INTRODUCTION:Bipolar depression (BD) is associated with altered intrinsic brain activity, and possibly impaired neurovascular coupling (NVC). Although rapid-acting chronotherapies are effective in BD, their neurophysiological mechanisms remain unclear. METHODS:In this longitudinal resting-state fMRI study, we examined fractional amplitude of low-frequency fluctuations (fALFF), indexing spontaneous neural activity, and hemodynamic response function (HRF) parameters, used as proxies of NVC, in 50 BD inpatients undergoing three cycles of combined total sleep deprivation and light therapy (TSD + LT), and in 30 healthy controls (HCs). Patients were scanned before (day 0) and after treatment (day 7), and depressive symptoms were evaluated with the Beck Depression Inventory Short Form. RESULTS:At baseline, BD patients showed reduced fALFF in frontal, temporal, insular-opercular, and cerebellar regions relative to HCs. After TSD + LT, fALFF increased in widespread occipito-temporal, frontal, and cerebellar clusters in BD patients. HRF analyses showed no baseline between-group differences, but revealed a significant post-treatment increase in HRF response height across occipital, temporal, frontal, and cerebellar regions. Remission after TSD + LT was associated with fALFF changes, whereas larger HRF response height increases were observed in patients who did not require antidepressant treatment switch or augmentation during hospitalization. CONCLUSION:TSD + LT was associated with modulation of both intrinsic neural activity and resting-state hemodynamic responses, with fALFF and HRF reflecting partly distinct aspects of short-term clinical outcome.

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.

Stressful life events are major precipitants of depressive episodes, yet their effects vary across individuals. Childhood trauma is a well-established vulnerability factor that may increase sensitivity to subsequent stress. However, the neural correlates of this interaction in major depressive disorder (MDD) remain poorly characterized. This study investigated whether childhood trauma moderates the association between recent stress exposure and brain structure and functional connectivity in MDD. Structural magnetic resonance imaging (MRI) data were obtained from 130 inpatients with MDD; resting-state functional MRI data were available for a subsample (n = 97). Whole-brain cortical thickness and surface-based functional connectivity measures, including global correlation (GCOR) and local correlation (LCOR), were examined to test interaction effects between childhood trauma and recent stress exposure. A significant interaction between childhood trauma and recent stress was observed in medial prefrontal regions, including the anterior cingulate cortex, where greater stress exposure was associated with reduced cortical thickness at higher levels of early adversity. Convergent interaction effects were also observed at the functional level, with greater recent stress associated with lower LCOR in the left superior frontal gyrus and precuneus at higher levels of childhood trauma. No interaction effects were observed for GCOR. Analyses of specific trauma dimensions indicated partially distinct effects of abuse and neglect. Childhood trauma moderated the association between recent stress exposure and structural and functional brain measures in MDD, particularly within prefrontal regulatory regions. These multimodal findings are consistent with stress sensitization models and suggest that early adversity may contribute to heterogeneity in neural correlates of stress in depression.

The purpose of the present study is to provide a preliminary evidence of the possible involvement of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) in antidepressant response. NAMPT is the major regulator of the cellular availability of nicotinamide adenine dinucleotide (NAD+), and, when released from the cells, it influences activity, energy expenditure, and neurotransmitter levels in mammals. We studied changes of blood circulating eNAMPT before and after treatment in 46 patients with major depressive disorder, treated with monoaminergic antidepressant drugs for 1 month, or with Bipolar Disorder, treated with antidepressant chronotherapeutics (repeated total sleep deprivation combined with light therapy) for 1 week. Participants showed high individual variation in eNAMPT before and after treatment. The increase in circulating eNAMPT concentration was associated with individual benefit from treatment independent of diagnosis or type of treatment. eNAMPT increase was not necessary to achieve response, but the best antidepressant effects were observed in patients showing the highest increase. These findings suggest that eNAMPT may facilitate treatment efficacy rather than acting as a direct mechanism of symptom reduction. Results are in agreement with the literature affirming a possible role of NAD+ homeostasis and mitochondrial mechanisms in mood disorders. If confirmed, they may pave the way to identify new targets for the treatment of depression.

