Key Points Question Is there evidence for a potential relationship between inflammation and brain structure, and is this relevant for schizophrenia and other neuropsychiatric disorders? Findings In this mendelian randomization study including 20 688 participants in the UK Biobank, genetically predicted levels of interleukin 6 were associated with gray matter volume and cortical thickness primarily in the middle temporal gyrus and superior frontal region. The middle temporal gyrus overexpressed a number of genes relevant to interleukin 6 pathway proteins and neuropsychiatric disorder ontologies, including schizophrenia and autism spectrum disorder. Meaning This study found that inflammation may be associated with brain structure and may be an early predeterminant of neuropsychiatric conditions, which has important implications for identification of risk and novel treatments.

Auditory verbal hallucinations (AVH) often lead to distress and functional disability, and are frequently associated with psychotic illness. Previously both state and trait magnetic resonance imaging (MRI) studies of AVH have identified activity in brain regions involving auditory processing, language, memory and areas of default mode network (DMN) and salience network (SN). Current evidence is clouded by research mainly in participants on long-term medication, with chronic illness and by choice of seed regions made ‘a priori’. Thus, the aim of this study was to elucidate the intrinsic functional connectivity in patients presenting with first episode psychosis (FEP). Resting state functional MRI data were available from 18 FEP patients, 9 of whom also experienced AVH of sufficient duration in the scanner and had symptom capture functional MRI (sc fMRI), together with 18 healthy controls. Symptom capture results were used to accurately identify specific brain regions active during AVH; including the superior temporal cortex, insula, precuneus, posterior cingulate and parahippocampal complex. Using these as seed regions, patients with FEP and AVH showed increased resting sb-FC between parts of the SN and the DMN and between the SN and the cerebellum, but reduced sb-FC between the claustrum and the insula, compared to healthy controls.It is possible that aberrant activity within the DMN and SN complex may be directly linked to impaired salience appraisal of internal activity and AVH generation. Furthermore, decreased intrinsic functional connectivity between the claustrum and the insula may lead to compensatory over activity in parts of the auditory network including areas involved in DMN, auditory processing, language and memory, potentially related to the complex and individual content of AVH when they occur.

Diagnostic heterogeneity within and across psychotic and affective disorders challenges accurate treatment selection, particularly in the early stages. Delineation of shared and distinct illness features at the phenotypic and brain levels may inform the development of more precise differential diagnostic tools. We aimed to identify prototypes of depression and psychosis to investigate their heterogeneity, with common, comorbid transdiagnostic symptoms. Analyzing clinical/neurocognitive and grey matter volume (GMV) data from the PRONIA database, we generated prototypic models of recent-onset depression (ROD) vs. recent-onset psychosis (ROP) by training support-vector machines to separate patients with ROD from patients with ROP, who were selected for absent comorbid features (pure groups). Then, models were applied to patients with comorbidity, ie, ROP with depressive symptoms (ROP+D) and ROD participants with sub-threshold psychosis-like features (ROD+P), to measure their positions within the affective-psychotic continuum. All models were independently validated in a replication sample. Comorbid patients were positioned between pure groups, with ROP+D patients being more frequently classified as ROD compared to pure ROP patients (clinical/neurocognitive model: χ2 = 14.874; P < .001; GMV model: χ2 = 4.933; P = .026). ROD+P patient classification did not differ from ROD (clinical/neurocognitive model: χ2 = 1.956; P = 0.162; GMV model: χ2 = 0.005; P = .943). Clinical/neurocognitive and neuroanatomical models demonstrated separability of prototypic depression from psychosis. The shift of comorbid patients toward the depression prototype, observed at the clinical and biological levels, suggests that psychosis with affective comorbidity aligns more strongly to depressive rather than psychotic disease processes. Future studies should assess how these quantitative measures of comorbidity predict outcomes and individual responses to stratified therapeutic interventions.

Abstract Depression frequently occurs in first-episode psychosis (FEP) and predicts longer-term negative outcomes. It is possible that this depression is seen primarily in a distinct subgroup, which if identified could allow targeted treatments. We hypothesize that patients with recent-onset psychosis (ROP) and comorbid depression would be identifiable by symptoms and neuroanatomical features similar to those seen in recent-onset depression (ROD). Data were extracted from the multisite PRONIA study: 154 ROP patients (FEP within 3 months of treatment onset), of whom 83 were depressed (ROP+D) and 71 who were not depressed (ROP−D), 146 ROD patients, and 265 healthy controls (HC). Analyses included a (1) principal component analysis that established the similar symptom structure of depression in ROD and ROP+D, (2) supervised machine learning (ML) classification with repeated nested cross-validation based on depressive symptoms separating ROD vs ROP+D, which achieved a balanced accuracy (BAC) of 51%, and (3) neuroanatomical ML-based classification, using regions of interest generated from ROD subjects, which identified BAC of 50% (no better than chance) for separation of ROP+D vs ROP−D. We conclude that depression at a symptom level is broadly similar with or without psychosis status in recent-onset disorders; however, this is not driven by a separable depressed subgroup in FEP. Depression may be intrinsic to early stages of psychotic disorder, and thus treating depression could produce widespread benefit.