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Treatmentresistant panic disorder: a systematic

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Expert Opinion on Pharmacotherapy

ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20

Treatmentresistant panic disorder: a systematic

review
Rafael C. Freire, Morena M. Zugliani, Rafael F. Garcia & Antonio E. Nardi
To cite this article: Rafael C. Freire, Morena M. Zugliani, Rafael F. Garcia & Antonio E.
Nardi (2015): Treatmentresistant panic disorder: a systematic review, Expert Opinion on
Pharmacotherapy, DOI: 10.1517/14656566.2016.1109628
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Date: 08 December 2015, At: 05:44

EXPERT OPINION ON PHARMACOTHERAPY, 2015

http://dx.doi.org/10.1517/14656566.2016.1109628

REVIEW

Treatmentresistant panic disorder: a systematic review

Rafael C. Freire

, Morena M. Zugliani, Rafael F. Garcia and Antonio E. Nardi

Downloaded by [Rafael Freire] at 05:44 08 December 2015

Laboratory of Panic and Respiration, Institute of Psychiatry, Federal University of Rio de Janeiro and National Institute for Translational
Medicine (INCT-TM), Rio de Janeiro, Brazil
ABSTRACT

ARTICLE HISTORY

Introduction: The prevalence of panic disorder (PD) in the population is high and these patients
have work impairment, high unemployment rates, seek medical treatment more frequently and
have more hospitalizations than people without panic symptoms. Despite the availability of
pharmacological, psychological and combined treatments, approximately one-third of all PD
patients have persistent panic attacks and other PD symptoms after treatment.
Areas covered: MEDLINE/Pubmed, CENTRAL, PsycINFO and Web of Science databases were
searched for clinical trials in treatmentresistant PD. Only studies published between 1980 and
2015, in English, with human subjects, considered journal articles and clinical trial were
included. We included trials recruiting only adult subjects with treatmentresistant PD, consistent
with criteria from DSM-III to DSM5. We included all prospective experimental studies. Case, case
series, retrospective studies or studies with <10 PD subjects were not included.
Expert opinion: Only 11 articles were included in this review. There were few quality studies, only
two were randomized, controlled and double blind. Augmentation of the pharmacological
treatment with cognitive-behavioral therapy demonstrated some short-term efficacy in treatmentresistant PD. There were also preliminary evidences of efficacy for monotherapy with
reboxetine and olanzapine, and augmentation with pindolol, divalproex sodium, aripiprazole
and olanzapine in short-term treatment.

Received 3 March 2015

Accepted 8 October 2015

1. Introduction
Anxiety disorders are very prevalent, with a 12-month
prevalence ranging from 14.0 to 19.9% in the general
population.[1,2] Along with chronic pain and mood
disorders, anxiety disorders are one of the most important causes of disability and work impairment.[35] In
the general population the 12-month prevalence of
panic disorder (PD) ranges from 1.1 to 2.8% and for
agoraphobia from 0.8 to 2.0%.[1,2,5,6] The lifetime prevalence is even higher, 7.2 28.3% for panic attacks, 3.4
4.7% for panic disorder and 1.9% for agoraphobia.
[5,6] Both patients with clinical and patients with subthreshold PD show significant work impairment, high
unemployment rates, seek medical treatment more frequently and have more hospitalizations than people
without panic attacks and other PD symptoms.[7]
It was hypothesized that panic attacks are acute anxiety and fear episodes with somatic symptoms that occur
in subjects with abnormally sensitive fear networks, such
as PD patients. In this network, the central nucleus of the
amygdala gathers information from different brain
regions and coordinates autonomic and behavioral

