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What are the effects of drug treatments for panic disorder?
  1. Shailesh Kumar1,
  2. Mark Oakley Browne2
  1. 1Division of Psychiatry
    Auckland Medical School
    New Zealand
  2. 2Professor of Rural Psychiatry
    Monash University
    Victoria, Australia

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This article is part of a new initiative in Evidence-based Mental Health, namely the serialisation of chapters of Clinical Evidence (a summary of the best available evidence on common clinical interventions updated regularly by the BMJ Publishing Group). This article is based on material presented in: . For this review, Clinical Evidence searched and appraised material published until May 2002. Studies with follow up periods of less than 6 months were excluded.

A panic attack is a period in which there is sudden onset of intense apprehension, fearfulness or terror, often associated with feelings of impending doom. Panic disorder occurs when there are recurrent, unpredictable attacks followed by at least 1 month of persistent concern about having another panic attack; worry about the possible implications or consequences of the panic attacks, or a significant behavioural change related to the attacks.1 The term “panic disorder” excludes panic attacks attributable to the direct physiological effects of a general medical condition, substance or another mental disorder. Panic disorder is sometimes categorised as “with” or “without agoraphobia.”1 Alternative categorisations focus on phobic anxiety disorders and specify agoraphobia with or without panic disorder.2

Prevalence

Panic disorder often starts around 20 years of age (between late adolescence and the mid-30s).3 Lifetime prevalence is 1–3%, and panic disorder is more common in women than in men.4 An Australian community study found 1 month prevalence rates for panic disorder (with or without agoraphobia) of 0.4% using International Classification of Diseases (ICD)-10 diagnostic criteria and of 0.5% using Diagnostic and Statistical Manual (DSM)-IV diagnostic criteria.5

Risk factors

Stressful life events tend to precede the onset of panic disorder,6,7 although a negative interpretation of these events in addition to their occurrence has been suggested as an important causal factor.8 Panic disorder is associated with major depression,9 social phobia, generalised anxiety disorder, obsessive compulsive disorder,10 and a substantial risk of drug and alcohol abuse.11 It is also associated with avoidant, histrionic and dependent personality disorders.10

Prognosis

The severity of symptoms in people with panic disorder fluctuates considerably, with periods of no attacks, or only mild attacks with few symptoms, being common. There is often a long delay between the initial onset of symptoms and presentation for treatment. Recurrent attacks may continue for several years, especially if associated with agoraphobia. Reduced social or occupational functioning varies among people with panic disorder and is worse in people with associated agoraphobia. Panic disorder is also associated with an increased rate of attempted, but unsuccessful, suicide.12

Treatment aims

To reduce the severity and frequency of panic attacks, phobic avoidance, and anticipatory anxiety; to improve social and occupational functioning, with minimal adverse effects of treatment.

Key messages

Evidence that treatment is beneficialTrade off between benefits and harms
tricyclic antidepressants (imipramine)benzodiazepines
selective serotonin reuptake inhibitors
Unknown effectiveness
monoamine oxidase inhibitors
buspirone

Benzodiazepines

One systematic review and one additional randomised trial have found that alprazolam versus placebo significantly reduces the number of panic attacks and improves symptoms. However, benzodiazepines are associated with a wide range of adverse effects, both during their use and after treatment has been withdrawn.

Buspirone

Randomised controlled trials found insufficient evidence on the effects of buspirone versus placebo.

Monoamine oxidase inhibitors

We found no randomised controlled trials on the effects of monoamine oxidase inhibitors.

Selective serotonin reuptake inhibitors

Two systematic reviews and one additional randomised controlled trial have found that selective serotonin reuptake inhibitors versus placebo improve symptoms in panic disorder. One randomised controlled trial found that discontinuation of sertraline in people with a good response significantly increased exacerbation of symptoms.

Tricyclic antidepressants (imipramine)

One systematic review and subsequent randomised controlled trials have found that imipramine versus placebo significantly improves symptoms. One randomised controlled trial found that imipramine significantly reduced relapse rates over 12 months.

Outcomes

Measures of panic attacks, agoraphobia, and associated disability (self reported and clinician rated, before and after treatment and longer term) using general scales or specific scales for panic disorder (eg the panic and agoraphobia scale, the mobility inventory for agoraphobia).

What are the effects of tricyclic antidepressants for panic disorder?

One systematic review and subsequent randomised controlled trials have found that imipramine versus placebo improves symptoms in people with panic disorder. One randomised controlled trial found that imipramine reduced relapse rates in people with panic disorder.

