J Inflamm Res. 2025 Dec 1;18:16761-16771. doi: 10.2147/JIR.S540859. eCollection 2025.

ABSTRACT

Schizophrenia, a complex psychiatric disorder, is increasingly understood to involve immune dysregulation intertwined with metabolic and mitochondrial dysfunction. Neuroinflammation, driven by microglial activation, aberrant cytokine signalling, and skewed T cell polarization, intersects with impaired cellular bioenergetics and oxidative stress. Metabolic and mitochondrial alterations, consistently observed in patients, may constitute both cause and consequence of immune imbalance, sustaining a pathological loop that links bioenergetic failure to neuroinflammation. The ketogenic diet (KD), a high-fat, very low-carbohydrate intervention has recently gained attention as a potential therapy for schizophrenia. Emerging clinical reports describe improvements in symptom burden, weight regulation, and sustained remission. However, this evidence remains preliminary and is limited to pilot studies and case series. Preclinical studies provide mechanistic evidence, demonstrating that KD and its primary ketone body, β-hydroxybutyrate, attenuate core pathological features including inflammation, synaptic pruning, mitochondrial dysfunction, T cell imbalances and epigenetic alterations. Mechanistically, KD reshapes immune balance by favoring regulatory T cell induction over T helper 17 cell polarization and dampening pro-inflammatory signalling. Further to this, it improves mitochondrial biogenesis, increases ATP yield and reduces reactive oxygens species through increased efficiency of ATP hydrolysis. Epigenetic regulation by multiple pathways provides an additional layer of transcriptional control that may sustain therapeutic benefits. By framing KD within the context of inflammation research, this review synthesises findings from clinical, preclinical and mechanistic studies to highlight its potential to address fundamental disease mechanisms.

PMID:41357841 | PMC:PMC12680732 | DOI:10.2147/JIR.S540859

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