CONTACT Rafael C. Freire

rafaelcrfreire@gmail.com
330/906, Rio de Janeiro, Brazil
2015 Taylor & Francis

KEYWORDS

Agoraphobia; anxiety;
clinical trial;
cognitive-behavioral
therapy; panic attack

responses. If there is a deficiency in the coordination of

stimuli from the cortex and brainstem, this could lead to
an abnormal activation of the amygdala, with behavioral,
autonomic and neuroendocrine activation. Compounds
that increase the transmission in the serotonin or -aminobutyric-acid (GABA) systems have an inhibitory effect in
the amygdala and on the fear-related structures. Some
antidepressants increase noradrenergic activity and modulate the noradrenaline releases related to stressful situations. These drugs probably act in the central nucleus of
the amygdala and its projections by decreasing the sensitivity of the fear network and thus reducing the severity
and frequency of panic attacks.[8,9]
Guidelines, meta-analysis and other review studies
indicate that several medications are effective in the
treatment of PD, including antidepressants, benzodiazepines and other classes of drugs.[2,1012] However,
many PD patients do not respond to adequate treatment with these drugs. In clinical trials with fluvoxamine, sertraline, citalopram, escitalopram, paroxetine
and clonazepam, with duration of 8 12 weeks, 17
61% of the PD patients did not respond to treatment.
[13,14] In clinical trials with venlafaxine, the response

Laboratory of Panic and Respiration, Federal University of Rio de Janeiro, Rua Visconde de Piraja

R. C. FREIRE ET AL.

Article highlights.

There was only one double-blind, randomized, controlled trial

with positive results in treatmentresistant PD, the study of
augmentation with pindolol.
CBT combined with antidepressants or anxiolytics demonstrated
some efficacy in treatmentresistant PD.
There were 12 sessions of group CBT in the clinical trials with
this treatment.
There was preliminary evidence of efficacy for the monotherapy
with reboxetine and olanzapine.
There was also evidence of efficacy for the combined treatment
of pindolol, divalproex sodium, aripiprazole or olanzapine with
well-established antipanic drugs.

Downloaded by [Rafael Freire] at 05:44 08 December 2015

This box summarizes key points contained in the article.

rates were somewhat higher, from 68 to 89%, but from

49 to 64% of the patients did not achieve remission
after 10 12 weeks of treatment.[15] In the general
population, almost one-half of PD patients do not
achieve remission in the first year of treatment and
after 2 years of treatment more than one-third of the
patients still have PD symptoms.[16]
The objective of this systematic review is to summarize and discuss the evidences regarding the treatment
of patients with treatmentresistant PD.

2. Methods
Articles were identified by a search of electronic
records, including the databases from MEDLINE/
Pubmed, the Cochrane Collaborations Clinical Trials
Register (CENTRAL), PsycINFO and Thomson Reuterss
Web of Science. The search terms used were: Panic
disorder AND (Treatmentresistant OR Treatment
resistance
OR
Pharmacotherapy-resistant
OR
Pharmacotherapy resistance OR Medication-resistant
OR Medication resistance OR Drug-resistant OR
Drug resistance OR Refractory OR Augmentation).
Only studies published in the years between 1980 and
2015, in English, with human subjects, considered journal articles and clinical trial were included. We
included trials recruiting only adult subjects with treatmentresistant PD, consistent with criteria from DSM-III
to DSM5.[1720] All definitions of treatmentresistance
were accepted. We included all prospective experimental studies including randomized-controlled trials,
quasi-random trials, crossover designs, and single arm
studies, blinded or open label. Case, case series, retrospective studies or studies with <10 PD subjects were
not included. Filters with this criteria were applied in
the databases were it was possible.
In the first step of the process, the first author (RCF)
screened the titles and abstracts of the articles and

manually excluded those that did not fit the criteria

mentioned above.
The second step was the study selection. Two independent reviewers (RCF and MMZ) assessed the full-text
articles for eligibility, this assessment was made in a
standardized manner. The same reviewers made the
data extraction in an independent manner.
Disagreements between the reviewers regarding the
study selection or data extraction were resolved by
consensus.
As we included trials with different designs, the presence of a controlling condition, randomization and
subject and observer blindness to treatment were
used as measures of strength of evidence.
The ideal confirmatory format of this review would
consist of meta-analyzes of interaction statistics of predictors and moderators effects of large, high quality,
randomized controlled trials. Since most trials did not
meet quality requirements, and a broad spectrum of
experimental designs was included, we performed a
qualitative systematic review of the evidence.

