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Safety of Using a Combinatorial Pharmacogenomic Test for Patients with Major Depressive Disorder in the GUIDED trial
- Sagar V. Parikh, Gabriela K. Khazanov, Michael E. Thase, Anthony J. Rothschild, Boadie W. Dunlop, Charles DeBattista, Charles R. Conway, Brent P. Forester, Richard C. Shelton, Matthew Macaluso, James Li, Kunbo Yu, Michael R. Jablonski, Stephanie Meek, John F. Greden
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- Journal:
- CNS Spectrums / Volume 26 / Issue 2 / April 2021
- Published online by Cambridge University Press:
- 10 May 2021, pp. 169-170
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Background
Pharmacogenomic testing has emerged to aid medication selection for patients with major depressive disorder (MDD) by identifying potential gene-drug interactions (GDI). Many pharmacogenomic tests are available with varying levels of supporting evidence, including direct-to-consumer and physician-ordered tests. We retrospectively evaluated the safety of using a physician-ordered combinatorial pharmacogenomic test (GeneSight) to guide medication selection for patients with MDD in a large, randomized, controlled trial (GUIDED).
Materials and MethodsPatients diagnosed with MDD who had an inadequate response to ≥1 psychotropic medication were randomized to treatment as usual (TAU) or combinatorial pharmacogenomic test-guided care (guided-care). All received combinatorial pharmacogenomic testing and medications were categorized by predicted GDI (no, moderate, or significant GDI). Patients and raters were blinded to study arm, and physicians were blinded to test results for patients in TAU, through week 8. Measures included adverse events (AEs, present/absent), worsening suicidal ideation (increase of ≥1 on the corresponding HAM-D17 question), or symptom worsening (HAM-D17 increase of ≥1). These measures were evaluated based on medication changes [add only, drop only, switch (add and drop), any, and none] and study arm, as well as baseline medication GDI.
ResultsMost patients had a medication change between baseline and week 8 (938/1,166; 80.5%), including 269 (23.1%) who added only, 80 (6.9%) who dropped only, and 589 (50.5%) who switched medications. In the full cohort, changing medications resulted in an increased relative risk (RR) of experiencing AEs at both week 4 and 8 [RR 2.00 (95% CI 1.41–2.83) and RR 2.25 (95% CI 1.39–3.65), respectively]. This was true regardless of arm, with no significant difference observed between guided-care and TAU, though the RRs for guided-care were lower than for TAU. Medication change was not associated with increased suicidal ideation or symptom worsening, regardless of study arm or type of medication change. Special attention was focused on patients who entered the study taking medications identified by pharmacogenomic testing as likely having significant GDI; those who were only taking medications subject to no or moderate GDI at week 8 were significantly less likely to experience AEs than those who were still taking at least one medication subject to significant GDI (RR 0.39, 95% CI 0.15–0.99, p=0.048). No other significant differences in risk were observed at week 8.
ConclusionThese data indicate that patient safety in the combinatorial pharmacogenomic test-guided care arm was no worse than TAU in the GUIDED trial. Moreover, combinatorial pharmacogenomic-guided medication selection may reduce some safety concerns. Collectively, these data demonstrate that combinatorial pharmacogenomic testing can be adopted safely into clinical practice without risking symptom degradation among patients.
FundingMyriad Neuroscience/Assurex Health
150 HAM-D6 Outcomes in a Randomized, Controlled Trial Evaluating the Utility of Combinatorial Pharmacogenomics in Depression
- Boadie W. Dunlop, Sagar V. Parikh, Maitrey Patel, Anthony J. Rothschild, Michael E. Thase, Charles DeBattista, Charles R. Conway, Brent P. Forester, Richard C. Shelton, Matthew Macaluso, James Li, Krystal Brown, Lisa Brown, Michael R. Jablonski, John F. Greden
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- Journal:
- CNS Spectrums / Volume 25 / Issue 2 / April 2020
- Published online by Cambridge University Press:
- 24 April 2020, pp. 295-296
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Background:
The Genomics Used to Improve DEpresssion Decisions (GUIDED) trial assessed outcomes associated with combinatorial pharmacogenomic (PGx) testing in patients with major depressive disorder (MDD). Analyses used the 17-item Hamilton Depression (HAM-D17) rating scale; however, studies demonstrate that the abbreviated, core depression symptom-focused, HAM-D6 rating scale may have greater sensitivity toward detecting differences between treatment and placebo. However, the sensitivity of HAM-D6 has not been tested for two active treatment arms. Here, we evaluated the sensitivity of the HAM-D6 scale, relative to the HAM-D17 scale, when assessing outcomes for actively treated patients in the GUIDED trial.
