{"title":"Postmortem evidence of decreased brain pH in major depressive disorder: a systematic review and meta-analysis.","authors":"Hideo Hagihara, Tsuyoshi Miyakawa","doi":"10.1038/s41398-024-03173-7","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Major depressive disorder (MDD) is a prevalent and debilitating mental disorder that shares symptoms, genetics, and molecular changes in the brain with other psychiatric disorders, such as schizophrenia and bipolar disorder. Decreased brain pH, associated with increased lactate levels due to altered energy metabolism and neuronal hyperexcitation, has been consistently observed in schizophrenia and bipolar disorder. We recently demonstrated similar brain alterations in various animal models of neuropsychiatric disorders, including MDD. However, our understanding of brain pH alterations in human patients with MDD remains limited.</p><p><strong>Methods: </strong>We conducted meta-analyses to assess postmortem brain pH in patients with MDD compared to control subjects, examining its relationships with recurrence of depressive episodes and illness duration, utilizing publicly available demographic data. Studies reporting individual raw pH data were identified through searches in the Stanley Medical Research Institute database, NCBI GEO database, PubMed, and Google Scholar. The data were analyzed using the random effects model, ANOVA, and ANCOVA.</p><p><strong>Results: </strong>The random effects model, using 39 curated datasets (790 patients and 957 controls), indicated a significant decrease in brain pH in patients with MDD (Hedges' g = -0.23, p = 0.0056). A two-way ANCOVA revealed that the effect of diagnosis on pH remained significant when considering covariates, including postmortem interval, age at death, and sex. Patients with recurrent episodes, but not a single episode, showed significantly lower pH than controls in both females and males (256 patients and 279 controls from seven datasets). Furthermore, a significant negative correlation was observed between brain pH and illness duration (115 patients from five datasets). Female preponderance of decreased pH was also found, possibly due to a longer illness duration and a higher tendency of recurrent episodes in females.</p><p><strong>Conclusion: </strong>This study suggests a decrease in brain pH in patients with MDD, potentially associated with recurrent episodes and longer illness duration. As suggested from previous animal model studies, altered brain energy metabolism, leading to decreased pH, may serve as a potential transdiagnostic endophenotype for MDD and other neuropsychiatric disorders.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"460"},"PeriodicalIF":5.8000,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535390/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Translational Psychiatry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41398-024-03173-7","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PSYCHIATRY","Score":null,"Total":0}
引用次数: 0
Abstract
Introduction: Major depressive disorder (MDD) is a prevalent and debilitating mental disorder that shares symptoms, genetics, and molecular changes in the brain with other psychiatric disorders, such as schizophrenia and bipolar disorder. Decreased brain pH, associated with increased lactate levels due to altered energy metabolism and neuronal hyperexcitation, has been consistently observed in schizophrenia and bipolar disorder. We recently demonstrated similar brain alterations in various animal models of neuropsychiatric disorders, including MDD. However, our understanding of brain pH alterations in human patients with MDD remains limited.
Methods: We conducted meta-analyses to assess postmortem brain pH in patients with MDD compared to control subjects, examining its relationships with recurrence of depressive episodes and illness duration, utilizing publicly available demographic data. Studies reporting individual raw pH data were identified through searches in the Stanley Medical Research Institute database, NCBI GEO database, PubMed, and Google Scholar. The data were analyzed using the random effects model, ANOVA, and ANCOVA.
Results: The random effects model, using 39 curated datasets (790 patients and 957 controls), indicated a significant decrease in brain pH in patients with MDD (Hedges' g = -0.23, p = 0.0056). A two-way ANCOVA revealed that the effect of diagnosis on pH remained significant when considering covariates, including postmortem interval, age at death, and sex. Patients with recurrent episodes, but not a single episode, showed significantly lower pH than controls in both females and males (256 patients and 279 controls from seven datasets). Furthermore, a significant negative correlation was observed between brain pH and illness duration (115 patients from five datasets). Female preponderance of decreased pH was also found, possibly due to a longer illness duration and a higher tendency of recurrent episodes in females.
Conclusion: This study suggests a decrease in brain pH in patients with MDD, potentially associated with recurrent episodes and longer illness duration. As suggested from previous animal model studies, altered brain energy metabolism, leading to decreased pH, may serve as a potential transdiagnostic endophenotype for MDD and other neuropsychiatric disorders.
期刊介绍:
Psychiatry has suffered tremendously by the limited translational pipeline. Nobel laureate Julius Axelrod''s discovery in 1961 of monoamine reuptake by pre-synaptic neurons still forms the basis of contemporary antidepressant treatment. There is a grievous gap between the explosion of knowledge in neuroscience and conceptually novel treatments for our patients. Translational Psychiatry bridges this gap by fostering and highlighting the pathway from discovery to clinical applications, healthcare and global health. We view translation broadly as the full spectrum of work that marks the pathway from discovery to global health, inclusive. The steps of translation that are within the scope of Translational Psychiatry include (i) fundamental discovery, (ii) bench to bedside, (iii) bedside to clinical applications (clinical trials), (iv) translation to policy and health care guidelines, (v) assessment of health policy and usage, and (vi) global health. All areas of medical research, including — but not restricted to — molecular biology, genetics, pharmacology, imaging and epidemiology are welcome as they contribute to enhance the field of translational psychiatry.