Ketosis is a metabolic state in which the body uses
ketones derived from breakdown of
fatty acids as the primary mitochondrial fuel source instead of
glucose. In recent years an accumulation of evidence for the beneficial effects of the ketotic state on the brain have heightened interest in its potential for use in neurological conditions. The
ketogenic diet (KD) induces
ketosis and is an effective treatment for medically resistant
epilepsy. There is significant comorbidity between
epilepsy and
bipolar disorder (BD) and both conditions are treated by anti-
convulsant drugs. In addition, reports on bipolar disease online fora have highlighted subjective mood stabilization effects associated with the KD. These KD reported effects could be explained if there was a disorder in the conversion of
pyruvate into
Acetyl-CoA (and subsequent impairment of oxidative phosphorylation) which was bypassed by
ketones providing an alternative substrate for oxidative phosphorylation. This is consistent with growing evidence that
mitochondrial dysfunction plays a causal role in BD and explains the reported TCA cycle dysfunction and elevated
pyruvate levels in BD. Reduced levels of
ATP affects the normal operation of the Na, K-
ATPase in the brain with differing levels of reduction either leading to reduced neuronal action potential and inhibition of
neurotransmitter release (consistent with the depressed state in BD) or increased neuronal resting potential and hyper-excitability (consistent with a [hypo]manic mood state). We hypothesize that the
mitochondrial dysfunction is due to a disorder of the
Pyruvate Dehydrogenase Complex (PDC) and/or Mitochondrial
Carrier Protein (MCP) shuttle which moves intracellular
pyruvate into mitochondria. The resultant reduction in
ATP generation could explain mood instability and cycling in BD (through mechanisms such as those delineated by Mallakh and Peters). This proposed novel causal pathway could explain mood de-stabilization in BD and the reported positive effects of KD. If true, this hypothesis would suggest that there should be increased research attention to PDC (and in particular the E1 alpha subunit) as potential therapeutic targets and further study of a possible role of KD in BD to improve mood stability. Experimental approaches, such as through a clinical trial of KD on mood stabilization in BD, are required to further investigate this hypothesis.