Biological Psychiatry

Understanding the mechanisms underlying the response to antipsychotic medications is critical for refining targets for new interventions and predicting clinical outcomes. This study presents a mega-analysis of individual participant data (N = 1,189) from 18 {superscript 1}H-MRS datasets to examine differences in neurometabolites in antipsychotic non-responsive compared to antipsychotic-responsive psychosis, accompanied by complementary meta-analyses across the wider published literature (23 stud...

ObjectiveThe pathophysiology of psychosis remains unclear. Preclinical, postmortem, and imaging evidence implicates iron and neuromelanin, but the consistency and magnitude of effects are uncertain. We aimed to characterise brain iron and neuromelanin alterations in psychosis through a systematic review and meta-analysis of iron-sensitive MRI and neuromelanin-sensitive MRI (NM-MRI) studies. MethodsWe searched EMBASE, PubMed, and PsycINFO from inception to October 31, 2025, for case-control stud...

Psychotic disorders are increasingly recognized as the extreme end of a progressive psychopathology continuum, with less advanced stages including the asymptomatic familial high-risk state (FHR), the help-seeking clinical high-risk state (CHR), and first episode psychosis (FEP). However, we lack a comprehensive study of clinical, cognitive, functional, and neuroanatomical markers across all three early stages of psychosis, limiting our understanding of how the multimodal phenotypes which define ...

Deficits in inhibitory control are common across a wide range of psychiatric disorders and are closely linked to symptom severity, including emotional dysregulation, anxiety, substance misuse, and self-harm, making them an appealing target for intervention. Cognitive training offers a low-cost, scalable, and non-invasive strategy to strengthen inhibitory control; however, most existing paradigms target only a single facet of inhibition and rarely account for environmental influences, such as aff...

BackgroundLipidomic alterations have been reported across schizophrenia (SCZ) and bipolar disorder (BD), but findings are heterogeneous and often overlap across diagnoses, limiting diagnostic specificity. Associations between lipid profiles and illness severity have also been inconsistent when assessed using single symptom scales, raising the possibility that unidimensional measures fail to capture biologically relevant variation. Whether plasma lipidomic alterations relate to multidimensional p...

Enzyme-mediated RNA modifications provide a versatile and dynamic regulatory layer that fine-tunes gene expression programs throughout brain development and in mature neural function. More than 100 RNA modification proteins (RMPs) have been identified to drive the dynamics of RNA modifications; yet how genetic variation in human RMP genes contributes to the risks of neurological disorders has not been systematically examined. Here we have curated 123 RMPs corresponding to 31 RNA modifications on...

BackgroundAuditory hallucinations are among the most disabling symptoms in individuals with schizophrenia (SZ) and are linked to aberrant signaling within deep-striatal circuits, such as the nucleus accumbens (NAc) and caudate head (CH). However, causal tests of striatal involvement have been limited by the inaccessibility of these structures using noninvasive neuromodulatory techniques. Low-intensity focused ultrasound (LIFU) provides millimeter-scale precision capable of modulating deep-brain ...

BackgroundEarly detection of individuals at risk for clinical deterioration in first-episode psychosis (FEP) remains a vital challenge in psychiatric care. Emerging evidence indicates that immune dysregulation might play a crucial role in the pathophysiology and progression of psychotic disorders. AimsThis study examined the predictive potential of a plasma cytokine and chemokine panel in anticipating clinical stage transition of FEP patients. MethodUsing multiplex immunoassays, plasma samples...

Schizophrenia spectrum disorders (SSDs) are clinically and biologically heterogeneous and lack reliable biomarkers for stratification and outcome prediction. Evidence from postmortem, fluid biomarker, and neuroimaging studies suggests that blood-brain barrier (BBB) dysfunction may contribute to pathophysiology in a biologically defined subgroup. However, findings are inconsistent and often based on cross-sectional or indirect measures. The IMPACT study is a longitudinal, multimodal investigatio...

Anxiety is marked by exaggerated vigilance which may be linked to impaired sensory habituation, yet the physiological mechanisms linking anxiety to dysregulated habituation in the brain remain unclear. The brains ability to filter sensory input is characteristic of healthy functioning and disruption of this can lead to over-responsiveness and hypervigilance that may underlie pathological anxiety. Here, we examined how state and trait anxiety relate to acoustic startle reflex habituation across s...