BENEFITS

We found one systematic review,13 one additional randomised controlled trial,14 and two subsequent randomised controlled trials.15,16 The systematic review (search date not stated, 27 randomised controlled trials, 2348 people) compared imipramine, selective serotonin reuptake inhibitors (paroxetine, fluvoxamine, zimelidine and clomipramine), and alprazolam versus placebo and versus each other.13 It found that imipramine versus placebo significantly increased the number of people judged to have improved (p<0.0001).

The additional randomised controlled trial (181 people with panic disorder with or without agoraphobia) compared 3 treatments: oral imipramine (maximum dose 225 mg); oral alprazolam (maximum dose 10 mg); and placebo.14 It found that imipramine versus placebo reduced the number of panic attacks after 8 months (results presented graphically, significance not calculated).

The first subsequent randomised controlled trial (56 adults with panic disorder and agoraphobia in stable remission after 24 weeks treatment with oral imipramine) comparing oral imipramine (2.25 mg/kg daily) versus placebo found that significantly fewer people taking imipramine relapsed after 12 months (1/29 [3%] with imipramine v 10/27 [37%] with placebo; RR 0.09, 95% CI 0.01 to 0.68; NNT 5, 95% CI 3 to 14).16

The second subsequent randomised controlled trial (312 people) compared five groups: oral imipramine (maximum dose 300 mg daily); cognitive behavioural therapy; placebo; cognitive behavioural therapy plus oral imipramine (maximum dose 300 mg daily); and cognitive behavioural therapy plus placebo.15 It found that imipramine versus placebo significantly increased the number of people judged to have responded using the panic disorder severity scale after 6 months (38% response rate with imipramine v 13% response rate with placebo; absolute numbers not provided; p=0.02).

HARMS

Adverse effects associated with imipramine treatment included blurred vision, tachycardia, palpitations, blood pressure changes, insomnia, nervousness, malaise, dizziness, headache, nausea, vomiting, and reduced appetite.14,17

COMMENT

The review included clomipramine as a serotonin reuptake inhibitor. This drug is also often described as a tricyclic antidepressant.13 The review used improvement as an outcome measure without a clear definition of this term. In the additional randomised controlled trial and the second subsequent randomised controlled trial, flexible dosing was used according to tolerance and therapeutic need.14,15 In the subsequent randomised controlled trial comparing imipramine versus placebo, relapse rate was not clearly defined.16

What are the effects of selective serotonin reuptake inhibitors (SSRI) for panic disorder?

Two systematic reviews and one additional randomised controlled trial have found that selective serotonin reuptake inhibitors versus placebo improve symptoms in panic disorder. One randomised controlled trial found that discontinuation of sertraline in people with a good response significantly increased exacerbation of symptoms.

BENEFITS

We found two systematic reviews,13,18 one additional randomised controlled trial,20 and one subsequent randomised controlled trial.19 The first systematic review (search date not stated, 27 randomised controlled trials, 2348 people) found that selective serotonin reuptake inhibitors (paroxetine, fluvoxamine, zimelidine and clomipramine) versus placebo significantly increased the number of people who improved (p<0.0001).13

The second systematic review (search date not stated, 12 randomised controlled trials, 1741 people) only reported combined results as an effect size against placebo (effect size 0.55), and did not report statistical significance.18

The additional randomised controlled trial (279 people) compared five groups: oral citalopram (10 or 15 mg daily); oral citalopram (20 or 30 mg daily); oral citalopram (40 or 60 mg daily); oral clomipramine (60 or 90 mg daily); and placebo.20 It found that citalopram (at all doses) versus placebo significantly increased the number of people who responded (defined as no panic attacks and either no episodic increases in anxiety or only slight increases in anxiety precipitated by definite events or activities) after 12 months (citalopram 10 or 15 mg daily v placebo p=0.05; citalopram 20 or 30 mg daily v placebo p=0.001; citalopram 40 or 60 mg daily v placebo p=0.003; results presented graphically).

The subsequent randomised controlled trial (182 people who had responded to open label sertraline for 52 wks) compared double blind placebo (discontinuation of sertraline) versus sertraline for 28 weeks.19 It found significantly more people on placebo had exacerbation of symptoms (33% with placebo v 13% with sertraline, p=0.005; CI not available).

