WO2010111080A2

WO2010111080A2 - Optimized treatment of schizophrenia

Info

Publication number: WO2010111080A2
Application number: PCT/US2010/027577
Authority: WO
Inventors: Anncatherine Marie Downing; Bruce Jerome Kinon; Sandra Louise Close Kirkwood; Wenlei Liu; Laura Kay Nisenbaum; Reuben Kirobi Njau
Original assignee: Eli Lilly And Company
Priority date: 2009-03-27
Filing date: 2010-03-17
Publication date: 2010-09-30
Also published as: WO2010111080A3

Abstract

The present invention relates to methods of treating schizophrenia with Group II mGlu receptor agonists wherein genetic variants are used to predict the clinical outcome of therapy.

Description

OPTIMIZED TREATMENT OF SCHIZOPHRENIA

The present invention relates to methods of treating schizophrenia with Group II metabotropic glutamate (mGlu) receptor agonists wherein genetic variants are used to predict the clinical outcome of therapy. More particularly, the present invention relates to a method of treating a patient suffering from schizophrenia with LY2140023 monohydrate wherein the patient has one or more variants in one or more of genes HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.

The mGlu receptors are G-protein-coupled receptors that modulate neuronal excitability. More particularly, altered glutamate neurotransmission has been linked to schizophrenia, but all commonly prescribed antipsychotics act on dopamine receptors. Various studies support Group II mGlu receptor activation for the treatment for schizophrenia (Conn et al, Trends in Pharm. ScL (2009) 30(1), 25-31; Chavez-Noriega et al, Current Drug Targets: CNS & Neurological Disorders (2002) 1(3), 261-281; Schoepp et al , Current Drug Targets: CNS & Neurological Disorders (2002) 1 (2), 215- 225). In particular, recent data suggest that a mGlu 2/3 receptor agonist has antipsychotic properties and may provide a new alternative for the treatment of schizophrenia (Patil et al, Nature Medicine (2007) 13(3), 1102-1107).

Various compounds that are Group II mGlu receptor agonists containing a bicyclohexane or heterobicyclohexane ring system have been described (e.g. WO 96/05175, WO 97/18199, WO 98/51655, WO 00/12464, WO 02/055481, WO 03/104217). One such agonist is LY2140023 monohydrate. This compound has the chemical name (li?,45^r,5«S,6«S')-4-(2'5^r-4'-methylthio-2'-aminobutanonyl)amino-2,2-dioxo- 2λ⁶-thia-bicyclo[3.1.0]hexane-4,6-dicarboxylic acid monohydrate and is disclosed in WO 03/104217.

A genetic variant is defined as a difference in DNA at a particular locus within a population. There are multiple types of genetic variants including mutation, polymorphism, single nucleotide polymorphism (SNP), copy number variant (CNV), copy number polymorphism (CNP), insertion, deletion, duplication, tandem repeat, microsatellite, short tandem repeat (STR), and variable number tandem repeat (VNTR). For further information on genetic variant types see, for example, Shelling et al, Mutation Research (2007) 622, 33-41. The most common source of genetic variants is single nucleotide polymorphisms (SNPs), which have a single base pair difference in the genomic DNA sequence. Particular SNPs can be linked with patient response to a drug and, thus, used as predictors of a drug's impact on a patient in view of the patient's genetic variation. A medical need exists to identify patients that will best respond to treatment regimens for schizophrenia by using genetic variants to predict the clinical outcome of therapy. While some SNPs have been identified as central nervous system disease susceptibility markers, no SNPs have been identified to predict patient response to treatment for schizophrenia with a Group II mGlu receptor agonist compound. Thus, there exists a need to have methods for predetermining or quickly determining if a patient will likely respond to treatment for schizophrenia with a Group II mGlu receptor agonist compound. Surprisingly, the present invention provides genetic variants that are useful to predict patient response to treatment for schizophrenia with the Group II (mGlu 2/3) receptor agonist compound LY2140023 monohydrate. The present invention involves a method of treating schizophrenia in a patient comprising administering an effective amount of LY2140023 monohydrate to a patient wherein the patient has one or more variants in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.

Furthermore, the present invention involves a method of treating schizophrenia in a patient comprising administering an effective amount of LY2140023 monohydrate to a patient wherein the patient has one or more single nucleotide polymorphisms in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.

Also, the present invention involves a method of treating schizophrenia in a patient comprising administering an effective amount of LY2140023 monohydrate to a patient wherein the patient has one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl. The present invention further involves a method of treating schizophrenia in a patient comprising administering an effective amount of LY2140023 monohydrate to a patient wherein the patient has one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.

