1 Response ‐ as defined by original studies Show forest plot

4

2262

Odds Ratio (M‐H, Random, 95% CI)

2.21 [1.10, 4.45]

2 Remission ‐ as defined by original studies Show forest plot

4

2262

Odds Ratio (M‐H, Random, 95% CI)

1.83 [1.07, 3.12]

3 Relapse ‐ as defined by original study Show forest plot

1

433

Odds Ratio (M‐H, Random, 95% CI)

0.18 [0.10, 0.30]

4 Global state: clinically important change Show forest plot

4

2262

Odds Ratio (M‐H, Random, 95% CI)

2.28 [1.01, 5.14]

5 Specific anxiety scale Show forest plot

5

Mean Difference (IV, Random, 95% CI)

Subtotals only

5.1 Short‐term HAM‐A change

4

2196

Mean Difference (IV, Random, 95% CI)

‐2.58 [‐4.00, ‐1.16]

5.2 Long‐term HAM‐A‐change

1

432

Mean Difference (IV, Random, 95% CI)

‐2.04 [‐3.25, ‐0.83]

6 Depressive Symptoms : MADRS change Show forest plot

3

Mean Difference (IV, Random, 95% CI)

Subtotals only

6.1 Short‐term MADRS‐change

2

867

Mean Difference (IV, Random, 95% CI)

‐3.05 [‐5.99, ‐0.10]

6.2 Long‐term MADRS change

1

432

Mean Difference (IV, Random, 95% CI)

‐1.85 [‐2.94, ‐0.76]

7 Leaving the study early Show forest plot

5

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

7.1 Short‐term adverse events

4

2262

Odds Ratio (M‐H, Random, 95% CI)

3.76 [2.64, 5.34]

7.2 Long‐term adverse events

1

433

Odds Ratio (M‐H, Random, 95% CI)

0.62 [0.20, 1.92]

8 At least one adverse effect Show forest plot

1

450

Odds Ratio (M‐H, Random, 95% CI)

1.84 [1.26, 2.69]

9 Extrapyramidal side effects ‐ general Show forest plot

5

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

9.1 Short‐term

4

2262

Odds Ratio (M‐H, Random, 95% CI)

1.80 [1.12, 2.90]

9.2 Long‐term

1

433

Odds Ratio (M‐H, Random, 95% CI)

2.39 [0.61, 9.36]

10 Weight ‐ number of patients with significant weight change Show forest plot

5

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

10.1 Short‐term

4

2262

Odds Ratio (M‐H, Random, 95% CI)

2.39 [1.23, 4.65]

10.2 Long‐term

1

433

Odds Ratio (M‐H, Random, 95% CI)

1.00 [0.20, 5.03]

11 Weight ‐ mean change of weight in kg Show forest plot

4

2201

Mean Difference (IV, Random, 95% CI)

0.63 [0.40, 0.86]

12 Prolactin ‐ increase in ng/mL Show forest plot

1

437

Mean Difference (IV, Random, 95% CI)

0.7 [‐1.09, 2.49]

13 Sedation Show forest plot

5

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

13.1 Short‐term

4

2262

Odds Ratio (M‐H, Random, 95% CI)

4.48 [2.65, 7.59]

13.2 Long‐term

1

433

Odds Ratio (M‐H, Random, 95% CI)

11.31 [0.62, 205.84]

14 Subgroup analysis: older versus younger participants ‐ response ‐ as defined by the original studies Show forest plot

4

2262

Odds Ratio (IV, Random, 95% CI)

2.21 [1.10, 4.45]

14.1 Younger participants (< 65 years)

3

1812

Odds Ratio (IV, Random, 95% CI)

1.49 [1.22, 1.81]

14.2 Older participants (> 65 years)

1

450

Odds Ratio (IV, Random, 95% CI)

6.86 [4.53, 10.39]

15 Sensitivity analysis ‐ exclusion of studies with imputed standard deviations Show forest plot

3

Mean Difference (IV, Random, 95% CI)

Subtotals only

15.1 HAM‐A change

3

1777

Mean Difference (IV, Random, 95% CI)

‐1.00 [‐5.26, ‐0.74]

15.2 MADRS change

1

448

Mean Difference (IV, Random, 95% CI)

‐4.72 [‐7.52, ‐1.92]

15.3 Weight ‐ mean change of weight in kg

1

436

Mean Difference (IV, Random, 95% CI)