HARMS

The additional randomised controlled trial reported that harms associated with citalopram included headache, tremor, dry mouth, and somnolence.20

COMMENT

The first review included clomipramine as a selective serotonin reuptake inhibitor, although this drug is often described as a tricyclic antidepressant.13 In addition, the review used improvement as an outcome measure without clearly defining this term. In the additional randomised controlled trial, only just over half of people (28/54 [52%]) completed the trial; analysis was by intention to treat and people who withdrew from the trial were counted as treatment failures.20 The randomised controlled trial used flexible dosing according to tolerance and therapeutic need. Selective serotonin reuptake inhibitors can cause initial increased anxiety, which can exacerbate a tendency to focus on internal sensations and to avoid situations that trigger these sensations (catastrophise somatic sensations). Education about this event is likely to improve adherence with medication. The second systematic review found smaller randomised controlled trials were associated with larger effect sizes suggesting the possibility of publication bias.18

What are the effects of monoamine oxidase inhibitors for panic disorder?

We found no evidence on the effects of monoamine oxidase inhibitors in panic disorder.

We found no systematic review and no randomised controlled trials. We found no evidence of harms associated specifically with the use of monoamine oxidase inhibitors in the long term treatment of panic disorder. Our search strategy excluded studies with follow up of less than 6 months.

What are the effects of buspirone for panic disorder?

Two randomised controlled trials found insufficient evidence on the effects of buspirone in people with panic disorder.

BENEFITS

We found no systematic review but found two randomised controlled trials.21,22 The first randomised controlled trial (48 people) compared oral buspirone (maximum 60 mg daily) plus cognitive behavioural therapy versus placebo plus cognitive behavioural therapy for 16 weeks.21 It found that oral buspirone plus cognitive behavioural therapy significantly improved self rated panic and agoraphobia scores after 1 year (using a 90 point symptom scale where each symptom was graded from 0=not present to 4=severe; p=0.03; absolute numbers not provided).

The second randomised controlled trial (41 people with panic disorder and agoraphobia) compared 16 weeks of oral buspirone (30 mg daily) plus cognitive behavioural therapy versus 16 weeks of placebo plus cognitive behavioural therapy.22 It found no significant difference in the number of people who had a reduction of at least 50% in their agoraphobic symptoms after 68 weeks (44% with buspirone plus cognitive behavioural therapy v 68% with placebo plus cognitive behavioural therapy; absolute numbers of people not provided).

HARMS

The randomised controlled trials did not report harms.

COMMENT

The first randomised controlled trial used a flexible dosing regimen with maximum dose adjustment according to tolerance and therapeutic need.21

What are the effects of benzodiazepines for panic disorder?

One systematic review and one additional randomised controlled trial have found that alprazolam reduces the numbers of panic attacks and improves symptoms in people with panic disorder. Benzodiazepines are associated with a wide range of adverse effects, both during their use and after treatment has been withdrawn.

BENEFITS

We found one systematic review (search date not stated, 27 randomised controlled trials, 2348 people),13 and one additional randomised controlled trial.14 The review found that alprazolam versus placebo significantly increased the number of people judged to have improved (p<0.0001).13

The additional randomised controlled trial (181 people with panic disorder with or without agoraphobia) compared three treatments: oral alprazolam (maximum 10 mg daily), oral imipramine (maximum 225 mg daily), and placebo.14 It found that alprazolam versus placebo was associated with fewer panic attacks after 8 months (results presented graphically; significance not calculated).

HARMS

The systematic review did not report harms.13 Adverse effects associated with alprazolam include sedation, insomnia, memory lapses, nervousness, irritability, dry mouth, tremor, impaired coordination, constipation, urinary retention, altered libido, and altered appetite.14 We found one non-systematic review of the effects of benzodiazepines in anxiety disorder in people with a history of substance abuse or dependence.23 The review reported that the mortality of long term benzodiazepine users was no higher than matched controls. It reported that the most pronounced adverse effects followed sudden withdrawal and included tinnitus, paraesthesia, vision disturbance, depersonalisation, seizures, withdrawal psychosis, and persistent discontinuation syndrome.

COMMENT

The review used improvement as an outcome measure without clearly defining this term.13 The additional randomised controlled trial used flexible dosing according to tolerance and therapeutic need.14 Many randomised controlled trials of psychological and pharmacological treatments (even those not involving benzodiazepines) allowed people to receive small amounts of anxiolytic drugs during the study because benzodiazepine abuse is quite prevalent in people who suffer from panic disorder.

References

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