BACKGROUND: Suicidal ideation is common among individuals with first episode psychosis (FEP), with prevalence estimates up to 56.5 %. Despite its high prevalence, relatively little is known about how sociodemographic, clinical and/or developmental characteristics contribute to the experience of suicidal ideation in individuals with FEP.
METHODS: In this cross-sectional study (FEP n = 551 and controls n = 857), univariate logistic regression analyses were performed to study the associations of sociodemographic, clinical, and developmental factors with suicidal ideation in individuals with FEP as well as controls. Suicidal ideation was assessed using the Community Assessment of Psychic Experiences (CAPE). In addition, multivariate logistic regression analyses were conducted based on a stepwise approach.
RESULTS: In FEP, only depressive symptoms remained significantly associated with suicidal ideation when all correlates were integrated into one model. In the multivariate model in controls, depressive symptoms, positive symptoms, and traumatic childhood experiences were significantly associated with suicidal ideation.
CONCLUSIONS: This study showed that depressive symptoms are an important factor relating to suicidal ideation in individuals with FEP, over and above other clinical, sociodemographic, and developmental factors. This underscores the relevance of screening for suicidal ideation in individuals with FEP, and highlights the need for a better understanding of the diagnostic uncertainty and course of mood symptoms in early psychosis.
CONCLUSIONS: Cross-sectional study design, self-reported questionnaires.

Deficits in N-methyl-d-aspartate receptor (NMDAR) signaling are implicated in the pathogenesis of schizophrenia. Luvadaxistat (TAK-831/NBI-1065844) is an investigational d-amino acid oxidase (DAAO) inhibitor that increases d-serine levels at NMDAR coagonist sites. INTERACT is a phase 2 randomized, placebo-controlled study that evaluated the efficacy and safety of three doses of luvadaxistat, covering a range of DAAO occupancy and d-serine levels, in patients with schizophrenia with persistent negative symptoms. The study included a 14-day, single-blinded placebo run-in period and a 12-week, double-blinded treatment period. The primary efficacy endpoint was the 12-week change from baseline in Positive and Negative Syndrome Scale-Negative Symptom Factor Score (PANSS NSFS). Secondary efficacy endpoints included the 12-week changes from baseline in Brief Assessment of Cognition in Schizophrenia (BACS) score and Schizophrenia Cognition Rating Scale (SCoRS) score. Safety endpoints included adverse event assessments. The full analysis set included all randomized patients (N = 256 [placebo, n = 87; luvadaxistat 50 mg, n = 58; 125 mg, n = 56; 500 mg, n = 55]); 228 patients completed the study. No significant improvements in PANSS NSFS were observed at any dose versus placebo at week 12. Improvements were observed with luvadaxistat 50 mg versus placebo in cognitive endpoints: BACS composite score (nominal one-sided p = 0.031) and SCoRS interviewer total score (nominal one-sided p = 0.011). Luvadaxistat did not significantly improve negative symptoms of schizophrenia. However, luvadaxistat 50 mg met the prespecified secondary endpoints for cognitive performance (BACS) and function (SCoRS), warranting further investigation in patients with cognitive impairment associated with schizophrenia. Luvadaxistat was well-tolerated in INTERACT, with no new safety signals observed. ClinicalTrials.gov: NCT03382639.

Many people with schizophrenia spectrum disorders (SSDs) experience profound amotivation, which is strongly related to anticipatory anhedonia. Yet, the neuropsychological fundamentals of anticipatory anhedonia and amotivation are barely understood, resulting in a lack of effective treatments for these patients. Aberrancies in positive mental imagery may interfere with the anticipation of pleasure and could thus explain anticipatory anhedonia and amotivation. However, the nature of mental imagery and its relationship with amotivational psychopathology in SSD is largely unknown. In this preregistered study, we therefore examined mental imagery characteristics and their relation to anticipatory anhedonia, amotivation, and daily life activity in SSD. TheN = 86 participants included individuals with SSD (n = 43) and demographically matched healthy controls (n = 43). Mental imagery, anticipatory pleasure, amotivation, and activity engagement were assessed with structured interviews and self-report questionnaires. Ecological momentary assessment was used to measure state anticipatory pleasure and activity engagement in daily life (n = 81). Compared to the control group, the SSD group showed comparable quantity, but less vividness of mental imagery. Reduced vividness of mental imagery in SSD was significantly associated with higher anticipatory anhedonia, amotivation, and low activity engagement in cross-sectional and prospective analyses. Reduced mental imagery vividness may cause a lack of internal incentive to seek pleasurable experiences and could explain amotivation. Interventions aiming to improve mental imagery vividness and related anticipatory pleasure responses in SSD may be effective in targeting amotivation.