BACKGROUND:Treatment-Resistant Depression (TRD) often persists despite adequate pharmacotherapy. Intranasal Esketamine and accelerated repetitive Transcranial Magnetic Stimulation (aTMS) are rapid-acting options, but head-to-head comparisons remain limited. METHODS:We conducted a retrospective study on TRD patients receiving either aTMS (n = 18) or Intranasal Esketamine (n = 22). Depression severity (Montgomery-Asberg Depression Rating Scale, MADRS) was assessed at baseline and 1, 3, and 6 months. Primary outcomes were response (≥50% MADRS reduction) and remission (MADRS <10). Longitudinal change was modelled with linear mixed-effects; moderators included clinical and demographics features. RESULTS:At 1 month, aTMS showed higher response (72.2% vs 20%; p < 0.001) and remission (66.6% vs 10%; p = 0.0031) than Esketamine. Between-group differences were not significant at 3 months or 6 months. Mixed-effects models showed greater MADRS reduction with aTMS at 1 (p < 0.001) and 3 months (p = 0.007), but not at 6 months (p = 0.057). Psychiatric comorbidities were associated with greater improvement at 3 and 6 months within the Esketamine subgroup, with no analogous association in the aTMS subgroup. CONCLUSIONS:aTMS showed a stronger early antidepressant effect, but its advantage over esketamine progressively diminished and was no longer evident at six months. Prospective, well-powered comparative trials are required to validate these findings.

Identifying generalizable brain-based biotypes across independent cohorts is critical for parsing heterogeneity in Major Depressive Disorder (MDD), yet robust subtypes spanning micro- and macroscales remain poorly defined. We applied stability-based clustering to cortical thickness data from 1,531 MDD individuals in UK Biobank (UKB), with external validation in 144 inpatients from IRCCS Ospedale San Raffaele (HSR). Two distinguishable clusters emerged (accuracy=87.5%), with one showing widespread cortical thinning, anergy-related symptoms, childhood trauma, and diabetes comorbidity. This profile generalized with 96.5% accuracy in a hold-out UKB sample and 80.6% in HSR. Mapping clusters cortical profiles onto Neurosynth meta-analytic activation patterns revealed a ventral-dorsal gradient linked with emotion regulation, interoceptive, and motivational processes. Spatial correlations with 19 neurotransmitter receptors and transporters obtained from positron emission tomography identified dopamine transporter as the dominant contributor in UKB, and histamine receptor H3 in HSR. These findings provide a reproducible framework linking MDD subtypes to multiscale biological complexity. ### Competing Interest Statement AS reports consultancy, advisory roles, or grant funding outside the current study: AbbVie, Angelini, AstraZeneca, Clinical Data, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarma-co, Janssen, Lundbeck, Pfizer, Polifarma, Sanofi, Servier, Taliaz, and Naurex. All other authors declare no competing interests. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The local ethical committee approved all the research activities (IRCCS Ospedale San Raffaele) and complied with the Helsinki Declaration of 1975, as revised in 2013. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data used to perform the analyses can be found at https://ordr.hsr.it/preview/w67mxvnsy8?a=17d38898-0b42-473a-8fae-ecb8ee357819. Volumetric PET images for neurotransmitter receptors and transporters are included in neuromaps (https://github.com/netneurolab/neuromaps). Neurosynth data are available at https://neurosynth.org/. [https://github.com/fede-colombo/colombo\_ukb\_clustering_validation][1] Ministero della Salute, GR-2019-12370616 [1]: https://github.com/fede-colombo/colombo_ukb_clustering_validation

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.

