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The rare cases of patients with 48-hour bipolar or unipolar ultra-rapid-cycling allow a more precise understanding of mood cycles in affective disorders, as the rhythmic changes in the psychopathological state and biological parameters are quite precise. A 73-year-old male patient with several years of recurrent affective-depressive disorder (International Classification of Diseases, 10th Revision: F33.1) developed unipolar 48-hour-ultra-rapid-cycling with 1 day of severe depression up to acute suicidality and 1 day of euthymia (International Classification of Diseases, 10th Revision: F31.8) at the beginning of 2024. Ultra-rapid-cycling could be objectified both psychopathologically (Beck Depression Inventory and visual analogue scale) and neurobiologically (especially serotonin using loudness dependence of auditory evoked potentials) at the end of the year. The patient responded promptly to the subsequent adjustment to 900 mg daily lithium and has been symptom-free and with-out a 48-hour rhythm ever since. Unipolar depressive 48-hour-ultra-rapid-cycling of marked mood and drive fluctuations is also associated with characteristic biological changes, and that lithium represents a successful treatment strategy here in contrast to "normal" rapid-cycling.
Background: Translational circuit neuroscience delivers many candidate neurons whose manipulation could ameliorate psychiatric symptoms. However, the translation of these cellular targets into molecular targets-proteins selectively expressed in those neurons that could be pharmacologically manipulated for treatment-remains scarce. To what extent such a translation is possible or is actually impeded by a lack of highly cell type-specific expression of druggable proteins is unknown. Methods: We performed combinatorial differential expression analysis for over 7200 putatively druggable genes (Illuminating the Druggable Genome database) on large-scale single-cell RNAseq datasets from mouse and human cortex (Allen Institute Cell Types Database) to identify selectively expressed genes in important cellular candidates: several pyramidal cell types and parvalbumin, somatostatin and VIP interneurons of the prefrontal and anterior cingulate cortex and hippocampus in mice, and the cingulate cortex in humans. Results: We identified dozens of targets, including some with psychiatric relevance and/or suitability to modulate neural activity, like ion channels, GPCRs and transporters. However, none of them were expressed with absolute specificity in any of the analysed target cell types but only stood out in some comparisons, not others. Generally, results depended strongly on selectivity criteria: less conservative approaches (such as moderate p-value adjustment or grouping of contrast cell sets) yielded more targets, whereas the introduction of additional plausible constraints (difference in proportion of expressing cells, beta; absence of expression in contrast cell type) drove numbers towards zero. Generally, interneurons showed more selectively expressed targets in comparison to cells of the same region compared to excitatory ones (intra-regional comparisons), whereas the reverse was found in inter-regional contrasts comparing the same cell type across regions. Conclusions: The lack of high selectivity in the expression of genes encoding druggable targets constitutes a principal biological limit for manipulating cortical neurons of one type, specifically to leverage therapeutic action. While, currently, this conclusion is limited to the investigated neocortical and hippocampal regions, it highlights the need to develop biological heuristics for identifying targets expressed with relative specificity.
Depression is a common mental disorder and a leading cause of global disease burden. Emerging evidence supports diet as an adjunct treatment for depression. Previous studies are limited, meaning it is unclear whether improvements are directly due to dietary change. The OPTIMISM trial aims to address this gap through a sham-controlled randomised feeding trial design.The OPTIMISM trial is a 4-week double-blind, sham-controlled, randomised feeding trial. A total of 44 participants with MDD in a current major depressive episode of moderate to severe severity will be recruited and randomised to a Mediterranean or a sham control diet, designed to reflect typical dietary intake of the general population. All food will be provided for four weeks. Participants will complete assessments and have blood and stool collected at baseline and four weeks. The primary outcome is the differential change in clinician-rated depressive severity at four weeks. Exploratory outcomes include patient-rated depressive and anxiety symptoms, and quality of life. Potential mechanisms will be evaluated through analysis of biological samples. An additional group of 22 healthy individuals without depression will also be recruited and will receive a Mediterranean diet for four weeks; their data will determine whether clinical and biological responses to the intervention are unique to depression and whether the diet treatment modulates depression-related pathology.If the intervention diet leads to a greater reduction in depressive symptoms compared with a sham control diet, this trial will provide preliminary evidence supporting the use of a Mediterranean diet in the treatment of depression.
