Abstract
Introduction: All atypical antipsychotics are associated with some degree of weight gain. We applied a novel statistical approach to identify moderators of aripiprazole-induced fat gain using clinical and genetic data from a randomized clinical trial (RCT) of treatment resistant depression in older adults. Materials and methods: Adults aged ≥60 years with non-response to a prospective trial of venlafaxine were randomized to 12 weeks of aripiprazole augmentation (n = 91) or placebo (n = 90). Dual energy x-ray absorptiometry (DEXA) measured adiposity at baseline and 12 weeks. Independent moderators of total body fat gain were used to generate two combined multiple moderators, one including clinical data alone and one including both clinical and genetic data to characterize individuals who gained fat during aripiprazole augmentation. Results: The value of the combined genetic + clinical multiple moderator (M cg ) was 0.57 [95% CI 0.46, 0.68] (effect size: 0.57), compared to the combined clinical moderator (M c ) value of 0.49 [0.34, 0.63] (effect size: 0.49). Individuals who gained adiposity in this study were more likely to be female and younger in age, have lower weight, fasting glucose and lipids at baseline and positive for the HTR2C polymorphism. Discussion: These results demonstrate a combined multiple moderator approach, including both clinical and genetic moderators, can be applied to existing clinical trial data to understand adverse treatment effects. This method allowed for more specific characterization of individuals at risk for the outcome of interest. Further work is needed to identify additional genetic moderators and to validate the approach.
Original language | English |
---|---|
Pages (from-to) | 67-74 |
Number of pages | 8 |
Journal | Journal of Psychiatric Research |
Volume | 114 |
DOIs | |
State | Published - Jul 2019 |
Keywords
- Adiposity
- Aripiprazole
- Older adults
- Treatment resistant depression
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In: Journal of Psychiatric Research, Vol. 114, 07.2019, p. 67-74.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Getting to precision psychopharmacology
T2 - Combining clinical and genetic information to predict fat gain from aripiprazole
AU - Oughli, H.
AU - Lenze, E. J.
AU - Locke, A. E.
AU - Yingling, M. D.
AU - Zhong, Y.
AU - Miller, J. P.
AU - Reynolds, C. F.
AU - Mulsant, B. H.
AU - Newcomer, J. W.
AU - Peterson, T. R.
AU - Müller, D. J.
AU - Nicol, G. E.
N1 - Funding Information: JPM has received research funding from the National Institutes of Health , The Food and Drug Administration and the Patient-Centered Outcomes Research Institute . EJL receives or has received support from NIH, FDA, Takeda, Lundbeck, Janssen, Aptinyx, Alkermes, the Taylor Family Institute for Innovative Psychiatric Research, the McKnight Brain Research Foundation, the Center for Brain Research in Mood Disorders, the Barnes/Jewish Foundation, and PCORI. CFR has received pharmaceutical support for NIH-sponsored research studies from Bristol-Myers Squibb, Eli Lilly, Forest, and Pfizer; grants from NIMH, the National Heart, Lung, and Blood Institute , the Center for Medicare and Medicaid Services (CMS) , PCORI, the Commonwealth of Pennsylvania, the John A. Hartford Foundation, the National Palliative Care Research Center, the Clinical and Translational Science Institute, and the American Foundation for Suicide Prevention; he has also served on the American Association for Geriatric Psychiatry editorial review board. CFR also receives an honorarium for serving as Editor-in-Chief for the American Journal of Geriatric Psychiatry, and he has received a speaking honorarium from MedScape/WebMD; is the co-inventor of psychometric analysis of the Pittsburgh Sleep Quality Index (licensed intellectual property PRO10050447 ). BHM receives research support from Brain Canada, the Canadian Institutes of Health Research, NIH, the Centre for Addiction and Mental Health Foundation; he has received medications for NIH-funded clinical trials from Bristol-Myers Squibb, Eli Lilly, Pfizer, and Pfizer/Wyeth and software used in studies from Capital Solution Design and HAPPYneuron; he owns stock in General Electric. JWN has received research funding from the NIH and Otsuka. He has served as a consultant for Auris, Sunovion, Indivior, Otsuka, Alkermes, and as a consultant to litigation, and served on a Data Safety Monitoring Board for Amgen. He has received honoraria for CME from the American Diabetes Association and the American Society for Clinical Psychopharmacology. DJM has received research support from the Canadian Institutes of Health Research , NIH , the Centre for Addiction and Mental Health Foundation (CAMH, Joanne Murphy Professorship), the Canadian Biomarker Integration Network in Depression, and the Ontario Brain Institute. GEN has