This study explores the global signal topography of core and periphery brain networks in Major Depressive Disorder (MDD), Bipolar disorder (BD-Dep) and healthy controls (HC) using resting-state fMRI. In a sample of 140 depressed MDD and BD patients, and 70 HC, we observed a significant shift toward increased activity in the transmodal-core regions (e.g., default mode network, frontoparietal network) at the expense of unimodal-periphery regions (e.g., visual, sensory-motor cortices) in both depressed MDD and BD patients compared to HC. Whole brain machine learning analyses further demonstrated that altered global signal dynamics can effectively distinguish MDD and BD from HC (ACC = 79% and 77% respectively). Notably, we identified a significant negative correlation between global signal correlation in unimodal-periphery networks and depressive symptom severity. Additionally, in a smaller sample of BD during mania (N = 22) a distinct topographic pattern was observed, with increased global representation in the unimodal-periphery compared to depressive states, suggesting mood state-dependent shifts in network organization. To assess multivariate discriminability across diagnostic groups, a Partial Least Squares (PLS) analysis revealed that higher Core and related network activity (DMN, FPN) predicted diagnostic assignment to MDD and BD-Dep, whereas higher Periphery and related network (e.g., visual and sensory-motor networks) predicted assignment to BD-Man and HC. The Core-Periphery (C-P) ratio emerged as the strongest predictor (VIP = 1.65). These results underscore the critical role of global signal topography in mood disorders, particularly the imbalance between core and peripheral brain networks, as a potential neurobiological marker for depressive states.

BACKGROUND: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. METHODS: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. RESULTS: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). CONCLUSIONS: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.

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 <8. α₁ was derived from actigraphy using detrended fluctuation analysis, with values close to 1 indicating optimal fractal regulation. α₁ was computed before and after TSD + LT, and Δα₁ represented treatment-related change. Sleep-wake and circadian parameters were examined. A subsample underwent multimodal magnetic resonance imaging (MRI). RESULTS:TSD + LT induced clinical improvement in 65.3% of patients. Responders showed a significant reduction in α₁ toward values close to 1, whereas nonresponders did not. Δα₁ correlated with symptom improvement (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 persistent cognitive deficits, but the biological mechanisms underlying these impairments remain unclear. Metabolic dysfunction, particularly insulin resistance (IR), may contribute to brain structural alterations and cognitive decline. However, diagnosis-specific metabolic effects on gray matter volumes (GMVs) and cognition have not been fully explored. Partial least squares path modeling was applied to examine associations among metabolic biomarkers, GMVs, and cognitive performance in mood disorders, stratifying by diagnosis. METHODS:A total of 81 inpatients with BD (55 female, 26 male) and 78 inpatients with MDD (45 female, 33 male) underwent neuropsychological evaluation with the Brief Assessment of Cognition in Schizophrenia. T1-weighted magnetic resonance images were processed to extract GMVs. Blood samples were collected to assess metabolic markers. RESULTS:In the whole sample, the metabolism latent construct negatively predicted both GMV and cognition, with the GMV factor positively affecting cognition. A significant diagnostic difference emerged for the metabolism-to-cognition path (p = .0196). Stratified analyses showed that in BD, metabolism was significantly associated with both reduced GMVs and poorer cognition, whereas no significant structural paths were identified in MDD. IR markers and leptin were the strongest positive contributors to the metabolism factor in both the whole sample and the BD group. The brain regions most affected encompassed areas central to cognitive and emotional regulation, characterized by a high density of insulin and leptin receptors. CONCLUSIONS:These findings highlight the role of IR and leptin in shaping cognition in mood disorders and underscore the potential of insulin-related pathways as therapeutic targets, especially in BD with metabolic comorbidities.

