Changes in Dosing and Dose Timing of D-Cycloserine Explain Its Apparent Declining Efficacy for Augmenting Exposure Therapy for Anxiety-related Disorders: An Individual Participant-data Meta-analysis

David Rosenfield, Jasper A.J. Smits, Stefan G. Hofmann, David Mataix-Cols, Lorena Fernández de la Cruz, Erik Andersson, Christian Rück, Benedetta Monzani, Ana Pérez-Vigil, Paolo Frumento, Michael Davis, Rianne A. de Kleine, Jo Ann Difede, Boadie W. Dunlop, Lara J. Farrell, Daniel Geller, Maryrose Gerardi, Adam J. Guastella, Gert Jan Hendriks, Matt G. KushnerFrancis S. Lee, Eric J. Lenze, Cheri A. Levinson, Harry McConnell, Jens Plag, Mark H. Pollack, Kerry J. Ressler, Thomas L. Rodebaugh, Barbara O. Rothbaum, Eric A. Storch, Andreas Ströhle, Candyce D. Tart, David F. Tolin, Agnes van Minnen, Allison M. Waters, Carl F. Weems, Sabine Wilhelm, Katarzyna Wyka, Margaret Altemus, Page Anderson, Judith Cukor, Claudia Finck, Gary R. Geffken, Fabian Golfels, Wayne K. Goodman, Cassidy A. Gutner, Isobel Heyman, Tanja Jovanovic, Adam B. Lewin, Joseph P. McNamara, Tanya K. Murphy, Seth Norrholm, Paul Thuras, Cynthia Turner, Michael W. Otto

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

The apparent efficacy of d-cycloserine (DCS) for enhancing exposure treatment for anxiety disorders appears to have declined over the past 14 years. We examined whether variations in how DCS has been administered can account for this “declining effect”. We also investigated the association between DCS administration characteristics and treatment outcome to find optimal dosing parameters. We conducted a secondary analysis of individual participant data obtained from 1047 participants in 21 studies testing the efficacy of DCS-augmented exposure treatments. Different outcome measures in different studies were harmonized to a 0-100 scale. Intent-to-treat analyses showed that, in participants randomized to DCS augmentation (n = 523), fewer DCS doses, later timing of DCS dose, and lower baseline severity appear to account for this decline effect. More DCS doses were related to better outcomes, but this advantage leveled-off at nine doses. Administering DCS more than 60 minutes before exposures was also related to better outcomes. These predictors were not significant in the placebo arm (n = 521). Results suggested that optimal DCS administration could increase pre-to-follow-up DCS effect size by 50%. In conclusion, the apparent declining effectiveness of DCS over time may be accounted for by how it has been administered. Optimal DCS administration may substantially improve outcomes. Registration: The analysis plan for this manuscript was registered on Open Science Framework (https://osf.io/c39p8/).

Original languageEnglish (US)
Article number102149
JournalJournal of Anxiety Disorders
Volume68
DOIs
StatePublished - Dec 2019

