Background Psychotic disorders such as schizophrenia have been associated with older-appearing brain structure, commonly quantified using the brain-age paradigm. However, it remains unclear whether these alterations are present at illness onset and whether antipsychotic treatment modifies their trajectory. Methods In this study, 61 (28 females and 33 males) antipsychotic-naïve people with first-episode psychosis were randomized to receive either a second-generation antipsychotic (risperidone or paliperidone) or placebo over a 6-month treatment period, alongside intensive psychosocial therapy. A healthy control group (n = 27, 17 females, 10 males) was also recruited. Structural MRI scans were collected at baseline, 3 months, and 12 months. Brain age was estimated using two pretrained and validated models (Pyment and CentileBrain). Results Brain-predicted age difference (brain-PAD) did not differ between patients and healthy controls at baseline (F(1,80) = 0.81, p = 0.37). There were also no significant effects of time, treatment group (antipsychotic, placebo, healthy control), or their interaction on brain-PAD across the first year (all p > 0.26). Findings were consistent across both brain-age models, and brain-PAD was not associated with clinical and lifestyle measures. Conclusion These findings suggest that altered structural brain aging is not evident during the earliest stages of psychosis and is not modified by early antipsychotic exposure over the first year of illness. Longer follow-up and approaches that account for illness heterogeneity may be needed to clarify when brain-age alterations emerge in psychotic disorders. Trial registration Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/; ACTRN12607000608460).
Background Stressful life events (SLEs) are a well-established etiologic risk factor for major depressive disorder (MDD). The kindling hypothesis proposes that their role diminishes as episodes recur, with illness becoming progressively autonomous from environmental triggers. It remains unclear whether this reflects true within-person change or a compositional shift-whereby more highly recurrent patients are those whose episodes were stress-independent from the outset.Methods We analyzed data from life history calendars, a structured method for reconstructing lifetime sequences of depressive episodes and antecedent life events, from 5843 Korean women with recurrent MDD (>= 2 lifetime episodes) contributing 17,338 episode observations (KOMOGEN-D), with replication in 708 Chinese women contributing 1905 episode observations (CONVERGE).Results Consistent with the kindling hypothesis, the proportion of episodes preceded by any SLE declined substantially and monotonically across episode order, from 94.8% (95% CI, 94.2%-95.4%) at the first episode to 77.7% (95% CI, 71.2%-84.2%) at the seventh (OR per episode increase, 0.66; 95% CI, 0.62-0.71). Inter-episodic intervals shortened with episode order (beta = -1.50 years; 95% CI, -1.61 to -1.38), indicating that episodes became more frequent. Within-individual analyses revealed that more participants had decreasing than increasing SLE counts across episodes, with more frequent transitions from SLE-associated to non-SLE-associated episodes than the reverse. Stratification by SLE type showed that independent SLEs decreased across episodes, whereas dependent SLEs increased. The main findings were replicated in CONVERGE, although some within-person transition analyses were limited by smaller sample size.Conclusions Across two large cohorts collected in different cultural settings, SLE involvement preceding episodes decreased across episode order while the rate of recurrence accelerated, and within-person analyses supported stress-episode decoupling as an individual-level process. These findings provide some of the strongest evidence yet assembled that the course of recurrent MDD is consistent with the kindling hypothesis: episodes become progressively less dependent on external stressors, shifting toward a more autonomous illness. These results have direct implications for stratifying recurrence risk by episode stage and for identifying the point in the illness course at which preventive strategies should shift emphasis from targeting environmental stressors toward sustained pharmacological or psychological relapse prevention.
Background Toxoplasma gondii (T. gondii) infection has been implicated in the pathophysiology of psychiatric disorders, yet no study has compared its seroprevalence between schizoaffective disorder (SZA) and other psychiatric conditions. This study aimed to compare T. gondii seroprevalence between patients with SZA, schizophrenia (SZ), and bipolar disorder (BD), and to examine whether seropositivity differentially affects innate immune markers across these diagnoses. Methods Overall 144 patients were included in this cross-sectional study. T. gondii seroprevalence was determined and leukocyte counts and derived immune ratios were compared across diagnostic groups according to T.gondii seroprevalence. Results T. gondii seroprevalence was significantly higher in SZA (68.8%) as compared to BD (44.2%; p = 0.02), but did not differ significantly from SZ (52.2%; p = 0.2). Relative to SZA, higher neutrophil (p < 0.01) and monocyte (p = 0.02) levels were associated with greater odds of BD, while higher NLR was associated with both BD (p = 0.04) and SZ (p = 0.02), and higher MLR with SZ (p = 0.02). However, none of these associations remained significant after Bonferroni correction. We observed a significant interaction between basophil counts and T. gondii in SZA versus BD (padj < 0.01) and SZ (padj < 0.01), indicating a diagnosis-specific immune modulation. Conclusion Our findings suggest that T. gondii seroprevalence in SZA is closer to SZ than BD. However, seropositivity appears to affect innate immune markers differently in SZA, without inflammatory activation. This immune profile suggests a unique pathophysiological signature in SZA and warrants further investigation.
Background Formal thought disorder (FTD) is a core dimension of schizophrenia, which has been associated in previous studies with increased brain functional connectivity between temporal gyri and striatal regions as measured with fMRI. Cannabis use is highly prevalent in schizophrenia population as compared with the general population and, in the context of elevated tetrahydrocannabinol/cannabidiol (THC/CBD) ratio, has been found to be associated with increased FTD in schizophrenia. Consequently, in this study, we aimed to investigate whether cannabis consumption in patients with schizophrenia is generally associated with both enhanced functional connectivity and FTD. Methods We explored the functional connectivity between the temporal gyri and striatal regions in 51 schizophrenia patients divided into two groups stratified by cannabis use. FTD was measured using the conceptual disorganization item from the Positive And Negative Syndrome Scale. Region-of-interest (ROI)-to-ROI and seed-based connectivity analyses, correlation tests, and mediation models were conducted using both frequentist and Bayesian approaches. Results No significant difference was found in terms of functional connectivity between cannabis users and non-users. THC/CBD ratio was not significantly associated with cortico-striatal connectivity or FTD. Overall, Bayesian results indicated moderate to strong evidence favoring the null hypothesis across most models. Conclusion Cannabis use was not robustly associated with an altered cortico-striatal connectivity in this sample. The convergence of frequentist and Bayesian evidence suggests that cannabis use may not account for previously reported FTD-related connectivity alterations in schizophrenia. Larger studies considering cannabis composition, dose-response relationships, and symptom dimensions are warranted to refine these findings.
