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
cytidine's efficacy in
bipolar depression and at assessing the longitudinal effects of
cytidine on cerebral
glutamate/
glutamine 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
glutamate/
glutamine 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; p=0.02, 0.001, 0.002, and 0.004, respectively) and also produced a greater reduction in cerebral
glutamate/
glutamine levels in patients with
bipolar depression (weeks 2, 4, and 12; p=0.004, 0.004, and 0.02, respectively).
Cytidine-related
glutamate/
glutamine decrements correlated with a reduction in depressive symptoms (p=0.001). 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,
cytidine's efficacy in
bipolar depression may be mediated by decreased levels of cerebral
glutamate and/or
glutamine, consistent with alterations in excitatory neurotransmission.