Comparing sensitivity to change using the 6-item versus the 17-item Hamilton depression rating scale in the GUIDED randomized controlled trial

Boadie W Dunlop, Sagar V Parikh, Anthony J Rothschild, Michael E Thase, Charles DeBattista, Charles R Conway, Brent P Forester, Francis M Mondimore, Richard C Shelton, Matthew Macaluso, Jennifer Logan, Paul Traxler, James Li, Holly Johnson, John F Greden, Boadie W Dunlop, Sagar V Parikh, Anthony J Rothschild, Michael E Thase, Charles DeBattista, Charles R Conway, Brent P Forester, Francis M Mondimore, Richard C Shelton, Matthew Macaluso, Jennifer Logan, Paul Traxler, James Li, Holly Johnson, John F Greden

Abstract

Background: Previous research suggests that the 17-item Hamilton Depression Rating Scale (HAM-D17) is less sensitive in detecting differences between active treatment and placebo for major depressive disorder (MDD) than is the HAM-D6 scale, which focuses on six core depression symptoms. Whether HAM-D6 shows greater sensitivity when comparing two active MDD treatment arms is unknown.

Methods: This post hoc analysis used data from the intent-to-treat (ITT) cohort (N = 1541) of the Genomics Used to Improve DEpression Decisions (GUIDED) trial, a rater- and patient-blinded randomized controlled trial. GUIDED compared combinatorial pharmacogenomics-guided care with treatment as usual (TAU) in patients with MDD. Percent of symptom improvement, response rate and remission rate from baseline to week 8 were evaluated using both scales. Analyses were performed for the full cohort and for the subset of patients who at baseline were taking medications predicted by the test to have moderate or significant gene-drug interactions. A Mokken scale analysis was conducted to compare the homogeneity of HAM-D17 with that of HAM-D6.

Results: At week 8, the guided-care arm demonstrated statistically significant benefit over TAU when the HAM-D6 (∆ = 4.4%, p = 0.023) was used as the continuous measure of symptom improvement, but not when using the HAM-D17 (∆ = 3.2%, p = 0.069). Response rates increased significantly for guided-care compared with TAU when evaluated using both HAM-D6 (∆ = 7.0%, p = 0.004) and HAM-D17 (∆ = 6.3%, p = 0.007). Remission rates also were significantly greater for guided-care versus TAU using both measures (HAM-D6 ∆ = 4.6%, p = 0.031; HAM-D17 ∆ = 5.5%, p = 0.005). Patients in the guided-care arm who at baseline were taking medications predicted to have gene-drug interactions showed further increased benefit over TAU at week 8 for symptom improvement (∆ = 7.3%, p = 0.004) response (∆ = 10.0%, p = 0.001) and remission (∆ = 7.9%, p = 0.005) using HAM-D6. All outcomes showed continued improvement through week 24. Mokken scale analysis demonstrated the homogeneity and unidimensionality of HAM-D6, but not of HAM-D17, across treatment arms.

Conclusions: The HAM-D6 scale identified a statistically significant difference in symptom improvement between combinatorial pharmacogenomics-guided care and TAU, whereas the HAM-D17 did not. The demonstrated utility of pharmacogenomics-guided treatment over TAU as detected by the HAM-D6 highlights its value for future biomarker-guided trials comparing active treatment arms.

Trial registration: Clinicaltrials.gov: NCT02109939. Registered 10 April 2014.

Keywords: Antidepressant; Assessment; Biomarker; Clinical trial; Clinical utility; Comparative effectiveness; Decision-making; Depression; Genetics; Pharmacogenomics.

Conflict of interest statement

BWD has received research support from Acadia, Assurex Health, Axsome, Janssen, and Takeda. Dr. Dunlop has served has a consultant for Assurex Health and Aptinyx.

SVP has received research funding from the Ontario Brain Institute, the Canadian Institutes of Health Research, the James and Ethel Flinn Foundation. Dr. Parikh has served as a consultant for Assurex Health. Dr. Parikh has received honoraria from Mensante Corporation, Takeda, and the Canadian Network for Mood and Anxiety Treatments (CANMAT). Dr. Parikh has equity in Mensante.