The present invention also involves a method of treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more variants in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample, and administering an effective amount of LY2140023 monohydrate to the patient if the DNA sample contains one or more variants in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.

The present invention additionally involves a method of treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more single nucleotide polymorphisms in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample, and administering an effective amount of LY2140023 monohydrate to the patient if the DNA sample contains one or more single nucleotide polymorphisms in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.

Also, the present invention involves a method of treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample, and administering an effective amount of LY2140023 monohydrate to the patient if the DNA sample contains one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl. -A-

The present invention additionally involves a method of treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample, and administering an effective amount of LY2140023 monohydrate to the patient if the DNA sample contains one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl. Furthermore, the present invention involves the use of LY2140023 monohydrate for the manufacture of a medicament for treating schizophrenia in a patient wherein the patient has one or more variants in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.

The present invention also involves the use of LY2140023 monohydrate for the manufacture of a medicament for treating schizophrenia in a patient wherein the patient has one or more single nucleotide polymorphisms in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.

The present invention additionally involves the use of LY2140023 monohydrate for the manufacture of a medicament for treating schizophrenia in a patient wherein the patient has one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl. Also, the present invention involves the use of LY2140023 monohydrate for the manufacture of a medicament for treating schizophrenia in a patient wherein the patient has one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl. Furthermore, the present invention involves the use of LY2140023 monohydrate for the manufacture of a medicament for treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more variants in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample; and administering an effective amount of LY2140023 monohydrate to the patient if the DNA sample contains one or more one or more variants in one or more genes selected from the group consisting of HTR2 A, NRG 1 , DRD2, DRD3 , COMT, GRM3 , and PKHD 1.

The present invention also involves the use of LY2140023 monohydrate for the manufacture of a medicament for treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more single nucleotide polymorphisms in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample, and administering an effective amount of LY2140023 monohydrate to the patient if the DNA sample contains one or more single nucleotide polymorphisms in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl. Additionally, the present invention involves the use of LY2140023 monohydrate for the manufacture of a medicament for treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3 C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample, and administering an effective amount of LY2140023 monohydrate to the patient if the DNA sample contains one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.

The present invention further involves the use of LY2140023 monohydrate for the manufacture of a medicament for treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3 A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample, and administering an effective amount of LY2140023 monohydrate to the patient if the DNA sample contains one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3 A, 3 B, 3 C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.

Furthermore, the present invention involves the use of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system for the manufacture of a medicament for treating schizophrenia in a patient wherein the patient has one or more variants in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.

The present invention also involves the use of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system for the manufacture of a medicament for treating schizophrenia in a patient wherein the patient has one or more single nucleotide polymorphisms in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.

The present invention additionally involves the use of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system for the manufacture of a medicament for treating schizophrenia in a patient wherein the patient has one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl. Also, the present invention involves the use of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system for the manufacture of a medicament for treating schizophrenia in a patient wherein the patient has one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.

Furthermore, the present invention involves the use of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system for the manufacture of a medicament for treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more variants in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample; and administering an effective amount of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system to the patient if the DNA sample contains one or more variants in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.

The present invention also involves the use of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system for the manufacture of a medicament for treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more single nucleotide polymorphisms in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample, and administering an effective amount of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system to the patient if the DNA sample contains one or more single nucleotide polymorphisms in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.

Additionally, the present invention involves the use of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system for the manufacture of a medicament for treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium to single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3 A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample, and administering an effective amount of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system to the patient if the DNA sample contains one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium to single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.

The present invention further involves the use of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system for the manufacture of a medicament for treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHD 1 is contained in the DNA sample, and administering an effective amount of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system to the patient if the DNA sample contains one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3 A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl. The present invention also involves a kit for assessing a sample acquired from a patient suffering from schizophrenia comprising DNA extraction reagents; a matrix to which the extracted DNA is bound; contaminant removal reagents; DNA elution solution; oligonucleotide primers and/or probes specific to one or more SNPs listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl; genotyping platform reagents; instructions on a genotyping platform for determining whether one or more SNPs listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3 A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the matrix to which the extracted DNA is bound; and instructions on sample, control sample, and reagent preparation requirements.

