bims-endanx Biomed News
on Endocrine Anxiety
Issue of 2025–02–23
sixteen papers selected by
Logan K. Townsend, McMaster University
  1. Mapping the GDF15 Arm of the Integrated Stress Response in Human Cells and Tissues.
  2. Blood mitochondrial health markers cf-mtDNA and GDF15 in human aging.
  3. Growth differentiation factor 15 aggravates sepsis-induced cognitive and memory impairments by promoting microglial inflammatory responses and phagocytosis.
  4. GDF15 Neutralization Ameliorates Muscle Atrophy and Exercise Intolerance in a Mouse Model of Mitochondrial Myopathy.
  5. Proinflammatory cytokines and neuropeptides in psoriasis, depression, and anxiety.
  6. APOE4 exacerbates glucocorticoid stress hormone-induced tau pathology via mitochondrial dysfunction.
  7. How chronic stress warps decision-making.
  8. Hypothalamus-pituitary-adrenal and gut-brain axes in biological interaction pathway of the depression.
  9. Overfeeding induces adipose tissue release of distinct mitochondria.
  10. Mitochondrial and Stress-Related Psychobiological Regulation of FGF21 in Humans.
  11. The flux of energy in critical illness and the obesity paradox.
  12. Developmentally distinct architectures in top-down pathways controlling threat avoidance.
  13. Evaluating animal consciousness.
  14. A short-term, high-caloric diet has prolonged effects on brain insulin action in men.
  15. The (neuro)inflammatory system in anxiety disorders and PTSD: Potential treatment targets.
  16. HPA axis in psychotic and non-psychotic major depression: Cortisol plasma levels and hippocampal volume.
  1. bioRxiv. 2025 Feb 01. pii: 2025.01.31.635929. [Epub ahead of print]
    Mapping the GDF15 Arm of the Integrated Stress Response in Human Cells and Tissues.
    Janell Lm Smith, Kamaryn Tanner, Jack Devine, Anna S Monzel, Alan A Cohen, Martin Picard.
      Mitochondrial stress activates the integrated stress response (ISR) and triggers cell-cell communication through secretion of the metabokine growth differentiation factor 15 (GDF15). However, the gene network underlying the ISR remains poorly defined, particularly across metabolically diverse cellular states and tissues. Using RNAseq data from fibroblasts subjected to metabolic perturbations, we develop an ISR GDF15 index quantifying the GDF15 arm of the ISR activation in human cells. Validation of ISR GDF15 index across 44 postmortem human tissues illustrates how this index can be applied to investigate tissue-specific and age-related ISR activation.
    DOI:  https://doi.org/10.1101/2025.01.31.635929
  2. bioRxiv. 2025 Jan 31. pii: 2025.01.28.635306. [Epub ahead of print]
    Blood mitochondrial health markers cf-mtDNA and GDF15 in human aging.
    Caroline Trumpff, Qiuhan Huang, Jeremy Michelson, Cynthia C Liu, David Shire, Christian G Habeck, Yaakov Stern, Martin Picard.
      Altered mitochondria biology can accelerate biological aging, but scalable biomarkers of mitochondrial health for population studies are lacking. We examined two potential candidates: 1) cell-free mitochondrial DNA (cf-mtDNA), a marker of mitochondrial signaling elevated with disease states accessible as distinct biological entities from plasma or serum; and 2) growth differentiation factor 15 (GDF15), an established biomarker of biological aging downstream of mitochondrial energy transformation defects and stress signaling. In a cohort of 430 participants aged 24-84 (54.2% women), we measured plasma and serum cf-mtDNA, and plasma GDF15 levels at two timepoints 5 years apart, then assessed their associations with age, BMI, diabetes, sex, health-related behaviors, and psychosocial factors. As expected, GDF15 showed a positive, exponential association with age (r=0.66, p<0.0001) and increased by 33% over five years. cf-mtDNA was not correlated with GDF15 or age. BMI and sex were also not related to cf-mtDNA nor GDF15. Type 2 diabetes was only positively associated with GDF15. Exploring potential drivers of systemic mitochondrial stress signaling, we report a novel association linking higher education to lower age-adjusted GDF15 (r=-0.14, p<0.0034), both at baseline and the 5-year follow up, highlighting a potential influence of psychosocial factors on mitochondrial health. Overall, our findings among adults spanning six decades of lifespan establish associations between age, diabetes and GDF15, an emerging marker of mitochondrial stress signaling. Further studies are needed to determine if the associations of blood GDF15 with age and metabolic stress can be moderated by psychosocial factors or health-related behaviors.