BACKGROUND:Major depressive disorder (MDD) exhibits substantial clinical heterogeneity complicating prognosis and treatment. Characterizing MDD subtypes could enhance personalized approaches. We developed a topological data analysis (TDA) framework with graph-based community detection to identify patient subgroups using multimodal data. METHODS:We implemented a TDA pipeline in MDD UK Biobank participants with gene-environment (G-E, N=20,715) and gene-environment-neuroimaging (G-E-I, N=3,044) data. We systematically compared genetic, environmental, and neuroimaging features, alone and combined, to stratify MDD individuals across 18 health-related outcomes. For each outcome's best-performing feature set, a novel feature ranking approach identified features driving graph construction and community-based outcome differentiation. Cross-cohort validation through selective, heterogeneous replication utilized two independent datasets: GSRD (G-E data, N=1,017) and HSR (G-E and imaging data, N=71-87). RESULTS:G-E combination demonstrated superior stratification performance for 13 outcomes, including treatment-resistant depression (TRD), symptom subtypes, and suicidal phenotypes. Community profiling revealed distinct patterns: trauma-stress exposures linked to TRD and episode severity, while substance-behavioral profiles associated with anxious symptoms. Environmental factors primarily determined most health-related outcomes, whereas neuroimaging features best discriminate medical comorbidities. Partial replication was observed for gene-environment sets in GSRD (self-harm behavior, anxious features) and preliminary imaging-based replication in HSR (vascular problems), with limited statistical power for imaging analyses. Environmental stress-related top-ranked features were consistent across cohorts. CONCLUSIONS:TDA successfully identified relevant MDD subgroups with domain-specific multimodal contributions. These findings underscore the value of multimodal integration for comprehensive health-related outcome stratification, with modalities contributing selectively to specific outcome domains. TDA-based community detection is a promising framework for MDD stratification and precision medicine.

Introduction Anhedonia, defined as the diminished ability to experience pleasure, is a core symptom of Depression and is associated with significant functional impairment, increased suicidality, and poor treatment outcomes (Rizvi et al., Neurosci Biobehav Rev 2016;65:21-35). This symptom often persists even after mood symptoms remit, suggesting that anhedonia may represent a distinct therapeutic target with unique clinical and neurobiological characteristics (Cooper et al., Front Psychiatry 2018;9:513). For this reason, it has more recently become a focus of novel therapeutic strategies, including repetitive Transcranial Magnetic Stimulation (rTMS), which has shown preliminary efficacy in modulating reward-related symptoms (Fukuda et al., Brain Behav 2021;11(9):e2329) . Objectives This study compared the effects of accelerated repetitive Transcranial Magnetic Stimulation (arTMS) versus standard rTMS on anhedonia in inpatients with Major Depressive Episodes (MDEs), including both unipolar and bipolar depression. Accelerated rTMS, which delivers multiple sessions per day over a shorter period, reduces treatment duration and is emerging as an effective alternative to standard rTMS. Methods In a single-blind randomized design, 33 inpatients diagnosed with MDE were assigned to receive either arTMS (4 sessions/day for 5 days; n=18) or standard rTMS (1 session/day for 4 weeks; n=15). Due to 2 dropouts in the standard rTMS group, the final analysis included 18 patients in the arTMS group and 13 in the rTMS group. Anhedonia was assessed using Item 8 of the Montgomery–Åsberg Depression Rating Scale (MADRS) and Items 4 and 12 of the Beck Depression Inventory-II (BDI-II) at baseline, day 28, and day 56. Results At day 28, MADRS Item 8 scores decreased by 2.1 points in the arTMS group compared to 0.8 in the rTMS group (p=0.003); at day 56, reductions were 2.4 and 1.0, respectively (p=0.002). For BDI-II Item 4, reductions at day 56 were 1.3 in the arTMS group versus 0.7 in the rTMS group (p=0.008); for Item 12, 1.0 versus 0.4 (p=0.01). No significant differences in adverse events were observed between groups. Conclusions These preliminary findings suggest that arTMS may lead to faster and greater improvements in anhedonia symptoms compared to standard rTMS in inpatients with MDE, without compromising safety or tolerability. This supports the potential of arTMS as a promising intervention for persistent symptoms like anhedonia, which often remain refractory to conventional treatments. Further large-scale, controlled studies are needed to confirm these results and clarify the underlying neurobiological mechanisms, including modulation of reward and motivational neural networks.References: 1. Rizvi SJ, Pizzagalli DA, Sproule BA, Kennedy SH. Assessing anhedonia in depression: Potentials and pitfalls. Neurosci Biobehav Rev. 2016;65:21–35. doi:10.1016/j.neubiorev.2016.03.004. 2. Cooper JA, Arulpragasam AR, Treadway MT. Anhedonia in depression: biological mechanisms and computational models. Curr Opin Behav Sci. 2018;22:128–135. doi:10.1016/j.cobeha.2018.01.024. 3. Fukuda AM, Kang JWD, Gobin AP, Tirrell E, Kokdere F, Carpenter LL. Effects of transcranial magnetic stimulation on anhedonia in treatment resistant major depressive disorder. Brain Behav. 2021;11(9):e2329. doi:10.1002/brb3.2329.

