Hydroxyzine for generalised anxiety disorder

Giuseppe Guaiana; Corrado Barbui; Andrea Cipriani

doi:10.1002/14651858.CD006815.pub2

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Figure 1

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

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Figure 2

Methodological quality summary: review authors' judgements about each methodological quality item for each included study

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Figure 3

Forest plot of comparison: 1 efficacy of hydroxyzine versus placebo, outcome: 1.1 Number of patients who did not show a response

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Figure 4

Forest plot of comparison: 5 acceptability of hydroxyzine versus placebo, outcome: 5.1 Number of patients who did not complete the study

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Figure 5

Forest plot of comparison: 7 tolerability of hydroxyzine versus placebo, outcome: 7.1 Number of patients with side effects

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Figure 6

Forest plot of comparison: 8 tolerability of hydroxyzine versus active comparator, outcome: 8.1 Number of patients with side effects

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Analysis 1.1

Comparison 1 Efficacy: Hydroxyzine versus placebo, Outcome 1 Number of patients who did not show a response.

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Analysis 1.2

Comparison 1 Efficacy: Hydroxyzine versus placebo, Outcome 2 Standardised mean difference.

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Analysis 2.1

Comparison 2 Efficacy: Hydroxyzine versus benzodiazepines, Outcome 1 Failure to respond.

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Analysis 2.2

Comparison 2 Efficacy: Hydroxyzine versus benzodiazepines, Outcome 2 Standardised mean difference.

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Analysis 3.1

Comparison 3 Efficacy: Hydroxyzine versus buspirone, Outcome 1 Failure to respond.

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Analysis 3.2

Comparison 3 Efficacy: Hydroxyzine versus buspirone, Outcome 2 Standardised mean difference.

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Analysis 4.1

Comparison 4 Efficacy of hydroxyzine in outpatient setting, Outcome 1 Failure to respond placebo.

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Analysis 4.2

Comparison 4 Efficacy of hydroxyzine in outpatient setting, Outcome 2 Failure to respond active comparator.

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Analysis 5.1

Comparison 5 Efficacy of hydroxyzine in primary care setting, Outcome 1 Failure to respond placebo.

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Analysis 5.2

Comparison 5 Efficacy of hydroxyzine in primary care setting, Outcome 2 Failure to respond active comparator.

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Analysis 5.3

Comparison 5 Efficacy of hydroxyzine in primary care setting, Outcome 3 Standardised mean difference placebo.

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Analysis 5.4

Comparison 5 Efficacy of hydroxyzine in primary care setting, Outcome 4 Standardised mean difference active comparator.

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Analysis 6.1

Comparison 6 Acceptability: Hydroxyzine versus placebo, Outcome 1 Failure to complete.

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Analysis 6.2

Comparison 6 Acceptability: Hydroxyzine versus placebo, Outcome 2 Failure to complete due to side effects.

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Analysis 7.1

Comparison 7 Acceptability: Hydroxyzine versus benzodiazepines, Outcome 1 Failure to complete.

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Analysis 7.2

Comparison 7 Acceptability: Hydroxyzine versus benzodiazepines, Outcome 2 Failure to complete due to side effects.

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Analysis 8.1

Comparison 8 Acceptability: Hydroxyzine versus buspirone, Outcome 1 Failure to complete.

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Analysis 8.2

Comparison 8 Acceptability: Hydroxyzine versus buspirone, Outcome 2 Failure to complete due to inefficacy.

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Analysis 9.1

Comparison 9 Tolerability: Hydroxyzine versus placebo, Outcome 1 Patients with side effects.

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Analysis 10.1

Comparison 10 Tolerability: Hydroxyzine versus benzodiazepines, Outcome 1 Patients with side effects.

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Analysis 11.1

Comparison 11 Tolerability: Hydroxyzine versus buspirone, Outcome 1 Patients with side effects.

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Analysis 12.1

Comparison 12 SE ‐ Agitation/anxiety/nervousness/tension, Outcome 1 Placebo.

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Analysis 12.2

Comparison 12 SE ‐ Agitation/anxiety/nervousness/tension, Outcome 2 Benzodiazepines.

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Analysis 13.1

Comparison 13 SE ‐ Confusion, Outcome 1 Placebo.

