Abstract Background Attention Deficit Hyperactivity Disorder (ADHD) affects a significant proportion of the population and is associated with numerous adverse outcomes including lower educational attainment, occupational challenges, increased substance use, and various mental health issues including psychosis. This study examined the demographic, clinical, cognitive, social cognitive and functional differences between youth at clinical high-risk (CHR) for psychosis with and without co-morbid ADHD. Method Data was drawn from the North American Prodrome Longitudinal Studies (NAPLS2 and NAPLS3), which included 764 and 710 CHR individuals, respectively. After applying exclusion criteria, the sample consisted of 271 CHR participants with ADHD and 1118 without ADHD. All data was examined cross-sectionally. Results Compared to the non-ADHD group, the ADHD group was younger, had more difficulties with role functioning, premorbid functioning, social cognition, were more likely to have a co-morbid learning disorder and reported less depression symptoms. There were no significant differences between the groups on positive or negative psychotic symptoms, transition rates, adverse events, or other co-morbid disorders including substance use and depression. Discussion Co-morbid ADHD is likely not a significant predictor of transition to psychosis among CHR youth, however those CHR with ADHD may experience symptoms at a younger age than those without and present with a distinct clinical profile.

Abstract Background and Hypothesis Gut microbiota has been implicated in the pathogenesis of schizophrenia (SZ) and relevant changes in the brain, but the underlying mechanism remains elusive. This study aims to investigate the microbiota-gut-brain crosstalk centered on peripheral inflammation in SZ patients. Study Design We recruited a cohort of 182 SZ patients and 120 healthy controls (HC). Multi-omics data, including fecal 16S rRNA, cytokine data, and neuroimaging data, were collected and synthesized for analysis. Multi-omics correlations and mediation analyses were utilized to determine the associations of gut microbiome with inflammatory cytokines and neuroimaging characteristics. Additionally, machine learning models for effective SZ diagnosis were separately generated based on gut microbial and neuroimaging data. Study Results Gut microbial dysbiosis, characterized by a decrease in butyrate-producing bacteria and an increase in pro-inflammatory bacteria, has been identified in SZ patients. These key microbial taxa were associated with increased inflammatory cytokines, potentially through mediating lipid metabolic pathways such as steroid biosynthesis and linoleic acid metabolism. Further analysis revealed altered microbial genera to be correlated with disrupted gray matter volume and regional homogeneity in SZ patients. Importantly, certain inflammatory cytokines mediated the relationship between the SZ-enriched genus Succinivibrio and aberrant activity of anterior cingulate cortex and left inferior temporal gyrus in the SZ group. Moreover, the classification model based on gut microbial data showed comparable efficacy to the model based on brain functional signatures in SZ diagnosis. Conclusions This study presents evidence for the dysregulated microbiota-gut-brain axis in SZ and emphasizes the central role of peripheral inflammation.

Despite recognition that early intervention for first-episode psychosis (FEP) improves outcomes, Black youth with FEP continue to experience critical disparities in care. A historical lack of scientific focus on racial and ethnic factors in the study of psychosis and scant investigations among publicly insured (ie, Medicaid-enrolled) youth hinder our ability to understand and address factors that contribute to disparities in early FEP care. Strategies for improving FEP services for Black youth are reliant on more precise identification of who faces disparities and when during the early course of illness disparities are experienced. A retrospective longitudinal analysis of Ohio Medicaid claims data was performed for 987982 youth aged 15-24 years between 2010 and 2020 to examine: (1) the likelihood of FEP diagnosis, (2) the type of psychotic disorder diagnosis received, and (3) receipt of treatment following psychosis onset. Non-Hispanic Black (NHB) youth, relative to non-Hispanic White (NHW) peers, were more likely to be diagnosed with a psychotic disorder and were further more likely to receive a diagnosis of schizophrenia relative to an affective psychotic disorder. In the first year following FEP diagnosis, NHB youth were also less likely to receive psychotherapy than NHW youth; this disparity was no longer present when examined at 2 years following FEP. In this study, Black youth experienced disparities in both the diagnosis and early treatment of FEP. Additional efforts are needed to understand and address these observed disparities and to promote equitable access to FEP care during the critical early illness phases.

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.

While continued cannabis use and misuse in individuals with schizophrenia is associated with a variety of negative outcomes, individuals with a history of use tend to show higher cognitive performance compared to non-users. While this is replicated in the literature, few studies have used task-based functional magnetic resonance imaging (fMRI) to evaluate whether the brain networks underpinning these cognitive features are similarly impacted. Forty-eight first-episode individuals with schizophrenia (FES) with a history of cannabis use (FES + CAN), 28 FES individuals with no history of cannabis use (FES-CAN), and 59 controls (CON) performed the AX-Continuous Performance Task during fMRI. FES+CAN showed higher cognitive control performance (d'-context) compared to FES-CAN (P < .05, ηp 2 = 0.053), and both FES+CAN (P < .05, ηp 2 = 0.049) and FES-CAN (P < .001, ηp 2 = 0.216) showed lower performance compared to CON. FES+CAN (P < .05, ηp 2 = 0.055) and CON (P < 0.05, ηp 2 = 0.058) showed higher dorsolateral prefrontal cortex (DLPFC) activation during the task compared to FES-CAN, while FES+CAN and CON were not significantly different. Within the FES+CAN group, the younger age of initiation of cannabis use was associated with lower IQ and lower global functioning. More frequent use was also associated with higher reality distortion symptoms at the time of the scan. These data are consistent with previous literature suggesting that individuals with schizophrenia and a history of cannabis use have higher cognitive control performance. For the first time, we also reveal that FES+CAN have higher DLPFC brain activity during cognitive control compared to FES-CAN. Several possible explanations for these findings are discussed.

