Zobrazit v EDS

The Role of Energy Homeostasis in Depression Pathophysiology and Its Heterogeneity.

Uloženo v:
Podrobná bibliografie
Název: The Role of Energy Homeostasis in Depression Pathophysiology and Its Heterogeneity.
Autoři: Pistis, Giorgio, Strippoli, Marie-Pierre F., van Dalfsen, Jens H., Vaucher, Julien, Kutalik, Zoltán, Vollenweider, Peter, Penninx, Brenda W. H. J., Preisig, Martin, Milaneschi, Yuri
Zdroj: JAMA Psychiatry; Oct2025, Vol. 82 Issue 10, p992-1001, 10p
Témata: ENERGY metabolism, METABOLIC regulation, HETEROGENEITY, SYMPTOMS, INDIVIDUALIZED medicine, MENTAL depression, MONOGENIC & polygenic inheritance (Genetics)
Abstrakt: Key Points: Question: Are dysregulations in energy homeostasis involved in the manifestation of distinct symptom profiles in major depressive disorder? Findings: The genetic liability of a homeostatic system encompassing metabolic, interoceptive, and motivational pathways was modeled. A polygenic score capturing this shared genetic liability was more strongly associated with a higher likelihood of manifesting increased appetite and sleep during depression in more than 5000 participants. Meaning: Altered energy homeostasis is associated with the expression of a specific symptom profile during depression; this bioclinical profile could identify patients with depression at higher metabolic risk and pave the way for the development of targeted treatments. Importance: Energy homeostatic dysregulation may constitute 1 module of the heterogeneous pathophysiology of major depressive disorder (MDD), potentially manifesting as a distinctive symptom profile. Objective: To test whether the shared genetic liability of metabolic, interoceptive, and motivational pathways involved in energy homeostasis regulation is associated with the expression of specific MDD symptoms. Design, Setting, and Participants: This study used summary-level data from large genome-wide association studies and individual-level data from 2 prospective psychiatric cohorts, the CoLaus|PsyCoLaus (population-based) and Netherlands Study of Depression and Anxiety (NESDA; clinically enriched) cohorts. Data were retrieved and analyzed from May 2023 through November 2024. A lifetime diagnosis of MDD was ascertained with semistructured diagnostic interviews. The sample comprised 1407 MDD cases and 2020 controls from CoLaus|PsyCoLaus and 1803 MDD cases and 266 controls from NESDA. Exposures: Genomic structural equation modeling was applied to model a unique underlying factor capturing the common genetic liability shared among metabolic and interoceptive signals (body mass index, triglycerides, fasting glucose, C-reactive protein, leptin) and motivational (anhedonia) processes. From this underlying factor, a polygenic score (PGS) was derived, indexing the shared genetic liability of traits potentially involved in energy homeostasis regulation. Main Outcomes and Measures: A total of 15 depressive symptoms endorsed by participants during MDD. Results: Among 1407 MDD cases (66.2% female; median year of birth [YOB], 1956) and 2020 controls (44.3% female; median YOB, 1955) from CoLaus|PsyCoLaus and 1803 MDD cases (68.3% female; median YOB, 1962) and 266 controls (56.0% female; median YOB, 1960) from NESDA, multiple significant bidirectional mendelian randomization estimates and genetic correlations (r = 0.11-0.81) indicated a shared genetic basis between the selected traits, which was modeled as a latent homeostatic factor with genomic structural equation modeling. In cohort data, the PGS indexing the latent homeostatic factor was significantly (false discovery rate, <5%) higher in MDD cases endorsing appetite increase and hypersomnia when contrasted with both controls (appetite increase odds ratio [OR], 2.25 [95% CI, 2.00-2.53]; P = 9.03 × 10−41; hypersomnia OR, 1.22 [95% CI, 1.10-1.35]; P = 1.15 × 10−04) and other MDD cases (appetite increase OR, 1.88 [95% CI, 1.63-2.18]; P = 2.38 × 10−17; hypersomnia OR, 1.18 [95% CI, 1.05-1.33]; P = 5.80 × 10−03). Conclusions and Relevance: This study identified a module of depression pathophysiology characterized by altered energy homeostasis and associated with the expression of specific symptoms reflecting energy saving and intake responses. These findings could be used to identify patients with depression at higher metabolic risk and could pave the way for the development of targeted treatments. This study examines whether the genetic liability of metabolic, interoceptive, and motivational pathways involved in energy homeostasis regulation is associated with specific symptoms of major depressive disorder. [ABSTRACT FROM AUTHOR]