3. Results
The searches of databases were conducted in January
of 2015 and yielded 18 articles in CENTRAL, 127 articles
in PsycINFO, 23 in MEDLINE/Pubmed and 128 in Web of
Science. The sum of articles after removing the duplicates was 231, after screening 38 articles remained.
Reviewers examined the full-texts and only 11 articles
met the inclusion criteria. The process of study identification and selection is shown in a Preferred Reporting
Items for Systematic Reviews and Meta-Analyses
(PRISMA) flow diagram (Figure 1).[21]
Only two articles were randomized controlled and
blinded clinical trials,[22,23] the other nine were open
studies. In four studies, the treatment was cognitivebehavioral therapy (CBT), in six studies, the treatment
was pharmacological, and in one study, pharmacological treatment and CBT were included. Two articles used
DSM-III-R [18] criteria for PD, all the other articles used
DSM-IV [19] criteria for this disorder. The number of
subjects in each study ranged from 10 to 71.
The criteria for treatmentresistant PD were very
heterogeneous. Some studies defined treatmentresistance as not responding to at least one [24,25] or two
[23,26,27] adequate 8-week treatment trials with drugs
recognized as effective for PD or standard course of
CBT. Other studies used the treatmentresistance criteria of not responding to at least one [22] or two [28]
6-week adequate treatment trials. Incomplete response
after 3 4 months of treatment defined treatment
resistance in four studies.[2932]

Identification

EXPERT OPINION ON PHARMACOTHERAPY

Records identified through database

searching
(n = 306)

Additional records identified through

other sources
(n = 0)

Eligibility

Included

Downloaded by [Rafael Freire] at 05:44 08 December 2015

Screening

Records after duplicates removed

(n = 231)

Records screened
(n = 231)

Records excluded
(n = 193)

Full-text articles assessed for

eligibility
(n = 38)

Full-text articles excluded

Studies included in
qualitative synthesis
(n = 11)

Not clinical trial

09

Less than 10 PD
patients
Not treatmentresistant patients
Retrospective study

07

Full-text not found

01

Not PD patients

01

07
02

Total
(n = 27)

Figure 1. PRISMA diagram of study identification and selection process.

The article from Simon et al. [22] included three

clinical trials, phases I, II and III. Phase I was not with
treatmentresistant PD and was not included in the
review, phases II and III were treated as independent
trials.
The studied drugs were divalproex sodium, reboxetine, pindolol, aripiprazole, olanzapine, sertraline, escitalopram and clonazepam. Among the 12 clinical trials,
the studied treatment was an augmentation of another
treatment in nine of them. The trial duration ranged
from 4 to 16 weeks. There were no significant differences between low and high dose of sertraline or escitalopram,[22] otherwise all studied treatments were
considered effective.
There were several limitations regarding the adequacy of treatment including doses and duration of
trials. There were trials with no augmentation, augmentation in part of the patients or in all patients.
Frequently the augmentation strategy varied across

subjects, possibly including bias. In few studies the

sample size was too small. The quality evaluation and
list of limitations were summarized in Table 1.

3.1. Randomized controlled double-blind trials

In the study from Hirschmann et al. [23] pindolol
7.5 mg/day or placebo were added to fluoxetine
20 mg/day in a 4-week clinical trial. Patients on pindolol
and fluoxetine had significant improvements in the
Panic Self-questionnaire (PSQ) (Cohens d = 2.72) and
Clinical Global Impression Improvement scale (CGI-I)
(Cohens d = 4.00), compared to patients taking fluoxetine alone. There were significant improvements in
other panic and anxiety scales, but no difference
regarding depression symptoms. There were already
significant improvements in anxiety symptoms after
2 weeks of treatment.

