Evidence for a Tetrahydrobiopterin Deficit in Schizophrenia

Abstract

Tetrahydrobiopterin (BH₄) is a vital cofactor maintaining availability of the amine neurotransmitters [dopamine (DA), noradrenaline (NA), and serotonin (5-HT)], regulating the synthesis of nitric oxide (NO) by nitric oxide synthase (NOS), and stimulating and modulating the glutamatergic system (directly and indirectly). These BH₄ properties and their potential relevance to schizophrenia led us to investigate the hypothesis of a study group (healthy controls, n = 37; schizophrenics, n = 154) effect on fasting plasma total biopterin levels (a measure of BH₄). Study analysis showed a highly significant deficit of total biopterins for the schizophrenic sample after partialling out the effects of potential confounds of gender, age, ethnicity, neuroleptic use history and dose of current use, 24-hour dietary phenylalanine/protein ratio (a dietary variable relevant to BH₄ synthesis), and plasma phenylalanine (which stimulates BH₄ synthesis). A mean decrement of 34% in plasma total biopterins for schizophrenics from control values supports clinical relevance for the finding. In a subsample (21 controls and 23 schizophrenics), sequence analysis was done of the GTP cyclohydrolase I feedback regulatory gene and no mutations were found in the coding region of the gene. A deficiency of BH₄ could lead to hypofunction of the systems of DA, NA, 5-HT, NOS/NO, and glutamate, all of which have been independently implicated in schizophrenia psychopathology. Further, evidence has been accumulating which implicates the critical interdependence of these neurotransmitter systems in schizophrenia; this concept, along with the present study finding of a biopterin deficit, suggests that further study of the BH₄ system in schizophrenia is warranted and desirable.

Nitric Oxide and Neopterin in Bipolar Affective Disorder

“…Thus, both the lower values of neopterin and the Cit-Arg ratio and the observed association between these parameters found in bipolar affective disorders, indicate a reduced activity of BH4 and a decreased formation of NO in this group, in contrast to the group of major depressive disorders with melancholic features or a seasonal pattern. These findings are in agreement with those reported recently by Richardson et al [32] in a large sample of patients with schizophrenia and support the idea that bipolar affective disorder and schizophrenia share common pathophysiological patterns [33] .…”

Alterations in dopamine and glutamate neurotransmission in tetrahydrobiopterin deficient spr-/- mice: relevance to schizophrenia

“…Another study reported that total biopterin levels were only low in plasma and but not in urine of patients diagnosed with schizophrenia (59). In contrast, more recent studies found profound reductions in plasma total biopterin levels in schizophrenia and schizoaffective patients (by 34% and 25%, respectively) compared to normal controls (60,61). Meta-analysis studies for the International Database of BH4 Deficiencies found significant correlation between biopterin levels in plasma and CSF but failed to establish such a correlation between biopterin levels in urine and CSF of schizophrenia patients (60).…”

Analysis of Plasma Biopterin Levels in Psychiatric Disorders Suggests a Common BH4 Deficit in Schizophrenia and Schizoaffective Disorder

“…Patient subjects did not have access to alcohol or drugs. Control and schizophrenic subject recruitment has been described previously [26]. Of note, for each normal control subject an interview was conducted and internal scale completed to determine no personal and/or family history for psychiatric, neurological, and medical conditions.…”

“…At 6:30 a.m. on the morning of the evaluation, a blood sample was drawn from the antecubital vein using a needle and evacuated tube (fasting period of at least 8.5 h). A 4 ml plasma sample was then immediately processed via iodine oxidation under acid conditions, and stored at (-70°C, prior to total plasma biopterin assay, as we have previously described [26]. Plasma phenylalanine was determined as previously described [26], and was assayed because of its known role in the biosynthesis of BH 4 via the attenuation of BH 4 -mediated GTPCH inhibition [32][33][34][35].…”

“…These mixed data clearly highlight the need for studies that shed light on BH 4 levels in psychiatric disorders, and recently we measured plasma biopterin levels in a large group of 154 schizophrenic subjects and observed a robust mean deficit of 34% when compared to a control subject group (n = 37) [26]. These significant study results led to this present investigation; a measurement of total biopterin plasma levels in a large cohort of subjects from two new study groups schizoaffective (n = 59) and bipolar disorders (n = 27), and testing for group differences among healthy control subjects and patients with schizophrenia, schizoaffective disorder, and bipolar disorder.…”