Randomized Controlled Trial

. 2022 Mar 14;12(1):101.

doi: 10.1038/s41398-022-01847-8.

Clinical utility of combinatorial pharmacogenomic testing in depression: A Canadian patient- and rater-blinded, randomized, controlled trial

Arun K Tiwari^#^{1

2}, Clement C Zai^#^{1

2

3

4}, C Anthony Altar⁵, Julie-Anne Tanner⁶, Paige E Davies⁶, Paul Traxler⁶, James Li⁶, Elizabeth S Cogan⁷, Matthew T Kucera⁷, Ana Gugila⁶, Nicole Braganza^{1

2}, Heather Emmerson^{1

2}, Gwyneth Zai^{1

2

3}, Daniel J Müller^{1

2

3}, Robert Levitan^{1

2

3}, Stefan Kloiber^{2

3

8}, Zafiris J Daskalakis⁹, Benicio N Frey^{10

11}, James M Bowen^{12

13

14}, Jean-Eric Tarride^{15

16

17}, Richard Tytus¹⁸, Ranjith Chandrasena¹⁹, Nicholas Voudouris²⁰, Valerie H Taylor²¹, Raymond Tempier^{22

23}, Verinder Sharma²⁴, Akshya Vasudev^{25

26}, Peter Dzongowski²⁷, Lew Pliamm²⁸, Todd Greenspoon²⁹, Bryan M Dechairo⁷, James L Kennedy^{30

31

32}

Affiliations

¹ Tanenbaum Centre for Pharmacogenetics, Neurogenetics Section, Molecular Brain Sciences Research Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
² Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
³ Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
⁴ Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
⁵ Splice Therapeutics, 20271 Goldenrod Lane, Lab 2071, Germantown, MD, 20876, USA.
⁶ Myriad Neuroscience, Mason, OH, USA.
⁷ Myriad Genetics, Salt Lake City, UT, USA.
⁸ Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
⁹ Department of Psychiatry, UC San Diego, San Diego, CA, USA.
¹⁰ Mood Disorders Treatment and Research Centre and Women's Health Concerns Clinic, St Joseph's Healthcare Hamilton, Hamilton, ON, Canada.
¹¹ Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada.
¹² Department of Health Research Methods, Evidence and Impact, Faculty of Health Sciences, McMaster University, Hamilton, Canada.
¹³ Program for Health System and Technology Evaluation, Ted Rogers Centre for Heart Research at Peter Munk Cardiac Centre, Toronto General Hospital Research Institute (TGHRI), Hamilton, Canada.
¹⁴ Toronto Health Economics and Technology Assessment (THETA) Collaborative, University Health Network (UHN), Hamilton, Canada.
¹⁵ Department of Health Research Methods, Evidence, and Impact (HEI), Faculty of Health Science, McMaster University, Hamilton, ON, Canada.
¹⁶ Programs for Assessment of Technology in Health (PATH), The Research Institute of St. Joe's Hamilton, St. Joseph's Healthcare Hamilton, Hamilton, ON, Canada.
¹⁷ Center for Health Economics and Policy Analysis (CHEPA), McMaster University, Hamilton, Canada.
¹⁸ Family Medicine, McMaster University, Hamilton, ON, Canada.
¹⁹ Chatham-Kent Health Alliance, Chatham, ON, Canada.
²⁰ Thornhill Medical Center, Toronto, ON, Canada.
²¹ Department of Psychiatry, University of Calgary, Hotchkiss Brain Institute, an Institute of the Cumming School of Medicine, Calgary, AB, Canada.
²² Hôpital Montfort, Ottawa, ON, Canada.
²³ Department of Psychiatry, University of Ottawa, Ottawa, ON, Canada.
²⁴ Department of Psychiatry, Western University, London, ON, Canada.
²⁵ Department of Psychiatry, Geriatric Psychiatry and Neurosciences, Western University, London, ON, Canada.
²⁶ Integrative Psychiatry Lab, Parkwood Institute of Mental Health, London, ON, Canada.
²⁷ Milestone Research, London, ON, Canada.
²⁸ Canadian Phase Onward Inc., Polyclinic Family and Specialty Medicine Facility, Polyclinic Family Health Group, Toronto, ON, Canada.
²⁹ Hamilton Community Health Centre, Hamilton, ON, Canada.
³⁰ Tanenbaum Centre for Pharmacogenetics, Neurogenetics Section, Molecular Brain Sciences Research Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada. jim.kennedy@camh.ca.
³¹ Department of Psychiatry, University of Toronto, Toronto, ON, Canada. jim.kennedy@camh.ca.
³² Institute of Medical Science, University of Toronto, Toronto, ON, Canada. jim.kennedy@camh.ca.

^# Contributed equally.