Studies have linked auditory hallucinations (AH) in schizophrenia spectrum disorders (SCZ) to altered cerebral white matter microstructure within the language and auditory processing circuitry (LAPC). However, the specificity to the LAPC remains unclear. Here, we investigated the relationship between AH and DTI among patients with SCZ using diffusion tensor imaging (DTI). We included patients with SCZ with (AH+; n = 59) and without (AH-; n = 81) current AH, and 140 age- and sex-matched controls. Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) were extracted from 39 fiber tracts. We used principal component analysis (PCA) to identify general factors of variation across fiber tracts and DTI metrics. Regression models adjusted for sex, age, and age2 were used to compare tract-wise DTI metrics and PCA factors between AH+, AH-, and healthy controls and to assess associations with clinical characteristics. Widespread differences relative to controls were observed for MD and RD in patients without current AH. Only limited differences in 2 fiber tracts were observed between AH+ and controls. Unimodal PCA factors based on MD, RD, and AD, as well as multimodal PCA factors, differed significantly relative to controls for AH-, but not AH+. We did not find any significant associations between PCA factors and clinical characteristics. Contrary to previous studies, DTI metrics differed mainly in patients without current AH compared to controls, indicating a widespread neuroanatomical distribution. This challenges the notion that altered DTI metrics within the LAPC is a specific feature underlying AH.

Exposure to childhood trauma has been linked to the development of psychosis and bodily self-disturbances, 2 hallmarks of schizophrenia (SZ). Prior work demonstrated that bodily disturbances serve as a bridge between childhood trauma and SZ symptomatology, but the diagnostic specificity of these connections remains unknown. This study uses network analysis to bridge this gap by comparing the interplays between childhood trauma, bodily self-disturbances, and schizotypy in clinical and general populations. Networks were constructed to examine the relationships between schizotypy (Schizotypal Personality Questionnaire; SPQ), bodily self-disturbances (Perceptual Aberration Scale; PAS), and childhood trauma (Childhood Trauma Questionnaire, CTQ) in 152 people with SZ and 162 healthy comparison participants (HC). The Fused Graphical Lasso was used to jointly estimate the networks in the 2 groups and the structure and strength of the networks were compared. Node centrality and shortest paths between CTQ, PAS, and schizotypy were examined. When comparing SZ and HC, the network of bodily self-disturbances, childhood trauma, and schizotypy were similarly structured, but the network was significantly stronger in SZ than HC. In both groups, bodily self-disturbances were on one of the shortest paths between childhood trauma to schizotypal experiences. Our findings revealed reliable associations between childhood trauma, bodily self-disturbance, and schizotypy, with bodily disturbances acting as a bridge from childhood trauma to schizotypy. The elevated strength of the SZ network indicates a more highly interconnected, and therefore reactive network in which exposure to childhood trauma can more easily activate bodily disturbances and schizotypy.

Oxidative stress pathways may play a role in schizophrenia through direct neuropathic actions, microglial activation, inflammation, and by interfering with NMDA neurotransmission. N-acetylcysteine (NAC) has been shown to improve negative symptoms of schizophrenia, however, results from trials of other compounds targeting NMDA neurotransmission have been mixed. This may reflect poor target engagement but also that risk mechanisms act in parallel. Sodium Benzoate (NaB) could have an additive with NAC to act on several pathophysiological mechanisms implicated in schizophrenia. A multicenter, 12 weeks, 2 × 2 factorial design, randomized double-blind placebo-controlled feasibility trial of NaB and NAC added to standard treatment in 68 adults with early schizophrenia. Primary feasibility outcomes included recruitment, retention, and completion of assessments as well as acceptability of the study interventions. Psychosis symptoms, functioning, and cognitive assessments were also assessed. We recruited our desired sample (n = 68) and retained 78% (n = 53) at 12 weeks, supporting the feasibility of recruitment and retention. There were no difficulties in completing clinical outcome schedules. Medications were well tolerated with no dropouts due to side effects. This study was not powered to detect clinical effect and as expected no main effects were found on the majority of clinical outcomes. We demonstrated feasibility of conducting a clinical trial of NaB and NAC. Given the preliminary nature of this study, we cannot draw firm conclusions about the clinical efficacy of either agent, and a large-scale trial is needed to examine if significant differences between treatment groups emerge. ClinicalTrials.gov: NCT03510741.