US 20170051350A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0051350 A1 Zhu et al. (43) Pub. Date: Feb. 23, 2017 (54) METHOD AND SYSTEM TO PREDICT (60) Provisional application No. 61/800,206, filed on Mar. RESPONSE TO TREATMENTS FOR 15, 2013, now abandoned, provisional application MENTAL DISORDERS No. 61/800,278, filed on Mar. 15, 2013, now aban doned. (71) Applicant: Pathway Genomics Corporation, San O Diego, CA (US) (72) Inventors: Guangdan Zhu, San Diego, CA (US); Publication Classification Cindy Wang, San Diego, CA (US); (51) Int. Cl Tanya Moreno, San Diego, CA (US); cio i/68 (2006.01) Andrew Hellman, San Diego, CA G06F 9/00 2006.01 (US); Alok Tomar, San Diego, CA ( .01) (US); Svetlana Ivanova Gramatikova, (52) U.S. Cl. San Diego, CA (US); Aditi Chawla, CPC ......... CI2O 1/6883 (2013.01); G06F 19/3431 San Diego, CA (US); Russell Kuo-fu (2013.01); G06F 19/704 (2013.01); C12O Del Tredici, San Diego, CA (US); (2013.01) Adrian Vilalta, San Diego, CA (US); K. David Becker, San Diego, CA (US); Michael Nova, San Diego, CA (US) (57) ABSTRACT (21) Appl. No.: 15/143,263 (22) Filed: Apr. 29, 2016 The present inventions relates to methods and assays to O O predict the response of an individual to a psychiatric treat Relatedelated U.S. Application DatUata ment and to a method to improve medical treatment of a (63) Continuation of application No. 13/917,573, filed on disorder, which is responsive to treatment with a psychiatric Jun. 13, 2013, now abandoned. treatment. Patent Application Publication Feb. 23, 2017 Sheet 1 of 6 US 2017/0051350 A1 2 Give Sample 110 FIGURE1 120 130 Display potential 140 Conflicts Or problems 105 e Confirm prescription, provide Warning and/or recommend alternative Patent Application Publication Feb. 23, 2017 Sheet 2 of 6 US 2017/0051350 A1 201 2O3 Efficacy e 202 FIGURE) Mental Drug Drug Health Efficacy 2. Eff 210 220 230 240 250 Assessment/Recommen dation e Patent Application Publication Feb. 23, 2017 Sheet 3 of 6 US 2017/0051350 A1 Caregiver logs in 30 s 310 s Prompt caregiver for patient information 350 Search database for patient genotype report 360 y Search database for Conflicts 380 s Display Conflicts 390 FIGURE3 Confirm prescription, provide Warning and/or recommend alternative Patent Application Publication Feb. 23, 2017 Sheet 4 of 6 US 2017/0051350 A1 Data Stores 402 O Genotype Database Patient Drug Genotype Database Database Inventory Health Insurance Database Database FIG. 4 Patent Application Publication Feb. 23, 2017 Sheet 5 of 6 US 2017/0051350 A1 505 s Working Memory 2 Storage Device(s) Operating System s 525 535 ? Input Device(s) 540 545 — Application ? Output Device(s) 52O 530 Communication 500 s Subsystem FIGURE5 Patent Application Publication Feb. 23, 2017 Sheet 6 of 6 US 2017/0051350 A1 US 2017/005 1350 A1 Feb. 23, 2017 METHOD AND SYSTEM TO PREDCT patient or an individual diagnosed with a particular disorder, RESPONSE TO TREATMENTS FOR determining the individuals likely response to a particular MENTAL DISORDERS treatment, more specifically a psychiatric medication, and thereafter displaying, or further, recommending a plan of FIELD OF THE INVENTION action or inaction. In particular, the present invention pro 0001. The invention relates to methods and assays to vides a grading method and system to profile an individuals predict the response of an individual to a treatment for a response to one or more psychiatric medications. In an mental disorder and to a method to improve medical treat alternate embodiment, the present invention is directed to a ment of a disorder, which is responsive to treatment with a method and system to recommend psychiatric medications psychiatric medication. suitable for the individual. 0007. These methods to identify gene mutation variants RELATED APPLICATIONS are not limited by the technique that is used to identify the mutation of the gene of interest. Methods for measuring 0002 The present application claims priority to U.S. gene mutations are well known in the art and include, but are Provisional Patent Application Ser. No. 61/800,206, not limited to, immunological assays, nuclease protection “Method And System To Predict Response To Treatments assays, northern blots, in situ hybridization, Polymerase For Mental Disorders', filed Mar. 15, 2013, the contents of Chain Reaction (PCR) such as reverse transcriptase Poly which are hereby incorporated by reference in their entirety. merase Chain Reaction (RT-PCR) or Real-Time Polymerase The present application also claims priority to U.S. Provi Chain Reaction, expressed sequence tag (EST) sequencing, sional Patent Application Ser. No. 61/800.278, “Method And cDNA microarray hybridization or gene chip analysis, Sub System To Predict Response To Treatments For Mental tractive cloning, Serial Analysis of Gene Expression Disorders', filed Mar. 15, 2013, the contents of which are (SAGE), Massively Parallel Signature Sequencing (MPSS). hereby incorporated by reference in their entirety. and Sequencing-By-Synthesis (SBS). BACKGROUND OF THE INVENTION 0008 After a patient has been identified