Evidence for a tetrahydrobiopterin deficit in schizophrenia

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. Copyright (C) 2005 S. Karger AG, Basel.