The present invention provides previously unknown association between genetic variants and the treatment of schizophrenia with a Group II mGlu receptor agonist compound. The detection of these variants provides robust and precise methods for identifying patients that can benefit from using a Group II mGlu receptor agonist in the treatment of schizophrenia. Preferably, the variant is a single nucleotide polymorphism (SNP). A preferred Group II mGlu receptor agonist is mGlu2/3 receptor agonist LY2140023 monohydrate. Examples of genes associated with the treatment of schizophrenia with a Group II mGlu receptor agonist preferably include HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl. GeneID information for each gene is as follows: HTR2A (GenelD 3356), NRGl (GenelD 3084), DRD2 (GenelD 1813), DRD3 (GenelD 1814), COMT (GenelD 1312), GRM3 (GenelD 2913 ), and PKHD 1 (GenelD 5314)

(http://www.ncbi.nlm.nih.gov/sites/entrez). More preferably, these genes include HTR2A, NRGl, DRD2, DRD3, and PKHDl. Most preferably, these genes include HTR2A and NRGl. Even more preferably, the genes individually are HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, or PKHDl. More particularly, the SNPs linked to these genes are correlated to the treatment of schizophrenia with a Group II mGlu receptor agonist. These SNPs include the SNPs provided in the Tables (e.g. Tables IA, 2A, 3A) provided herein. In addition to these SNPs, additional SNPs in linkage disequilibrium with these listed SNPs will likewise be correlated to the treatment of schizophrenia with a Group II mGlu receptor agonist. As linkage disequilibrium is the tendency for alleles at two linked loci to be associated in the population, any SNP in linkage disequilibrium with one or more SNPs that are correlated to the treatment of schizophrenia with a Group II mGlu receptor agonist would, by implication, be itself correlated to the same treatment response.

The present invention includes the identification of variants relating to HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl to aid in the prediction of patient outcome and the informed selection of therapies for the use in the treatment of schizophrenia. The present invention employs genetic variants in HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl as the preferred marker. Also, genetic variants in the genes known to be in the biological pathways related to HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl are also markers of success with therapy with an Group II mGlu receptor agonist.

The present invention includes use of Group II mGlu receptor agonists for treating schizophrenia in a patient having one or more variants in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl. Preferably, compounds that are Group II mGlu receptor agonists used for treating schizophrenia in a patent having one or more of these variants contain a pharmacophore associating this agonism to particular atoms within the compounds. For example, compounds within the scope of the present invention have the common structural feature of a bicyclohexane or heterobicyclohexane ring system which is associated with Group II mGlu receptor agonism. More preferably, the Group II mGlu receptor agonists for treating schizophrenia in a patient having one or more variants in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl are mGlu2/3 receptor agonists. Even more preferably, compounds that are mGlu2/3 receptor agonists contain a pharmacophore associating this agonism to particular atoms within the compounds. For example, compounds within the scope of the present invention have the common structural feature of a bicyclohexane or heterobicyclohexane ring system which is associated with mGlu2/3 receptor agonism. In the present invention, the most preferred mGlu2/3 receptor agonist with a heterobicyclohexane ring system is LY2140023 monohydrate.

One embodiment of the invention involves a method for determining a patient's response to treatment for schizophrenia with LY2140023 monohydrate by detecting one or more variants in a plurality of genes comprising one or more of the following genes: HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.

Response to psychiatric disorder drug therapy is measured by a scoring system based on scales which assess a variety of symptoms in patients. One scoring system is the Positive and Negative Syndrome Scale (PANSS; Kay et al, Schizophr. Bull. (1987) 13(2), 261-276.). For the methods described herein relevant to schizophrenia treatment, the response is deemed beneficial if there is a significant improvement in the PANSS Total rating scale from baseline after treatment with a Group II mGlu receptor agonist, preferably a mGlu2/3 receptor agonist compound. Therefore, a patient with one or more genetic variants in HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl will show the greatest response in PANSS Total from baseline and, thus, likely respond to treatment with a Group II mGlu receptor agonist compound, preferably a mGlu2/3 receptor agonist compound, such as LY2140023 monohydrate. More particularly, the response is deemed beneficial if there is a significant improvement in the PANSS Total rating scale from baseline in a patient with schizophrenia after treatment with LY2140023 monohydrate.

The following definitions are provided to aid those of ordinary skill in the art in understanding the disclosure herein. These definitions are intended to be representative of those known in the art, and are therefore not limited to the specific elements presented, but encompass concepts and features disclosed in cited and/or contemporary publications or patents.