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Analysis 13.2

Comparison 13 SE ‐ Confusion, Outcome 2 Benzodiazepines.

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Analysis 14.1

Comparison 14 SE ‐ Dizziness, Outcome 1 Placebo.

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Analysis 14.2

Comparison 14 SE ‐ Dizziness, Outcome 2 Active comparator.

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Analysis 15.1

Comparison 15 SE ‐ Dry mouth, Outcome 1 Placebo.

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Analysis 15.2

Comparison 15 SE ‐ Dry mouth, Outcome 2 Benzodiazepines.

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Analysis 16.1

Comparison 16 SE ‐ Headache and migraine, Outcome 1 Placebo.

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Analysis 16.2

Comparison 16 SE ‐ Headache and migraine, Outcome 2 Buspirone.

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Analysis 17.1

Comparison 17 SE ‐ Insomnia, Outcome 1 Placebo.

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Analysis 17.2

Comparison 17 SE ‐ Insomnia, Outcome 2 Benzodiazepines.

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Analysis 18.1

Comparison 18 SE ‐ Pharyngitis, Outcome 1 Placebo.

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Analysis 18.2

Comparison 18 SE ‐ Pharyngitis, Outcome 2 Benzodiazepines.

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Analysis 19.1

Comparison 19 SE ‐ Restlessness, Outcome 1 Placebo.

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Analysis 19.2

Comparison 19 SE ‐ Restlessness, Outcome 2 Benzodiazepines.

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Analysis 20.1

Comparison 20 SE ‐ Sleepiness/drowsiness/somnolence, Outcome 1 Placebo.

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Analysis 20.2

Comparison 20 SE ‐ Sleepiness/drowsiness/somnolence, Outcome 2 Active comparator.

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Analysis 21.1

Comparison 21 SE ‐ Weakness, Outcome 1 Placebo.

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Analysis 21.2

Comparison 21 SE ‐ Weakness, Outcome 2 Benzodiazepines.

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Analysis 22.1

Comparison 22 SE ‐ Weight gain, Outcome 1 Placebo.

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Analysis 23.1

Comparison 23 Sensitivity analysis: efficacy of hydroxyzine 25‐50 mg against all other agents, Outcome 1 Failure to respond.

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Analysis 23.2

Comparison 23 Sensitivity analysis: efficacy of hydroxyzine 25‐50 mg against all other agents, Outcome 2 Standardised mean difference.

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Analysis 24.1

Comparison 24 Sensitivity analysis: efficacy of hydroxyzine 100 mg and above against all other agents, Outcome 1 Failure to respond.

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Analysis 25.1

Comparison 25 Sensitivity analysis: excluding dropout rates > 20%, Outcome 1 Failure to respond.

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Analysis 25.2

Comparison 25 Sensitivity analysis: excluding dropout rates > 20%, Outcome 2 Standardised mean difference.

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Analysis 26.1

Comparison 26 Sensitivity analysis: excluding non‐standardised diagnostic criteria, Outcome 1 Failure to respond.

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Analysis 26.2

Comparison 26 Sensitivity analysis: excluding non‐standardised diagnostic criteria, Outcome 2 Standardised mean difference.

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Analysis 27.1

Comparison 27 Sensitivity analysis: excluding standardised diagnostic criteria, Outcome 1 Failure to respond.

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Analysis 28.1

Comparison 28 Sensitivity analysis: excluding psychiatric comorbidity, Outcome 1 Failure to respond.

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Analysis 28.2

Comparison 28 Sensitivity analysis: excluding psychiatric comorbidity, Outcome 2 Standardised mean difference.

