Cristina Colombo

Background. Bipolar disorder (BD) is characterized by circadian rhythm disruptions, contributing to mood instability and recurrence. These rhythms are regulated by clock genes in the suprachiasmatic nucleus, including the CLOCK 3111T/C (rs1801260) polymorphism that has been linked to delayed sleep phase, insomnia, and altered circadian expression. Both circadian disruption and adverse childhood experiences (ACEs) correlate with white matter (WM) abnormalities. We hypothesized that rs1801260 moderates ACE effects on WM microstructure in BD. Methods. We enrolled 137 BD patients in depressive episodes. Participants underwent 3T MRI, rs1801260 genotyping and completed the Childhood Trauma Questionnaire. Moderation (PROCESS) tested genotype–ACE interactions on whole-brain fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) values; voxel-wise TBSS (FSL Randomize) localized effects, with sex-stratified and GLZ analyses for genotype–sex interactions. Results. Significant rs1801260 × ACE interactions emerged for FA and RD across physical abuse, physical neglect, and emotional neglect. Higher ACEs were associated with lower FA/higher RD only in CLOCK rs1801260*C carriers, mainly females. TBSS showed physical abuse × rs1801260 interaction in the corpus callosum, internal capsule and corona radiata. A GLZ model with separate slopes confirmed physical abuse × sex × rs1801260 interactions on FA/RD, with effects specific to female CLOCK rs1801260*C carriers but genotype-independent in males. Conclusions. rs1801260 moderates the impact of early-life stress on WM integrity in BD, particularly in emotion-regulation tracts, with CLOCK rs1801260*C carriers showing greater vulnerability. Effects are genotype-specific in females but genotype-independent in males, possibly reflecting sex-dimorphic neurodevelopment driven by estrogen–androgen modulation of clock genes, HPA axis, and myelination.

Aim: Bipolar disorder (BD) is characterized by circadian dysregulation, altered sleep–wake behaviors, and heterogeneous antidepressant response. Chronotherapeutic interventions such as total sleep deprivation combined with light therapy (TSD + LT) produce rapid antidepressant effects, but predictors of outcome are lacking. We investigated whether fractal dynamics of motor activity, indexed by the short‐term scaling exponent α₁, are associated with antidepressant response, sleep–wake regulation, and structural brain measures and may serve as a biomarker of treatment responsiveness. Methods: Sixty‐eight BD inpatients underwent three cycles of TSD + LT. Depressive symptoms were assessed with the Hamilton Depression Rating Scale (HDRS), and treatment response was defined as a post‐treatment HDRS score P = 0.035) and was independently associated with treatment response ( P = 0.039). Baseline α₁ was associated with sleep–wake parameters, cerebellar gray matter volume, and white‐matter microstructure, including cerebellar peduncles and thalamo‐cortical tracts. Circadian rhythmicity increased in responders and decreased in nonresponders. Conclusion: Fractal motor activity tracks clinical changes during chronotherapeutic treatment in BD and may represent a candidate marker of treatment‐related behavioral regulation. Its association with cerebellar and white‐matter measures suggests multimodal relevance, warranting validation in larger longitudinal studies.

Background: Major depressive disorder (MDD) and bipolar disorder (BD) are associated with increased suicide risk and commonly feature metabolic dysfunctions such as insulin resistance (IR) and obesity. These conditions are also linked to systemic inflammation and white matter (WM) alterations, which may underlie suicidal behaviors. This study explores how immune‐metabolic markers affect WM integrity and suicidality in mood disorders. Methods: Inpatients with BD ( n = 93) and MDD ( n = 88) underwent diffusion tensor imaging to assess WM integrity. Blood samples were analyzed for insulin, glucose, and inflammatory markers. IR was assessed via HOMA ‐ IR and QUICKI . Suicide risk was measured using the Beck Scale for Suicide Ideation ( BSI ) and the Hamilton Depression Rating Scale ( HDRS ). Results: BD patients showed higher IR, BMI, and inflammation compared to MDD patients. In BD, both insulin and HOMA‐IR positively correlated with suicide risk and were associated with increased suicidal ideation. BMI indirectly predicted suicide risk through IR, but not via inflammation. WM analysis revealed that in high‐suicide‐risk BD patients, higher insulin and HOMA‐IR were associated with reduced fractional anisotropy and increased mean and radial diffusivity—markers of axonal and myelin disruption. These effects were not observed in MDD or BD patients with lower suicide risk. Conclusion: Insulin resistance emerges as a key contributor to suicidality in BD, possibly via its impact on WM integrity. Although BMI did not directly predict suicide risk, its effect through IR suggests metabolic health may be a modifiable target. Early intervention on IR and inflammation could benefit high‐risk BD individuals.