0.70 [0.23, 1.17]

1 Response ‐ as defined by original studies Show forest plot

2

858

Odds Ratio (M‐H, Random, 95% CI)

1.11 [0.84, 1.46]

2 Remission ‐ as defined by original studies Show forest plot

2

858

Odds Ratio (M‐H, Random, 95% CI)

1.01 [0.76, 1.34]

3 Global state: clinically important change Show forest plot

2

858

Odds Ratio (M‐H, Random, 95% CI)

1.14 [0.86, 1.51]

4 Specific anxiety scale Show forest plot

2

Mean Difference (IV, Random, 95% CI)

Subtotals only

4.1 HAM‐A change

2

842

Mean Difference (IV, Random, 95% CI)

‐0.35 [‐1.73, 1.03]

5 Depressive symptoms Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

5.1 MADRS change

1

410

Mean Difference (IV, Random, 95% CI)

‐0.40 [‐2.43, 1.63]

6 Leaving the study early Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

6.1 Adverse events

2

858

Odds Ratio (M‐H, Random, 95% CI)

2.18 [1.44, 3.31]

7 Extrapyramidal side effects ‐ general Show forest plot

2

858

Odds Ratio (M‐H, Random, 95% CI)

0.88 [0.51, 1.51]

8 Weight ‐ number of of patients with significant weight gain Show forest plot

2

858

Odds Ratio (M‐H, Random, 95% CI)

2.55 [0.43, 15.00]

9 Weight ‐ mean change of weight in kg Show forest plot

2

845

Mean Difference (IV, Random, 95% CI)

0.96 [0.66, 1.25]

10 Prolactin ‐ increase in ng/mL Show forest plot

1

437

Mean Difference (IV, Random, 95% CI)

‐2.53 [‐5.06, ‐0.00]

11 Sedation Show forest plot

2

858

Odds Ratio (M‐H, Random, 95% CI)

2.80 [1.95, 4.02]

12 Sensitivity analysis ‐ exclusion of studies with imputed statistics Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

12.1 HAM‐A change

1

432

Mean Difference (IV, Random, 95% CI)

0.55 [‐1.62, 2.72]

12.2 Weight ‐ mean change in kg

1

434

Mean Difference (IV, Random, 95% CI)

0.8 [0.44, 1.16]

1 Response ‐ as defined by original study Show forest plot

1

22

Odds Ratio (M‐H, Random, 95% CI)

1.44 [0.27, 7.71]

2 Remission ‐ as defined by original study Show forest plot

1

22

Odds Ratio (M‐H, Random, 95% CI)

2.57 [0.36, 18.33]

3 Global state: clinically important change Show forest plot

1

22

Odds Ratio (M‐H, Random, 95% CI)

1.44 [0.27, 7.71]

4 Specific anxiety scale Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

4.1 HAM‐A endpoint

1

22

Mean Difference (IV, Random, 95% CI)

‐1.91 [‐8.74, 4.92]

5 Depressive symptoms: MADRS endpoint Show forest plot

1

22

Mean Difference (IV, Random, 95% CI)

‐1.37 [‐6.92, 4.18]

6 Leaving the study early Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

6.1 Any reason

1

22

Odds Ratio (M‐H, Random, 95% CI)

8.33 [0.78, 89.47]

6.2 Adverse events

1

22

Odds Ratio (M‐H, Random, 95% CI)

13.80 [0.65, 295.25]

6.3 Inefficacy

1

22

Odds Ratio (M‐H, Random, 95% CI)

0.30 [0.01, 8.32]

7 Weight ‐ mean change of weight in kg Show forest plot

1

22

Mean Difference (IV, Random, 95% CI)

0.0 [‐1.35, 1.35]

1 Response ‐ as defined by original study Show forest plot

1

15

Odds Ratio (M‐H, Random, 95% CI)

3.24 [0.13, 80.99]

2 Global state: clinically important change Show forest plot

1

15

Odds Ratio (M‐H, Random, 95% CI)

7.62 [0.33, 175.01]

3 Specific anxiety scale Show forest plot

1

15

Mean Difference (IV, Random, 95% CI)

31.10 [‐85.41, 147.61]

3.1 BSPS endpoint

1

15

Mean Difference (IV, Random, 95% CI)

31.10 [‐85.41, 147.61]

1 Response ‐ as defined by original study Show forest plot

1

12

Odds Ratio (M‐H, Random, 95% CI)

