Australian and New Zealand clinical practice guidelines for the ...

Australian and New Zealand clinical practice
guidelines for the treatment of panic disorder
and agoraphobia
Royal Australian and New Zealand College of Psychiatrists Clinical Practice
Guidelines Team for Panic Disorder and Agoraphobia
Background: The Royal Australian and New Zealand College of Psychiatrists is co-
ordinating the development of clinical practice guidelines (CPGs) in psychiatry, funded under
the National Mental Health Strategy (Australia) and the New Zealand Health Funding
Authority.
Method: For these guidelines, the CPG team reviewed the treatment outcome literature,
consulted with practitioners and patients and conducted a meta-analysis of recent outcome
research.
Treatment recommendations: Education for the patient and significant others covering: (i)
the nature and course of panic disorder and agoraphobia; (ii) an explanation of the
psychopathology of anxiety, panic and agoraphobia; (iii) rationale for the treatment, likelihood
of a positive response, and expected time frame.
Cognitive behaviour therapy (CBT) is more effective and more cost-effective than medication.
Tricyclic antidepressants (TCAs) and serotonin selective reuptake inhibitors are equal in
efficacy and both are to be preferred to benzodiazepines. Treatment choice depends on the
skill of the clinician and the patient’s circumstances. Drug treatment should be complemented
by behaviour therapy.
If the response to an adequate trial of a first-line treatment is poor, another evidence-based
treatment should be used. A second opinion can be useful. The presence of severe
agoraphobia is a negative prognostic indicator, whereas comorbid depression, if properly
treated, has no consistent effect on outcome.
Key words: agoraphobia, panic disorder, treatment outcomes.
Australian and New Zealand Journal of Psychiatry 2003; 37:641–656

These guidelines, provided to promote good clinical
randomised controlled trials. There are aspects about
care, are designed for mental health professionals trained
which less is known and lower orders of evidence have
to assess, diagnose and treat panic disorder (PD). Spe-
been used. The levels of evidence can be used as a guide
cialist clinicians should consider, but not be limited to,
to the robustness of the evidence.
the treatments recommended. Panic disorder has been
much studied in the past 30 years. The literature is exten-
Definitions and main features
sive and there are numbers of systematic reviews of
Anxiety is a normal emotion that can be adaptive and
aid performance. We all suffer from uncomfortable
Gavin Andrews, Chair (Correspondence)
levels of anxiety at some time. In fact, 40% of young
CPG Team for Panic and Agoraphobia, Clinical Research Unit for
people have had at least one spontaneous panic attack
Anxiety Disorders, St Vincents Hospital, 299 Forbes Street,
Darlinghurst NSW 2010. E-mail: gavina@crufad.unsw.edu.au
[1], although they will not have repeated attacks and do
Received 27 November 2003; accepted 28 November 2002.
not meet the criteria for PD (Table 1).

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CPGS FOR PANIC DISORDER AND AGORAPHOBIA
Panic attacks, the sudden experience of fear accompa-
but that have fewer than four somatic or cognitive symp-
nied by symptoms of the ‘flight or fight’ response, occur
toms are called limited-symptom attacks [2].
in people with a range of anxiety, depressive and sub-
Agoraphobia is anxiety about and avoidance of places
stance use disorders. The key feature of a panic attack
or situations from which escape might be difficult or
that is part of PD is fear about the consequences of the
help unavailable in the event of a panic attack. Such
attack. People with PD worry that the panics are evi-
situations commonly include being alone, crowds, public
dence of something physically or mentally wrong with
transport, driving alone, and being on a bridge or in a lift.
them that might lead to illness, loss of control or death.
The DSM-IV criteria (Table 3) and the ICD-10 criteria
Panic disorder is characterized by discrete periods of
are similar. In cases of agoraphobia without a history of
intense fear, with symptoms of the ‘flight or fight’
panic, which do occur in the community [3] but are rare
response. There is persistent concern about having
in clinical practice [4], situations are avoided for fear of
another attack and worry about the consequences of that
uncomfortable symptoms, usually of anxiety.
attack. Some attacks seem to come out of the blue, others
are accompanied by a sense of impending doom and an
urge to flee the situation. Agoraphobia may or may not
Epidemiology
be present (Table 2). Attacks that meet all other criteria
Anxiety disorders are the most common mental dis-
orders. In Australia 3.8% of adults met criteria for a
DSM-IV anxiety disorder within the past month [5].
Table 1.
DSM-IV criteria for a panic attack
Anxiety disorders account for a quarter of the burden of
disease attributed to mental disorders [6].
