The therapeutic potential of the ketogenic diet in selected neurodegenerative diseases and psychiatric disorders
Background: Pharmacoresistance in central nervous system (CNS) pathologies remains a major clinical challenge. The ketogenic diet (KD) is emerging as a potential multimodal metabolic therapy. Ketone bodies appear to remodel neuronal bioenergetics and modulate neurotransmission, laying the groundwork for the developing field of metabolic psychiatry. Aim & Methods: This narrative review (2010–2026) evaluates the neurobiochemical mechanisms of ketone bodies and the potential of the KD as an adjuvant intervention in selected neurodegenerative (Alzheimer's, Parkinson's) and psychiatric (bipolar disorder, schizophrenia, treatment-resistant depression) conditions. Results: Evidence suggests that β-hydroxybutyrate (BHB) crosses the blood-brain barrier via monocarboxylate transporters to fuel the tricarboxylic acid cycle, potentially bypassing the neuronal insulin resistance—often termed type 3 diabetes—implicated in Alzheimer's disease. At the cellular level, BHB may exert neuroprotective effects by inhibiting the NLRP3 inflammasome, which appears to reduce the release of proinflammatory cytokines. Furthermore, ketosis is associated with amino acid pathway remodeling; it may stimulate glutamic acid decarboxylase (GAD) activity, potentially shifting the neurotransmitter balance toward inhibitory GABAergic transmission relevant to mood stabilization. Additionally, BHB acts as an endogenous histone deacetylase (HDAC) inhibitor, which might upregulate brain-derived neurotrophic factor (BDNF) expression and facilitate neurogenesis. Conclusions: The KD is a promising neurometabolic intervention that may target underlying CNS pathomechanisms through mitochondrial optimization, anti-inflammatory effects, and epigenetic modifications. Despite encouraging initial reports, widespread implementation requires strict metabolic monitoring. Large-cohort randomized trials remain necessary before integrating ketogenic protocols into standard neuro-psychiatric treatment algorithms.