System and Method for Diagnosis and Treatment of Neuropsychiatric Disorders

Abstract

An assay for a GCH1 allele and associated genotype for the screening, prediction, diagnosis, prognosis, treatment and treatment response of psychiatric, neuropsychiatric, and neurological disorders, such as schizophrenia, schizoaffective disorder and bipolar disorder, and for defining treatments of such disorders. The presence of a variant in the GCH1 gene, alone or in conjunction with a measurement of low or altered biopterin, or altered BH4 system measures, is used to screen or diagnose subjects at risk for developing a psychiatric, neuropsychiatric, or neurological disorder. The genetic assay, with or without a biopterin or BH4 system assay, may also be used to determine treatment regimens. For subjects with an impaired BH4 system, treatments to increase or normalize biopterin, BH4, or the BH4 system can also be used, such as BH4 supplementation, lithium treatment, phenylalanine treatment, or other treatments and therapies.

1 . A method of evaluating a subject for schizophrenia or schizoaffective disorder, comprising the step of determining a GTP cyclohydrase I (GCH1) genotype of the patient. 
     
     
         2 . The method of  claim 1 , wherein the GCH1 genotype of the subject comprises the GCH1-959 nt G/A GCH1 genotype. 
     
     
         3 . The method of  claim 1 , further comprising the step of determining the level of at least one of total biopterins, BH4, 7,8-dihydrobiopterin, and fully oxidized biopterin of the subject. 
     
     
         4 . The method of  claim 2 , further comprising the step of diagnosing the subject as having schizophrenia or a schizoaffective disorder based on the GCH1 genotype and said level of at least one total biopterins, BH4, 7,8-dihydrobiopterin, and fully oxidized biopterin of the subject. 
     
     
         5 . The method of  claim 4 , wherein the GCH1 genotype of the subject comprises the GCH1-959 nt G/A GCH1 genotype. 
     
     
         6 . The method of  claim 5 , wherein the step of diagnosing the subject as having schizophrenia or a schizoaffective disorder comprises the step of determining the presence and allele dose of the “A” allele of the GCH1-959 nt G/A GCH1 genotype. 
     
     
         7 . The method of  claim 6 , wherein the step of diagnosing the subject as having schizophrenia or a schizoaffective disorder further comprises determining that the subject has a decreased levels of at least one of total biopterins, BH4, 7,8-dihydrobiopterin, and fully oxidized biopterin 
     
     
         8 . A method of treating a subject for the risk or presence of schizophrenia or schizoaffective disorder, comprising the steps of:
 determining a GTP cyclohydrase I (GCH1) genotype of the subject;   determining the levels of at least one of total biopterins, BH4, 7,8-dihydrobiopterin, and fully oxidized biopterin of the subject; and   treating the subject based on the genotype or biopterin level.   
     
     
         9 . The method of  claim 8 , wherein the step of treating the subject comprises the administration of a therapeutic amount of natural or synthetic tetrahydrobiopterin (BH4). 
     
     
         10 . The method of  claim 8 , wherein the step of treating the subject comprises modulating the level of at least one of, total biopterins, BH4, 7,8-dihydrobiopterin, and fully oxidized biopterin in the subject. 
     
     
         11 . The method of  claim 10 , wherein modulating the level of at least one of, total biopterins, BH4, 7,8-dihydrobiopterin, and fully oxidized biopterin in the subject comprises increasing the level of at least one of, total biopterins, BH4, 7,8-dihydrobiopterin, and fully oxidized biopterin in the subject if the at least one of total biopterins, BH4, 7,8-dihydrobiopterin, and fully oxidized biopterin levels are below a predetermined threshold. 
     
     
         12 . The method of  claim 8 , wherein the step of treating the subject comprises providing the subject with an effective amount of at least one compound selected from the group consisting of pterin, biopterin, dihydrobiopterin, neopterin, 6-pyruvoyl-tetrahydrobiopterin, tetrahydrobiopterin, phenylalanine, aspartame, sepiapterin, and sapropterin dihydrochloride. 
     
     
         13 . The method of  claim 8 , wherein the step of treating the subject comprises providing the subject with an effective amount of at least one compound selected from the group consisting of haloperidol, risperidone, Chlorpromazine, Fluphenazine, Perphenazine, Prochlorperazine, Thioridazine, Trifluoperazine, Mesoridazine, Promazine, Triflupromazine, Levomepromazine, Chlorprothixene, Flupenthixol, Thiothixene, Zuclopenthixol, Droperidol, Pimozide, Melperone, Clozapine, Olanzapine, Risperidone, Quetiapine, Ziprasidone, Amisulpride, fluoxetine, Paliperidone, Aripiprazole, LY2140023, Lithium compounds, Lithium chloride, Lithium carbonate, Valproic acid, divalproate, divalproex sodium, sodium valproate, valproate, Lamotrigine, Carbamazepine, Gabapentin, Oxcarbazepine, and Topiramate 
     
     
         14 . The method of  claim 8 , further comprising the step of determining the level of at least one of total biopterins, BH4, 7,8-dihydrobiopterin, and fully oxidized biopterin of the subject after the step of treating the subject. 
     
     
         15 . A method of treating a subject for the risk or presence of schizophrenia or schizoaffective disorder, comprising the step of administering of a therapeutic amount of one or more of natural or synthetic pterin, biopterin, dihydrobiopterin, neopterin, sepiapterin, 6-pyruvoyl-tetrahydrobiopterin, tetrahydrobiopterin, sapropterin. 
     
     
         16 . The method of  claim 15 , further comprising the step of determining the levels of at least one of total biopterins, BH4, 7,8-dihydrobiopterin, and fully oxidized biopterin of the subject prior to and after administering said one or more of natural or synthetic pterin, biopterin, dihydrobiopterin, neopterin, sepiapterin, 6-pyruvoyl-tetrahydrobiopterin, tetrahydrobiopterin, sapropterin, or synthetic forms of the above. 
     
     
         17 . The method of  claim 16 , further comprising the step of determining a GTP cyclohydrase I (GCH1) genotype of the subject.