received research funding from NIMH, Otsuka America, Inc., Alkermes, The Sidney R. Baer, Jr. Foundation, the Center for Brain Research in Mood Disorders (CBRiMD) and the Center for Diabetes Translational Research (CDTR) at Washington University, and serves as a consultant for Alkermes, Sunovion and Supernus Pharmaceuticals, Inc. HO, YZ. AEL and TRP have no disclosures. Funding Information: The parent study is registered with ClinicalTrials.gov , number NCT00892047 , and was funded by the National Institute of Mental Health R01 MH083648 to Washington University, and R01 MH083643 to University of Toronto , with additional funding provided by the University of Pittsburgh Medical Center Endowment in Geriatric Psychiatry, the Taylor Family Institute for Innovative Psychiatric Research (at Washington University), the Washington University Institute of Clinical and Translational Sciences grant ( UL1 TR000448 ) from the National Center for Advancing Translational Sciences (NCATS), and the Campbell Family Mental Health Research Institute at the Centre for Addiction and Mental Health (CAMH), Toronto. Bristol-Myers Squibb contributed aripiprazole and placebo tablets, and Pfizer contributed venlafaxine extended-release capsules for the parent study. Funding sources for this study had no role in the design or conduct of the research, including in the collection, management, analysis, and interpretation of the data, nor in the preparation, review, or approval of the manuscript, or in the decision to submit the manuscript for publication. Research reported in this publication was supported by the National Institute of Mental Health , award number R25 MH112473 . Funding Information: The parent study is registered with ClinicalTrials.gov, number NCT00892047, and was funded by the National Institute of Mental Health R01 MH083648 to Washington University, and R01 MH083643 to University of Toronto, with additional funding provided by the University of Pittsburgh Medical Center Endowment in Geriatric Psychiatry, the Taylor Family Institute for Innovative Psychiatric Research (at Washington University), the Washington University Institute of Clinical and Translational Sciences grant (UL1 TR000448) from the National Center for Advancing Translational Sciences (NCATS), and the Campbell Family Mental Health Research Institute at the Centre for Addiction and Mental Health (CAMH), Toronto. Bristol-Myers Squibb contributed aripiprazole and placebo tablets, and Pfizer contributed venlafaxine extended-release capsules for the parent study. Funding sources for this study had no role in the design or conduct of the research, including in the collection, management, analysis, and interpretation of the data, nor in the preparation, review, or approval of the manuscript, or in the decision to submit the manuscript for publication. Research reported in this publication was supported by the National Institute of Mental Health, award number R25 MH112473.JPM has received research funding from the National Institutes of Health, The Food and Drug Administration and the Patient-Centered Outcomes Research Institute. EJL receives or has received support from NIH, FDA, Takeda, Lundbeck, Janssen, Aptinyx, Alkermes, the Taylor Family Institute for Innovative Psychiatric Research, the McKnight Brain Research Foundation, the Center for Brain Research in Mood Disorders, the Barnes/Jewish Foundation, and PCORI. CFR has received pharmaceutical support for NIH-sponsored research studies from Bristol-Myers Squibb, Eli Lilly, Forest, and Pfizer; grants from NIMH, the National Heart, Lung, and Blood Institute, the Center for Medicare and Medicaid Services (CMS), PCORI, the Commonwealth of Pennsylvania, the John A. Hartford Foundation, the National Palliative Care Research Center, the Clinical and Translational Science Institute, and the American Foundation for Suicide Prevention; he has also served on the American Association for Geriatric Psychiatry editorial review board. CFR also receives an honorarium for serving as Editor-in-Chief for the American Journal of Geriatric Psychiatry, and he has received a speaking honorarium from MedScape/WebMD; is the co-inventor of psychometric analysis of the Pittsburgh Sleep Quality Index (licensed intellectual property PRO10050447). BHM receives research support from Brain Canada, the Canadian Institutes of Health Research, NIH, the Centre for Addiction and Mental Health Foundation; he has received medications for NIH-funded clinical trials from Bristol-Myers Squibb, Eli Lilly, Pfizer, and Pfizer/Wyeth and software used in studies from Capital Solution Design and HAPPYneuron; he owns stock in General Electric. JWN has received research funding from the NIH and Otsuka. He has served as a consultant for Auris, Sunovion, Indivior, Otsuka, Alkermes, and as a consultant to litigation, and served on a