A discrete period of intense fear or discomfort, in which four
(or more) of the following symptoms developed abruptly and
reached a peak within 10 minutes:
Prevalence
Palpitations, pounding heart or accelerated heart rate
Sweating
Studies across the developed world indicate a life-
Trembling or shaking
time prevalence of PD between 1.4% and 2.9%, with
Sensations of shortness of breath or smothering
Feeling of choking
higher rates for women [7]. Panic disorder without
Chest pain or discomfort
agoraphobia typically presents with a more equal sex
Nausea or abdominal distress
ratio [8] than does agoraphobia, where around three-
Feeling dizzy, unsteady, lightheaded or faint
Derealization or depersonalization
quarters of sufferers are women [9,10]. The point-
Fear of losing control or going crazy
prevalence of the panic cluster of disorders in the
Fear of dying
Australian National Mental Health Survey was 0.7%,
Paresthesias (numbness or tingling sensations)
Chills or hot flushes
and the male : female ratio 1 : 2 [5]. In community
samples, one-third to one-half of those diagnosed with
Table 2.
DSM-IV criteria for panic disorder without agoraphobia
A. Both of the following:
●
recurrent and unexpected panic attacks
●
at least one of the attacks has been followed by one month (or more) of one (or more) of the following:
– persistent concern about having additional attacks
– worry about the implications of the attack or its consequences (e.g. having a heart attack, going crazy)
– a significant change in behaviour related to the attacks
B. Absence of agoraphobia
C. The panic attacks are not due to the direct physiological effects of a substance or a general medication condition.
D. The anxiety or phobic avoidance is not better accounted for by another mental disorder, such as social phobia (e.g. avoidance
limited to social situations because of fear of embarrassment); specific phobia (e.g. avoidance limited to single situation like
elevators); obsessive-compulsive disorder (e.g. avoidance of dirt in someone with an obsession about contamination);
post-traumatic stress disorder (e.g. avoidance of stimuli associated with a severe stressor); or separation anxiety disorder
(e.g. avoidance of leaving home or relatives).
The DSM-IV criteria for panic disorder with agoraphobia are the same as above, except that agoraphobia is present.

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Table 3.
DSM-IV Criteria for agoraphobia
● Anxiety about being in places or situations from which escape might be difficult (or embarrassing) or in which help may not be
available in the event of an unexpected or situationally predisposed panic attack or panic-like symptoms. Agoraphobia fears
typically involve characteristic clusters of situations that include being outside the home alone; being in a crowd or standing in line;
being on a bridge; and travelling in a bus, train or car.
● The situations are avoided or else are endured with marked distress or with anxiety about having a panic attack or panic-like
symptoms, or require the presence of a companion.
● The anxiety or phobic avoidance is not better accounted for by another mental disorder, such as social phobia (e.g. avoidance
limited to social situations because of fear of embarrassment); specific phobia (e.g. avoidance limited to single situations like
elevators); obsessive-compulsive disorder (e.g. avoidance of dirt in someone with an obsession about contamination);
post-traumatic stress disorder (e.g. avoidance of stimuli associated with a severe stressor); or separation anxiety disorder
(e.g. avoidance of leaving home or relatives).
PD also report agoraphobia [11]. The rate is higher in
direct (e.g. medical care, prescription drugs) and indirect
clinical samples.
(e.g. lost productivity).
In Western Australia, people with PD had significantly
Course and prognosis
higher medical-use rates and incurred higher costs than
either non-anxious controls or people with social phobia
Panic disorder begins between late adolescence and
[23]. Over a 12-month period, they averaged a direct
the mid-30s [3,7,11,12], although the first panic attack
cost (including visits to primary care physicians, special-
may have been experienced years earlier [9]. The course
ist consultations, diagnostic tests and ambulance and
is usually chronic but will often wax and wane. Typi-
emergency department services) of $AU1118, compared
cally there is a substantial period between initial onset
with $99 for non-anxious age-matched controls.
and presentation for treatment. But even when people do
Many people with PD do not seek treatment, and much
present, PD is both under-diagnosed and under-treated
of the economic cost is indirect (e.g. work disability and
[13–15].
family dysfunction) [24,25]. A diagnosis of PD is asso-
As with other anxiety disorders, stressful life events
ciated with pervasive social and health consequences
tend to precede the onset of PD [16,17]. It seems that it
similar to or greater than those associated with depres-
is not the stressful life events in themselves that are
sion [26,27].
critical, but the negative interpretation of the consequent
symptoms [18]. The frequency of panic attacks varies
Method
widely. One person housebound with agoraphobia might
have only one panic attack in 12 months in which she
Key features of the development of this guideline have
anticipates collapse or death. Another person, not house-
been: (i) a comprehensive review of relevant literature;
bound, may have attacks of similar severity on a daily
(ii) meta-analysis of randomised controlled trials;
basis. Recurrent attacks may continue for years. There
(iii) development of evidence tables; (iv) initial drafting
may be periods of full or partial remission, with no
by a work group with clinical and research expertise;
panics or only mild attacks with few symptoms. Panic
(v) patient review and input; and (vi) multiple drafting
disorder may be associated with minimal impairment in
following widespread input.
social or occupational functioning, or else with extreme
Literature searches were of English language MEDLINE
impairment, as in severe agoraphobia.
(1966–1999), PsychINFO (1984–1999), EMBASE (1988–
1999) and the Cochrane Library (1966–1999). Key words
Economic and social implications
for searches were: ‘clinical trial’; ‘controlled clinical
trial’; ‘review’; ‘systematic review’; ‘meta-analysis’; ‘panic
The economic and social costs are considerable
disorder’; ‘agoraphobia’; ‘psychotherapy’; ‘psychiatry’.