The term "allele" is either of a pair (or series) of alternative forms of a gene that can occupy the same locus on a particular chromosome and that control the same character.

The term "chromosome" is a structure within the cell that bears the genetic material as a threadlike linear strand of DNA bonded to various proteins in the nucleus.

The term "position" is the location of the SNP along the chromosome. The term "DNA sample" refers to a sample containing human DNA obtained from, for example, blood, hair, or skin of a patient.

The term "effective amount" refers to the amount or dose of a mGlu2/3 agonist compound or pharmaceutically acceptable salt, upon which single or multiple dose administration to a patient, provides the desired treatment. The term "gene" is one or more sequence(s) of nucleotides in a genome that together encode one or more expressed molecule, e.g. an RNA, or polypeptide.

The term "genetic variant" (alternatively, "variant") is a locus that is variable; that is, within a population, the nucleotide sequence at a genetic variant has more than one version. There are multiple types of genetic variants including mutation, polymorphism, single nucleotide polymorphism (SNP), copy number variant (CNV), copy number polymorphism (CNP), insertion, deletion, duplication, tandem repeat, microsatellite, short tandem repeat (STR), and variable number tandem repeat (VNTR). The most common source of genetic variants is single nucleotide polymorphisms (SNPs), which have a single base pair difference in the genomic DNA sequence, i.e. the nucleotide at the specified position varies between individuals or populations.

The term "genome" refers to all of the genetic information, the entire genetic complement, all of the hereditary material possessed by an organism.

The term "major allele" refers to the allele that is found in the majority of individuals within a given population. The term "minor allele" refers to the allele that is found in the minority of individuals within a given population. The term "major homozygous" refers to individuals with two major alleles at a specific locus.

The term "heterozygous" refers to individuals with one major allele and one minor at a specific locus. The term "minor homozygous" refers to individuals with two minor alleles at a specific locus.

The term "linkage disequilibrium" is the non-random association of alleles at two or more loci.

The term "single nucleotide polymorphism" (SNP) is a genetic variant at a single position in a genome, i.e. the nucleotide at the specified position varies between individuals or populations.

The term "single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C" are SNPs in linkage disequilibrium with the SNPs listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C that are associated with the treatment of schizophrenia with a Group II mGlu receptor agonist. This term can also be modified to include different combinations of the noted Tables provided herein. As linkage disequilibrium is the tendency for alleles at two linked loci to be associated in the population, any SNP in linkage disequilibrium with one or more SNPs that are correlated with the treatment of schizophrenia with a Group II mGlu receptor agonist would be itself correlated to the same treatment response.

The term "locus" is a chromosomal position or region. The plural of the term "locus" is "loci."

The term "marker" refers to a nucleotide sequence or encoded product thereof (e.g. a protein) used as a point of reference that is predictive of patient outcome when the patient is treated for schizophrenia.

The term "patient" is a mammal, preferably a human. More preferably, the patient is a Caucasian human.

The term "phenotype" is a trait or collection of traits that are qualitatively or quantitatively observable in an individual or population.

The term "p-value" is the probability of obtaining a result at least as extreme as the one that was actually observed, assuming that the null hypothesis is true. The term "treating" (or "treat" or "treatment") means slowing, stopping, reducing, or reversing the progression or severity of a symptom, disorder, condition, or disease.

Example 1 Activation of mGlu2/3 Receptors to Treat Schizophrenia in a Randomized Phase 2

Clinical Trial (HBBD)

A randomized, three-armed, double-blind, placebo-controlled phase II clinical trial evaluates LY2140023 monohydrate in schizophrenic patients. See Patil et al. (2007) Nature Medicine 13(9): 1102-1107. Pharmacogenomic efforts on DNA samples are collected from this study and are supplemented with DNA samples from a randomized, double-blind, phase IV clinical trial of olanzapine (see Kinon et al., (2008) J CHn Psychopharmacol 28(4): 392-400; HGLF) have been ongoing to identify genetic markers that are associated with improved outcomes for patients treated with LY2140023 monohydrate.

