Postmortem Evidence of Decreased Brain PH in Major Depressive Disorder: a Systematic Review and Meta-analysis

Overview

Journal Transl Psychiatry

Specialties Psychiatry
Public Health

Date 2024 Nov 4

PMID 39496593

Authors

Hideo Hagihara

Tsuyoshi Miyakawa

Affiliations

Soon will be listed here.

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.

Citing Articles

Gene Expression Signatures of Immaturity, Decreased pH, and Neural Hyperexcitation in the Hippocampus of Alzheimer's Disease Model Mice.

Naganishi S, Hagihara H, Miyakawa T Neuropsychopharmacol Rep. 2025; 45(1):e70001.

PMID: 39907034 PMC: 11795175. DOI: 10.1002/npr2.70001.

References

Sharma A, Ren X, Zhang H, Pandey G . Effect of depression and suicidal behavior on neuropeptide Y (NPY) and its receptors in the adult human brain: A postmortem study. Prog Neuropsychopharmacol Biol Psychiatry. 2021; 112:110428. PMC: 8489679. DOI: 10.1016/j.pnpbp.2021.110428. View

Kuhn S, Gallinat J . Resting-state brain activity in schizophrenia and major depression: a quantitative meta-analysis. Schizophr Bull. 2011; 39(2):358-65. PMC: 3576173. DOI: 10.1093/schbul/sbr151. View

Tanaka M, Sato A, Kasai S, Hagino Y, Kotajima-Murakami H, Kashii H . Brain hyperserotonemia causes autism-relevant social deficits in mice. Mol Autism. 2018; 9:60. PMC: 6258166. DOI: 10.1186/s13229-018-0243-3. View

Di Narzo A, Kozlenkov A, Roussos P, Hao K, Hurd Y, Lewis D . A unique gene expression signature associated with serotonin 2C receptor RNA editing in the prefrontal cortex and altered in suicide. Hum Mol Genet. 2014; 23(18):4801-13. PMC: 4140462. DOI: 10.1093/hmg/ddu195. View

Seney M, Huo Z, Cahill K, French L, Puralewski R, Zhang J . Opposite Molecular Signatures of Depression in Men and Women. Biol Psychiatry. 2018; 84(1):18-27. PMC: 6014892. DOI: 10.1016/j.biopsych.2018.01.017. View

Holmes A, Murphy D, Crawley J . Abnormal behavioral phenotypes of serotonin transporter knockout mice: parallels with human anxiety and depression. Biol Psychiatry. 2003; 54(10):953-9. DOI: 10.1016/j.biopsych.2003.09.003. View

Bach-Mizrachi H, Underwood M, Tin A, Ellis S, Mann J, Arango V . Elevated expression of tryptophan hydroxylase-2 mRNA at the neuronal level in the dorsal and median raphe nuclei of depressed suicides. Mol Psychiatry. 2008; 13(5):507-13, 465. PMC: 2361383. DOI: 10.1038/sj.mp.4002143. View

Martin-Hernandez D, Caso J, Meana J, Callado L, Madrigal J, Garcia-Bueno B . Intracellular inflammatory and antioxidant pathways in postmortem frontal cortex of subjects with major depression: effect of antidepressants. J Neuroinflammation. 2018; 15(1):251. PMC: 6122627. DOI: 10.1186/s12974-018-1294-2. View

Xiang L, Szebeni K, Szebeni A, Klimek V, Stockmeier C, Karolewicz B . Dopamine receptor gene expression in human amygdaloid nuclei: elevated D4 receptor mRNA in major depression. Brain Res. 2008; 1207:214-24. PMC: 2577810. DOI: 10.1016/j.brainres.2008.02.009. View

10.

Li J, Vawter M, Walsh D, Tomita H, Evans S, Choudary P . Systematic changes in gene expression in postmortem human brains associated with tissue pH and terminal medical conditions. Hum Mol Genet. 2004; 13(6):609-16. DOI: 10.1093/hmg/ddh065. View

11.

Hagihara H, Catts V, Katayama Y, Shoji H, Takagi T, Huang F . Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders. Neuropsychopharmacology. 2017; 43(3):459-468. PMC: 5770757. DOI: 10.1038/npp.2017.167. View

12.

Shelton R, Sanders-Bush E, Manier D, Lewis D . Elevated 5-HT 2A receptors in postmortem prefrontal cortex in major depression is associated with reduced activity of protein kinase A. Neuroscience. 2008; 158(4):1406-15. PMC: 9208662. DOI: 10.1016/j.neuroscience.2008.11.036. View

13.

Ernst J, Hock A, Henning A, Seifritz E, Boeker H, Grimm S . Increased pregenual anterior cingulate glucose and lactate concentrations in major depressive disorder. Mol Psychiatry. 2016; 22(1):113-119. DOI: 10.1038/mp.2016.73. View

14.

Pruett B, Meador-Woodruff J . Evidence for altered energy metabolism, increased lactate, and decreased pH in schizophrenia brain: A focused review and meta-analysis of human postmortem and magnetic resonance spectroscopy studies. Schizophr Res. 2020; 223:29-42. DOI: 10.1016/j.schres.2020.09.003. View

15.

Golden S, Covington 3rd H, Berton O, Russo S . A standardized protocol for repeated social defeat stress in mice. Nat Protoc. 2011; 6(8):1183-91. PMC: 3220278. DOI: 10.1038/nprot.2011.361. View

16.

Dean B, Gibbons A, Boer S, Uezato A, Meador-Woodruff J, Scarr E . Changes in cortical N-methyl-D-aspartate receptors and post-synaptic density protein 95 in schizophrenia, mood disorders and suicide. Aust N Z J Psychiatry. 2015; 50(3):275-83. PMC: 7683009. DOI: 10.1177/0004867415586601. View

17.

Tripp A, Oh H, Guilloux J, Martinowich K, Lewis D, Sibille E . Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder. Am J Psychiatry. 2012; 169(11):1194-202. PMC: 3638149. DOI: 10.1176/appi.ajp.2012.12020248. View

18.

Roy B, Wang Q, Palkovits M, Faludi G, Dwivedi Y . Altered miRNA expression network in locus coeruleus of depressed suicide subjects. Sci Rep. 2017; 7(1):4387. PMC: 5491496. DOI: 10.1038/s41598-017-04300-9. View

19.

Xue X, Zong W, Glausier J, Kim S, Shelton M, Phan B . Molecular rhythm alterations in prefrontal cortex and nucleus accumbens associated with opioid use disorder. Transl Psychiatry. 2022; 12(1):123. PMC: 8960783. DOI: 10.1038/s41398-022-01894-1. View

20.

Ismail Z, Elbayoumi H, Fischer C, Hogan D, Millikin C, Schweizer T . Prevalence of Depression in Patients With Mild Cognitive Impairment: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2016; 74(1):58-67. DOI: 10.1001/jamapsychiatry.2016.3162. View