[13,19–21], and are greater than for schizophrenia or
Searches used extra key words such as: ‘assessment’;
mood disorder. Anxiety disorders cost the US economy
‘comorbidity’; ‘outcome’; ‘course’; and ‘medical inves-
$US46.6 billion annually [22]. These costs are both
tigations’. Key texts and review articles were sourced

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CPGS FOR PANIC DISORDER AND AGORAPHOBIA
(e.g. Treatments that work [28]), and existing guidelines
Once details of the panic and related avoidance have
consulted.
been established, the clinician should establish the onset
An excellent meta-analysis conducted by Gould et al.
and the course of the disorder, factors that maintain the
[29] included 43 studies. Our meta-analysis focused on
problem, and coping strategies that have been successful
trials not included there or published subsequently. Of
in the past. It is important to enquire about past treat-
137 studies identified, 58 were randomized placebo
ment, including response and attitude towards them.
(psychological or pharmacological) controlled trials
A psychiatric and medical history should be taken to
from which data could be coded. This and the Gould
determine whether there is concurrent depression or a
et al. meta-analysis provide the basis for our recommen-
physical basis for the symptoms [31,32]. The person’s
dations. While this guideline was in review, two more
psychosocial circumstances should be established (e.g.
meta-analyses appeared; their results are noted. Evi-
family, partners, accommodation, education, occupation
dence from the meta-analyses has been supplemented by
and social relationships). Disability should be estab-
lower-level evidence, including expert consensus, when
lished (What do the panics/agoraphobia stop you
more rigorous scientific evidence is lacking.
doing?). Assessment should consider cultural issues in
the expression and experience of anxiety (see Appen-
dix).
General issues in treatment
The consequences of panic must be identified. A
common type is avoidance, with subtle strategies such as
Aims of treatment
carrying medication or a mobile phone, or distracting
oneself in the feared situation. Recognizing the link
Effective treatment has these goals: (i) control and
between panic attacks and avoidance facilitates CBT
cessation of panic attacks; (ii) control and cessation of
(e.g. ‘I avoid crowded trains because the air may run out
fear-driven avoidance; and (iii) reduction in vulner-
given that everyone is breathing it’).Typical beliefs asso-
ability to relapse.
ciated with PD include: ‘I might have a heart attack’;
Both psychological and pharmacological treatments can
‘I might lose control of myself’; ‘I am going crazy’; and
achieve the first two goals but there is no evidence that
‘I might die’. People with PD also fear embarrassment
drugs are able to reduce vulnerability. Cognitive behav-
but this is not a primary concern. The main worry is
ioural therapy can, through education about panic and the
about what will happen to them as a result of their
provision of skills to deal with anxiety, reduce the proba-
symptoms; the fear of bodily collapse is paramount.
bility of relapse. Treatment of panic rarely requires hos-
The differential diagnoses in DSM-IV include medical
pitalization unless there is concurrent suicidal depression
conditions that can cause panic-like attacks such as
or substance use requiring detoxification. Panic disorder
hyperthyroidism, hyperparathyroidism, seizure disorders
alone is not an indication for admission.
and cardiac conditions like arrhythmias. Onset after age
45 or the presence of neurological symptoms during a
Assessment
panic attack (e.g. vertigo, loss of consciousness, loss of
bladder or bowel control, headaches, slurred speech or
As panic attacks may occur in a number of disorders
amnesia) suggest the possibility that a general medical
apart from PD, a behavioural assessment facilitates thor-
condition/organic syndrome may be causing the panic-
ough understanding [30]. The major differential diag-
like symptoms. If the presentation is complex, conduct a
noses are panic attacks in the other anxiety disorders and
thorough behavioural analysis and consider contacting
in depression. If the panic attacks occur only in social
other medical professionals regarding past investiga-
situations and there is a fear of shame, this is consistent
tions. Panic attacks can occur with most recreational
with social phobia. If the panic relates to obsessional
drugs, especially as part of withdrawal. If symptoms
fears in obsessive compulsive disorder (OCD), to situa-
persist after intoxication or withdrawal have ended, a
tional fears in specific phobia, or is directly attributable
primary diagnosis of PD should be considered.
to the physiological changes in drug withdrawal or
depression (when attacks occur upon waking), the diag-
Investigations
nosis is unlikely to be PD. The attacks relate to fear of
the consequences of panic. People fear that they will
It is rare for people with a long history of PD to have
have a heart attack, collapse, go mad or die. The situa-
an undiagnosed medical condition. Many have sought
tion that is feared, endured or avoided merely adds to the
medical advice on numerous occasions and continue to
risk of not being able to escape or get help. The danger
do so despite negative tests. If a person presents in the
in a panic attack is the danger to the self by the self.
early stages, and the history suggests a psychological

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RANZCP CPG TEAM FOR PANIC DISORDER AND AGORAPHOBIA
645
trigger, it is appropriate to begin treatment without first
Current treatment evidence
investigating. If after 6 weeks panic symptoms are still
prominent and cannot be clearly explained by psycho-
We offer recommendations about psychological and
logical factors, it is prudent to conduct special investiga-
pharmacological treatments when there is consistent evi-
tions to rule out a medical cause. Remember that PD and
dence of efficacy from three or more randomised control-
medical conditions can coexist. There is no diagnostic
led trials from more than one research group. Two
test specific to PD.
statistics summarize the overall treatment effect (Table 4).