PMID: 35288545
PMCID: PMC8921325
DOI: 10.1038/s41398-022-01847-8

Randomized Controlled Trial

Clinical utility of combinatorial pharmacogenomic testing in depression: A Canadian patient- and rater-blinded, randomized, controlled trial

Arun K Tiwari et al. Transl Psychiatry. 2022.

. 2022 Mar 14;12(1):101.

doi: 10.1038/s41398-022-01847-8.

Authors

Affiliations

¹ Tanenbaum Centre for Pharmacogenetics, Neurogenetics Section, Molecular Brain Sciences Research Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
² Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
³ Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
⁴ Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
⁵ Splice Therapeutics, 20271 Goldenrod Lane, Lab 2071, Germantown, MD, 20876, USA.
⁶ Myriad Neuroscience, Mason, OH, USA.
⁷ Myriad Genetics, Salt Lake City, UT, USA.
⁸ Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
⁹ Department of Psychiatry, UC San Diego, San Diego, CA, USA.
¹⁰ Mood Disorders Treatment and Research Centre and Women's Health Concerns Clinic, St Joseph's Healthcare Hamilton, Hamilton, ON, Canada.
¹¹ Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada.
¹² Department of Health Research Methods, Evidence and Impact, Faculty of Health Sciences, McMaster University, Hamilton, Canada.
¹³ Program for Health System and Technology Evaluation, Ted Rogers Centre for Heart Research at Peter Munk Cardiac Centre, Toronto General Hospital Research Institute (TGHRI), Hamilton, Canada.
¹⁴ Toronto Health Economics and Technology Assessment (THETA) Collaborative, University Health Network (UHN), Hamilton, Canada.
¹⁵ Department of Health Research Methods, Evidence, and Impact (HEI), Faculty of Health Science, McMaster University, Hamilton, ON, Canada.
¹⁶ Programs for Assessment of Technology in Health (PATH), The Research Institute of St. Joe's Hamilton, St. Joseph's Healthcare Hamilton, Hamilton, ON, Canada.
¹⁷ Center for Health Economics and Policy Analysis (CHEPA), McMaster University, Hamilton, Canada.
¹⁸ Family Medicine, McMaster University, Hamilton, ON, Canada.
¹⁹ Chatham-Kent Health Alliance, Chatham, ON, Canada.
²⁰ Thornhill Medical Center, Toronto, ON, Canada.
²¹ Department of Psychiatry, University of Calgary, Hotchkiss Brain Institute, an Institute of the Cumming School of Medicine, Calgary, AB, Canada.
²² Hôpital Montfort, Ottawa, ON, Canada.
²³ Department of Psychiatry, University of Ottawa, Ottawa, ON, Canada.
²⁴ Department of Psychiatry, Western University, London, ON, Canada.
²⁵ Department of Psychiatry, Geriatric Psychiatry and Neurosciences, Western University, London, ON, Canada.
²⁶ Integrative Psychiatry Lab, Parkwood Institute of Mental Health, London, ON, Canada.
²⁷ Milestone Research, London, ON, Canada.
²⁸ Canadian Phase Onward Inc., Polyclinic Family and Specialty Medicine Facility, Polyclinic Family Health Group, Toronto, ON, Canada.
²⁹ Hamilton Community Health Centre, Hamilton, ON, Canada.
³⁰ Tanenbaum Centre for Pharmacogenetics, Neurogenetics Section, Molecular Brain Sciences Research Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada. jim.kennedy@camh.ca.
³¹ Department of Psychiatry, University of Toronto, Toronto, ON, Canada. jim.kennedy@camh.ca.
³² Institute of Medical Science, University of Toronto, Toronto, ON, Canada. jim.kennedy@camh.ca.

^# Contributed equally.

PMID: 35288545
PMCID: PMC8921325
DOI: 10.1038/s41398-022-01847-8

Erratum in

Correction: Clinical utility of combinatorial pharmacogenomic testing in depression: A Canadian patient- and rater-blinded, randomized, controlled trial.
Tiwari AK, Zai CC, Altar CA, Tanner JA, Davies PE, Traxler P, Li J, Cogan ES, Kucera MT, Gugila A, Braganza N, Emmerson H, Zai G, Müller DJ, Levitan R, Kloiber S, Daskalakis ZJ, Frey BN, Bowen JM, Tarride JE, Tytus R, Chandrasena R, Voudouris N, Taylor VH, Tempier R, Sharma V, Vasudev A, Dzongowski P, Pliamm L, Greenspoon T, Dechairo BM, Kennedy JL. Tiwari AK, et al. Transl Psychiatry. 2022 May 30;12(1):214. doi: 10.1038/s41398-022-01963-5. Transl Psychiatry. 2022. PMID: 35637185 Free PMC article. No abstract available.

