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.

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:Although subtle differences in cortico-striato-thalamo-cortical circuit structure and function are critical to the current understanding of the neurocircuitry in obsessive-compulsive disorder (OCD), emerging evidence suggests that the cerebellum may also be involved. However, much of this evidence comes from studies with small samples and notable methodological heterogeneity. METHODS:We conducted a mega-analysis of individual-participant data on cerebellar subregional volumes, comparing individuals with OCD and healthy controls (HCs) from the ENIGMA-OCD Working Group. Three-dimensional T1-weighted volumetric structural brain magnetic resonance imaging (MRI) scans from 1954 individuals with OCD and 2091 HCs across 22 sites (40 datasets) were processed using the ACAPULCO (Automatic Cerebellum Anatomical parcellation using U-Net Locally Constrained Optimization) pipeline to extract cerebellar parcellations. We harmonized the volume measures across sites using the ComBat algorithm. Multiple linear regression models were fitted to estimate group differences separately within the pediatric (<12 years), adolescent (12-17 years), and adult (from 18 years) samples, adjusting for age, gender, and intracranial volume. RESULTS:In adults with OCD (vs. HCs), we found significantly smaller volumes of the corpus medullare (d = -0.093, false discovery rate (FDR)-corrected p = .036), left VIIb (d = -0.085, pFDR = .039) and right VIIb (d = -0.091, pFDR = .036). None of the comparisons between children or adolescents with OCD versus HCs remained statistically significant after FDR correction. In all 3 age groups, cerebellar (subregional) volumes were significantly moderated by medication status. CONCLUSIONS:We report novel findings implicating specific cerebellar subregions across developmental stages of OCD and the key impact of medication status. Additional research on the functional significance of these findings may offer new translational leads.

Studies of brain morphology in mental illness often focus on a few neuroimaging phenotypes. Here we present a comprehensive morphological characterization in obsessive-compulsive disorder (OCD) in a large sample (2255 OCD, 2264 controls) using nine cortical and four subcortical phenotypes, including several not previously examined in OCD, among them a subcortical structural similarity network phenotype developed here. Spatially distinct regional alterations emerged across structural phenotypes: cortical curvature alterations in default mode and frontoparietal networks, increased structural similarity network node degree in sensorimotor regions, widespread volume reductions associated with medication use, and localized subcortical shape alterations. In brain-behavior predictive models, curvature phenotypes showed the strongest associations with clinical features. Cortical alterations, especially in structural similarity networks, were associated with specific gene expression patterns, implicating dysregulation of excitatory neurons. RNA-sequencing data from tissue collected during functional neurosurgery revealed that genes downregulated in the dorsolateral prefrontal cortex in OCD contributed to the gene expression patterns linked to cortical alterations. Previously reported differentially expressed genes from postmortem brain studies of OCD also contributed. These findings support the importance of a comprehensive approach to characterizing brain morphology and suggest that cortical curvature and structural similarity alterations reflect key pathophysiological processes in OCD.

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.

Chronotherapeutics are nonpharmacologic interventions whose development stems from investigations into sleep and circadian rhythm abnormalities associated with mood disorder. These therapies utilize controlled exposure to environmental cues (light, darkness) to regulate biologic rhythms. They encompass sleep-wake manipulations (partial/total sleep deprivation, sleep phase adjustment) and light therapy approaches. Growing evidence supports the safety and efficacy of chronotherapeutics in clinical settings. Indeed, they target core depressive symptoms, including suicidality and may represent a novel therapeutic approach for treatment-resistant depression. This makes them a viable treatment option, both as a monotherapy and in combination with existing psychopharmacologic medications and paves the way for their potential inclusion as first-line treatments for mood disorders.

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.

BackgroundThe rate of suicide attempts by patients with bipolar disorder is high. In addition to patient and country specific factors, environmental factors may contribute to suicidal behavior. Sunlight has multiple diverse impacts on human physiology and behavior. Solar insolation is defined as the electromagnetic energy from the sun striking a surface area on earth. We previously found that a large change in solar insolation between the minimum and maximum monthly values was associated with an increased risk of suicide attempts in patients with bipolar I disorder.MethodsThe association between solar insolation and a history of suicide attempts in bipolar disorder was again investigated using an international database with 15% more data and more sites at diverse locations and countries.ResultsData were available from 5641 patients with bipolar I disorder living at a wide range of latitudes in 41 countries in both hemispheres. A large change in solar insolation between the minimum and maximum monthly values was associated with a history of suicide attempts in patients with bipolar I disorder, a replication of our prior analysis. The estimated model also associated state sponsored religion in the onset country, female gender, a history of alcohol or substance abuse, and being part of a younger birth cohort with a history of suicide attempts.ConclusionsA large change between the minimum and maximum monthly values of solar insolation was associated with a history of suicide attempts in bipolar I disorder, replicating our prior research. Physicians should be aware that daylight has wide ranging physiological and psychiatric impacts, and that living with large changes in solar insolation may be associated with an increased suicide risk.