    DOI:  https://doi.org/10.1101/2025.01.28.635306
  3. J Neuroinflammation. 2025 Feb 21. 22(1): 44
    Growth differentiation factor 15 aggravates sepsis-induced cognitive and memory impairments by promoting microglial inflammatory responses and phagocytosis.
    Lijiao Chen, Shiyuan Luo, Ting Liu, Zhewei Shuai, Yifan Song, Qianzi Yang, Ying Wang, Hongjun Huang, Yan Luo.
       BACKGROUND: Sepsis-associated encephalopathy (SAE) is a severe neurological condition caused by sepsis, and presents with symptoms ranging from delirium and coma to long-term cognitive dysfunction. SAE is acknowledged as a widespread brain impairment characterized by the activation of microglia. However, the specific pathological mechanisms that drive this activation are still not clearly understood. Growth differentiation factor 15 (GDF15) levels have been noted to be considerably increased in patients with sepsis, where they are linked to disease severity and can independently predict short- and long-term mortality risk. Serum levels of GDF15 have also been negatively associated with gray matter volume and predict cognitive impairment in older individuals. However, the impact of GDF15 on sepsis-induced cognitive and memory impairments, as well as the mechanisms behind these effects, are poorly understood.
    METHODS: To examine the role of GDF15 in SAE, a sepsis model was created in adult C57BL/6J mice using intraperitoneal administration of lipopolysaccharide (LPS). GDF15 levels in plasma and cerebrospinal fluid were measured by ELISA. The anti-GDF15 monoclonal antibody ponsegromab was injected intracerebroventricularly before modeling, and cognitive and memory functions of the septic mice were assessed using fear-conditioning and novel object recognition tests. Microglial activation and phagocytosis were evaluated using immunofluorescence and Golgi staining. Additionally, an in vitro investigation of LPS-stimulated microglia was conducted to evaluate the impacts of GDF15 on inflammatory cytokine productions and microglial phagocytic activity. Mechanisms were explored using RNA sequencing, qPCR, western blotting, flow cytometry, and immunofluorescence assays.
    RESULTS: In the cerebrospinal fluid of septic mice, levels of GDF15 were notably elevated after intraperitoneal injection of LPS. Lateral ventricular injection of the anti-GDF15 antibody alleviated both cognitive and memory impairment in the septic mice, together with microglial activation and phagocytosis in the hippocampus, thereby protecting against synaptic loss.
    CONCLUSION: The levels of GDF15 were elevated in the brains of septic mice. Targeting GDF15 with an anti-GDF15 antibody was found to improve sepsis-induced cognitive and memory impairment by reducing the microglial inflammatory response and phagocytosis. These results indicate that GDF15 could serve as an important therapeutic target for treating SAE.
    Keywords:  GDF15; Microglial phagocytosis; Neuroinflammation; Sepsis; Sepsis-associated encephalopathy
    DOI:  https://doi.org/10.1186/s12974-025-03369-8
  4. J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13715
    GDF15 Neutralization Ameliorates Muscle Atrophy and Exercise Intolerance in a Mouse Model of Mitochondrial Myopathy.
    Stephen E Flaherty, LouJin Song, Bina Albuquerque, Anthony Rinaldi, Mary Piper, Dinesh Hirenallur Shanthappa, Xian Chen, John Stansfield, Shoh Asano, Evanthia Pashos, Trenton Thomas Ross, Srinath Jagarlapudi, Abdul Sheikh, Bei Zhang, Zhidan Wu.
