Investigation of Biopterin Deficit in Bipolar Disorder

  • Dr Catherine Clelland, Columbia University, United States
  • Dr Laura Read, The Nathan Kline Institute for Psychiatric Researech, New York University School of Medicine, United States
  • Dr Kishor Malavade, New York University School of Medicine, United States
  • Ms Amanda Baraldi, Arizona State Universty, United States
  • Ms Carrie Pappas, The Nathan Kline Institute for Psychiatric Researech, New York University School of Medicine, United States
  • Dr James Clelland, The Nathan Kline Institute for Psychiatric Researech, New York University School of Medicine, United States

    • Objective: Tetrahydrobiopterin (BH4) is a vital cofactor maintaining availability of amine neurotransmitters (dopamine, noradrenaline, serotonin), regulating nitric oxide synthesis, and stimulating and modulating the glutamatergic system. Neurotransmitter dysregulation is implicated in bipolar disorder (BPD), and the GCH1 gene, which encodes GTPCH, the rate limiting enzyme in BH4 biosynthesis, was recently associated with BPD. We investigated plasma biopterin (a measure of BH4) and observed lower biopterin in schizoaffective disorder and schizophrenia than controls. BPD patients however, were not different from controls. 89% of the BPD subjects were Lithium (Li) treated, and Li causes GCH1 mRNA upregulation. We therefore investigated mood stabilizers for effects on biopterin in BPD.

    Methods: Plasma biopterin was determined by HPLC. Peripheral leukocyte GCH1 mRNA levels were assayed by microarray.

    Results: Study 1: We measured fasting biopterin (~90% as BH4) in controls (n=37) and BPD (n=27) and tested for group effects on biopterin, with the covariate of Li use. When Li (Y/N) was added to the final model, post hoc Tukey testing demonstrated that BPD (p=0.0179) also differed from controls. Study 2: GCH1 expression correlates with BH4. A second study (S2) of BPD (n=29), tested GCH1 mRNA, for mood stabilizer effects. Subjects received Li doses significantly lower than in S1. (S2: 780mg +/- 113.6 versus S1: 1132mg +/- 74.8, p=0.0137. We found no Li effect in S2., and hypothesize that Li doses in S2 were below a threshold needed to stimulate GCH1 expression. Valproic acid (VPA) shares Li inositol pathway effects. In S2. VPA increased GCH1 expression in BPD (11 VPA-treated, 18 not VPA-treated,(p<0.0001). Additionally, the greatest increase in expression was in patients with the BPD-associated GCH1 A/A genotype (p=0.0028).

    Conclusions: These findings suggest treatment with VPA and Li, can upregulate expression of GCH1 via inositol depletion, and concomitantly increases BH4 biosynthesis, alleviating biopterin deficit in BPD.