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.

AIM:Bipolar disorder (BD) and schizophrenia (SCZ) share many clinical and neurobiological features, and a continuum between the two has been postulated. Bipolar patients leaning toward the SCZ pole of the continuum may have a higher risk of neuroprogression. Here we investigated the relationships between illness course, white matter integrity, levels of N-acetylaspartate (NAA), and polygenic score (PRS) of SCZ. METHODS:A sample of 103 depressed bipolar inpatients underwent magnetic resonance imaging (MRI) acquisition to perform diffusion tensor imaging (DTI) analysis and magnetic resonance spectroscopy to assess NAA. Genotyping and PRS calculation were also performed in a subsample of 75 patients. Associations between illness course, NAA, and white matter microstructure were explored; indirect effects were investigated through mediation models; further, a possible moderating effect of SCZ-PRS was tested. RESULTS:Negative associations emerged between number of affective episodes and NAA. Manic episodes were also negatively associated with white matter integrity, and NAA significantly mediated the effect of manic episodes on DTI metrics. SCZ-PRS moderated the relation between illness duration and NAA. Moderated mediation analyses showed that only at high SCZ-PRS, illness duration negatively affected NAA, which in turn was linked to reduced fractional anisotropy. CONCLUSION:Our results support the concept of neuroprogression in BD, suggesting a deleterious effect of acute episodes, particularly manic ones, on neurochemical and white matter alterations. Further, patients with a higher SCZ-PRS seem to show detrimental effects related to illness duration, possibly suggesting a longitudinal course closer to SCZ.

INTRODUCTION:Depressive disorders are a leading cause of global disease burden, particularly with the challenge of treatment-resistant depression (TRD). Research points to a complex bidirectional relationship between cardiovascular (CV) risk factors and TRD, with CV risk negatively impacting brain structure and potentially influencing antidepressant resistance. Moreover, the association between depression and the genetic vulnerability to cardiovascular disease suggests a shared pathophysiological process between the two. This study investigates the mediating role of brain structural alterations in the relationship between CV and cerebrovascular (CeV) risk and treatment resistance in depression. METHODS:We assessed 165 inpatients with Major depressive disorder. Each patient's CV risk was assessed via the QRISK 3 calculator. For a subset of patients, CV and CeV disease polygenic risk scores (PRS) were obtained. All patients underwent a 3 T MRI scan, and white matter hyperintensities estimates and indicators of brain trophic state were obtained. RESULTS:Both CV risk and CV disease PRSs are associated with treatment resistance status, white matter hyperintensities, and indicators of brain atrophy. Mediation analyses suggested that CV-induced brain alterations might underlie the relation between CV genetic and phenotypic risk and antidepressant treatment resistance. CONCLUSION:These results underscore the need to explore cardiovascular risk management as part of treatment strategies for depression, pointing toward a shared pathophysiological process linking heart and brain health in treatment-resistant depression.

