Why is this review important?
Many people suffer from anxiety and related disorders (post-traumatic stress disorder, social anxiety disorder, panic disorder with or without agoraphobia, specific phobia and obsessive compulsive disorder). These disorders are disabling and can affect a person’s ability to function well at work and in social situations. Current treatment options include talking therapies such as cognitive and behavioural therapies. Many patients, however, do not respond as well as hoped to these treatments. Using cognitive and behavioural therapies in combination with certain medicines, for example d-cycloserine (DCS), is one option that may improve treatment response. In this review we examined the evidence for DCS combined with cognitive behavioural therapies as a treatment for anxiety and related disorders in children, adolescents and adults.
Who may be interested in this review?
- People with anxiety and related disorders.
- Families and friends of people who suffer from anxiety and related disorders.
- General practitioners, psychiatrists, psychologists and pharmacists.
- Professionals working in adult as well as child and adolescent mental health services.
What does this review aim to answer?
- Is treatment with DCS in combination with cognitive and behavioural therapies more effective than treatment with placebo (dummy pill) and cognitive and behavioural therapies for anxiety and related disorders?
- Is treatment with a combination of DCS and cognitive and behavioural therapies more effective in some anxiety and related disorders compared to others?
- How acceptable is DCS to patients and do people withdraw from treatment?
Which studies were included in the review?
We searched medical databases to find reports of clinical trials (specifically randomised controlled trials) published up to 12 March 2015 that investigated the treatment of anxiety and related disorders using DCS combined with cognitive and behavioural therapies. To be included in the review, trials had to compare the combined treatment of DCS and a cognitive and behavioural therapy with combined treatment of a placebo and a cognitive and behavioural therapy for anxiety and related disorders. We included studies with participants of all ages.
We included 21 studies in the review, with a total of 788 participants.
What does the evidence from the review tell us?
There was no evidence of a difference between combined treatment with DCS and cognitive and behavioural therapies, and combined treatment with placebo and cognitive and behavioural therapies for anxiety and related disorders in children, adolescents or adults. This conclusion was based on low quality evidence mainly due to small sample sizes and inconsistency across studies.
There was no evidence of a difference in the number of children, adolescents and adults who withdrew from treatment with DCS in addition to cognitive behavioural therapies, and those who withdrew from treatment with placebo in addition to psychological therapies.
What should happen next?
More trials are needed to enable a clearer understanding of the effect of treatment with DCS in combination with cognitive and behavioural therapies.
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 from heterogenous studies with 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. Given there is some promising preliminary data from individual studies, further research is necessary to assess 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.
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 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 and one included children, adolescents and adults. The 21 RCTs investigated OCD (number of RCTs (N) = 6), PTSD (N = 5), SAnD (N = 5), SPh (N = 3) and PD (N = 2). Most information from the studies was rated as having either low risk or unclear risk of bias.
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 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.