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(12) United States Patent (10) Patent No.: US 7,906,283 B2 Mcmahon Et Al

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(12) United States Patent (10) Patent No.: US 7,906,283 B2 Mcmahon Et Al US007906283B2 (12) United States Patent (10) Patent No.: US 7,906,283 B2 McMahon et al. (45) Date of Patent: Mar. 15, 2011 (54) METHODS TO IDENTIFY PATIENTSAT RISK GeneCard for the PAPLN gene available via url: <genecards.org/cgi OF DEVELOPING ADVERSE EVENTS bin/carddisp.pl?gene=Papln&snp=299fisnp>, printed on Dec. 15, DURING TREATMENT WITH 2009.* ANTDEPRESSANT MEDICATION GeneCard for the IL28RA gene available via url: <genecards.org/ cgi-bin/carddisp.pl?gene=II28ra&snp=284iisnp>, printed on Dec. (75) Inventors: Francis J. McMahon, Bethesda, MD 15, 2009.* (US); Gonzalo E. Laje, Potomac, MD Thisted, R.A. May 25, 1998; available online via url: <statuchicago. (US); Silvia Paddock, Solna (SE): edu/~thisted, pp. 1-6.* Husseini K. Manji, Cabin John, MD Laje et al. American Journal of Human Genetics. 141B, Issue 7, pp. 724-725, abstract O22.3, available online Sep. 11, 2006.* (US); A. John Rush, Dallas, TX (US) Choi et al., Neuropsychobiology, 52, 155-162 (2005). (73) Assignees: The United States of America as Lipsky et al., Neuropsychopharmacology, 31(No. Suppl. I), S23-S24 represented by the Department of (2006). McMahon, American Journal of Medical Genetics, 141B(No. 7), Health and Human Services, 689-690 (2006). Washington, DC (US); Board of McMahon, Neuropsychopharmacology, 31(No. Suppl. I), S38-S39 Regents, the University of Texas (2006). System, Austin, IL (US) Murphy et al., American Journal Psychiatry, 160(10), 1830-1835 (2003). (*) Notice: Subject to any disclaimer, the term of this GenBank Accession No. AAH32004 (Jul 15, 2006). patent is extended or adjusted under 35 GenBank Accession No. AAH37954 (Sep. 1, 2006). U.S.C. 154(b) by 337 days. GenBank Accession No. BC032004 (Jul. 15, 2006). GenBank Accession No. BC037954 (Sep. 1, 2006). (21) Appl. No.: 11/925,334 GenBank Accession No. NM 000827 (Sep. 24, 2007). GenBank Accession No. NM 000828 (Sep. 17, 2007). (22) Filed: Oct. 26, 2007 GenBank Accession No. NM 000833 (Sep. 25, 2007). GenBank Accession No. NM 001018064 (Oct. 28, 2007). (65) Prior Publication Data GenBank Accession No. NM 006028 (Sep. 3, 2007). US 2008/O1 O2467 A1 May 1, 2008 GenBank Accession No. NM 021956 (Oct. 22, 2007). GenBank Accession No. NM 170743 (Sep. 25, 2007). Related U.S. Application Data GenBank Accession No. NM 173462 (Jun. 26, 2007). Mannet al., “ACNPTask Force reporton SSRIs and suicidal behavior (60) Provisional application No. 60/854,978, filed on Oct. in youth.” Neuropsychopharmacology, 31 (3), 473-492 (2006). 27, 2006. McMahon et al., “Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment.” (51) Int. Cl. Am. J. Hum. Genet., 78. 804-814 (2006). CI2O I/68 (2006.01) Rush et al., “Sequenced treatment alternatives to relieve depression CI2P 19/34 (2006.01) (STAR*D): rationale and design.” Control Clin. Trials, 25 (1), 119 C7H 2L/02 (2006.01) 142 (2004). C7H 2L/04 (2006.01) Trivedi et al., “Evaluation of outcomes with citalopram for depres (52) U.S. Cl. ........ 435/6; 435/91.2:536/23.5:536/24.31 sion using measurement-based care in STAR*D: implications for (58) Field of Classification Search ........................ None clinical practice.” Am. J. Psychiatry, 163 (1), 28-40 (2006). See application file for complete search history. * cited by examiner (56) References Cited Primary Examiner — Carla Myers (74) Attorney, Agent, or Firm — Leydig, Voit & Mayer U.S. PATENT DOCUMENTS 7,083,921 B2 8/2006 Murphy et al. (57) ABSTRACT 2004/0265825 A1 12/2004 Tartakovsky 2005, OO69936 A1 3/2005 Diamond et al. The invention provides a method of Screening patients to 2006.01601 19 A1 7/2006 Turner et al. identify those patients more likely to exhibit an increased risk 2007/OOO3931 A1 1/2007 Mrazek et al. of treatment-emergent Suicidal ideation comprising: (a) 2008, 0299.125 A1 12, 2008 Hinds et al. obtaining a sample of genetic material from the patients, and OTHER PUBLICATIONS (b) assaying the sample for the presence of a genotype in the patients which is associated with an increased risk of treat Halushka et al. Nature. Ju1 1999. 22: 239-247. ment-emergent Suicidal ideation, wherein the genotype is Lucentini et al. The Scientist (2004) vol. 18, p. 20.* Wacholder et al. J. Natl. Cancer Institute (2004) 96(6):434-442.* characterized by a polymorphism in a gene selected from the Ioannidis et al. Nature genetics (2001) 29:306-309.* group consisting of glutamine receptor, ionotropic, kainate 2 Kato et al. Neuropsychobiology. 2006.53: 186-195.* (GRIK2); glutamate receptor ionotropic AMPA 3 (GRIA3); Menke et al. American Journal of Psychiatry, 2008. 165(7): 917 and combinations thereof. 918.* Laje et al. American Journal of Psychiatry, 2007. 164: 1530-1538.* 4 Claims, No Drawings US 7,906,283 B2 1. 