Major depressive disorder (MDD) exhibits substantial clinical heterogeneity complicating prognosis definition and treatment selection. Characterizing MDD subtypes through distinct clinical manifestations could enhance personalized therapeutic approaches. We developed a topological data analysis (TDA) framework with graph-based community detection to identify homogeneous patient subgroups using multimodal data integration. We implemented a TDA pipeline in UK Biobank MDD participants with gene-environment (G-E, N=20,715) and gene-environment-neuroimaging (G-E-I, N=3,044) data. We systematically compared predictive capabilities across genetic, environmental, and neuroimaging features, alone and combined, for 18 health-related outcomes. For the best-predictive set of features identified for each outcome, a novel two-stage feature ranking approach identified features relevant for graph construction and community-based outcome differentiation. Cross-cohort validation utilized two independent datasets. G-E interactions demonstrated superior predictive performance for 13 clinical outcomes, including treatment-resistant depression (TRD), symptom subtypes, and suicidal phenotypes. Community profiling revealed distinct vulnerability pathways: trauma-stress exposures linked to TRD and episode severity, while substance-behavioral profiles associated with anxious symptoms. Environmental factors emerged as primary determinants of most health outcomes, whereas neuroimaging features optimally predict medical comorbidities. Cross-cohort validation confirmed replication for multiple outcomes: self-harm behavior and anxious features (GSRD), TRD and vascular diseases (HSR), with consistent environmental stress-related predictive features across cohorts. TDA successfully identified clinically relevant MDD subgroups with unique multimodal signatures. These findings underscore the essential role of integrating genetic, environmental, and neuroimaging characteristics for robust health outcome prediction, establishing TDA-based community detection as an effective framework for MDD patient stratification and advancing precision medicine approaches in depression management. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research has been conducted using the UK Biobank Resource under Application Number 56514. Stratification of health outcomes in mood disorders. The study was supported by the Italian Ministry of Health (DEPTYPE project, grant n. GR201912370616). PB was partially supported by grants from the Italian Ministry of Education and Research - MUR (Dipartimenti di Eccellenza Programme 202327 - Dept. of Pathophysiology and Transplantation, Universita degli Studi di Milano), the Italian Ministry of Health (Hub Life Science- Diagnostica Avanzata, HLSDA, PNCE3202223683266CUP: C43C22001630001 / MI0117; Ricerca Corrente 2025), and by the ERANET Neuron JTC 2023 (ERP-2023-23684211 - ResilNet) and Eranet Neuron JTC 2024 (ER202423684536 - BRAWO Project). EM was partly supported by the Italian Ministry of University and Research (PRIN 2022 PNRR, grant n. P20229MFRC). The European Group for the Study of Resistant Depression (GSRD) obtained an unrestricted grant sponsored by Lundbeck A/S. We acknowledge the contributions of the GSRD network members: Siegfried Kasper, Joseph Zohar, Daniel Souery, Stuart Montgomery, Panagiotis Ferentinos, Dan Rujescu, and Julien Mendlewicz. The sponsor played no role in designing the study, data collection and analyses, interpretation of the data, writing of the manuscript, and in the decision to submit the research for publication. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All procedures were performed in compliance with relevant laws and institutional guidelines. Informed consent was obtained for studies on human subjects. The institutional committee of IRCCS Ospedale San Raffaele has approved the HRS study (date 16/12/2020; ref. number, 211/INT/2020). The European Group for the Study of Resistant Depression (GSRD) study protocol was approved by the Ethics Committee of the coordinating center at Hopital Erasme, Cliniques universitaires de Bruxelles (Universite Libre de Bruxelles, approval number B406201213479), Belgium, and the local ethical committees of all participating centres. The UKB obtained ethics approval from the North West Multi-centre Research Ethics Committee with approval number 11/NW/0382. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes There are restrictions prohibiting the provision of data in this manuscript. The data in this manuscript were obtained from a third party, UK Biobank, upon application. The genetic, environmental, brain imaging and clinical outcomes data have been deposited with the UK Biobank and are freely available to approved researchers, as has been done with other datasets to date. Interested parties can apply for data from UK Biobank directly, at http://www.ukbiobank.ac.uk. UK Biobank will consider data applications from bona fide researchers for health-related research that is in the public interest. By accessing data from UK Biobank, readers will be obtaining it in the same manner as we did. The central code of the main work is available upon request at https://osf.io/cphj6/?view_only=cc5f359232494a828ad4807f544ae1eb.