PRIME Care (PRecision Medicine In MEntal Health Care) (PRIME Care)

The focus of this application is on the impact of providing depressed Veterans and their providers with the results of pharmacogenetic (PGx) testing for psychotropic medications. The project focuses on whether and how patients and providers use genetic test results given to them at the time an antidepressant is to be initiated to treat Major Depressive Disorder (MDD) and whether use of the test results improves patient outcomes. MDD is one of the most common conditions associated with military service and combat exposure, increases suicide risk, and worsens the course of common medical conditions, making it a leading cause of functional impairment and mortality. Validation of a PGx test to personalize the treatment of MDD represents an important opportunity to improve the healthcare of Veterans.

Background: In the last several years, commercial pharmacogenetic (PGx) testing for psychotropic medications has become widespread as a means of implementing "precision medicine", with some insurers electing to cover the cost of testing. These developments have put increasing pressure on the Veterans Health Administration to implement a mental health focused PGxs program, especially for treating depression, but without sufficient scientific study to support the utility of clinical application. Objectives: The investigators propose a program of research to evaluate the utility of PGx testing in treating Major Depressive Disorder. Methods: The investigators plan a multi-site RCT (n=2000), patient/provider dyads will be randomly assigned to receive results of the PGx battery right after randomization (i.e. intervention group) or after 6 months of treatment as usual (i.e. delayed results group)The study will test the following hypotheses: Veterans with MDD whose care is guided by the results of the PGx battery (the intervention group) will have a higher rate of remission of depression than the delayed results group. (Primary Hypothesis) Provider/patient dyads in the intervention group will use fewer medications that have potential gene-drug interactions based on commercial PGx test results than dyads in the delayed results group (Primary Hypothesis).

The study intervention is the provision of pharmacogenetic test results which can then be used to choice appropriate medication.

Pharmacogenetic test results will be provided to the provider within 72 hours of randomization in order to facilitate choice in selecting antidepressants.

The comparator arm will not receive results at the time of randomization but will get results after the 24 week assessment (thus the results are delayed).

The intervention is a battery of pharmacogenetic test results that mostly affect the metabolism of antidepressants and other medications.

The investigators will use the Patient Health Questionnaire 9 (PHQ9) as a self assessed marker of depression remission. The scale ranges from 0 to 27 with lower scores indicating less depression severity.

The investigators will examine the proportion of antidepressants used that have the potential for gene-drug interactions.

Self reported assessment of side effects related to antidepressants. Specific questions about nausea, headache, vomiting, GI distress, and sexual dysfunction. Each item rated as not present, mild, moderate, severe

We will examine the availability of antidepressants by creating a possession ratio of the number of days that a prescription was filled and available to the Veteran.

The investigators will use the Patient Health Questionnaire 9 (PHQ9) as a self assessed marker of depression remission. The scale ranges from 0 to 27 with lower scores indicating less depression severity. This measure will use the PHQ9 as a continuous measure.

The investigators will use the Patient Health Questionnaire 9 (PHQ9) as a self assessed marker of depression remission. The scale ranges from 0 to 27 with lower scores indicating less depression severity. Remission will be measured by a 50% reduction in scores from baseline to each time point.

Inclusion Criteria: PHQ-9 score 10 and a presumptive diagnosis of MDD per PHQ-9 criteria at least one prior treatment exposure for MDD (psychotherapy or antidepressant intent to start treatment of the MDD with an antidepressant, simple dose increases will not be considered inclusionary willingness to provide signed, informed consent to participate in the study Exclusion Criteria: current serious co-occurring psychiatric illness, i.e.: schizophrenia bipolar disorder psychotic major depression borderline or antisocial personality disorder eating disorder active alcohol or other drug use disorder current use of an antipsychotic medication augmentation therapy, e.g.: use of two or more antidepressants at the time of randomization (trazodone at a dosage < 150 mg/day will not be considered augmentation and thus allowed) patients requiring urgent care or inpatient hospitalization at the time of consent currently incarcerated

Access to a final data set will be by request only. The investigators will set up a formal approval process which will include a request form. The investigators will require requests to include hypotheses and specify data variables requested. Requests will be reviewed by the Executive Committee for approval. If approved, the requestor will be given a user agreement specifying how the data may be used. Once the agreement is signed and returned, the investigators will provide the requester with an anonymized data set via secure transit method. The investigators will also publish a data dictionary and a primer of our research methods.