2 METHODS TO DENTIFY PATIENTSAT RISK objects and advantages of the invention, as well as additional OF DEVELOPING ADVERSE EVENTS inventive features, will be apparent from the description of the DURING TREATMENT WITH invention provided herein. ANTIDEPRESSANT MEDCATION BRIEF SUMMARY OF THE INVENTION CROSS-REFERENCE TO RELATED APPLICATIONS The invention provides a method of Screening patients to identify those patients more likely to exhibit an increased risk This patent application claims the benefit of U.S. Provi of treatment-emergent Suicidal ideation comprising (a) sional Patent Application No. 60/854,978, filed Oct. 27, 2006, 10 obtaining a sample of genetic material from the patients, and which is incorporated by reference. (b) assaying the sample for the presence of a genotype in the patients which is associated with an increased risk of treat STATEMENT REGARDING FEDERALLY ment-emergent Suicidal ideation, wherein the genotype is SPONSORED RESEARCH AND DEVELOPMENT characterized by a polymorphism in a gene selected from the 15 group consisting of glutamine receptor, ionotropic, kainate 2 (GRIK2); glutamate receptor ionotropic AMPA 3 (GRIA3); This invention was made with Government support under and combinations thereof. Grant N01MH90003 awarded by the National Institutes of Health. DETAILED DESCRIPTION OF THE INVENTION INCORPORATION-BY-REFERENCE OF The biological basis for treatment emergent Suicidal ide MATERIAL SUBMITTED ELECTRONICALLY ation (TESI) following treatment with antidepressants, such as SSRIs, previously was unknown. The inventors have deter Incorporated by reference in its entirety herein is a com mined that specific genetic markers can shed light on the puter-readable nucleotide?amino acid sequence listing Sub 25 causes of TESI and help to identify individuals that are at mitted concurrently herewith and identified as follows: One high-risk for TESI and that can benefit from closer monitor 8,236 Byte ASCII (Text) file named “702157ST25.TXT,” ing, alternative treatments, and/or specialty care. created on Oct. 25, 2007. The inventors utilized the Sequenced Treatment Alterna tives to Relieve Depression (STAR*D) trial, which is a large BACKGROUND OF THE INVENTION 30 prospective treatment trial for major depression to test whether specific genetic markers could predict TESI in Depression is a disease that affects a large proportion of the patients treated with the selective serotonin reuptake inhibitor population and is a result of multiple factors. According to the (SSRI) citalopram. World Health Organization (WHO), depression ranks among The inventors identified genetic markers that identify the ten leading causes of disability and will become the sec 35 patients at high risk of developing Suicidal thoughts during ond-largest cause of the global health burden by 2020. An treatment with the SSRI citalopram. The markers reside in the estimated 121 million people worldwide suffer from a depres genes glutamine receptor, ionotropic, kainate 2 (GRIK2) and sive disorder for which they require treatment. It is estimated glutamate receptor ionotropic AMPA 3 (GRIA3). that 5.8% of all men and 9.5% of all women will Suffer from GRIK2 and GRIA3 encode receptors for the excitatory 40 neurotransmitter glutamate. Glutamate receptors are the pre a depressive disorder in any given year and that 17% of all dominant excitatory neurotransmitter receptors in the mam men and women will suffer from a depressive disorder at malian brain and are activated in a variety of normal neuro Some point in their lives. physiologic processes. These receptors are heteromeric Several types of antidepressant medications are used to protein complexes with multiple subunits, each possessing treat depressive disorders, such as selective serotonin 45 transmembrane regions, and all arranged to form a ligand reuptake inhibitors (SSRIs), tricyclics, and monoamine oxi gated ion channel. The classification of glutamate receptors is dase inhibitors (MAOIs). The SSRIs and other medications based on their activation by different pharmacologicagonists. that affect neurotransmitters, such as dopamine and norepi GRIK2 encodes a subunit of a kainate glutamate receptor. nephrine, generally have fewer side effects than tricyclics. GRIK2 also is known as EAA4, GLR6, GLUR6, GLuR-6, However, studies report a potential link between antidepres 50 and GluR-6. GRIK2 is located on chromosome 6q 16.3-q21. sant use and the emergence of Suicidal tendencies. According GRIK2 is identified by GenBank Accession Numbers to some studies Suicidal ideation (SI) is an uncommon but BC037954 and AAH37954, as well as IMAGE clone potentially dangerous phenomenon that can emerge during 5728492. antidepressant treatment. Although there is no clear under GRIA3 belongs to a family of alpha-amino-3-hydroxy-5- standing of the basis for the observed linkage, the Food and 55 methyl-4-isoxazole propionate (AMPA) receptors. Alterna Drug Administration (FDA) issued a black box warning tive splicing results in several different isoforms which may regarding the potential risk of worsening depression and/or vary in their signal transduction properties. GRIA3 also is emergence of Suicidality (i.e., development of Suicidal known as GLUR-K3, GLUR3, GLURC, GluR-3, GluR-K3, thoughts or behavior) in both adult and pediatric patients and gluR-C.
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