White matter pathways, typically studied with diffusion tensor imaging (DTI), have been implicated in the neurobiology of obsessive-compulsive disorder (OCD). However, due to limited sample sizes and the predominance of single-site studies, the generalizability of OCD classification based on diffusion white matter estimates remains unclear. Here, we tested classification accuracy using the largest OCD DTI dataset to date, involving 1336 adult participants (690 OCD patients and 646 healthy controls) and 317 pediatric participants (175 OCD patients and 142 healthy controls) from 18 international sites within the ENIGMA OCD Working Group. We used an automatic machine learning pipeline (with feature engineering and selection, and model optimization) and examined the cross-site generalizability of the OCD classification models using leave-one-site-out cross-validation. Our models showed low-to-moderate accuracy in classifying (1) “OCD vs. healthy controls” (Adults, receiver operator characteristic-area under the curve = 57.19 ± 3.47 in the replication set; Children, 59.8 ± 7.39), (2) “unmedicated OCD vs. healthy controls” (Adults, 62.67 ± 3.84; Children, 48.51 ± 10.14), and (3) “medicated OCD vs. unmedicated OCD” (Adults, 76.72 ± 3.97; Children, 72.45 ± 8.87). There was significant site variability in model performance (cross-validated ROC AUC ranges 51.6–79.1 in adults; 35.9–63.2 in children). Machine learning interpretation showed that diffusivity measures of the corpus callosum, internal capsule, and posterior thalamic radiation contributed to the classification of OCD from HC. The classification performance appeared greater than the model trained on grey matter morphometry in the prior ENIGMA OCD study (our study includes subsamples from the morphometry study). Taken together, this study points to the meaningful multivariate patterns of white matter features relevant to the neurobiology of OCD, but with low-to-moderate classification accuracy. The OCD classification performance may be constrained by site variability and medication effects on the white matter integrity, indicating room for improvement for future research.

Abstract Background Sunlight contains ultraviolet B (UVB) radiation that triggers the production of vitamin D by skin. Vitamin D has widespread effects on brain function in both developing and adult brains. However, many people live at latitudes (about > 40 N or S) that do not receive enough UVB in winter to produce vitamin D. This exploratory study investigated the association between the age of onset of bipolar I disorder and the threshold for UVB sufficient for vitamin D production in a large global sample. Methods Data for 6972 patients with bipolar I disorder were obtained at 75 collection sites in 41 countries in both hemispheres. The best model to assess the relation between the threshold for UVB sufficient for vitamin D production and age of onset included 1 or more months below the threshold, family history of mood disorders, and birth cohort. All coefficients estimated at P ≤ 0.001. Results The 6972 patients had an onset in 582 locations in 70 countries, with a mean age of onset of 25.6 years. Of the onset locations, 34.0% had at least 1 month below the threshold for UVB sufficient for vitamin D production. The age of onset at locations with 1 or more months of less than or equal to the threshold for UVB was 1.66 years younger. Conclusion UVB and vitamin D may have an important influence on the development of bipolar disorder. Study limitations included a lack of data on patient vitamin D levels, lifestyles, or supplement use. More study of the impacts of UVB and vitamin D in bipolar disorder is needed to evaluate this supposition.

Circadian rhythm disruption is a core symptom of bipolar disorder (BD), also reflected in altered patterns of melatonin release. Reductions of grey matter (GM) volumes are well documented in BD. We hypothesized that levels and timing of melatonin secretion in bipolar depression could be associated with depressive psychopathology and brain GM integrity. The onset of melatonin secretion under dim light conditions (DLMO) and the amount of time between DLMO and midsleep (i.e. phase angle difference; PAD) were used as circadian rhythm markers. To study the time course of melatonin secretion, an exponential curve fitting the melatonin values was calculated, and the slope coefficients (SLP) were obtained for each participant. Significant differences were found between HC and BD in PAD measures and melatonin profiles. Correlations between PAD and depressive psychopathology were identified. Melatonin secretion patterns were found to be associated with GM volumes in the Striatum and Supramarginal Gyrus in BD. Our findings emphasized the role of melatonin secretion role as a biological marker of circadian synchronization in bipolar depression and provided a novel insight for a link between melatonin release and brain structure.