Background: Non-invasive brain stimulation (NIBS) is increasingly used as an adjunctive option in late-life depression (≥60 years), a condition frequently complicated by multimorbidity and incomplete response to standard treatments. Comparative real-world evidence between repetitive Transcranial Magnetic Stimulation (rTMS) and transcranial Direct Current Stimulation (tDCS), particularly including functional outcomes, remains limited. Methods: We conducted a retrospective, naturalistic comparative study of 104 depressed inpatients (≥60 years), either unipolar or bipolar, treated with rTMS (n = 48) or tDCS (n = 56) as part of routine care. Depression severity was assessed with the 21-item Hamilton Depression Rating Scale (HDRS21) at baseline, 2 weeks, and 1 month; response was defined as ≥50% HDRS21 score reduction and remission as HDRS21 < 7 at 1 month. Global Assessment of Functioning (GAF) was assessed at admission and discharge (baseline and 1 month). Longitudinal changes were examined using covariate-adjusted mixed-effects models; categorical outcomes were compared using χ² tests. Propensity score matching was applied as an additional approach to reduce confounding due to the observational design. Results: At 1 month, response and remission rates were significantly higher in the rTMS group than in the tDCS group (87.5% vs. 55.4%, p < 0.001; 62.5% vs. 41.1%, p = 0.047, respectively). rTMS showed greater HDRS21 score reductions at 2 weeks and 1 month (Time × Treatment, p < 0.001). GAF scores significantly improved over time in both groups (Time effect, p < 0.001) without between-technique differences (Time × Treatment, p = 0.56), and GAF scores did not differ by response/remission status. Conclusions: In this cohort of inpatients aged ≥ 60 years with depressive episodes, rTMS was associated with greater short-term reductions in HDRS21 scores compared with tDCS, whereas both modalities showed comparable improvements in GAF from admission to discharge.

Low‐grade systemic inflammation is linked to cardiometabolic diseases and increased cardiovascular risk. Patients with mood disorders, such as Major Depressive Disorder (MDD) and Bipolar Disorder (BD), also show elevated cardiovascular risk and inflammatory markers, suggesting shared biological pathways between mood and cardiometabolic conditions. The kynurenine (KYN) pathway, activated by inflammatory cytokines and involved in neurotransmitter systems linked to mood, provides a promising area to explore inflammatory‐related genetic overlaps in these disorders, with increasing interest in the SH2B3 rs3184504 SNP. Imaging markers like white matter hyperintensities (WMHs) and white matter (WM) microstructure alterations are associated with mood and cardiovascular disorders. This study aimed to investigate the genetic load linked to KYN levels, such as KYN polygenic risk score (PRS) and its effect on white matter hyperintensities (WMHs), outcomes of presumed vascular suffering, and WM microstructure in a sample of 95 MDD and 80 BD patients. Higher PRS for KYN was associated with increased circulating KYN levels and KYN/TRP ratio. KYN PRS predicted the presence of WMHs. The SH2B3 rs3184504 T variant was associated with increased PRS for KYN and a higher number of WMHs. KYN levels and KYN/TRP ratio were not associated with WMHs, while KYN PRS positively correlated with higher axial (AD) and mean diffusivity (MD), with a nominal significance for radial diffusivity (RD). The findings support a genetic contribution to elevated KYN and WM integrity alterations in mood disorders. PRS for KYN indicates a potential predisposition to inflammatory and vascular dysregulation, and SH2B3 rs3184504 may modulate this risk.

Background: The genetic determinants of peripartum depression (PPD) are not fully understood. Using a multi-polygenic score approach, we characterized the relationship between genome-wide information and the history of PPD in patients with mood disorders, with the hypothesis that multiple polygenic risk scores (PRSs) could potentially influence the development of PPD. Methods: We calculated 341 PRSs for 178 parous mood disorder inpatients affected by major depressive disorder (MDD) or bipolar disorder (BD) with (n = 62) and without (n = 116) a history of PPD. We used partial least squares regression in a novel machine learning pipeline to rank PRSs based on their contribution to the prediction of PPD, in the whole sample and separately in the two diagnostic groups. Results: The PLS linear regression in the whole sample defined a model explaining 27.12% of the variance in the presence of PPD history, 56.73% of variance among MDD, and 42.96% of variance in BD. Our findings highlight that multiple genetic factors related to circadian rhythms, inflammation, and psychiatric diagnoses are top contributors to the prediction of PPD. Specifically, in MDD, the top contributing PRS was monocyte count, while in BD, it was chronotype, with PRSs for inflammation and psychiatric diagnoses significantly contributing to both groups. Conclusions: These results confirm previous literature about the immune system dysregulation in postpartum mood disorders, and shed light on which genetic factors are involved in the pathophysiology of PPD.

Seasonal rhythms affect the immune system. Evidence supports the involvement of immuno-inflammatory mechanisms in bipolar disorder (BD), with the neutrophil to lymphocyte ratio (NLR), and the systemic immune-inflammatory index (SII; platelets × neutrophils/lymphocytes) consistently reported to be higher in patients with BD than in HC, but seasonal rhythms of innate and adaptive immunity have never been studied. We retrospectively studied NLR and SII in 824 participants divided into three groups: 321 consecutively admitted inpatients affected by a major depressive episode in course of BD, and 255 consecutively admitted inpatients affected by obsessive–compulsive disorder (OCD; positive psychiatric control), and 248 healthy controls (HC). Patients with BD showed markedly higher markers of systemic inflammation in autumn and winter, but not in spring and summer, in respect to both HC and patients with OCD, thus suggesting a specific effect of season on inflammatory markers in BD, independent of a shared hospital setting and drug treatment. Given that systemic inflammation is emerging as a new marker and as target for treatment in depressive disorders, we suggest that seasonal rhythms should be considered for tailoring antidepressant immuno-modulatory treatments in a precision medicine approach.