GUIDELINE

Panic disorder
C P Szabo

1. Introduction symptoms.[2] Therefore the goal remains to reduce the severity

Panic disorder (PD) is a prevalent anxiety disorder with lifetime and intensity of panic attacks, avoidance, fearful anticipation, and
prevalence rates ranging from 1.1% to 3.7% in the general population cognitive distortions. Of specific relevance is the unpredictability of
and 3.0% to 8.3% in clinic settings.[1] The presence of agoraphobia in episodes and the need for clinicians to meaningfully reassure patients
patients with PD is associated with substantial severity, comorbidity of the planned intervention in terms of outcome, for both future
(e.g. major depression, other anxiety disorders, alcohol abuse) and episodes and functioning.
functional impairment.[1] The disorder is more common in women
than in men, with a 3:1 ratio in patients with agoraphobia and 2:1 in 4.2 General aspects of treatment
patients without agoraphobia. While panic attacks are a core feature of Two broad categories of intervention have demonstrable efficacy,
PD, panic attacks are also experienced by patients with post-traumatic i.e. pharmacological and psychotherapeutic. Both interventions
stress disorder, social anxiety disorder and specific phobias. However, may serve as first-line treatments, as meta-analytic reviews and
unlike in PD, these are typically cued by exposure to or anticipation of large-scale comparative trials have shown comparable efficacy, with
specific anxiety-provoking situations.[2] high remission rates (60 - 80%) and maintenance of gains over time
for both modalities.[4] Systematic reviews have also confirmed that
2. Diagnosis and clinical characteristics a combination of the two is most effective in the acute phase with
PD is an anxiety disorder characterised by recurrent panic attacks ongoing superior effectiveness following the acute-phase treatment.
involving intense fear/discomfort and accompanied by at least 4 of 13 This is compared to pharmacotherapy alone; however, combination
somatic or cognitive symptoms which develop abruptly and reach a therapy may offer only limited benefits beyond that derived from
peak within 10 minutes (Diagnostic and Statistical Manual of Mental psychotherapy alone (viz. cognitive-behavioural therapy (CBT)).
Disorders, Fourth Edition, Text Revision (DSM-IV-TR)).[2] Attacks Pharmacotherapy includes the use of both antidepressant agents
should not be substance-induced, nor related to a medical condition and benzodiazepines. Psychotherapeutic approaches include both
or as a consequence of another psychiatric disorder, and should be cognitive and behavioural components either individually or in
spontaneous in nature. Panic attacks that occur with fewer than 4 of the combination.[5]
13 panic symptoms are termed limited symptom attacks.[2] To make the
diagnosis of PD, at least one of the attacks must be followed by a month 4.3 Pharmacological treatment: Acute
or more of persistent concern regarding the possibility of a subsequent The first-line pharmacotherapy of choice in this anxiety disorder is
attack, worry about the implications of the attacks and/or behavioural the selective serotonin reuptake inhibitors (SSRIs, e.g. fluoxetine/
change, e.g. avoidant behaviours such as agoraphobia – anxiety about paroxetine/fluvoxamine/sertraline/citalopram/escitalopram), or the
being in places from which escape might be difficult or where help serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine
may not be available in the event of a panic attack.[2] PD may occur (including the extended-release formulation), with multiple
with or without agoraphobia.[2] The disorder has been described as a randomised controlled trials (RCTs) showing their efficacy and
‘common, persistent and disabling’ condition.[3] Notwithstanding such a safety.[3] PD also responds to certain other antidepressants, such as
description, both pharmacological and psychotherapeutic interventions the tricyclic antidepressants (TCAs) (while of equivalent efficacy to
have established efficacy. SSRIs, their use is limited by side-effects).[3] Very-low-dose treatment
should be initiated in PD (e.g. fluoxetine 5 mg/venlafaxine ER 75
3. Assessment mg) with gradual upward titration as required. At least 6 - 8 weeks
Based on the clinical characteristics, and awareness of the potential of adequate doses of medication are required to assess whether an
diagnostic pitfalls, i.e. substance/medically/other related psychiatric acute intervention is effective or not. While such an approach appears
disorders, the assessment requires not only a careful history but also reasonable, the use of antidepressants as stand-alone, first-line
the possibility of toxic screening and physical investigation to rule out intervention has, on the basis of systematic review, been cautioned
medically or substance-related presentations. against.[4] Although there is less evidence available for children/
adolescents, SSRIs may again be useful.[6,7]
4. Treatment Given concerns about their side-effect profile (as well as tolerance
4.1 Treatment goals and dependency), the use of high-potency benzodiazepines should
The initial goal of any intervention is symptom relief together with generally be limited to short-term augmentation of antidepressant
maintenance of functioning, followed by ongoing alleviation of medication to rapidly stabilise PD symptoms.[8] Certainly the use
symptoms accompanied by optimal functioning. PD represents a of combination treatment (clonazepam/sertraline) has been found
specific challenge, given the experience of panic attacks as events to provide rapid – and safe – stabilisation of panic symptoms.[9]
characterised by fear and accompanied by a range of somatic Benzodiazepines (alprazolam, clonazepam and lorazepam) are effective