The number needed to treat (NNT) is an estimate of
the number of people who would need to be treated for
Concurrent disorders
one of them to achieve designated treatment success. In
this guideline, NNT is based on the percentage of people
Clinical studies indicate that the rate of major depres-
who are panic-free at the end of active treatment. For
sion may be higher than 30% [14,33,34]. Panic disorder
example, a pooled NNT of 3 means that a clinician needs
occurring only in the context of depression is excluded
to treat three people to achieve panic-free status in one.
by the criteria (see DSM-IV), but having concurrent
Thus an NNT of 2 is better than a NNT of 6.
depression can result in a poorer response to treatment
The effect size (ES) illustrates the extent of improve-
[34–40]. A history of other anxiety disorders is also
ment in the average patient. It is the difference between
common, particularly social phobia (21%), generalized
the treatment and control group expressed in standard
anxiety disorder (56%) and OCD (24%) [9,41]. People
deviation units, thereby allowing comparisons across
with PD are more likely to abuse alcohol and sedative-
different outcomes and treatments. An ES of 1.0 indi-
hypnotics than the general population [42,43]. The effect
cates that the average treated person would be better than
of alcohol use both on the underlying psychiatric dis-
86% of untreated patients.
order and on the effectiveness of drug and psychological
Levels of evidence for various treatments are specified
therapy is stressed in the literature [44]. The rate of
in roman numerals before the reference numbers. For
Axis II disorders in those with PD varies widely between
example, [I] [29] means that the level of evidence is 1,
studies [45–48], and the effect on treatment outcome is
and the reference corresponding is 29.
unclear.
Suicide ideation is common and should be carefully
Beneficial interventions
assessed. The high rate of suicide attempts is not
always reflected in completed suicides [49,50]. This
Cognitive behaviour therapy (CBT)
may be related to the high level of comorbid major
depression and the disinhibiting effects of substance
Acute management
abuse [33,51–53] and may not differ from other mental
disorders [52], but PD in the young may be more
Cognitive behavioural thereapy is the most consist-
serious [54].
ently efficacious treatment for PD, according to three
Table 4.
Effect sizes (ES) and number needed to treat (NNT) at post-treatment and follow-up for the Gould et al.
meta-analysis and our meta-analysis
Post-treatment
Follow-up
Drug
95% CI†
Psych.
Drug
Psych.
therapies
therapies
95% CI†
therapies
95% CI†
therapies
95% CI†
Gould et al. (1995)
0.47
0.38–0.54
0.68
0.58–0.78
0.01
–
0.74
–
CPG analysis: all measures‡
0.40
0.27–0.52
0.61
0.35–0.87
0.00
0.27–0.27
0.57
0.24–0.91
CPG analysis: revised all
0.43
0.30–0.55
0.59
0.34–0.83
0.00
0.27–0.27
0.65
0.31–1.00
measures§
CPG analysis: NNT
6
5–7
3
3–5
6
4–4
3
3–5
†Confidence interval; ‡measures from which ESs were calculable–the decision rule used by Gould et al. §excludes measures not
directly related to panic and agoraphobia (e.g. personality and depression). ES estimator method = Glass’ Delta. Effect sizes for our
guideline combined a random effects model.

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CPGS FOR PANIC DISORDER AND AGORAPHOBIA
meta-analyses [I] [2,29,55–58]. The elements included
sessions can be a useful continuing resource for self-
in most trials are psychoeducation, anxiety management
treatment. Evidence is accumulating that CBT better
(control of hyperventilation and relaxation), cognitive
prevents relapse [II] [73–76] than medication [I] [29].
therapy, and in vivo and interoceptive exposure. Cogni-
Cognitive behavioural therapy confers skills, and this
tive behavioural thereapy showed the strongest ESs in
new knowledge produces future benefits that may not
both systematic reviews, as well as the greatest percent-
always be enhanced by additional treatment [77]. In a
age of people who were panic-free at the end of treat-
study of routine functioning, benefits were maintained at
ment (74.3%). Dropout rates were low [I] (56%)[29];
2-year follow-up [II] [78]. This is an important finding,
(11.7%) [56].
for patients with comorbid depression or personality
Although in vivo exposure alone may be helpful [I] [59],
disorders were not excluded, as in many randomised
it is not the treatment of choice [I] [56,60]. Interoceptive
controlled trials.
exposure is an important treatment, but we cannot conclude
that it is superior to in vivo exposure or can replace it [I]
Tricyclic antidepressants (TCAs)
[61–63]. Cognitive therapy without behavioural techniques
showed a strong effect in our meta-analysis, although
Acute management
further investigation with larger sample sizes is required
before recommending it as the sole treatment [I] [56].