++
++
+++
++
+++
++
+++
+
++

Heldt et al. 2006(1) [31]

Heldt et al. 2006(2) [30]

Hirschmann et al. 2000 [23]

Hoge et al. 2008 [25]

Hollifield et al. 2005 [27]

Pollack et al. 1994 [29]

Sepede et al. 2006 [28]

Simon et al. 2009 phase II [22]

Simon et al. 2009 phase III [22]

HHRCT

OS
RCDBCT

OS
OS

RCDBCT
OS

OS

OS

OS
OS

Type
OS

++

++
++

+++
++

+
++

++

++

++
++

Treatment design
++

++
++

+
++

++
+

+++

+++

++
++

Analysis design
+

Limitations
Non-responders to one previous trial were considered treatmentresistant; concurrent use of
benzodiazepines and antidepressants is some of the patients; small sample size
Short washout before study; short duration of trial and small sample size
The treatmentresistance criterion was incomplete remission after 4 months of treatment, just one
previous trial; concurrent use of antianxiety or antidepressant medications; small sample size
The treatmentresistance criterion was incomplete remission after 4 months of treatment, just one
previous trial; concurrent use of antianxiety or antidepressant medications
The treatmentresistance criterion was incomplete remission after 4 months of treatment, just one
previous trial; concurrent use of antianxiety, antidepressant medications or lithium
Low dose of medication (fluoxetine) and short duration of the trial; small sample size
Non-responders to one previous trial were considered treatmentresistant; some patients had
comorbidy with GAD; concurrent use of antidepressant, benzodiazepine or both; very small sample size
Very small sample size
Treatment resistance was defined by incomplete response after adequate 12-week trial with
medication; concurrent use of clonazepam, alprazolam, fluoxetine, TCA or lithium; very small sample
size
Concurrent use of antidepressants; small sample size
Treatmentresistance was defined by no response after one 6-week trial with SSRI; short trial duration;
small sample size
Treatmentresistance was defined by no response after one 12-week trial with SSRI; concurrent use of
escitalopram or sertraline; very small sample size

GAD: Generalized anxiety disorder; HHRCT: Head-to-head randomized clinical trial; OS: Open study; RCDBCT: Randomized controlled double-blind clinical trial; SSRI: Serotonin selective reuptake inhibitor; TCA: tricyclic
antidepressant; TRPD: Treatmentresistant panic disorder.
Treatment design adequacy of dose, drug, trial duration and augmentation strategy.
Analysis design adequacy of scales, sample size, statistical analysis and power.

+++
++

TRPD criteria
++

Dannon et al. 2002 [26]

Heldt et al. 2003 [32]

Study
Baetz and Bowen 1998 [24]

Table 1. Evaluation of study quality and limitations.

Downloaded by [Rafael Freire] at 05:44 08 December 2015

4
R. C. FREIRE ET AL.

EXPERT OPINION ON PHARMACOTHERAPY

Table 2. Randomized, controlled and double-blind clinical trials.

Trial
Hirschmann et al. 2000 [23]

Simon et al. 2009 phase II

[22]

TRPD criteria
Previous treatment
with at least two
antidepressants
and no response
after a 8-week trial
with fluoxetine
20 mg/day
No response after
6-week trial with
sertraline (up to
100 mg/day) or
escitalopram (up
to 15 mg/day)

Number of
patients
(completed)

Drug

Dose

Trial
duration
(in weeks)

Outcome

Other information

26 (25)

Fluoxetine +
pindolol or
fluoxetine +
PBO

Fluoxetine
20 mg/day;
pindolol
7.5 mg/day

Superior to PBO;
significant differences
in PSQ (ES: 2.72),
CGI-I (ES: 4.00),
HAM-A, CAS+PA and
NIMH Anxiety Scale *

The clinical changes

noted with pindolol
were evident by the
second week of the
study

24 (19)

Sertraline or
escitalopram
high dose or
PBO (no dose
increase)