Genetic variants in eight candidate genes related to the mechanism of action of LY2140023 or the atypical antipsychotic olanzapine are examined. Altogether, 488 SNPs are tested in 180 Caucasian individuals. SNPs in these genes are detected using standard genotyping technology such as the Sequenom MassARRAY platform. The methodology employs an initial locus-specific PCR reaction, followed by single base extension using mass-modified dideoxynucleotide terminators of an oligonucleotide primer which anneals immediately upstream of the polymorphic site of interest. Using MALDI-TOF mass spectrometry, the distinct mass of the extended primer identifies the SNP allele (Gabriel et al., 2009). Statistical analysis is performed using ANCOVA (LOCF) in which the dependent variable is change in PANSS total and the independent variables are gender, baseline PANSS total, age at enrollment, trial (HBBD versus HGLF), treatment, genotype (assuming an additive disease inheritance model) and treatment by genotype interaction Associations between LY2140023 monohydrate response (change in PANSS Total score) and genotypes are identified for SNPs within the HTR2A, NRGl, DRD2, DRD3, COMT, GRM3 and PKHDl genes. Three SNPs (1 in NRGl, rslO954863; 2 in HTR2A, rs7330461 and rs7330636) have a statistically significantly association at an unadjusted p-value < 0.001 with LY2140023 monohydrate response at 28 days as measured by change in PANSS Total. For each of these SNPs, the minor homozygous group shows the greatest improvement in PANSS Total score (Tables IA, IB). Twenty-three SNPs (1 in NRGl, 16 in HTR2A, 1 in DRD2, 4 in DRD3, and 1 in PKHDl) are associated at an unadjusted p-value < 0.01 with LY2140023 monohydrate treatment arm at 28 days (Table 2A), while 65 SNPs (2 in NRGl, 26 in HTR2A, 23 in DRD2, 4 in DRD3, 3 in PKHDl, 3 in GRM3, and 4 in COMT) have unadjusted p-values < 0.05 in LY2140023 monohydrate treatment arm at 28 days (Table 3A). An alternative analysis using MMRM with genotypic assumption model was performed as well. Thus genetic variants in HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and

PKHDl are associated with improved outcome for subgroups of patients treated with LY2140023 monohydrate. Therefore, a patient with one or more genetic variants in HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl will show the greatest response in PANSS Total and, thus, likely respond to treatment with LY2140023 monohydrate.

The tables provided herein are divided into three separate sections for all data relevant to a particular unadjusted p-value. For example, Tables IA, IB, and 1C involve data for unadjusted p-value <0.001. Tables IA, 2A, and 3 A lists the SNPs that are associated with LY2140023 monohydrate treatment response with an unadjusted p value < 0.001, <0.01, and <0.05, respectively, along with their related Chromosome, Gene, and Chromosomal Position. For each of the SNPs, the overall p value is listed for the LY2140023 monohydrate group at 28 days of treatment as well as the model based mean change in PANSS Total score for each of the three genotype groups (Major Homozygous, Heterozygous, and Minor Homozygous; see Tables IB, 2B, and 3B). The larger the decrease in the PANSS Total change score, the greater the symptom improvement in this group. The Minor Allele column lists the nucleotide found in the minority of Caucasian patients within HBBD whereas the Major Allele column lists the nucleotide found in the majority of Caucasian patients within HBBD (see Tables 1C, 2C, and 3C). As an example, if G is listed as the Minor Allele and A is the Major Allele, the Minor Homozygous genotype group will consist of patients with G/G at this SNP, the

Heterozygous group will have G/A and the Major Homozygous group will have A/A. The Responsive Allele column lists the allele associated with enhanced treatment response (see Tables 1C, 2C, and 3C). The Responsive Genotype Group (e.g. Minor) column lists the genotype group associated with the greatest improvement in PANSS Total score for a particular SNP and the Responsive Genotype identifies the actual genotype associated with the greatest improvement (see Tables 1C, 2C, and 3C). Thus, patients with the Responsive Genotype at one of the SNPs would be likely to respond to LY2140023 monohydrate for the treatment of schizophrenia.

