Abstract Background and Hypothesis Negative symptoms in schizophrenia spectrum disorders (SSD) are commonly assessed using clinician-rated instruments, which are vulnerable to bias and have limited ecological validity. Ambulatory and passive measures capturing real-world data may address these limitations but have unestablished psychometric properties. The latter are evaluated in this systematic review Study Design Databases were systematically searched using search terms relating to SSD, Negative Symptoms, and Measures. The ambulatory and passive measures’ psychometric properties, acceptability and feasibility regarding negative symptoms were evaluated and synthesised narratively due to methodological heterogeneity across eligible studies. Risk of bias was assessed using the COSMIN (COnsensus-based Standards for the selection of health Measurement INstruments) checklist. Inclusion criteria were: (1) Written in English; (2) compared ambulatory measures against established negative symptom measures; (3) involved predominantly adult samples with SSD. Study Results Sixty-six articles representing 39 unique samples (total N = 2,678) were included. Evidence for construct validity was most consistent for Ecological Momentary Assessments of motivation/goal-directed behaviour and emotion regulation-related affective dynamics, and passive accelerometry and geolocation measures of travel. Moderate to high compliance indicated good feasibility. Construct validity was widely explored, reliability and internal consistency were rarely assessed, and other properties remain unexplored. Conclusion Ambulatory and passive measures show promise for assessing negative symptoms, particularly behavioural and motivational domains. However, methodological heterogeneity, limited psychometric evaluation, and inadequate reporting constrain interpretation. Future research should prioritise co-development with SSD populations, comprehensive psychometric testing, transparent reporting, and addressing privacy considerations. Other The protocol was registered on PROSPERO (CRD42020208475).
Abstract Background and Hypothesis Clinical high risk (CHR) for psychosis status is associated with poor social functioning. Previous studies suggest that childhood trauma and reduced amplitude of the P300 event-related potential (ERP) component elicited by infrequent target stimuli (P3b) are associated with poor social function. Here, we examined whether reduced P3b mediates the relationship between reported trauma history and social function in CHR individuals, possibly reflecting the impact of past trauma on neurophysiological processes subserving attention that ultimately influence social functioning. Study Design Target P3b ERP amplitudes from visual and auditory oddball tasks acquired at baseline in the Accelerating Medicines Partnership® Schizophrenia (AMP SCZ) study were analyzed. The mediating effects of auditory and visual P3b amplitude on the relationship between trauma history (Childhood Trauma Questionnaire total score) and Negative Symptom Inventory-Psychosis Risk Asociality (NSI-PR) as well as social functioning (Global Functioning: Social (GFS) scores were examined. Study Results Data from 931 CHR participants (average age 21.29 years, 36.3% male) were included in mediation analyses. Visual P3b showed significant (p < .05) mediation of the relationship between trauma load and GFS score (5.4% mediation) as well as mediation of the relationship between trauma history and NSI-PR asociality (9.3% mediation). Auditory P3b did not significantly mediate either relationship. Conclusions These results suggest that visual, but not auditory, P3b mediates the relationship between past trauma load and social functioning in CHR, suggesting the effect of trauma on the neurophysiological processes subserving visual target detection may contribute to social functioning deficits in CHR individuals.
Abstract Background There is robust evidence that belief inflexibility is critical to the maintenance of delusion conviction. While cognitive control abilities (inhibitory control, mental set shifting, and working memory updating) are instrumental to information processing in general, and there is evidence that these abilities are disrupted in patients with schizophrenia, the extent to which these processes are associated with delusions as well as belief flexibility is less studied. Method Adult patients with schizophrenia spectrum disorders and active delusions (N = 66) completed three cognitive control tasks (negative priming, alternating runs, and n-back) at baseline and 6 months after. Cross-sectional and repeated measures associations between cognitive control abilities, belief flexibility, and delusions were evaluated. Results At baseline, the reaction time switch cost of mental set shifting was positively correlated with level of delusion severity. Over 6 months, an increase in working updating ability was associated with a decrease in delusion conviction, and an increase in negative priming effect was associated with an increase in belief flexibility. There was no evidence for belief flexibility as a mediator between cognitive control and delusions, either cross-sectionally or over time. Discussion This is the first study reporting the association between three cognitive control abilities, belief flexibility, and delusions using a single-symptom approach (involving patients with psychotic delusions). If replicated, these findings may attest to the potential of further ameliorating drug-resistant delusions through targeting cognitive control as well as belief flexibility.
Background and Hypothesis:Cognitive models conceptualize paranoia in schizophrenia spectrum disorders as driven and maintained by mechanisms, which can be targeted by cognitive behavioral therapy for paranoia (CBTp). This study examined potential mechanisms as mediators. Safety behaviors, belief inflexibility, and core beliefs about self and others were hypothesized to differentially mediate outcomes in virtual reality-based CBTp (VR-CBTp) and CBTp, with safety behaviors expected to be more influential in VR-CBTp, and belief inflexibility and self-related core beliefs in CBTp. Study Design:This secondary analysis of the FaceYourFears trial included a per-protocol sample with complete data (VR-CBTp: n = 96; CBTp: n = 90). Groups were comparable, except for greater in-session exposure in VR-CBTp. Pearson correlations, linear regression analyses and structural equation modeling (SEM), examined each mediator separately. Causal inferences could not be drawn. Study Results:Pearson correlations of change scores showed that positive safety behaviors and negative self- and others-related core beliefs were associated with paranoia across both interventions. Regression analyses without covariate adjustment showed no significant between-group differences, except for belief inflexibility (P = .041), which became non-significant with covariate adjustment (age, sex, depression). SEM showed no differential mediation effects. Conclusions:No mediators differed between interventions, and no hypotheses were supported. These results suggest similar mechanistic pathways in CBTp and VR-CBTp. Treatment selection may instead best be guided by factors such as symptom profile, patient preference, accessibility, and engagement. Findings are discussed in relation to prior mediation studies within the field, with implications for future research.
Research on schizophrenia increasingly highlights altered excitation-inhibition regulation in cortical circuits. Excitatory Glutamatergic pyramidal cells propagate activity, whereas inhibitory Gamma Amino Butyric Acid (GABA) interneurons periodically inhibit this activity. Their interaction supports gamma synchronization and the integration of information, while dysfunctional glutamatergic transmission (especially at the N-methyl-D-aspartate receptor [NMDA]-receptor) disrupts information flow. This framework invites a restricted reconsideration of Kraepelin's concept of dementia praecox. While Kraepelin erred in proposing a uniform, deteriorating course (schizophrenia is a heterogeneous neurodevelopmental spectrum disorder and many patients remain stable or recover) his emphasis on an early disturbance of mental integration in schizophrenia may have been prescient. In schizophrenia, cognitive differences often precede psychosis, while genetic, experimental, postmortem, electrophysiological, and pharmacological findings converge on aberrations in the ecosystem of the NMDA-receptor in schizophrenic patients and members of high-risk groups for schizophrenia. D-serine, glycine, kynurenic acid, and redox state are important co-regulators of the NMDA receptor and constitute possible therapeutic targets. Negative trials of D-serine and glycine-transporter inhibitors, however, challenge simple augmentation strategies while leaving the developmental circuit hypothesis open, which would call for much earlier interventions. We argue that the decisive test for this hypothesis are biomarker-defined studies near illness onset; precisely when gamma synchronization or mismatch negativity already indicates impaired coordination. Excitation-inhibition imbalance thus gives Kraepelin's clinical observation a modern and experimentally tractable form.