This study investigates changes in stress parameters in individuals with schizophrenia spectrum disorders participating in mindfulness-based group therapy (MBGT). N = 45 participants were randomised to MBGT or Treatment as Usual over four weeks. Before and after each session, psychological and biological stress markers by self-rating scales and cortisol saliva samples were assessed in the active group (n = 22). Oxytocin was assessed before and after the first and last sessions. Results indicated significant reductions in general stress, symptom-related distress and cortisol levels. Oxytocin showed increases during the first session and decreases during the last session. Exploratory analyses showed correlations between psychological and biological stress markers, and between stress reduction and changes in self-reported negative symptoms. MBGT may provide stress relief in patients with SSD with potential associations with negative symptoms. The study did not include a session-specific control group. Further studies with larger samples and corresponding control conditions are warranted to test causality.
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The etiology of major depressive disorder (MDD) is multifactorial with both genetic and environmental factors, such as adverse/stressful life events, contributing to risk. There is some evidence suggesting that microRNAs (miRNAs) mediate environmental-genetic interaction leading to the brain dysfunctions that underlie MDD. However, changes in miRNAs expression in human brain regions due to stress and associated with MDD are unclear. To increase the evidence in this regard, miRNA sequencing was performed on tissue samples of subgenual anterior cingulate cortex (sgACC) obtained from depressed patients and control subjects, as well on tissue samples of medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) from mice exposed to chronic social stress (CSS) and control animals. DESeq2 was applied to identify differentially expressed miRNAs (DEMs) and weighted co-expression network preservation analysis to uncover conserved molecular mechanisms between species. Finally, pathways obtained from DESeq2 and preservation analyses were overlapped to robustly identify MDD-related processes across bioinformatic approaches.Eighteen DEMs were identified in the human sgACC, 11 in the mPFC and 9 in the BLA of mice. The human sgACC DEMs were involved mainly in intracellular signaling and immune system-related pathways. The mouse mPFC and BLA DEMs were mainly involved in, respectively, intracellular signaling and nervous system functions. Preservation patterns between humans and mice indicated an over-representation of processes related to cellular signaling. Transcriptional regulation by MECP2 and Protein Kinase A signaling were the two pathways consistently altered across species, brain regions, and bioinformatic approaches. Although further studies are needed, they could represent a novel target for intervention strategies and confirm the dysregulation of intracellular signaling, immune, neuronal and synaptic functions in MDD.
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Major depressive disorder (MDD) and treatment-resistant depression (TRD) are biologically heterogeneous conditions with substantial suicide risk, yet current diagnostic frameworks lack validated biological markers for patient stratification. This narrative review examines the role of ceramides and lipid metabolism as immunometabolic drivers and potential biomarkers in MDD, TRD, and suicidal vulnerability. We integrate evidence from lipidomic, neuroinflammatory, and translational studies to characterize how ceramides, generated through de novo synthesis, sphingomyelinase-mediated pathways, and salvage mechanisms, participate in microglial priming, blood-brain barrier compromise, synaptic dysfunction, and regulated cell death. Ceramide accumulation, modulated by HPA axis dysregulation, adiposity, and comorbid metabolic conditions, intersects with tryptophan-kynurenine pathway alterations and mitochondrial bioenergetic deficits, converging on a multi-level immunometabolic framework relevant to depressive and treatment-resistant phenotypes. Circulating ceramide species, particularly C16-C24:1, show consistent elevations in MDD and correlate with symptom severity, antidepressant exposure, and sex-specific patterns, while indirect evidence links lipid dysregulation to suicidal behavior. Acid sphingomyelinase inhibition by functional antidepressants highlights a pharmacologically relevant axis. Current evidence is constrained by cross-sectional designs, small samples, and heterogeneous platforms. Longitudinal, multi-omic studies with harmonized protocols are needed to determine whether ceramide profiles can inform risk stratification and personalized interventions in precision psychiatry.