AJR has received research support from Allergan, AssureRx, Janssen, the National Institute of Mental Health, Takeda, Eli-Lilly, and Pfizer; Consultant: Alkermes, GlaxoSmithKline, Myriad Genetics, and Sage Therapeutics. Dr. Rothschild receives royalties for the Rothschild Scale for Antidepressant Tachyphylaxis (RSAT)®; Clinical Manual for the Diagnosis and Treatment of Psychotic Depression, American Psychiatric Press, 2009; The Evidence-Based Guide to Antipsychotic Medications, American Psychiatric Press, 2010; The Evidence-Based Guide to Antidepressant Medications, American Psychiatric Press, 2012, and UpToDate®.

MET has received research support from Assurex Health, Acadia, Agency for Healthcare Research and Quality, Alkermes, Avanir, Forest, Intracellular, Janssen, National Institute of Mental Health, Otsuka, Patient-Centered Outcomes Research Institute, Takeda. Dr. Thase has served as a consultant for Acadia, Akilii, Alkermes, Allergan (Forest, Naurex), AstraZeneca, Cerecor, Eli Lilly, Fabre-Kramer, Gerson Lehrman Group, Guidepoint Global, Johnson & Johnson (Janssen, Ortho-McNeil), Lundbeck, MedAvante, Merck, Moksha8, Nestlé (PamLab), Novartis, Otsuka, Pfizer, Shire, Sunovion, Takeda. Dr. Thase receives royalties from American Psychiatric Press, Guilford Publications, Herald House, W.W. Norton & Company, Inc.

CD has received research support from Assurex Health and Brain Resources.

CRC has received research support from LivaNova and Bristol-Myers Squibb, the Stanley Medical Research Institute, the National Institute of Mental Health, NeoSync Inc., The Taylor Family Institute for Innovative Psychiatric Research, The August Busch IV Foundation, and the Barnes-Jewish Hospital Foundation. Dr. Conway has received speaking fees from Bristol-Myers Squibb and Otsuka Pharmaceuticals. Dr. Conway has served as a research design consultant for LivaNova. Dr. Conway is a part time employee of the John Cochran Veterans Administration Hospital in St. Louis.

BPF has received research funding from the National Institutes of Health, Rogers Family Foundation, Spier Family Foundation, Assurex Health, Eli Lilly, and Biogen. Dr. Forester has served as a consultant for Biogen.

FMM has received research funding from Assurex Health.

RCS has received research funding from Acadia Pharmaceuticals, Alkermes, Inc., Allergan, Assurex Health, Avanir Pharmaceuticals, Cerecor, Inc., Genomind, Intracellular Therapies, Janssen Pharmaceutica, Otsuka Pharmaceuticals, and Takeda Pharmaceuticals. Dr. Shelton has served as a consultant for Acadia Pharmaceuticals, Allergan Inc., Cerecor, Inc., Janssen Pharmaceutica, Lundbeck A/S, and Takeda Pharmaceuticals.

MM has conducted clinical trials research as principal investigator for Acadia, Alkermes, Allergan, Assurex Health, Eisai, Lundbeck, Janssen, Naurex/Aptinyx, and Neurim; all study contracts and payments were made to Kansas University Medical Cancer Research Institute.

JL is employed by Myriad Genetics Inc.

JLi is employed by Assurex Health, Inc./Myriad Neuroscience.

HJ is employed by Assurex Health, Inc./Myriad Neuroscience.

JFG has served as a scientific advisor for Janssen Pharmaceutical, Naurex (Allergan) Pharmaceutical, Cerecor Pharmaceutical, NeuralStem, Sage Therapeutics and Genomind. Dr. Greden has received reimbursement as a speaker for Assurex Health in 2014. All work performed as an unpaid consultant to Assurex Health and Myriad Genetics.

Figures

Fig. 1
Fig. 1
Outcomes at week 8 for the full patient cohort. The pharmacogenomics guided-care arm (N = 621) was compared with treatment as usual (TAU) (N = 677). Symptom improvement, response and remission outcomes were evaluated using the HAM-D6 and HAM-D17 depression rating scales
Fig. 2
Fig. 2
Outcomes at week 8 for patients taking medications with gene-drug interactions. The pharmacogenomics guided-care arm (n = 357) was compared with treatment as usual (TAU) (n = 429). Symptom improvement, response and remission outcomes were evaluated using the HAM-D6 and HAM-D17 depression rating scales
Fig. 3
Fig. 3
Durability of improvements in patient outcomes in the pharmacogenomics guided-care study arm. Symptom improvement, response and remission outcomes were evaluated at week 4 (N = 685), week 8, (N = 621), week 12 (N = 585), and week 24 (N = 522) using the HAM-D6 depression rating scale

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