Why is this review important?

People with panic disorder are profoundly impacted by this condition, often experiencing challenges with work, education and social or family life. We wanted to evaluate which medications, if any, are the most effective and safe. In particular, we aimed to assess whether the network meta-analysis findings were valid enough to identify the best medications, in order to improve care. These analyses have also generated suggestions for future research to reduce key uncertainties in the evidence.

Who will be interested in this research?

The research in this Cochrane Review will interest:

‐ people who decide policy, and influence decisions about the prescription of medications for panic disorder;

‐ people who prescribe these medicines to people with panic disorder;

‐ people with panic disorder;

‐ those who support and care for them.

What did we want to find out?

We wanted to find out how well antidepressants, benzodiazepines and azapirones work to improve panic disorder symptoms in adults (i.e. people aged 18 years or older).

We wanted to know how these medications affect:

‐ the symptoms of panic disorder;

- dropout from studies, as a measure of the side effects of medication;

‐ recovery: no longer meeting the diagnostic criteria for panic disorder;

‐ response or remission: scores on a scale indicating an important reduction in panic or no longer experiencing panic;

- reduction in the frequency of panic attacks;

- reduction in agoraphobia (fear of being in situations where escape might be difficult or that help would not be available if things go wrong).

What did we do?

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 antidepressants, benzodiazepines, azapirones and placebo in adults with a diagnosis of panic disorder, with or without agoraphobia. We only included studies in which the patients and clinicians did not know which treatment they received. We included 70 studies in our review with a total of 12,703 participants. The date of our search was 26 May 2022.

What does the evidence from the review tell us?

- We found that most medications may be more effective in the response outcome than placebo. In particular, diazepam, alprazolam, clonazepam, paroxetine, venlafaxine, clomipramine, fluoxetine and adinazolam showed the strongest effect. Also, most medications were either associated with a reduced or similar risk of dropouts to placebo. Alprazolam and diazepam were associated with a lower dropout rate than placebo and were ranked as the most tolerated of all the medications examined.

- Most medications may have been more effective than placebo in remitting the symptoms of panic disorder and their effects were clinically meaningful. In terms of the reduction in panic scale scores, brofaromine, clonazepam and reboxetine seem to have the strongest reductions in panic symptoms compared to placebo, but the results were based on either one trial or very small trials. For the frequency of panic attacks outcome, only clonazepam and alprazolam showed a strong reduction in the frequency of attacks compared to placebo. The strongest reductions in agoraphobia symptoms were found for citalopram, reboxetine, escitalopram, clomipramine and diazepam, compared to placebo.

- If we consider the classes of medications together (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), mono-amine oxidase inhibitors (MAOIs) and benzodiazepines), all classes of medications examined were more effective than placebo. TCAs as a class ranked as the most effective, followed by benzodiazepines and MAOIs. SSRIs as a class ranked fifth on average, while SNRIs were ranked as the lowest.

- If classes of medication are compared with each other for the response outcome, no difference is found between classes. For the dropout outcome, benzodiazepines were the only class associated with a lower dropout than placebo, and they were ranked as first in terms of tolerability. The other classes did not show any difference in dropouts compared to placebo.

- It is important to note that, while the quality of the studies comparing antidepressants with placebo was acceptable, the quality of the studies comparing benzodiazepines with placebo and antidepressants was low. This may limit the certainty of our results.

- Our review has limitations as it is based on short-term studies.

What should happen next?

- Almost all the studies examined in this network meta-analysis were of short duration. For benzodiazepines, there has been considerable debate about whether they can be used in the long term given their propensity for abuse and the possible risk of tolerance. More research on their long-term effects (i.e. longer than eight weeks and maybe up to one year) is needed.

- It will be important to systematically assess the efficacy of medications compared to talking therapies, perhaps in a network meta-analysis. Data for depression seem to show that psychotherapies can lead to a more sustained effect. The same may apply to anxiety disorders in general and panic disorder in particular and this needs to be investigated.