High dose
sertraline 150
200 mg/
day;
escitalopram
20 30 mg/
day

Not superior to PBO,

no significant
differences in CGI-S
(ES: 0.16) and PDSS
(ES: 0.01); significant
improvement in PDSS
in both groups **

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CAS + PA: Clinical Anxiety Scale with panic attacks; CGI-I: Clinical Global Impression Improvement; ES: effect size compared to placebo, Cohens d; HAM-A:
Hamilton Rating Scale for Anxiety; NIMH: National Institute of Mental Health; PBO: Placebo; PDSS: Panic Disorder Severity Scale; PSQ: Panic SelfQuestionnaire; TRPD: Treatmentresistant panic disorder.
* Response and remission were not defined in this study.
** Remission status was defined as zero panic attacks for at least 1 week and a Clinical Global Impression Severity score of 1 or 2.

In the study from Simon et al. [22] patients who

tolerated sertraline 100 mg/day or escitalopram
15 mg/day but did not achieve remission after
6 weeks of treatment with these drugs were included
in next phase of this study. In the second phase of the
same study, patients were randomized in double-blind
fashion either to receive a higher dose of selective
serotonin reuptake inhibitor (SSRI) or to remain in the
same dose. Both groups had a decrease in the Panic
Disorder Severity Scale (PDSS) scores, there were no
differences regarding other anxiety and depression
scales. The high SSRI dose group failed to show differences compared with the low dose group.
Findings from these studies are summarized in Table 2.

3.2. Open pharmacological trials

Among the five open pharmacological trials, three of
them were augmentation studies and there was concurrent use of antidepressants or benzodiazepines.
[24,25,28] Patients treated with aripiprazole, olanzapine
and divalproex sodium had significant improvements
regarding the PD symptoms. In the study from Baetz
et al. [24] only patients with comorbid mood disorder
and self-reported mood instability were included.
Besides the improvement of anxiety and panic symptoms, there was also improvement of depressive and
mood instability symptoms.
Washout of previous medications was performed in
two open studies.[26,27] The noradrenaline reuptake inhibitor (NRI) Reboxetine 2 8 mg/day and the antipsychotic
olanzapine 2.5 20 mg/day were effective in treatment
resistant PD with no concurrent medications. There was

significant improvement in the panic attacks, anticipatory

anxiety agoraphobia, general anxiety and impairment.
Findings from these studies are summarized in
Table 3.

3.3. Cognitive-behavioral therapy studies

Four CBT trials [2932] did not include comparisons to
placebo, wait list or other treatments. In one randomized trial,[22] CBT and clonazepam were compared
as augmentation to SSRI and both treatments were
equally effective. All studies had limitations regarding
the treatmentresistance criteria and concurrent use of
multiple pharmacological agents such as antidepressants, benzodiazepines and lithium. (Table 1)
All protocols [22,2932] included 12 sessions of
group therapy. CBT was effective as an augmentation
in all five trials, with improvements in panic attacks,
anticipatory anxiety, agoraphobia, other panic symptoms, general anxiety and quality of life. A decrease in
the use of medications was also observed.[31,32] The
improvement of panic symptoms persisted for at least a
couple of months after the end of the CBT.[29] Findings
from these studies are summarized in Table 4.

4. Conclusion
Studies regarding the treatment of treatmentresistant
PD were scant, quality studies regarding this subject
were exiguous. Regarding the pharmacological treatment there was preliminary evidence of efficacy in
treatmentresistant PD for monotherapy with reboxetine and olanzapine. The augmentation of antidepressants, anxiolytics and other drugs with CBT, pindolol,

Not respond to two 8-week

adequate trials (medication or
CBT)

Not responded previously to

adequate therapeutic trials of
either medication or CBT and
not responded to current
treatment (at least 6 weeks with
paroxetine 40 mg/day or
sertraline 150 mg/day)

Hollifield et al. 2005 [27]

Sepede et al. 2006 [28]

Dose

Olanzapine

Aripiprazole

Reboxetine

5.0 mg/day

2.5 20 mg/day
(average 12.3 mg/
day)

5 30 mg/day

2 8 mg/day

Divalproex sodium Minimum 500 mg/

day; serum level
45 90 g/ml

Drug

Yes. Concurrent
Olanzapine
use of paroxetine
40 mg/day or
sertraline
150 mg/day

No

Yes. Concurrent
use of
antidepressant,
benzodiazepine
or both

Yes. 40% of
subjects using
concurrent
benzodiazepines,
antidepressants
or both
No

Augmentation
study?