Abstract

The pharmacological treatment of depression consists of stages of trial and error, with less than 40% of patients achieving remission during first medication trial. However, in a large, randomized-controlled trial (RCT) in the U.S. ("GUIDED"), significant improvements in response and remission rates were observed in patients who received treatment guided by combinatorial pharmacogenomic testing, compared to treatment-as-usual (TAU). Here we present results from the Canadian "GAPP-MDD" RCT. This 52-week, 3-arm, multi-center, participant- and rater-blinded RCT evaluated clinical outcomes among patients with depression whose treatment was guided by combinatorial pharmacogenomic testing compared to TAU. The primary outcome was symptom improvement (change in 17-item Hamilton Depression Rating Scale, HAM-D17) at week 8. Secondary outcomes included response (≥50% decrease in HAM-D17) and remission (HAM-D17 ≤ 7) at week 8. Numerically, patients in the guided-care arm had greater symptom improvement (27.6% versus 22.7%), response (30.3% versus 22.7%), and remission rates (15.7% versus 8.3%) compared to TAU, although these differences were not statistically significant. Given that the GAPP-MDD trial was ultimately underpowered to detect statistically significant differences in patient outcomes, it was assessed in parallel with the larger GUIDED RCT. We observed that relative improvements in response and remission rates were consistent between the GAPP-MDD (33.0% response, 89.0% remission) and GUIDED (31.0% response, 51.0% remission) trials. Together with GUIDED, the results from the GAPP-MDD trial indicate that combinatorial pharmacogenomic testing can be an effective tool to help guide depression treatment in the context of the Canadian healthcare setting (ClinicalTrials.gov NCT02466477).

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Conflict of interest statement

AKT is a co-inventor on a patent for antipsychotic-induced weight gain at the time of this study (U.S. patent no. 10,662,475). CCZ had a patent on antipsychotic-induced weight gain markers at the time of this study. CAA had ownership/partnership in Splice Therapeutics at the time of this study, and also serves on the advisory board for AxoSim Inc. and the board of directors for ASENT. JAT, PED, PT, JL, MTK, and AG were employed by Myriad Neuroscience/Assurex Health at the time of this study. MTK and ESC were employed by Myriad Genetics at the time of this study. DJM was a co-inventor on two patents assessing risk for antipsychotic-induced weight gain at the time of this study and was also a co-investigator on two pharmacogenetic studies where genetic test kits were provided as in-kind contribution by Myriad Neuroscience but did not receive any salary, equity, stocks, or options from any pharmacogenetic companies. SK received research support from the University of Toronto, Department of Psychiatry Academic Scholar Award, the Labatt Family Innovation Fund in Brain Health, and the Canadian Institutes of Health Research (CIHR) at the time of this study, and received honorarium from Empowerpharm for past consultation. JMB and JET received funding and payment from Myriad Neuroscience to conduct the GAPP-MDD trial until the contract was terminated by Myriad Neuroscience. BMD was employed by Myriad Genetics at the time of this study and received salary and stock options. JLK is an unpaid member of the Myriad Neuroscience Scientific Advisory Board. All other authors declare no conflicts of interest.

Figures

**Fig. 1. HAM-D17 clinical outcomes at 8 weeks by treatment arm in the GAPP-MDD clinical trial and the previous GUIDED trial [14].**
A Per-protocol (PP) cohort. GAPP-MDD trial: Guided care arm N = 127, TAU arm N = 69; GUIDED trial: Guided care arm N = 560, TAU arm N = 607. B Intent-to-treat (ITT) cohort. GAPP-MDD trial: Guided care arm N = 211, TAU arm N = 97); GUIDED trial: Guided care arm N = 621, TAU arm N = 677.

**Fig. 2. Medication congruency by week in the Per-Protocol cohort of the GAPP-MDD clinical trial and the previous GUIDED trial [14].**
The proportion of patients taking genetically congruent medications from the GAPP-MDD and GUIDED trials are shown in blue and orange, respectively. Squares represent Guided-Care treatment arms, and circles represent TAU treatment arms.

**Fig. 3. Meta-analysis of randomized-controlled trials evaluating combinatorial pharmacogenomic testing.**
A Meta-analysis of symptom improvement. B Meta-analysis of response. C Meta-analysis of remission.

See this image and copyright information in PMC

References

1. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–17. doi: 10.1176/ajp.2006.163.11.1905. - DOI - PubMed
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Clinical utility of combinatorial pharmacogenomic testing in depression: A Canadian patient- and rater-blinded, randomized, controlled trial

Affiliations

Clinical utility of combinatorial pharmacogenomic testing in depression: A Canadian patient- and rater-blinded, randomized, controlled trial

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

References

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MeSH terms

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Associated data

LinkOut - more resources

Full Text Sources

Medical