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GUIDELINE

and use patterns have demonstrated that this class of drug is the most may induce mania.[17] Further, the presence of mood instability in
commonly used, notwithstanding guidelines recommending SSRIs as PD patients may worsen the condition, as well as lead to resistance
the preferred treatment.[10] Data regarding the use of benzodiazepine to antidepressants.[18 ]A recently published trial of sodium valproate,
treatment combined with psychotherapy versus benzodiazepine at doses of 600 - 700 mg daily (commencing at 300 mg daily),
treatment alone suggest superiority of combined treatment; however, co-administered with an antidepressant or as monotherapy in
there is a paucity of good-quality evidence, either supportive or non- PD patients with comorbid bipolar disorder, produced symptom
supportive.[11] Of note is a systematic review that failed to identify remission.[18] There are limited controlled data in this regard; hence
quality studies comparing benzodiazepines to newer antidepressants Perugi et al.[18] provide limited but objective evidence to support the
(now regarded as the first line of pharmacological intervention), use of mood stabilisers as treatment for PD, in both ‘antidepressant-
with the suggestion that the promoted move away from first-line and resistant’ sufferers as well as those with comorbid bipolar disorder.
maintenance treatment with benzodiazepines has occurred without Another population of interest are those suffering from migraine
appropriate evidence to support this approach.[12] Most typically the where PD is strongly associated, with either condition impacting
benzodiazepines are seen to have value as ‘rescue’ agents, specifically on the other bidirectionally.[19] It is clear that clinical assessment
alprazolam (including the extended-release formulation),[13] in spite regarding comorbidity covers a range of conditions and is critical
of a lack of evidence-based data supporting such use, notwithstanding for outcome and optimal treatment of PD. Of specific interest are
clinician and patient support and preference for such use.[14] those patients with anxiety disorders, including PD, who have
comorbid substance-related conditions, specifically in relation to
4.4 Pharmacological treatment: Maintenance benzodiazepine use. It appears that the evidence does not preclude
Maintenance treatment at the same dose on which improvement the use of such agents in these patients.[20]
occurred should be continued for at least 1 year. Relapse rates
following discontinuation have shown varying outcomes, with rates 4.7 Partial and non-responders
ranging from 25% to 50%.[2] Of particular interest is that ongoing Reviewing the studies for pharmacological management strategies,
psychotherapy (CBT) is as effective as combination treatment the majority of patients treated with a range of antidepressant
(pharmacotherapy/psychotherapy), which suggests that this may be agents achieve panic-free status during a trial of medication (with
the preferred option in the longer term. no clear cut dose-response relationship) with generally high rates
of response and somewhat lower rates of remission.[3] It should be
4.5 Non-pharmacological treatment noted that placebo response rates of up to 50% also occur,[3] and when
CBT has been shown to be effective for the treatment of anxiety existing data have been subjected to systematic review, combination
disorders in multiple RCTs.[3] CBT for PD consists of components treatment (pharmacotherapy plus psychotherapy) response rates
of psycho-education, cognitive restructuring, and behavioural of just over 50% have been found.[5] Most patients do respond, to
interventions, with the combination of exposure therapy, relaxation varying degrees, to active treatment with a range of interventions
exercises and breathing retraining providing the most consistent that include both pharmacotherapy and psychotherapy, either alone
evidence for efficacy.[4] The typical duration of treatment is 12 - 15 or in combination. Obviously when either partial or non-response is
sessions, but even briefer treatments have shown efficacy.[4] The encountered, accurate diagnosis is paramount; careful reassessment
combination of pharmacotherapy and psychotherapy may have should occur. Multiple agents, at optimal doses for adequate duration
particular advantages (e.g. preventing relapse after medication as well as combination treatment, are all considerations when
discontinuation) and has been suggested as a first line of treatment confronted with partial or non-response – specifically combinations
(together with psychotherapy alone).[5] In addition to these more of antidepressant medication and benzodiazepines. It has been
traditional non-pharmacological interventions, the role of education, suggested that benzodiazepine use be reserved for treatment-resistant
self-management and internet-based interventions have shown patients,[15,21] but it appears that actual clinical practice sees the use
benefit and appear worthy of further study for select patients of benzodiazepines far more routinely and in various ways.[22] While
and situations.[3] Also, the use of virtual-reality exposure therapy there are limited data related to treatment resistance, the role of mood
represents an interesting development, although it has not been clearly instability has been postulated as a factor contributing to ‘resistance
demonstrated to be superior to CBT.[3] to antidepressants’ with a study of sodium valproate demonstrating
improved outcomes where used as an adjunct or as monotherapy
4.6 Special populations (doses ranging from 300 to 700 mg daily).[18] Various other agents, i.e.
Comorbidity is common among psychiatric populations. Within the gabapentin, olanzapine and quetiapine, have demonstrated efficacy
context of PD, the impact of panic symptoms in relation to outcomes in the treatment of PD and could potentially be considered under
of mood disorders is of relevance, because persistent panic symptoms circumstances of partial or non-response.[17] Within this context
appear to negatively influence treatment outcomes of major there has been increasing interest in the use of natural remedies for
depression.[15] Further, PD comorbid with bipolar disorder confers the treatment of anxiety disorders, of which inositol has been studied
an increased risk for suicide.[16] This underscores data demonstrating with regard to PD.[23] In the most recent of such studies inositol (18 g/
that PD is independently associated with risk for suicide attempts.[16 ] day) was compared to fluvoxamine (150 mg/day) using a double-blind
The treatment of PD among patients with comorbid bipolar disorder crossover approach which demonstrated equivalent overall efficacy
represents a challenge in so far as the use of antidepressant agents in the treatment of PD with inositol demonstrating superiority with