Table IA: Unadjusted p-value < 0.001

Table IB: Unadjusted p-value < 0.001

Change in PANSS Total Score from Baseline

Table 1C: Unadjusted p-value < 0.001

Table 2Λ i.: Unadjusted p-value < 0.01

Gene SNP Chromosome Position p value

NRGl rslO954863 8 32576053 0.00070

HTR2A rsl745837 13 46322813 0.00788

HTR2A rsl923885 13 46321087 0.00181

HTR2A rsl923887 13 46322294 0.00456

HTR2A rsl923888 13 46322386 0.00772

DRD3 rs2134655 3 115340891 0.00518

DRD2 rs2242593 11 112781475 0.00882

HTR2A rs2296972 13 46326472 0.00772

HTR2A rs2770300 13 46325046 0.00781

DRD3 rs3732790 3 115329973 0.00849

PKHDl rs4715227 6 51599843 0.00350

HTR2A rs621494 13 46325792 0.00248

HTR2A rs622337 13 46325627 0.00687

HTR2A rs643627 13 46326612 0.00795

HTR2A rs655854 13 46326201 0.00792

HTR2A rs655888 13 46326182 0.00835

HTR2A rs6561332 13 46317821 0.00196

HTR2A rs7330461 13 46321566 0.00048

HTR2A rs7330636 13 46321593 0.00063

HTR2A rs9316232 13 46324723 0.00456

HTR2A rs9567739 13 46322945 0.00572

DRD3 rs963468 3 115345577 0.00856

DRD3 rs9817063 3 115329798 0.00726

Table 2B: Unadjusted p-value < 0.01

Change in PANSS Total Score from Baseline

Table 3A: Unadjusted p-value < 0.05

Table 3B: Unadjusted p-value < 0.05

Change in PANSS Total Score from Baseline

Change in PANSS Total Score from Baseline

Table 3C: Unadjusted p-value < 0.05

Example 2

LY2140023 Monohydrate to Treat Schizophrenia in a Randomized Phase 2 Clinical Trial (HBBI)

A double-blind, placebo- and active comparator-controlled trial are conducted in which schizophrenia patients are randomized, to receive 5 mg, 20 mg, 40 mg, or 80 mg twice daily LY2140023 monohydrate, placebo twice daily, or placebo once each morning and 15 mg olanzapine once each evening in a 2:2:2:2:2: 1 ratio. Genetic variants identified in trial HBBD that have an unadjusted p<0.001 (n=3 SNPs) are prospectively tested in DNA samples collected from patients in HBBI (n=350 DNA samples). SNPs in these genes are measured using standard genotyping technology such as the Sequenom MassARRAY platform. The methodology employs an initial locus-specific PCR reaction, followed by single base extension using mass-modified dideoxynucleotide terminators of an oligonucleotide primer which anneals immediately upstream of the polymorphic site of interest. Using MALDI-TOF mass spectrometry, the distinct mass of the extended primer identifies the SNP allele (Gabriel et al, 2009).

The primary response measure (PANSS Total Score) has failed to demonstrate statistically significant separation between the treatment group receiving the active comparator (olanzapine) and the placebo-treated group within the intent to treat population in HBBI. Also, the primary response measure (PANSS Total Score) has failed to demonstrate statistically significant separation between the treatment group receiving LY2140023 monohydrate and the placebo-treated group within the intent to treat population in HBBI.

Within the LY2140023 monohydrate treatment group in Caucasian patients in HBBI, the minor homozygous group of the HTR2A SNPs, rs7330461 and rs7330636, and the NRGl SNP, rs 10954863, show the greatest improvement in the PANSS Total Score, similar to what is observed in HBBD for these SNPs. However, the difference among genotype groups for these SNPs does not reach statistical significance in HBBI.

Identifying Genetic Subgroups

Utilizing Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3 C, combinations of SNPs are identified based on the strength of evidence, e.g. p-values alone or p-values in combination with multiple testing corrections (e.g. false discovery rate, Bonferroni correction) for association with LY2140023 monohydrate treatment response, i.e. change in PANSS Total score. Next, associations are assessed in a second pharmacogenomic analysis in a pre-specified manner, with the strength of evidence encompassing, for example, p-values alone, p-values in combination with multiple testing corrections, or consistencies in the directionality and magnitude of the observed genetic effects on treatment response with those in the first pharmacogenomic analysis. For the SNPs with the highest degree of replication, information from both pharmacogenomic analyses are combined to provide the best estimates of LY2140023 monohydrate treatment response for both genotype groups determined by a single SNP and composite genotype groups jointly determined by a pair of SNPs. Finally, a number of options for the genetic subgroup, which vary in terms of the SNP(s) involved and how genotypes are grouped, are ranked according to their potential clinical utility, e.g. positive predictive value and/or negative predictive value, which is influenced by the expected proportion and effect size of each subgroup.

