Title: Augmentation of psychotherapy with d-cycloserine for anxiety disorders.
Funder: Department of Health (England)

Abstract: Research Question: D-cycloserine augmentation of behavioural therapy for the treatment of anxiety disorders 1.Intervention: D-cycloserine as an augmentation strategy for psychotherapy.2.Patient group: Adults and children with anxiety disorders – exact inclusion criteria to be defined and justified by applicants.3.Setting: Any4.Control: Placebo or another appropriate control or comparator.5.Study design: Evidence synthesis by systematic review of the best available evidence. Findings for adults and children should be reported separately. Subgroup analysis by type and severity of anxiety disorder and any other relevant groups should be carried out if data allow. 6.Outcomes: Reduction in symptom severity; health related quality of life; acceptability; treatment compliance; adverse effects; research recommendations.NHS decision problem to be addressed by this research:A significant number of patients with anxiety disorders such as panic disorder post-traumatic stress disorder social phobia and specific phobia fail to respond optimally to psychotherapy treatment. To help address this D-cycloserine a partial N-methyl-D-aspartate receptor agonist has been tested as an adjunct to psychological interventions in clinical trials. D-cycloserine is thought to facilitate fear extinction and exposure therapy.A meta-analysis of randomised controlled trials (RCTs) published prior to the mid-2011 reported that compared to placebo the addition of D-cycloserine significantly enhanced the effect of behavioural therapy for anxiety disorders. Data suggested that the benefit of D-cycloserine may depend on the type of anxiety disorder. However only a limited number of small trials were included and moderate statistical heterogeneity was found. Since the meta-analysis many more RCTs have published including a couple of large trials. An up to date evidence synthesis is needed that builds on previous reviews that could inform clinical guidelines and that provides recommendations for future primary research.Source of topic This topic came from a systematic review that was abstracted in DARE in May 2013. Bontempo A Panza KE Bloch MH. D-cycloserine augmentation of behavioral therapy for the treatment of anxiety disorders: a meta-analysis. Journal of Clinical Psychiatry 2012; 73(4): 533-537.NICE guidance The only reference to d-cycloserine within NICE guidelines was during a review of interventions for social anxiety disorder (NICE CG159: Social anxiety disorder: recognition assessment and treatment 2013). There were no specific recommendations regarding its use.Published researchEvidence Synthesis:•Bontempo A Panza KE Bloch MH. D-cycloserine augmentation of behavioral therapy for the treatment of anxiety disorders: a meta-analysis. Journal of Clinical Psychiatry 2012; 73(4): 533-537. CRD commentary: The authors concluded that D-cycloserine seemed to be an effective addition to behavioural therapy for anxiety disorders. Given the unknown risk of bias and the lack of evidence the authors conclusions seem overly strong. NOTE: searches were performed in June 2011 and several RCTs have since published (see below).•Norberg MM Krystal JH Tolin DF. A meta-analysis of D-cycloserine and the facilitation of fear extinction and exposure therapy. Biological Psychiatry 2008; 63(12): 1118-1126.Primary Research:Several RCTs have been published since the search dates of the most recent meta-analysis:•Hofmann SG Smits JA Rosenfield D Simon N Otto MW Meuret AE Marques L Fang A Tart C Pollack MH. D-Cycloserine as an augmentation strategy with cognitive-behavioral therapy for social anxiety disorder. Am J Psychiatry. 2013; 170: 751-8. •Tart CD Handelsman PR Deboer LB Rosenfield D Pollack MH Hofmann SG Powers MB Otto MW Smits JA.Augmentation of exposure therapy with post-session administration of D-cycloserine. J Psychiatr Res. 2013; 47: 168-74.•Nave AM Tolin DF Stevens MC. Exposure therapy D-cycloserine and functional magnetic resonance imaging in patients with snake phobia: a randomized pilot study. The Journal of clinical psychiatry 2012 73 1179-86.•Litz BT Salters-Pedneault K Steenkamp MM Hermos JA Bryant RA Otto MW Hofmann SG. A randomized placebo-controlled trial of D-cycloserine and exposure therapy for posttraumatic stress disorder. Journal of psychiatric research 2012 46: 1184-90.