Vita-Salute San Raffaele University

Chronotherapeutic interventions have been proposed as non-pharmacological strategies for the rapid modulation of depressive symptoms in bipolar disorder. Total sleep deprivation (TSD) may induce short-term mood improvements, and morning bright light therapy (BLT) has been suggested to help stabilize these effects. However, the impact of these interventions on service-level outcomes, including length of hospital stay (LOS), has not been systematically evaluated. We analyzed two non-overlapping retrospective cohorts (1994-1998 and 2015-2024) from the same Mood Disorders Unit, including adults hospitalized for a bipolar depressive episode. Within each cohort, patients received either treatment as usual (TAU) or TAU with chronotherapy, consisting of TSD in the earlier cohort and TSD with morning BLT in the later one. LOS was examined with general linear models adjusted for age and sex. The combined sample included 1241 admissions (706 from 1994-1998; 535 from 2015-2024). In both cohorts, LOS was shorter with TSD than with TAU (1994-1998: 20.99±11.09 days vs 23.23±13.34, F = 5.31, p = 0.02; 2015-2024: 24.00±8.24 vs 27.62±8.67, F = 15.46, p < 0.01), with a small effect size in the earlier cohort (d = 0.176) and a small-to-moderate effect in the later one (d = 0.425). Treatment × Cohort interaction was not significant (F = 0.55, p = 0.46). Across three decades, the use of chronotherapy was consistently associated with shorter LOS in bipolar depression, despite major changes in clinical practice, organizational structure, and environmental circadian stressors. While causality cannot be inferred due to the observational design, these findings suggest that TSD-based chronotherapeutic interventions may represent a promising approach within acute inpatient care pathways, potentially contributing to improved hospitalization trajectories and discharge readiness in bipolar depression.

Social anxiety disorder (SAD) frequently co-occurs with major depressive disorder (MDD). We examined the prevalence and clinical correlates of SAD across three heterogeneous MDD cohorts. Secondary analyses were conducted in adult (CO-MED: n=482; GSRD: n=1398) and late-life (IRL-GREY: n=438) patients. SAD was assessed dimensionally (PDSQ) and categorically (MINI; SCID-1). Cohort-specific instruments were used to assess depressive severity (QIDS; MADRS), suicidality (CHRT; MADRS; SIS) and hypomanic symptoms (ASRM; YMRS). In late-life depression, neurocognitive tests were administered. Multivariate models were adjusted for depression and anxiety levels. SAD prevalence varied markedly by samples and diagnostic definitions (CO-MED: 46.7% with PDSQ≥6; 17.0% with PDSQ>12; GSRD: 3.0%; IRL-GREY: 8.7%). Across cohorts, SAD was associated with earlier MDD onset (CO-MED: p<0.001 d=-0.36; GSRD: p=0.014 d=-0.39; IRL-GREY: p=0.002 d=-0.54) and greater anxiety comorbidity (CO-MED: GAD: p<0.001 d=1.24; panic: p<0.001 d=1.29; GSRD: GAD: p<0.001; panic: p<0.001; IRL-GREY: agoraphobia: p<0.001). After controlling for depression and anxiety levels, SAD was linked to higher suicide risk in both adult cohorts (CO-MED: OR 1.04 (1.01-1.08); GSRD: OR 1.29 (1.04-1.64)) and to lower 6-week remission in CO-MED cohort (OR 0.51 (0.29-0.91)). In MDD, SAD has consistent associations with earlier illness onset and anxiety burden, modest associations with suicidality and antidepressant outcomes, and reduced impact in late life.

