Panic disorder is characterized by recurrent and unexpected panic attacks associated with several comorbid psychiatric and non-psychiatric conditions such as anxiety, depression and cardiovascular diseases and impaired social, work and family life function.
Agoraphobia is a strong fear or anxiety caused by actual or anticipated exposure to a wide range of situations and is often associated with panic disorder.
There are several pharmacological treatments available for panic disorder, including tricyclic antidepressants, benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors, and serotonin and norepinephrine reuptake inhibitors (SNRIs).
Several guidelines recommend SSRIs as primary treatment due to their long-term safety, preferable to benzodiazepines and tricyclic antidepressants. However, it remains unclear which SSRI is most effective with the lowest risk of adverse events given the limited availability of direct comparisons between SSRIs and other drug classes.
A systematic review and meta-analysis was conducted to identify which drug classes: tricyclic antidepressants, benzodiazepines, β-blockers, monoamine oxidase inhibitors, norepinephrine and dopamine reuptake inhibitors (buspirone), SSRIs, SNRIs, reuptake inhibitors of noradrenaline, and specific noradrenergic and serotonergic antidepressants provided greater benefits (remission) with lower risk (adverse events) for the treatment of panic disorder. Individual SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline, escitalopram and citalopram) were also compared.
| Results of interest |
The primary outcomes were remission, defined as absence of panic attack for at least one week at the end of the study, and dropout, defined as patients who stopped treatment or withdrew before the end of the study due to adverse events, protocol violation or lack of effectiveness of the treatment.
Secondary outcomes were anxiety and depression symptom scores and any adverse events (e.g., sedation, fatigue or weakness, malaise, ataxia, slurred speech, cognitive impairment, sleep problems, sexual dysfunctions, tachycardia, palpitations, dry throat). mouth, diarrhea, constipation, nausea or vomiting, gastrointestinal problems, chest pain, nervousness, headache, lack of coordination, blurred vision, difficulty urinating, menstrual irregularity, change in appetite, change in weight, upper respiratory tract infection , irritability, agitation, paresthesia, diaphoresis, tremor, anxiety, depressive symptoms, asthenia and orthostatic hypotension).
| Results |
A total of 2,019 studies were identified , of which 87 (12,800 participants) met the inclusion criteria. The mean age of the participants was 35.0 years and 63.7% were women.
The most common duration of treatment was eight weeks (35%), followed by 12 weeks (19%). The majority compared benzodiazepines with placebo and SSRIs with placebo, followed by tricyclic antidepressants vs. benzodiazepines, tricyclic antidepressants vs. SSRIs and SSRIs vs. SSRIs, and tricyclic antidepressants vs. placebo.
| Referrals |
Significant effects on remission were shown for tricyclic antidepressants, benzodiazepines, paroxetine, sertraline, and venlafaxine compared with placebo.
No significant difference in remission was found between benzodiazepines and tricyclic antidepressants.
Relative treatment effects indicated that monotherapy with tricyclic antidepressants, benzodiazepines, monoamine oxidase inhibitors, SSRIs, and SNRIs were significantly associated with greater remission than placebo. Only benzodiazepines were associated with significant improvement compared to β-blockers and SNRIs.
Benzodiazepines, tricyclic antidepressants, and SSRIs were identified as the three best treatments for remission. β-blockers and buspirone were ranked the worst.
| Dropouts |
A total of 72 studies (10,911 participants) reported attrition rate. Tricyclic antidepressants and benzodiazepines were associated with a significantly lower dropout rate than placebo, while buspirone was associated with a higher dropout rate than placebo.
Attrition was significantly higher with tricyclic antidepressants than with benzodiazepines in studies with a high percentage of women, mean age <60 years, and treatment duration less than eight weeks.
Benzodiazepines were associated with significantly lower discontinuation rates than monoamine oxidase inhibitors, buspirone, SSRIs, SNRIs, and placebo. Buspirone was associated with significantly higher dropout rates than SSRIs and SNRIs.
Tricyclic antidepressants were associated with significantly lower dropout rates than buspirone, SSRIs, and placebo, while the dropout rate associated with tricyclic antidepressants was significantly higher compared to benzodiazepines.
Benzodiazepines were identified as the highest ranked treatment in association with lower discontinuation rates, followed by combined benzodiazepines and tricyclic antidepressants and specific noradrenergic and serotonergic antidepressants, while buspirone and monoamine oxidase inhibitors were ranked worst.
| Anxiety scores |
Anxiety scores were reported in 39 studies (4112 participants), in which SSRIs vs. placebo were the most common comparisons, followed by benzodiazepines vs. placebo.