8.56 [0.34, 212.94]

2 Global state: clinically important change Show forest plot

1

12

Odds Ratio (M‐H, Random, 95% CI)

8.56 [0.34, 212.94]

3 Specific anxiety scale: BSPS‐endpoint Show forest plot

1

12

Mean Difference (IV, Random, 95% CI)

‐22.50 [‐35.25, ‐9.75]

4 Leaving the study early Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

4.1 Any reason

1

12

Odds Ratio (M‐H, Random, 95% CI)

1.13 [0.11, 11.60]

4.2 Adverse event

1

12

Odds Ratio (M‐H, Random, 95% CI)

0.67 [0.03, 14.03]

5 Weight ‐ number of patients with significant weight gain Show forest plot

1

12

Odds Ratio (M‐H, Random, 95% CI)

0.2 [0.01, 6.04]

6 Weight ‐ mean change of weight in kg Show forest plot

1

12

Mean Difference (IV, Random, 95% CI)

‐0.36 [‐2.35, 1.63]

1 Response ‐ as defined by original study Show forest plot

1

24

Odds Ratio (M‐H, Random, 95% CI)

7.86 [0.75, 82.13]

2 Remission ‐ as defined by original study Show forest plot

1

24

Odds Ratio (M‐H, Random, 95% CI)

5.5 [0.51, 59.01]

3 Specific anxiety scale Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

3.1 HAM‐A endpoint

1

21

Mean Difference (IV, Random, 95% CI)

‐8.30 [‐14.98, ‐1.62]

4 Depressive symptoms Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

4.1 HAM‐D endpoint

1

21

Mean Difference (IV, Random, 95% CI)

‐5.6 [‐10.24, ‐0.96]

5 At least one adverse effect Show forest plot

1

24

Odds Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

6 Leaving the study early Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

6.1 Any reason

1

24

Odds Ratio (M‐H, Random, 95% CI)

3.57 [0.53, 23.95]

6.2 Adverse events

1

24

Odds Ratio (M‐H, Random, 95% CI)

5.5 [0.51, 59.01]

7 Weight ‐ number of patients with significant weight gain Show forest plot

1

24

Odds Ratio (M‐H, Random, 95% CI)

5.95 [0.26, 138.25]

8 Weight ‐ mean change of weight in kg Show forest plot

1

24

Mean Difference (IV, Random, 95% CI)

4.7 [3.26, 6.14]

9 Sedation Show forest plot

1

24

Odds Ratio (M‐H, Random, 95% CI)

15.40 [1.47, 160.97]

1 Response ‐ as defined by original study Show forest plot

2

457

Odds Ratio (M‐H, Random, 95% CI)

1.19 [0.62, 2.31]

2 Remission Show forest plot

1

417

Odds Ratio (M‐H, Random, 95% CI)

1.07 [0.65, 1.78]

3 Global state: clinically important change Show forest plot

1

40

Odds Ratio (M‐H, Random, 95% CI)

2.27 [0.64, 8.11]

4 Specific anxiety scale Show forest plot

2

Mean Difference (IV, Random, 95% CI)

Subtotals only

4.1 HAM‐A change

2

408

Mean Difference (IV, Random, 95% CI)

‐1.56 [‐4.90, 1.77]

5 Depressive symptoms: MADRS endpoint Show forest plot

1

39

Mean Difference (IV, Random, 95% CI)

‐0.10 [‐2.33, 2.13]

6 Leaving the study early Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

6.1 Any reason

2

457

Odds Ratio (M‐H, Random, 95% CI)

1.19 [0.78, 1.79]

6.2 Adverse event

2

457

Odds Ratio (M‐H, Random, 95% CI)

2.26 [1.08, 4.74]

6.3 Inefficacy

1

417

Odds Ratio (M‐H, Random, 95% CI)

1.56 [0.59, 4.12]

7 Additional benzodiazepine treatment ‐ number of patients Show forest plot

1

40

Odds Ratio (M‐H, Random, 95% CI)

1.0 [0.29, 3.48]

8 Weight ‐ mean change of weight in kg Show forest plot

2

445

Mean Difference (IV, Random, 95% CI)

0.34 [‐0.72, 1.40]

9 Sedation Show forest plot

1

40

Odds Ratio (M‐H, Random, 95% CI)

4.64 [1.02, 21.00]

10 Extrapyramidal side effects ‐ use of antiparkinson medication Show forest plot

1

40

Odds Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]