A significant number of patients who suffer with anxiety and related disorders (that is post-traumatic stress disorder (PTSD), social anxiety disorder (SAnD), panic disorder with or without agoraphobia (PD), specific phobia (SPh) and obsessive compulsive disorder (OCD)) fail to respond optimally to first-line treatment with medication or cognitive and behavioural therapies. The addition of d-cycloserine (DCS) to cognitive and behavioural therapies may improve treatment response by impacting the glutamatergic system. This systematic review aimed to investigate the effects of adding DCS to cognitive and behavioural therapies by synthesising data from relevant randomised controlled trials and following the guidelines recommended by Cochrane to minimise systematic sources of bias.
To assess the effect of DCS augmentation of cognitive and behavioural therapies compared to placebo augmentation of cognitive and behavioural therapies in the treatment of anxiety and related disorders. Additionally, to assess the efficacy and tolerability of DCS across different anxiety and related disorders.
This review fully incorporates studies identified from a search of the Cochrane Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR) to 12 March 2015. This register includes relevant randomised controlled trials (RCTs) from: the Cochrane Library (all years), EMBASE (1974 to date), MEDLINE (1950 to date), PsycINFO (1967 to date), the World Health Organization's trials portal (ICTRP) and ClinicalTrials.gov . Reference lists from previous meta-analyses and reports of RCTs were also checked. No restrictions were placed on language, setting, date or publication status.
All RCTs of DCS augmentation of cognitive and behavioural therapies versus placebo augmentation of cognitive and behavioural therapies for anxiety and related disorders were included.
Two authors (RO and TA) independently assessed RCTs for eligibility and inclusion, extracted outcomes and risk of bias data and entered these into a customised extraction form. Investigators were contacted to obtain missing data. In addition, data entry and analysis were performed by two review authors (KSW and HB).
Twenty-one published RCTs, with 788 participants in outpatient settings, were included in the review. Sixteen studies had an age range of 18 to 75 years, while four investigated paediatric populations aged 8 to 17 years. The 21 RCTs investigated OCD (number of RCTs (N) = 6), PTSD (N = 5), SAnD (N = 5), SPh (N = 3) and PD (N = 2).There was no evidence of a difference between DCS augmentation of cognitive and behavioural therapies and placebo augmentation of cognitive and behavioural therapies for the treatment of anxiety and related disorders in adults at the endpoint (treatment responders, N = 9, risk ratio (RR) 1.10; 95% confidence interval (CI) 0.89 to 1.34; number of participants (n) = 449; low quality evidence) and between 1 and 12 months follow-up (N = 7, RR 1.08; 95% CI 0.90 to 1.31; n = 383). DCS augmentation of cognitive and behavioural therapies was not superior to placebo augmentation of cognitive and behavioural therapies for children and adolescents, both at the endpoint (N = 4, RR 1.01; 95% CI 0.78 to 1.31; n = 121; low quality evidence) and between 3 and 12 months follow-up (N = 3, RR 0.86; 95% CI 0.67 to 1.09; n = 91).There was no evidence of a difference in treatment acceptability for DCS augmentation of cognitive and behavioural therapies compared with placebo augmentation of cognitive and behavioural therapies in adults (N = 16, RR 0.88; 95% CI 0.61 to 1.25; n = 740), nor in children and adolescents (N = 4, RR 0.90; 95% CI 0.17 to 4.69; n = 131). These conclusions were based on moderate quality evidence for adults, and very low quality evidence for children and adolescents. Although the observed difference was small, it is noteworthy that there was a high baseline efficacy of exposure-based therapies alone in the included trials. Due to the limited number of studies, subgroup analysis of moderating factors for clinical and methodological effect could not take place.Most information from the studies was rated as having either low risk or unclear risk of bias. The imprecision found in study measures, marked inconsistency across studies and lack of generalisability of outpatient settings are important limitations.
This review found no evidence of a difference between DCS augmentation of cognitive and behavioural therapies and placebo augmentation of cognitive and behavioural therapies for treating anxiety and related disorders in children, adolescents and adults. These findings are based on low quality evidence, small sample sizes and incomplete data for clinical response, which precludes us from drawing conclusions on the use of DCS augmentation of cognitive and behavioural therapies at this stage.Further research is necessary to assess the use of DCS compared with placebo augmentation of cognitive and behavioural therapies, and determine mechanisms of action as well as magnitude of effect in anxiety and related disorders. More trials could provide a more precise estimate of treatment effects of DCS and would allow for a more comprehensive look at sources of heterogeneity between trial results.