       BACKGROUND: Primary mitochondrial myopathies (PMMs) are disorders caused by mutations in genes encoding mitochondrial proteins and proteins involved in mitochondrial function. PMMs are characterized by loss of muscle mass and strength as well as impaired exercise capacity. Growth/Differentiation Factor 15 (GDF15) was reported to be highly elevated in PMMs and cancer cachexia. Previous studies have shown that GDF15 neutralization is effective in improving skeletal muscle mass and function in cancer cachexia. It remains to be determined if the inhibition of GDF15 could be beneficial for PMMs. The purpose of the present study is to assess whether treatment with a GDF15 neutralizing antibody can alleviate muscle atrophy and physical performance impairment in a mouse model of PMM.
    METHODS: The effects of GDF15 neutralization on PMM were assessed using PolgD257A/D257A (POLG) mice. These mice express a proofreading-deficient version of the mitochondrial DNA polymerase gamma, leading to an increased rate of mutations in mitochondrial DNA (mtDNA). These animals display increased circulating GDF15 levels, reduced muscle mass and function, exercise intolerance, and premature aging. Starting at 9 months of age, the mice were treated with an anti-GDF15 antibody (mAB2) once per week for 12 weeks. Body weight, food intake, body composition, and muscle mass were assessed. Muscle function and exercise capacity were evaluated using in vivo concentric max force stimulation assays, forced treadmill running and voluntary home-cage wheel running. Mechanistic investigations were performed via muscle histology, bulk transcriptomic analysis, RT-qPCR and western blotting.
    RESULTS: Anti-GDF15 antibody treatment ameliorated the metabolic phenotypes of the POLG animals, improving body weight (+13% ± 8%, p < 0.0001), lean mass (+13% ± 15%, p < 0.001) and muscle mass (+35% ± 24%, p < 0.001). Additionally, the treatment improved skeletal muscle max force production (+35% ± 43%, p < 0.001) and exercise performance, including treadmill (+40% ± 29%, p < 0.05) and voluntary wheel running (+320% ± 19%, p < 0.05). Mechanistically, the beneficial effects of GDF15 neutralization are linked to the reversal of the transcriptional dysregulation in genes involved in autophagy and proteasome signalling. The treatment also appears to dampen glucocorticoid signalling by suppressing circulating corticosterone levels in the POLG animals.
    CONCLUSIONS: Our findings highlight the potential of GDF15 neutralization with a monoclonal antibody as a therapeutic avenue to enhance physical performance and mitigate adverse clinical outcomes in patients with PMM.
    Keywords:  GDF15; antibody; mice; mitochondria; muscle; primary mitochondrial myopathy
    DOI:  https://doi.org/10.1002/jcsm.13715
  5. Acta Physiol (Oxf). 2025 Mar;241(3): e70019
    Proinflammatory cytokines and neuropeptides in psoriasis, depression, and anxiety.
    Emily L Keenan, Richard D Granstein.
      Psoriasis vulgaris has established associations with psychiatric conditions such as depression, anxiety, and chronic stress. This review aims to evaluate current theories and evidence regarding the role of proinflammatory cytokines and neuropeptides in connecting systemic inflammation, psychological stress, and inflammatory skin diseases, namely psoriasis. A literature review was conducted to analyze studies that explore the connections between psoriasis, psychiatric conditions, and biological mediators, including inflammatory cytokines [interferon (IFN)-γ, interleukin (IL)-1, IL-2, IL-6, IL-12, tumor necrosis factor (TNF)-α, IL-22, IL-17], neuropeptides [calcitonin gene-related peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP)], as well as the hypothalamic-pituitary-adrenal (HPA) axis. Existing literature indicates that psychiatric state can influence cutaneous conditions through immune, neural, and endocrine mediators. The elevated rates of anxiety and depression observed in psoriasis patients are likely due to both the inflammatory process itself and the chronic stress associated with disease management, highlighting the importance of managing stress, and addressing mental health to improve clinical outcomes. While the literature suggests proinflammatory cytokines and neuropeptides may be key links between systemic inflammation, psoriasis, and psychiatric comorbidities, further research is necessary to continue to elucidate physiological mechanisms and explore the potential for new treatment modalities.
