Why is this review important?
Panic disorder is common in the general population and is characterised by recurrent unexpected panic attacks consisting of a wave of intense fear that reaches a peak within a few minutes. Agoraphobia often develops after one or more panic attacks and is a fear of being in situations where escape may be difficult or help would not be available if needed. Panic disorder is treated with psychological interventions and medication, often used in combination. Although not usually recommended as first-line treatment, benzodiazepines are frequently used in the treatment of panic disorder. Benzodiazepines show a rapid onset of action, but they also have a high risk of dependency and withdrawal symptoms.
Who will be interested in this review?
Patients and general practitioners.
What questions does this review aim to answer?
How effective is treatment with benzodiazepine compared to placebo (a sham treatment) in treating panic disorder with or without agoraphobia?
How acceptable are benzodiazepines compared to placebo in treating panic disorder with or without agoraphobia?
How many people with panic disorder with or without agoraphobia who are treated with benzodiazepines experience side effects compared to placebo?
Which studies were included in the review?
We searched electronic databases and study registers to find all relevant studies. We only included randomised controlled trials (a type of study in which participants are assigned to a treatment group using a random method) that compared treatment with benzodiazepine and placebo in adults with a diagnosis of panic disorder with or without agoraphobia. We only included studies in which patients and the clinicians did not know which treatment they received. We included 24 studies with a total of 4233 participants in our review.
What does the evidence from the review tell us?
We found consistent evidence for a possible advantage of benzodiazepines in the improvement of panic symptoms and in the number of participants dropping out of treatment. Furthermore, benzodiazepines may improve social functioning more than placebo. However, there may be more dropouts due to side effects and more participants who experience at least one side effect when treated with benzodiazepines. We found several severe limitations in the design of the included studies. For example, it seems that at least in some studies participants and physicians were able to guess to which treatment arm the participants were allocated, thus it is possible that some trials were not really blinded. These limitations may have led to an overestimation of the treatment effect. Another major limitation is that our included studies were only short-term studies and did not reflect the risks of dependency and withdrawal symptoms. Furthermore, it is unclear if the effect is maintained after the end of treatment.
What should happen next?
High-quality long-term studies should be carried out to establish whether the benefits of treatment can be maintained and to put the benefits in context of withdrawal effects and the risk of dependency. However, it is unlikely that the general conclusions regarding the short-term efficacy and the dependency potential of benzodiazepines will change. Comparisons with other active treatment including psychotherapy, for example in multiple-treatment meta-analyses, may thus be more suitable to inform clinical practise.
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.
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.
To assess the efficacy and acceptability of benzodiazepines versus placebo in the treatment of panic disorder with or without agoraphobia in adults.
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.
All double-blind (blinding of patients and personnel) controlled trials randomising adults with panic disorder with or without agoraphobia to benzodiazepine or placebo.
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.
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).