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Med Hypotheses. 2014 Mar;82(3):395-7. doi: 10.1016/j.mehy.2014.01.011. Epub 2014 Jan 20.

6R-l-erythro-5,6,7,8-tetrahydrobiopterin (BH4): a potential treatment for all symptom domains of schizophrenia.

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University of Texas Harris County Psychiatric Center, Houston, TX, USA; Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, TX, USA. Electronic address:


Current psychopharmacological treatment of schizophrenia is suboptimal and the available antipsychotic medications have little or no effect on negative and cognitive symptom domains of the disorder. 6R-l-erythro-5,6,7,8-tetrahydrobiopterin (BH4) is a cofactor involved in the synthesis of dopamine, serotonin and nitric oxide which have all been implicated in the pathophysiology of schizophrenia. BH4 may potentiate dopaminergic neurotransmission via mechanisms independent of dopamine biosynthesis. BH4 may also potentiate NMDA neurotransmission through its cofactor effect on nitric oxide synthase (NOS). The hypothesis being advanced is that BH4 will be effective in treating all symptom domains of schizophrenia. The hypothesis is based on the findings of: (1) reduced BH4 levels in schizophrenia patients; (2) negative and cognitive symptoms of schizophrenia are related to reduced dopamine neurotransmission in some parts of the brain and BH4 may correct this abnormality by potentiating dopaminergic neurotransmission in these brain regions; (3) there is reduced cellular expression of neuronal NOS in certain brain regions of schizophrenia patients relative to healthy controls, an abnormality which may be corrected via BH4 cofactor effect on NOS; (4) there is increased neuroinflammation in schizophrenia, and BH4 may be anti-inflammatory; (5) schizophrenia is associated with hyperphenyalaninemia (which maybe neurotoxic) and BH4 has clinical utility in normalizing phenylalanine levels. Confirming this hypothesis would advance the knowledge of the pathophysiology of schizophrenia and also meet a significant treatment need in the overall management of this severe and chronic illness.

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