Katharine Chisholm

BACKGROUND: Specific cognitive impairments are common in major depressive disorder, impacting functioning and quality of life. However, the longitudinal course of cognitive functioning in depression is unclear. AIMS: This study aimed to determine the longitudinal course of cognitive functioning following a recent onset of depression, as compared to healthy controls. METHODS: Healthy controls and individuals experiencing a recent onset of depression (within two years) were recruited across ten European sites, completing the baseline and nine-month follow-up clinical, demographic, and cognitive assessment for the “PRONIA” study. RESULTS: The sample comprised 421 participants (depression, N=152; healthy controls, N=269) aged 15-40 years (M = 25.4, SD = 6.1; 55% female). Linear mixed effects models demonstrated baseline cognitive deficits in the depression group across most domains, except for visual memory, visuospatial working memory, and emotion recognition. Deficits in verbal learning and memory, attention, processing speed, mental flexibility, phonetic and semantic verbal fluency remained stable. Auditory verbal working memory showed a lag trajectory, with healthy controls improving at a greater rate than the depression group. Finally, sustained attention followed a catch-up trajectory, with baseline deficits normalising over time relative to healthy controls. In the depression group, most cognitive improvements were associated with reductions in depression symptomatology, except for verbal learning and memory, and verbal fluency. The catch-up trajectory of sustained attention was associated with reductions in depression. CONCLUSIONS: Specific cognitive impairments can already be evident at the first episode of depression, but cognitive functions show differential longitudinal trajectories irrespective of depressive course. Tailored treatment addressing cognition should be provided early to promote cognitive health and functional recovery.

Symptom heterogeneity characterizes psychotic disorders and hinders the delineation of underlying biomarkers. Here, we identify symptom-based subtypes of recent-onset psychosis (ROP) patients from the multi-center PRONIA (Personalized Prognostic Tools for Early Psychosis Management) database and explore their multimodal biological and functional signatures. We clustered N = 328 ROP patients based on their maximum factor scores in an exploratory factor analysis on the Positive and Negative Syndrome Scale items. We assessed inter-subgroup differences and compared to N = 464 healthy control (HC) individuals regarding gray matter volume (GMV), neurocognition, polygenic risk scores, and longitudinal functioning trajectories. Finally, we evaluated factor stability at 9- and 18-month follow-ups. A 4-factor solution optimally explained symptom heterogeneity, showing moderate longitudinal stability. The ROP-MOTCOG (Motor/Cognition) subgroup was characterized by GMV reductions within salience, control and default mode networks, predominantly throughout cingulate regions, relative to HC individuals, had the most impaired neurocognition and the highest genetic liability for schizophrenia. ROP-SOCWD (Social Withdrawal) patients showed GMV reductions within medial fronto-temporal regions of the control, default mode, and salience networks, and had the lowest social functioning across time points. ROP-POS (Positive) evidenced GMV decreases in salience, limbic and frontal regions of the control and default mode networks. The ROP-AFF (Affective) subgroup showed GMV reductions in the salience, limbic, and posterior default-mode and control networks, thalamus and cerebellum. GMV reductions in fronto-temporal regions of the salience and control networks were shared across subgroups. Our results highlight the existence of behavioral subgroups with distinct neurobiological and functional profiles in early psychosis, emphasizing the need for refined symptom-based diagnosis and prognosis frameworks.

Background: Autism and psychosis co-occur at elevated rates, with implications for clinical outcomes, functioning, and suicidality. The PANSS-Autism-Severity-Score (PAUSS) is a measure of autism trait severity which has not yet been validated externally or longitudinally. Study Design: Participants were derived from the GROUP and SCOPE datasets. Participants included 1448 adults with schizophrenia spectrum disorder (SSD), 800 SSD-siblings, 103 adults diagnosed with an autistic spectrum condition (ASC), and 409 typically-developing controls (TC). Analyses from the original validation study were conducted with SSD participants, and extended into ASC, SSD-sibling, and TC participants. Test–retest reliability of the PAUSS at 2-weeks and long-term stability 3 and 6-years was also examined. Study Results: Results differed in important ways from the original validation. SSD participants reported higher PAUSS scores than other groups, with only a fraction of ASC participants scoring as “PAUSS-Autistic.” Cronbach’s alpha was acceptable for the SSD cohort only. Two-week stability of the PAUSS was fair to good for all PAUSS scores. Long-term stability was poor for most PAUSS items but fair for total PAUSS score. Conclusions: Results suggest that the PAUSS does not appear appropriate for assessing autism, with the low rate of PAUSS-Autistic in the ASC population suggesting the PAUSS may not accurately reflect characteristics of autism. The relative lack of long-term stability is cause for concern and suggestive that the PAUSS is capturing features of psychosis rather than autism traits.