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Comparison 1. Efficacy: Hydroxyzine versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of patients who did not show a response Show forest plot	4	417	Odds Ratio (M‐H, Random, 95% CI)	0.30 [0.15, 0.58]

2 Standardised mean difference Show forest plot	2	381	Std. Mean Difference (IV, Random, 95% CI)	‐0.42 [‐0.62, ‐0.21]

Comparison 1. Efficacy: Hydroxyzine versus placebo

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Comparison 2. Efficacy: Hydroxyzine versus benzodiazepines

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Failure to respond Show forest plot	1		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Chlordiazepoxide	1	106	Odds Ratio (M‐H, Random, 95% CI)	0.75 [0.35, 1.62]
2 Standardised mean difference Show forest plot	1		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only

2.1 Bromazepam	1	221	Std. Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.27, 0.26]

Comparison 2. Efficacy: Hydroxyzine versus benzodiazepines

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Comparison 3. Efficacy: Hydroxyzine versus buspirone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Failure to respond Show forest plot	1		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Buspirone	1	163	Odds Ratio (M‐H, Random, 95% CI)	0.76 [0.40, 1.42]
2 Standardised mean difference Show forest plot	1		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only

2.1 Buspirone	1	163	Std. Mean Difference (IV, Random, 95% CI)	‐0.26 [‐0.57, 0.05]

Comparison 3. Efficacy: Hydroxyzine versus buspirone

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Comparison 4. Efficacy of hydroxyzine in outpatient setting

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Failure to respond placebo Show forest plot	3	254	Odds Ratio (M‐H, Random, 95% CI)	0.22 [0.12, 0.40]

1.1 Placebo	3	254	Odds Ratio (M‐H, Random, 95% CI)	0.22 [0.12, 0.40]
2 Failure to respond active comparator Show forest plot	1	106	Odds Ratio (M‐H, Random, 95% CI)	0.75 [0.35, 1.62]

2.1 Chlordiazepoxide	1	106	Odds Ratio (M‐H, Random, 95% CI)	0.75 [0.35, 1.62]

Comparison 4. Efficacy of hydroxyzine in outpatient setting

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Comparison 5. Efficacy of hydroxyzine in primary care setting

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Failure to respond placebo Show forest plot	2	242	Odds Ratio (M‐H, Random, 95% CI)	0.49 [0.28, 0.84]

1.1 Placebo	2	242	Odds Ratio (M‐H, Random, 95% CI)	0.49 [0.28, 0.84]
2 Failure to respond active comparator Show forest plot	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Buspirone	1	163	Odds Ratio (M‐H, Random, 95% CI)	0.76 [0.40, 1.42]
2.2 Chlordiazepoxide	1	106	Odds Ratio (M‐H, Random, 95% CI)	0.75 [0.35, 1.62]
3 Standardised mean difference placebo Show forest plot	2	381	Std. Mean Difference (IV, Random, 95% CI)	‐0.42 [‐0.62, ‐0.21]

3.1 Placebo	2	381	Std. Mean Difference (IV, Random, 95% CI)	‐0.42 [‐0.62, ‐0.21]
4 Standardised mean difference active comparator Show forest plot	2		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only

4.1 Buspirone	1	163	Std. Mean Difference (IV, Random, 95% CI)	‐0.26 [‐0.57, 0.05]
4.2 Bromazepam	1	221	Std. Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.27, 0.26]

Comparison 5. Efficacy of hydroxyzine in primary care setting

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Comparison 6. Acceptability: Hydroxyzine versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Failure to complete Show forest plot	4	584	Odds Ratio (M‐H, Random, 95% CI)	1.00 [0.63, 1.58]

2 Failure to complete due to side effects Show forest plot	3	505	Odds Ratio (M‐H, Random, 95% CI)	1.37 [0.50, 3.76]

Comparison 6. Acceptability: Hydroxyzine versus placebo

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Comparison 7. Acceptability: Hydroxyzine versus benzodiazepines

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Failure to complete Show forest plot	2	327	Odds Ratio (M‐H, Random, 95% CI)	1.20 [0.69, 2.09]

1.1 Chlordiazepoxide	1	106	Odds Ratio (M‐H, Random, 95% CI)	1.31 [0.56, 3.06]
1.2 Bromazepam	1	221	Odds Ratio (M‐H, Random, 95% CI)	1.13 [0.54, 2.34]
2 Failure to complete due to side effects Show forest plot	1		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Bromazepam	1	221	Odds Ratio (M‐H, Random, 95% CI)	1.4 [0.37, 5.36]

Comparison 7. Acceptability: Hydroxyzine versus benzodiazepines

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Comparison 8. Acceptability: Hydroxyzine versus buspirone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Failure to complete Show forest plot	1		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Buspirone	1	163	Odds Ratio (M‐H, Random, 95% CI)	1.13 [0.45, 2.83]
2 Failure to complete due to inefficacy Show forest plot	1	163	Odds Ratio (M‐H, Random, 95% CI)	1.01 [0.14, 7.37]

