Drug treatment for panic disorder with or without agoraphobia: systematic review and network meta-analysis of randomised controlled trials

Abstract

Objective: To identify drug classes and individual selective serotonin reuptake inhibitors (SSRIs) with high rates of remission and low risk of adverse events in the treatment of panic disorder with or without agoraphobia.

Design: Systematic review and network meta-analysis.

Data sources: Embase, Medline, and ClinicalTrials.gov from inception to 17 June 2021.

Eligibility criteria for study selection: Randomised controlled trials that included adults aged ≥18 years with a diagnosis of panic disorder, compared drugs used to treat the panic disorder, and measured the outcomes of interest, including remissions, dropouts, and adverse events.

Methods: Risk of bias in the included studies was assessed using the revised Cochrane risk of bias tool for randomised trials. Direct meta-analyses were performed using random effects models. A two stage network meta-analysis with surface under the cumulative ranking curve (SUCRA) was used to estimate the comparative efficacy of drug classes and individual SSRIs.

Results: 87 studies including a total of 12 800 participants and 12 drug classes were eligible for inclusion. Almost all the studies (86/87) had some concern or were at high risk of bias. Network meta-analysis of remission with consistent results indicated that tricyclic antidepressants, benzodiazepines, monoamine oxidase inhibitors, SSRIs, and serotonin-noradrenaline reuptake inhibitors (SNRIs) were associated with significantly higher remission rates than placebo, with risk ratios of 1.39 (95% confidence interval 1.26 to 1.54), 1.47 (1.36 to 1.60), 1.30 (1.00 to 1.69), 1.38 (1.26 to 1.50), and 1.27 (1.12 to 1.45), respectively. SUCRAs identified benzodiazepines (84.5%, mean rank=2.4), tricyclic antidepressants (68.7%, 3.8), and SSRIs (66.4%, 4.0) as the top three best treatments for remission. However, tricyclic antidepressants, benzodiazepines, and SSRIs were also significantly associated with increased risk of adverse events compared with placebo, with risk ratios of 1.79 (1.47 to 2.19), 1.76 (1.50 to 2.06), and 1.19 (1.01 to 1.41), respectively. Consistency assumption of adverse events was upheld but could still be present on removal of studies with high percentages of women participants and those with agoraphobia. A SUCRA cluster ranking plot considering both remission and adverse events among all drug classes indicated that SSRIs were associated with high remission and low risk of adverse events. Among individual SSRIs, sertraline and escitalopram provided high remission with an acceptable risk of adverse events.

Conclusion: The findings suggest that SSRIs provide high rates of remission with low risk of adverse events for the treatment of panic disorder. Among SSRIs, sertraline and escitalopram were associated with high remission and low risk of adverse events. The findings were, however, based on studies of moderate to very low certainty levels of evidence, mostly as a result of within study bias, inconsistency, and imprecision of the findings reported.

Systematic review registration: PROSPERO CRD42020180638.

Fig 1

Study selection in review

Fig 2

Network maps of outcomes. Size of nodes represents number of participants randomly assigned to treatment comparison. Width of lines represents number of studies comparing the two connected treatments. Number over each line indicates number of studies comparing the two connected treatments. BZD=benzodiazepine; MAOI=monoamine oxidase inhibitor; NaSSA=noradrenergic and specific serotonergic antidepressant; NRI=noradrenaline reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor; SNRI=serotonin-noradrenaline reuptake inhibitor; TCA=tricyclic antidepressant

Fig 3

Estimation of relative treatment effects on remission (above diagonal line) and dropout (below diagonal line). Results are risk ratios (95% confidence intervals) between each pair of treatments from network meta-analysis. Comparisons are read from right to left. For example, the risk ratio for remission with tricyclic antidepressants (TCAs) compared with benzodiazepines (BZDs) is 0.94 (0.85 to 1.05). For dropout, the effect of TCAs compared with BZDs on the risk of dropout is 1.54 (1.19 to 1.99). Bold font indicates statistical significance. GRADE certainty of evidence of each comparison is: light green=moderate; light red=low; dark red=very low. MAOI=monoamine oxidase inhibitor; NaSSA=noradrenergic and specific serotonergic antidepressant; NRI=noradrenaline reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor; SNRI=serotonin-noradrenaline reuptake inhibitor

Fig 4

Estimation of relative treatment effects on anxiety score (above diagonal line) and depression score (below diagonal line). Results are standardised mean differences (95% confidence intervals) between each pair of treatments from network meta-analysis. Comparisons are read from right to left. For example, the standardised mean difference for anxiety score with tricyclic antidepressants (TCAs) compared with benzodiazepines (BZDs) is 0.15 (−0.50 to 0.79). For depression score, the effect of TCAs compared with BZDs on depression score is 0.05 (−0.53 to 0.62). Bold font indicates statistical significance. MAOIs=monoamine oxidase inhibitors; NRI=noradrenaline reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor; SNRI=serotonin-noradrenaline reuptake inhibitor

Fig 5

Estimation of relative treatment effects on adverse events. Results are risk ratios (95% confidence intervals) between each pair of treatments from network meta-analysis. Comparisons are read from right to left. For example, the risk ratio for adverse events with tricyclic antidepressants (TCAs) compared with benzodiazepines (BZDs) is 1.02 (95% confidence interval 0.83 to 1.25). Bold font indicates statistical significance. GRADE certainty of evidence of each comparison is: light green=moderate; light red=low; dark red=very low. MAOI=monoamine oxidase inhibitor; NaSSA=noradrenergic and specific serotonergic antidepressant; NRI=noradrenaline reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor; SNRI=serotonin-noradrenaline reuptake inhibitor

Fig 6

Cluster ranking plot of surface under cumulative ranking curves (SUCRA) of remission and adverse drug events. The plot is based on cluster analysis of SUCRA values. Each plot represents SUCRA values for two outcomes (ie, remission and adverse events). Treatments in the upper right corner are more effective (ie, increased remission rate) and safer (ie, lower risk of adverse events) compared with the other treatments. BZD=benzodiazepine; MAOI=monoamine oxidase inhibitor; NaSSA=noradrenergic and specific serotonergic antidepressant; NRI=noradrenaline reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor; SNRI=serotonin-noradrenaline reuptake inhibitor; TCA=tricyclic antidepressant