Copyright of JAMA Psychiatry is the property of American Medical Association and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Databáze: Complementary Index
Popis
Abstrakt:Key Points: Question: Are dysregulations in energy homeostasis involved in the manifestation of distinct symptom profiles in major depressive disorder? Findings: The genetic liability of a homeostatic system encompassing metabolic, interoceptive, and motivational pathways was modeled. A polygenic score capturing this shared genetic liability was more strongly associated with a higher likelihood of manifesting increased appetite and sleep during depression in more than 5000 participants. Meaning: Altered energy homeostasis is associated with the expression of a specific symptom profile during depression; this bioclinical profile could identify patients with depression at higher metabolic risk and pave the way for the development of targeted treatments. Importance: Energy homeostatic dysregulation may constitute 1 module of the heterogeneous pathophysiology of major depressive disorder (MDD), potentially manifesting as a distinctive symptom profile. Objective: To test whether the shared genetic liability of metabolic, interoceptive, and motivational pathways involved in energy homeostasis regulation is associated with the expression of specific MDD symptoms. Design, Setting, and Participants: This study used summary-level data from large genome-wide association studies and individual-level data from 2 prospective psychiatric cohorts, the CoLaus|PsyCoLaus (population-based) and Netherlands Study of Depression and Anxiety (NESDA; clinically enriched) cohorts. Data were retrieved and analyzed from May 2023 through November 2024. A lifetime diagnosis of MDD was ascertained with semistructured diagnostic interviews. The sample comprised 1407 MDD cases and 2020 controls from CoLaus|PsyCoLaus and 1803 MDD cases and 266 controls from NESDA. Exposures: Genomic structural equation modeling was applied to model a unique underlying factor capturing the common genetic liability shared among metabolic and interoceptive signals (body mass index, triglycerides, fasting glucose, C-reactive protein, leptin) and motivational (anhedonia) processes. From this underlying factor, a polygenic score (PGS) was derived, indexing the shared genetic liability of traits potentially involved in energy homeostasis regulation. Main Outcomes and Measures: A total of 15 depressive symptoms endorsed by participants during MDD. Results: Among 1407 MDD cases (66.2% female; median year of birth [YOB], 1956) and 2020 controls (44.3% female; median YOB, 1955) from CoLaus|PsyCoLaus and 1803 MDD cases (68.3% female; median YOB, 1962) and 266 controls (56.0% female; median YOB, 1960) from NESDA, multiple significant bidirectional mendelian randomization estimates and genetic correlations (r = 0.11-0.81) indicated a shared genetic basis between the selected traits, which was modeled as a latent homeostatic factor with genomic structural equation modeling. In cohort data, the PGS indexing the latent homeostatic factor was significantly (false discovery rate, <5%) higher in MDD cases endorsing appetite increase and hypersomnia when contrasted with both controls (appetite increase odds ratio [OR], 2.25 [95% CI, 2.00-2.53]; P = 9.03 × 10<sup>−41</sup>; hypersomnia OR, 1.22 [95% CI, 1.10-1.35]; P = 1.15 × 10<sup>−04</sup>) and other MDD cases (appetite increase OR, 1.88 [95% CI, 1.63-2.18]; P = 2.38 × 10<sup>−17</sup>; hypersomnia OR, 1.18 [95% CI, 1.05-1.33]; P = 5.80 × 10<sup>−03</sup>). Conclusions and Relevance: This study identified a module of depression pathophysiology characterized by altered energy homeostasis and associated with the expression of specific symptoms reflecting energy saving and intake responses. These findings could be used to identify patients with depression at higher metabolic risk and could pave the way for the development of targeted treatments. This study examines whether the genetic liability of metabolic, interoceptive, and motivational pathways involved in energy homeostasis regulation is associated with specific symptoms of major depressive disorder. [ABSTRACT FROM AUTHOR]
ISSN:2168622X
DOI:10.1001/jamapsychiatry.2025.1858