2.1 Buspirone	1	163	Odds Ratio (M‐H, Random, 95% CI)	1.01 [0.14, 7.37]

Comparison 8. Acceptability: Hydroxyzine versus buspirone

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Comparison 9. Tolerability: Hydroxyzine versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Patients with side effects Show forest plot	4	584	Odds Ratio (M‐H, Random, 95% CI)	1.49 [0.92, 2.40]

Comparison 9. Tolerability: Hydroxyzine versus placebo

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Comparison 10. Tolerability: Hydroxyzine versus benzodiazepines

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Patients with side effects Show forest plot	2	327	Odds Ratio (M‐H, Random, 95% CI)	1.07 [0.60, 1.93]

1.1 Bromazepam	1	221	Odds Ratio (M‐H, Random, 95% CI)	0.85 [0.50, 1.45]
1.2 Chlordiazepoxide	1	106	Odds Ratio (M‐H, Random, 95% CI)	1.57 [0.71, 3.49]

Comparison 10. Tolerability: Hydroxyzine versus benzodiazepines

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Comparison 11. Tolerability: Hydroxyzine versus buspirone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Patients with side effects Show forest plot	1		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Buspirone	1	163	Odds Ratio (M‐H, Random, 95% CI)	1.07 [0.57, 2.02]

Comparison 11. Tolerability: Hydroxyzine versus buspirone

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Comparison 12. SE ‐ Agitation/anxiety/nervousness/tension

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Placebo Show forest plot	2	203	Odds Ratio (M‐H, Random, 95% CI)	1.43 [0.36, 5.76]

2 Benzodiazepines Show forest plot	1	106	Odds Ratio (M‐H, Random, 95% CI)	0.93 [0.06, 15.20]

2.1 Chlordiazepoxide	1	106	Odds Ratio (M‐H, Random, 95% CI)	0.93 [0.06, 15.20]

Comparison 12. SE ‐ Agitation/anxiety/nervousness/tension

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Comparison 13. SE ‐ Confusion

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Placebo Show forest plot	1	79	Odds Ratio (M‐H, Random, 95% CI)	1.33 [0.13, 13.45]

2 Benzodiazepines Show forest plot	1	106	Odds Ratio (M‐H, Random, 95% CI)	2.88 [0.29, 28.66]

2.1 Chlordiazepoxide	1	106	Odds Ratio (M‐H, Random, 95% CI)	2.88 [0.29, 28.66]

Comparison 13. SE ‐ Confusion

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Comparison 14. SE ‐ Dizziness

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Placebo Show forest plot	2	242	Odds Ratio (M‐H, Random, 95% CI)	1.15 [0.06, 24.03]

2 Active comparator Show forest plot	2	269	Odds Ratio (M‐H, Random, 95% CI)	0.52 [0.02, 11.20]

2.1 Benzodiazepines (Chrlodiazepoxide)	1	106	Odds Ratio (M‐H, Random, 95% CI)	1.8 [0.56, 5.78]
2.2 Buspirone	1	163	Odds Ratio (M‐H, Random, 95% CI)	0.09 [0.00, 1.59]

Comparison 14. SE ‐ Dizziness

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Comparison 15. SE ‐ Dry mouth

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Placebo Show forest plot	2	203	Odds Ratio (M‐H, Random, 95% CI)	1.07 [0.41, 2.82]

2 Benzodiazepines Show forest plot	1	106	Odds Ratio (M‐H, Random, 95% CI)	2.88 [0.29, 28.66]

2.1 Chlordiazepoxide	1	106	Odds Ratio (M‐H, Random, 95% CI)	2.88 [0.29, 28.66]

Comparison 15. SE ‐ Dry mouth

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Comparison 16. SE ‐ Headache and migraine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Placebo Show forest plot	1	163	Odds Ratio (M‐H, Random, 95% CI)	4.21 [0.46, 38.49]

2 Buspirone Show forest plot	1	163	Odds Ratio (M‐H, Random, 95% CI)	0.8 [0.21, 3.09]

Comparison 16. SE ‐ Headache and migraine

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Comparison 17. SE ‐ Insomnia