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regard to reduction in the number of panic attacks.[24] Such a study References

would need to be replicated before a firm recommendation could 1. Kessler RC, Chiu WT, Jin R, et al. The epidemiology of panic attacks, panic disorder,
and agoraphobia in the National Comorbidity Survey Replication. Arch Gen Psychiatry
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D-cycloserine (a partial agonist at the N-methyl-d-aspartate receptor) 2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders,
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5. Conclusion 4. McHugh RK, Smits JA, Otto MW. Empirically supported treatments for panic disorder.
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of choice, and that the judicious use of benzodiazepines together 6. American Academy of Child and Adolescent Psychiatry. Practice parameters for the
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8. Ballenger JC, Davidson JRT, Lecrubier Y, et al. Consensus statement on panic disorder from
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• Both pharmacological therapies and CBT are considered first-line Psychopharmacology Bulletin 2008;41:39-47.
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alprazolam-CT in panic disorder. Psychopharmacology Bulletin 2007;40;63-81.
• Antidepressant agents have proven efficacy in the treatment of PD.
14. Westra HA, Stewart SH. As-needed use of benzodiazepines in managing clinical anxiety:
• Agents from within the SSRIs and SNRIs are the preferred incidence and Implications. Current Pharmaceutical Design 2002;8:59-74.
options, namely the SSRIs citalopram, escitalopram, fluvoxamine, 15. 15. DeVeaugh-Geiss AM, West SL, Miller WC, et al. Depression and comorbid panic in
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• Adjunctive benzodiazepines have a role in treatment. 16. 16. Kilbane EJ, Gokbayrak NS, Galykner I, et al. A review of panic and suicide in bipolar
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and CBT is likely to be more effective than either therapy alone. 17. 17. El-Mallakh RS, Hollifield M. Comorbid anxiety in bipolar disorder alters treatment and
prognosis. Psychiatr Q 2008;79:139-150. [http://dx.doi.org/10.1007/s11126-008-9071-5]
• CBT and pharmacotherapy are not necessarily added concurrently
18. 18. Perugi G, Frare F, Toni C, et al. Adjunctive valproate in panic disorder patients with
– there is some evidence that adding CBT to patients previously comorbid bipolar disorder or otherwise resistant to standard antidepressants: a 3 year
‘open’ follow-up study. Eur Arch Psychiatry ClinNeurosci 2010;260:553-560. [http://dx.doi.
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• Treatment with psychotherapy alone may be the preferred longer- 19. 19. Nepon J, Belik SL, Bolton J, Sareen J. The relationship between anxiety disorders and
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psychotherapy or pharmacotherapy + pharmacotherapy (e.g. HADAS study. Journal of Headache and Pain 2010;11:141-150.
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• Maintenance treatment: Combination treatment or psychotherapy 22. 22. Posternak MA, Mueller TI. Assessing the risks and benefits of benzodiazepines for
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• In children and adolescents with PD, there are only non- 23. 23. Kinrys G, Coleman E, Rothstein E. Natural remedies for anxiety disorders: potential use
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• CBT is a good alternative for women with PD who plan to become 25. 24. Palatnik A, Frolov K, Fux M, Benjamin J. Double-blind, controlled, crossover trial of
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2001;21:335-339.
medication.

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