Borderline Personality Disorder (BPD) is characterized by emotional dysregulation and high-risk behaviors, including self-harm and suicide attempts. Despite the high prevalence of suicidal behavior in BPD, the neurobiological substrates underlying suicide vulnerability remain poorly understood. This study aimed to investigate differences in BPD and a history of suicide attempt (BPD-SA) with those without such a history (BPD-NA) using multimodal magnetic resonance imaging (MRI). Neuroimaging data from 60 individuals with BPD were analyzed. Acquisitions included high-resolution T1-weighted, Fluid-Attenuated Inversion Recovery sequences, and Diffusion Weighted Imaging. Imaging features were compared between BPD-SA (n = 30) and BPD-NA (n = 30) subgroups, adjusting for alcohol and substance abuse. Pearson's correlation was used to examine associations between imaging features and clinical questionnaires, including childhood trauma and symptom severity. Significant differences (p < 0.05) were found between BPD-SA and BPD-NA in brain volume, cortical thickness, and Fractional Anisotropy. The most pronounced changes were localized to limbic structures (hippocampus and fornix), the frontal cortex, corpus callosum, and cortico-thalamic pathways, with BPD-SA showing more severe white matter alterations. Correlation analyses revealed that imaging abnormalities in BPD-SA were negatively correlated with the Childhood Trauma Questionnaire (CTQ). In contrast, Zanarini Rating Scale (ZAN-BPD) scores were negatively correlated with MRI-assessed neurobiological alterations only in the BPD-NA subgroup. This study provides preliminary evidence that BPD-SA may exhibit distinct patterns of structural and white matter alterations compared to BPD-NA. Such neuroimaging differences may reflect underlying neurobiological dimensions related to vulnerability, illness severity, and developmental risk exposure.
Understanding public beliefs about patients at memory centers may inform efforts to promote early diagnosis and guide clinical discussions of Alzheimer's disease (AD). Adults (N=3,527) read a vignette describing a fictional person at a memory center and rated the person's condition as a mental illness, part of typical aging, and psychological or biological origins. Vignettes varied by AD biomarker result, symptom stage, and treatment availability. Participants most strongly believed that the condition was part of typical aging and biological in origin, though beliefs varied across subgroups. Black and Asian participants reported stronger beliefs than White participants that the condition was a mental illness (β=0.39, P<0.001) and psychological (β=0.46, P<0.001). Men reported stronger beliefs that the condition was a mental illness (β=0.19, P<0.001), psychological (β=0.14, P<0.001), and part of typical aging (β=-0.08, P=0.04). Biomarker positivity heightened biological and lowered psychological attributions (all P<0.05). The findings offer specific insights to guide intervention.
Neuropsychiatric diseases are characterized by complex molecular underpinnings that remain challenging to fully elucidate. Molecular dynamics (MD) simulations have emerged as a powerful computational tool, providing a crucial bridge between static genetic data and the dynamic functional consequences of molecular alterations. This review offers a comprehensive overview of the application of MD simulations in studying the molecular basis of neuropsychiatric disorders. We highlight key applications, including the assessment of mutation pathogenicity in disease-associated proteins, the influence of post-translational modifications on protein function, folding, misfolding, and aggregation, and the characterization of psychopharmacological drug-target interactions at atomic resolution. Through relevant examples from research on psychiatric and neurodegenerative diseases, we illustrate how these computational methods are implemented to gain mechanistic insights. Importantly, this review traces the historical development of MD simulations in biological applications, critically examines the method's limitations, and outlines future perspectives for simulating long-timescale physiological processes, large molecular ensembles, and even whole-cell environments. Ultimately, this work highlights MD simulations as a useful and complementary tool for modern neuropsychiatry research, capable of revealing disease mechanisms and guiding the development of novel therapeutic strategies.
