Stephan Ruhrmann

Childhood adversities and trauma (CAT) are linked to cognitive impairment, but their effects may vary across clinical profiles and in the presence of ongoing environmental stressors. We investigated CAT-cognition associations across recent-onset psychosis (ROP), clinical high risk for psychosis (CHR), recent-onset depression (ROD), and healthy controls (HC), and whether recent life events and perceived discrimination moderated these associations. We used baseline data from the PRONIA cohort (ROP: N = 150; CHR: N = 142; ROD: N = 148; HC: N = 282). Cognitive performance was assessed across social cognition, speed of processing, working and verbal memory, attention, and global cognition. Associations were tested using covariate-adjusted linear regression models based on HC-derived normative residualization, followed by moderation analyses. In ROP, higher CAT were associated with increased speed of processing (β = 0.29, p _fdr = .046). In CHR, CAT was associated with poorer social cognition, but higher attention and working memory scores (b = -0.20 to 0.44, p _fdr ≤ .042). In HC, increased physical neglect was associated with poorer attention (b = -0.64, p _fdr < .001). Perceived discrimination moderated associations between emotional abuse and attention in the ROP group (β = -4.721, 95% CI [-7.81, -1.63]), and between emotional abuse and social cognition in the ROD group (β = 7.834, 95% CI [2.430, 13.238]). CAT-cognition associations were heterogeneous across clinical groups, with perceived discrimination moderating specific associations. Relationships between CAT, particularly emotional neglect, and cognitive performance is not uniform but may vary depending on clinical context and ongoing psychosocial stressors.

White matter (WM) alterations are well documented in individuals at clinical high-risk for psychosis (CHR-P) and with recent-onset psychosis (ROP), yet it remains unclear whether they reflect vulnerability, psychosis-related symptom severity, or general impairments shared with other disorders such as depression. To disentangle these correlates, we analyzed diffusion MRI data from 882 individuals (457 females) of the multisite Personalized Prognostic Tools for Early Psychosis Management (PRONIA) study, including 183 CHR-P, 206 ROP, 298 healthy controls, and 195 individuals with depression who were assessed as a clinical comparison group of observed associations. Fractional anisotropy (FA) was extracted from 25 WM regions. Analyses of covariance tested group differences across CHR-P, ROP, and healthy controls. Canonical correlation analysis then identified multivariate correlation components between FA and a broad set of twelve clinical, two cognitive, and two risk-related measures in CHR-P and ROP, restricted to regions with group effects. To identify if these findings are not specific to psychosis, we additionally tested whether the correlation components were expressed in the depression comparison group. Group differences emerged in 17 of 25 regions. Canonical correlation analysis identified two significant correlation components. Component 1 linked widespread lower FA with impaired cognition and functioning, representing general impairment. Component 2 linked focal lower FA with more severe psychosis-related symptoms and absence of familial risk. Component 1, but not Component 2, showed also a significant association in the depression group emphasizing its relevance for general impairment. Disentangling general impairment from psychosis-related symptom severity suggests potentially different underlying processes. Developing imaging biomarkers accounting for these processes may guide early detection strategies and targeted interventions.

Individuals with psychosis and depression show widespread alterations in brain resting-state functional connectivity (rs-FC), affecting both sensory and higher-order brain regions. In this study, we investigate disruptions in the hierarchical organization of brain functional networks in individuals with psychotic and affective disorders. We derived functional brain gradients, low dimensional representations of rs-FC that capture cortical hierarchy, in a sample of 1071 (56.3% female) participants, including clinical high-risk for psychosis (CHR-P) individuals, recent-onset psychosis (ROP) patients, recent-onset depression (ROD) patients, and healthy controls (HC). We examined regional alterations, network-level alterations and functional differentiation and their relationship to clinical symptoms. In addition, we linked case-control differences to receptor expression maps to explore underlying neurobiological mechanisms. All clinical groups exhibited alterations in the visual-to-sensorimotor gradient, while only ROP patients showed alterations in the sensory-to-association gradient. CHR-P and ROP individuals exhibited lower values in the ventral attention network. Clinical groups combined showed higher values in the somatomotor network, a reduced gradient range and altered between-network dispersion. ROD patients showed reduced within-network dispersion in the attentional networks and a reduced range. Correlational analysis revealed weak associations of gradient measures with functioning, visual dysfunctions and cognition. Case-control differences showed associations to receptor expression maps, suggesting the involvement of neurotransmitter systems in these disruptions. Our findings reveal transdiagnostic and disease-specific alterations of hierarchical brain organization. These alterations indicate deficits in functional integration across psychiatric diseases, highlighting the role of attentional and sensory networks in disease processes.

