Participants described the app as accessible and easy to navigate, even among those with limited digital experience. The reported benefits included improved coping, increased motivation, increased social interest and skills, new thought patterns, and engagement with structured daily routines. Implementation considerations included technical issues, a desire for more personalization, and the influence of psychiatric symptoms. This study provides early insights into patient experiences after using CT-155 beta. The findings support the acceptability of the app and offer user-informed direction for future development. These results informed updates to the study app, which has been evaluated in a phase III confirmatory study.

The Cognitive Assessment Interview (CAI) is an interview-based scale measuring cognitive impairment and its impact on functioning in subjects with schizophrenia (SCZ). It is approved as a coprimary measure of performance-based instruments, such as the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB). Recent research highlights negative symptoms, social cognition, and functional capacity as mediators of cognitive impairment's impact on functioning. This study compared mediation analysis outcomes using CAI or MCCB scores, providing insights into the utility of interview-based tools in research and clinical practice. The study included 618 individuals diagnosed with schizophrenia, recruited from 24 Italian psychiatric clinics. Neurocognitive assessments utilized both CAI and MCCB. Mediation analyses explored negative symptoms, social cognition, and functional capacity as mediators of the impact of neurocognition on real-life functioning domains. The study's results extend the validation of the CAI as a coprimary measure that provides valid information on the impact of cognitive impairment on real-life functioning and its possible mediators, complementing the information obtained using the MCCB. Interview-based cognitive assessment might be essential for understanding schizophrenia complexity and its impact on various cognitive and functional domains for clinicians, patients, and caregivers.

This network meta-analysis evaluated the efficacy and safety of cariprazine, asenapine, xanomeline-trospium chloride, and lumateperone in treating acute exacerbations of schizophrenia in adults, compared with placebo. A systematic search of PubMed, Scopus, Cochrane Central, and ClinicalTrials.gov identified 12 randomized controlled trials (RCTs; n&#x2009;=&#x2009;4584 patients). Efficacy was assessed using changes in Positive and Negative Syndrome Scale (PANSS) total scores; safety outcomes included adverse events (AEs), treatment discontinuation, and specific side effects. Asenapine (MD&#x2009;=&#x2009;-9.83; 95% CI, -13.49 to -6.18), xanomeline-trospium (MD&#x2009;=&#x2009;-9.80; 95% CI, -13.00 to -6.60), and cariprazine (MD&#x2009;=&#x2009;-8.41; 95% CI, -11.33 to -5.50) showed statistically significant PANSS score reductions. Lumateperone, however, did not reach statistical significance (MD&#x2009;=&#x2009;-2.79; 95% CI, -6.60 to 1.01). Safety profiles varied: cariprazine had the lowest risk of serious AEs (RR&#x2009;=&#x2009;0.52), while xanomeline-trospium was associated with gastrointestinal AEs (RR&#x2009;=&#x2009;3.86), and asenapine with weight gain (RR&#x2009;=&#x2009;3.12). This network meta-analysis found that among asenapine, xanomeline-trospium, lumateperone and cariprazine, asenapine, xanomeline-trospium, and cariprazine were effective in reducing PANSS total score compared with placebo, whereas lumateperone did not show statistically significant reduction compared with placebo. These findings offer important insights into efficacy and safety of these 4 medications in the treatment of acute exacerbation of schizophrenia. However, further head-to-head comparisons with standard treatments are needed to guide a more evidence-based selection. Future trials with longer durations and more diverse populations are warranted to confirm and extend these findings.

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Psychosis-related environmental risks in autism, along with genetic overlaps between autism and psychosis, have been well-established. However, their moderating roles in the relationship between autistic traits (ATs) and psychotic experiences (PEs) remain underexplored. First-wave data from 792 twins and siblings (mean age: 17.47&#x2005;&#xb1;&#x2005;3.6, 60.23% female) in the TwinssCan Project were analyzed. PEs and ATs were assessed using the Community Assessment of Psychic Experiences and the Autism-Spectrum Quotient, respectively. Polygenic risk scores for schizophrenia and psychosis-associated environmental factors (ie, childhood trauma (CT), bullying, negative life events, obstetric complications, cannabis use, winter birth, and hearing impairment) were tested for their independent effects on PEs and their interaction effects with ATs in moderating the relationship between ATs and PEs using separate multilevel linear regression models with Bonferroni's correction. ATs, all CT subtypes, bullying, and negative life events were positively associated with PEs (all P&#x2005;<&#x2005;.004). Moderation analyses revealed that the association between ATs and PEs was amplified by emotional abuse (B:0.08, 95% CI, 0.05-0.11, P&#x2005;<&#x2005;.001), physical abuse (B:0.11, P&#x2005;=&#x2005;.001), sexual abuse (B:0.09, 95% CI, 0.03-0.15, P&#x2005;=&#x2005;.002), and physical neglect (B:0.06, 95% CI, 0.03-0.10, P&#x2005;=&#x2005;.001), emotional neglect (B:0.04, 95% CI, 0.01-0.07, P&#x2005;=&#x2005;.007), and negative life events (B:0.007, 95% CI, 0.0005-0.014, P&#x2005;=&#x2005;.04), although the latter 2 risks did not survive Bonferroni's correction. No significant main or interacting effects of genetic and other risk factors were found. People with high ATs were more likely to have PEs when exposed to CT. Trauma screening and early interventions might be warranted in this at-risk population.