Methods:Outpatients (N=1,298) diagnosed with MDD and an inadequate treatment response to >1 psychotropic medication were randomized into treatment as usual (TAU) or combinatorial PGx-guided (guided-care) arms. Combinatorial PGx testing was performed on all patients, though test reports were only available to the guided-care arm. All patients and raters were blinded to study arm until after week 8. Medications on the combinatorial PGx test report were categorized based on the level of predicted gene-drug interactions: ‘use as directed’, ‘moderate gene-drug interactions’, or ‘significant gene-drug interactions.’ Patient outcomes were assessed by arm at week 8 using HAM-D6 and HAM-D17 rating scales, including symptom improvement (percent change in scale), response (≥50% decrease in scale), and remission (HAM-D6 ≤4 and HAM-D17 ≤7).
Results:At week 8, the guided-care arm demonstrated statistically significant symptom improvement over TAU using HAM-D6 scale (Δ=4.4%, p=0.023), but not using the HAM-D17 scale (Δ=3.2%, p=0.069). The response rate increased significantly for guided-care compared with TAU using both HAM-D6 (Δ=7.0%, p=0.004) and HAM-D17 (Δ=6.3%, p=0.007). Remission rates were also significantly greater for guided-care versus TAU using both scales (HAM-D6 Δ=4.6%, p=0.031; HAM-D17 Δ=5.5%, p=0.005). Patients taking medication(s) predicted to have gene-drug interactions at baseline showed further increased benefit over TAU at week 8 using HAM-D6 for symptom improvement (Δ=7.3%, p=0.004) response (Δ=10.0%, p=0.001) and remission (Δ=7.9%, p=0.005). Comparatively, the magnitude of the differences in outcomes between arms at week 8 was lower using HAM-D17 (symptom improvement Δ=5.0%, p=0.029; response Δ=8.0%, p=0.008; remission Δ=7.5%, p=0.003).
Conclusions:Combinatorial PGx-guided care achieved significantly better patient outcomes compared with TAU when assessed using the HAM-D6 scale. These findings suggest that the HAM-D6 scale is better suited than is the HAM-D17 for evaluating change in randomized, controlled trials comparing active treatment arms.
Funding Acknowledgements:Assurex Health, Inc.
49 Combinatorial Pharmacogenomics to Guide Treatment Selection for Major Depressive Disorder: A Large, Blinded, Randomized Controlled Trial
- John F. Greden, Anthony J. Rosthschild, Michael Thase, Boadie W. Dunlop, DMH Charles DeBattista, Charles R. Conway, Brent P. Forester, Francis M. Mondimore, Richard C. Shelton, James Li, Alexa Gilbert, Lindsey Burns, Michael Jablonski, Bryan Dechairo, Sagar Parikh
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- Journal:
- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, pp. 202-203
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Background
Major depressive disorder (MDD) is a leading cause of disease burden worldwide, with lifetime prevalence in the United States of 17%. Here we present the results of the first prospective, large-scale, patient- and rater-blind, randomized controlled trial evaluating the clinical importance of achieving congruence between combinatorial pharmacogenomic (PGx) testing and medication selection for MDD.
