Abstract Background and Hypothesis Sleep disturbance is a well-established risk factor for suicide, though few studies to date have examined whether sleep disturbance contributes to suicide risk among individuals at clinical high risk for psychosis (CHR). The current study addressed this gap in the literature. We hypothesized that sleep disturbance would have a unique relationship with suicidal ideation/attempts when accounting for other variables in the model. We also hypothesized that the interaction between sleep disturbance/attenuated positive symptoms and sleep disturbance/stress would be related to suicidal ideation/attempts in CHR. Study Design The current study used data generated by the Accelerating Medicines Partnership® Schizophrenia Observational Study. The total sample included 1,048 participants (827 CHR and 221 community controls). Participants completed measures of suicidal ideation/attempts, attenuated positive symptoms, depressive symptoms, perceived stress, and sleep disturbance. Study Results Results supported a relationship between sleep disturbance and suicidal ideation/attempts in CHR, with participants who had lifetime ideation and attempts experiencing more sleep disturbance than those with no ideation or attempts. We also found small, but significant positive correlations between sleep disturbance and suicide risk in CHR. When accounting for other variables in the model, the effect of sleep disturbance remained significant for past month ideation, but not lifetime ideation or attempts. Both interaction models were non-significant. Conclusions Our findings highlight the potential value of sleep measures in early identification and treatment of suicide risk in CHR. Further research in this area is warranted.
H. Wastler, Aubrey M. Moe, Alexandra M Blouin et al.· Schizophrenia Bulletin Open· 0 citations
Importance
Dopaminergic dysregulation has been considered the final common pathway for pathophysiology of schizophrenia and related disorders (SRD). However, this model does not adequately explain treatment resistance, cognitive impairment, negative symptoms, and marked biological heterogeneity across patients.
Objective
To examine whether SRD are best conceptualized as resulting from a final common dopaminergic pathway or from several partially independent neurochemical mechanisms and to evaluate the implications of these models for treatment development.
Evidence Review
Neuroimaging, postmortem and genetic investigations, pharmacologic challenge paradigms, clinical trials, and animal models published between 1980 and 2025 were synthesized. Studies were identified through expert knowledge and targeted searches of PubMed and related databases. Systematic reviews, meta-analyses, and multimodal convergent findings were emphasized. Evidence was appraised qualitatively with attention to consistency, specificity, and translational relevance.
Findings
Positive psychotic symptoms are strongly linked to increased presynaptic dopaminergic activity in the associative striatum, which predicts response to dopamine D2 receptor antagonists. However, approximately one-third of patients exhibit treatment resistance and show no increase in striatal dopamine synthesis capacity. Increasing evidence implicates glutamatergic, gamma-aminobutyric acid (GABA)ergic, serotonergic, cholinergic, endocannabinoid, and opioidergic systems, as well as nonneurotransmitter processes including oxidative stress, mitochondrial dysfunction, and neuroinflammation. The efficacy of the muscarinic M1/M4-preferring agonist xanomeline-trospium, which lacks direct D2 receptor antagonism, suggests that nondopaminergic mechanisms can reduce psychotic symptoms. Neurochemically distinct subgroups within SRD may cut across overlapping clinical phenotypes.
Conclusions and Relevance
Dopaminergic hyperactivity may be a key mechanism for core psychotic symptoms in many patients, but it is unlikely that dopamine dysregulation is a universal final common pathway across symptom domains. A pluralistic model-recognizing multiple interacting neurochemical and cellular processes-may better account for heterogeneity and translational failures. Future development of novel treatments may depend on biomarker-informed stratification, mechanism-based clinical trials, and integration of molecular, circuit-level, and clinical phenotypes.
M. Keshavan, Henry Nasrallah, A. Abi-Dargham et al.· JAMA psychiatry· 0 citations
Associations between patterns of brain connectivity and brain structural features have transdiagnostic relevance to psychopathology. There is considerable evidence for disruptions to the hippocampus and temporoparietal brain systems in psychotic disorders. The present study examines structure–function relationships—specifically, the relation of hippocampal volume with patterns of temporoparietal effective connectivity—in youth at clinical high-risk for psychosis (CHR-P) and healthy controls (HCs). Participants at CHR-P and HCs completed clinical symptom measures and magnetic resonance imaging at baseline (n = 388, 42.5% female, age = 19.8 ± 4.2) in the second cohort of the North American Prodrome Longitudinal Study. Group Iterative Multiple Model Estimation established a common functional network of temporoparietal effective connectivity in the full sample. Next, supervised (assuming the CHR-P and HC groups represent classes) and unsupervised (data-driven) clustering procedures interrogated effective connectivity parameters relevant to subsamples. Mean difference tests by unsupervised cluster membership determined whether clusters formed based on temporoparietal effective connectivity differed in hippocampal volume. Clusters were also compared on representation of CHR-P and positive and negative symptom totals to determine whether unsupervised clustering recovered clinical features. Unsupervised clustering generated two clusters that differed significantly in right hippocampal volume and attenuated positive and negative symptoms with small-to-medium effect sizes. The cluster demonstrating reduced right hippocampal volume reported greater symptoms. Unsupervised clustering did not recover diagnostic groups. Findings are consistent with literature indicating the transdiagnostic relevance of hippocampal volume to organizational properties of brain functional networks and patterns of temporoparietal connectivity.
K. Aberizk, B. Ku, Hengyi Cao et al.· Brain Structure and Function· 0 citations