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; JoAnn Difede; Boadie W Dunlop; Lara J Farrell; Daniel Geller; Maryrose Gerardi; Adam J Guastella; Gert-Jan Hendriks; Matt G Kushner; Francis 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

doi:10.1016/j.janxdis.2019.102149

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

J Anxiety Disord. 2019 Dec:68:102149. doi: 10.1016/j.janxdis.2019.102149. Epub 2019 Sep 23.

Authors

David Rosenfield¹, Jasper A J Smits², Stefan G Hofmann³, David Mataix-Cols⁴, Lorena Fernández de la Cruz⁴, Erik Andersson⁵, Christian Rück⁴, Benedetta Monzani⁶, Ana Pérez-Vigil⁵, Paolo Frumento⁷, Michael Davis⁸, Rianne A de Kleine⁹, JoAnn Difede¹⁰, Boadie W Dunlop⁸, Lara J Farrell¹¹, Daniel Geller¹², Maryrose Gerardi⁸, Adam J Guastella¹³, Gert-Jan Hendriks¹⁴, Matt G Kushner¹⁵, Francis S Lee¹⁰, Eric J Lenze¹⁶, Cheri A Levinson¹⁶, Harry McConnell¹⁷, Jens Plag¹⁸, Mark H Pollack¹⁹, Kerry J Ressler²⁰, Thomas L Rodebaugh⁸, Barbara O Rothbaum⁸, Eric A Storch²¹, Andreas Ströhle¹⁸, Candyce D Tart²², David F Tolin²³, Agnes van Minnen²⁴, Allison M Waters²⁵, Carl F Weems²⁶, Sabine Wilhelm¹², Katarzyna Wyka²⁷, Margaret Altemus²⁸, Page Anderson²⁹, Judith Cukor¹⁰, Claudia Finck³⁰, Gary R Geffken³¹, Fabian Golfels³², Wayne K Goodman³³, Cassidy A Gutner³⁴, Isobel Heyman³⁵, Tanja Jovanovic⁸, Adam B Lewin³⁶, Joseph P McNamara³⁷, Tanya K Murphy³⁶, Seth Norrholm⁸, Paul Thuras¹⁵, Cynthia Turner³⁸, Michael W Otto³

Affiliations

¹ Department of Psychology, Southern Methodist University, Dallas, USA. Electronic address: drosenfi@smu.edu.
² Institute for Mental Health Research and Department of Psychology, The University of Texas, Austin, USA.
³ Department of Psychological and Brain Sciences, Boston University, Boston, USA.
⁴ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
⁵ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁶ Department of Psychology, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
⁷ Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁸ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, USA.
⁹ Institute of Psychology, Leiden University, The Netherlands.
¹⁰ Department of Psychiatry, Weill Cornell Medical College, NY, USA.
¹¹ School of Applied Psychology, Griffith University, Brisbane, Australia; Menzies Health Institute of Queensland, Brisbane, Australia.
¹² Department of Psychiatry, Massachusetts General Hospital, Boston, USA; Harvard Medical School, Boston, USA.
¹³ Brain and Mind Research Institute, Central Clinical School, University of Sydney, Sydney, Australia.
¹⁴ Behavioral Science Institute, Radboud University Nijmegen, The Netherlands; Overwaal Center of Expertise for Anxiety Disorders OCD and PTSD, Institution for Integrated Mental Health Care Pro Persona, Nijmegen, the Netherlands.
¹⁵ Department of Psychiatry, University of Minnesota-Twin Cities, Minneapolis, USA.
¹⁶ Department of Psychiatry, Washington University School of Medicine, St Louis, USA.
¹⁷ Menzies Health Institute of Queensland, Brisbane, Australia; School of Medicine, Griffith University, Brisbane, Australia.
¹⁸ Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité - University Medicine Berlin, Germany.
¹⁹ Department of Psychiatry, Rush University Medical Center, Chicago, USA.
²⁰ Harvard Medical School, Boston, USA; McLean Hospital, Belmont, USA.
²¹ Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, USA.
²² New Mexico VA Health Care System, Albuquerque, USA.
²³ The Institute of Living, Hartford, USA; Yale University School of Medicine, New Haven, USA.
²⁴ Behavioral Science Institute, Radboud University Nijmegen, The Netherlands.
²⁵ School of Applied Psychology, Griffith University, Brisbane, Australia.
²⁶ Department of Human Development and Family Studies, Iowa State University, Ames, USA.
²⁷ Department of Psychiatry, Weill Cornell Medical College, NY, USA; City University of New York Graduate School of Public Health and Health Policy, New York, USA.
²⁸ Yale University School of Medicine, New Haven, USA.
²⁹ Department of Psychology, Georgia State University, Atlanta, USA.
³⁰ DRK Kliniken Berlin Wiegmann Klinik, Berlin, Germany.
³¹ Geffken Group, PLLC, Gainesville, FL, USA.
³² Woltersdorf Hospital, Woltersdorf, Germany.
³³ Department of Psychiatry, Baylor College of Medicine, USA.
³⁴ Department of Psychiatry, Boston University School of Medicine, Boston, USA.
³⁵ Great Ormond Street Hospital for Children, London, UK; University College, London, UK.
³⁶ Department of Pediatrics, University of South Florida, Tampa, USA.
³⁷ Department of Psychiatry, University of Florida, Gainesville, USA.
³⁸ Primary Care Clinical Unit, Faculty of Medicine, The University of Queensland, Brisbane, Australia.

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/).

Keywords: augmentation; d-cycloserine; decline effect; dosing; exposure.

Publication types

Meta-Analysis

MeSH terms

Adolescent
Adult
Aged
Anxiety / psychology
Anxiety / therapy
Anxiety Disorders / drug therapy
Anxiety Disorders / psychology*
Anxiety Disorders / therapy*
Child
Combined Modality Therapy / methods*
Cycloserine / administration & dosage*
Cycloserine / therapeutic use*
Female
Humans
Implosive Therapy / methods*
Male
Middle Aged
Treatment Outcome
Young Adult

Substances

Cycloserine

Abstract

Publication types

MeSH terms

Substances

Grants and funding