Precision clinical trials: a framework for getting to precision medicine for neurobehavioural disorders

Precision clinical trials: a framework for getting to precision medicine for neurobehavioural disorders

J Psychiatry Neurosci 2021;46(1):E97-E110 | PDF

Eric J. Lenze, MD; Ginger E. Nicol, MD; Dennis L. Barbour, MD, PhD; Thomas Kannampallil, PhD; Alex W.K. Wong, PhD; Jay Piccirillo, MD; Andrew T. Drysdale, MD, PhD; Chad M. Sylvester, MD, PhD; Rita Haddad, MD; J. Philip Miller, AB; Carissa A. Low, PhD; Shannon N. Lenze, PhD; Kenneth E. Freedland, PhD; Thomas L. Rodebaugh, PhD

The goal of precision medicine (individually tailored treatments) is not being achieved for neurobehavioural conditions such as psychiatric disorders. Traditional randomized clinical trial methods are insufficient for advancing precision medicine because of the dynamic complexity of these conditions. We present a pragmatic solution: the precision clinical trial framework, encompassing methods for individually tailored treatments. This framework includes the following: (1) treatment-targeted enrichment, which involves measuring patients’ response after a brief bout of an intervention, and then randomizing patients to a full course of treatment, using the acute response to predict longterm outcomes; (2) adaptive treatments, which involve adjusting treatment parameters during the trial to individually optimize the treatment; and (3) precise measurement, which involves measuring predictor and outcome variables with high accuracy and reliability using techniques such as ecological momentary assessment. This review summarizes precision clinical trials and provides a research agenda, including new biomarkers such as precision neuroimaging, transcranial magnetic stimulation–electroencephalogram digital phenotyping and advances in statistical and machine-learning models. Validation of these approaches — and then widespread incorporation of the precision clinical trial framework — could help achieve the vision of precision medicine for neurobehavioural conditions.


Submitted Feb. 27, 2020; Revised Jul. 8, 2020; Accepted Jul. 10, 2020; Early-released Nov. 18, 2020

Acknowledgements: Research reported in this publication was supported by the Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. Additional funding is from the Taylor Family Institute for Innovative Psychiatric Research and Center for Brain Research in Mood Disorders (at Washington University) to Dr. E. Lenze. The funding source(s) had no role in the preparation, review, or approval of the manuscript.

Affiliations: From the Washington University School of Medicine, St. Louis, Missouri (Lenze, Nicol, Kannampallil Wong, Piccirillo, Drysdale, Sylvester, Haddad, Miller, Lenze, Freedland); the Washington University McKelvey School of Engineering, St. Louis, MO (Barbour); the University of Pittsburgh, Pittsburgh, PA (Low); and the Washington University School of Arts & Sciences, St. Louis, MO (Rodebaugh).

Competing interests: E. Lenze has received research support from NIH, the Patient Centered Outcomes Research Institute, the McKnight Brain Research Foundation, the Taylor Family Institute for Innovative Psychiatric Research and the Center for Brain Research in Mood Disorders (Department of Psychiatry, Washington University), the Barnes Jewish Foundation, MagStim, Aptinyx, Takeda, Acadia, and Lundbeck; he has served as a consultant for Janssen and Jazz Pharmaceuticals. G. Nicol has received research funding from NIMH, Otsuka America, Inc., Alkermes, the Center for Brain Research in Mood Disorders, the Center for Diabetes Translational Research, the Institute for Public Health and the McDonnell Center for Neuroscience at Washington University, and the Barnes Jewish Hospital Foundation. She also serves as a consultant for Sunovion, Alkermes and Supernus Pharmaceuticals, Inc. D. Barbour has received research support from the National Institute of Deafness and other Communication Disorders, the National Center for Advancing Translational Sciences, the National Science Foundation, the McDonnell Center for Systems Neuroscience, the Children’s Discovery Institute, the Center for Integration of Medicine and Innovative Technology, the Hope Center for Neurological Disorders, the Wallace H. Coulter Foundation, the American Hearing Research Foundation and the Skandalaris Center for Interdisciplinary Innovation and Entrepreneurship. Dr. Barbour has equity ownership in Bonauria, LLC. T. Kannampallil has research support from the Agency for Healthcare Research and Quality, the National Institute for Nursing Research and Pfizer. A. Wong has received research support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (National Center for Medical Rehabilitation Research), the National Institute on Disability, Independent Living, and Rehabilitation, and the Craig H. Neilsen Foundation. J. Piccirillo has received research funding from the National Institute on Deafness and Other Communication Disorders, Barnes Jewish Hospital Foundation and Bind On-Demand Health Care. C. Sylvester has received research support from NIMH, the McDonnell Foundation, the Brain and Behavior Research Foundation, the Taylor Family Foundation, and the Parker Fund. J.P. Miller has received research support from the Patient Outcomes Research Institute and NIH. S. Lenze has received research support from NIMH, the Center for Brain Research in Mood Disorders, the Barnes Jewish Hospital Foundation, the Center for Dissemination and Implementation (Washington University Institute for Public Health), and the McDonnell Center for Neuroscience. K. Freedland has research support from NIH and receives an editorial honorarium from the Society for Health Psychology (Division 38 of the American Psychological Association). T. Rodebaugh has received research support from NIMH, the National Institute on Deafness and other Communication Disorders, the Brain Behavior Research Foundation, and the McDonnell Center for Systems Neuroscience.

Contributors: G. Nicol, D. Barbour, A. Wong, J. Piccirillo, C. Sylvester, R. Haddad, J. Miller, C. Low, S. Lenze, K Freedland and T. Rodebaugh designed the study. E. Lenze acquired the data, which G. Nicol, T. Kannampallil, A. Drysdale, C. Sylvester and S. Lenze analyzed. D. Barbour, T. Kannampallil, A. Wong, A. Drysdale, C. Sylvester, R. Haddad, J. Miller, C. Low, S. Lenze, K. Freedland and T. Rodebaugh wrote the article, which E. Lenze, G. Nicol, D. Barbour, T. Kannampallil, A. Wong, J. Piccirillo, R. Haddad, C. Low and T. Rodebaugh reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.

Content licence: This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is non-commercial (i.e. research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/

DOI: 10.1503/jpn.200042

Correspondence to: E. Lenze, Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid, Box 8134, St. Louis, MO 63110, USA; lenzee@wustl.edu