Abstract White matter pathways, typically studied with diffusion tensor imaging (DTI), have been implicated in the neurobiology of obsessive-compulsive disorder (OCD). However, due to limited sample sizes and the predominance of single-site studies, the generalizability of OCD classification based on diffusion white matter estimates remains unclear. Here, we tested classification accuracy using the largest OCD DTI dataset to date, involving 1,336 adult participants (690 OCD patients and 646 healthy controls) and 317 pediatric participants (175 OCD patients and 142 healthy controls) from 18 international sites within the ENIGMA OCD Working Group. We used an automatic machine learning pipeline (with feature engineering and selection, and model optimization) and examined the cross-site generalizability of the OCD classification models using leave-one-site-out cross-validation. Our models showed low-to-moderate accuracy in classifying (1) “OCD vs. healthy controls'' (Adults, receiver operator characteristic-area under the curve = 57.19 ± 3.47 in the replication set; Children, 59.8 ± 7.39), (2) “unmedicated OCD vs. healthy controls” (Adults, 62.67 ± 3.84; Children, 48.51 ± 10.14), and (3) “medicated OCD vs. unmedicated OCD” (Adults, 76.72 ± 3.97; Children, 72.45 ± 8.87). There was significant site variability in model performance (cross-validated ROC AUC ranges 51.6–79.1 in adults; 35.9–63.2 in children). Machine learning interpretation showed that diffusivity measures of the corpus callosum, internal capsule, and posterior thalamic radiation contributed to the classification of OCD from HC. The classification performance appeared greater than the model trained on grey matter morphometry in the prior ENIGMA OCD study (our study includes subsamples from the morphometry study). Taken together, this study points to the meaningful multivariate patterns of white matter features relevant to the neurobiology of OCD, but with low-to-moderate classification accuracy. The OCD classification performance may be constrained by site variability and medication effects on the white matter integrity, indicating room for improvement for future research.

Objective: Circadian rhythm disruption is commonly observed in bipolar disorder (BD). Daylight is the most powerful signal to entrain the human circadian clock system. This exploratory study investigated if solar inso-lation at the onset location was associated with the polarity of the first episode of BD I. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area of the Earth. Methods: Data from 7488 patients with BD I were collected at 75 sites in 42 countries. The first episode occurred at 591 onset locations in 67 countries at a wide range of latitudes in both hemispheres. Solar insolation values were obtained for every onset location, and the ratio of the minimum mean monthly insolation to the maximum mean monthly insolation was calculated. This ratio is largest near the equator (with little change in solar insolation over the year), and smallest near the poles (where winter insolation is very small compared to summer insolation). This ratio also applies to tropical locations which may have a cloudy wet and clear dry season, rather than winter and summer. Results: The larger the change in solar insolation throughout the year (smaller the ratio between the minimum monthly and maximum monthly values), the greater the likelihood the first episode polarity was depression. Other associated variables were being female and increasing percentage of gross domestic product spent on country health expenditures. (All coefficients: P <= 0.001). Conclusion: Increased awareness and research into circadian dysfunction throughout the course of BD is warranted.