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Placebo Show forest plot	2	203	Odds Ratio (M‐H, Random, 95% CI)	1.09 [0.32, 3.73]

2 Benzodiazepines Show forest plot	1	106	Odds Ratio (M‐H, Random, 95% CI)	0.93 [0.06, 15.20]

2.1 Chlordiazepoxide	1	106	Odds Ratio (M‐H, Random, 95% CI)	0.93 [0.06, 15.20]

Comparison 17. SE ‐ Insomnia

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Comparison 18. SE ‐ Pharyngitis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Placebo Show forest plot	1	218	Odds Ratio (M‐H, Random, 95% CI)	0.92 [0.30, 2.82]

2 Benzodiazepines Show forest plot	1	221	Odds Ratio (M‐H, Random, 95% CI)	0.64 [0.23, 1.83]

2.1 Bromazepam	1	221	Odds Ratio (M‐H, Random, 95% CI)	0.64 [0.23, 1.83]

Comparison 18. SE ‐ Pharyngitis

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Comparison 19. SE ‐ Restlessness

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Placebo Show forest plot	1	79	Odds Ratio (M‐H, Random, 95% CI)	0.26 [0.04, 1.70]

2 Benzodiazepines Show forest plot	1	106	Odds Ratio (M‐H, Random, 95% CI)	4.81 [0.23, 102.69]

2.1 Chlordiazepoxide	1	106	Odds Ratio (M‐H, Random, 95% CI)	4.81 [0.23, 102.69]

Comparison 19. SE ‐ Restlessness

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Comparison 20. SE ‐ Sleepiness/drowsiness/somnolence

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Placebo Show forest plot	4	584	Odds Ratio (M‐H, Random, 95% CI)	2.15 [0.76, 6.07]

2 Active comparator Show forest plot	2	269	Odds Ratio (M‐H, Random, 95% CI)	1.74 [0.86, 3.53]

2.1 Benzodiazepines (Chlordiazepoxide)	1	106	Odds Ratio (M‐H, Random, 95% CI)	1.58 [0.67, 3.73]
2.2 Buspirone	1	163	Odds Ratio (M‐H, Random, 95% CI)	2.14 [0.62, 7.40]

Comparison 20. SE ‐ Sleepiness/drowsiness/somnolence

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Comparison 21. SE ‐ Weakness

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Placebo Show forest plot	1	79	Odds Ratio (M‐H, Random, 95% CI)	1.75 [0.44, 6.94]

2 Benzodiazepines Show forest plot	1	106	Odds Ratio (M‐H, Random, 95% CI)	1.34 [0.49, 3.66]

2.1 Chlordiazepoxide	1	106	Odds Ratio (M‐H, Random, 95% CI)	1.34 [0.49, 3.66]

Comparison 21. SE ‐ Weakness

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Comparison 22. SE ‐ Weight gain

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Placebo Show forest plot	1	124	Odds Ratio (M‐H, Random, 95% CI)	1.28 [0.40, 4.04]

Comparison 22. SE ‐ Weight gain

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Comparison 23. Sensitivity analysis: efficacy of hydroxyzine 25‐50 mg against all other agents

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Failure to respond Show forest plot	2	450	Odds Ratio (M‐H, Random, 95% CI)	0.48 [0.25, 0.93]

1.1 Buspirone	1	163	Odds Ratio (M‐H, Random, 95% CI)	0.76 [0.40, 1.42]
1.2 Placebo	2	287	Odds Ratio (M‐H, Random, 95% CI)	0.37 [0.15, 0.93]
2 Standardised mean difference Show forest plot	2	765	Std. Mean Difference (IV, Random, 95% CI)	‐0.27 [‐0.47, ‐0.07]

2.1 Bromazepam	1	221	Std. Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.27, 0.26]
2.2 Buspirone	1	163	Std. Mean Difference (IV, Random, 95% CI)	‐0.26 [‐0.57, 0.05]
2.3 Placebo	2	381	Std. Mean Difference (IV, Random, 95% CI)	‐0.42 [‐0.62, ‐0.21]

Comparison 23. Sensitivity analysis: efficacy of hydroxyzine 25‐50 mg against all other agents