Background: Autism and psychosis co-occur at elevated rates, with implications for clinical outcomes, functioning, and suicidality. The PANSS-Autism-Severity-Score (PAUSS) is a measure of autism trait severity which has not yet been validated externally or longitudinally. Study Design: Participants were derived from the GROUP and SCOPE datasets. Participants included 1448 adults with schizophrenia spectrum disorder (SSD), 800 SSD-siblings, 103 adults diagnosed with an autistic spectrum condition (ASC), and 409 typically-developing controls (TC). Analyses from the original validation study were conducted with SSD participants, and extended into ASC, SSD-sibling, and TC participants. Test-retest reliability of the PAUSS at 2-weeks and long-term stability 3 and 6-years was also examined.Study Results: Results differed in important ways from the original validation. SSD participants reported higher PAUSS scores than other groups, with only a fraction of ASC participants scoring as ‘PAUSS-Autistic’. Cronbach’s alpha was acceptable for the SSD cohort only. Two-week stability of the PAUSS was fair to good for all PAUSS scores. Long-term stability was poor for most PAUSS items but fair for total PAUSS score.Conclusions: Results suggest that the PAUSS does not appear appropriate for assessing autism, with the low rate of PAUSS-Autistic in the ASC population suggesting the PAUSS may not accurately reflect characteristics of autism. The relative lack of long-term stability is cause for concern and suggestive that the PAUSS is capturing features of psychosis rather than autism traits.

Functional impairment is a core feature of both autism and schizophrenia spectrum disorders. While diagnostically independent, they can co-occur in the same individual at both the trait and diagnostic levels. The effect of such co-occurrence is hypothesized to worsen functional impairment. The diametric model, however, suggests that the disorders are etiologically and phenotypically diametrical, representing the extreme of a unidimensional continuum of cognition and behavior. A central prediction of this model is that functional impairment would be attenuated in individuals with mixed symptom expressions or genetic liability to both disorders. We tested this hypothesis in two clinical populations and one healthy population. In individuals with chronic schizophrenia and in individuals with first episode psychosis we evaluated the combined effect of autistic traits and positive psychotic symptoms on psychosocial functioning. In healthy carriers of alleles of copy number variants (CNVs) that confer risk for both autism and schizophrenia, we also evaluated whether variation in psychosocial functioning depended on the combined risk conferred by each CNV. Relative to individuals with biased symptom/CNV risk profiles, results show that functional impairments are attenuated in individuals with relatively equal levels of positive symptoms and autistic traits—and specifically stereotypic behaviors—, and in carriers of CNVs with relatively equal risks for either disorder. However, the pattern of effects along the “balance axis” varied across the groups, with this attenuation being generally less pronounced in individuals with high-high symptom/risk profile in the schizophrenia and CNV groups, and relatively similar for low-low and high-high individuals in the first episode psychosis group. Lower levels of functional impairments in individuals with “balanced” symptom profile or genetic risks would suggest compensation across mechanisms associated with autism and schizophrenia. CNVs that confer equal risks for both disorders may provide an entry point for investigations into such compensatory mechanisms. The co-assessment of autism and schizophrenia may contribute to personalized prognosis and stratification strategies.

Adult gyrification provides a window into coordinated early neurodevelopment when disruptions predispose individuals to psychiatric illness. We hypothesized that the echoes of such disruptions should be observed within structural gyrification networks in early psychiatric illness that would demonstrate associations with developmentally relevant variables rather than specific psychiatric symptoms. We employed a new data-driven method (Orthogonal Projective Non-Negative Matrix Factorization) to delineate novel gyrification-based networks of structural covariance in 308 healthy controls. Gyrification within the networks was then compared to 713 patients with recent onset psychosis or depression, and at clinical high-risk. Associations with diagnosis, symptoms, cognition, and functioning were investigated using linear models. Results demonstrated 18 novel gyrification networks in controls as verified by internal and external validation. Gyrification was reduced in patients in temporal-insular, lateral occipital, and lateral fronto-parietal networks (p^FDR < 0.01) and was not moderated by illness group. Higher gyrification was associated with better cognitive performance and lifetime role functioning, but not with symptoms. The findings demonstrated that gyrification can be parsed into novel brain networks that highlight generalized illness effects linked to developmental vulnerability. When combined, our study widens the window into the etiology of psychiatric risk and its expression in adulthood.

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.