BACKGROUND: The cognitive model of negative symptoms of schizophrenia suggests that defeatist performance beliefs (DPB), or overgeneralized negative beliefs about one\'s performance, are an intermediary variable along the pathway from impaired neurocognitive performance to negative symptoms and functioning in daily life. Although reliable associations between these variables have been established in chronic schizophrenia, less is known about the nature of these relationships in recent-onset schizophrenia (ROSz). This current study tested the associations between DPB and variables in the cognitive model (neurocognitive performance, negative symptoms, functioning) as well as mediation by DPB of the association between neurocognitive performance and negative symptoms in ROSz.
METHODS: A total of 52 participants (32 adults with ROSz and 20 non-psychiatric healthy comparators; HC) completed in-lab measures of neurocognitive performance, self-reported defeatist performance beliefs, and clinician administered measures of negative symptoms and functional outcome. Bivariate relationships among these variables were tested with Pearson correlations. Bootstrapped regression analyses were conducted to test the strength of the indirect effect of neurocognitive performance on negative symptoms through DPB.
RESULTS: Defeatist performance beliefs were significantly elevated in ROSz, and were associated with neurocognitive performance, negative symptoms, and functional outcome as predicted by the cognitive model. There was a significant indirect effect of neurocognition on experiential negative symptoms through DPB, indicating DPB are a partial mediator of the relationship between neurocognitive performance and negative symptoms.
CONCLUSIONS: These findings are consistent with the cognitive model of negative symptoms and extend previous findings in both ROSz and established schizophrenia. Specifically, these data demonstrate that DPB are elevated among ROSz and the associations with neurocognition and clinical outcomes (e.g., negative symptoms and functioning) are of similar magnitude to those reported in chronic schizophrenia. DPB may therefore be a viable treatment target in the early course of illness.

UNASSIGNED: Negative symptoms of schizophrenia (NSS) have been linked with poor functional outcomes. A literature review was performed to identify instruments used to assess functional outcomes and quality of life in clinical trials and observational studies conducted in groups of people with NSS.
UNASSIGNED: Literature search strings were designed using Medical Subject Headings combined with free-text terms and searches were performed using the PubMed, Embase and the Cochrane Library databases. For inclusion, articles were required to be published as full-text articles, in English, over the period 2011-2021, include at least one group or treatment arm of people with NSS and report either functional outcomes or quality of life (QoL).
UNASSIGNED: Literature searches identified a total of 3,268 unique hits. After two rounds of screening, 37 publications (covering 35 individual studies) were included in the review. A total of fourteen different instruments were used to assess functional outcomes and eleven different instruments were used to assess QoL. In studies in people with NSS, the most frequently used functional outcome measures were the Personal and Social Performance scale and the Global Assessment of Functioning. The most frequently used QoL instruments included the Manchester Short Assessment of Quality of Life, the Heinrich Carpenter Quality of Life Scale, the Schizophrenia Quality of Life Scale and the EQ-5D.
UNASSIGNED: A large number of measures have been used to assess functional outcomes and QoL in people with NSS, these include both generic and condition-specific as well as both interviewer-administered and self-reported instruments.

BACKGROUND: Early Psychosis patients (EP, within 3 years after psychosis onset) show significant variability, making outcome predictions challenging. Currently, little evidence exists for stable relationships between neural microstructural properties and symptom profiles across EP diagnoses, limiting the development of early interventions.
METHODS: A data-driven approach, Partial Least Squares (PLS) correlation, was used across two independent datasets to examine multivariate relationships between white matter (WM) properties and symptomatology, to identify stable and generalizable signatures in EP. The primary cohort included EP patients from the Human Connectome Project-Early Psychosis (n=124). The replication cohort included EP patients from the Feinstein Institute for Medical Research (n=78). Both samples included individuals with schizophrenia, schizoaffective disorder, and psychotic mood disorders.
RESULTS: In both cohorts, a significant latent component (LC) corresponded to a symptom profile combining negative symptoms, primarily diminished expression, with specific somatic symptoms. Both LCs captured comprehensive features of WM disruption, primarily a combination of subcortical and frontal association fibers. Strikingly, the PLS model trained on the primary cohort accurately predicted microstructural features and symptoms in the replication cohort. Findings were not driven by diagnosis, medication, or substance use.
CONCLUSIONS: This data-driven transdiagnostic approach revealed a stable and replicable neurobiological signature of microstructural WM alterations in EP, across diagnoses and datasets, showing a strong covariance of these alterations with a unique profile of negative and somatic symptoms. This finding suggests the clinical utility of applying data-driven approaches to reveal symptom domains that share neurobiological underpinnings.

