Methods for screening drugs to predict tardive dyskinesia

Abstract

The present invention provides screening methods for identifying compounds which induce tardive dyskinesia (TD) when administered to an animal. In particular, the methods involve assaying for intermediates and end product of reactions associated with candidate compound mediated reduction of reducible substrates. Also provided are high-throughput screening methods for determining whether compounds induce TD when administered to an animal. Further, provided are methods for treating psychoses comprising testing antipsychotic drugs to identify those which will not induce TD when administered to an animal and administering one or more such drugs to a patient in need thereof.

What is claimed is:  
     
         1 . A method for determining whether a candidate compound induces tardive dyskinesia comprising: 
 (a) contacting said candidate compound with a reducible substrate,    (b) assaying for the production of one or more intermediates or products of reactions associated with the reduction of said reducible substrate, and    (c) comparing the production of said intermediates or products to a standard production in a standard reaction mixture, wherein a significant increase over the standard indicates that the candidate compound induces tardive dyskinesia when administered to an animal.    
     
     
         2 . The method of  claim 1 , wherein the reducible substrate has a standard reduction potential between 0 and 2.0 E°/V.  
     
     
         3 . The method of  claim 2 , wherein the reducible substrate is a complex ion.  
     
     
         4 . The method of  claim 2 , wherein the reducible substrate is Cu(II).  
     
     
         5 . The method of  claim 1 , wherein the reaction product assayed is hydrogen peroxide.  
     
     
         6 . The method of  claim 1 , wherein the reaction product assayed is hydroxyl radical.  
     
     
         7 . The method of  claim 1 , wherein the reaction product assayed is superoxide anion.  
     
     
         8 . The method of  claim 1 , wherein the reaction product assayed is reduced reducible substrate.  
     
     
         9 . The method of  claim 1 , wherein the ability of the candidate compound to induce tardive dyskinesia is confirmed by animal testing.  
     
     
         10 . The method of  claim 1 , wherein the ability of the candidate compound to induce tardive dyskinesia is confirmed by performing assays for multiple intermediates and/or end products of the reactions which induce tardive dyskinesia.  
     
     
         11 . The method of  claim 1 , wherein assaying for reaction product(s) is performed using a high-throughput assay.  
     
     
         12 . The method of  claim 11 , wherein the reaction product is determined calorimetrically.  
     
     
         13 . The method of  claim 11 , wherein the reaction product is determined fluorometrically.  
     
     
         14 . The method of  claim 11 , wherein the assay is performed using samples contained in a multicontainer carrier.  
     
     
         15 . The method of  claim 11 , wherein said candidate compound is an antipsychotic drug.  
     
     
         16 . A method for determining whether a candidate compound induces tardive dyskinesia comprising: 
 (a) incubating a candidate compound with a reducible substrate, and    (b) assaying for the production of a reactive oxygen species, whereby a determination of whether the reactive oxygen species has been produced is made by comparison to a standard reaction mixture, wherein a significant increase over the standard indicates that the candidate compound induces tardive dyskinesia when administered to an animal.    
     
     
         17 . The method of  claim 16 , wherein the reactive oxygen species is superoxide anion.  
     
     
         18 . The method of  claim 16 , wherein the reactive oxygen species is hydroxyl radical.  
     
     
         19 . The method of  claim 16 , wherein the reactive oxygen species is hydrogen peroxide.  
     
     
         20 . A methods for treating an individual afflicted with a psychosis comprising: 
 (a) the testing of candidate compounds to identify those which will not induce tardive dyskinesia when administered to an animal, and    (b) administering one or more candidate compounds identified in (a) to a patient in need thereof.