Association between ketone metabolism and the risk of depression: An observational and Mendelian randomization study

Ketone bodies (KBs) can serve as an alternative fuel source to glucose for the brain. Pre-clinical evidence suggests that KBs have neuroprotective properties, which might benefit depression.

This study aimed to examine the association between KBs and the risk of depression using observational and genetic approaches.

Observational studies analyzed data collected between 2006 and 2010 from 245,459 participants in the UK Biobank, with follow-up to 31 October 2022. Genetic studies were firstly performed using one-sample Mendelian randomization (MR) with individual-level data from the UK Biobank; secondly, two-sample MR was performed using summary-level data from the largest available genome-wide association studies. KBs were measured by β-hydroxybutyrate with nuclear magnetic resonance spectroscopy. Depression outcomes were measured by linked hospital-based clinical depression diagnosis and Patient Health Questionnaire-9 (PHQ-9). Cox proportional hazard models and linear regression were used to examine the association of KBs with depression incidence and severity, and to compare the risks between individuals in light nutritional ketosis (≥0.5 mmol/l) and those not.

Observational analyses showed that each SD increase in KBs was associated with a 6 % (95 % CI, 1.03-1.08) increase in PHQ-9 scores in the fully adjusted model. Patients with KBs above 0.5 mmol/l had a higher risk of depression (HR 1.57; 95 % CI, 1.13-2.17) compared to those with KBs <0.5 mmol/l. In one-sample MR, there were no significant associations between genetically predicted KBs and depression and PHQ-9 scores. In two-sample MR analyses, we found no evidence of KBs (IVW OR1.06; 95 % CI, 0.91-1.24) with the risk of depression.

There was observational evidence that higher KB concentration was associated with an increased risk of depression, but MR suggests this is not causal. The efficacy of ketone therapy for depression remains unclear and warrants further investigation.