The Cochrane database of systematic reviewsNov 28, 2023

Comparing drug treatments for panic disorder in adults

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Feb 14, 2026

Abstract

Evidence from 70 trials involving up to 12,310 participants indicates that most medications are more effective than placebo in treating panic disorder.

Diazepam, alprazolam, and clonazepam rank as the most effective medications for panic disorder.
Alprazolam and diazepam are associated with lower dropout rates compared to placebo, indicating better tolerability.
Most medications, including desipramine and fluoxetine, demonstrate clinically meaningful effectiveness in achieving remission.
Clonazepam and alprazolam significantly reduce the frequency of panic attacks compared to placebo.
Among medication classes, tricyclic antidepressants (TCAs) ranked highest in effectiveness, followed by benzodiazepines (BDZs).
The overall quality of evidence for these findings is moderate to low, with significant risk of bias in many studies.

Simplified

BACKGROUND: 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.

OBJECTIVES: 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.

SEARCH METHODS: We searched the Cochrane Common Mental Disorders Specialised Register, CENTRAL, CDSR, MEDLINE, Ovid Embase and PsycINFO to 26 May 2022.

SELECTION CRITERIA: 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.

DATA COLLECTION AND ANALYSIS: 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.

MAIN RESULTS: 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.

AUTHORS' CONCLUSIONS: 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.

Funding

Competing interests

GG: is a Cochrane Editor. He was not involved in the editorial process for the manuscript. He is a diplomate of the Academy of Cognitive Therapy. NM: is a Cochrane Editor. He was not involved in the editorial process for the manuscript. CB: is a Cochrane Editor. He was not involved in the editorial process for the manuscript. SJCD: is a Cochrane Editor. He was not involved in the editorial process for the manuscript. He is a member of the European College of Neuropsychopharmacology and co‐chair of their Anxiety Disorders Research Network. He has published opinions in medical journals relevant to the interventions in this review. He is a member of the Anxiety Disorders Research Network of the European College of Neuropsychopharmacology (ECNP) and of the British Association of Psychopharmacology (BAP). TAF: has received lecture fees from Eli Lilly, Meiji, Mochida, MSD, Otsuka, Pfizer, Shionogi and Mitsubishi‐Tanabe, and consultancy fees from Sekisui Chemicals and Takeda Science Foundation. He has received royalties from Igaku‐Shoin, Seiwa‐Shoten and Nihon Bunka Kagaku‐sha publishers. He has received grant or research support from the Japanese Ministry of Education, Science, and Technology, the Japanese Ministry of Health, Labor and Welfare, the Japan Foundation for Neuroscience and Mental Health, Mitsubishi‐Tanabe and Mochida. He is a diplomate of the Academy of Cognitive Therapy. TAF has a patent 2018‐177688 pending. HI: received an honorarium for a lecture from Otsuka. SD: no conflicts of interest. DC: no conflicts of interest. MK: no conflicts of interest. AT: received lecture fees from Sumitomo Dainippon Pharma, Eisai, Janssen Pharmaceutical, Meiji‐Seika Pharma, Mitsubishi Tanabe Pharma, Otsuka and Takeda Pharmaceutical. IB: is Deputy Co‐ordinating Editor of Cochrane Schizophrenia. She was not involved in the editorial process for the current review. AP: no conflicts of interest. AC: is supported by the National Institute for Health Research (NIHR) Oxford Cognitive Health Clinical Research Facility, by an NIHR Research Professorship (grant RP‐2017‐08‐ST2‐006), by the NIHR Oxford and Thames Valley Applied Research Collaboration and by the NIHR Oxford Health Biomedical Research Centre (grant BRC‐1215‐20005). The views expressed are those of the authors and not necessarily those of the UK National Health Service, the NIHR or the UK Department of Health. He has received research, educational and travel support from INCiPiT (Italian Network for Paediatric Trials), CARIPLO Foundation, Lundbeck and Angelini Pharma. He is the CI/PI of two trials about seltorexant in depression, sponsored by Janssen. SDn: is a Cochrane Editor. She was not involved in the editorial process for the manuscript. LR: no conflicts of interest.

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Comparing drug treatments for panic disorder in adults

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