Genotyping Defined SNPs

The appropriate sample from a patient suffering from schizophrenia is collected. Possible sample types include, but are not limited to, anti-coagulated whole blood (e.g. citrate, EDTA, or heparin tubes), lymphocytes, saliva, buccal swabs, dried blood spots, plasma, serum, or other body fluids. DNA is extracted from the sample using standard methods and standard DNA extraction reagents. For example, cell lysis typically uses a chaotropic salt such as Guanidine Thiocyanate, binding the extracted DNA to a matrix (e.g. magnetic particles, DNA binding resin). Once the extracted DNA is bound to the matrix, contaminant removal reagents (e.g. alcohol, acetone) are used. The now purified extracted DNA is eluted from the matrix using the appropriate DNA elution solution (e.g. Tris-based buffer, H₂O). See e.g. Riemann et al, J. Clin. Lab. Anal. (2007) 21, 244-248; Baumgartner et ah, Biochemica Newsletter (2005) No. 2).

Extracted DNA is then used with the chosen genotyping platform to determine the defined SNP(s) genotype. The SNP(s) genotype may be determined using a number of methods. These may include, for example, PCR amplification or direct SNP detection which may be used in a single or multiplex assay (e.g. microarray platforms).

In PCR amplification, the DNA is mixed with the appropriate oligonucleotide primers and/or probes, which are short sequences of DNA surrounding the SNP to be genotyped, and appropriate genotyping platform reagents (e.g. nucleotides, buffers, and Taq Polymerase). This mixture is then cycled through various temperatures that are used to denature the DNA, anneal the primers/probes to the DNA, and finally to extend the DNA using the activity of the Taq Polymerase. In some cases fluorescent dyes are incorporated during the extension phase of PCR allowing detection of amplified products. See e.g. Kok et al., Human Mutation (2002) 19, 554-559). For direct SNP detection, the sample DNA is directly hybridized to capture oligonucleotide probes without DNA amplification. Typically, these oligonucleotide probes are allele specific and are arrayed onto a solid support (e.g. glass slide, film chip, bead). Additional probes are used to surround the bound DNA and incorporate a fluorescent dye, other light emitting molecule, or electrochemical molecule that is used to visualize or detect the reaction. Once the reaction is complete the solid support is exposed to a light source or electric current resulting in the detection and/or quantitation of the reaction signal. It is also possible for DNA amplified as described above, to be hybridized to a solid support and then detected using oligonucleotide probes to incorporate molecules necessary for detection and/or quantitation. See e.g. Storhoff, et al, Nature Biotechnology (2004) 22 (7), 883-887; Liu et al, IVDT (May 2008), 31.

Depending on the genotyping platform used, the reagents and steps described above are done manually or are self-contained in a cartridge utilizing automation and/or microfluidics. For genotyping platforms that process multiple samples at once, a DNA sample is typically supplied with the platform as a positive control sample. This DNA will have a genotype previously confirmed by sequencing or some other validated method, and it is typically included in each run to confirm the assay is reproducible. A negative control sample such as water is typically also included, and it is confirmed that no result is detected. For self-contained systems where a single sample is processed at a time, a separate control sample is not typically used but rather internal assay control samples are usually utilized. For example, an array will contain spots designated as image control samples, negative control samples, and possibly assay control samples. The image control samples are designed to react and confirm that the image is being captured. If there is no detection at these spots then it is known there has been a reagent failure. Negative control sample spots serve the same purpose as the negative control sample described above; no DNA is present so no reaction should be detected at these locations. Assay control samples may also be used. These confirm that the probes for the different SNPs are working because they have a known sequence at that location.

A kit for assessing a sample acquired from a patient suffering from schizophrenia contains - in addition to the various reagents, matrix, and oligonucleotide primers and/or probes provided herein - instructions on the genotyping platform used and instructions on sample, control sample, and reagent preparation requirements.

Claims

WE CLAIM:

1. A method of treating schizophrenia in a patient comprising administering an effective amount of LY2140023 monohydrate to a patient wherein the patient has one or more variants in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.

2. The method of Claim 1, wherein one or more genes is selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, and PKHDl.

3. The method of Claim 1, wherein one or more genes is selected from the group consisting of HTR2A and NRG 1.

4. The method of Claim 1, wherein the gene is HTR2A.

5. The method of Claim 1, wherein the gene is NRGl .

6. The method of Claim 1, wherein the gene is DRD2.

7. The method of Claim 1, wherein the gene is DRD3.

8. The method of Claim 1, wherein the gene is COMT.

9. The method of Claim 1, wherein the gene is GRM3.

10. The method of Claim 1, wherein the gene is PKHDl.

11. A method of treating schizophrenia in a patient, comprising: a) obtaining a DNA sample from the patient; b) determining whether one or more single nucleotide polymorphisms in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample; and c) administering an effective amount of LY2140023 monohydrate to the patient if the DNA sample contains one or more single nucleotide polymorphisms in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.