Methods1,167 outpatients diagnosed with MDD and an inadequate response to ≥1 psychotropic medications were enrolled and randomized 1:1 to a Treatment as Usual (TAU) arm or PGx-guided care arm. Combinatorial PGx testing categorized medications in three groups based on the level of gene-drug interactions: use as directed, use with caution, or use with increased caution and more frequent monitoring. Patient assessments were performed at weeks 0 (baseline), 4, 8, 12 and 24. Patients, site raters, and central raters were blinded in both arms until after week 8. In the guided-care arm, physicians had access to the combinatorial PGx test result to guide medication selection. Primary outcomes utilized the Hamilton Depression Rating Scale (HAM-D17) and included symptom improvement (percent change in HAM-D17 from baseline), response (50% decrease in HAM-D17 from baseline), and remission (HAM-D17<7) at the fully blinded week 8 time point. The durability of patient outcomes was assessed at week 24. Medications were considered congruent with PGx test results if they were in the ‘use as directed’ or ‘use with caution’ report categories while medications in the ‘use with increased caution and more frequent monitoring’ were considered incongruent. Patients who started on incongruent medications were analyzed separately according to whether they changed to congruent medications by week8.
ResultsAt week 8, symptom improvement for individuals in the guided-care arm was not significantly different than TAU (27.2% versus 24.4%, p=0.11). However, individuals in the guided-care arm were more likely than those in TAU to achieve remission (15% versus 10%; p<0.01) and response (26% versus 20%; p=0.01). Remission rates, response rates, and symptom reductions continued to improve in the guided-treatment arm until the 24week time point. Congruent prescribing increased to 91% in the guided-care arm by week 8. Among patients who were taking one or more incongruent medication at baseline, those who changed to congruent medications by week 8 demonstrated significantly greater symptom improvement (p<0.01), response (p=0.04), and remission rates (p<0.01) compared to those who persisted on incongruent medications.
ConclusionsCombinatorial PGx testing improves short- and long-term response and remission rates for MDD compared to standard of care. In addition, prescribing congruency with PGx-guided medication recommendations is important for achieving symptom improvement, response, and remission for MDD patients.
Funding Acknowledgements: This study was supported by Assurex Health, Inc.
The Synthesis and Characterization of Nano-hydroxyapatite (nHAP)-g-poly(lactide-co-glycolide)-g-collagen Polymer for Tissue Engineering Scaffolds
- Didarul Bhuiyan, Michael J. Jablonsky, John Middleton, Rina Tannenbaum
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- Journal:
- MRS Online Proceedings Library Archive / Volume 1569 / 2013
- Published online by Cambridge University Press:
- 25 June 2013, pp. 27-32
- Print publication:
- 2013
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Bone grafts, commonly performed to augment bone regeneration from autologous or alleogeneic sources, carry an enormous cost, estimated at upwards of 21 billion dollars per year. Hydroxyapatite (HAP) bio-ceramic has been widely used in clinic as a bone graft substitute material due to its biocompatibility and the similarity of its structure and composition to bone mineral. However, its applications are limited due to its lack of strength and toughness. Researchers have attempted to overcome these issues by combining HAP bio-ceramics into resorbable polymers to improve their mechanical properties. However, poor bonding between the HAP and the polymer caused separation at the polymer-filler interface. To overcome this, short chains of polymers were grafted directly from the hydroxyl groups on the surface of nanocrystalline HAP. Collagens, being the most abundant proteins in the body, and having suitable properties such as biodegradability, bioabsorbability with low antigenicity, high affinity to water, and the ability to interact with cells through integrin recognition, makes them a very promising candidate for the modification of the polymer surface. In this study, a novel method of synthesizing nano-hydroxyapatite (nHAP)-g-poly(lactide-co-glycolide)-g-collagen polymer was introduced. The synthesis process was carried out in several steps. First, poly (lactide-co-glycolide) (PLGA) polymer was directly grafted onto the hydroxyl group of the surface of n-HAP particles by ring-opening polymerization, and subsequently coupled with succinic anhydride. In order to activate the co-polymer for collagen attachment, the carboxyl end group obtained from succinic anhydride was reacted with N-hydroxysuccinimide (NHS) in the presence of dicyclohexylcarbodiimide (DCC) as the cross-linking agent. Finally, the activated co-polymer was attached to calf skin collagen type I, in hydrochloric acid/phosphate buffer solution and the precipitated co-polymer with attached collagen was isolated. The synthesis was monitored by 1H NMR and FTIR spectroscopies and the products after each step were characterized by thermal analysis (TGA and DSC). These composite materials will be tested as potential scaffolds for tissue engineering applications.