Background: Major depressive disorder (MDD) is clinically heterogeneous, hindering identification of reproducible biomarkers. Using a semi-supervised machine learning approach, HYDRA, we previously identified two neuroanatomical dimensions from structural MRI in medication-free MDD from COORDINATE-MDD consortium. These dimensions (D1, D2) showed differential responses to selective serotonin reuptake inhibitor (SSRI) antidepressants and placebo. External replication in UK Biobank linked D2, characterized by widespread subtle neuroanatomical reductions, to an immuno-metabolic profile. Here, we examined whether these dimensions are detectable early in the course of illness. Methods: We applied the pre-trained model to structural MRI data from the multisite PRONIA cohort, comprising individuals with recent-onset depression (ROD; n = 377; mean age 25.8 years, SD 6.0; 51.3% female) and healthy controls (n = 267; mean age 25.5 years, SD 6.4; 61.0% female). Participants were assigned to clusters (C1, C2) corresponding to the previously identified dimensions (D1, D2). Clusters were compared on clinical symptom profiles, peripheral inflammatory markers, and in a subset (n = 107), proteomic ageing indices. Results: Two neuroanatomical clusters were identified in PRONIA. C1 (n = 265) showed higher negative symptom severity and elevated interleukin-2 levels. C2 (n = 140) was associated with higher residual proteomic age. Overall depressive symptom severity did not differ significantly between clusters. Conclusions: Neuroanatomical dimensions of MDD are reproducible and detectable at illness onset. Associations with negative symptom severity, inflammatory signalling, and proteomic ageing suggest these dimensions capture biologically meaningful heterogeneity early in depression. These findings support a biologically informed framework for stratified treatment approaches in MDD.

Deeper understanding of Subtle Visual Dysfunctions (VisDys) in the early stage of mental illness and their neurobiological underpinnings, as reflected by microstructural brain texture features, could advance our understanding of the underlying disease perceptual mechanisms that mediate susceptibility to psychosis. In this study, we aim a) to investigate the utility of brain texture features for the prediction of VisDys in recent onset psychosis (ROP) and clinical high-risk syndromes for psychosis (CHR-P), respectively, b) to test prediction models established in ROP and CHR-P in an independent validation sample with recent onset depression (ROD) diagnoses and c) to test for symptom expression related brain features associated with VisDys. sMRI were acquired in a training sample including 128 ROP (67 patients with VisDys), 134 CHR-P (71 patients with VisDys). Independent validation sets included 46 ROP (19 with VisDys), 124 CHR-P (68 patients with VisDys) and a sample of 256 ROD (50 patients with VisDys). Both classification schemas in ROP and CHR-P presented balanced accuracy >77% and >64% in the independent validation samples of ROP, CHR-P, and ROD, respectively. Statistically significant associations were identified with scores from the Positive and Negative Symptom Scale, psychosocial functioning, and the Scale of Negative Symptoms.

Symptom diversity in psychoses complicates the search for biological markers. Using Positive and Negative Symptom Scale data from 362 recent-onset patients in the multicenter PRONIA study, we identified four subgroups with dominant symptom patterns: motor/cognitive, positive, social withdrawal, and affective. Subgroups were compared against each other and to 338 healthy controls across neurocognition, brain imaging, and genetic risk. Patient subgroups shared a profile of impaired processing speed and altered functional connectivity, with increased coupling in sensorimotor networks and reduced connectivity within and between default-mode, salience, and control networks. Variations in modality-specific neurobiological underpinnings differentiated subgroups, with fronto-temporal gray-matter loss characterizing the motor/cognitive and positive subgroups, and elevated genetic risk best separating the positive subgroup from the rest. The motor/cognitive group showed the most severe alterations across modalities, reaching the highest multimodal separability from controls (Balanced Accuracy=82.1%, sensitivity=74.9%, specificity=89.3%). Our findings support a framework of shared biological dysfunction with modality-selective vulnerabilities shaping symptom heterogeneity in early-stage psychotic disorders.