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Comparison 24. Sensitivity analysis: efficacy of hydroxyzine 100 mg and above against all other agents

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Failure to respond Show forest plot	2	236	Odds Ratio (Peto, Fixed, 95% CI)	0.42 [0.24, 0.74]

1.1 Chlordiazepoxide	1	106	Odds Ratio (Peto, Fixed, 95% CI)	0.75 [0.35, 1.62]
1.2 Placebo	2	130	Odds Ratio (Peto, Fixed, 95% CI)	0.22 [0.10, 0.50]

Comparison 24. Sensitivity analysis: efficacy of hydroxyzine 100 mg and above against all other agents

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Comparison 25. Sensitivity analysis: excluding dropout rates > 20%

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Failure to respond Show forest plot	3	456	Odds Ratio (M‐H, Random, 95% CI)	0.43 [0.22, 0.84]

1.1 Buspirone	1	163	Odds Ratio (M‐H, Random, 95% CI)	0.76 [0.40, 1.42]
1.2 Placebo	3	293	Odds Ratio (M‐H, Random, 95% CI)	0.32 [0.13, 0.78]
2 Standardised mean difference Show forest plot	2	765	Std. Mean Difference (IV, Random, 95% CI)	‐0.27 [‐0.47, ‐0.07]

2.1 Bromazepam	1	221	Std. Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.27, 0.26]
2.2 Buspirone	1	163	Std. Mean Difference (IV, Random, 95% CI)	‐0.26 [‐0.57, 0.05]
2.3 Placebo	2	381	Std. Mean Difference (IV, Random, 95% CI)	‐0.42 [‐0.62, ‐0.21]

Comparison 25. Sensitivity analysis: excluding dropout rates > 20%

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Comparison 26. Sensitivity analysis: excluding non‐standardised diagnostic criteria

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Failure to respond Show forest plot	2	450	Odds Ratio (M‐H, Random, 95% CI)	0.48 [0.25, 0.93]

1.1 Buspirone	1	163	Odds Ratio (M‐H, Random, 95% CI)	0.76 [0.40, 1.42]
1.2 Placebo	2	287	Odds Ratio (M‐H, Random, 95% CI)	0.37 [0.15, 0.93]
2 Standardised mean difference Show forest plot	3	875	Std. Mean Difference (IV, Random, 95% CI)	‐0.34 [‐0.55, ‐0.12]

2.1 Bromazepam	1	221	Std. Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.27, 0.26]
2.2 Buspirone	1	163	Std. Mean Difference (IV, Random, 95% CI)	‐0.26 [‐0.57, 0.05]
2.3 Placebo	3	491	Std. Mean Difference (IV, Random, 95% CI)	‐0.47 [‐0.65, ‐0.29]

Comparison 26. Sensitivity analysis: excluding non‐standardised diagnostic criteria

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Comparison 27. Sensitivity analysis: excluding standardised diagnostic criteria

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Failure to respond Show forest plot	2	236	Odds Ratio (M‐H, Random, 95% CI)	0.33 [0.11, 0.97]

1.1 Chlordiazepoxide	1	106	Odds Ratio (M‐H, Random, 95% CI)	0.75 [0.35, 1.62]
1.2 Placebo	2	130	Odds Ratio (M‐H, Random, 95% CI)	0.20 [0.06, 0.66]

Comparison 27. Sensitivity analysis: excluding standardised diagnostic criteria

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Comparison 28. Sensitivity analysis: excluding psychiatric comorbidity

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Failure to respond Show forest plot	1	163	Odds Ratio (M‐H, Random, 95% CI)	0.57 [0.30, 1.09]

1.1 Placebo	1	163	Odds Ratio (M‐H, Random, 95% CI)	0.57 [0.30, 1.09]
2 Standardised mean difference Show forest plot	2	549	Std. Mean Difference (IV, Random, 95% CI)	‐0.33 [‐0.69, 0.03]

2.1 Bromazepam	1	221	Std. Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.27, 0.26]
2.2 Placebo	2	328	Std. Mean Difference (IV, Random, 95% CI)	‐0.49 [‐0.77, ‐0.21]

Comparison 28. Sensitivity analysis: excluding psychiatric comorbidity

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