Trained immunity is the ability of the innate immune system to mount a heightened response to an environmental stimulus after a previous encounter with a noxious trigger. This effect is mediated by metabolic rewiring and epigenetic reprogramming in innate immune cells. In the context of neuroinflammation, trained immunity may represent a major contributor to the pathogenesis of neurological diseases, exerting both detrimental and potentially beneficial effects. While the general mechanisms and systemic implications of trained immunity are widely discussed, evidence in central nervous system (CNS) diseases remains fragmented and largely confined to individual pathological conditions. As a result, a comprehensive framework integrating these findings and identifying shared mechanisms across neurological disorders is still lacking. In this review, we explore the concept of trained immunity with a focus on neuroinflammatory and neurodegenerative diseases, synthetizing evidence from multiple CNS pathologies, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, and cerebrovascular disorders. We first critically examine preclinical and experimental studies addressing innate immune memory in the CNS and subsequently integrate these findings with emerging clinical evidence, aiming to identify convergent mechanisms and disease-relevant immune memory signatures. Finally, we discuss potential therapeutic targets identified in preclinical settings and outline key unresolved issues, including the nature of triggering stimuli, thresholds, and temporal dynamics shaping innate immune memory in the CNS. By highlighting current limitations and defining critical questions for future research, this review presents a unifying perspective on trained immunity in neurological diseases and underscores the translational potential to modulate neuroinflammation and to influence disease progression.

To describe a novel optical coherence tomography finding called "scolex sign" in cases of central serous chorioretinopathy. This retrospective multicenter study included patients with central serous chorioretinopathy with serous pigment epithelial detachments (PEDs) greater than 100 µ m, with or without subretinal fluid. Eyes showing a distinct hyperreflective focus on the PED wall (scolex sign) were analyzed. An equal number of age-matched controls with PEDs but without the scolex sign were included. Multimodal imaging data were reviewed. A subgroup analysis based on subretinal fluid status was also performed. Of 291 eyes with large serous PEDs, 52 eyes exhibited the "scolex sign" and were compared with 52 age-matched controls. Baseline characteristics including sex, systemic comorbidities, best-recorded visual acuity and optical coherence tomography parameters were similar in both the groups. However, eyes with the "scolex" sign exhibited a greater number of central PEDs and shorter distance from the foveal center. On follow-up, eyes with the "scolex" sign showed a higher rate of PED flattening and subretinal fluid resolution trended to be higher compared with controls. The "scolex" sign represents a novel, benign optical coherence tomography feature seen in a subset of central serous chorioretinopathy cases. While not associated with poorer outcomes or adverse sequelae, it may reflect ongoing reparative changes, indicating a resolving stage of the disease.

While fatigue is highly reported in newly diagnosed people with Multiple Sclerosis (pwMS) and motor fatigability is reported in about 20% of non-disabled patients, relationship among them in early MS has been less studied. To evaluate correlations between fatigue and motor fatigability in early pwMS, and their clinical, radiological, psychological underpinnings. Relapsing pwMS aged 18-65 years, Expanded Disability Status Scale (EDSS) score <2.0, disease duration <5 years were recruited. PwMS underwent clinical, cognitive, radiological assessment. They performed a 6-minute-walking-test; fatigability was calculated as the ratio of distance walked in the final minute to the first minute (distance walking index, DWI6−1). Fatigue was evaluated through the Modified Fatigue Impact Scale (MFIS). Spearman ρ examined the relationship among variables; linear regression analyses examined predictors of fatigue and fatigability. 70 pwMS (age 37.8+11years; female n=50, 71.4%, EDSS 1.5[1;2]) were enrolled. 15 (21.4%) reported significant levels of fatigue, 14 (20%) presented motor fatigability. Fatigue and motor fatigability were not significantly correlated with one another (ρ=0.100;p=0.425) or with other clinical, cognitive, radiological features. Fatigue was related to Hospital Anxiety and Depression Scale (HADS) anxiety subscale (ρ=0.375,p=0.002), Beck Depression Inventory (BDI-II) (ρ=0.543;p<0.001), neuroticism (ρ=0.313;p=0.006), and all subscales of MS-Quality-Of-Life 54. We did not find predictors of fatigability, while HADS-anxiety (b=0.76; p=0.003) and BDI-II (b=0.33; p=0.009) significantly predicted fatigue. Our results support different neurobiological underpinnings for motor fatigue and fatigability and reinforce the need for a multidimensional assessment from the earliest stages of the disease, to tailor therapeutic and rehabilitation strategies.