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Munn-Chernoff MA, Johnson EC, Chou YL, Coleman JRI, Thornton LM, Walters RK, Yilmaz Z, Baker JH, Hubel C, Gordon S, Medland SE, Watson HJ, Gaspar HA, Bryois J, Hinney A, Leppa VM, Mattheisen M, Ripke S, Yao S, Giusti-Rodriguez P, Hanscombe KB, Adan RAH, Alfredsson L, Ando T, Andreassen OA, Berrettini WH, Boehm I, Boni C, Boraska Perica V, Buehren K, Burghardt R, Cassina M, Cichon S, Clementi M, Cone RD, Courtet P, Crow S, Crowley JJ, Danner UN, Davis OSP, de Zwaan M, Dedoussis G, Degortes D, DeSocio JE, Dick DM, Dikeos D, Dina C, Dmitrzak-Weglarz M, Docampo E, Duncan LE, Egberts K, Ehrlich S, Escaramis G, Esko T, Estivill X, Farmer A, Favaro A, Fernandez-Aranda F, Fichter MM, Fischer K, Focker M, Foretova L, Forstner AJ, Forzan M, Franklin CS, Gallinger S, Giegling I, Giuranna J, Gonidakis F, Gorwood P, Gratacos Mayora M, Guillaume S, Guo Y, Hakonarson H, Hatzikotoulas K, Hauser J, Hebebrand J, Helder SG, Herms S, Herpertz-Dahlmann B, Herzog W, Huckins LM, Hudson JI, Imgart H, Inoko H, Janout V, Jimenez-Murcia S, Julia A, Kalsi G, Kaminska D, Karhunen L, Karwautz A, Kas MJH, Kennedy JL, Keski-Rahkonen A, Kiezebrink K, Kim YR, Klump KL, Knudsen GPS, La Via MC, Le Hellard S, Levitan RD, Li D, Lilenfeld L, Lin BD, Lissowska J, Luykx J, Magistretti PJ, Maj M, Mannik K, Marsal S, Marshall CR, Mattingsdal M, McDevitt S, McGuffin P, Metspalu A, Meulenbelt I, Micali N, Mitchell K, Monteleone AM, Monteleone P, Nacmias B, Navratilova M, Ntalla I, O'Toole JK, Ophoff RA, Padyukov L, Palotie A, Pantel J, Papezova H, Pinto D, Rabionet R, Raevuori A, Ramoz N, Reichborn-Kjennerud T, Ricca V, Ripatti S, Ritschel F, Roberts M, Rotondo A, Rujescu D, Rybakowski F, Santonastaso P, Scherag A, Scherer SW, Schmidt U, Schork NJ, Schosser A, Seitz J, Slachtova L, Slagboom PE, Slof-Op't Landt MCT, Slopien A, Sorbi S, Swiatkowska B, Szatkiewicz JP, Tachmazidou I, Tenconi E, Tortorella A, Tozzi F, Treasure J, Tsitsika A, Tyszkiewicz-Nwafor M, Tziouvas K, van Elburg AA, van Furth EF, Wagner G, Walton E, Widen E, Zeggini E, Zerwas S, Zipfel S, Bergen AW, Boden JM, Brandt H, Crawford S, Halmi KA, Horwood LJ, Johnson C, Kaplan AS, Kaye WH, Mitchell J, Olsen CM, Pearson JF, Pedersen NL, Strober M, Werge T, Whiteman DC, Woodside DB, Grove J, Henders AK, Larsen JT, Parker R, Petersen LV, Jordan J, Kennedy MA, Birgegard A, Lichtenstein P, Norring C, Landen M, Mortensen PB, Polimanti R, McClintick JN, Adkins AE, Aliev F, Bacanu SA, Batzler A, Bertelsen S, Biernacka JM, Bigdeli TB, Chen LS, Clarke TK, Degenhardt F, Docherty AR, Edwards AC, Foo JC, Fox L, Frank J, Hack LM, Hartmann AM, Hartz SM, Heilmann-Heimbach S, Hodgkinson C, Hoffmann P, Hottenga JJ, Konte B, Lahti J, Lahti-Pulkkinen M, Lai D, Ligthart L, Loukola A, Maher BS, Mbarek H, McIntosh AM, McQueen MB, Meyers JL, Milaneschi Y, Palviainen T, Peterson RE, Ryu E, Saccone NL, Salvatore JE, Sanchez-Roige S, Schwandt M, Sherva R, Streit F, Strohmaier J, Thomas N, Wang JC, Webb BT, Wedow R, Wetherill L, Wills AG, Zhou H, Boardman JD, Chen D, Choi DS, Copeland WE, Culverhouse RC, Dahmen N, Degenhardt L, Domingue BW, Frye MA, Gaebel W, Hayward C, Ising M, Keyes M, Kiefer F, Koller G, Kramer J, Kuperman S, Lucae S, Lynskey MT, Maier W, Mann K, Mannisto S, Muller-Myhsok B, Murray AD, Nurnberger JI, Preuss U, Raikkonen K, Reynolds MD, Ridinger M, Scherbaum N, Schuckit MA, Soyka M, Treutlein J, Witt SH, Wodarz N, Zill P, Adkins DE, Boomsma DI, Bierut LJ, Brown SA, Bucholz KK, Costello EJ, de Wit H, Diazgranados N, Eriksson JG, Farrer LA, Foroud TM, Gillespie NA, Goate AM, Goldman D, Grucza RA, Hancock DB, Harris KM, Hesselbrock V, Hewitt JK, Hopfer CJ, Iacono WG, Johnson EO, Karpyak VM, Kendler KS, Kranzler HR, Krauter K, Lind PA, McGue M, MacKillop J, Madden PAF, Maes HH, Magnusson PKE, Nelson EC, Nothen MM, Palmer AA, Penninx BWJH, Porjesz B, Rice JP, Rietschel M, Riley BP, Rose RJ, Shen PH, Silberg J, Stallings MC, Tarter RE, Vanyukov MM, Vrieze S, Wall TL, Whitfield JB, Zhao H, Neale BM, Wade TD, Heath AC, Montgomery GW, Martin NG, Sullivan PF, Kaprio J, Breen G, Gelernter J, Edenberg HJ, Bulik CM, Agrawal A. Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies. Addict Biol. 2021 Jan;26(1):e12880. doi: 10.1111/adb.12880. Epub 2020 Feb 16.