Two meta-analyses showed no significant difference
A variety of delivery methods for CBT have been
in outcome between TCAs and benzodiazepines (BZDs).
researched. Brief cognitive therapy, with only 6.5 h of
Tricyclic antidepressants showed a higher dropout rate
therapist time, has been shown to be as efficacious as
(25.4%) than BZDs (13.1%) [I] [29,79]. In our meta-
standard CBT (12 – 15 h) [II] [64]. In two trials, self-help
analysis TCAs were the pharmacological treatment with
books were as efficacious as group CBT, with gains main-
the strongest ES across a range of measures, and showed
tained at 6-month follow-up; this presents a potentially
similar efficacy to CBT [I] [56]. Seven of the eight
cost-effective option [II] [65,66]. Telephone-administered
available meta-analyses show imipramine to be effective
exposure instructions have been shown to be an effective
[I] [59]. The optimal dose was 100–225 mg daily, and
alternative for people who are not willing to be treated
benefit was obvious within 8–12 weeks. Clomipramine
outside their home [II] [67,68], although it is probably
(a TCA with serotonin reuptake inhibitory effects) has
best reserved for those who would otherwise not receive
been found to be beneficial [I, II] [80] at doses of
treatment. A related approach, CBT with reduced thera-
50–100 mg for 6–12 weeks. The evidence about desi-
pist contact (some by telephone), has proved to be viable
pramine is equivocal. In a 12-week randomised control-
and cost-effective [II] [69]. Computer-assisted therapy
led trial, desipramine was not shown to be more helpful
may be a useful treatment approach [II] [70].
than placebo [II] [81], although a less well-controlled
Cost analysis conducted in the US has shown that
study showed it to be as beneficial as fluoxetine [82].
imipramine and group CBT are the lowest cost interven-
tions [I] [29]. Cognitive behavioural therapy had slightly
Harms
better efficacy and a higher rate of tolerability (retention)
than imipramine, and so appears to be the most cost-
Many patients on TCAs drop out (a quarter in our
effective and tolerable treatment available.
meta-analysis) due to side-effects [I, II] [79,83]. Anti-
cholinergic effects are frequently associated with imi-
Harms
pramine and clomipramine. In one review, 43% reported
such effects, including dry mouth, excessive sweating,
In our meta-analysis, dropouts for in vivo exposure
constipation, blurred vision, urinary retention and
alone (21.3%) were higher than for either cognitive
mydriasis [II] [84].
therapy alone (1.8%) or combined CBT (11.8%) [56].
We identified no adverse events. A disadvantage of CBT
Maintenance and long-term management
is that therapists need training [71] and there is a dearth
of trained CBT clinicians. Generic counselling is less
Maintenance treatment with a constant dose of imi-
effective than properly conducted CBT [72].
pramine over a year has a protective effect against
relapse in patients who showed good initial response to
Maintenance and long-term management
the drug [II] [85]. A relapse rate of more than a third
within the first year of imipramine discontinuation was
Most courses of CBT include one or more follow-up
reported in the same study. Similarly, a group main-
sessions. Manuals which are personalized during the
tained on a constant dose of imipramine or alprazolam

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647
did slightly better on symptom measures than a placebo
agitation in the initial weeks of treatment than with other
group, although less than 40% in both groups continued
drugs in this class [92]. Hostility is a possible side-effect
medication [II] [83]. Relapses usually occur 4–6 months
[I] [97].
after discontinuation [II] [85]. One trial found that after
Paroxetine Four double-blind, placebo-controlled
6 months on imipramine, relapse can be prevented for up
clinical trials have demonstrated efficacy in short-term
to an additional year by maintenance on half the original
treatment [II] [98–100]. Clear superiority over placebo
dose [86]. Paucity of long-term data precludes recom-
and equivalent effectiveness to clomipramine were
mendations about long-term management with TCAs but
observed, and a threshold dosage of 40 mg/day is recom-
expert consensus suggests 12 months of medication and
mended [101]. One double-blind trial compared paroxe-
then tapered withdrawal.
tine plus cognitive therapy to placebo plus cognitive
therapy [II] [100]. Significantly, more patients in the
Serotonin selective reuptake inhibitors (SSRIs)
paroxetine group achieved a 50% reduction in panic
frequency. Paroxetine reduces the number of panic attacks
Benefits
and prevents relapse for up to 9 months [II] [99,102]. It
has a similar side-effect profile to other SSRIs, most
Evidence for efficacy is conflicting. One meta-analysis
notably nausea and sweating, and there is a problem with
found SSRIs (including paroxetine, fluvoxamine, zime-
discontinuation.
lidine, and clomipramine) more effective than low dose,
Sertraline Two randomised, double-blind, placebo-
but no high dose, imipramine and clonazepam [I] [57].
controlled trials [II] [103,104] found sertraline to be
The Gould et al. meta-analysis was conducted before
superior to placebo at 50, 100 and 200 mg, with no
evidence about SSRIs accumulated. In our meta-analysis,
difference in the efficacy of different doses [II] [103].