    Keywords:  calcitonin gene‐related peptide (CGRP); chronic psychological stress; inflammation in anxiety and depression; proinflammatory cytokines and neuropeptides; psoriasis pathogenesis; psychiatric comorbidities in psoriasis
    DOI:  https://doi.org/10.1111/apha.70019
  6. bioRxiv. 2025 Feb 05. pii: 2025.02.03.636364. [Epub ahead of print]
    APOE4 exacerbates glucocorticoid stress hormone-induced tau pathology via mitochondrial dysfunction.
    Qing Yu, Fang Du, Jeffrey Goodman, Clarissa L Waites.
      APOE4 is the leading genetic risk factor for Alzheimer's disease, and chronic stress is a leading environmental risk factor. Studies suggest that APOE4 confers vulnerability to the behavioral and neuropathological effects of chronic stress, representing a potential mechanism by which this genetic variant accelerates Alzheimer's onset and progression. Whether and how APOE4 -mediated stress vulnerability manifests in neurons of the hippocampus, a brain region particularly susceptible to stress and Alzheimer's pathology, remains unexplored. Using a combination of in vivo and in vitro experiments in humanized APOE4 and APOE3 knockin mice and primary hippocampal neurons from these animals, we investigate whether and how APOE4 confers sensitivity to glucocorticoids, the main stress hormones. We find that a major hallmark of stress/glucocorticoid-induced brain damage, tau pathology (i.e., tau accumulation, hyperphosphorylation, and spreading) is exacerbated in APOE4 versus APOE3 mice. Moreover, APOE4 animals exhibit underlying mitochondrial dysfunction and enhanced glucocorticoid receptor activation in the hippocampus, factors that likely contribute to tau pathogenesis in both the presence and absence of stress/glucocorticoids. Supporting this concept, we show that opening of the mitochondrial permeability transition pore drives mitochondrial dysfunction and tau pathology in APOE4 mice, and that pharmacological inhibition of pore opening is protective against ApoE4-mediated mitochondrial damage, tau phosphorylation and spreading, and downstream hippocampal synapse loss. These findings shed light on the mechanisms of stress vulnerability in APOE4 carriers and identify the mitochondrial permeability transition pore as a potential therapeutic target for ameliorating Alzheimer's pathogenesis in this population.
    DOI:  https://doi.org/10.1101/2025.02.03.636364
  7. Nature. 2025 Feb 19.
    How chronic stress warps decision-making.
    Traci Watson.
      
    Keywords:  Brain; Medical research; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-00502-8
  8. Front Neurosci. 2025 ;19 1541075
    Hypothalamus-pituitary-adrenal and gut-brain axes in biological interaction pathway of the depression.
    Amanda Gollo Bertollo, Camila Ferreira Santos, Margarete Dulce Bagatini, Zuleide Maria Ignácio.
      The hypothalamus-pituitary-adrenal (HPA) and gut-brain axes are vital biological pathways in depression. The HPA axis regulates the body's stress response, and chronic stress can lead to overactivation of the HPA axis, resulting in elevated cortisol levels that contribute to neuronal damage, particularly in regions such as the hippocampus and prefrontal cortex, both of which are involved in mood regulation and mental disorders. In parallel, the gut-brain axis, a bidirectional communication network between the gut microbiota and the central nervous system, influences emotional and cognitive functions. Imbalances in gut microbiota can affect the HPA axis, promoting inflammation and increasing gut permeability. This allows endotoxins to enter the bloodstream, contributing to neuroinflammation and altering neurotransmitter production, including serotonin. Since the majority of serotonin is produced in the gut, disruptions in this pathway may be linked to depressive symptoms. This review explores the interplay between the HPA axis and the gut-brain axis in the context of depression.