BACKGROUND: First-Episode Psychosis (FEP) is a devastating mental health condition that commonly emerges during early adulthood, and is characterised by a disconnect in perceptions of reality. Current evidence suggests that inflammation and perturbed immune responses are involved in the pathology of FEP and may be associated specifically with negative symptoms. Exercise training is a potent anti-inflammatory stimulus that can reduce persistent inflammation, and can improve mood profiles in general populations. Therefore, exercise may represent a novel adjunct therapy for FEP. The aim of this study was to assess the effect of exercise on biomarkers of inflammation, negative symptoms of psychosis, and physiological health markers in FEP.
METHODS: Seventeen young males (26.67 ± 6.64 years) were recruited from Birmingham Early Intervention in Psychosis Services and randomised to a 6-week exercise programme consisting of two-to-three sessions per week that targeted 60-70 % heart-rate max (HRMax), or a treatment as usual (TAU) condition. Immune T-helper (Th-) cell phenotypes and cytokines, symptom severity, functional wellbeing, and cognition were assessed before and after 6-weeks of regular exercise.
RESULTS: Participants in the exercise group (n = 10) achieved 81.11 % attendance to the intervention, with an average exercise intensity of 67.54 % ± 7.75 % HRMax. This led to favourable changes in immune cell phenotypes, and a significant reduction in the Th1:Th2 ratio (-3.86 %) compared to the TAU group (p = 0.014). After the exercise intervention, there was also a significant reduction in plasma IL-6 concentration (-22.17 %) when compared to the TAU group (p = 0.006). IL-8, and IL-10 did not show statistically significant differences between the groups after exercise. Symptomatically, there was a significant reduction in negative symptoms after exercise (-13.54 %, Positive and Negative Syndrome Scale, (PANSS) Negative) when compared to the TAU group (p = 0.008). There were no significant change in positive or general symptoms, functional outcomes, or cognition (all p > 0.05).
CONCLUSIONS: Regular moderate-to-vigorous physical activity is feasible and attainable in clinical populations. Exercise represents a physiological tool that is capable of causing significant inflammatory biomarker change and concomitant symptom improvements in FEP cohorts, and may be useful for treatment of symptom profiles that are not targeted by currently prescribed antipsychotic medication.

UNASSIGNED: Our object is to examine the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) on the symptoms, cognitive functions and subjective experiences in patients with chronic schizophrenia and to enhance the overall understanding of the TMS method.
UNASSIGNED: Thirty three patients who had chronic schizophrenia were included in the study. Seventeen patients received rTMS and 16 received sham. The Positive and Negative Syndrome Scale, Repeatable Battery for the Assessment of Neuropsychological Status Scale, Insight and Treatment Attitudes Questionnaire and a self-experience checklist developed by the researchers to evaluate post-TMS experiences were applied to all patients.
UNASSIGNED: There were no statistical differences between the groups with regard to symptoms, cognitive functions and insight. However rTMS group reported overall better treatment experience and more positive subjective experiences.
UNASSIGNED: rTMS treatment did not cause any improvement in symptoms, cognitive functions and insight but provided a better self-experience, which might improve treatment compliance.

UNASSIGNED: The onset of psychotic symptoms occurs prior to age 19 in 39% of the patients with schizophrenia. There are limited approved treatment options for adolescents with schizophrenia. Brexpiprazole was approved by the United States Food and Drug Administration (FDA) for treatment of schizophrenia in adolescents in 2022.
UNASSIGNED: Extrapolation of adult data to youth and use of pharmacologic modeling coupled with open long-term safety data were used by the FDA to approve brexpiprazole for adolescent schizophrenia. They were all reviewed herein.
UNASSIGNED: D2 receptor partial agonist antipsychotic agents are preferred in the early phase of treatment of psychotic disorders. Approval of brexpiprazole in adolescent schizophrenia provides an additional option. Brexpiprazole was approved by the FDA on the basis of extrapolation of adult data without controlled trials in adolescents. This reduces placebo exposure in young people. Two previous agents (asenapine and ziprasidone) approved for adult schizophrenia failed to separate from placebo in adolescent schizophrenia studies; this partially undermines the process of extrapolation. For brexpiprazole, the paucity of data in adolescents relegates it to a second-line agent. More research on brexpiprazole is needed to delineate its relative role in the management of adolescent schizophrenia.

UNASSIGNED: Negative symptoms and cognitive impairments are highly frequent in schizophrenia spectrum disorders (SSD), associated with adverse functional outcomes and quality of life. Repetitive transcranial magnetic stimulation (rTMS) has been considered a promising therapeutic option in SSD. However, placebo effects of rTMS on these symptoms remained unclear.
UNASSIGNED: To investigate placebo effects of rTMS on alleviating negative symptoms and cognitive impairment in patients with SSD and to explore potential moderators.
UNASSIGNED: We systematically searched five electronic databases up to 15 July 2023. Randomized, double-blind, sham-controlled trials investigating effects of rTMS on negative symptoms or cognition in patients with SSD were included. The pooled placebo effect sizes, represented by Hedges\' g, were estimated using the random-effects model. Potential moderators were explored through subgroup analysis and meta-regression.
UNASSIGNED: Forty-four randomized controlled trials with 961 patients (mean age 37.53 years; 28.1% female) in the sham group were included. Significant low-to-moderate pooled placebo effect sizes were observed for negative symptoms (g=0.44, p<0.001), memory (g=0.31, p=0.010), executive function (g=0.35, p<0.001), working memory (g=0.26, p=0.004), and processing speed (g=0.36, p=0.004). Subgroup analysis indicated that placebo effects were affected by sham stimulation methods, rTMS targeting approaches, and stimulation frequency.
UNASSIGNED: Placebo effects of rTMS on negative symptoms and cognition in patients with SSD are significant in a small-to-moderate magnitude, which might be mediated by rTMS parameters. Our findings will provide new insights for practitioners to further optimize and establish standardized rTMS protocols for future RCTs tackling cardinal symptoms in SSD.
UNASSIGNED: https://www.crd.york.ac.uk/prospero/, identifier CRD42023390138.