Tetrahydrobiopterin (BH4) is a vital cofactor that maintains availability of amine neurotransmitters (NT) such as Dopamine and Serotonin, regulates Nitric Oxide synthesis, and stimulates and modulates the Glutamatergic system. Dysregulation of NT systems has been implicated in the pathogenesis of psychiatric disorders, including bipolar disorder (BPD). BPD has a large genetic component, and of great significance to this application, the GCH1 gene (which encodes GTPCH, the first and rate-limiting enzyme in the BH4 biosynthesis pathway), was recently associated with BPD. We have observed that patients with psychiatric disorders (including BPD) have a deficit of plasma total biopterin (a measure of BH4) compared to control subjects, that appears to be alleviated via lithium (Li) treatment. This finding, along with a) the known roles of BH4 in NT maintenance, and b) the association of the BH4 biosynthesis gene GCH1 with BPD, supports our hypothesis that our measured plasma biopterin deficit is involved in the etiology of BPD. Furthermore, animal study data showing upregulation of GCH1 mRNA via Li, supports our finding that Li treatment increases biopterin levels. Based on the central roles of BH4 in NT synthesis, we now hypothesize that BPD susceptibility is influenced by a GCH1 gene variant that decreases GCH1 mRNA levels, leading to a BH4 deficit that can be alleviated by Li. This new hypothesis, which will be tested during this study, is based on striking preliminary data: In 30 BPD subjects and 46 controls, we confirmed that GCH1 is significantly associated with BPD (OR, 3.2,p=0.038), and importantly, we also showed that subjects with the BPD-associated GCH1 allele have lower GCH1 mRNA. In addition, analysis of 17 BPD subjects (9 Li treated and 8 not Li treated), showed that a) Li increases GCH1 expression, and b) that Li treatment elevation of GCH1 mRNA is highest in patients without the BPD-associated GCH1 allele, a finding which suggests Li treatment may be less effective in patients with the associated allele. Based on these very exciting data, this exploratory study is designed to test our hypothesis that BPD subjects have a plasma BH4 deficit (reflecting a CNS deficit) that can be alleviated by Li treatment, particularly in patients without the BPD- associated GCH1 allele.
The Specific Aims of this study are:1) To recruit 280 BPD subjects, genotype each for the GCH1 allele previously associated with BPD, and compare to genotypes of 280 matched controls. 2a) To collect pre- and post-Li treatment bloods from the 280 BPD subjects recruited under Aim 1. 2b) To Assay peripheral GCH1 mRNA expression in the pre and post-treatment samples 2c) Assay plasma biopterin levels in the collected in the pre and post samples, and 2d) To test for interactions between GCH1 genotype, GCH1 mRNA levels, and biopterin in pre- and post-Li treated BPD subjects and test for correlations with assessment scales. Understanding the roles of GCH1 and BH4 in BPD etiology may allow improved treatment and clinical outcomes for patients, and early interventions for those at risk of developing this devastating illness.
|Clelland, C L; Drouet, V; Rilett, K C et al. (2016) Evidence that COMT genotype and proline interact on negative-symptom outcomes in schizophrenia and bipolar disorder. Transl Psychiatry 6:e891|