    Keywords:  depression; gut microbiota; gut-brain axis; hypothalamus-pituitary-adrenal axis; stress response
    DOI:  https://doi.org/10.3389/fnins.2025.1541075
  9. Cell Rep. 2025 Feb 18. pii: S2211-1247(25)00089-0. [Epub ahead of print]44(2): 115318
    Overfeeding induces adipose tissue release of distinct mitochondria.
    Joshua H Goodman, Chloé Berland, Rajesh K Soni, Anthony W Ferrante.
      Overfeeding animals beyond what they eat ad libitum causes rapid adipose tissue expansion, leading to an unusual form of obesity characterized by low immune cell accumulation in fat and sustained anorexia. To investigate how overfeeding affects adipose tissue, we studied the protein secretome of fat from equally obese overfed and ad libitum-fed mice. Fat from overfed animals secretes lower amounts of immune regulatory proteins. Unexpectedly, fat from overfed mice releases larger amounts of mitochondrial proteins. Microscopy identified mitochondria in the conditioned medium of cultured fat that were found not within extracellular vesicles but rather as free extracellular organelles. The protein profile of released mitochondria was distinct from the mitochondrial protein profile of the whole fat, suggesting that the metabolic stress of overfeeding leads to the release of a mitochondrial subset favoring de novo lipogenesis. These findings add to growing evidence that cells alter their energy profiles through the release of mitochondria.
    Keywords:  CP: Metabolism; adipose tissue; mitochondria; obesity; overfeeding
    DOI:  https://doi.org/10.1016/j.celrep.2025.115318
  10. medRxiv. 2025 Feb 03. pii: 2025.01.30.25321437. [Epub ahead of print]
    Mitochondrial and Stress-Related Psychobiological Regulation of FGF21 in Humans.
    Mangesh Kurade, Natalia Bobba-Alves, Catherine Kelly, Alexander Behnke, Quinn Conklin, Robert-Paul Juster, Michio Hirano, Caroline Trumpff, Martin Picard.
      FGF21 is a metabolic hormone induced by fasting, metabolic stress, and mitochondrial oxidative phosphorylation (OxPhos) defects that cause mitochondrial diseases (MitoD). Here we report that acute psychosocial stress alone (without physical exertion) decreases serum FGF21 by an average of 20% ( p <0.0001) in healthy controls but increases FGF21 by 32% ( p <0.0001) in people with MitoD-pointing to a functional interaction between the stress response and OxPhos capacity in regulating FGF21. We further define co-activation patterns between FGF21 and stress-related neuroendocrine hormones and report novel associations between FGF21 and psychosocial factors related to stress and wellbeing, highlighting a potential role for FGF21 in meeting the energetic needs of acute and chronic psychosocial stress.
    DOI:  https://doi.org/10.1101/2025.01.30.25321437
  11. Physiol Rev. 2025 Feb 21.
    The flux of energy in critical illness and the obesity paradox.
    Ariel Jaitovich, Jesse B Hall.
      During critical illness, systemic inflammation causes organ-specific metabolic changes. In the immune and inflammatory compartments, predominantly anabolic reprogramming supports cellular replication and inflammatory response execution. Pari passu, catabolism of adipose tissue and skeletal muscle supplies carbon skeletons and enthalpy for inflammatory and immune cell anabolism. The liver plays a key role during these metabolic shifts in enabling adequate supply of glucose and ketone bodies to the circulation. While often perceived as passive surrogates of prehospitalization frailty, body mass constituents are active parties of an over-arching metabolic trade-off that is key for survival following acute insults. Muscle and adipose tissue remodel in response to critical illness and thus profoundly influence the systemic metabolic landscape during and after hospitalization. Whether obesity's effect on patient systemic metabolism and survival is paradoxically beneficial or not remains controversial. Substrate-induced epigenetic changes lead to abnormal transcriptional programs which in turn regulate metabolic pathways critical to patient survival. We present a summary of major mechanisms involved in the flux of energy in critical illness from body mass into immune response execution and suggest future research avenues focused on perturbed immune metabolic and epigenetic programs that could lead to improved understanding of these process, and eventually to better outcomes for the critically ill.