12

Trial duration
(in weeks)

Other information

Short washout
(paroxetine 4
days; fluoxetine
21 days) before
study
Significant improvement in CGI-S
Significant
scores (17% decrease); no
improvement in
difference in PDSS scores (14%
CGI-S and HAM-A
decrease); 10% achieved remission in the combined
***
group (PD and
GAD)
Significant improvement in PAI
PA frequency (ES: 1.83), intensity
(ES: 1.36) and anticipatory anxiety
(ES: 1.18); significant improvement
in PPPDS anticipatory anxiety (ES:
3.65), phobic avoidance (ES: 2.59)
and impairment (ES: 2.18);
significant improvement in CGI-S
scores (ES: 2.61) **
Significant improvement in PAAAS Improvements in
HAM-D and GAF
PA frequency (ES: 2.36), PA
duration (ES: 3.35) and anticipatory scales; significant
anxiety (ES: 3.74); significant
and similar
improvement in ACQ and HAM-A improvement in
scores; response 81%; remission
patients with or
58% ****
without
agoraphobia

Outcome
Significant improvement in PA
(65% decrease in frequency), HAMA, BAI, PGI (70% much or very
much improved) and CGI-I (90%
much or very much improved)
scores **
Significant improvement in PSQ
(90% decrease), HAM-A and GAF
scores in patients with and without
agoraphobia **

ACQ: Agoraphobic Cognitions Questionnaire; BAI: Beck Anxiety Inventory; CBT: Cognitive-behavioral therapy; CGI-I: Clinical Global Impression Improvement; CGI-S: Clinical Global Impression Severity; ES: Effect size
compared to baseline scores, Cohens d; GAD: Generalized anxiety disorder; GAF: Global Assessment of Functioning; HAM-A: Hamilton Rating Scale for Anxiety; HAM-D: Hamilton Rating Scale for Depression; PA: Panic
attack; PAAAS: Panic Attack and Anticipatory Anxiety Scale; PAI: Panic Attack Inventory; PDSS: Panic Disorder Severity Scale; PGI: Patient Global Impression; PPPDS: Physicians Panic and Phobic Disorders Scale; PSQ:
Panic Self-Questionnaire; SSRI: Selective serotonin reuptake inhibitor; TRPD: Treatmentresistant panic disorder.
* Subsample of patients with comorbid mood disorder and self-reported mood instability.
** Response and remission were not defined in this study.
*** Remission criteria CGI-S score of 1 or 2.
**** Response criteria: 50% decrease in number of panic attacks and CGI-I score of 1 or 2; remission criteria: no panic attacks and HAM-A score 7.

31(26)

15(10)

10(7)

29(24)

Not respond to two adequate

trials with SSRI (paroxetine
40 mg/day and fluoxetine
40 mg/day, duration 8.4 4.3
weeks)
Not respond to one 8-week
adequate trial (SSRI, SNRI,
benzodiazepines, trazodone or
bupropion)

Dannon et al. 2002 [26]

Hoge et al. 2008 [25]

13(10)

TRPD criteria

Number of
patients
(completed)

Baetz and Bowen 1998* [24] Not respond to one trial with
CBT and medication
(benzodiazepines or
antidepressants)

Trial

Table 3. Open pharmacological studies.