SSRIs were modestly useful, with less demonstrated
Since the difference from placebo on many measures
efficacy than imipramine and alprazolam [I] [56]. They
was not significant in one of these trials [104], more
were less beneficial than CBT. Two subsequent meta-
trials are needed. In one trial, a third dropped out
analyses [58,87] concluded that SSRIs were equal to
because of adverse experiences or insufficient response
TCAs but were better tolerated, although onset of benefit
[92,104,105].
was slower. There are no data on the optimum length of
Citalopram A double-blind, placebo and clomi-
treatment following initial response.
pramine-controlled, parallel group, 8-week study with a
large sample size found citalopram superior to placebo
Harms
[II] [106]. The most advantageous benefit/risk ratio was
at a dose of 20–30 mg/day. Side-effects are similar to
The main side-effects of SSRIs include headaches,
other SSRIs [II] [106].
irritability, nausea and other gastrointestinal complaints,
insomnia, sexual dysfunction, increased anxiety, drowsi-
Interventions with a trade-off between benefits
ness and tremor. A withdrawal syndrome caused by
and harms
abrupt discontinuation of SSRIs [88] may occur. In our
meta-analysis a large proportion (26%) of those taking
Literature that would allow the calculation of the
SSRIs dropped out of treatment [I].
number needed to harm could not be found.
Specific SSRIs
High-potency benzodiazepines (BZDs)
Fluvoxamine At least six double-blind, placebo-
Acute management
controlled trials show this to be a useful treatment, with
similar benefits to clomipramine [II] [89–92]. A dose of
In both our meta-analysis and that of Gould et al.
100–200 mg is recommended. Negative trials exist [II]
BZDs were found to have a small to moderate effect [I]
[93]. The side-effect profile is similar to that of other
(ES = 0.39; ES = 0.40) [29,56]. They have often been
SSRIs [92], and commonly includes sleepiness, sweat-
found to have similar efficacy to TCAs, although in our
ing, diarrhea and nausea [94].
meta-analysis they were less effective [I] [60]. They
Fluoxetine There is evidence of efficacy at a daily
were found to be more tolerated than TCAs, with fewer
dose of 5–20 mg [II] [95,96]. In one trial comparing 10
dropouts [I] [79]. The BZD with the most data is alpra-
and 20 mg, 20 mg was associated with greater improve-
zolam, although controlled trials of diazepam, lorazepam,
ment, though the difference was not large compared with
andinazolam and clonazepam suggest similar benefits
placebo [96]. There is more anxiety, nervousness and
[II] (e.g. 107–110). Alprazolam works in the range of

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648
CPGS FOR PANIC DISORDER AND AGORAPHOBIA
4–15 mg given for 4–15 weeks. Even with a slow taper,
into the process (see below for discussion of combined
relapse rates of 50% or higher following discontinuation
treatments) [138].
are typical [II] [111,112].
Interventions likely to be beneficial
Harms
For the following sections, evidence is not categorized
into acute, maintenance and long-term treatment as there
BZDs carry a risk of iatrogenic dependence as well as
is insufficient information available at this stage.
industrial and road traffic accidents [113,114]. They
have been found to cause impairment in attention, con-
Monoamine oxidase inhibitors (MAOIs)
centration and short-term memory up to 24 weeks fol-
lowing withdrawal [II] [115,116]. Rebound anxiety on
Only early open-label studies are available. Both
withdrawal has been reported in 15–30% of patients
studies on RIMAs, one a double-blind comparison of
[113,117,118]. Side-effects include sedation or drowsi-
brofaromine and clomipramine [II] [139] and the other
ness (38–75%), memory impairment (up to 15%) [II]
an open study of brofaromine [III] [140], showed
[119], unsteadiness, slurring of speech, occasional
antipanic and antiphobic value.
forgetfulness, irritability and reduced motivation [120].
Other adverse reactions to alprazolam (4–21%) include
Applied relaxation
amnesia, aggression and mood changes [121,122]. Hos-
tility occurred in 10% of one group receiving alprazolam
This may be a useful treatment [II] [141,142]. One trial
[123]. The attrition rate is lower for BZDs than for TCAs
showed similar efficacy to cognitive therapy, with 65%
[II] [124,110]. In our meta-analysis 12.8% of patients
in the applied relaxation group and 74% in the cognitive
taking BZDs dropped out [I] [56], and higher rates than
therapy group panic-free at the end of 12 sessions [II]
this have been reported [125]. Benzodiazepines should
[142]. Results were maintained 1 years later. It should be
be avoided in late pregnancy and while breast-feeding
noted that cognitive therapy did not involve traditional
[126]. The most common and serious interaction with
cognitive restructuring, but superficial techniques such
other medications is enhancement of alcohol and aug-
as distraction [143]. Negative trials exist.
mentation of opiate-induced euphoria [127].