Bibliographical note

Funding Information:
All authors with the exception of Drs. Fernández de la Cruz, Frumento, and Pérez-Vigil were investigators on one or more of the original randomized controlled trials that contributed data to the individual patient data and secured grant funding for these trials. Drs. Davis and Ressler hold patents for the use of D-cycloserine and psychotherapy, targeting PAC1 receptor for extinction, targeting tachykinin 2 for prevention of fear, targeting angiotensin to improve extinction of fear. Dr. Davis and Dr. Ressler are also co-founding members of Extinction Pharmaceuticals to develop D-cycloserine to augment the effectiveness of psychotherapy, for which he has received no equity or income within the last three years. Dr. Davis retired in 2012 and has received no financial support from any source since his retirement. Dr. Rosenfield reports funds from the National Institute of Mental Health , the National Institute on Drug Abuse , CPRIT , and Behavior Research and Therapy . Dr. Smits is funded by the NIH , CPRIT and has been a paid consultant for Big Health, Ltd. Ms Pérez-Vigil is supported by a grant from the Alicia Koplowitz Foundation . Dr. Farrell reports funds from the Rotary Mental Health Research Fund Australia . Dr. Geller reports funds from the National Institute of Mental Health. Dr. Hofmann reports funds from the National Center for Complementary and Integrative Health (R01AT007257) and the National Institute of Mental Health (R01MH099021, R34MH099311, R34MH086668, R21MH102646, R21MH101567, and K23MH100259), the James S. McDonnell Foundation 21 st Century Science Initiative in Understanding Human Cognition – Special Initiative , and the Department of the Army . Dr. Kushner reports funds from the National Institute on Alcohol Abuse and Alcoholism (R01AA015069). Dr. Levinson reports funds from the National Institutes of Health (5T32DA007261-17). Dr. McConnell reports funds form the Rotary Mental Health Research Fund. Dr. Otto reports current funds from the National Institute of Mental Health (R21MH102646 and R34MH099311), and recent or past support from National Institute of Mental Health (R01MH081116, R21DA030808, and R01MH078308). In addition, Dr. Otto reports serving, in the last three years, as a paid consultant for MicroTransponder Inc., Concert Pharmaceuticals, and ProPhase, providing expert consensus opinion for Otsuka Pharmaceuticals, receiving royalty support for use of the SIGH-A from ProPhase, and receiving book royalties from Oxford University Press, Routledge, and Springer. Dr. Plag serves as a consultant for Pfizer, Inc. Dr. Pollack reports funds from the National Institute of Mental Health, the National Institutes of Health, Janssen, and Edgemont. In addition, Dr. Pollack serves as consultant/advisor for Clintara, Edgemont Pharmaceuticals, and Palo Alto Health Sciences. Dr. Pollack reports the following patents/royalties: SIGH-A, SAFER interviews. Dr. Pollack’s equity disclosure includes Doyen Medical, Medavante, Mensante Corporation, Mindsite, and Targia Pharmaceuticals. Dr. Ressler reports current or past funds from the National Institute of Mental Health, the Howard Hughes Medical Institute , the Brain & Behavior Research Foundation (formerly NARSAD), Burroughs Wellcome Fund . In addition, Dr. Ressler is on the Scientific Advisory Boards for Resilience Therapeutics, Sheppard Pratt-Lieber Research Institute, Laureate Institute for Brain Research, The Army STARRS Project, and the Anxiety and Depression Association of America. Dr. Rodebaugh reports current funds from the Behavior Brain Research Foundation (NARSAD Independent Investigator Award) and the McDonnell Center for Systems Neuroscience and past funds from the National Institute of Mental Health (R21MH090308-01A). Dr. Rothbaum reports funds from the National Institute of Mental Health (R01MH70880). In addition, Dr. Rothbaum owns equity in Virtually Better, Inc. that creates virtual environments. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies. Dr. Storch reports funds from National Institute of Mental Health, the National Institutes of Health, the Agency for Healthcare Research and Quality , and All Children's Hospital Research Foundation . In addition, Dr. Storch reports Royalties from Elsevier, the American Psychological Association, Springer, Wiley Inc., and Lawrence Erlbaum, and is consultant for Ruijin Hospital and Rogers Memorial Hospital. Dr. Ströhle reports funds from the German Federal Ministry of Education and Research (BMBF), the German Research Foundation (DFG), the European Commission (FP6), and Lundbeck. In addition, Dr. Ströhle serves as speaker honoraria for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly & Co, Lundbeck, Pfizer, Wyeth, and UCB, and was a consultant for Actelion. Dr. Ströhle’s educational grants were given by the Stifterverband für die Deutsche Wissenschaft, the Berlin Brandenburgische Akademie der Wissenschaften, the Boehringer Ingelheim Fonds, the Eli Lilly International Foundation, Janssen-Cilag, Pfizer, and Eli Lilly & Co. Dr. Tart reports funds from National Institute of Mental Health. Dr. van Minnen reports funds from Stichting Achmea Slachtoffer en Samenleving and Vereniging tot Christelijke Verzorging van Geestes- en Zenuwzieken. Dr. Waters reports funds from the Rotary Mental Health Research Fund Australia. Dr. Weems reports funds from the National Institute of Mental Health (5RC1MH088969-02). Dr. Wilhelm has received research funding and salary support from the NIH, she has also received research support in the form of free medication, and matching placebo from Forest Laboratories for clinical trials funded by the NIH. Dr. Wilhelm is a presenter for the Massachusetts General Hospital Psychiatry Academy in educational programs supported through independent medical education grants from pharmaceutical companies; she has received royalties from Elsevier Publications, Guilford Publications, and New Harbinger Publications from Oxford University Press. Dr. Wilhelm has also received speaking honorarium from various academic institutions and foundations, including the International Obsessive Compulsive Disorder Foundation and the Tourette’s Syndrome Association. In addition, she received payment from the Association for Behavioral and Cognitive Therapies for her role as Associate Editor for the Behavior Therapy journal, as well as from John Wiley & Sons, Inc. for her role as Associate Editor on the journal Depression & Anxiety. Dr. Wilhelm has also received salary support from Novartis. Dr. Rück is supported by a grant from the Swedish Research Council (K2013-61P-22168). Dr. Gutner reports funds from the National Institute of Mental Health (1K23MH103396). No other disclosures were reported.

