Effect of D-Cycloserine on the Effect of Concentrated Exposure and Response Prevention in Difficult-to-Treat Obsessive-Compulsive Disorder: A Randomized Clinical Trial

Gerd Kvale, Bjarne Hansen, Kristen Hagen, Jonathan S Abramowitz, Tore Børtveit, Michelle G Craske, Martin E Franklin, Svein Haseth, Joseph A Himle, Sigurd Hystad, Unn Beate Kristensen, Gunvor Launes, Anders Lund, Stian Solem, Lars-Göran Öst, Gerd Kvale, Bjarne Hansen, Kristen Hagen, Jonathan S Abramowitz, Tore Børtveit, Michelle G Craske, Martin E Franklin, Svein Haseth, Joseph A Himle, Sigurd Hystad, Unn Beate Kristensen, Gunvor Launes, Anders Lund, Stian Solem, Lars-Göran Öst

Abstract

Importance: Evidence is lacking for viable treatment options for patients with difficult-to-treat obsessive-compulsive disorder (OCD). It has been suggested that D-cycloserine (DCS) could potentiate the effect of exposure and response prevention (ERP) treatment, but the hypothesis has not been tested among patients with difficult-to-treat OCD.

Objective: To evaluate whether DCS potentiates the effect of concentrated ERP among patients with difficult-to-treat OCD.

Design, setting, and participants: The study was a randomized placebo-controlled triple-masked study with a 12-month follow-up. Participants were adult outpatients with difficult-to-treat OCD. A total of 220 potential participants were referred, of whom 36 did not meet inclusion criteria and 21 declined to participate. Patients had either relapsed after (n = 100) or not responded to (n = 63) previous ERP treatment. A total of 9 specialized OCD teams within the public health care system in Norway participated, giving national coverage. An expert team of therapists from the coordinating site delivered treatment. Inclusion of patients started in January 2016 and ended in August 2017. Data analysis was conducted February to September 2019.

Interventions: All patients received individual, concentrated ERP treatment delivered during 4 consecutive days in a group setting (the Bergen 4-day treatment format) combined with 100 mg DCS, 250 mg DCS, or placebo.

Main outcomes and measures: Change in symptoms of OCD and change in diagnostic status. Secondary outcomes measures included self-reported symptoms of OCD, anxiety, depression, and quality of life.

Results: The total sample of 163 patients had a mean (SD) age of 34.5 (10.9) years, and most were women (117 [71.8%]). They had experienced OCD for a mean (SD) of 16.2 (10.2) years. A total of 65 patients (39.9%) were randomized to receive 100 mg DCS, 67 (41.1%) to 250 mg of DCS, and 31 (19.0%) to placebo. Overall, 91 (56.5%) achieved remission at posttreatment, while 70 (47.9%) did so at the 12-month follow-up. There was no significant difference in remission rates among groups. There was a significant reduction in symptoms at 12 months, and within-group effect sizes ranged from 3.01 (95% CI, 2.38-3.63) for the group receiving 250 mg DCS to 3.49 (95% CI, 2.78-4.18) for the group receiving 100 mg DCS (all P < .001). However, there was no significant effect of treatment group compared with placebo in obsessive-compulsive symptoms (250 mg group at posttreatment: d = 0.33; 95% CI, -0.10 to 0.76; 100 mg group at posttreatment: d = 0.36; 95% CI, -0.08 to 0.79), symptoms of depression and anxiety (eg, Patient Health Questionnaire-9 score among 250 mg group at 12-month follow-up: d = 0.30; 95% CI, -0.17 to 0.76; Generalized Anxiety Disorder-7 score among 100 mg group at 12-month follow-up: d = 0.27; 95% CI, -0.19 to 0.73), and well-being (250 mg group: d = 0.10; 95% CI, -0.42 to 0.63; 100 mg group: d = 0.34; 95% CI, -0.19 to 0.86). No serious adverse effects were reported.

Conclusions and relevance: In this study, DCS did not potentiate ERP treatment effect, but concentrated ERP treatment was associated with improvement.

Trial registration: ClinicalTrials.gov identifier: NCT02656342.

Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure.. Study Flowchart
Figure.. Study Flowchart

References

    1. Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):617-627. doi:10.1001/archpsyc.62.6.617
    1. Karno M, Golding JM, Sorenson SB, Burnam MA. The epidemiology of obsessive-compulsive disorder in five US communities. Arch Gen Psychiatry. 1988;45(12):1094-1099. doi:10.1001/archpsyc.1988.01800360042006
    1. Anholt GE, Aderka IM, van Balkom AJLM, et al. . Age of onset in obsessive-compulsive disorder: admixture analysis with a large sample. Psychol Med. 2014;44(1):185-194. doi:10.1017/S0033291713000470
    1. Öst LG, Havnen A, Hansen B, Kvale G. Cognitive behavioral treatments of obsessive-compulsive disorder: a systematic review and meta-analysis of studies published 1993-2014. Clin Psychol Rev. 2015;40:156-169. doi:10.1016/j.cpr.2015.06.003
    1. Skapinakis P, Caldwell DM, Hollingworth W, et al. . Pharmacological and psychotherapeutic interventions for management of obsessive-compulsive disorder in adults: a systematic review and network meta-analysis. Lancet Psychiatry. 2016;3(8):730-739. doi:10.1016/S2215-0366(16)30069-4
    1. Hood WF, Compton RP, Monahan JB. D-cycloserine: a ligand for the N-methyl-D-aspartate coupled glycine receptor has partial agonist characteristics. Neurosci Lett. 1989;98(1):91-95. doi:10.1016/0304-3940(89)90379-0
    1. Sheinin A, Shavit S, Benveniste M. Subunit specificity and mechanism of action of NMDA partial agonist D-cycloserine. Neuropharmacology. 2001;41(2):151-158. doi:10.1016/S0028-3908(01)00073-9
    1. Kushner MG, Kim SW, Donahue C, et al. . D-cycloserine augmented exposure therapy for obsessive-compulsive disorder. Biol Psychiatry. 2007;62(8):835-838. doi:10.1016/j.biopsych.2006.12.020
    1. Wilhelm S, Buhlmann U, Tolin DF, et al. . Augmentation of behavior therapy with D-cycloserine for obsessive-compulsive disorder. Am J Psychiatry. 2008;165(3):335-341. doi:10.1176/appi.ajp.2007.07050776
    1. Mataix-Cols D, Fernández de la Cruz L, Monzani B, et al. ; the DCS Anxiety Consortium . D-cycloserine augmentation of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders: a systematic review and meta-analysis of individual participant data. JAMA Psychiatry. 2017;74(5):501-510. doi:10.1001/jamapsychiatry.2016.3955
    1. Xia J, Du Y, Han J, Liu G, Wang X. D-cycloserine augmentation in behavioral therapy for obsessive-compulsive disorder: a meta-analysis. Drug Des Devel Ther. 2015;9:2101-2117.
    1. Ori R, Amos T, Bergman H, Soares-Weiser K, Ipser JC, Stein DJ. Augmentation of cognitive and behavioural therapies (CBT) with D-cycloserine for anxiety and related disorders. Cochrane Database Syst Rev. 2015;(5):CD007803. doi:10.1002/14651858.CD007803.pub2
    1. Bürkner P-C, Bittner N, Holling H, Buhlmann U. D-cycloserine augmentation of behavior therapy for anxiety and obsessive-compulsive disorders: a meta-analysis. PLoS One. 2017;12(3):e0173660. doi:10.1371/journal.pone.0173660
    1. Storch EA, Merlo LJ, Bengtson M, et al. . D-cycloserine does not enhance exposure-response prevention therapy in obsessive-compulsive disorder. Int Clin Psychopharmacol. 2007;22(4):230-237. doi:10.1097/YIC.0b013e32819f8480
    1. Storch EA, Wilhelm S, Sprich S, et al. . Efficacy of augmentation of cognitive behavior therapy with weight-adjusted D-cycloserine vs placebo in pediatric obsessive-compulsive disorder: a randomized clinical trial. JAMA Psychiatry. 2016;73(8):779-788. doi:10.1001/jamapsychiatry.2016.1128
    1. de Leeuw AS, van Megen HJ, Kahn RS, Westenberg HG. D-cycloserine addition to exposure sessions in the treatment of patients with obsessive-compulsive disorder. Eur Psychiatry. 2017;40:38-44. doi:10.1016/j.eurpsy.2016.06.011
    1. Andersson E, Hedman E, Enander J, et al. . D-cycloserine vs placebo as adjunct to cognitive behavioral therapy for obsessive-compulsive disorder and interaction with antidepressants: a randomized clinical trial. JAMA Psychiatry. 2015;72(7):659-667. doi:10.1001/jamapsychiatry.2015.0546
    1. Farrell LJ, Waters AM, Boschen MJ, et al. . Difficult-to-treat pediatric obsessive-compulsive disorder: feasibility and preliminary results of a randomized pilot trial of D-cycloserine-augmented behavior therapy. Depress Anxiety. 2013;30(8):723-731. doi:10.1002/da.22132