Self-reported low positive mood is common in youth anxiety disorders and has been associated with poorer treatment response. Functioning of neural affective systems may have distinct associations with treatment relative to self-reported measures and be useful for understanding biological processes related to treatment. This study examined associations between self-reported mood and pre-treatment functional connectivity network patterns during positive mood and treatment response in 73 youth (mean age = 11.1) diagnosed with anxiety disorders. Participants engaged in an fMRI autobiographical memory-based mood induction task in the scanner that successfully improved mood. Participants then completed 16 sessions of cognitive-behavioral or child-centered anxiety treatment. We found no significant differences in how mood changed during the induction task between youth who did and did not recover or respond to treatment. We then used a person-centered method to estimate effective connectivity networks at group, subgroup, and individual levels for each participant. No subgroup-level paths were identified that distinguished treatment responder subgroups. However, treatment responders showed stronger homologous connectivity in the bilateral nucleus accumbens and bilateral amygdala. Responders also showed greater centrality (network influence) of the nucleus accumbens, amygdala, and medial prefrontal cortex on the broader connectivity network. Findings suggest that greater influence of the nucleus accumbens and amygdala on distributed reward and emotion systems is associated with better treatment response, supporting a view that treatment responders capitalize on more responsive reward- and emotion-related brain networks. Future studies should replicate this finding in larger samples and investigate implicated networks as possible treatment targets.
Schizophrenia outcomes remain suboptimal due to relapses, treatment resistance and limited measurement tools for assessing treatment goals and effectiveness. This study identified predictors of symptomatic improvement (≥50% Positive and Negative Syndrome Scale (PANSS) reduction) during 12-week treatment of acute episodes using a multi-dimensional approach encompassing psychopathological, psychological, and biological factors. Forty patients (22.68 ± 7.39 years) were assessed during psychotic decompensation. Blood markers (biochemical, metabolic, inflammatory), demographic and clinical data (e.g. PANSS, Beck Depression Inventory (BDI-II)) were analyzed at 1st and 12th week of the hospitalization. Central neurochemical profiles and white matter integrity were measured at baseline using 1.5 T Magnetic Resonance Spectroscopy (MRS) and Diffusion Tensor Imaging (DTI). Greater clinical improvement was significantly correlated with lower childhood trauma, fewer prior episodes, lower baseline depression, and lower inflammatory marker levels. Multinomial logistic regression identified scale-specific predictors: higher baseline PCr + Cr in the left frontal lobe (FL) for the Positive scale (OR = 3.96), higher glucose (OR = 4.90) and lower NAA/Cr (OR = 0.07) in the left FL for the Negative scale and higher fractional anisotropy (FA) in the left anterior cingulate cortex (ACC), alongside higher glucose and NAA in the left FL for the Total scale. No variables met inclusion criteria for the General subscale. Baseline neurochemical and structural parameters in the left hemisphere serve as isolated predictors of robust symptomatic improvement. These findings support the utility of multi - modal biomarkers integrating neurochemistry and structural integrity for clinical prognosis in acute schizophrenia.