Direct meta-analyses indicated that anxiety scores associated with benzodiazepines, tricyclic antidepressants, and paroxetine were significantly lower than those associated with placebo.
Anxiety scores associated with tricyclic antidepressants, benzodiazepines, monoamine oxidase inhibitors, buspirone, SSRIs, and SNRIs were significantly higher than for SSRIs and β-blockers combined.
| Depression scores |
Depression scores were reported in 21 studies (1453 participants), with benzodiazepines vs. placebo as the most common comparison. Benzodiazepines were associated with lower depression scores than placebo.
Tricyclic antidepressants, benzodiazepines, SSRIs, and SSRIs plus β-blockers were significantly associated with a lower depression score than placebo.
Tricyclic antidepressants, benzodiazepines, β-blockers, monoamine oxidase inhibitors, buspirone, SSRIs, norepinephrine reuptake inhibitors, and SSRIs plus benzodiazepines were significantly associated with higher depression scores than SSRIs plus β-blockers.
| Adverse events |
Fifty-two studies (9957 participants) reported adverse events in association with 11 interventions.
Benzodiazepines, tricyclic antidepressants, and venlafaxine were significantly associated with increased risk of adverse events compared to placebo.
Tricyclic antidepressants were associated with a nonsignificant increased risk of adverse events compared with benzodiazepines.
Tricyclic antidepressants were significantly associated with an increased risk of adverse effects compared to buspirone, SSRIs, SNRIs, norepinephrine reuptake inhibitors, and placebo.
Benzodiazepines also showed significantly higher associations with adverse events compared to buspirone, SSRIs, SNRIs, norepinephrine reuptake inhibitors, and placebo. SSRIs were significantly associated with an increased risk of adverse events compared to placebo.
| Clustered Ranking Chart |
The pooled ranking plot for remission and adverse events indicated SSRIs as the most effective treatment with the lowest risk of adverse events for panic disorder.
Other classes of drugs, such as norepinephrine reuptake inhibitors, monoamine oxidase inhibitors and SNRIs also showed promising efficacy in remission and acceptability of the risk of adverse reactions.
Buspirone showed low efficacy in remission despite the high acceptability of the treatment. Sertraline and escitalopram were the most effective agents with the lowest risk of adverse effects. Fluvoxamine, paroxetine, and fluoxetine had favorable efficacy but increased risk of adverse reactions, and citalopram showed minimal efficacy in remission and high risk of adverse events.
| Discussion |
The network meta-analysis identified 11 current drug classes for the treatment of panic disorder, highlighting benzodiazepines, tricyclic antidepressants, and SSRIs as the highest-ranked treatments for remission. Although benzodiazepines were associated with the lowest likelihood of discontinuation, they were also associated with the highest risk of adverse events.
Overall, SSRIs provided high benefit (remission) with low risk of adverse events. As individual SSRIs, sertraline and escitalopram were identified as the most effective agents with low risk of adverse events.
The findings suggest that fluoxetine, fluvoxamine, paroxetine, and sertraline were more effective than placebo in achieving remission. SNRIs ranked lower than SSRIs in remission and adverse events and may represent a second treatment option for panic disorder. Tricyclic antidepressants were statistically superior to placebo in dropout, remission, anxiety, and depression scores, but worse for adverse events.
For additional treatment options not included in previous meta-analyses, monoamine oxidase inhibitors were found to be significantly superior to placebo for remission, but were not different from placebo for other outcomes. However, monoamine oxidase inhibitors have very limited use in real practice given their adverse effect profile, increased risk of hypertensive crisis, and multiple drug interactions. Norepinephrine reuptake inhibitors did not show much effect compared to placebo.
There is also insufficient evidence to recommend the use of specific noradrenergic and serotonergic antidepressants given their associated high rate of drowsiness and weight gain. Buspirone should not currently be considered a viable treatment option for panic disorder.
| Conclusion |
The findings suggest that SSRIs offer an important benefit with low risk in the pharmacological treatment of panic disorder.
When individual agents were explored, sertraline and escitalopram were associated with high remission and low risk of adverse events compared to other SSRIs. However, the findings should be interpreted with caution, as the results were based on evidence with moderate to very low levels of certainty.