Interventions of unknown efficacy
Maintenance and long-term management
Other drugs
There is concern that maintenance alprazolam might
There is insufficient information to recommend
lead to dependence, withdrawal, continued treatment and
nefazodone, moclobemide or venlafaxine [144–146].
further dependence [128], and it is not recommended for
None of the following has been found to be useful:
long-term use. A number of studies have found that
buspirone [II] [147,148]; beta blockers such as propa-
people find it difficult to withdraw from alprazolam,
nolol [149,143]; BZDs such as flurazepam, temazepam
with most suggesting that up to half are unable to dis-
and triazolam; and bupropion [31].
continue within a month [128,129]. Only 27–47% of
patients are off high-potency BZDs 12–30 months later
Client-centred therapy
[130–132]. In one study most remained in need of their
drug 2 years after initial treatment [133]. Common
A randomised controlled trial of client-centred therapy
symptoms of withdrawal are nervousness, irritability,
compared to insight-orientated therapy plus exposure
sleep difficulties, loss of appetite, tremor, myalgia and,
found improvement in both groups [II] [150]. The com-
in rare cases, seizures [128,134]. Propranolol, buspirone
bined group was superior in the first 6-month follow-up
and clonidine have been reported to be ineffective or
period, but there were no differences at 1 year.
of modest efficacy in attenuating BZD withdrawal
syndrome [128], but carbamazepine may assist [II]
Psychodynamic therapy
[128,135,136].
If BZDs are prescribed, alprazolam should be contin-
Adding 15 weekly sessions of dynamic psychotherapy
ued for six symptom-free months, with a slow taper
to treatment with clomipramine reduced the relapse rate
between 6 and 12 months after remission [V] [137,118].
over 9 months [III] [151] after clomipramine was with-
A threefold increase in successful discontinuation from
drawn. Long-term psychodynamic therapy may be of
high-potency BZDs occurs when CBT is incorporated
value when there are comorbid personality disorders.

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RANZCP CPG TEAM FOR PANIC DISORDER AND AGORAPHOBIA
649
Eye movement desensitization and reprocessing
many people remain symptomatic [II] [77,130,158–
160]. The rate of relapse following discontinuation of
Compared to wait-list control, any short-term benefits
drugs is high [III] [161]. In one study only a quarter
had dissipated 3 months after treatment, suggesting that
discontinuing antidepressants sustained remission for
this is not a treatment of choice for long-term control [II]
2 years or longer [162]. In a long-term follow-up study
[152].
of 367 patients treated with drugs, over half continued to
have occasional panic attacks, 40% still experienced
Hypnosis
avoidance and half were still taking medication [163].
The goal of treatment should be the disappearance of
There is no evidence that hypnosis is useful [153].
residual and subclinical panic and agoraphobic avoid-
ance [142]. Long-term course is improved by CBT
Interventions likely to be ineffective or harmful
[74,75,165,166]. Follow-up studies indicate that at
15–24 month follow-up, about 85% are panic-free but
Antipsychotics
30–50% have residual avoidance. Follow-up data for
CBT and for drug therapy should be interpreted cau-
There is no evidence that conventional antipsychotics
tiously, as studies are naturalistic [167]. Increase in
have a role, and the risk of side-effects outweighs any
benefit by combining antidepressants and CBT has not
potential benefit [31].
been demonstrated, and combination with BZDs may
worsen end-state functioning [167,168].
Clonidine
Psychological treatments
Limited evidence suggests unsuitability [III]
[154,155].
The average duration of CBT was 10 weeks and the
average pharmacological trial was 8 weeks. Some CBT
Is combining two forms of treatment better?
trials included a follow-up period of up to a year (mean
29 weeks) whereas only one pharmacological trial incor-
CBT and medication
porated follow-up. Average dropout rates were lower for
CBT (12%) than for medication (21%). Both in vivo
Cognitive behavioural therapy before and during drug
exposure and cognitive therapy showed a strong effect
discontinuation improves maintenance of treatment
on reducing frequency of panic attacks [I] [29,56].
effects in patients initially treated with medication [III]
[138,112]. The opposite approach (adding medication to
Pharmacological treatments
CBT) possibly provides short-term treatment gains but
may reduce the long-term benefits of CBT [156]. In six of
Tricyclic antidepressants and SSRIs were the most
eight studies examining imipramine plus exposure, there
beneficial, while BZDs were moderately so [I] [56]. A
was no greater benefit from the combination than from
number of trials show that relapse following discontinu-
imipramine alone [I] [29]. Clinical observation suggests
ation of medication is common.
that the use of alprazolam during CBT, especially during
How do effective treatments compare? (i) Most
later sessions, undermines the value of CBT [157]. Use of
patients show a positive response to either drugs or CBT.
BZDs during CBT has been associated with poorer
(ii) The number needed to treat to get one person panic
outcome at both 3- and 24-month follow-up [77], possibly
free is 3 for CBT and 6 for medication. (iii) Cognitive
because they prevent the evocation of anxiety necessary
behavioural therapy exerts a more enduring effect than
for emotional processing [157]. There are no data to
medication. (iv) Dropout rates for medication are higher
support the use of BZDs as occasion requires instead of
than for CBT.