Prenatal stress has been implicated in alterations of maternal hypothalamic-pituitary-adrenal (HPA) axis functioning, yet evidence linking psychosocial stressors to long-term cortisol biology remains inconsistent. Hair cortisol concentration (HCC) provides an integrated measure of cumulative glucocorticoid exposure, allowing investigation of whether diverse prenatal stressors shape maternal cortisol trajectories during pregnancy and postpartum. We analyzed data from a prospective population-based birth cohort from São Paulo, Brazil. Pregnant women (n = 185) were assessed in the third trimester for exposure to intimate partner violence (IPV), emotional responses to pregnancy, and anxiety or depression using standardized instruments (WHO-VAW, MINI). Maternal HCC was quantified from 7 cm hair segments representing the last four months of pregnancy and the first two postpartum months. We compared cortisol levels across exposure groups using t-tests and Mann-Whitney tests, and estimated longitudinal associations with linear mixed-effects models. Cortisol levels declined significantly from pregnancy to postpartum (p < 0.001). Most prenatal stressors-including psychological IPV, anxiety, depression, and negative emotional responses to pregnancy-were not associated with HCC at individual time points nor in longitudinal models. Acute prenatal physical/sexual IPV was associated with lower HCC at specific prepartum time points and with lower mean HCC in longitudinal analyses. In this cohort, maternal cortisol biology showed limited sensitivity to most psychosocial stressors during pregnancy. Only acute physical or sexual IPV was associated with reduced cumulative cortisol levels. These findings highlight the specificity of severe interpersonal violence as a biological stressor and underscore the complexity of interpreting cortisol as a biomarker of prenatal stress.
Differentiating Alzheimer's disease (AD) from frontotemporal dementia (FTD) remains a major clinical challenge, particularly in early disease stages when phenotypic overlap is common and in later stages when cortical degeneration becomes widespread. Structural magnetic resonance imaging (MRI) provides a widely available, non-invasive framework for assessing region-specific brain atrophy patterns associated with these disorders. This narrative review synthesizes current evidence on MRI-based approaches for distinguishing FTD from AD across disease stages. FTD, particularly the behavioral variant, is characterized by early and prominent degeneration of frontal and anterior temporal networks, frequently with hemispheric asymmetry and early behavioral change, including apathy as a core feature. In contrast, AD typically demonstrates a posterior-predominant pattern, with medial temporal and temporoparietal atrophy reflecting a posterior-to-anterior trajectory, while frontal involvement emerges later except in atypical variants. Quantitative MRI techniques, including voxel-based morphometry, cortical thickness analysis, and asymmetry indices, together with validated visual rating scales, enhance the detection of these spatial patterns. Fluid-attenuated inversion recovery imaging supports interpretation by identifying vascular burden, and complementary biomarkers, including FDG-PET, cerebrospinal fluid, and blood-based markers, provide molecular and functional context in diagnostically ambiguous cases. The diagnostic specificity of frontal atrophy is greatest in early stages and decreases as AD and FTD converge anatomically in moderate to advanced disease. Accurate differential diagnosis, therefore, requires a stage-aware, integrative framework that combines structural MRI with longitudinal clinical assessment, neuropsychological profiling, and biomarker information. Structural MRI remains the cornerstone of differentiation, with regional atrophy patterns interpreted within a broader clinical and biological context rather than in isolation.
Emerging evidence suggests a possible link between anorexia nervosa (AN) and alterations in the gut microbiota. This study aimed to characterize the gut microbiota profile in a cohort of Chinese female patients with AN. A comparative analysis of the gut microbiota was conducted between 30 female patients with AN and 30 sex- and age-matched healthy controls (HCs). Fecal samples were collected for 16S rRNA gene sequencing analysis. All participants were assessed using the Eating Disorder Inventory (EDI) and the Childhood Trauma Questionnaire (CTQ). Bioinformatics analysis was performed using QIIME2, and statistical analyses were carried out with SPSS 26.0 and R software. Correlations between microbiota differences and body mass index (BMI), EDI, and CTQ were further investigated. The analysis revealed differences in beta diversity and the abundances of specific microbial taxa between the two groups; however, no significant differences were observed in alpha diversity nor in the associations between gut microbiota and BMI, disease severity, or childhood trauma. This study identified limited differences in the gut microbiota composition between patients with AN and HCs. Critically, no robust associations between gut microbiota and clinical features were found after rigorous multiple comparison correction. While nominal (uncorrected) correlations were observed between the specific microbiota and psychological traits, these results are exploratory and should be considered hypothesis-generating. They highlight a potential avenue for future research but require validation in larger, longitudinal cohorts to determine their reproducibility and biological significance.