Funding Information:
All authors with the exception of Drs. Fernández de la Cruz, Frumento, and Pérez-Vigil were investigators on one or more of the original randomized controlled trials that contributed data to the individual patient data and secured grant funding for these trials. Drs. Davis and Ressler hold patents for the use of D-cycloserine and psychotherapy, targeting PAC1 receptor for extinction, targeting tachykinin 2 for prevention of fear, targeting angiotensin to improve extinction of fear. Dr. Davis and Dr. Ressler are also co-founding members of Extinction Pharmaceuticals to develop D-cycloserine to augment the effectiveness of psychotherapy, for which he has received no equity or income within the last three years. Dr. Davis retired in 2012 and has received no financial support from any source since his retirement. Dr. Rosenfield reports funds from the National Institute of Mental Health, the National Institute on Drug Abuse, CPRIT, and Behavior Research and Therapy. Dr. Smits is funded by the NIH, CPRIT and has been a paid consultant for Big Health, Ltd. Ms Pérez-Vigil is supported by a grant from the Alicia Koplowitz Foundation. Dr. Farrell reports funds from the Rotary Mental Health Research Fund Australia. Dr. Geller reports funds from the National Institute of Mental Health. Dr. Hofmann reports funds from the National Center for Complementary and Integrative Health (R01AT007257) and the National Institute of Mental Health (R01MH099021, R34MH099311, R34MH086668, R21MH102646, R21MH101567, and K23MH100259), the James S. McDonnell Foundation 21st Century Science Initiative in Understanding Human Cognition – Special Initiative, and the Department of the Army. Dr. Kushner reports funds from the National Institute on Alcohol Abuse and Alcoholism (R01AA015069). Dr. Levinson reports funds from the National Institutes of Health (5T32DA007261-17). Dr. McConnell reports funds form the Rotary Mental Health Research Fund. Dr. Otto reports current funds from the National Institute of Mental Health (R21MH102646 and R34MH099311), and recent or past support from National Institute of Mental Health (R01MH081116, R21DA030808, and R01MH078308). In addition, Dr. Otto reports serving, in the last three years, as a paid consultant for MicroTransponder Inc. Concert Pharmaceuticals, and ProPhase, providing expert consensus opinion for Otsuka Pharmaceuticals, receiving royalty support for use of the SIGH-A from ProPhase, and receiving book royalties from Oxford University Press, Routledge, and Springer. Dr. Plag serves as a consultant for Pfizer, Inc. Dr. Pollack reports funds from the National Institute of Mental Health, the National Institutes of Health, Janssen, and Edgemont. In addition, Dr. Pollack serves as consultant/advisor for Clintara, Edgemont Pharmaceuticals, and Palo Alto Health Sciences. Dr. Pollack reports the following patents/royalties: SIGH-A, SAFER interviews. Dr. Pollack's equity disclosure includes Doyen Medical, Medavante, Mensante Corporation, Mindsite, and Targia Pharmaceuticals. Dr. Ressler reports current or past funds from the National Institute of Mental Health, the Howard Hughes Medical Institute, the Brain & Behavior Research Foundation (formerly NARSAD), Burroughs Wellcome Fund. In addition, Dr. Ressler is on the Scientific Advisory Boards for Resilience Therapeutics, Sheppard Pratt-Lieber Research Institute, Laureate Institute for Brain Research, The Army STARRS Project, and the Anxiety and Depression Association of America. Dr. Rodebaugh reports current funds from the Behavior Brain Research Foundation (NARSAD Independent Investigator Award) and the McDonnell Center for Systems Neuroscience and past funds from the National Institute of Mental Health (R21MH090308-01A). Dr. Rothbaum reports funds from the National Institute of Mental Health (R01MH70880). In addition, Dr. Rothbaum owns equity in Virtually Better, Inc. that creates virtual environments. