Summary of findings for the main comparison. DCS and cognitive and behavioural therapies compared to placebo and cognitive and behavioural therapies for anxiety disorders in adults.
| Augmentation of cognitive and behavioural therapies with DCS compared to placebo for anxiety disorders in adults at end of treatment | ||||||
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Patient or population: Adults with anxiety disorders
Settings: Outpatient settings in Australia, Germany, the Netherlands and the USA
Intervention: Augmentation of cognitive and behavioural therapies with DCS Comparison: Cognitive and behavioural therapies and placebo pill | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No of participants (studies) | Quality of the evidence (GRADE) | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo and cognitive and behavioural therapies | DCS and cognitive and behavioural therapies | |||||
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Treatment efficacy: treatment responders As assessed per study |
59 per 100 | 65 per 100 (53 to 79) | RR 1.1 (0.89 to 1.34) | 449 (9 studies) | ⊕⊕⊝⊝ low1,2 | Subgroups included: OCD (1 study), PD (1), PTSD (3), SAnD (1), and SPh (3). For PD a single study showed an improvement with DCS compared to placebo, RR 2.25 (1.04 to 4.86) |
| Treatment acceptability: withdrawals from treatment | 23 per 100 | 20 per 100 (14 to 28) | RR 0.88 (0.61 to 1.25) | 740 (16 studies) | ⊕⊕⊕⊝ moderate3 | Subgroups included: OCD (3), PD (1), PTSD (4), SAnD (5), and SPh (3) |
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In remission As assessed per study |
30 per 100 | 35 per 100 (24 to 52) | RR 1.16 (0.79 to 1.71) | 292 (5 studies) | ⊕⊕⊕⊝ moderate4 | Subgroups included: OCD (1), PTSD (2), SAnD (1), and SPh (1) |
| Condition‐specific anxiety symptoms As assessed by LSAS5 (scale from: 0 to 144, better indicated by a lower score. 55 to 65 points = moderate social anxiety disorder (Liebowitz 1987)) | The mean condition‐specific anxiety symptoms in the control groups was 57.79 points | The mean condition‐specific anxiety symptoms in the intervention groups was 6.55 points lower (11.88 to 1.43 lower), which may represent a clinically important improvement since the mean in the control group was 57.79 points (moderate social anxiety on the LSAS scale) and the mean in the intervention group was 6.55 points lower (below the cut‐off for moderate social anxiety on the LSAS scale). |
MD** ‐6.55 (‐11.88 to ‐1.43) |
735 (17 studies) | ⊕⊕⊕⊝ moderate6 | Subgroups included: OCD (3), PD (2), PTSD (4), SAnD (5), and SPh (3). Little or no difference was found with DCS compared to placebo for OCD, SMD ‐0.14 (‐0.61 to 0.33); PTSD, SMD ‐0.06 (‐0.52 to 0.39); SAnD, SMD ‐0.39 (‐0.99 to 0.21); and SP, SMD ‐0.51 (‐1.14 to 0.13) |
| Co‐morbid symptoms of depression As assessed by BDI‐II7 (scale from: 0 to 63, better indicated by a lower score) | The mean co‐morbid symptoms of depression in the control groups was 10.73 points | The mean co‐morbid symptoms of depression in the intervention groups was 2.25 points lower (7.2 lower to 2.79 higher) |
MD** ‐2.25 (‐7.22 to 2.79) |
178 (5 studies) | ⊕⊕⊕⊝ moderate8 | Subgroups included: OCD (2), PD (1), and PTSD (2). For OCD two studies found an improvement with DCS compared to placebo, SMD ‐1.64 (‐1.23 to ‐0.04) |
| Co‐morbid anxiety symptoms As assessed by BAI9 (scale from: 0 to 63, better indicated by a lower score. 8 to 15 points = mild anxiety, 16 to 25 points = moderate anxiety (Beck 1993)) | The mean co‐morbid anxiety symptoms in the control groups was 19.5 points | The mean co‐morbid anxiety symptoms in the intervention groups was 8.82 points lower (13.85 to 3.64 lower), which may represent a clinically important improvement since the mean in the control group was 19.5 points (moderate anxiety on the BAI scale) and the mean in the intervention group was 8.82 points lower (mild anxiety on the BAI scale). |
MD** ‐8.82 (‐13.85 to ‐3.64) |
122 (3 studies) | ⊕⊕⊝⊝ low10,11 | Subgroups included: PD (1), PTSD (1) and (SAnD (1). Little or no difference was found with DCS compared to placebo for PD, MD ‐1.52 (‐1.16 to 0.12), and for SAnD, MD ‐0.70 (‐1.73 to 0.32) |
| Quality of life Assessed by LIS (scale from: 0 to 48, better indicated by a lower score) | The mean quality of life in the control group was 30.75 points | The mean quality of life in the intervention group was 5.32 points lower (9.87 to 0.77 lower) |
MD ‐5.32 (‐9.87 to ‐0.77) |
56 (1 study) | ⊕⊝⊝⊝ very low12,13 | Subgroups included: SAnD (1) |
| *The basis for the assumed risk is the control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ** Back‐estimated from the SMD, see footnotes for further details. BAI: Beck Anxiety Inventory; BDI‐II: Beck Depression Inventory‐II; CI: Confidence interval; DCS: d‐cycloserine; LSAS: Liebowitz Social Anxiety Scale; LIS: Life Interference Scale; MD: mean difference; OCD: Obsessive compulsive disorder; PD: Panic disorder; PTSD: Post‐traumatic stress disorder; RR: Risk ratio; SAnD: social anxiety disorder; SMD: standardised mean difference; SPh: Specific phobia | ||||||
| GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. | ||||||
1 Downgraded 1 step due to risk of bias: five out of the nine included studies did not report on method of allocation concealment sufficiently. 2 Downgraded 1 step due to inconsistency: there was substantial heterogeneity between subgroups (I2 = 57%). 3 Downgraded 1 step for indirectness: withdrawals from treatment is not a direct measure of treatment acceptability to the participants. There could be other reasons for dropping out.
4 Downgraded 1 step for risk of bias: In remission is at risk of selective reporting bias as only five out of 16 studies reported on this important outcome.
5Five of the 16 studies used the LSAS. Scores were back‐estimated to the LSAS from the SMD ‐0.32 (‐0.58 to ‐0.07) using the control group SD 20.4802 from the representative study Hofmann 2013. 6 Downgraded 1 step for inconsistency: there was substantial heterogeneity between subgroups (I2 = 60%).
7 Three of the five studies used the BDI‐II. Scores were back‐estimated to the BDI‐II from the SMD ‐0.25 (‐0.80 to 0.31) using the control group SD 9.0 from the representative study Storch 2007. 8 Downgraded 1 step for inconsistency: there was substantial heterogeneity between subgroups (I2 = 68%). 9 One of the two studies used the BAI. Scores were back‐estimated to the BAI from the SMD ‐0.63 (‐0.99 to ‐0.26) using the control group SD 13.9921 from the representative study Siegmund 2011.
10 Downgraded 1 step for risk of bias: Two out of the three included studies had a high drop‐out rate and one study was of high risk of bias for allocation concealment and blinding.
11 Downgraded 1 step for imprecision: the total sample size is lower than the calculated optimal information size. 12 Downgraded 2 steps for imprecision: the total sample size is lower than the calculated optimal information size, and one study reported on this outcome. 13 Downgraded 1 step for indirectness: measuring the impact of an individual’s social fears on various components of their life is not a direct measure of quality of life, which includes many more factors.