Polimanti R, Walters RK, Johnson EC, McClintick JN, Adkins AE, Adkins DE, Bacanu SA, Bierut LJ, Bigdeli TB, Brown S, Bucholz KK, Copeland WE, Costello EJ, Degenhardt L, Farrer LA, Foroud TM, Fox L, Goate AM, Grucza R, Hack LM, Hancock DB, Hartz SM, Heath AC, Hewitt JK, Hopfer CJ, Johnson EO, Kendler KS, Kranzler HR, Krauter K, Lai D, Madden PAF, Martin NG, Maes HH, Nelson EC, Peterson RE, Porjesz B, Riley BP, Saccone N, Stallings M, Wall TL, Webb BT, Wetherill L; Psychiatric Genomics Consortium Substance Use Disorders Workgroup; Edenberg HJ, Agrawal A, Gelernter J. Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium. Mol Psychiatry. 2020 Aug;25(8):1673-1687. doi: 10.1038/s41380-020-0677-9. Epub 2020 Feb 26.

Muniz Carvalho C, Wendt FR, Maihofer AX, Stein DJ, Stein MB, Sumner JA, Hemmings SMJ, Nievergelt CM, Koenen KC, Gelernter J, Belangero SI, Polimanti R. Dissecting the genetic association of C-reactive protein with PTSD, traumatic events, and social support. Neuropsychopharmacology. 2021 May;46(6):1071-1077. doi: 10.1038/s41386-020-0655-6. Epub 2020 Mar 16.

Hunter-Zinck H, Shi Y, Li M, Gorman BR, Ji SG, Sun N, Webster T, Liem A, Hsieh P, Devineni P, Karnam P, Gong X, Radhakrishnan L, Schmidt J, Assimes TL, Huang J, Pan C, Humphries D, Brophy M, Moser J, Muralidhar S, Huang GD, Przygodzki R, Concato J, Gaziano JM, Gelernter J, O'Donnell CJ, Hauser ER, Zhao H, O'Leary TJ; VA Million Veteran Program; Tsao PS, Pyarajan S. Genotyping Array Design and Data Quality Control in the Million Veteran Program. Am J Hum Genet. 2020 Apr 2;106(4):535-548. doi: 10.1016/j.ajhg.2020.03.004.

Wendt FR, Carvalho CM, Pathak GA, Gelernter J, Polimanti R. Polygenic risk for autism spectrum disorder associates with anger recognition in a neurodevelopment-focused phenome-wide scan of unaffected youths from a population-based cohort. PLoS Genet. 2020 Sep 17;16(9):e1009036. doi: 10.1371/journal.pgen.1009036. eCollection 2020 Sep.

