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PRISMA study flow diagram.
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Figure 1

PRISMA study flow diagram.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Forest plot of comparison: 1 Pharmacotherapy versus placebo, outcome: 1.1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales).
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Figure 4

Forest plot of comparison: 1 Pharmacotherapy versus placebo, outcome: 1.1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales).

Forest plot of comparison: 2 Tricyclic antidepressants versus new‐generation antidepressants, outcome: 2.1 Reduction of the level of severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales).
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Figure 5

Forest plot of comparison: 2 Tricyclic antidepressants versus new‐generation antidepressants, outcome: 2.1 Reduction of the level of severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales).

Forest plot of comparison: 3 New‐generation antidepressants (serotonin antagonist and reuptake inhibitors (SARI), noradrenergic and specific serotonergic antidepressant (NaSSA), selective serotonin reuptake inhibitor (SSRI)) versus other new‐generation antidepressants, outcome: 3.1 Reduction of the level of severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales).
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Figure 6

Forest plot of comparison: 3 New‐generation antidepressants (serotonin antagonist and reuptake inhibitors (SARI), noradrenergic and specific serotonergic antidepressant (NaSSA), selective serotonin reuptake inhibitor (SSRI)) versus other new‐generation antidepressants, outcome: 3.1 Reduction of the level of severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales).

Comparison 1 Pharmacotherapy versus placebo, Outcome 1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales).
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Analysis 1.1

Comparison 1 Pharmacotherapy versus placebo, Outcome 1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales).

Comparison 1 Pharmacotherapy versus placebo, Outcome 2 Acceptability.
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Analysis 1.2

Comparison 1 Pharmacotherapy versus placebo, Outcome 2 Acceptability.

Comparison 1 Pharmacotherapy versus placebo, Outcome 3 Anxiety (post‐treatment score on self report and clinician‐rated scales).
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Analysis 1.3

Comparison 1 Pharmacotherapy versus placebo, Outcome 3 Anxiety (post‐treatment score on self report and clinician‐rated scales).

Comparison 1 Pharmacotherapy versus placebo, Outcome 4 Depression (post‐treatment score on self report and clinician‐rated scales).
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Analysis 1.4

Comparison 1 Pharmacotherapy versus placebo, Outcome 4 Depression (post‐treatment score on self report and clinician‐rated scales).

Comparison 1 Pharmacotherapy versus placebo, Outcome 5 Dysfunctional cognitions, emotions, and behaviours (post‐treatment score on self report scales).
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Analysis 1.5

Comparison 1 Pharmacotherapy versus placebo, Outcome 5 Dysfunctional cognitions, emotions, and behaviours (post‐treatment score on self report scales).

Comparison 1 Pharmacotherapy versus placebo, Outcome 6 Adverse effects.
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Analysis 1.6

Comparison 1 Pharmacotherapy versus placebo, Outcome 6 Adverse effects.

Comparison 1 Pharmacotherapy versus placebo, Outcome 7 Treatment response (post‐treatment score on self report and clinician‐rated scales).
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Analysis 1.7

Comparison 1 Pharmacotherapy versus placebo, Outcome 7 Treatment response (post‐treatment score on self report and clinician‐rated scales).

Comparison 1 Pharmacotherapy versus placebo, Outcome 8 Functional disability and quality of life (post‐treatment score on self report scales).
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Analysis 1.8

Comparison 1 Pharmacotherapy versus placebo, Outcome 8 Functional disability and quality of life (post‐treatment score on self report scales).

Comparison 2 Tricyclic antidepressants versus another medication, Outcome 1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales).
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Analysis 2.1

Comparison 2 Tricyclic antidepressants versus another medication, Outcome 1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales).

Comparison 2 Tricyclic antidepressants versus another medication, Outcome 2 Acceptability.
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Analysis 2.2

Comparison 2 Tricyclic antidepressants versus another medication, Outcome 2 Acceptability.

Comparison 2 Tricyclic antidepressants versus another medication, Outcome 3 Anxiety (post‐treatment score on self report and clinician‐rated scales).
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Analysis 2.3

Comparison 2 Tricyclic antidepressants versus another medication, Outcome 3 Anxiety (post‐treatment score on self report and clinician‐rated scales).

Comparison 2 Tricyclic antidepressants versus another medication, Outcome 4 Depression (post‐treatment score on self report and clinician‐rated scales).
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Analysis 2.4

Comparison 2 Tricyclic antidepressants versus another medication, Outcome 4 Depression (post‐treatment score on self report and clinician‐rated scales).

Comparison 2 Tricyclic antidepressants versus another medication, Outcome 5 Adverse effects.
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Analysis 2.5

Comparison 2 Tricyclic antidepressants versus another medication, Outcome 5 Adverse effects.

Comparison 2 Tricyclic antidepressants versus another medication, Outcome 6 Treatment response (post‐treatment score on self report and clinician‐rated scales).
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Analysis 2.6

Comparison 2 Tricyclic antidepressants versus another medication, Outcome 6 Treatment response (post‐treatment score on self report and clinician‐rated scales).

Comparison 3 New‐generation antidepressants (SARI, NaSSA, SSRI) versus another medication, Outcome 1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales).
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Analysis 3.1

Comparison 3 New‐generation antidepressants (SARI, NaSSA, SSRI) versus another medication, Outcome 1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales).

Comparison 3 New‐generation antidepressants (SARI, NaSSA, SSRI) versus another medication, Outcome 2 Acceptability.
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Analysis 3.2

Comparison 3 New‐generation antidepressants (SARI, NaSSA, SSRI) versus another medication, Outcome 2 Acceptability.

Comparison 3 New‐generation antidepressants (SARI, NaSSA, SSRI) versus another medication, Outcome 3 Depression (post‐treatment score on self report and clinician‐rated scales).
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Analysis 3.3

Comparison 3 New‐generation antidepressants (SARI, NaSSA, SSRI) versus another medication, Outcome 3 Depression (post‐treatment score on self report and clinician‐rated scales).

Comparison 3 New‐generation antidepressants (SARI, NaSSA, SSRI) versus another medication, Outcome 4 Adverse effects.
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Analysis 3.4

Comparison 3 New‐generation antidepressants (SARI, NaSSA, SSRI) versus another medication, Outcome 4 Adverse effects.

Comparison 4 Pharmacotherapy versus a combination of medications, Outcome 1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales).
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Analysis 4.1

Comparison 4 Pharmacotherapy versus a combination of medications, Outcome 1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales).

Comparison 4 Pharmacotherapy versus a combination of medications, Outcome 2 Acceptability.
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Analysis 4.2

Comparison 4 Pharmacotherapy versus a combination of medications, Outcome 2 Acceptability.

Comparison 4 Pharmacotherapy versus a combination of medications, Outcome 3 Anxiety (post‐treatment score on self report and clinician‐rated scales).
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Analysis 4.3

Comparison 4 Pharmacotherapy versus a combination of medications, Outcome 3 Anxiety (post‐treatment score on self report and clinician‐rated scales).

Comparison 4 Pharmacotherapy versus a combination of medications, Outcome 4 Depression (post‐treatment score on self report and clinician‐rated scales).
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Analysis 4.4

Comparison 4 Pharmacotherapy versus a combination of medications, Outcome 4 Depression (post‐treatment score on self report and clinician‐rated scales).

Comparison 4 Pharmacotherapy versus a combination of medications, Outcome 5 Adverse effects.
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Analysis 4.5

Comparison 4 Pharmacotherapy versus a combination of medications, Outcome 5 Adverse effects.

Comparison 4 Pharmacotherapy versus a combination of medications, Outcome 6 Treatment response (post‐treatment score on self report and clinician‐rated scales).
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Analysis 4.6

Comparison 4 Pharmacotherapy versus a combination of medications, Outcome 6 Treatment response (post‐treatment score on self report and clinician‐rated scales).