Downloaded by [Rafael Freire] at 05:44 08 December 2015

6
R. C. FREIRE ET AL.

Yes. Concurrent 12/group sessions

use of
antianxiety,
antidepressant
medications or
lithium
Yes. Concurrent 12/group sessions
use of
clonazepam,
alprazolam,
fluoxetine, TCA
or lithium
Yes. Concurrent 12/group sessions
use of
escitalopram
(1530 mg/day)
or sertraline (100
200 mg/day)

36(32)

19(17)

18(15)

Yes. Concurrent 12/group sessions

use of antianxiety
or antidepressant
medications

71(64)

Number of
patients
Augmentation
Number/type of
(completed)
study?
sessions
32(29)
Yes. Concurrent 12/group sessions
use of antianxiety
or antidepressant
medications

12

12

CLZ 0.5
4.0 mg/day

16

16

Trial duration
(in weeks)
16

No

No

No

Comparison
No

No significant difference between the two

treatments; significant improvement in
CGI-S (ES: 1.0) and PDSS (ES: 0.6);
remission CLZ 11%, CBT 10% **

Significant improvement in PA (ES: 0.5)

and CGI-S (ES: 1.6); remission 40% ***

Significant improvement in CGI-S (ES: 2.3),

PA (ES: 0.5), agoraphobia (ES: 1.0) (PI),
anticipatory anxiety (ES: 0.9)(PI), HAM-A
(ES: 1.1) and quality of life scores (ES: 0.9)
(WHOQOL); no PA 75%; remission 44% **

Significant improvement in CGI-S (ES: 2.2),

PA (ES: 0.6), agoraphobia (ES: 1.3) (PI),
anticipatory anxiety (ES: 1.1) (PI) and HAMA scores (ES: 1.3); no PA 81%; remission
64% *

Persistent
improvement
after 1 8
months of
follow-up

Decrease in use
of
benzodiazepines
and
antidepressants

Other
Outcome
information
Significant improvement in CGI-S (ES: 1.5), Decrease in use
PA frequency (ES: 1.0), PA intensity (ES:
of
1.0), agoraphobia (PI) (ES: 1.5),
benzodiazepines
anticipatory anxiety (PI) (ES: 1.0) and HAMA scores (ES: 1.3); No PA 81%

CBT: Cognitive-behavioral therapy; CGI-S: Clinical Global Impression Severity; CLZ: Clonazepam; ES: Effect size compared to baseline scores, Cohens d; HAM-A: Hamilton Rating Scale for Anxiety; PA: Panic attack; PDSS:
Panic Disorder Severity Scale; PI: Panic Inventory; SSRI: Selective serotonin reuptake inhibitor; TCA: Tricyclic antidepressant; TRPD: Treatmentresistant panic disorder; WHOQOL: World Health Organization Quality of Life
Instrument Short Version.
* Remission was defined by no panic attacks and CGI-S < 3 for at least 2 months (evaluation made 12 months after the end of the treatment).
** Remission was defined as the absence of PA and CGI-S < 3.
*** Remission was defined as CGI-S < 3.

TRPD criteria
Residual symptoms of
panic attacks, anticipatory
anxiety and phobic
avoidance after adequate
trial with SSRI; on SSRI for
4 months
Heldt et al. 2006(1) [32]
Residual symptoms of
panic attacks, anticipatory
anxiety and phobic
avoidance after adequate
trial with SSRI; on SSRI for
4 months
Heldt et al. 2006(2) [30]
Residual symptoms of
panic attacks, anticipatory
anxiety and phobic
avoidance after adequate
trial with SSRI; on SSRI for
4 months
Pollack et al. 1994 [29]
Incomplete response after
adequate 12-week trial
with medication
(imipramine, fluoxetine,
phenelzine, clonazepam or
alprazolam)
Simon et al. 2009 phase III [22] No response after 12-week
trial with sertraline (up to
200 mg/day) or
escitalopram (up to 30 mg/
day)

Trial
Heldt et al. 2003 [32]

Table 4. Cognitive-behavioral therapy studies.