Simultaneous super-resolution imaging of multiple fluorophores remains a major challenge in STimulated Emission Depletion (STED) microscopy due to spectral overlap of STED-compatible fluorophores. The combination of STED microscopy and Fluorescence Lifetime Imaging Microscopy (FLIM) offers a powerful alternative for super-resolved, multiplexed imaging of biological samples but is hindered by lifetime convergence at high depletion powers. Here, we present an analysis method, two-species Separation of Photons by LIfetime Tuning (SPLIT)-STED, that uses a linear system of equations in phasor-based STED-FLIM to enhance both fluorophore unmixing and spatial resolution. It defines the fluorescence signal as a mixture of three lifetime components: the two target fluorophores and a short-lifetime contribution from peripheral fluorescence photons. Two-species SPLIT-STED disentangles overlapping lifetimes and selectively filters low-resolution signal. The method enables accurate unmixing of spectrally overlapping fluorophores and, by enhancing resolution through lifetime-based filtering, allows the use of lower depletion powers, thereby improving fluorescence lifetime separation.
Early institutional rearing is associated with adverse biological and health outcomes in later life, including accelerated cellular aging as measured by telomere length. However, the extent to which foster care intervention can mitigate these risks, and whether telomere dynamics predict cardiometabolic health in young adulthood remains unclear. The present study aimed to estimate the association between early institutional care, randomization to foster care (intent-to-treat), and longitudinal changes in telomere length from ages 12-22 years among participants of the Bucharest Early Intervention Project (BEIP), and to determine whether the rate of telomere shortening predicts cardiometabolic health in early adulthood. The study included 156 BEIP participants who had been randomly assigned to either foster care or care-as-usual, with an additional comparison group of never-institutionalized peers. Buccal DNA was collected, and telomere length (T/S ratio) was measured at two to five timepoints between the ages 12 and 22. Cardiometabolic health at age 22 was assessed using metabolic z-scores and criteria for metabolic syndrome. Participants assigned to foster care exhibited a significantly slower decline in telomere length over the 10-year period compared to those in care-as-usual. Ever-institutionalized and never-institutionalized groups had similar overall patterns of telomere decline. Sex-specific analyses indicated that among the foster care group, males had shorter telomere length at age 12 than females, but rates of telomere shortening were similar between sexes over time. The rate of telomere attrition between ages 12 and 22 was not associated with cardiometabolic outcomes at age 22. Foster care intervention during early childhood may protect against telomere shortening among previously institutionalized children, highlighting its role in buffering the long-term impact of early adversity on cellular aging. However, variation in telomere shortening during adolescence and young adulthood did not predict cardiometabolic risk at age 22.
Major advances have been made in understanding the biological mechanisms underlying the Dark Triad - Machiavellianism, narcissism, and psychopathy - yet existing research remains fragmented and rarely examines these traits as an integrated construct. Previous studies have identified structural and functional brain correlates of individual components, but findings are often inconsistent and isolated. This systematic review addresses this gap by synthesizing evidence from 16 empirical studies with a total sample of N = 4246 participants. Integrating results from neuroimaging, lesion, and genetic research, the review provides the first comprehensive overview of the neural architecture of the Dark Triad. The findings indicate a shared core of heightened striatal reward sensitivity, alongside distinct neural profiles: Machiavellianism is associated with enhanced prefrontal and insular activity, psychopathy with deficits in amygdala-orbitofrontal circuits, and narcissism with altered default mode network functioning related to self-referential processing. Overall, the Dark Triad is best understood as emerging from distributed, interacting neural systems rather than isolated brain regions.