Decreased glutamateglutamine levels may mediate cytidines efficacy in treating bipolar depression: A longitudinal proton magnetic resonance spectroscopy study

Targeting the glutamatergic system has been suggested as a promising new option for developing treatment strategies for bipolar depression. Cytidine, a pyrimidine, may exert therapeutic effects through a pathway that leads to altered neuronal-glial glutamate cycling. Pyrimidines are also known to exert beneficial effects on cerebral phospholipid metabolism, catecholamine synthesis, and mitochondrial function, which have each been linked to the pathophysiology of bipolar depression. This study was aimed at determining cytidines efficacy in bipolar depression and at assessing the longitudinal effects of cytidine on cerebral glutamateglutamine levels. Thirty-five patients with bipolar depression were randomly assigned to receive the mood-stabilizing drug valproate plus either cytidine or placebo for 12 weeks. Midfrontal cerebral glutamateglutamine levels were measured using proton magnetic resonance spectroscopy before and after 2, 4, and 12 weeks of oral cytidine administration. Cytidine supplementation was associated with an earlier improvement in depressive symptoms (weeks 1-4; p0.02, 0.001, 0.002, and 0.004, respectively) and also produced a greater reduction in cerebral glutamateglutamine levels in patients with bipolar depression (weeks 2, 4, and 12; p0.004, 0.004, and 0.02, respectively). Cytidine-related glutamateglutamine decrements correlated with a reduction in depressive symptoms (p0.001). In contrast, these relationships were not observed in the placebo add-on group. The study results suggest that cytidine supplementation of valproate is associated with an earlier treatment response in bipolar depression. Furthermore, cytidines efficacy in bipolar depression may be mediated by decreased levels of cerebral glutamate andor glutamine, consistent with alterations in excitatory neurotransmission.