Tardive Dyskinesia (TD), an abnormal movement disorder which occurs secondary to neuroleptic (NL) treatment in vulnerable individuals is seen in substantial numbers of chronic psychiatric patients (pts), particularly schizophrenics, for whom these drugs are the prime treatment medium and as such is a major international health concern. The application's broad long-term objectives are to define the pathogenesis and pathophysiology of TD, to use TD as a research tool to better understand the neurochemistry of schizophrenia and other psychotic disorders in which TD is manifest and to develop more successful and less troublesome treatment modalities for these disorders.
The specific aims are: a) to replicate and extend the findings which define the metabolism of the amino acid, phenylalanine (Phe) to be a significant risk factor for TD. b) to verify the hypothesis that the antecedent condition of chronically higher levels of Phe for TD-Yes over TD-No leads to chronically lower levels of DA, NE and 5-HT for that group, c) to propose treatment strategies for TD based on the manipulation of plasma amino acid levels (e.g. dietary, as for PKU), d) to define TD vulnerability or invulnerability as a marker for a schizophrenic or psychotic subgroup, e) to create a database of neurochemical measures and clinical symptoms in a sufficient number of pts to allow for hypothesis generation and testing beyond the scope of the present application and to serve as a baseline for future studies. Study pts (N=361) will be drawn from 2 sites, Rockland Psychiatric Center (n=291, primarily schizophrenic) and Hillside Hospital (N=70, neuroleptic treated affective disorder pts). Pts will participate in 2 experimental sessions 2 years apart (E1,E2), in which fasting bloods will be drawn, Phe load given, 2-Hour post- loading bloods drawn. Plasma measures will consist of 11 amino acids, 7 amine acidic metabolites (IAA, PAA. DOPAC, MHPG, VMA, HVA, 5HIAA), PEA, m-and p-tyramine, DA, NE, 5-HT and biopterin. TD will be assessed at a minimum of 3 evaluations to a maximum of 6, over the 5 year study period. The BPRS, HAM-D, MRS will be administered at E1 and E2 and lifetime diagnosis performed. NL use data will be collected for the period from 2 weeks prior to E1 and E2. Data analysis will answer study questions by use of univariate screening to develop models for simultaneous, multivariable analyses such as logistic regression which will generate a prediction model. The study will meet TD literature gaps by intra-patient replication overtime, an """"""""n"""""""" sufficient to detect between group differences, covering more than one amine at more than one metabolic step and rigorous TD evaluation.
| Richardson, Mary Ann; Read, Laura L; Reilly, Margaret A et al. (2007) Analysis of plasma biopterin levels in psychiatric disorders suggests a common BH4 deficit in schizophrenia and schizoaffective disorder. Neurochem Res 32:107-13 |
| Richardson, Mary Ann; Chao, Helen M; Read, Laura L et al. (2006) Investigation of the phenylalanine hydroxylase gene and tardive dyskinesia. Am J Med Genet B Neuropsychiatr Genet 141B:195-7 |
| Richardson, M A; Read, Laura L; Taylor Clelland, Catherine L et al. (2005) Evidence for a tetrahydrobiopterin deficit in schizophrenia. Neuropsychobiology 52:190-201 |
| Richardson, Mary Ann; Small, Arthur M; Read, Laura L et al. (2004) Branched chain amino acid treatment of tardive dyskinesia in children and adolescents. J Clin Psychiatry 65:92-6 |
| Richardson, Mary Ann; Read, Laura L; Clelland, James D et al. (2003) Phenylalanine hydroxylase gene in psychiatric patients: screening and functional assay of mutations. Biol Psychiatry 53:543-53 |
| Richardson, M A; Reilly, M A; Read, L L et al. (1999) Phenylalanine kinetics are associated with tardive dyskinesia in men but not in women. Psychopharmacology (Berl) 143:347-57 |