BACKGROUND:Widely used psychotropic medications for obsessive-compulsive disorder (OCD) may change the volumes of subcortical brain structures, and differently in children vs. adults. We measured subcortical volumes cross-sectionally in patients finely stratified for age taking various common classes of OCD drugs. METHODS:The ENIGMA-OCD consortium sample (1081 medicated/1159 unmedicated OCD patients and 2057 healthy controls aged 6-65) was divided into six successive 6-10-year age-groups. Individual structural MRIs were parcellated automatically using FreeSurfer into 8 regions-of-interest (ROIs). ROI volumes were compared between unmedicated and medicated patients and controls, and between patients taking serotonin reuptake inhibitors (SRIs), tricyclics (TCs), antipsychotics (APs), or benzodiazepines (BZs) and unmedicated patients. RESULTS:Compared to unmedicated patients, volumes of accumbens, caudate, and/or putamen were lower in children aged 6-13 and adults aged 50-65 with OCD taking SRIs (Cohen's d = -0.24 to -0.74). Volumes of putamen, pallidum (d = 0.18-0.40), and ventricles (d = 0.31-0.66) were greater in patients aged 20-29 receiving APs. Hippocampal volumes were smaller in patients aged 20 and older taking TCs and/or BZs (d = -0.27 to -1.31). CONCLUSIONS:Results suggest that TCs and BZs could potentially aggravate hippocampal atrophy of normal aging in older adults with OCD, whereas SRIs may reduce striatal volumes in young children and older adults. Similar to patients with psychotic disorders, OCD patients aged 20-29 may experience subcortical nuclear and ventricular hypertrophy in relation to APs. Although cross-sectional, present results suggest that commonly prescribed agents exert macroscopic effects on subcortical nuclei of unknown relation to therapeutic response.

BACKGROUND:Dysfunctional glutamatergic neurotransmission has been proposed both, as a biological underpinning of mood disorder and as a target for rapid-acting antidepressant treatments. Total sleep deprivation and light therapy (TSD + LT) can prompt antidepressant response in drug-resistant bipolar depression. Here we explored the effects of TSD + LT on dorsolateral prefrontal cortex (DLPFC) glutamate and/or glutamine+glutamate (Glx) levels. METHODS:We studied single voxel 1H-MRS measures of DLPFC Glu and Glx levels of 48 healthy participants and 55 inpatients with a major depressive episode in course of Bipolar Disorder, a subset of which (N = 23) underwent three cycles of repeated TSD + LT and were evaluated before and after treatment. Treatment effects of mood and on Glu and Glx concentrations were analyzed in the context of the Generalized Linear Model (GLM), correcting for age, sex and ongoing lithium treatment. RESULTS:Higher concentration of Glu (adjusted Z = -2189, p = 0,0285) and Glx (adjusted Z = -3,13, p = 0,0017) were observed in BD patients compared to HC. Treatment caused a significant rapid reduction of depressive symptom severity over time (F = 63.98, p < 0.01). Change in depression levels after TSD + LT treatment was significantly influenced by delta change in Glu levels (LR χ2 = 4.619, p = 0.0316) and in Glx levels (LR χ2 = 4.486, p = 0.0341). CONCLUSION:A reduction in Glu and Glx levels associated with depression could contribute to the mechanism of action of TSD + LT, directly acting on glutamatergic neurons, or to the interaction between the glutamatergic system and dopamine (DA) and serotonin (5-HT) levels, known to be targeted by TSD. This is in line with several studies showing a glutamatergic modulation effects of antidepressants and mood stabilizing agents. This finding deepens our understanding of antidepressant effect of chronoterapeutics.

• A link has been suggested between depressive cognition and time perception. • More severe depressive cognition was related to a longer produced time interval. • Tendency toward self-blame was found to be a robust correlate of time perception.

Introduction Higher thalamic volume has been found in children with obsessive-compulsive disorder (OCD) and children with clinical-level symptoms within the general population (Boedhoe et al. 2017, Weeland et al. 2021a). Functionally distinct thalamic nuclei are an integral part of OCD-relevant brain circuitry. Objectives We aimed to study the thalamic nuclei volume in relation to subclinical and clinical OCD across different age ranges. Understanding the role of thalamic nuclei and their associated circuits in pediatric OCD could lead towards treatment strategies specifically targeting these circuits. Methods We studied the relationship between thalamic nuclei and obsessive-compulsive symptoms (OCS) in a large sample of school-aged children from the Generation R Study (N = 2500) (Weeland et al. 2021b). Using the data from the ENIGMA-OCD working group we conducted mega-analyses to study thalamic subregional volume in OCD across the lifespan in 2,649 OCD patients and 2,774 healthy controls across 29 sites (Weeland et al. 2021c). Thalamic nuclei were grouped into five subregions: anterior, ventral, intralaminar/medial, lateral and pulvinar (Figure 1). Results Both children with subclinical and clinical OCD compared with controls show increased volume across multiple thalamic subregions. Adult OCD patients have decreased volume across all subregions (Figure 2), which was mostly driven by medicated and adult-onset patients. Conclusions Our results suggests that OCD-related thalamic volume differences are global and not driven by particular subregions and that the direction of effects are driven by both age and medication status. Disclosure No significant relationships.