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SDR 16-348 – HSR&D Study

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SDR 16-348
PRIME Care (PRecision medicine In MEntal health Care)
David W. Oslin MD
Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
Philadelphia, PA
Funding Period: July 2016 - June 2022

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.

We propose a program of research to evaluate the utility of PGx testing in treating Major Depressive Disorder.

We 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:

1.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)

2.Provider/patient dyads in the intervention group will use fewer contraindicated medications based on established PGx criteria than the delayed results group. (Primary Hypothesis)

The following patient inclusion and exclusion criteria will be used:

Patient Inclusion Criteria. a) age 18 to 80 years, inclusive; b) PHQ-9 score 10 and a presumptive diagnosis of MDD per PHQ-9 criteria; c) at least one prior treatment exposure for MDD (psychotherapy or antidepressant); d) intent to start treatment of the MDD with an antidepressant (simple dose increases will not be considered inclusionary), and e) willingness to provide signed, informed consent to participate in the study.

Patient Exclusion Criteria. a) current serious co-occurring psychiatric illness (i.e., schizophrenia, bipolar disorder, psychotic major depression, borderline or antisocial personality disorder, eating disorder; b) active alcohol or other drug use disorder; c) PTSD checklist (PCL-5) score > 39; d) current use of an antipsychotic medication; e) 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); f) patients requiring urgent care or inpatient hospitalization at the time of consent; or g) currently incarcerated.

None at this time, the project is recruiting at this time.

Despite such a compelling epidemiological imperative, the treatment of depression is often inadequate. As shown now in several studies, to achieve remission from depression, patients and providers must be persistent and try multiple treatments until they find one that is both tolerable and effective. However, with each round of treatment, there is greater attrition from treatment. Replication of the results from the limited PGx implementation studies that have been conducted to date could usher in a new era in the treatment of MDD and provide an impetus for early diagnosis and treatment, resulting in more rapid and higher rates of remission. No change in the impact.