Neuroticism is a core personality trait linked to emotional instability and increased risk for anxiety, depression, and schizophrenia. Most genome-wide association studies (GWAS) have focused on European populations, limiting the discovery of ancestry-specific genetic influences. To address this gap, we conducted the most diverse multi-ancestry GWAS meta-analysis of neuroticism to date, analyzing 668,780 individuals across African (AFR), European (EUR), East Asian (EAS), and South Asian (SAS) po...

Bullying is an adverse childhood experience affecting up to one-third of the global population and linked to psychosis-like experiences (PLEs), which increase the risk of psychotic disorders. This study aimed to investigate the association between the severity and persistence of bullying and PLEs and the neurobiological pathways from bullying to psychosis-like experiences by assessing multiscale brain functional network connectivity (msFNC). We used data from the ABCD Study, a large, ongoing, mu...

BackgroundCerebellar transcranial magnetic stimulation (TMS) may serve as an adjuvant therapy for psychosis symptoms, most recently we have shown improvements in negative symptoms. Historically, cerebellum TMS has not utilized functional neuroanatomy for targeting, and the precision of TMS to the cerebellum is unclear. A classical view of the cerebellum as solely involved in motor computations has been updated with the discovery of rich non-motor connectivity including the default, dorsal attent...

BackgroundUnderstanding how variation in brain structure and function contributes to psychiatric and behavioral phenotypes remains a key challenge. The absence of neuroimaging data in many study samples limits this effort. MethodsWe used genome-wide association study (GWAS) summary statistics from the UK Biobank to impute 301 brain imaging-derived phenotype (IDP) genetic scores (IGS) in the Yale-Penn cohort, which is enriched for substance use disorders (n = 10,275; 52.8% European-like [EUR] an...

Changes in basic associative learning processes have been identified in several psychiatric conditions. However, it remains unknown whether these findings result from ongoing psychopathology or represent an underlying transdiagnostic risk factor for multiple clinical states. In this study, 72 participants with subclinical psychopathology, 23 of whom met criteria for the clinical high-risk for psychosis transdiagnostic risk syndrome (CHR+), completed a fear conditioning and generalization paradig...

Background and HypothesisAbnormal default mode network (DMN) connectivity was observed in both tobacco use and psychotic spectrum disorders, but it remains unknown how psychosis impacts the relationship between connectivity and tobacco use. Interventions targeting the left lateral parietal DMN node (LLPDMN) have modulated DMN connectivity and nicotine craving in psychosis. We aimed to investigate relationships between DMN connectivity, psychotic illness, and tobacco use. Study Design336 partici...

BackgroundAntipsychotics are central to relapse prevention in schizophrenia, but longer-term use is associated with adverse effects that often prompt dose reduction or discontinuation. Although relapse risk increases after discontinuation, the nature of relapse remains unclear. Specifically, it is uncertain whether relapse reflects re-emergence of underlying illness or pharmacological withdrawal. MethodsWe analysed longitudinal symptom data (Positive and Negative Syndrome Scale; PANSS) from 417...

ObjectiveWe examined the clinical utility of resting state electroencephalography (rsEEG) by evaluating its temporal stability, discriminant validity for B-SNIP psychosis Biotypes, and suitability as a treatment target for brain stimulation. MethodsWe collected 5 minutes of eyes-open rsEEG from 1401 participants with psychosis and 750 healthy persons. A subset of participants was re-tested after 6 months and 12 months (N=109). In a pilot target engagement study (n=5) we collected rsEEG before a...

Obsessive-compulsive symptoms, characterized by intrusive thoughts and repetitive behaviors, are prevalent among youth. These symptoms are known to be moderately heritable and linked to structural brain changes involved in their pathophysiology. This study investigates the connections between structural brain alterations (cortical thickness, surface area and subcortical volume), genetic variation, and childhood obsessive-compulsive symptom scores within 143 samples of healthy control participant...

Major depression (MD) is a disorder class that exhibits substantial phenotypic and clinical heterogeneity, yet many large-scale molecular genetic investigations treat MD as a unitary outcome. Here, we applied Genomic Structural Equation Modeling (Genomic SEM) to characterize the genetic variation in two clinically relevant MD subtypes, childhood-onset (child-onset) and treatment-resistant MD, that are independent of the field-standard GWAS of MD in all its forms. In addition, we fit a complement...