Hull LE, Lynch KG, Oslin DW. VA Primary Care and Mental Health Providers' Comfort with Genetic Testing: Survey Results from the PRIME Care Study. J Gen Intern Med. 2019 Jun;34(6):799-801. doi: 10.1007/s11606-018-4776-0. No abstract available.

Chanfreau-Coffinier C, Hull LE, Lynch JA, DuVall SL, Damrauer SM, Cunningham FE, Voight BF, Matheny ME, Oslin DW, Icardi MS, Tuteja S. Projected Prevalence of Actionable Pharmacogenetic Variants and Level A Drugs Prescribed Among US Veterans Health Administration Pharmacy Users. JAMA Netw Open. 2019 Jun 5;2(6):e195345. doi: 10.1001/jamanetworkopen.2019.5345.

Hull LE, Chanfreau-Coffinier C, Tuteja S, Berlowitz D, Lehmann LS, Oslin DW, Pyne JM, DuVall SL, Lynch JA. Early adoption of pharmacogenetic testing for veterans prescribed psychotropic medications. Pharmacogenomics. 2019 Jul;20(11):781-789. doi: 10.2217/pgs-2019-0065. Epub 2019 Aug 8.

Oslin DW, Chapman S, Duvall SL, Gelernter J, Ingram EP, Kranzler HR, Lehmann LS, Lynch JA, Lynch KG, Pyne JM, Shih MC, Stone A, Thase ME, Wray LO. Study design and implementation of the PRecision Medicine In MEntal health Care (PRIME Care) Trial. Contemp Clin Trials. 2021 Feb;101:106247. doi: 10.1016/j.cct.2020.106247. Epub 2020 Dec 11.

Vest BM, Wray LO, Brady LA, Thase ME, Beehler GP, Chapman SR, Hull LE, Oslin DW. Primary care and mental health providers' perceptions of implementation of pharmacogenetics testing for depression prescribing. BMC Psychiatry. 2020 Oct 28;20(1):518. doi: 10.1186/s12888-020-02919-z.

Ramsey CM, Lynch KG, Thase ME, Gelernter J, Kranzler HR, Pyne JM, Shih MC, Stone A; PRIME Care Executive Committee; Oslin DW. Prevalence of predicted gene-drug interactions for antidepressants in the treatment of major depressive disorder in the Precision Medicine in Mental Health Care Study. J Affect Disord. 2021 Mar 1;282:1272-1277. doi: 10.1016/j.jad.2021.01.034. Epub 2021 Jan 14.

Ziobrowski HN, Cui R, Ross EL, Liu H, Puac-Polanco V, Turner B, Leung LB, Bossarte RM, Bryant C, Pigeon WR, Oslin DW, Post EP, Zaslavsky AM, Zubizarreta JR, Nierenberg AA, Luedtke A, Kennedy CJ, Kessler RC. Development of a model to predict psychotherapy response for depression among Veterans. Psychol Med. 2023 Jun;53(8):3591-3600. doi: 10.1017/S0033291722000228. Epub 2022 Feb 11.

Oslin DW, Lynch KG, Shih MC, Ingram EP, Wray LO, Chapman SR, Kranzler HR, Gelernter J, Pyne JM, Stone A, DuVall SL, Lehmann LS, Thase ME; PRIME Care Research Group; Aslam M, Batki SL, Bjork JM, Blow FC, Brenner LA, Chen P, Desai S, Dieperink EW, Fears SC, Fuller MA, Goodman CS, Graham DP, Haas GL, Hamner MB, Helstrom AW, Hurley RA, Icardi MS, Jurjus GJ, Kilbourne AM, Kreyenbuhl J, Lache DJ, Lieske SP, Lynch JA, Meyer LJ, Montalvo C, Muralidhar S, Ostacher MJ, Paschall GY, Pfeiffer PN, Prieto S, Przygodzki RM, Ranganathan M, Rodriguez-Suarez MM, Roggenkamp H, Schichman SA, Schneeweis JS, Simonetti JA, Steinhauer SR, Suppes T, Umbert MA, Vassy JL, Voora D, Wiechers IR, Wood AE. Effect of Pharmacogenomic Testing for Drug-Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trial. JAMA. 2022 Jul 12;328(2):151-161. doi: 10.1001/jama.2022.9805.

Ramsey CM, Lynch KG, Gehrman PR, Vairavan S, Narayan VA, Li QS, Oslin DW. Daily steps and depressive symptoms: A longitudinal evaluation of patients with major depressive disorder in the precision medicine in mental health care study. J Affect Disord. 2022 Mar 1;300:334-340. doi: 10.1016/j.jad.2021.12.116. Epub 2022 Jan 1.