Journal Articles

  1. Vreeker A, Fears SC, Service SK, Pagani L, Takahashi JS, Araya C, Araya X, Bejarano J, Lopez MC, Montoya G, Montoya CP, Teshiba TM, Escobar J, Cantor RM, López-Jaramillo C, Macaya G, Molina J, Reus VI, Sabatti C, Ophoff RA, Freimer NB, Bearden CE. Genetic analysis of activity, brain and behavioral associations in extended families with heavy genetic loading for bipolar disorder. Psychological medicine. 2019 Dec 9; 1-9.
  2. Roggenkamp HC, Abbass A, Town JM, Kisley S, Johansson R. Healthcare cost reduction and psychiatric symptom improvement in posttraumatic stress disorder patients treated with intensive short-term dynamic psychotherapy. European Journal of Trauma & Dissociation. 2019 Sep 23;
  3. 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 1; 20(11):781-789.
  4. de Zwarte SMC, Brouwer RM, Agartz I, Alda M, Aleman A, Alpert KI, Bearden CE, Bertolino A, Bois C, Bonvino A, Bramon E, Buimer EEL, Cahn W, Cannon DM, Cannon TD, Caseras X, Castro-Fornieles J, Chen Q, Chung Y, De la Serna E, Di Giorgio A, Doucet GE, Eker MC, Erk S, Fears SC, Foley SF, Frangou S, Frankland A, Fullerton JM, Glahn DC, Goghari VM, Goldman AL, Gonul AS, Gruber O, de Haan L, Hajek T, Hawkins EL, Heinz A, Hillegers MHJ, Hulshoff Pol HE, Hultman CM, Ingvar M, Johansson V, Jönsson EG, Kane F, Kempton MJ, Koenis MMG, Kopecek M, Krabbendam L, Krämer B, Lawrie SM, Lenroot RK, Marcelis M, Marsman JC, Mattay VS, McDonald C, Meyer-Lindenberg A, Michielse S, Mitchell PB, Moreno D, Murray RM, Mwangi B, Najt P, Neilson E, Newport J, van Os J, Overs B, Ozerdem A, Picchioni MM, Richter A, Roberts G, Aydogan AS, Schofield PR, Simsek F, Soares JC, Sugranyes G, Toulopoulou T, Tronchin G, Walter H, Wang L, Weinberger DR, Whalley HC, Yalin N, Andreassen OA, Ching CRK, van Erp TGM, Turner JA, Jahanshad N, Thompson PM, Kahn RS, van Haren NEM. The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder. Biological psychiatry. 2019 Oct 1; 86(7):545-556.
  5. 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 Network Open. 2019 Jun 5; 2(6):e195345.
  6. Hull LE, Lynch KG, Oslin DW. VA Primary Care and Mental Health Providers' Comfort with Genetic Testing: Survey Results from the PRIME Care Study. Journal of general internal medicine. 2019 Jun 1; 34(6):799-801.
  7. McIntyre RS, Subramaniapillai M, Lee Y, Pan Z, Carmona NE, Shekotikhina M, Rosenblat JD, Brietzke E, Soczynska JK, Cosgrove VE, Miller S, Fischer EG, Kramer NE, Dunlap K, Suppes T, Mansur RB. Efficacy of Adjunctive Infliximab vs Placebo in the Treatment of Adults With Bipolar I/II Depression: A Randomized Clinical Trial. JAMA psychiatry. 2019 May 8.
  8. Ward RE, Cho K, Nguyen XT, Vassy JL, Ho YL, Quaden RM, Gagnon DR, Wilson PWF, Gaziano JM, Djoussé L, VA Million Veteran Program. Omega-3 supplement use, fish intake, and risk of non-fatal coronary artery disease and ischemic stroke in the Million Veteran Program. Clinical nutrition (Edinburgh, Scotland). 2020 Feb 1; 39(2):574-579.
  9. Raghavan S, Vassy JL, Ho YL, Song RJ, Gagnon DR, Cho K, Wilson PWF, Phillips LS. Diabetes Mellitus-Related All-Cause and Cardiovascular Mortality in a National Cohort of Adults. Journal of the American Heart Association. 2019 Feb 19; 8(4):e011295.
  10. Kramer NE, Cosgrove VE, Dunlap K, Subramaniapillai M, McIntyre RS, Suppes T. A clinical model for identifying an inflammatory phenotype in mood disorders. Journal of psychiatric research. 2019 Jun 1; 113:148-158.
  11. Leroux AJ, Waid-Ebbs JK, Wen PS, Helmer DA, Graham DP, O'Connor MK, Ray K. An Investigation of Exposure Control Methods With Variable-Length CAT Using the Partial Credit Model. Applied psychological measurement. 2019 Nov 1; 43(8):624-638.
  12. Gonzalez R, Gonzalez SD, Mallawaarachchic I, Suppes P. The relationship between circadian gene single nucleotide polymorphisms and clinical and behavioral assessments of sleep and rhythms and course of illness characteristics in subjects with bipolar type I disorder. Personalized medicine. 2019 Feb 12; 2019(13-14):11-18.
  13. van der Markt A, Klumpers UM, Draisma S, Dols A, Nolen WA, Post RM, Altshuler LL, Frye MA, Grunze H, Keck PE, McElroy SL, Suppes T, Beekman AT, Kupka RW. Testing a clinical staging model for bipolar disorder using longitudinal life chart data. Bipolar disorders. 2019 May 1; 21(3):228-234.