    Keywords:  Body mass; Immune reprogramming; critical illness; obesity paradox; skeletal muscle
    DOI:  https://doi.org/10.1152/physrev.00029.2024
  12. Nat Neurosci. 2025 Feb 19.
    Developmentally distinct architectures in top-down pathways controlling threat avoidance.
    Cassandra B Klune, Caitlin M Goodpaster, Michael W Gongwer, Christopher J Gabriel, Jennifer An, Rita Chen, Nico S Jones, Owen H Williams, Meelan Shari, Makayla Ramirez, Aliza Hacking, Timothy Andrade, Lindsay A Schwarz, Laura A DeNardo.
      The medial prefrontal cortex (mPFC) is critical for learning and decision-making processes, including responding to threats. The protracted maturation of the mPFC extends into early adulthood. Although prominent models suggest that increasing top-down control by the mPFC eventually allows adult behavioral repertoires to emerge, it is unclear how progressive strengthening can produce nonlinear behavioral changes observed across development. We use fiber photometry and optogenetics to establish causal links between frontolimbic pathway activity and threat avoidance strategies in juvenile, adolescent and adult mice. We uncover multiple developmental switches in the roles of mPFC pathways targeting the nucleus accumbens and basolateral amygdala. These changes are accompanied by axonal pruning, strengthening of synaptic connectivity and altered functional connectivity with downstream cell types, which occur in the mPFC-basolateral amygdala and mPFC-nucleus accumbens pathways at different rates. Our results reveal how developing mPFC pathways pass through distinct architectures that may make them optimally adapted to age-specific challenges.
    DOI:  https://doi.org/10.1038/s41593-025-01890-w
  13. Science. 2025 Feb 21. 387(6736): 822-824
    Evaluating animal consciousness.
    Kristin Andrews, Jonathan Birch, Jeff Sebo.
      An emerging field shows how animal feelings can be studied scientifically.
    DOI:  https://doi.org/10.1126/science.adp4990
  14. Nat Metab. 2025 Feb 21.
    A short-term, high-caloric diet has prolonged effects on brain insulin action in men.
    Stephanie Kullmann, Lore Wagner, Robert Hauffe, Anne Kühnel, Leontine Sandforth, Ralf Veit, Corinna Dannecker, Jürgen Machann, Andreas Fritsche, Nobert Stefan, Hubert Preissl, Nils B Kroemer, Martin Heni, André Kleinridders, Andreas L Birkenfeld.
      Brain insulin responsiveness is linked to long-term weight gain and unhealthy body fat distribution. Here we show that short-term overeating with calorie-rich sweet and fatty foods triggers liver fat accumulation and disrupted brain insulin action that outlasted the time-frame of its consumption in healthy weight men. Hence, brain response to insulin can adapt to short-term changes in diet before weight gain and may facilitate the development of obesity and associated diseases.
    DOI:  https://doi.org/10.1038/s42255-025-01226-9
  15. Pharmacol Ther. 2025 Feb 19. pii: S0163-7258(25)00037-3. [Epub ahead of print] 108825
    The (neuro)inflammatory system in anxiety disorders and PTSD: Potential treatment targets.
    Anupam Sah, Nicolas Singewald.