Comparison 5 Subgroup analysis 1: Co‐morbidity (based on the comparison pharmacotherapy versus placebo), Outcome 1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales).
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Analysis 5.1

Comparison 5 Subgroup analysis 1: Co‐morbidity (based on the comparison pharmacotherapy versus placebo), Outcome 1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales).

Comparison 5 Subgroup analysis 1: Co‐morbidity (based on the comparison pharmacotherapy versus placebo), Outcome 2 Acceptability.
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Analysis 5.2

Comparison 5 Subgroup analysis 1: Co‐morbidity (based on the comparison pharmacotherapy versus placebo), Outcome 2 Acceptability.

Comparison 6 Subgroup analysis 2: Source of funding (based on the comparison pharmacotherapy versus placebo), Outcome 1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales).
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Analysis 6.1

Comparison 6 Subgroup analysis 2: Source of funding (based on the comparison pharmacotherapy versus placebo), Outcome 1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales).

Comparison 6 Subgroup analysis 2: Source of funding (based on the comparison pharmacotherapy versus placebo), Outcome 2 Acceptability.
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Analysis 6.2

Comparison 6 Subgroup analysis 2: Source of funding (based on the comparison pharmacotherapy versus placebo), Outcome 2 Acceptability.

Comparison 7 Subgroup analysis 3: Source outcome rating (based on the comparison pharmacotherapy versus placebo), Outcome 1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score).
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Analysis 7.1

Comparison 7 Subgroup analysis 3: Source outcome rating (based on the comparison pharmacotherapy versus placebo), Outcome 1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score).

Comparison 8 Best‐case/worst‐case analysis (based on comparison 'new‐generation antidepressants versus placebo'), Outcome 1 Treatment response (post‐treatment score on self report and clinician‐rated scales).
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Analysis 8.1

Comparison 8 Best‐case/worst‐case analysis (based on comparison 'new‐generation antidepressants versus placebo'), Outcome 1 Treatment response (post‐treatment score on self report and clinician‐rated scales).

Comparison 9 Best‐case/worst‐case analysis (based on comparison 'natural products versus placebo'), Outcome 1 Treatment response (post‐treatment score on self report and clinician‐rated scales).
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Analysis 9.1

Comparison 9 Best‐case/worst‐case analysis (based on comparison 'natural products versus placebo'), Outcome 1 Treatment response (post‐treatment score on self report and clinician‐rated scales).

Summary of findings for the main comparison. Tricyclic antidepressants versus placebo for somatoform disorders in adults

Tricyclic antidepressants versus placebo for somatoform disorders in adults

Patient or population: somatoform disorders in adults
Settings: outpatient setting
Intervention: tricyclic antidepressants versus placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Tricyclic antidepressants versus placebo

Severity/intensity of MUPS (post‐treatment score on self report scales)
Different self report scales (SCL‐90‐R Somatisation Subscore, VAS)1
Follow‐up: 6‐12 weeks

The mean severity/intensity of MUPS (post‐treatment score on self report scales) in the intervention groups was
0.13 standard deviations lower
(0.39 lower to 0.13 higher)

239
(2 studies)

⊕⊕⊝⊝
low2,3

SMD ‐0.13 (95% CI ‐0.39 to 0.13)

Acceptability (all‐cause drop‐outs)

No data available

Anxiety (post‐treatment score on self report and clinician‐rated scales)

No data available

Depression (post‐treatment score on self report and clinician‐rated scales)

No data available

Adverse effects (drop‐outs due to adverse effects)

No data available

Treatment response (post‐treatment score on self report and clinician‐rated scales)

No data available

Functional disability and quality of life (post‐treatment score on self report and clinician‐rated scales)

No data available

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. 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).
CI: confidence interval; MUPS: medically unexplained physical symptoms; SCL: Symptom Checklist; SMD: standardised mean difference; VAS: visual analogue scale.

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 SCL‐90‐R and VAS: high scale scores correspond to a negative outcome.
2 We considered the results to have a serious risk of bias and so we downgraded the quality of evidence by 1 point because none of the following criteria was met: a low risk of bias for sequence generation, allocation concealment, blinding of participants and assessors, incomplete outcome data, and selective outcome reporting.
3 We considered the results to be imprecise because the total population size was fewer than 400 and so we downgraded the quality of evidence by 1 point.

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Summary of findings for the main comparison. Tricyclic antidepressants versus placebo for somatoform disorders in adults
Summary of findings 2. New‐generation antidepressants versus placebo for somatoform disorders in adults

New‐generation antidepressants versus placebo for somatoform disorders in adults

Patient or population: somatoform disorders in adults
Settings: outpatient setting
Intervention: new‐generation antidepressants (SSRI, SNRI) versus placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

New‐generation antidepressants versus placebo

Severity/intensity of MUPS (post‐treatment score on self report scales)
Different self report scales (PHQ‐15, MOSPM)1
Follow‐up: 8‐12 weeks

The mean severity/intensity of MUPS in the intervention groups was
0.91 standard deviations lower
(1.36 to 0.46 lower)

243
(3 studies)

⊕⊝⊝⊝
very low2,3,4

SMD ‐0.91 (95% CI ‐1.36 to ‐0.46)

Acceptability (all‐cause drop‐outs)5

Follow‐up: mean 12 weeks

Study population

RR 1.01
(0.64 to 1.61)

163
(2 studies)

⊕⊕⊝⊝
low2,6

265 per 1000

268 per 1000
(170 to 427)

Moderate

193 per 1000

195 per 1000
(124 to 311)

Anxiety (post‐treatment score on self report and clinician‐rated scales)
Clinician‐rated scales (HARS)7
Follow‐up: mean 12 weeks

The mean anxiety score in the intervention groups was
0.88 standard deviations lower
(1.81 lower to 0.05 higher)

163
(2 studies)

⊕⊝⊝⊝
very low2,3,4

SMD ‐0.88 (95% CI ‐1.81 to 0.05)

Depression (post‐treatment score on self report and clinician‐rated scales)
Different clinician‐rated scales (HDRS, MADRS)8
Follow‐up: mean 12 weeks

The mean depression score in the intervention groups was
0.56 standard deviations lower
(0.88 to 0.25 lower)

163
(2 studies)

⊕⊝⊝⊝
very low2,3,4

SMD ‐0.56 (95% CI ‐0.88 to ‐0.25)

Adverse effects (drop‐outs due to adverse effects)5
Follow‐up: mean 12 weeks

Study population

RR 2.26
(0.52 to 9.81)

163
(2 studies)

⊕⊕⊝⊝
low2,6

24 per 1000

54 per 1000
(13 to 236)

Moderate

18 per 1000

41 per 1000
(9 to 177)

Treatment response (post‐treatment score on self report and clinician‐rated scales)
Different self report and clinician‐rated scales (PHQ‐15, CGI ‐ Improvement Scale)
Follow‐up: mean 12 weeks

Study population

RR 2
(0.9 to 4.43)

163
(2 studies)

⊕⊝⊝⊝
very low2,3,6

337 per 1000

675 per 1000
(304 to 1000)

Moderate

319 per 1000

638 per 1000
(287 to 1000)

Functional disability and quality of life (post‐treatment score on self report scales)
Different self report scales (SF‐36, SDS)9
Follow‐up: mean 12 weeks

The mean functional disability score/quality of life score in the intervention groups was
0.52 standard deviations lower/higher
(1 to 0.04 lower/higher)

163
(2 studies)

⊕⊝⊝⊝
very low2,3,4

SMD ‐0.52 (95% CI ‐1 to ‐0.04)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. 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).
CGI: Clinical Global Impression Scale; CI: confidence interval; HARS: Hamilton Anxiety Rating Scale; HDRS: Hamilton Depression Rating Scale; MADRS: Montgomery‐Åsberg Depression Rating Scale; MOSPM: Medical Outcomes Study Pain Measures; MUPS: medically unexplained physical symptoms; PHQ: Patient Health Questionnaire; RR: risk ratio; SDS: Sheehan Disability Scale; SF‐36: 36‐item Short Form; SMD: standardised mean difference; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor.

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 PHQ‐15 and MOSPM: high scale scores correspond to a negative outcome.
2 We considered the results to have a serious risk of bias and so we downgraded the quality of evidence by 1 point because none of the following criteria was met: a low risk of bias for sequence generation, allocation concealment, blinding of participants and assessors, incomplete outcome data, and selective outcome reporting.
3 We assumed that in 1 study, the SE instead of SD were reported (Muller 2008). Therefore, we re‐calculated the values of variance before we entered them into the meta‐analysis. The effect size of this study was still quite high in comparison to the other studies and could be considered as an outlier. A sensitivity analysis where we excluded this study did not change the pooled effect size significantly. Therefore, we considered the results to be inconsistent and so we downgraded the quality of evidence by 1 point.
4 We considered the results to be imprecise because the total population size was fewer than 400 and so we downgraded the quality of evidence by 1 point.
5 We calculated this rate as a proportion of the total number of randomised participants.
6 We considered the results to be imprecise because the total number of events was fewer than 300 and so we downgraded the quality of evidence by 1 point.
7 HARS: high scale scores correspond to a negative outcome.
8 HDRS and MADRS: high scale scores correspond to a negative outcome.
9 SF‐36: high scale scores correspond to a positive outcome and had to be re‐coded; SDS: high scale scores correspond to a negative outcome.

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Summary of findings 2. New‐generation antidepressants versus placebo for somatoform disorders in adults
Summary of findings 3. Natural products versus placebo for somatoform disorders in adults

Natural products versus placebo for somatoform disorders in adults

Patient or population: somatoform disorders in adults
Settings: outpatient setting
Intervention: natural products versus placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Natural products versus placebo

Severity/intensity of MUPS (post‐treatment score on self report scales)
Different self report scales (SOMS‐7, SCL‐90‐R Somatisation Subscore)1
Follow‐up: mean 6 weeks

The mean severity/intensity of MUPS in the intervention groups was
0.74 standard deviations lower
(0.97 to 0.51 lower)

322
(2 studies)

⊕⊕⊝⊝
low2,3

SMD ‐0.74 (95% CI ‐0.97 to ‐0.51)

Acceptability (all‐cause drop‐outs4)
Follow‐up: 2‐6 weeks

Study population

RR 0.85
(0.4 to 1.78)

506
(3 studies)

⊕⊕⊝⊝
low2,5

58 per 1000

50 per 1000
(23 to 104)

Moderate

68 per 1000

58 per 1000
(27 to 121)

Anxiety (post‐treatment score on self report and clinician‐rated scales)
Different self report and clinician‐rated scales (HARS, VAS)6
Follow‐up: 2‐6 weeks

The mean anxiety score in the intervention groups was
0.83 standard deviations lower
(1.13 to 0.52 lower)

321
(2 studies)

⊕⊕⊝⊝
low2,3

SMD ‐0.83 (95% CI ‐1.13 to ‐0.52)

Depression (post‐treatment score on self report and clinician‐rated scales)
Different self report and clinician‐rated scales (HDRS, BDI)7
Follow‐up: 2‐6 weeks

The mean depression score in the intervention groups was
0.64 standard deviations lower
(0.87 to 0.41 lower)

321
(2 studies)

⊕⊕⊝⊝
low2,3

SMD ‐0.64 (95% CI ‐0.87 to ‐0.41)

Adverse effects (drop‐outs due to adverse effects4)
Follow‐up: 2‐6 weeks

Study population

RR 0.54
(0.08 to 3.5)

506
(3 studies)

⊕⊕⊝⊝
low2,5

13 per 1000

7 per 1000
(1 to 47)

Moderate

16 per 1000

9 per 1000
(1 to 56)

Treatment response (post‐treatment score on self report and clinician‐rated scales)
Different self report and clinician‐rated scales (PHQ‐15, CGI ‐ Improvement Scale)
Follow‐up: mean 12 weeks

Study population

RR 1.77
(1.34 to 2.34)

324
(2 studies)

⊕⊝⊝⊝
very low2,5,8

340 per 1000

601 per 1000
(455 to 794)

Moderate

352 per 1000

623 per 1000
(472 to 824)

Functional disability and quality of life (post‐treatment score on self report scales)

No data available

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. 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).
BDI: Beck Depression Inventory; CGI: Clinical Global Impression Scale; CI: confidence interval; HARS: Hamilton Anxiety Rating Scale; HDRS: Hamilton Depression Rating Scale; MUPS: medically unexplained physical symptoms; PHQ: Patient Health Questionnaire; RR: risk ratio; SCL: Symptom Checklist; SMD: standardised mean difference; SOMS: Screening for Somatoform Symptoms; VAS: visual analogue scale.

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 SOMS‐7 and SCL‐90‐R: high scale scores correspond to a negative outcome.
2 We considered the results to have a serious risk of bias and so we downgraded the quality of evidence by 1 point because none of the following criteria was met: a low risk of bias for sequence generation, allocation concealment, blinding of participants and assessors, incomplete outcome data, and selective outcome reporting.
3 We considered the results to be imprecise because the total population size was fewer than 400 and so we downgraded the quality of evidence by 1 point.
4 We calculated this rate as a proportion of the total number of randomised participants.
5 We considered the results to be imprecise because the total number of events was fewer than 300 and so we downgraded the quality of evidence by 1 point.
6 HARS and VAS: high scale scores correspond to a negative outcome.
7 HDRS and BDI: high scale scores correspond to a negative outcome.
8 We assumed that in 1 study, the SE instead of SD were reported (Muller 2008). Therefore, we re‐calculated the values of variance in SE before we entered them in the meta‐analysis. The effect size of this study was still quite high in comparison to the other studies and could be considered as an outlier. A sensitivity analysis where we excluded this study did not change the pooled effect size significantly. Therefore, we considered the results to be inconsistent and so we downgraded the quality of evidence by 1 point.

Figuras y tablas -
Summary of findings 3. Natural products versus placebo for somatoform disorders in adults
Summary of findings 4. Tricyclic antidepressants versus another medication for somatoform disorders in adults

Tricyclic antidepressants versus another medication for somatoform disorders in adults

Patient or population: somatoform disorders in adults
Settings: outpatient and inpatient setting
Intervention: tricyclic antidepressants versus another medication

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Tricyclic antidepressants versus another medication

Severity/intensity of MUPS (post‐treatment score on self report scales)
Different self report scales (VAS‐Pain, SCL‐90‐R Somatisation Subscore)1
Follow‐up: 6‐8 weeks

The mean severity/intensity of MUPS in the intervention groups was
0.16 standard deviations lower
(0.55 lower to 0.23 higher)

177
(3 studies)

⊕⊕⊝⊝
low2,3

SMD ‐0.16 (95% CI ‐0.55 to 0.23)

Acceptability (all‐cause drop‐outs4)
Follow‐up: 4‐8 weeks

Study population

RR 1.48
(0.59 to 3.72)

556
(8 studies)

⊕⊕⊝⊝
low2,5

28 per 1000

41 per 1000
(16 to 103)

Moderate

0 per 1000

0 per 1000
(0 to 0)

Anxiety (post‐treatment score on self report and clinician‐rated scales)
Different self report and clinician‐rated scales (HARS, SCL‐90 Anxiety Subscore)6
Follow‐up: 6‐8 weeks

The mean anxiety score in the intervention groups was
0.37 standard deviations higher
(0.21 lower to 0.95 higher)

255
(4 studies)

⊕⊝⊝⊝
very low2,3,7

SMD 0.37 (95% CI ‐0.21 to 0.95)

Depression (post‐treatment score on self report and clinician‐rated scales)
Different self report and clinician‐rated scales (VAS Sadness, HDRS, SCL‐90 Depression Subscore, ZDS)8
Follow‐up: 6‐8 weeks

The mean depression score in the intervention groups was
0.17 standard deviations higher
(0.07 lower to 0.4 higher)

395
(6 studies)

⊕⊕⊝⊝
low2,3

SMD 0.17 (95% CI ‐0.07 to 0.4)

Adverse effects (drop‐outs due to adverse effects4)
Follow‐up: 4‐8 weeks

Study population

RR 2.37
(0.39 to 14.28)

556
(8 studies)

⊕⊕⊝⊝
low2,5

10 per 1000

25 per 1000
(4 to 148)

Moderate

0 per 1000

0 per 1000
(0 to 0)

Treatment response (post‐treatment score on self report and clinician‐rated scales)
CGI ‐ Improvement Scale
Follow‐up: mean 8 weeks

Study population

RR 0.93
(0.73 to 1.19)

130
(2 studies)

⊕⊕⊝⊝
low2,9

677 per 1000

630 per 1000
(494 to 806)

Moderate

681 per 1000

633 per 1000
(497 to 810)

Functional disability and quality of life

No data available

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. 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).
CGI: Clinical Global Impression Scale; CI: confidence interval; HARS: Hamilton Anxiety Rating Scale; HDRS: Hamilton Depression Rating Scale; MUPS: medically unexplained physical symptoms; RR: risk ratio; SCL: Symptom Checklist; SMD: standardised mean difference; VAS: Visual Analogue Scale; ZDS: Zung Depression Scale.

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 VAS ‐ Pain and SCL‐90‐R: high scale scores correspond to a negative outcome.
2 We considered the results to have a serious risk of bias and so we downgraded the quality of evidence by 1 point because none of the following criteria was met: a low risk of bias for sequence generation, allocation concealment, blinding of participants and assessors, incomplete outcome data, and selective outcome reporting.
3 We considered the results to be imprecise because the total population size was fewer than 400 and so we downgraded the quality of evidence by 1 point.
4 We calculated this rate as a proportion of the total number of randomised participants.
5 We considered the results to be imprecise because the 95% CI around the pooled effect included both 1. no effect and 2. appreciable benefit or appreciable harm. Therefore, we downgraded the quality of evidence by 1 point.
6 HARS: high scale scores correspond to a negative outcome.
7 We considered the results to be inconsistent because the I2 value was large. Therefore, we downgraded the quality of evidence by 1 point.
8 VAS Sadness, HDRS, SCL‐90, and ZDS: high scale scores correspond to a negative outcome.
9 We considered the results to be imprecise because the total number of events was fewer than 300 and so we downgraded the quality of evidence by 1 point.

Figuras y tablas -
Summary of findings 4. Tricyclic antidepressants versus another medication for somatoform disorders in adults
Summary of findings 5. Antidepressants versus a combination of medications for somatoform disorders in adults

Antidepressants versus a combination of medications for somatoform disorders in adults

Patient or population: somatoform disorders in adults
Settings: outpatient setting
Intervention: antidepressants versus a combination of antidepressant and antipsychotic

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Pharmacotherapy versus a combination of medications

Severity/intensity of MUPS (post‐treatment score on self report scales)
Different self report and clinician‐rated scales (SOMS‐7, SCL‐90 Somatisation Score)1
Follow‐up: 6‐8 weeks

The mean severity/intensity of MUPS in the intervention groups was
0.77 standard deviations higher
(0.32 to 1.22 higher)

107
(2 studies)

⊕⊕⊝⊝
low2,3

SMD 0.77 (95% CI 0.32 to 1.22)

Acceptability (all‐cause drop‐outs4)
Follow‐up: 6‐8 weeks

Study population

RR 0.8
(0.25 to 2.52)

118
(2 studies)

⊕⊕⊝⊝
low2,5

190 per 1000

152 per 1000
(47 to 478)

Moderate

186 per 1000

149 per 1000
(47 to 469)

Anxiety (post‐treatment score on self report and clinician‐rated scales)
Different self report and clinician‐rated scales (HARS, SCL‐90 Anxiety Subscore)6
Follow‐up: 6‐8 weeks

The mean anxiety in the intervention groups was
0.95 standard deviations higher
(0.91 lower to 2.82 higher)

107
(2 studies)

⊕⊝⊝⊝
very low2,3,7

SMD 0.95 (95% CI ‐0.91 to 2.82)

Depression (post‐treatment score on self report and clinician‐rated scales)
Different self report and clinician‐rated scales (HDRS, SCL‐90 depression subscore)8
Follow‐up: 6‐8 weeks

The mean depression in the intervention groups was
0.58 standard deviations higher
(0.33 lower to 1.48 higher)

107
(2 studies)

⊕⊝⊝⊝
very low2,3,7

SMD 0.58 (95% CI ‐0.33 to 1.48)

Adverse effects (drop‐outs due to adverse effects)

No data available

Treatment response (post‐treatment score on self report and clinician‐rated scales)

No data available

Functional disability and quality of life

No data available

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. 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).
CI: confidence interval; HARS: Hamilton Anxiety Rating Scale; HDRS: Hamilton Depression Rating Scale; MUPS: medically unexplained physical symptoms; RR: risk ratio; SCL: Symptom Checklist; SMD: standardised mean difference; SOMS: Screening for Somatoform Symptoms.

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 SOMS‐7 and SCL‐90 Somatisation Score: high scale scores correspond to a negative outcome.
2 We considered the results to have a serious risk of bias and so we downgraded the quality of evidence by 1 point because none of the following criteria was met: a low risk of bias for sequence generation, allocation concealment, blinding of participants and assessors, incomplete outcome data, and selective outcome reporting.
3 We considered the results to be imprecise because the total population size was fewer than 400 and so we downgraded the quality of evidence by 1 point.
4 We calculated this rate as a proportion of the total number of randomised participants.
5 We considered the results imprecise because the total number of events was fewer than 300 and so we downgraded the quality of evidence by 1 point.
6 HARS and SCL‐90: high scale scores correspond to a negative outcome.
7 We considered the results to be inconsistent because the I2 value was large. Therefore, we downgraded the quality of evidence by 1 point.
8 HDRS and SCL‐90 Depression Subscore: high scale scores correspond to a negative outcome.

Figuras y tablas -
Summary of findings 5. Antidepressants versus a combination of medications for somatoform disorders in adults
Table 1. Diagnostic categories of somatoform disorders

Diagnostic category

Eligible for the current review?

DSM‐IV

ICD‐10

yes

no

Somatisation disorder (300.81)

Somatisation disorder (F45.0)

x

Undifferentiated somatoform disorder (300.82)

Undifferentiated somatoform disorder (F45.1)

x

Somatoform autonomic dysfunction (F45.3)

x

Pain disorder (307.8)

Persistent somatoform pain disorder (F45.4)

x

Hypochondriasis (300.7)

Hypochondriacal disorder (F45.2)

x

Other somatoform disorders (F45.8)

x

Somatoform disorders, unspecified (300.82)

Somatoform disorders, unspecified (F45.9)

x

Body dysmorphic disorder (300.7)

Body dysmorphic disorder (F45.2)

x

Conversion disorder (300.11)

Dissociative and conversion disorders (F44)*

x

DSM‐IV: Diagnostic and Statistical Manual of Mental Disorders; ICD‐10: International Classification of Diseases.

Note. *Conversion disorder is not classified as a somatoform disorder in ICD‐10 but is a separate diagnostic category.

Figuras y tablas -
Table 1. Diagnostic categories of somatoform disorders
Table 2. Co‐morbid mental disorders or exclusion of co‐morbid mental conditions in trials comparing pharmacotherapy versus placebo or other medication (see also subgroup analyses 'Pharmacotherapy versus placebo (subgrouped by co‐morbidity of participants)')

Trial ID

Experimental treatment group ‐ medication class

Control treatment group ‐ medication class

Co‐morbid mental disorders? Yes/no/ns

Detailed information about co‐morbid diagnoses in participants

or exclusion of participants with co‐morbid diagnoses (for studies that do not provide details about co‐morbid conditions)

Detailed information about the exclusion of participants with co‐morbid diagnoses

Kroenke 2006

SNRI

Yes

Major depression, generalised anxiety disorder, social anxiety disorder

People with current/past history of mania, bipolar disorder, schizophrenia, or other psychotic disorder; history of serious or clinically unstable psychiatric condition; known or suspected alcohol or drug abuse within 6 months of screening

Luo 2009

SSRI

Yes

38/80 participants had depression (17 item‐HDRS ≥ 17)

People with co‐exist depressive symptoms occurred prior to pain with HDRS ‐ Total Score ≥ 17

Melzer 2009

NP

No

People with historically known or clinical indication of a psychiatric disorder

Müller 2004

NP

ns

People with co‐morbid depression, drug/alcohol abuse, schizophrenia, or schizo‐affective disorder

Muller 2008

SSRI

Yes

Dysthymia (27.5%); major depressive episode (2.0%); anxiety disorder (panic disorder/agoraphobia/social anxiety disorder/generalised anxiety disorder) (52.9%)

People with somatic symptoms that were judged to be secondary to a psychiatric disorder other than MDS; current or past psychotic disorder; significant suicidal risk

Pilowsky 1990

TCA

ns

People with psychotic illness (including MDS), organic brain syndrome, or alcohol dependence

Volz 2000

TCA

No

People with other significant Axis I diagnoses (e.g. panic disorder, major depressive disorder, substance abuse)

Volz 2002

NP

ns

People with an additional diagnosis of depression, schizophrenia, schizo‐affective disorder, or dementia

Altamura 1991

AP

AP

Yes

Dysthymia (n = 27), anxiety disorder NOS (n = 6)

ns

Aragona 2005

SSRI

NRI

No

People with a diagnosis of another mental disorder

Eberhard 1988

TeCA

TCA

ns

People with major depressive disorder, abuse of drugs, and other psychiatric illnesses

Han 2008b

SSRI

SSRI

ns

People with history of or current (or both) psychotic disorders (such as schizophrenia, schizoaffective disorder, and bipolar disorder); current DSM Axis I disorders that could possibly account for the somatic symptoms (e.g. MDD, anxiety disorders, factitious disorder, malingering, or another somatoform disorder such as somatisation disorder); substance abuse of dependence in the previous 12 months; effect of co‐morbid psychiatric disorders on the effects of the antidepressants cannot be excluded because of the absence of a structured clinical interview, although participants were rigorously evaluated according to DSM‐IV criteria

Huang 2012

SSRI + AP

SSRI

no

People with a diagnosis of another mental disorder (e.g. panic disorder, MDD, or substance abuse)

Jiang 2005

SNRI

TCA

ns

People with drug dependence, severe psychosis, or paranoia

Ju 2003

SNRI

TCA

ns

People with psychotic symptoms, severe brain injury, or substance abuse

Kong 2004

SSRI

TCA

ns

ns

Li 2006

SSRI + AP

SSRI

ns

ns

Ouyang 2006

NaSSA

TCA

Yes

38/80 participants had depression (17 item‐HDRS ≥ 17). No information about other co‐morbidities in the sample was provided

People whose pain was caused by depression, anxiety, or schizophrenia

Sanada 2010

SSRI

SNRI

ns

ns

Wang 2003

SARI

NSAID

Yes

Based on diagnostic criteria in CCMD‐3: depression (n = 46), dysthymia (n = 50), hypochondriasis (n = 20)

Severely depressed, suicidal people

Yang 2006

SNRI

TCA

ns

ns

Ye 2006

NaSSA

TCA

ns

ns

People with any type of drug dependence

Xu 2004

SNRI

TCA

ns

ns

Zhao 2006

NaSSA

TCA

no

People with other mental disorders

Zitman 1991

TCA + AP

TCA

yes

Atypical depression (n = 1), dysthymic disorder (n = 1), panic disorder (n = 1), nicotine abuse (n = 1), tea abuse (n = 1), benzodiazepine abuse (n = 1)

People with a serious psychiatric disease necessitating immediate treatment; or who were alcohol or illicit drug dependent

Anxiety disorder NOS: anxiety disorder not otherwise specified; AP: antipsychotic; CCMD: Chinese Classification of Mental Disorders; SARI: serotonin antagonist and reuptake inhibitor; DSM: Diagnostic and Statistical Manual of Mental Disorders; HDRS: Hamilton Depression Rating Scale; ID: identification; ns: not specified; MDD: major depressive disorder; MDS: major depressive syndrome; n: number; NaSSA: noradrenergic specific serotonergic antidepressant; NP: natural product; NRI: noradrenaline reuptake inhibitor; NSAID: non‐steroidal anti‐inflammatory drug; SNRI: serotonin noradrenaline reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; TCA: tricyclic antidepressant; TeCA: tetracyclic antidepressant.

Figuras y tablas -
Table 2. Co‐morbid mental disorders or exclusion of co‐morbid mental conditions in trials comparing pharmacotherapy versus placebo or other medication (see also subgroup analyses 'Pharmacotherapy versus placebo (subgrouped by co‐morbidity of participants)')
Table 3. Concomitant treatments or exclusion/permission of concomitant treatments in trials comparing pharmacotherapy versus placebo or other medication

Trial ID

Experimental treatment group ‐ medication class

Control treatment group ‐ medication class

Detailed information about the exclusion of or permission of concomitant treatments

Detailed information about concomitant treatments

Kroenke 2006

SNRI

Exclusion: use of triptans, psychoactive herbal medications, or any other psychoactive drugs or having a positive urine drug test at screening

Permitted: zaleplon, zopiclone (1 dose nightly) as needed for insomnia for up to 6 nights during the 14 days immediately following randomisation and short‐term treatments for symptoms of allergies, colds, or influenza (without psychotropic effects)

‐ Proportion of participants who took at least 1 concomitant medication in venlafaxine ER groups vs. placebo were 63.6% vs. 63.3%; for NSAIDs 10% vs. 13%; for paracetamol (acetaminophen) 7% vs. 9%; for COX‐2 inhibitors 8% vs. 3%; and for salicylates 4% vs. 4%

Luo 2009

SSRI

Exclusion: use of antidepressants for the treatment of pain or depression

Melzer 2009

NP

Exclusion: psychotherapy, physiotherapy, acupuncture, or using psychoactive drugs including central stimulants and α‐/β‐blockers were excluded

Permitted: in case of sleeping disorders, chloral hydrate was allowed up to 3 g/day

Müller 2004

NP

Exclusion: use of psychotropic drugs 4 weeks before and during the study, concomitant psychotherapy, and concomitant treatment with phenprocoumon or cyclosporin (or both)

Muller 2008

SSRI

Exclusion: use of psychotropics or cognitive‐behavioural therapy

Pilowsky 1990

TCA

Volz 2000

TCA

Volz 2002

NP

Exclusion: concomitant treatment with psychopharmacological active compounds

Altamura 1991

AP

AP

Aragona 2005

SSRI

NRI

Exclusion: psychotropic drugs endowed with an analgesic action (e.g. amitriptyline)

Permitted: benzodiazepines at low doses for people with sleep disturbances

‐ Because people with other mental disorders were excluded, participants did not take any other type of psychotropic drugs

Eberhard 1988

TeCA

TCA

Exclusion: other central nervous system‐active drugs

Han 2008a

NaSSA

Exclusion: other psychotropic medications; use of prescription analgesics, muscle relaxants, and corticosteroids

Permitted: hypnosedatives and benzodiazepines only for temporary control of insomnia or anxiety; concomitant medications such as non‐prescription paracetamol were allowed only on an as‐needed basis

‐ Mirtazapine group: 46% lorazepam, 10% alprazolam

‐ Venlafaxine group: 32% lorazepam, 29% alprazolam

Han 2008b

SSRI

SSRI

Exclusion: other psychotropic medications; use of prescription analgesics, muscle relaxants, and corticosteroids

Permitted: hypnosedatives and benzodiazepines only for temporary control of insomnia or anxiety; concomitant medications such as non‐prescription paracetamol were allowed only on an as‐needed basis

‐ Fluoxetine group: 32.1% lorazepam, 7.1% alprazolam

‐ Sertraline group: 35.3% lorazepam, 17.6% alprazolam

Huang 2012

SSRI + AP

SSRI

Exclusion: other psychotropic medications

Permitted: benzodiazepines for insomnia, only for temporary control of the symptoms

Jiang 2005

SNRI

TCA

Permitted: treatment of adverse effects insomnia/anxiety with benzodiazepines and nausea with vitamin B6

Ju 2003

SNRI

TCA

Exclusion: antidepressant and AP medication

Permitted: sleep medication alprazolam (0.4‐0.8 mg/day)

Kong 2004

SSRI

TCA

Permitted: alprazolam of a maximum dose of 0.8 mg/day

Li 2006

SSRI + AP

SSRI

Ouyang 2006

NaSSA

TCA

Exclusion: any other medication

Permitted: exception of benzodiazepines for participants with sleep difficulties

Sanada 2010

SSRI

SNRI

Wang 2003

DAS

NSAID

Exclusion: any other medication

Xu 2004

SNRI

TCA

Yang 2006

SNRI

TCA

Permitted: alprazolam (0.4‐0.8 mg/day) for participants with sleep difficulties

Ye 2006

NaSSA

TCA

Permitted: zolpidem for participants with sleep difficulties

Zhao 2006

NaSSA

TCA

Exclusion: use of MAOI or other antidepressants during the first 2 weeks of treatment; use of other medication such as antidepressants, mood stabiliser, antipsychotic medication, or electroconvulsive therapy during the 8 treatment weeks

Permitted: benzodiazepines were allowed for participants with insomnia. Benzhexol was allowed for participants with extrapyramidal adverse effects

Zitman 1991

TCA + AP

TCA

Permitted: benzodiazepines and non‐narcotic analgesics could be continued during the trial, but the participants were asked to keep the dose as low as possible

AP: antipsychotic; COX: cyclo‐oxygenase; DAS: ; ER: extended release; ID: identification; MAOI: monoamine oxidase inhibitors; NaSSA: noradrenergic specific serotonergic antidepressant; NP: natural product; NRI: noradrenaline reuptake inhibitor; NSAID: non‐steroidal anti‐inflammatory drug; SNRI: serotonin noradrenaline reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; TCA: tricyclic antidepressant; TeCA: tetracyclic antidepressant.

Figuras y tablas -
Table 3. Concomitant treatments or exclusion/permission of concomitant treatments in trials comparing pharmacotherapy versus placebo or other medication
Table 4. Attrition rate (acceptability: proportion of participants who dropped out during the experimental as well as the comparator intervention, calculated as a proportion of the total number of randomised participants)

Trial ID

Experimental treatment

Placebo

Control treatment

Medication class

Chemical

agent

Attrition

Total

% attrition

Attrition

Total

% attrition

Medication class

Chemical agent

Attrition

Total

% attrition

Pilowsky 1990

TCA

Amitriptyline

ns

26

25.0

ns

24

31.0

Kong 2004

TCA

Amitriptyline

0

15

0

SSRI

Paroxetinea

0

45

0

Jiang 2005

TCA

Amitriptyline

0

32

0

SNRI

Venlafaxine

0

36

0

Yang 2006

TCA

Amitriptyline

0

35

0

SNRI

Venlafaxine

0

35

0

Xu 2004

TCA

Amitriptyline

0

35

0

SNRI

Venlafaxine

0

35

0

Ouyang 2006

TCA

Amitriptyline

0

40

0

NaSSA

Mirtazapine

0

40

0

Zhao 2006

TCA

Amitriptyline

ns

30

ne

NaSSA

Mirtazapine

ns

30

ne

Zitman 1991

TCA

Amitriptyline

ns

ns

ne

TCA + AP

Amitriptyline + flupentixol

ns

ns

ne

Ye 2006

TCA

Clomipramine

2

35

5.7

NaSSA

Mirtazapine

2

35

5.7

Eberhard 1988

TCA

Clomipramine

13

40

32.5

TeCA

Maprotiline

5

30

16.7

Ju 2003

TCA

Doxepin

0

34

0

SNRI

Venlafaxine

0

34

0

Volz 2000

TCA

Opipramol

14

104

13.5

13

104

12.4

Zitman 1991

TCA + AP

Amitriptyline + flupentixol

ns

ns

ne

TCA

Amitriptyline

ns

ns

ne

Kong 2004

SSRI

Paroxetinea

0

45

0

TCA

Amitriptyline

0

15

0

Li 2006

SSRI

Paroxetine

0

30

0

SSRI + AP

Paroxetine + quetiapine

2

28

7.1

Sanada 2010

SSRI

Paroxetine

3

11

27.3

SNRI

Milnacipran

5

10

50.0

Luo 2009

SSRI

Fluoxetine

ns

40

ne

ns

40

ne

Han 2008b

SSRI

Fluoxetine

8

28

28.6

SSRI

Sertraline

5

17

29.4

Huang 2012

SSRI

Citalopram

9

30

30.0

SSRI + AP

Citalopram + paliperidone

9

30

30.0

Aragona 2005

SSRI

Citalopram

6

17

35.3

NRI

Reboxetine

9

18

50.0

Muller 2008

SSRI

Escitalopram

1

25

4.0

0

26

0

Han 2008b

SSRI

Sertraline

5

17

29.41

SSRI

Fluoxetine

8

28

28.6

Huang 2012

SSRI + AP

Citalopram + paliperidone

9

30

30.0

SSRI

Citalopram

9

30

30.00

Li 2006

SSRI + AP

Paroxetine + quetiapine

0

30

0

SSRI

Paroxetine

2

28

7.1

Kroenke 2006b

SNRI

Venlafaxine (extended release)

21

55

38.2

22

57

38.6

Jiang 2005

SNRI

Venlafaxine

0

36

0

TCA

Amitriptyline

0

32

0

Yang 2006

SNRI

Venlafaxine

0

35

0

TCA

Amitriptyline

0

35

0

Xu 2004

SNRI

Venlafaxine

0

35

0

TCA

Amitriptyline

0

35

0

Ju 2003

SNRI

Venlafaxine

0

34

0

TCA

Doxepin

0

34

0

Han 2008a

SNRI

Venlafaxine

13

45

28.9

NaSSA

Mirtazapine

11

50

22.0

Sanada 2010

SNRI

Milnacipran

5

10

50.0

SSRI

Paroxetine

3

11

27.3

Ouyang 2006

NaSSA

Mirtazapine

0

40

0

TCA

Amitriptyline

0

40

0

Ye 2006

NaSSA

Mirtazapine

2

35

5.7

TCA

Clomipramine

2

35

5.7

Zhao 2006

NaSSA

Mirtazapine

ns

30

ne

TCA

Amitriptyline

ns

30

ne

Han 2008a

NaSSA

Mirtazapine

11

50

22.0

SNRI

Venlafaxine

13

45

28.9

Eberhard 1988

TeCA

Maprotiline

5

30

16.7

TCA

Clomipramine

13

40

32.5

Aragona 2005

NRI

Reboxetine

9

18

50.0

SSRI

Citalopram

6

17

35.29

Wang 2003

SARI

Traxodone

0

70

0

NSAID

Ibuprofen

0

70

0

Altamura 1991

AP

Levosulpride

2

15

13.3

AP

Racemic sulpiride

2

15

13.3

Altamura 1991

AP

Racemic sulpiride

2

15

13.3

AP

Levosulpride

2

15

13.3

Müller 2004

NP

St. John's wort LI 160

5

87

5.8

6

88

6.8

Volz 2002d

NP

St. John's wort LI 160

0

75

0.0

2

74

2.7

Melzer 2009

NP

Ze 185 3‐/4‐combinationc

10

121

8.3

5

61

8.2

AP: antipsychotic; ID: identification; NaSSA: noradrenergic specific serotonergic antidepressant; ns: not specified; ne: not estimable; NP: natural product; NRI: noradrenaline reuptake inhibitor, SARI: serotonin antagonist and reuptake inhibitor; SNRI: serotonin noradrenaline reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; TCA: tricyclic antidepressant; TeCA: tetracyclic antidepressant.

