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Meta-Analysis
. 2019 Mar 28;3(3):CD010677.
doi: 10.1002/14651858.CD010677.pub2.

Benzodiazepines Versus Placebo for Panic Disorder in Adults

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Free PMC article
Meta-Analysis

Benzodiazepines Versus Placebo for Panic Disorder in Adults

Johanna Breilmann et al. Cochrane Database Syst Rev. .
Free PMC article

Abstract

Background: Panic disorder is characterised by recurrent unexpected panic attacks consisting of a wave of intense fear that reaches a peak within a few minutes. Panic disorder is a common disorder, with an estimated lifetime prevalence of 1% to 5% in the general population and a 7% to 10% prevalence in primary care settings. Its aetiology is not fully understood and is probably heterogeneous.Panic disorder is treated with psychological and pharmacological interventions, often used in combination. Although benzodiazepines are frequently used in the treatment of panic disorder, guidelines recommend antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs), as first-line treatment for panic disorder, particularly due to their lower incidence of dependence and withdrawal reaction when compared to benzodiazepines. Despite these recommendations, benzodiazepines are widely used in the treatment of panic disorder, probably because of their rapid onset of action.

Objectives: To assess the efficacy and acceptability of benzodiazepines versus placebo in the treatment of panic disorder with or without agoraphobia in adults.

Search methods: We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR Studies and References), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1950-), Embase (1974-), and PsycINFO (1967-) up to 29 May 2018. We handsearched reference lists of relevant papers and previous systematic reviews. We contacted experts in the field for supplemental data.

Selection criteria: All double-blind (blinding of patients and personnel) controlled trials randomising adults with panic disorder with or without agoraphobia to benzodiazepine or placebo.

Data collection and analysis: Two review authors independently checked the eligibility of studies and extracted data using a standardised form. Data were then entered data into Review Manager 5 using a double-check procedure. Information extracted included study characteristics, participant characteristics, intervention details, settings, and outcome measures in terms of efficacy, acceptability, and tolerability.

Main results: We included 24 studies in the review with a total of 4233 participants, of which 2124 were randomised to benzodiazepines and 1475 to placebo. The remaining 634 participants were randomised to other active treatments in three-arm trials. We assessed the overall methodological quality of the included studies as poor. We rated all studies as at unclear risk of bias in at least three domains. In addition, we judged 20 of the 24 included studies as having a high risk of bias in at least one domain.Two primary outcomes of efficacy and acceptability showed a possible advantage of benzodiazepines over placebo. The estimated risk ratio (RR) for a response to treatment was 1.65 (95% confidence interval (CI) 1.39 to 1.96) in favour of benzodiazepines, which corresponds to an estimated number needed to treat for an additional beneficial outcome (NNTB) of 4 (95% CI 3 to 7). The dropout rate was lower among participants treated with benzodiazepines (RR 0.50, 95% CI 0.39 to 0.64); the estimated NNTB was 6 (95% CI 5 to 9). We rated the quality of the evidence as low for both primary outcomes. The possible advantage of benzodiazepine was also seen for remission (RR 1.61, 95% CI 1.38 to 1.88) and the endpoint data for social functioning (standardised mean difference (SMD) -0.53, 95% CI -0.65 to -0.42), both with low-quality evidence. We assessed the evidence for the other secondary outcomes as of very low quality. With the exception of the analyses of the change score data for depression (SMD -0.22, 95% CI -0.48 to 0.04) and social functioning (SMD -0.32, 95% CI -0.88 to 0.24), all secondary outcome analyses showed an effect in favour of benzodiazepines compared to placebo. However, the number of dropouts due to adverse effects was higher with benzodiazepines than with placebo (RR 1.58, 95% CI 1.16 to 2.15; low-quality evidence). Furthermore, our analyses of adverse events showed that a higher proportion of participants experienced at least one adverse effect when treated with benzodiazepines (RR 1.18, 95% CI 1.02 to 1.37; low-quality evidence).

Authors' conclusions: Low-quality evidence shows a possible superiority of benzodiazepine over placebo in the short-term treatment of panic disorders. The validity of the included studies is questionable due to possible unmasking of allocated treatments, high dropout rates, and probable publication bias. Moreover, the included studies were only short-term studies and did not examine the long-term efficacy nor the risks of dependency and withdrawal symptoms. Due to these limitations, our results regarding the efficacy of benzodiazepines versus placebo provide only limited guidance for clinical practice. Furthermore, the clinician's choice is not between benzodiazepines and placebo, but between benzodiazepines and other agents, notably SSRIs, both in terms of efficacy and adverse effects. The choice of treatment should therefore be guided by the patient's preference and should balance benefits and harms from treatment in a long-term perspective.

Conflict of interest statement

JB: none.

FG: none.

GG: none.

CB: none.

AC: none.

MC: none.

IB: none.

SJD: none.

TAF has received lecture fees from Eli Lilly, Janssen, Meiji, Mitsubishi‐Tanabe, MSD, and Pfizer and consultancy fees from Takeda Science Foundation. He has received royalties from Igaku‐Shoin and Nihon Bunka Kagaku‐sha publishers. He has received research support from Mochida and Mitsubishi‐Tanabe. He is diplomate of the Academy of Cognitive Therapy.

MK: none.

Figures

1
1
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 Benzodiazepines versus placebo, outcome: 1.1 Treatment response.
5
5
Forest plot of comparison: 1 Benzodiazepines versus placebo, outcome: 1.2 Total number of dropouts.
6
6
Funnel plot of comparison: 1 Benzodiazepines versus placebo, outcome: 1.1 Treatment response.
7
7
Funnel plot of comparison: 1 Benzodiazepines versus placebo, outcome: 1.2 Total number of dropouts.
1.1
1.1. Analysis
Comparison 1 Benzodiazepines versus placebo, Outcome 1 Treatment response.
1.2
1.2. Analysis
Comparison 1 Benzodiazepines versus placebo, Outcome 2 Total number of dropouts.
1.3
1.3. Analysis
Comparison 1 Benzodiazepines versus placebo, Outcome 3 Treatment remission.
1.4
1.4. Analysis
Comparison 1 Benzodiazepines versus placebo, Outcome 4 Panic symptom scales and global judgement on a continuous scale.
1.5
1.5. Analysis
Comparison 1 Benzodiazepines versus placebo, Outcome 5 Frequency of panic attacks.
1.6
1.6. Analysis
Comparison 1 Benzodiazepines versus placebo, Outcome 6 Agoraphobia.
1.7
1.7. Analysis
Comparison 1 Benzodiazepines versus placebo, Outcome 7 General anxiety (HAMA).
1.8
1.8. Analysis
Comparison 1 Benzodiazepines versus placebo, Outcome 8 Depression.
1.9
1.9. Analysis
Comparison 1 Benzodiazepines versus placebo, Outcome 9 Social functioning.
1.10
1.10. Analysis
Comparison 1 Benzodiazepines versus placebo, Outcome 10 Number of dropouts due to adverse effects.
1.11
1.11. Analysis
Comparison 1 Benzodiazepines versus placebo, Outcome 11 Number of participants experiencing at least 1 adverse effect.
1.12
1.12. Analysis
Comparison 1 Benzodiazepines versus placebo, Outcome 12 Subgroup analysis: drugs ‐ response.
1.13
1.13. Analysis
Comparison 1 Benzodiazepines versus placebo, Outcome 13 Subgroup analysis: drugs ‐ dropouts.
1.14
1.14. Analysis
Comparison 1 Benzodiazepines versus placebo, Outcome 14 Sensitivity analysis: exclusion high risk of bias ‐ response.
1.15
1.15. Analysis
Comparison 1 Benzodiazepines versus placebo, Outcome 15 Sensitivity analysis: exclusion high risk of bias ‐ dropouts.
1.16
1.16. Analysis
Comparison 1 Benzodiazepines versus placebo, Outcome 16 Sensitivity analysis: exclusion > 20% dropouts ‐ response.
1.17
1.17. Analysis
Comparison 1 Benzodiazepines versus placebo, Outcome 17 Sensitivity analysis: exclusion > 20% dropouts ‐ dropouts.
1.18
1.18. Analysis
Comparison 1 Benzodiazepines versus placebo, Outcome 18 Sensitivity analysis: exclusion comorbidities ‐ response.
1.19
1.19. Analysis
Comparison 1 Benzodiazepines versus placebo, Outcome 19 Sensitivity analysis: exclusion comorbidities ‐ dropouts.

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  • Cochrane Database Syst Rev. doi: 10.1002/14651858.CD010677

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