as likely to be responsive to the therapy based on the identity of one or 0003 Major depressive disorder (MDD) is currently the more of the genetic markers identified herein, the method leading cause of disability in North America as well as other may further comprise administering or delivering an effec countries and, according to the WHO, may become the tive amount of a treatment or an alternative treatment, to the second leading cause of disability worldwide (after heart patient, based on the outcome of the determination. Methods disease) by the year 2020. Over the years, the elusive and of administration of pharmaceuticals and biologicals are highly variable nature of psychiatric disorders has led to known in the art and are incorporated herein by reference. drug therapy treatment that largely relies on empiricism to ascertain individual patient differences. This empirical 0009. It is conceivable that one of skill in the art will be approach has resulted in a high rate of refractory and adverse able to analyze and identify genetic markers in situ at Some responses to drug therapies, rendering treatment of MDD point in the future. Accordingly, the inventions of this one of the most significant challenges in psychiatry. application are not to be limited to requiring isolation of the 0004. The genetic make-up of a person can contribute to genetic material prior to analysis. the individually different responses of persons to a medicine 0010. These methods also are not limited by the tech (Roses, Nature 405:857-865, 2000). Examples of genetic nique that is used to identify the polymorphism of interest. factors, which determine drug tolerance, are drug allergies Suitable methods include but are not limited to the use of and severely reduced metabolism due to genetic absence of hybridization probes, antibodies, primers for PCR analysis, suitable enzymes. A case of a lethal lack of metabolism due and gene chips, slides and Software for high throughput to cytochrome P-450 2D6 genetic deficiency is reported by analysis. Additional genetic markers can be assayed and Sallee et at J Child & Adolesc. Psychopharmacol, 10: 27-34, used as negative controls. 2000. The metabolic enzymes in the liver occur in polymor 0011. This invention also provides a panel, kit, gene chip phic variants, causing some persons to metabolize certain and software for patient sampling and performance of the drugs slowly and making them at risk for side effects due to methods of this invention. The kits contain gene chips, excessively high plasma drug levels. slides, software, probes or primers that can be used to 0005. Both published literature studies and clinical expe amplify and/or for determining the molecular structure, rience reveal great variability in an individuals response to mutations, or expression level of the genetic markers iden psychotropic drug treatment with regard to drug metabo tified above. Instructions for using the materials to carry out lism, side effects and efficacy. the methods are further provided. 0012. This invention also provides for a panel of genetic SUMMARY OF THE INVENTION markers selected from, but not limited to the genetic poly 0006. The present invention is related to methods and morphisms identified herein or in combination with each systems to the present invention for predicting an individu other. The panel comprises probes or primers that can be als likely response to a psychiatric medication comprising used to amplify and/or for determining the molecular struc genotyping (including sequencing) genetic variations in an ture of the polymorphisms identified above. The probes or individual to determine the individuals propensity for 1) primers can be used for all RT-PCR methods as well as by metabolizing a psychiatric medication, 2) likely response to a solid phase Support Such as, but not limited to a gene chip a medication and 3) adverse reaction to a medication; and or microarray. The probes or primers can be detectably the Software and algorithms to analyze the genetic informa labeled. This aspect of the invention is a means to identify tion. In particular, the invention comprises analyzing a the genotype of a patient sample for the genes of interest biological sample provided by an individual, typically a identified above. US 2017/005 1350 A1 Feb. 23, 2017 BRIEF DESCRIPTION OF THE DRAWINGS lessness or guilt) episodes, or combinations thereof. In a 0013 FIG. 1 displays the interaction of an individual and preferred embodiment, the psychiatric disease or disorder is his caregiver in the system. Schizophrenia. 0014 FIG. 2 describes the mechanism for providing 0023. A “mental disorder or “mental illness” or “mental warnings or recommendations to particular psychiatric treat disease' or “psychiatric or neuropsychiatric disease or ill ments based on the efficacy of a particular treatment bal ness or disorder” refers to mood disorders (e.g., major anced against any potential conflicts or problems as they depression, mania, and bipolar disorders), psychotic disor relate to the genotype of an individual.