•de Kleine RA Hendriks GJ Kusters WJ Broekman TG van Minnen A. A randomized placebo-controlled trial of D-cycloserine to enhance exposure therapy for posttraumatic stress disorder. Biological psychiatry 2012 71: 962-8.•Behar E McHugh RK Peckham A Otto MW. D-cycloserine for the augmentation of an attentional training intervention for trait anxiety. Journal of anxiety disorders 2010 24: 440-5.•Smits JA Rosenfield D Otto MW Powers MB Hofmann SG Telch MJ Pollack MH Tart CD. D-cycloserine enhancement of fear extinction is specific to successful exposure sessions: evidence from the treatment of height phobia. Biol Psychiatry. 2013; 73: 1054-8.•Smits JA Rosenfield D Otto MW Marques L Davis ML Meuret AE Simon NM Pollack MH Hofmann SG. D-cycloserine enhancement of exposure therapy for social anxiety disorder depends on the success of exposure sessions. J Psychiatr Res. 2013; 47: 1455-61.•Scheeringa MS1 Weems CF. Randomized Placebo-Controlled D-Cycloserine with Cognitive Behavior Therapy for Pediatric Posttraumatic Stress. J Child Adolesc Psychopharmacol. 2014. [Epub ahead of print].•Difede J Cukor J Wyka K Olden M Hoffman H Lee FS Altemus M. D-Cycloserine Augmentation of Exposure Therapy for Post-Traumatic Stress Disorder: A Pilot Randomized Clinical Trial. Neuropsychopharmacology. 2013 [Epub ahead of print]•Mataix-Cols D Turner C Monzani B Isomura K Murphy C Krebs G Heyman I. Cognitive-behavioural therapy with post-session D-cycloserine augmentation for paediatric obsessive-compulsive disorder: pilot randomised controlled trial. Br J Psychiatry. 2014; 204: 77-8.Research in progressEvidence Synthesis:Ipser JC Sander C Seifan A Stein DJ. Augmentation of psychotherapy with d-cycloserine for anxiety disorders (Protocol). Cochrane Database of Systematic Reviews 2009 Issue 2. Art. No.: CD007803. DOI: 10.1002/14651858.CD007803. NOTE: the managing editor of the Cochrane Depression Anxiety & Neurosis Group was contacted about this protocol. He said “Unfortunately this review is seriously delayed because the lead person undertaking the review is off on long term sick leave. At present the timeline is completely unknown as a result.” He went on to suggest that the Cochrane group would need to find new authors to carry out the review.RCTsAdults:•A randomised double-blind placebo-controlled pilot study of D-cycloserine-augmented exposure therapy in adolescents with obsessive-compulsive disorder. Sample: 24. Listed as ongoing with no end date. UK EudraCT Number: 2008-006947-38.•The Effect of a Single-dose of D-cycloserine on the Basic Effects of Cognitive-behaviour Therapy for Panic Disorder - a Randomized Placebo-controlled Trial. Sample: 50. Estimated completion: September 2014. Oxford UK. MRC funded NCT01680107.•D-cycloserine enhancement of exposure and response prevention therapy in OCD (n=60) and panic disorder with agoraphobia (n=60): a randomised controlled trial. - DCS study. Sample: 120. Planned closing date: Jan 2012 but no publications found. Netherlands. NTR2050.•Augmentation of Exposure Therapy With D-cycloserine in Patients With Agoraphobia With or Without Panic Disorder. Sample: 72 Estimated completion date: November 2013 but no publications found. Germany NCT01928823.•A Randomized Double-blind Placebo-controlled Trial of D-cycloserine Augmentation of Behavior Therapy for Body Dysmorphic Disorder. Sample: 50 estimated completion: December 2013 but no publications found. USA NCT00842309.•A Double Blind Clinical Trial of DCS for Food Anxiety for Patients With Anorexia and Bulimia Nervosa. Sample: 70 estimated completion: January 2014. USA NCT01996644.•Internet-based cognitive behavior therapy in combination with D-Cycloserine for Obsessive Compulsive Disorder: A double blinded randomized controlled trial. Sample: 128. Estimated completion: March 2014. Sweden NCT01649895.•The effect of the addition of D-cycloserine to exposure sessions in the treatment of patients with obsessive-compulsive disorder - A randomized placebo-controlled trial. Sample: 40. Listed as ongoing with no estimated end date. Netherlands. EudraCT Number: 2007-000367-18.•D-cycloserine augmented exposure therapy in patients with agoraphobia. Sample: 78 listed as ongoing with no estimated end date. Germany EudraCT Number: 2011-001398-19•Exposure D-cycloserine Enhancement and Genetic Modulators in Panic Disorder. Sample: 192 estimated completion date: March 2014. USA NCT00790868. •D-cycloserine as Enhancer of One-Session Treatment for Phobia of Heights in Adults. Sample: 80 estimated completion: December 2014. USA NCT01037101.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH