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.
In terms of efficacy, SSRIs, SNRIs (venlafaxine), TCAs, MAOIs and BDZs may be effective, with little difference between classes. However, it is important to note that the reliability of these findings may be limited due to the overall low quality of the studies, with all having unclear or high risk of bias across multiple domains. Within classes, some differences emerged. For example, amongst the SSRIs paroxetine and fluoxetine seem to have stronger evidence of efficacy than sertraline. Benzodiazepines appear to have a small but significant advantage in terms of tolerability (incidence of dropouts) over other classes.
A panic attack is a discrete period of fear or anxiety that has a rapid onset and reaches a peak within 10 minutes. The main symptoms involve bodily systems, such as racing heart, chest pain, sweating, shaking, dizziness, flushing, churning stomach, faintness and breathlessness. Other recognised panic attack symptoms involve fearful cognitions, such as the fear of collapse, going mad or dying, and derealisation (the sensation that the world is unreal). Panic disorder is common in the general population with a prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions, including antidepressants and benzodiazepines.
To compare, via network meta‐analysis, individual drugs (antidepressants and benzodiazepines) or placebo in terms of efficacy and acceptability in the acute treatment of panic disorder, with or without agoraphobia.
To rank individual active drugs for panic disorder (antidepressants, benzodiazepines and placebo) according to their effectiveness and acceptability.
To rank drug classes for panic disorder (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), mono-amine oxidase inhibitors (MAOIs) and benzodiazepines (BDZs) and placebo) according to their effectiveness and acceptability.
To explore heterogeneity and inconsistency between direct and indirect evidence in a network meta-analysis.
We searched the Cochrane Common Mental Disorders Specialised Register, CENTRAL, CDSR, MEDLINE, Ovid Embase and PsycINFO to 26 May 2022.
We included randomised controlled trials (RCTs) of people aged 18 years or older of either sex and any ethnicity with clinically diagnosed panic disorder, with or without agoraphobia. We included trials that compared the effectiveness of antidepressants and benzodiazepines with each other or with a placebo.
Two authors independently screened titles/abstracts and full texts, extracted data and assessed risk of bias. We analysed dichotomous data and continuous data as risk ratios (RRs), mean differences (MD) or standardised mean differences (SMD): response to treatment (i.e. substantial improvement from baseline as defined by the original investigators: dichotomous outcome), total number of dropouts due to any reason (as a proxy measure of treatment acceptability: dichotomous outcome), remission (i.e. satisfactory end state as defined by global judgement of the original investigators: dichotomous outcome), panic symptom scales and global judgement (continuous outcome), frequency of panic attacks (as recorded, for example, by a panic diary; continuous outcome), agoraphobia (dichotomous outcome). We assessed the certainty of evidence using threshold analyses.
Overall, we included 70 trials in this review. Sample sizes ranged between 5 and 445 participants in each arm, and the total sample size per study ranged from 10 to 1168. Thirty-five studies included sample sizes of over 100 participants.
There is evidence from 48 RCTs (N = 10,118) that most medications are more effective in the response outcome than placebo. In particular, diazepam, alprazolam, clonazepam, paroxetine, venlafaxine, clomipramine, fluoxetine and adinazolam showed the strongest effect, with diazepam, alprazolam and clonazepam ranking as the most effective. We found heterogeneity in most of the comparisons, but our threshold analyses suggest that this is unlikely to impact the findings of the network meta‐analysis.
Results from 64 RCTs (N = 12,310) suggest that most medications are associated with either a reduced or similar risk of dropouts to placebo. Alprazolam and diazepam were associated with a lower dropout rate compared to placebo and were ranked as the most tolerated of all the medications examined.
Thirty-two RCTs (N = 8569) were included in the remission outcome. Most medications were more effective than placebo, namely desipramine, fluoxetine, clonazepam, diazepam, fluvoxamine, imipramine, venlafaxine and paroxetine, and their effects were clinically meaningful. Amongst these medications, desipramine and alprazolam were ranked highest.
Thirty-five RCTs (N = 8826) are included in the continuous outcome reduction in panic scale scores. Brofaromine, clonazepam and reboxetine had the strongest reductions in panic symptoms compared to placebo, but results were based on either one trial or very small trials.
Forty-one RCTs (N = 7853) are included in the frequency of panic attack outcome. Only clonazepam and alprazolam showed a strong reduction in the frequency of panic attacks compared to placebo, and were ranked highest.
Twenty-six RCTs (N = 7044) provided data for agoraphobia. The strongest reductions in agoraphobia symptoms were found for citalopram, reboxetine, escitalopram, clomipramine and diazepam, compared to placebo.
For the pooled intervention classes, we examined the two primary outcomes (response and dropout). The classes of medication were: SSRIs, SNRIs, TCAs, MAOIs and BDZs.
For the response outcome, all classes of medications examined were more effective than placebo. TCAs as a class ranked as the most effective, followed by BDZs and MAOIs. SSRIs as a class ranked fifth on average, while SNRIs were ranked lowest. When we compared classes of medication with each other for the response outcome, we found no difference between classes. Comparisons between MAOIs and TCAs and between BDZs and TCAs also suggested no differences between these medications, but the results were imprecise.
For the dropout outcome, BDZs were the only class associated with a lower dropout compared to placebo and were ranked first in terms of tolerability. The other classes did not show any difference in dropouts compared to placebo. In terms of ranking, TCAs are on average second to BDZs, followed by SNRIs, then by SSRIs and lastly by MAOIs. BDZs were associated with lower dropout rates compared to SSRIs, SNRIs and TCAs.
The quality of the studies comparing antidepressants with placebo was moderate, while the quality of the studies comparing BDZs with placebo and antidepressants was low.