Abstract: Forty-one unique RCTs including 9377 participants overall, of whom we included 8252 in the 49 placebo-controlled arms of interest (antidepressant as monotherapy and placebo alone) in this review. The majority of studies were of moderate to low quality due to inconsistency, imprecision and unclear risk of selection and performance bias. We found low-quality evidence that revealed a benefit for antidepressants as a group in comparison with placebo in terms of efficacy measured as failure to respond (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.66 to 0.79; participants = 6500; studies = 30). The magnitude of effect corresponds to a number needed to treat for an additional beneficial outcome (NNTB) of 7 (95% CI 6 to 9): that means seven people would need to be treated with antidepressants in order for one to benefit. We observed the same finding when classes of antidepressants were compared with placebo. Moderate-quality evidence suggested a benefit for antidepressants compared to placebo when looking at number of dropouts due to any cause (RR 0.88, 95% CI 0.81 to 0.97; participants = 7850; studies = 30). The magnitude of effect corresponds to a NNTB of 27 (95% CI 17 to 105); treating 27 people will result in one person fewer dropping out. Considering antidepressant classes, TCAs showed a benefit over placebo, while for SSRIs and serotonin-norepinephrine reuptake inhibitor (SNRIs) we observed no difference. When looking at dropouts due to adverse effects, which can be considered as a measure of tolerability, we found moderate-quality evidence showing that antidepressants as a whole are less well tolerated than placebo. In particular, TCAs and SSRIs produced more dropouts due to adverse effects in comparison with placebo, while the confidence interval for SNRI, noradrenergic reuptake inhibitors (NRI) and other antidepressants were wide and included the possibility of no difference. The identified studies comprehensively address the objectives of the present review. Based on these results, antidepressants may be more effective than placebo in treating panic disorder. Efficacy can be quantified as a NNTB of 7, implying that seven people need to be treated with antidepressants in order for one to benefit. Antidepressants may also have benefit in comparison with placebo in terms of number of dropouts, but a less favourable profile in terms of dropout due to adverse effects. However, the tolerability profile varied between different classes of antidepressants. The choice of whether antidepressants should be prescribed in clinical practice cannot be made on the basis of this review. Limitations in results include funding of some studies by pharmaceutical companies, and only assessing short-term outcomes. Data from the present review will be included in a network meta-analysis of psychopharmacological treatment in panic disorder, which will hopefully provide further useful information on this issue.

Plain-language summary: We found evidence showing that antidepressants are better than placebo in terms of effectiveness and number of people leaving the study early. However, our findings also showed that antidepressants are less well tolerated than placebo, producing more dropouts due to adverse effects. Results are limited in the following ways: some studies were funded by pharmaceutical companies, and only short-term outcomes were assessed. We found almost no data on other clinically relevant outcomes, such as functioning and quality of life. The quality of the available evidence ranged from very low to high. Studies with outcomes assessed at longer-term follow-up visits should be carried out to establish whether the effect is transient or maintained. Trials should better report any harms experienced by participants during the trial. In addition, a further analysis with an approach called 'network meta-analysis' will include all psychopharmacological treatments available for panic disorder, and will likely shed further light on this compelling issue, also being able to provide more information with regard to comparative efficacy of different available interventions.