Decreased Glutamate/Glutamine Levels May Mediate Cytidine’s Efficacy in Treating Bipolar Depression: A Longitudinal Proton Magnetic Resonance Spectroscopy Study

Abstract

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 ¼ 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 ¼ 0.004, 0.004, and 0.02, respectively). Cytidinerelated glutamate/glutamine decrements correlated with a reduction in depressive symptoms (p ¼ 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.

Neurochemical Alterations in Methamphetamine-Dependent Patients Treated with Cytidine-5′-Diphosphate Choline: A Longitudinal Proton Magnetic Resonance Spectroscopy Study

“…The midfrontal VOI was positioned by using a priori rules, as in earlier publications (Ham et al , 2007; Sung et al , 2007; Yoon et al , 2009) (Figure 1). Throughout the entire study period, the same examiner positioned study subjects in the basis set and reported as mmol/l (Provencher, 2001; Barker et al , 1993).…”

Contributions of animal models to the study of mood disorders

“…However, this theory alone cannot fully explain the neurobiology of depression; therefore, other neurotransmission systems and signaling pathways have been implicated in the pathophysiological mechanisms of depression, such as acetylcholine (ACh), glutamate, gamma-aminobutyric acid (GABA), and endogenous opiates. [28][29][30][31][32] Functional imaging studies have shown that blood flow and glucose levels are higher in some parts of the brain (e.g., the frontal cortex, amygdala, thalamus, and lower parts of the striatum) of patients with major depression as compared with controls.…”

Open-Label Uridine for Treatment of Depressed Adolescents with Bipolar Disorder

“…Studies of pyrimidines in adults with bipolar disorder have been promising as monotherapy (Repligen 2006(Repligen , 2008Jensen et al 2008) and as an adjunct to valproate (Yoon et al 2009). Notably, participants treated with cytidine þ valproate in the latter study experienced a rapid improvement in depressive symptoms in weeks 1-4, when compared with placebo þ valproate patients.…”

“…Pyrimidines have beneficial effects on cerebral phospholipid metabolism (Cansev 2006), catecholamine synthesis (Martinet et al 1978(Martinet et al , 1979, and mitochondrial function (Lehninger et al 2008)-each of which has been linked to the pathophysiology of bipolar disorder (Yoon et al 2009). The pyrimidines that have been studied as treatments for adults with bipolar depression include cytidine (Yoon et al 2009) and triacetyluridine ( Jensen et al 2008).…”

“…The pyrimidines that have been studied as treatments for adults with bipolar depression include cytidine (Yoon et al 2009) and triacetyluridine ( Jensen et al 2008).…”