The efficacy of ketogenic interventions on neuropsychological & metabolic outcomes in serious mental illness & neurocognitive disorders: a systematic review & meta-analysis

Abstract

Ketogenic interventions have garnered attention for their potential benefits in individuals with psychiatric and neurocognitive disorders. This review analyzed findings from studies investigating the impact of ketogenic interventions on clinical outcomes in individuals with serious mental illness (SMI) and neurocognitive disorders. A comprehensive search was conducted to identify studies reporting on psychopathology or cognitive performance in individuals with schizophrenia spectrum, major mood, mild cognitive impairment (MCI), or major neurocognitive disorders/dementia treated with a ketogenic intervention. Changes in body composition, metabolic parameters, adherence, and safety were also assessed. Evidence was organized by population and outcome of interest, and supplemented by a quantitative meta-analysis. Seventy-three studies (SMI k = 31; neurocognitive disorders k = 42) were included, with treatment durations ranging from single-dose interventions up to 12 years. Evidence in SMI was largely limited to case reports and single-arm trials reporting symptom remission, reductions in positive and negative symptoms, and mood improvements. Controlled trials in neurocognitive disorders provided more substantiated evidence amenable to meta-analysis. Ketogenic interventions improved cognitive performance (SMD 0.24, 95% CI [0.06, 0.43], p = 0.01, n = 587, k = 14, I² = 61%) and reduced body weight (MD − 3.13 kg, 95% CI [−5.91, −0.35], p = 0.03, n = 80, k = 3, I² = 6%) in this population. Gastrointestinal symptoms were the most frequently reported adverse event. While the evidence for ketogenic interventions differs by population, promising findings emerge. In neurocognitive disorders, controlled trial data support modest cognitive and metabolic benefits. In SMI, preliminary evidence highlights the evolving nature of this field and the need for more rigorous investigation, including RCTs, to establish clinical safety and efficacy.