      Targeting the immune system has recently garnered attention in the treatment of stress- associated psychiatric disorders resistant to existing pharmacotherapeutics. While such approaches have been studied in considerable detail in depression, the role of (neuro)inflammation in anxiety-related disorders, or in anxiety as an important transdiagnostic symptom, is much less clear. In this review we first critically review preclinical and clinical evidence of central and peripheral immune dysregulation in anxiety disorders and post-traumatic stress disorder (PTSD) and briefly discuss proposed mechanisms of how inflammation can affect anxiety-related symptoms. We then give an overview of existing and potential future targets in inflammation-associated signal transduction pathways and discuss effects of different immune-modulatory drugs in anxiety-related disorders. Finally, we discuss key gaps in current clinical trials such as the lack of prospective studies involving anxiety patient stratification strategies based on inflammatory biomarkers. Overall, although evidence is rather limited so far, there is data to indicate that increased (neuro)inflammation is present in subgroups of anxiety disorder patients. Although exact identification of such immune subtypes of anxiety disorders and PTSD is still challenging, these patients will likely particularly benefit from therapeutic targeting of aspects of the inflammatory system. Different anti-inflammatory treatment approaches (microglia-directed treatments, pro-inflammatory cytokine inhibitors, COX-inhibitors, phytochemicals and a number of novel anti-inflammatory agents) have indeed shown some efficacy even in non-stratified anxiety patient groups and appear promising as novel alternative or complimentary therapeutic options in specific ("inflammatory") subtypes of anxiety disorder and PTSD patients.
    Keywords:  Anti-inflammatory; Anxiolytic; Cytokines; Inflammation; Microbiome; Microglia; Minocycline
    DOI:  https://doi.org/10.1016/j.pharmthera.2025.108825
  16. J Affect Disord. 2025 Feb 13. pii: S0165-0327(25)00211-3. [Epub ahead of print]377 14-22
    HPA axis in psychotic and non-psychotic major depression: Cortisol plasma levels and hippocampal volume.
    U Rabl, L Bartova, P Sezen, J Keller, A Schatzberg, L Pezawas.
       BACKGROUND: Psychotic major depression (PMD) differs from non-psychotic MD (NPMD) in psychopathology and is linked to changes in brain volumetry and hypothalamic-pituitary-adrenal (HPA) axis function that can be reflected by its principal output - the glucocorticoid cortisol. NPMD patients exhibit smaller hippocampi than healthy controls (HC), purportedly representing exposure to chronic stress. However, the relationship between the individual clinical phenotype, hippocampal volume and diurnal cortisol signaling remains unclear.
    METHODS: Since understanding the interplay among symptoms, neuroimaging and HPA function is crucial for discerning biological differences between PMD and NPMD, this study explored the link between clinical phenotype, hippocampal structural MRI and circadian plasma cortisol levels in 32 HC, 27 NPMD and 26 PMD patients.
    RESULTS: PMD patients showed significantly elevated evening (6 p.m. - 1 a.m.) cortisol levels compared to NPMD and HC, while NPMD and HC did not differ. No group differences in hippocampal volume were observed, but a significant interaction effect emerged between overnight (1 a.m. - 9 a.m.) cortisol levels, hippocampal volume, and clinical phenotype. NPMD patients displayed a negative correlation between overnight cortisol levels and hippocampal volume, which was specific to the ascending cortisol curve (2 a.m. - 5 a.m.) and absent in PMD and HC. The hippocampus-cortisol interaction was associated with depressive symptom severity in NPMD but not PMD, where cortisol alone predicted greater severity.
    CONCLUSIONS: These findings imply a time-dependent relationship between hippocampal volume and overnight cortisol in NPMD, which is absent in PMD and HC. In contrast, PMD patients exhibited increased evening cortisol levels. In an exploratory analysis, these effects were also related to symptom severity at similar timepoints. While correlational, these results point to distinct neurobiological mechanisms underlying NPMD and PMD, which are potentially related to the heterogeneous clinical manifestations.
    Keywords:  Cortisol; HPA axis; Magnetic resonance imaging; Major depressive disorder; Psychotic symptoms; hippocampus volume
    DOI:  https://doi.org/10.1016/j.jad.2025.02.014
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