12. The method of Claim 11, wherein one or more single nucleotide polymorphisms in one or more genes is selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, and PKHDl.

13. The method of Claim 11, wherein one or more single nucleotide polymorphisms in one or more genes is selected from the group consisting of HTR2A and NRGl.

14. The method of Claim 11, wherein one or more single nucleotide polymorphisms is in HTR2A

15. The method of Claim 11, wherein one or more single nucleotide polymorphisms is in NRG 1.

16. The method of Claim 11, wherein one or more single nucleotide polymorphisms is in DRD2.

17. The method of Claim 11, wherein one or more single nucleotide polymorphisms is in DRD3.

18. The method of Claim 11, wherein one or more single nucleotide polymorphisms is in COMT.

19. The method of Claim 11, wherein one or more single nucleotide polymorphisms is in GRM3.

20. The method of Claim 11, wherein one or more single nucleotide polymorphisms is in PKHD 1.

21. A method of treating schizophrenia in a patient, comprising: a) obtaining a DNA sample from the patient; b) determining whether one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3 A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample; and c) administering an effective amount of LY2140023 monohydrate to the patient if the DNA sample contains one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3 A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.

22. The method of Claim 21, wherein one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3 A, 3B, 3C in one or more genes is selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, and PKHDl.

23. The method of Claim 21 , wherein one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3 A, 3B, 3C in one or more genes is selected from the group consisting of HTR2A and NRGl.

24. The method of Claim 21, wherein one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C is in HTR2A.

25. The method of Claim 21, wherein one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C is in NRGl.

26. The method of Claim 21, wherein one or more single nucleotide polymorphisms listed in Tables 2A, 2B, 2C and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables 2A, 2B, 2C and/or 3A, 3B, 3C is in DRD2.

27. The method of Claim 21, wherein one or more single nucleotide polymorphisms listed in Tables 2A, 2B, 2C and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables 2A, 2B, 2C and/or 3A, 3B, 3C is in DRD3.

28. The method of Claim 21, wherein one or more single nucleotide polymorphisms listed in Tables 3 A, 3B, 3 C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables 3A, 3B, 3C is in COMT.

29. The method of Claim 21, wherein one or more single nucleotide polymorphisms listed in Tables 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables 3 A, 3 B, 3 C is in GRM3.

30. The method of Claim 21, wherein one or more single nucleotide polymorphisms listed in Tables 2A, 2B, 2C and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables 2A, 2B, 2C and/or 3 A, 3B, 3C is in PKHDl.

31. A method of treating schizophrenia in a patient, comprising: a) obtaining a DNA sample from the patient; b) determining whether one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3 A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample; and c) administering an effective amount of LY2140023 monohydrate to the patient if the DNA sample contains one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3 A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.

32. The method of Claim 31, wherein one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3 A, 3B, 3C in one or more genes is selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, and PKHDl.

33. The method of Claim 31, wherein one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3 A, 3B, 3C in one or more genes is selected from the group consisting of HTR2A and NRGl.

34. The method of Claim 31, wherein one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C is in HTR2A.

35. The method of Claim 31, wherein one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C is in NRGl.

36. The method of Claim 31, wherein one or more single nucleotide polymorphisms listed in Tables 2A, 2B, 2C and/or 3A, 3B, 3C is in DRD2.

37. The method of Claim 31, wherein one or more single nucleotide polymorphisms listed in Tables 2A, 2B, 2C and/or 3A, 3B, 3C is in DRD3.

38. The method of Claim 31, wherein one or more single nucleotide polymorphisms listed in Tables 3 A, 3B, 3 C is in COMT.

39. The method of Claim 31, wherein one or more single nucleotide polymorphisms listed in Tables 3 A, 3 B, 3 C is in GRM3.

40. The method of Claim 31, wherein one or more single nucleotide polymorphisms listed in Tables 2A, 2B, 2C and/or 3 A, 3B, 3C is in PKHDl.

41. A kit for assessing a sample acquired from a patient suffering from schizophrenia comprising: a) DNA extraction reagents; b) a matrix to which the extracted DNA is bound; c) contaminant removal reagents; d) DNA elution solution; e) oligonucleotide primers and/or probes specific to one or more SNPs listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl; f) genotyping platform reagents; g) instructions on a genotyping platform for determining whether one or more SNPs listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3 A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the matrix to which the extracted DNA is bound; and h) instructions on sample, control sample, and reagent preparation requirements.