    1. Kvale G, Hansen B, Björgvinsson T, et al. . Successfully treating 90 patients with obsessive compulsive disorder in eight days: the Bergen 4-day treatment. BMC Psychiatry. 2018;18(1):323. doi:10.1186/s12888-018-1887-4
    1. Launes G, Laukvik IL, Sunde T, et al. . The Bergen 4-day treatment for obsessive-compulsive disorder: does it work in a new clinical setting? Front Psychol. 2019;10:1069. doi:10.3389/fpsyg.2019.01069
    1. Havnen A, Hansen B, Öst LG, Kvale G. Concentrated ERP delivered in a group setting: a replication study. Behav Cogn Psychother. 2017;45(5):530-536. doi:10.1017/S1352465817000091
    1. Havnen A, Hansen B, Öst L-G, Kvale G. Concentrated ERP delivered in a group setting: an effectiveness study. J Obsessive Compuls Relat Disord. 2014;3(4):319-324. doi:10.1016/j.jocrd.2014.08.002
    1. Launes G, Hagen K, Sunde T, et al. . A randomized controlled trial of concentrated ERP, self-help and waiting list for obsessive-compulsive disorder: the Bergen 4-day treatment. Front Psychol. 2019;10:2500. doi:10.3389/fpsyg.2019.02500
    1. Hansen B, Kvale G, Hagen K, Havnen A, Öst LG. The Bergen 4-day treatment for OCD: four years follow-up of concentrated ERP in a clinical mental health setting. Cogn Behav Ther. 2019;48(2):89-105. doi:10.1080/16506073.2018.1478447
    1. Mataix-Cols D, Fernández de la Cruz L, Nordsletten AE, Lenhard F, Isomura K, Simpson HB. Towards an international expert consensus for defining treatment response, remission, recovery and relapse in obsessive-compulsive disorder. World Psychiatry. 2016;15(1):80-81. doi:10.1002/wps.20299
    1. Hofmann SG. D-cycloserine for treating anxiety disorders: making good exposures better and bad exposures worse. Depress Anxiety. 2014;31(3):175-177. doi:10.1002/da.22257
    1. Sheehan DV, Lecrubier Y, Sheehan KH, et al. . The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(suppl 20):22-33.
    1. First MB, Williams JBW, Karg RS, Spitzer RL. Structured Clinical Interview for DSM-5—Research Version. American Psychiatric Association; 2015.
    1. Goodman WK, Price LH, Rasmussen SA, et al. . The Yale-Brown Obsessive-Compulsive Scale: I. development, use, and reliability. Arch Gen Psychiatry. 1989;46(11):1006-1011. doi:10.1001/archpsyc.1989.01810110048007
    1. Jacobson NS, Truax P. Clinical significance: a statistical approach to defining meaningful change in psychotherapy research. J Consult Clin Psychol. 1991;59(1):12-19. doi:10.1037/0022-006X.59.1.12
    1. Eilertsen T, Hansen B, Kvale G, Abramowitz JS, Holm SEH, Solem S. The Dimensional Obsessive-Compulsive Scale: development and validation of a short form (DOCS-SF). Front Psychol. 2017;8:1503. doi:10.3389/fpsyg.2017.01503
    1. Foa EB, Huppert JD, Leiberg S, et al. . The Obsessive-Compulsive Inventory: development and validation of a short version. Psychol Assess. 2002;14(4):485-496. doi:10.1037/1040-3590.14.4.485
    1. Spitzer RL, Kroenke K, Williams JB, Löwe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006;166(10):1092-1097. doi:10.1001/archinte.166.10.1092
    1. Kroenke K, Spitzer RL, Williams JBW. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9):606-613. doi:10.1046/j.1525-1497.2001.016009606.x
    1. Nguyen TD, Attkisson CC, Stegner BL. Assessment of patient satisfaction: development and refinement of a service evaluation questionnaire. Eval Program Plann. 1983;6(3-4):299-313. doi:10.1016/0149-7189(83)90010-1
    1. Stewart-Brown S, Janmohamed K Warwick-Edinburgh mental well-being scale. Updated September 12, 2018. Accessed July 16, 2020.
    1. Norberg MM, Krystal JH, Tolin DF. A meta-analysis of D-cycloserine and the facilitation of fear extinction and exposure therapy. Biol Psychiatry. 2008;63(12):1118-1126. doi:10.1016/j.biopsych.2008.01.012
    1. Singer JD, Willett JB. Applied Longitudinal Data Analysis: Modeling Change and Event Occurrence. Oxford University Press; 2003. doi:10.1093/acprof:oso/9780195152968.001.0001
    1. Lakens D. Calculating and reporting effect sizes to facilitate cumulative science: a practical primer for t-tests and ANOVAs. Front Psychol. 2013;4:863. doi:10.3389/fpsyg.2013.00863
    1. Rosenfield D, Smits JAJ, Hofmann SG, et al. . 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;68:102149. doi:10.1016/j.janxdis.2019.102149

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren