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Meta-Analysis
. 2014 Nov 7;2014(11):CD010628.
doi: 10.1002/14651858.CD010628.pub2.

Pharmacological interventions for somatoform disorders in adults

Maria Kleinstäuber  1 , Michael Witthöft, Andrés Steffanowski, Harm van Marwijk, Wolfgang Hiller, Michael J Lambert
Affiliations
Meta-Analysis

Pharmacological interventions for somatoform disorders in adults

Maria Kleinstäuber et al. Cochrane Database Syst Rev. .

Abstract

Background: Somatoform disorders are characterised by chronic, medically unexplained physical symptoms (MUPS). Although different medications are part of treatment routines for people with somatoform disorders in clinics and private practices, there exists no systematic review or meta-analysis on the efficacy and tolerability of these medications. We aimed to synthesise to improve optimal treatment decisions.

Objectives: To assess the effects of pharmacological interventions for somatoform disorders (specifically somatisation disorder, undifferentiated somatoform disorder, somatoform autonomic dysfunction, and pain disorder) in adults.

Search methods: We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR) (to 17 January 2014). This register includes relevant randomised controlled trials (RCTs) from The Cochrane Library (all years), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to date). To identify ongoing trials, we searched ClinicalTrials.gov, Current Controlled Trials metaRegister, the World Health Organization International Clinical Trials Registry Platform, and the Chinese Clinical Trials Registry. For grey literature, we searched ProQuest Dissertation & Theses Database, OpenGrey, and BIOSIS Previews. We handsearched conference proceedings and reference lists of potentially relevant papers and systematic reviews and contacted experts in the field.

Selection criteria: We selected RCTs or cluster RCTs of pharmacological interventions versus placebo, treatment as usual, another medication, or a combination of different medications for somatoform disorders in adults. We included people fulfilling standardised diagnostic criteria for somatisation disorder, undifferentiated somatoform disorder, somatoform autonomic dysfunction, or somatoform pain disorder.

Data collection and analysis: One review author and one research assistant independently extracted data and assessed risk of bias. Primary outcomes included the severity of MUPS on a continuous measure, and acceptability of treatment.

Main results: We included 26 RCTs (33 reports), with 2159 participants, in the review. They examined the efficacy of different types of antidepressants, the combination of an antidepressant and an antipsychotic, antipsychotics alone, or natural products (NPs). The duration of the studies ranged between two and 12 weeks.One meta-analysis of placebo-controlled studies showed no clear evidence of a significant difference between tricyclic antidepressants (TCAs) and placebo for the outcome severity of MUPS (SMD -0.13; 95% CI -0.39 to 0.13; 2 studies, 239 participants; I(2) = 2%; low-quality evidence). For new-generation antidepressants (NGAs), there was very low-quality evidence showing they were effective in reducing the severity of MUPS (SMD -0.91; 95% CI -1.36 to -0.46; 3 studies, 243 participants; I(2) = 63%). For NPs there was low-quality evidence that they were effective in reducing the severity of MUPS (SMD -0.74; 95% CI -0.97 to -0.51; 2 studies, 322 participants; I(2) = 0%).One meta-analysis showed no clear evidence of a difference between TCAs and NGAs for severity of MUPS (SMD -0.16; 95% CI -0.55 to 0.23; 3 studies, 177 participants; I(2) = 42%; low-quality evidence). There was also no difference between NGAs and other NGAs for severity of MUPS (SMD -0.16; 95% CI -0.45 to 0.14; 4 studies, 182 participants; I(2) = 0%).Finally, one meta-analysis comparing selective serotonin reuptake inhibitors (SSRIs) with a combination of SSRIs and antipsychotics showed low-quality evidence in favour of combined treatment for severity of MUPS (SMD 0.77; 95% CI 0.32 to 1.22; 2 studies, 107 participants; I(2) = 23%).Differences regarding the acceptability of the treatment (rate of all-cause drop-outs) were neither found between NGAs and placebo (RR 1.01, 95% CI 0.64 to 1.61; 2 studies, 163 participants; I(2) = 0%; low-quality evidence) or NPs and placebo (RR 0.85, 95% CI 0.40 to 1.78; 3 studies, 506 participants; I(2) = 0%; low-quality evidence); nor between TCAs and other medication (RR 1.48, 95% CI 0.59 to 3.72; 8 studies, 556 participants; I(2) =14%; low-quality evidence); nor between antidepressants and the combination of an antidepressant and an antipsychotic (RR 0.80, 95% CI 0.25 to 2.52; 2 studies, 118 participants; I(2) = 0%; low-quality evidence). Percental attrition rates due to adverse effects were high in all antidepressant treatments (0% to 32%), but low for NPs (0% to 1.7%).The risk of bias was high in many domains across studies. Seventeen trials (65.4%) gave no information about random sequence generation and only two (7.7%) provided information about allocation concealment. Eighteen studies (69.2%) revealed a high or unclear risk in blinding participants and study personnel; 23 studies had high risk of bias relating to blinding assessors. For the comparison NGA versus placebo, there was relatively high imprecision and heterogeneity due to one outlier study. Although we identified 26 studies, each comparison only contained a few studies and small numbers of participants so the results were imprecise.

