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Antidepressants versus placebo for panic disorder in adults

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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.


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; and

3. 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.

Plain language summary

Antidepressants for panic disorder in adults

Why is this review important?

Panic disorder is common in the general population. It is characterised by panic attacks, periods of fear or anxiety with a rapid onset in which other characteristic symptoms are experienced (involving bodily systems and fearful thoughts). The treatment of panic disorder includes psychological and pharmacological interventions, often used in combination. Among pharmacological interventions, the standard treatment suggested by guidelines is different classes of antidepressants. Evidence for their effectiveness and acceptability is unclear.

Who will be interested in this review?

People with panic disorder and general practitioners.

What questions does this review aim to answer?

How effective are antidepressants compared to a sham treatment (known as placebo) in treating panic disorder?

What is the acceptability of antidepressants compared to placebo in treating panic disorder?

How many unintended and untoward effects (adverse effects) do antidepressants have compared to placebo in people with panic disorder?

Which studies were included in the review?

We searched electronic databases to find all relevant studies. The medical studies included in the review compared treatment with antidepressants or placebo in adults with a diagnosis of panic disorder. The studies also had to be randomised controlled trials (RCTs), which means adults were allocated at random (by chance alone) to receive the treatment or placebo. We included 41 RCTs for a total of 9377 people in the review.

What does the evidence from the review tell us?

We found evidence showing that antidepressants are better than placebo in terms of effectiveness and number of people leaving the study early. However, our findings also showed that antidepressants are less well tolerated than placebo, producing more dropouts due to adverse effects. Results are limited in the following ways: some studies were funded by pharmaceutical companies, and only short-term outcomes were assessed. We found almost no data on other clinically relevant outcomes, such as functioning and quality of life. The quality of the available evidence ranged from very low to high.

What should happen next?

Studies with outcomes assessed at longer-term follow-up visits should be carried out to establish whether the effect is transient or maintained. Trials should better report any harms experienced by participants during the trial. In addition, a further analysis with an approach called 'network meta-analysis' will include all psychopharmacological treatments available for panic disorder, and will likely shed further light on this compelling issue, also being able to provide more information with regard to comparative efficacy of different available interventions.

Laienverständliche Zusammenfassung

Antidepressiva für Panikstörung bei Erwachsenen

Warum ist dieser Review wichtig?

Panikstörungen kommen in der Allgemeinbevölkerung häufig vor. Sie zeichnen sich durch Panikattacken, Phasen von Furcht oder Angst mit einem schnellen Eintritt aus, in denen andere charakteristische Symptome auftreten (die die Körpersysteme und ängstliche Gedanken einschließen). Die Behandlung der Panikstörung umfasst psychologische und pharmakologische Interventionen, die oft in Kombination angewendet werden. Unter den pharmakologischen Interventionen werden als Standardbehandlung, gemäß den Leitlinien, verschiedene Klassen von Antidepressiva vorgeschlagen. Die Evidenz für ihre Wirksamkeit und Akzeptanz ist unklar.

Wer wird sich für diesen Review interessieren?

Menschen mit einer Panikstörung und Allgemeinmediziner.

Welche Fragen möchte dieser Review beantworten?

Wie wirksam sind Antidepressiva im Vergleich zu einer Scheinbehandlung (bekannt als Placebo) für die Behandlung der Panikstörung?

Wie ist die Akzeptanz von Antidepressiva im Vergleich zu Placebo für die Behandlung der Panikstörung?

Wie viele unbeabsichtigte und ungewollte Wirkungen (unerwünschte Wirkungen) haben Antidepressiva im Vergleich zu Placebo bei Menschen mit Panikstörung?

Welche Studien wurden in diesen Review eingeschlossen?

Wir haben in elektronischen Datenbanken gesucht, um alle relevanten Studien zu finden. Die medizinischen Studien, die in diesen Review eingeschlossen wurden, verglichen die Behandlung mit Antidepressiva oder Placebo bei Erwachsenen mit einer diagnostizierten Panikstörung. Die Studien mussten randomisierte, kontrollierte Studien (RCTs) sein, was bedeutet, dass die Erwachsenen zufällig aufgeteilt wurden, um die Behandlung oder Placebo zu erhalten. Wir haben 41 RCTs mit insgesamt 9377 Menschen in den Review eingeschlossen.

Was sagt uns die in diesem Review zusammengefasste Evidenz?

Wir haben Evidenz gefunden, die zeigt, dass Antidepressiva besser sind als Placebo hinsichtlich der Wirksamkeit und der Anzahl an Personen, die die Studie abbrechen. Jedoch zeigen unsere Ergebnisse auch, dass Antidepressiva weniger gut vertragen werden als Placebo und deshalb mehr Studienabbrüche aufgrund von unerwünschten Wirkungen verursachen. Die Ergebnisse sind wie folgt eingeschränkt: einige Studien wurden durch pharmazeutische Unternehmen finanziert und es wurden nur kurzfristige Endpunkte beurteilt. Wir haben fast keine Daten zu anderen klinisch relevanten Endpunkten, wie z. B. Funktionsfähigkeit und Lebensqualität, gefunden. Die Qualität der verfügbaren Evidenz reichte von sehr niedrig bis hoch.

Was sollte als Nächstes passieren?

Studien, die Endpunkte basierend auf längerfristigen Nachbeobachtungen beurteilen, sollten durchgeführt werden, um festzustellen, ob die Wirkung vorübergehend ist oder aufrechterhalten werden kann. Studien sollten besser über jegliche Schäden, die die Teilnehmer während der Studie erleben, berichten. Zusätzlich wird eine weitere Analyse mit einem Ansatz namens „Netzwerk-Metaanalyse“ alle verfügbaren psychopharmakologischen Behandlungen für Panikstörung umfassen und wahrscheinlich weiteren Aufschluss über dieses wichtige Thema geben und dabei auch mehr Informationen hinsichtlich der vergleichenden Wirksamkeit von verschiedenen vorhandenen Interventionen liefern.

Anmerkungen zur Übersetzung

J. Metzing, freigegeben durch Cochrane Deutschland.