  14. Hidalgo-Mazzei D, Berk M, Cipriani A, Cleare AJ, Florio AD, Dietch D, Geddes JR, Goodwin GM, Grunze H, Hayes JF, Jones I, Kasper S, Macritchie K, McAllister-Williams RH, Morriss R, Nayrouz S, Pappa S, Soares JC, Smith DJ, Suppes T, Talbot P, Vieta E, Watson S, Yatham LN, Young AH, Stokes PRA. Treatment-resistant and multi-therapy-resistant criteria for bipolar depression: consensus definition. The British journal of psychiatry : the journal of mental science. 2019 Jan 1; 214(1):27-35.
  15. Imran TF, Posner D, Honerlaw J, Vassy JL, Song RJ, Ho YL, Kittner SJ, Liao KP, Cai T, O'Donnell CJ, Djousse L, Gagnon DR, Gaziano JM, Wilson PW, Cho K. A phenotyping algorithm to identify acute ischemic stroke accurately from a national biobank: the Million Veteran Program. Clinical epidemiology. 2018 Oct 16; 10:1509-1521.
  16. Post RM, Altshuler LL, Kupka R, McElroy SL, Frye MA, Rowe M, Grunze H, Suppes T, Keck PE, Leverich GS, Nolen WA. Multigenerational transmission of liability to psychiatric illness in offspring of parents with bipolar disorder. Bipolar disorders. 2018 Jun 21.
  17. Nielsen DA, Spellicy CJ, Harding MJ, Graham DP. Apolipoprotein E DNA methylation and posttraumatic stress disorder are associated with plasma ApoE level: A preliminary study. Behavioural brain research. 2019 Jan 1; 356:415-422.
  18. Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Bond DJ, Frey BN, Sharma V, Goldstein BI, Rej S, Beaulieu S, Alda M, MacQueen G, Milev RV, Ravindran A, O'Donovan C, McIntosh D, Lam RW, Vazquez G, Kapczinski F, McIntyre RS, Kozicky J, Kanba S, Lafer B, Suppes T, Calabrese JR, Vieta E, Malhi G, Post RM, Berk M. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar disorders. 2018 Mar 14; 20(2):97-170.
  19. Gonzalez R, Suppes T, Zeitzer J, McClung C, Tamminga C, Tohen M, Forero A, Dwivedi A, Alvarado A. The association between mood state and chronobiological characteristics in bipolar I disorder: a naturalistic, variable cluster analysis-based study. International journal of bipolar disorders. 2018 Feb 19; 6(1):5.
  20. Post RM, Leverich GS, McElroy S, Kupka R, Suppes T, Altshuler L, Nolen W, Frye M, Keck P, Grunze H, Hellemann G. Prevalence of axis II comorbidities in bipolar disorder: relationship to mood state. Bipolar disorders. 2018 Jun 1; 20(4):303-312.
  21. Williams LM, Pines A, Goldstein-Piekarski AN, Rosas LG, Kullar M, Sacchet MD, Gevaert O, Bailenson J, Lavori PW, Dagum P, Wandell B, Correa C, Greenleaf W, Suppes T, Perry LM, Smyth JM, Lewis MA, Venditti EM, Snowden M, Simmons JM, Ma J. The ENGAGE study: Integrating neuroimaging, virtual reality and smartphone sensing to understand self-regulation for managing depression and obesity in a precision medicine model. Behaviour Research and Therapy. 2018 Feb 1; 101:58-70.
  22. Lippard ETC, Jensen KP, Wang F, Johnston JAY, Spencer L, Pittman B, Gelernter J, Blumberg HP. Genetic variation of ANK3 is associated with lower white matter structural integrity in bipolar disorder. Molecular Psychiatry. 2017 Sep 1; 22(9):1225.
  23. Stein MB, Chen CY, Jain S, Jensen KP, He F, Heeringa SG, Kessler RC, Maihofer A, Nock MK, Ripke S, Sun X, Thomas ML, Ursano RJ, Smoller JW, Gelernter J, Army STARRS Collaborators. Genetic risk variants for social anxiety. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 2017 Jun 1; 174(4):470-482.
  24. Polimanti R, Zhang H, Smith AH, Zhao H, Farrer LA, Kranzler HR, Gelernter J. Genome-wide association study of body mass index in subjects with alcohol dependence. Addiction Biology. 2017 Mar 1; 22(2):535-549.
  25. Stein MB, Chen CY, Jain S, Jensen KP, He F, Heeringa SG, Kessler RC, Maihofer A, Nock MK, Ripke S, Sun X, Thomas ML, Ursano RJ, Smoller JW, Gelernter J, Army STARRS Collaborators. Genetic risk variants for social anxiety. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 2017 Mar 1; 174(2):120-131.
Journal Other

  1. Vieta E, Berk M, Schulze TG, Carvalho AF, Suppes T, Calabrese JR, Gao K, Miskowiak KW, Grande I. Bipolar disorders. [Book Review]. Nature reviews. Disease primers. 2018 Mar 8; 4:18008.

DRA: Mental, Cognitive and Behavioral Disorders, Substance Abuse and Addiction
DRE: none
Keywords: Substance Use and Abuse
MeSH Terms: none

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