Authors' conclusions: The current review found very low-quality evidence for NGAs and low-quality evidence for NPs being effective in treating somatoform symptoms in adults when compared with placebo. There was some evidence that different classes of antidepressants did not differ in efficacy; however, this was limited and of low to very low quality. These results had serious shortcomings such as the high risk of bias, strong heterogeneity in the data, and small sample sizes. Furthermore, the significant effects of antidepressant treatment have to be balanced against the relatively high rates of adverse effects. Adverse effects produced by medication can have amplifying effects on symptom perceptions, particularly in people focusing on somatic symptoms without medical causes. We can only draw conclusions about short-term efficacy of the pharmacological interventions because no trial included follow-up assessments. For each of the comparisons where there were available data on acceptability rates (NGAs versus placebo, NPs versus placebo, TCAs versus other medication, and antidepressants versus a combination of an antidepressant and an antipsychotic), no clear differences between the intervention and comparator were found.Future high-quality research should be carried out to determine the effectiveness of medications other than antidepressants, to compare antidepressants more thoroughly, and to follow-up participants over longer periods (the longest follow up was just 12 weeks). Another idea for future research would be to include other outcomes such as functional impairment or dysfunctional behaviours and cognitions as well as the classical outcomes such as symptom severity, depression, or anxiety.

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Conflict of interest statement

Maria Kleinstäuber: none known.

Michael Witthöft: none known.

Andrés Steffanowski: none known.

Harm van Marwijk: none known.

Wolfgang Hiller: none known.

Michael Lambert: none known.

Figures

1
1
PRISMA study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
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).
5
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).
6
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).
1.1
1.1. Analysis
Comparison 1 Pharmacotherapy versus placebo, Outcome 1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales).
1.2
1.2. Analysis
Comparison 1 Pharmacotherapy versus placebo, Outcome 2 Acceptability.
1.3
1.3. Analysis
Comparison 1 Pharmacotherapy versus placebo, Outcome 3 Anxiety (post‐treatment score on self report and clinician‐rated scales).
1.4
1.4. Analysis
Comparison 1 Pharmacotherapy versus placebo, Outcome 4 Depression (post‐treatment score on self report and clinician‐rated scales).
1.5
1.5. Analysis
Comparison 1 Pharmacotherapy versus placebo, Outcome 5 Dysfunctional cognitions, emotions, and behaviours (post‐treatment score on self report scales).
1.6
1.6. Analysis
Comparison 1 Pharmacotherapy versus placebo, Outcome 6 Adverse effects.
1.7
1.7. Analysis
Comparison 1 Pharmacotherapy versus placebo, Outcome 7 Treatment response (post‐treatment score on self report and clinician‐rated scales).
1.8
1.8. Analysis
Comparison 1 Pharmacotherapy versus placebo, Outcome 8 Functional disability and quality of life (post‐treatment score on self report scales).
2.1
2.1. Analysis
Comparison 2 Tricyclic antidepressants versus another medication, Outcome 1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales).
2.2
2.2. Analysis
Comparison 2 Tricyclic antidepressants versus another medication, Outcome 2 Acceptability.
2.3
2.3. Analysis
Comparison 2 Tricyclic antidepressants versus another medication, Outcome 3 Anxiety (post‐treatment score on self report and clinician‐rated scales).
2.4
2.4. Analysis
Comparison 2 Tricyclic antidepressants versus another medication, Outcome 4 Depression (post‐treatment score on self report and clinician‐rated scales).
2.5
2.5. Analysis
Comparison 2 Tricyclic antidepressants versus another medication, Outcome 5 Adverse effects.
2.6
2.6. Analysis
Comparison 2 Tricyclic antidepressants versus another medication, Outcome 6 Treatment response (post‐treatment score on self report and clinician‐rated scales).
3.1
3.1. Analysis
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).
3.2
3.2. Analysis
Comparison 3 New‐generation antidepressants (SARI, NaSSA, SSRI) versus another medication, Outcome 2 Acceptability.
3.3
3.3. Analysis
Comparison 3 New‐generation antidepressants (SARI, NaSSA, SSRI) versus another medication, Outcome 3 Depression (post‐treatment score on self report and clinician‐rated scales).
3.4
3.4. Analysis
Comparison 3 New‐generation antidepressants (SARI, NaSSA, SSRI) versus another medication, Outcome 4 Adverse effects.
4.1
4.1. Analysis
Comparison 4 Pharmacotherapy versus a combination of medications, Outcome 1 Severity/intensity of medically unexplained physical symptoms (post‐treatment score on self report scales).
4.2
4.2. Analysis
Comparison 4 Pharmacotherapy versus a combination of medications, Outcome 2 Acceptability.
4.3
4.3. Analysis
Comparison 4 Pharmacotherapy versus a combination of medications, Outcome 3 Anxiety (post‐treatment score on self report and clinician‐rated scales).
4.4
4.4. Analysis
Comparison 4 Pharmacotherapy versus a combination of medications, Outcome 4 Depression (post‐treatment score on self report and clinician‐rated scales).
4.5
4.5. Analysis
Comparison 4 Pharmacotherapy versus a combination of medications, Outcome 5 Adverse effects.
4.6
4.6. Analysis
Comparison 4 Pharmacotherapy versus a combination of medications, Outcome 6 Treatment response (post‐treatment score on self report and clinician‐rated scales).
5.1
5.1. Analysis
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).
5.2
5.2. Analysis
Comparison 5 Subgroup analysis 1: Co‐morbidity (based on the comparison pharmacotherapy versus placebo), Outcome 2 Acceptability.
6.1
6.1. Analysis
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).
6.2
6.2. Analysis
Comparison 6 Subgroup analysis 2: Source of funding (based on the comparison pharmacotherapy versus placebo), Outcome 2 Acceptability.
7.1
7.1. Analysis
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).
8.1
8.1. Analysis
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).
9.1
9.1. Analysis
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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Update of

References

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Agger 2014 {published and unpublished data}
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