Data Safety Monitoring Board for Amgen. He has received honoraria for CME from the American Diabetes Association and the American Society for Clinical Psychopharmacology. DJM has received research support from the Canadian Institutes of Health Research, NIH, the Centre for Addiction and Mental Health Foundation (CAMH, Joanne Murphy Professorship), the Canadian Biomarker Integration Network in Depression, and the Ontario Brain Institute. GEN has received research funding from NIMH, Otsuka America, Inc., Alkermes, The Sidney R. Baer, Jr. Foundation, the Center for Brain Research in Mood Disorders (CBRiMD) and the Center for Diabetes Translational Research (CDTR) at Washington University, and serves as a consultant for Alkermes, Sunovion and Supernus Pharmaceuticals, Inc. HO, YZ. AEL and TRP have no disclosures. The authors thank David Dixon, PhD for his assistance with data management and analytic support for this study, and Amanda Ricchio, BA for administrative assistance in manuscript preparation and submission. Publisher Copyright: © 2019
PY - 2019/7
Y1 - 2019/7
N2 - Introduction: All atypical antipsychotics are associated with some degree of weight gain. We applied a novel statistical approach to identify moderators of aripiprazole-induced fat gain using clinical and genetic data from a randomized clinical trial (RCT) of treatment resistant depression in older adults. Materials and methods: Adults aged ≥60 years with non-response to a prospective trial of venlafaxine were randomized to 12 weeks of aripiprazole augmentation (n = 91) or placebo (n = 90). Dual energy x-ray absorptiometry (DEXA) measured adiposity at baseline and 12 weeks. Independent moderators of total body fat gain were used to generate two combined multiple moderators, one including clinical data alone and one including both clinical and genetic data to characterize individuals who gained fat during aripiprazole augmentation. Results: The value of the combined genetic + clinical multiple moderator (M cg ) was 0.57 [95% CI 0.46, 0.68] (effect size: 0.57), compared to the combined clinical moderator (M c ) value of 0.49 [0.34, 0.63] (effect size: 0.49). Individuals who gained adiposity in this study were more likely to be female and younger in age, have lower weight, fasting glucose and lipids at baseline and positive for the HTR2C polymorphism. Discussion: These results demonstrate a combined multiple moderator approach, including both clinical and genetic moderators, can be applied to existing clinical trial data to understand adverse treatment effects. This method allowed for more specific characterization of individuals at risk for the outcome of interest. Further work is needed to identify additional genetic moderators and to validate the approach.
AB - Introduction: All atypical antipsychotics are associated with some degree of weight gain. We applied a novel statistical approach to identify moderators of aripiprazole-induced fat gain using clinical and genetic data from a randomized clinical trial (RCT) of treatment resistant depression in older adults. Materials and methods: Adults aged ≥60 years with non-response to a prospective trial of venlafaxine were randomized to 12 weeks of aripiprazole augmentation (n = 91) or placebo (n = 90). Dual energy x-ray absorptiometry (DEXA) measured adiposity at baseline and 12 weeks. Independent moderators of total body fat gain were used to generate two combined multiple moderators, one including clinical data alone and one including both clinical and genetic data to characterize individuals who gained fat during aripiprazole augmentation. Results: The value of the combined genetic + clinical multiple moderator (M cg ) was 0.57 [95% CI 0.46, 0.68] (effect size: 0.57), compared to the combined clinical moderator (M c ) value of 0.49 [0.34, 0.63] (effect size: 0.49). Individuals who gained adiposity in this study were more likely to be female and younger in age, have lower weight, fasting glucose and lipids at baseline and positive for the HTR2C polymorphism. Discussion: These results demonstrate a combined multiple moderator approach, including both clinical and genetic moderators, can be applied to existing clinical trial data to understand adverse treatment effects. This method allowed for more specific characterization of individuals at risk for the outcome of interest. Further work is needed to identify additional genetic moderators and to validate the approach.
KW - Adiposity
KW - Aripiprazole
KW - Older adults
KW - Treatment resistant depression
UR - http://www.scopus.com/inward/record.url?scp=85065105175&partnerID=8YFLogxK
U2 - 10.1016/j.jpsychires.2019.04.017
DO - 10.1016/j.jpsychires.2019.04.017
M3 - Article
C2 - 31039482
AN - SCOPUS:85065105175
SN - 0022-3956
VL - 114
SP - 67
EP - 74
JO - Journal of Psychiatric Research
JF - Journal of Psychiatric Research
ER -