Evidence for perturbed metabolic patterns in bipolar disorder subjects associated with lithium responsiveness

Bipolar disorder (BD) is multifactorial mood disorder characterized by alternating episodes of hyperactive mania and severe depression. Lithium is one of the most preferred drug used as mood stabilizer in treating BD. In this study, we examined the changes in plasma metabolome in BD subjects in the context of lithium responsiveness. Plasma samples from clinically defined, age and gender matched unrelated healthy controls and BD subjects (lithium responders and non-responders) were obtained and processed in positive and negative mode using untargeted liquid chromatography/mass spectrometry analysis. We identified significant alterations in plasma levels of dopamine along with its precursors (tyrosine and phenylalanine), branched chain amino acid such as valine and excitatory neurotransmitter glutamate between healthy control and BD subjects. Lipid molecules such as, eicosenoic acid and retinyl ester also showed distinguished patterns between control and BD individuals. Lithium responsiveness was markedly associated with significant differences in proline, L-gamma-glutamyl-isoleucine, dopamine, palmitic acid methyl ester, cholesterol sulfate, androsterone sulfate and 9S,12S,13S-triHOME levels. Altered metabolites enriched with key biochemical pathways associated with neuropsychiatry disorders. We hypothesize that BD pathogenesis and lithium responsiveness is associated with impaired homeostasis of amino acid and lipid metabolism.