Postmortem evidence of decreased brain pH in major depressive disorder: a systematic review and meta-analysis.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:39496593", "kind": "science-record", "revision": 3, "content_hash": "sha256:6d9b1beaf112a79b57b4301a0c32e649fad78d94de0ac6efebea24a874ab11ed", "created_at": "2026-11-01T20:29:45Z", "updated_at": "2026-11-01T22:13:03Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Postmortem evidence of decreased brain pH in major depressive disorder: a systematic review and meta-analysis.", "doi": "10.1038/s41398-024-03173-7", "pmid": "39496593", "authors": ["Hideo Hagihara", "Tsuyoshi Miyakawa"], "journal": "Translational psychiatry", "year": 2024, "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.\nMETHODS: 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.\nRESULTS: 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.\nCONCLUSION: 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.", "claims": [{"id": "claim-method", "statement": "The random effects model was applied using the function metagen in the R package meta (version 6.5-0).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:39496593", "locator": "sections[4] \"Data analysis\" paragraph 2", "quote": "The random effects model was applied using the function metagen in the R package meta (version 6.5-0)."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The raw data analyzed in this study are provided in Table S1.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:39496593", "locator": "sections[4] \"Data analysis\" paragraph 2", "quote": "The raw data analyzed in this study are provided in Table S1."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Postmortem brain pH was significantly decreased in patients with MDD compared with control subjects.", "kind": "quantitative", "target": {"value": 0.0056, "unit": "p-value", "tolerance": null, "source": "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)."}, "evidence": [{"asset": "source:pmid:39496593", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "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)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Postmortem brain pH was significantly decreased in patients with MDD compared with control subjects.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:39496593"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE101521"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE101521"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:39496593", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1038/s41398-024-03173-7", "sha256": 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