Total sample sizes and attrition rates refer to the total number of randomised participants.

a Trial included 3 arms: paroxetine, open paroxetine, and placebo; we combined the attrition rate of paroxetine and open paroxetine.

b 117 participants were originally randomised but information about sample sizes of treatment and control group were missing. However, study authors stated that in the intention‐to‐treat (ITT) population, they only included participants who had at least 1 post‐baseline efficacy evaluation yielding in an ITT sample of 112. No information was provided about how the 117 participants were distributed among treatment groups. Therefore, we calculated drop‐out rate based on the 112 sample.

c Trial included 3 arms: Ze 185 4‐combination, Ze 185 3‐combination, and placebo; we combined the attrition rate of the Ze 185 3‐combination and 4‐combination.

d Originally 151 participants were randomised. No participants were excluded after the placebo run‐in phase. However, study authors defined ITT population as a sample of all randomised participants with at least 1 assessment under trial medication. 2 participants had to be excluded from the analysis due to missing values for the primary efficacy variable after baseline. Therefore, the ITT sample included 149 participants. No information was provided how the original 151 participants were distributed among groups. Therefore, we calculated drop‐out rate based on the sample.

Figuras y tablas -
Table 4. Attrition rate (acceptability: proportion of participants who dropped out during the experimental as well as the comparator intervention, calculated as a proportion of the total number of randomised participants)
Comparison 1. Pharmacotherapy versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales) Show forest plot

7

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

1.1 Tricyclic antidepressants versus placebo

2

239

Std. Mean Difference (IV, Random, 95% CI)

‐0.13 [‐0.39, 0.13]

1.2 New‐generation antidepressants (serotonin noradrenaline reuptake inhibitor (SNRI), selective serotonin reuptake inhibitor (SSRI)) versus placebo

3

243

Std. Mean Difference (IV, Random, 95% CI)

‐0.91 [‐1.36, ‐0.46]

1.3 Natural products (St. John's wort LI 160) versus placebo

2

322

Std. Mean Difference (IV, Random, 95% CI)

‐0.74 [‐0.97, ‐0.51]

2 Acceptability Show forest plot

6

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Tricyclic antidepressant versus placebo

1

208

Risk Ratio (M‐H, Random, 95% CI)

1.08 [0.53, 2.18]

2.2 New‐generation antidepressants (SNRI, SSRI) versus placebo

2

163

Risk Ratio (M‐H, Random, 95% CI)

1.01 [0.64, 1.61]

2.3 Natural products (St. John's wort LI 160, Ze 185 3‐/4‐combination) versus placebo

3

506

Risk Ratio (M‐H, Random, 95% CI)

0.85 [0.40, 1.78]

3 Anxiety (post‐treatment score on self report and clinician‐rated scales) Show forest plot

5

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

3.1 Tricyclic antidepressants versus placebo

1

200

Std. Mean Difference (IV, Random, 95% CI)

‐0.01 [‐0.29, 0.26]

3.2 New‐generation antidepressants (SNRI, SSRI) versus placebo

2

163

Std. Mean Difference (IV, Random, 95% CI)

‐0.88 [‐1.81, 0.05]

3.3 Natural products (St. John's wort LI 160, Ze 185 3‐/4‐combination) versus placebo

2

321

Std. Mean Difference (IV, Random, 95% CI)

‐0.83 [‐1.13, ‐0.52]

4 Depression (post‐treatment score on self report and clinician‐rated scales) Show forest plot

5

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

4.1 Tricyclic antidepressant versus placebo

1

200

Std. Mean Difference (IV, Random, 95% CI)

‐0.27 [‐0.55, 0.01]

4.2 New‐generation antidepressants (SSRI, SNRI) versus placebo

2

163

Std. Mean Difference (IV, Random, 95% CI)

‐0.56 [‐0.88, ‐0.25]

4.3 Natural products (St. John's wort, Ze 185) versus placebo

2

321

Std. Mean Difference (IV, Random, 95% CI)

‐0.64 [‐0.87, ‐0.41]

5 Dysfunctional cognitions, emotions, and behaviours (post‐treatment score on self report scales) Show forest plot

1

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

5.1 New‐generation antidepressants (SSRI) versus placebo

1

51

Std. Mean Difference (IV, Random, 95% CI)

0.26 [‐0.29, 0.81]

6 Adverse effects Show forest plot

6

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

6.1 Tricyclic antidepressant versus placebo

1

208

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.21, 4.84]

6.2 New‐generation antidepressants (SNRI, SSRI) versus placebo

2

163

Risk Ratio (M‐H, Random, 95% CI)

2.26 [0.52, 9.81]

6.3 Natural products (St. John's wort LI 160, Ze 185 3‐/4‐combination) versus placebo

3

506

Risk Ratio (M‐H, Random, 95% CI)

0.54 [0.08, 3.50]

7 Treatment response (post‐treatment score on self report and clinician‐rated scales) Show forest plot

5

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

7.1 Tricyclic antidepressant versus placebo

1

208

Risk Ratio (M‐H, Random, 95% CI)

1.29 [0.95, 1.73]

7.2 New‐generation antidepressants (SNRI, SSRI) versus placebo

2

163

Risk Ratio (M‐H, Random, 95% CI)

2.00 [0.90, 4.43]

7.3 Natural products (St. John's wort LI 160) versus placebo

2

324

Risk Ratio (M‐H, Random, 95% CI)

1.77 [1.34, 2.34]

8 Functional disability and quality of life (post‐treatment score on self report scales) Show forest plot

3

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

8.1 Tricyclic antidepressant versus placebo

1

44

Std. Mean Difference (IV, Random, 95% CI)

0.01 [‐0.58, 0.60]

8.2 New‐generation antidepressants (SNRI, SSRI) versus placebo

2

163

Std. Mean Difference (IV, Random, 95% CI)

‐0.52 [1.00, ‐0.04]

Figuras y tablas -
Comparison 1. Pharmacotherapy versus placebo
Comparison 2. Tricyclic antidepressants versus another medication

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales) Show forest plot

3

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

1.1 Tricyclic antidepressants versus new‐generation antidepressants (noradrenergic and specific serotonergic antidepressant (NaSSA), tetracyclic antidepressant (TeCA))

3

177

Std. Mean Difference (IV, Random, 95% CI)

‐0.16 [‐0.55, 0.23]

2 Acceptability Show forest plot

8

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Tricyclic antidepressants versus new‐generation antidepressants (NaSSA, serotonin noradrenaline reuptake inhibitor (SNRI), TeCA)

8

556

Risk Ratio (M‐H, Random, 95% CI)

1.48 [0.59, 3.72]

3 Anxiety (post‐treatment score on self report and clinician‐rated scales) Show forest plot

4

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

3.1 Tricyclic antidepressants versus new‐generation antidepressants (NaSSA, SNRI, SSRI)

4

255

Std. Mean Difference (IV, Random, 95% CI)

0.37 [‐0.21, 0.95]

4 Depression (post‐treatment score on self report and clinician‐rated scales) Show forest plot

6

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

4.1 Tricyclic antidepressants versus new‐generation antidepressants (NaSSA, SNRI, TeCA)

6

395

Std. Mean Difference (IV, Random, 95% CI)

0.17 [‐0.07, 0.40]

5 Adverse effects Show forest plot

8

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

5.1 Tricyclic antidepressant versus new‐generation antidepressants (NaSSA, SNRI, TeCA)

8

556

Risk Ratio (M‐H, Random, 95% CI)

2.37 [0.39, 14.28]

6 Treatment response (post‐treatment score on self report and clinician‐rated scales) Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

6.1 Tricyclic antidepressant versus new‐generation antidepressants (NaSSA)

2

130

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.73, 1.19]