CBT to cope with acute panic attacks. State-dependent
learning or attributing gains to drugs can lessen the effi-
Methodological concerns
cacy of CBT. There are insufficient data to evaluate the
combination of CBT and SSRIs, other TCAs or MAOIs.
Reduction in panic and phobic symptoms have been
reported in agoraphobic patients receiving 2 weeks of
Overview of outcome
placebo [169]. The placebo response was not transient,
and a quarter of patients showed marked response after
Research on long-term outcome shows that although
10 weeks. In an 8-week trial, 70% of those receiving an
improvement is common with either CBT or medication,
active agent (alprazolam or imipramine) and 50% of the

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650
CPGS FOR PANIC DISORDER AND AGORAPHOBIA
placebo group were panic-free [124]. One explanation
competence and patient adherence erode potential effec-
for the small difference between placebo and active
tiveness of a proven treatment. It would not be surprising
treatment response may be that trials exclude those
if effectiveness were half that of the efficacy demon-
likely to have a complicated disorder [170].
strated in research.
People with PD are vigilant to changes in their bodies.
They fear side-effects of medications, particularly since
Acknowledgements
these may resemble symptoms of anxiety from which
they are trying to escape. It is essential to educate the
CPG team
patient about side-effects and to caution against random
changes in medication. In particular, response to SSRIs
Gavin Andrews (Clinical Research Unit for Anxiety
may show an increase in anxiety that peaks over the first
and Depression [CRUfAD], School of Psychiatry,
week and then subsides. Follow the dose rule, ‘start low
UNSW at St. Vincent’s Hospital, Sydney), Justine Corry
and go slow’.
(CRUfAD, Sydney), Mark Oakley-Browne (Monash
It is not advisable to discontinue medication after
University, Traralgon) and Louise Shepherd (CRUfAD,
control of panic until avoidance behaviour has been
Sydney).
overcome. Cessation of medication used to manage
anxiety can cause rebound anxiety, a discontinuation
Consultant reviewers
syndrome or relapse. All medications should be tailed
off gradually, over at least 4 weeks and longer for BZDs.
Catriona Angus (Anxiety Disorders Foundation of
During discontinuation, patients should be encouraged
Australia, NSW), Andrew Baillie (Anxiety Disorders
to increase the use of relaxation strategies, continue
Foundation of Australia, NSW), John Bushnell (Univer-
exercise and avoid stimulant drugs (such as caffeine and
sity of Otago, Wellington), David Castle (University of
nicotine).
Melbourne), Fiona Judd (Monash University, Bendigo),
Andrew Page (University of Western Australia, Perth)
Cost-effectiveness of treatment
and Kitsa Yanniotis (Anxiety Disorders Foundation of
Australia, NSW).
Cognitive behavioural therapy is the most cost-effec-
tive treatment available in Australia and the finding is
Editorial consultants
similar to that of Gould et al. based on US data [29].
Cost-analysis compared imipramine, clomipramine, par-
We thank Clinical Evidence, no. 2, December 1999,
oxetine and individual CBT (all provided by a psychia-
for literature search results and Jean Dunn and Sidney
trist).
Bloch for their editorial comments.
The cost alternatives of various treatments were calcu-
lated by adding medication cost and cost in psychiatrists’
Disclaimer
time to diagnose and treat a person for 12 months. At
1 year the cost of CBT is less than that of average drug
This document was compiled for the Royal Australian
therapy (CBT becomes cheaper than paroxetine at
and New Zealand College of Psychiatrists (RANZCP).
8 months, clomipramine at 11 months and imipramine
The information and advice it contains is based on
at 13 months). During the second and subsequent years
current medical knowledge and practice at the date of
the superiority of CBT increases whether or not drugs
publication. It is intended as a guide only. The RANZCP
are continued. If the drugs are continued, then their costs
accepts no responsibility for any consequences arising
continue. If they are not, then relapse occurs in about
from relying upon the above information.
half of those withdrawn from drugs, and the net benefit
due to drug therapy declines. Relapse is not associated
with CBT follow-up, at least for the first 5 years, so there
References
is no change to cost or benefit.
If one takes the number to treat to produce one
1.
Norton GF, Cairns SL, Wozney KA, Malan J. Panic attacks and
psychopathology in non-clinical panickers. Journal of Anxiety
panic free person, then the cost (in 2003 figures) is
Disorders 1988; 2:319–331.
$A9000 for imipramine, $A10 500 for clomipramine,
2.
American Psychiatric Association. Diagnostic and statistical
$A10 000 for paroxetine and $A6500 for CBT. On the
manual of mental disorders. 4th edn. Washington DC: American
basis of cost and efficacy, CBT clearly surpasses medi-
Psychiatric Press, 2000.
3.
Robins LN, Regier DA eds. Psychiatric disorders in America:
cation. However, effectiveness in practice is another
the Epidemiologic Catchment Area Study. New York: Free Press,
issue since it is always less than efficacy; clinician
1991.

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