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies. Dr. Storch reports funds from National Institute of Mental Health, the National Institutes of Health, the Agency for Healthcare Research and Quality, and All Children's Hospital Research Foundation. In addition, Dr. Storch reports Royalties from Elsevier, the American Psychological Association, Springer, Wiley Inc. and Lawrence Erlbaum, and is consultant for Ruijin Hospital and Rogers Memorial Hospital. Dr. Ströhle reports funds from the German Federal Ministry of Education and Research (BMBF), the German Research Foundation (DFG), the European Commission (FP6), and Lundbeck. In addition, Dr. Ströhle serves as speaker honoraria for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly & Co, Lundbeck, Pfizer, Wyeth, and UCB, and was a consultant for Actelion. Dr. Ströhle's educational grants were given by the Stifterverband für die Deutsche Wissenschaft, the Berlin Brandenburgische Akademie der Wissenschaften, the Boehringer Ingelheim Fonds, the Eli Lilly International Foundation, Janssen-Cilag, Pfizer, and Eli Lilly & Co. Dr. Tart reports funds from National Institute of Mental Health. Dr. van Minnen reports funds from Stichting Achmea Slachtoffer en Samenleving and Vereniging tot Christelijke Verzorging van Geestes- en Zenuwzieken. Dr. Waters reports funds from the Rotary Mental Health Research Fund Australia. Dr. Weems reports funds from the National Institute of Mental Health (5RC1MH088969-02). Dr. Wilhelm has received research funding and salary support from the NIH, she has also received research support in the form of free medication, and matching placebo from Forest Laboratories for clinical trials funded by the NIH. Dr. Wilhelm is a presenter for the Massachusetts General Hospital Psychiatry Academy in educational programs supported through independent medical education grants from pharmaceutical companies; she has received royalties from Elsevier Publications, Guilford Publications, and New Harbinger Publications from Oxford University Press. Dr. Wilhelm has also received speaking honorarium from various academic institutions and foundations, including the International Obsessive Compulsive Disorder Foundation and the Tourette's Syndrome Association. In addition, she received payment from the Association for Behavioral and Cognitive Therapies for her role as Associate Editor for the Behavior Therapy journal, as well as from John Wiley & Sons, Inc. for her role as Associate Editor on the journal Depression & Anxiety. Dr. Wilhelm has also received salary support from Novartis. Dr. Rück is supported by a grant from the Swedish Research Council (K2013-61P-22168). Dr. Gutner reports funds from the National Institute of Mental Health (1K23MH103396). No other disclosures were reported.

Publisher Copyright:
© 2019 Elsevier Ltd

Keywords

  • augmentation
  • d-cycloserine
  • decline effect
  • dosing
  • exposure

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