Figuras y tablas -
Comparison 2. Tricyclic antidepressants versus another medication
Comparison 3. New‐generation antidepressants (SARI, NaSSA, SSRI) versus another medication

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales) Show forest plot

4

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

1.1 New‐generation antidepressants (noradrenergic and specific serotonergic antidepressant (NaSSA), selective serotonin reuptake inhibitor (SSRI)) versus other new‐generation antidepressants (noradrenaline reuptake inhibitor (NRI), serotonin noradrenaline reuptake inhibitor (SNRI), SSRI)

4

182

Std. Mean Difference (IV, Random, 95% CI)

‐0.16 [‐0.45, 0.14]

2 Acceptability Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 New‐generation antidepressants (NaSSA, SSRI) versus other new‐generation antidepressants (NRI, SNRI, SSRI)

4

196

Risk Ratio (M‐H, Random, 95% CI)

0.92 [0.60, 1.40]

3 Depression (post‐treatment score on self report and clinician‐rated scales) Show forest plot

4

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

3.1 New‐generation antidepressants (NaSSA, SSRI) versus other new‐generation antidepressants (NRI, SNRI, SSRI)

3

169

Std. Mean Difference (IV, Random, 95% CI)

0.41 [0.00, 0.82]

3.2 New‐generation antidepressant (serotonin antagonist and reuptake inhibitors (SARI)) versus non‐steroidal anti‐inflammatory drugs

1

140

Std. Mean Difference (IV, Random, 95% CI)

‐3.87 [‐4.44, ‐3.31]

4 Adverse effects Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.1 New‐generation antidepressants (NaSSA, SSRI) versus other new‐generation antidepressants (NRI, SNRI, SSRI)

4

196

Risk Ratio (M‐H, Random, 95% CI)

0.84 [0.35, 2.03]

Figuras y tablas -
Comparison 3. New‐generation antidepressants (SARI, NaSSA, SSRI) versus another medication
Comparison 4. Pharmacotherapy versus a combination of medications

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales) Show forest plot

3

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

1.1 Tricyclic antidepressant versus tricyclic antidepressant + antipsychotic

1

34

Std. Mean Difference (IV, Random, 95% CI)

0.26 [‐0.42, 0.94]

1.2 Selective serotonin reuptake inhibitor versus selective serotonin reuptake inhibitor + antipsychotic

2

107

Std. Mean Difference (IV, Random, 95% CI)

0.77 [0.32, 1.22]

2 Acceptability Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Selective serotonin reuptake inhibitor versus selective serotonin reuptake inhibitor + antipsychotic

2

118

Risk Ratio (M‐H, Random, 95% CI)

0.80 [0.25, 2.52]

3 Anxiety (post‐treatment score on self report and clinician‐rated scales) Show forest plot

2

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

3.1 Selective serotonin reuptake inhibitor versus selective serotonin reuptake inhibitor + antipsychotic

2

107

Std. Mean Difference (IV, Random, 95% CI)

0.95 [‐0.91, 2.82]

4 Depression (post‐treatment score on self report and clinician‐rated scales) Show forest plot

3

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

4.1 Tricyclic antidepressant versus tricyclic antidepressant + antipsychotic

1

34

Std. Mean Difference (IV, Random, 95% CI)

0.79 [0.09, 1.49]

4.2 Selective serotonin reuptake inhibitor versus selective serotonin reuptake inhibitor + antipsychotic

2

107

Std. Mean Difference (IV, Random, 95% CI)

0.58 [‐0.33, 1.48]

5 Adverse effects Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

5.1 Selective serotonin reuptake inhibitor versus selective serotonin reuptake inhibitor + antipsychotic

2

118

Risk Ratio (M‐H, Random, 95% CI)

0.6 [0.16, 2.29]

6 Treatment response (post‐treatment score on self report and clinician‐rated scales) Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

6.1 Selective serotonin reuptake inhibitor versus selective serotonin reuptake inhibitor + antipsychotic

1

60

Risk Ratio (M‐H, Random, 95% CI)

1.7 [0.94, 3.08]

Figuras y tablas -
Comparison 4. Pharmacotherapy versus a combination of medications
Comparison 5. Subgroup analysis 1: Co‐morbidity (based on the comparison pharmacotherapy versus placebo)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales) Show forest plot

4

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

1.1 Co‐morbid mental disorders

3

243

Std. Mean Difference (IV, Random, 95% CI)

‐0.91 [‐1.36, ‐0.46]

1.2 No co‐morbid mental disorders

1

200

Std. Mean Difference (IV, Random, 95% CI)

‐0.07 [‐0.35, 0.21]

2 Acceptability Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Co‐morbid mental disorder

2

163

Risk Ratio (M‐H, Random, 95% CI)

1.01 [0.64, 1.61]

2.2 No co‐morbid mental disorder

2

390

Risk Ratio (M‐H, Random, 95% CI)

1.05 [0.59, 1.89]

Figuras y tablas -
Comparison 5. Subgroup analysis 1: Co‐morbidity (based on the comparison pharmacotherapy versus placebo)
Comparison 6. Subgroup analysis 2: Source of funding (based on the comparison pharmacotherapy versus placebo)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales) Show forest plot

7

804

Std. Mean Difference (IV, Random, 95% CI)

‐0.66 [‐0.97, ‐0.36]

1.1 Funding by pharmaceutical industry

5

685

Std. Mean Difference (IV, Random, 95% CI)

‐0.64 [‐1.02, ‐0.27]

1.2 No funding by pharmaceutical industry

2

119

Std. Mean Difference (IV, Random, 95% CI)

‐0.75 [‐1.29, ‐0.21]

2 Acceptability Show forest plot

6

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Funding by pharmaceutical industry

6

877

Risk Ratio (M‐H, Random, 95% CI)

0.99 [0.70, 1.40]

Figuras y tablas -
Comparison 6. Subgroup analysis 2: Source of funding (based on the comparison pharmacotherapy versus placebo)
Comparison 7. Subgroup analysis 3: Source outcome rating (based on the comparison pharmacotherapy versus placebo)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score) Show forest plot

7

1377

Std. Mean Difference (IV, Random, 95% CI)

‐0.75 [‐1.00, ‐0.49]

1.1 Self report scales

7

804

Std. Mean Difference (IV, Random, 95% CI)

‐0.66 [‐0.97, ‐0.36]

1.2 Clinician‐rated scales

4

573

Std. Mean Difference (IV, Random, 95% CI)

‐0.91 [‐1.42, ‐0.40]

Figuras y tablas -
Comparison 7. Subgroup analysis 3: Source outcome rating (based on the comparison pharmacotherapy versus placebo)
Comparison 8. Best‐case/worst‐case analysis (based on comparison 'new‐generation antidepressants versus placebo')

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Treatment response (post‐treatment score on self report and clinician‐rated scales) Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Complete‐case analysis

2

119

Risk Ratio (M‐H, Random, 95% CI)

2.02 [0.82, 4.97]

1.2 Best‐case analysis

2

163

Risk Ratio (M‐H, Random, 95% CI)

2.59 [1.90, 3.53]

1.3 Worst‐case analysis

2

163

Risk Ratio (M‐H, Random, 95% CI)

1.41 [0.30, 6.63]

Figuras y tablas -
Comparison 8. Best‐case/worst‐case analysis (based on comparison 'new‐generation antidepressants versus placebo')
Comparison 9. Best‐case/worst‐case analysis (based on comparison 'natural products versus placebo')

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Treatment response (post‐treatment score on self report and clinician‐rated scales) Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Complete‐case analysis

2

311

Risk Ratio (M‐H, Random, 95% CI)

1.75 [1.29, 2.36]

1.2 Best‐case analysis

2

324

Risk Ratio (M‐H, Random, 95% CI)

1.92 [1.26, 2.94]

1.3 Worst‐case analysis

2

324

Risk Ratio (M‐H, Random, 95% CI)

1.57 [1.27, 1.93]

Figuras y tablas -
Comparison 9. Best‐case/worst‐case analysis (based on comparison 'natural products versus placebo')