Background and objectives: The functional outcome of patients with psychotic disturbances is associated with several overlapping premorbid, societal, neuropsychological, and clinical factors. Extracting the factors associated with functional outcomes is important for designing effective mental health interventions. Methods: In a naturalistic prospective European multicentre study, we analysed the effects of sociodemographic, preadmission, admission, and postadmission precursors on functional outcomes in 296 patients with recent-onset psychosis (ROP) and 262 patients at clinically high risk of psychosis (CHR-P). Functioning was assessed with the Global Assessment of Functioning—symptoms and deficits version—at baseline and at the 9- and 18-month follow-ups. Results: In the overall sample, male sex, childhood adversities, poor sociability, scholastic problems, neurocognitive deficits, and greater severity of baseline and follow-up symptoms were associated with poor functional outcomes. In contrast, a favourable work/educational situation and preadmission treatment for nonpsychotic disorders were associated with better functional outcomes. Among ROP patients, neurocognitive deficits and the severity of baseline and follow-up affective and psychotic symptoms were strongly associated with functional outcomes. Among CHR-P patients, premorbid sociability, previous treatment for affective disorders, and follow-up affective symptoms played more significant roles. Conclusions: To improve functioning in patients in the early stages of psychosis, several factors should be considered, such as sex, childhood adversities, psychosocial development, baseline neurocognitive deficits, work/educational situation, clinical presentations, and follow-up symptoms. Personalized and integrated treatment and rehabilitation measures should be actively continued beyond the first admission period, with a particular focus on addressing both baseline and follow-up affective disturbances.

Deeper understanding of Subtle Visual Dysfunctions (VisDys) in the early stage of mental illness and their neurobiological underpinnings, as reflected by microstructural brain texture features, could advance our understanding of the underlying disease perceptual mechanisms that mediate susceptibility to psychosis. In this study, we aim a) to investigate the utility of brain texture features for the prediction of VisDys in recent onset psychosis (ROP) and clinical high-risk syndromes for psychosis (CHR-P), respectively, b) to test prediction models established in ROP and CHR-P in an independent validation sample with recent onset depression (ROD) diagnoses and c) to test for symptom expression related brain features associated with VisDys. sMRI were acquired in a training sample including 128 ROP (67 patients with VisDys), 134 CHR-P (71 patients with VisDys). Independent validation sets included 46 ROP (19 with VisDys), 124 CHR-P (68 patients with VisDys) and a sample of 256 ROD (50 patients with VisDys). Due to the heterogeneity of the CHR-P group, a clustering analysis was performed to identify proof of concept clusters of brain relevance specifically associated with symptoms in patients with and without VisDys, respectively. Both classification schemas in ROP and CHR-P presented good prediction accuracy in the independent validation samples of ROP, CHR-P and ROD, respectively.

Obsessive–compulsive disorder (OCD) affects ~1% of children and adults and is partly caused by genetic factors. We conducted a genome-wide association study (GWAS) meta-analysis combining 53,660 OCD cases and 2,044,417 controls and identified 30 independent genome-wide significant loci. Gene-based approaches identified 249 potential effector genes for OCD, with 25 of these classified as the most likely causal candidates, including WDR6, DALRD3 and CTNND1 and multiple genes in the major histocompatibility complex (MHC) region. We estimated that ~11,500 genetic variants explained 90% of OCD genetic heritability. OCD genetic risk was associated with excitatory neurons in the hippocampus and the cortex, along with D₁ and D₂ type dopamine receptor-containing medium spiny neurons. OCD genetic risk was shared with 65 of 112 additional phenotypes, including all the psychiatric disorders we examined. In particular, OCD shared genetic risk with anxiety, depression, anorexia nervosa and Tourette syndrome and was negatively associated with inflammatory bowel diseases, educational attainment and body mass index.

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.