Clinician Article

Antidepressants versus placebo for panic disorder in adults.

  • Bighelli I
  • Castellazzi M
  • Cipriani A
  • Girlanda F
  • Guaiana G
  • Koesters M, et al.
Cochrane Database Syst Rev. 2018 Apr 5;4(4):CD010676. doi: 10.1002/14651858.CD010676.pub2. (Review)
PMID: 29620793
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  • FM/GP/Mental Health
    Relevance - 6/7
    Newsworthiness - 5/7
  • Family Medicine (FM)/General Practice (GP)
    Relevance - 6/7
    Newsworthiness - 4/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 6/7
    Newsworthiness - 4/7
  • Psychiatry
    Relevance - 6/7
    Newsworthiness - 4/7


BACKGROUND: Panic disorder is characterised by repeated, unexpected panic attacks, which represent a discrete period of fear or anxiety that has a rapid onset, reaches a peak within 10 minutes, and in which at least four of 13 characteristic symptoms are experienced, including racing heart, chest pain, sweating, shaking, dizziness, flushing, stomach churning, faintness and breathlessness. It is common in the general population with a lifetime prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions. Amongst pharmacological agents, the National Institute for Health and Care Excellence (NICE) and the British Association for Psychopharmacology consider antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs), as the first-line treatment for panic disorder, due to their more favourable adverse effect profile over monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). Several classes of antidepressants have been studied and compared, but it is still unclear which antidepressants have a more or less favourable profile in terms of effectiveness and acceptability in the treatment of this condition.

OBJECTIVES: To assess the effects of antidepressants for panic disorder in adults, specifically:1. to determine the efficacy of antidepressants in alleviating symptoms of panic disorder, with or without agoraphobia, in comparison to placebo;2. to review the acceptability of antidepressants in panic disorder, with or without agoraphobia, in comparison with placebo; and3. to investigate the adverse effects of antidepressants in panic disorder, with or without agoraphobia, including the general prevalence of adverse effects, compared to placebo.

SEARCH METHODS: We searched the Cochrane Common Mental Disorders' (CCMD) Specialised Register, and CENTRAL, MEDLINE, EMBASE and PsycINFO up to May 2017. We handsearched reference lists of relevant papers and previous systematic reviews.

SELECTION CRITERIA: All double-blind, randomised, controlled trials (RCTs) allocating adults with panic disorder to antidepressants or placebo.

DATA COLLECTION AND ANALYSIS: Two review authors independently checked eligibility and extracted data using a standard form. We entered data into Review Manager 5 using a double-check procedure. Information extracted included study characteristics, participant characteristics, intervention details and settings. Primary outcomes included failure to respond, measured by a range of response scales, and treatment acceptability, measured by total number of dropouts for any reason. Secondary outcomes included failure to remit, panic symptom scales, frequency of panic attacks, agoraphobia, general anxiety, depression, social functioning, quality of life and patient satisfaction, measured by various scales as defined in individual studies. We used GRADE to assess the quality of the evidence for each outcome MAIN RESULTS: 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.

AUTHORS' CONCLUSIONS: 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.

Clinical Comments

Family Medicine (FM)/General Practice (GP)

The best evidence suggests a weak benefit (NNTB of 7), but the authors add the caveat that the evidence is so weak they're not sure of this, and can't recommend antidepressants for panic attacks. They are apparently planning a network analysis that may provide more accurate estimates.

FM/GP/Mental Health

Top-notch meta-analysis done by the Cochrane team that reveals the tolerability and effectiveness of antidepressants in panic disorder management (NNT 7-27). It definitely matters in my practice.

General Internal Medicine-Primary Care(US)

It is reassuring that the authors are planning a network meta-analysis, because this article is not very helpful for clinical practice.

General Internal Medicine-Primary Care(US)

The Cochrane group found low-quality evidence across 42 studies to support using tricyclic antidepressants (TCAs), SSRIs, MAOIs and SNRIs for patients with anxiety (NNT 7 for a response). Of these three classes, only TCAs had statistically fewer dropouts. All three classes had a small-to-moderate effect on reducing panic symptoms. The authors were reluctant to suggest one type of antidepressant over another based on these findings. Until head-to-head trials are conducted, I`m afraid this meta-analysis of short-term outcomes is the best evidence we will have on which to base this decision. I think the manuscript provides information to adjust a general internist`s approach to managing anxiety with antidepressants.


It is a fact that serotonin uptake inhibiting (TCAs, SSRIs, SNRIs) and MAO inhibiting drugs help block panic attacks. All clinical psychiatrists with adequate psychopharmacologic training and experience know this. It is also a fact that benzodiazepines play an important role in treatment of panic disorder, at least for the first 4-6 weeks of treatment and often indefinitely. Studies included here all omitted the initial use of concomitant benzodiazepines. Therefore, it is not at all surprising that the benefits reported were measly. SSRIs and SNRIs administered alone often cause early exacerbation of panic, resulting in premature termination of treatment. This review will become more of a realistic representation of clinical practice if benzodiazepines continue to be "eased" out of use by state regulatory authorities. Then patients with panic disorder will really be in a fix.


Limited value.

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