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EXPERT OPINION ON PHARMACOTHERAPY

7

R. C. FREIRE ET AL.

divalproex sodium, aripiprazole and olanzapine demonstrated some efficacy. Dose escalation after initial lack
of response produced little improvement or no
improvement at all. More randomized, controlled and
blind clinical trials are needed to ascertain adequate
strategies for treatmentresistant PD.

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5. Expert opinion
The lifetime prevalence of PD in the population is high,
[5,6] among these patients approximately 30% of them
have persistent panic symptoms despite pharmacological and psychological treatment.[16,33] Improving the
treatments for PD and finding alternatives for patients
who do not respond to conventional treatments is a
matter of public health with crucial importance.
There is no consensus about the definition of treatmentresistant PD and currently there are no operational criteria for classifying these patients. We opted
to accept all criteria for treatmentresistance, otherwise
very few articles would be included in this review. The
authors believe that the best criteria for treatment
resistant PD were those used by Dannon et al. [26]
and Hollifield et al. [27]: not responding to at least
two adequate 8-week treatment trials with drugs recognized as effective for PD in adequate doses or standard
course of CBT. Patients who have poor response to the
first medication trial could respond very well in a second trial. In addition, patients who take small doses of
medication and have poor response after 6 weeks of
treatment could improve if the doses were increased
and the trial was prolonged. These patients cannot be
considered treatmentresistant.
Treatmentresistance in PD may be the consequence
of untreated comorbid disorders and patients could
benefit from treatments directed to the causes.
Patients with comorbid bipolar spectrum disorders
would probably benefit from mood stabilizers and antipsychotics. Switching the antidepressant including
tricyclic antidepressants (TCA) and monoamine oxidase
inhibitors (MAOI) in the treatment options or combining two antidepressants should be a good strategy for
patients with comorbid major depressive disorder.
Psychotherapy would probably be the best augmentation strategy for patients with treatmentresistant PD
and comorbid avoidant or dependent personality disorders, agoraphobia or other phobias.
Antidepressants, particularly SSRI and serotonin, and
noradrenaline reuptake inhibitors (SNRI), are highly
recommended by current guidelines [2,11,12] among
the pharmacological agents used in the treatment of PD.
Due to their high efficacy and low risk of adverse reactions
the SSRI escitalopram, citalopram, sertraline, fluoxetine,

paroxetine, fluvoxamine and the SNRI venlafaxine have

the highest recommendation grades. The NRI reboxetine,
the MAOI phenelzine, and the TCA clomipramine, desipramine, imipramine and lofepramine are efficacious, but
they have less favorable side-effects profile. Reboxetine,
moclobemide, duloxetine, milnacipran, nefazodone and
mirtazapine also have some evidence of efficacy in the
treatment of PD.[2,10] There is only one open study with
antidepressants for treatmentresistant PD patients and it
showed that these patients may benefit from augmentation with reboxetine.[26] Other strategies for treatment
resistant PD with antidepressants such as switching the
antidepressant to TCA or MAOI, or combining two antidepressants are used in clinical practice but have not
been systematically studied. There is preliminary evidence
indicating that escitalopram and venlafaxine are more
effective in the treatment of PD than citalopram and
paroxetine, respectively.[2,13] These evidences make
these antidepressants good candidates as drugs to treat
treatmentresistant PD, but there are still no clinical trials
with these drugs for treatmentresistant PD.
The benzodiazepines alprazolam, clonazepam, diazepam and lorazepam are efficacious in acute treatment of
PD, but have lower recommendation grades due to side
effects and risks.[2,11,12] Despite the fact that benzodiazepines are frequently combined to antidepressants in clinical practice, there are no trials with benzodiazepines as
monotherapy or augmentation for treatmentresistant PD.
Atypical antipsychotics are not recommended by the
current guidelines [2,11,12] as first-line agents for the
treatment of PD, however, aripiprazole, olanzapine, risperidone and sulpiride have demonstrated some efficacy
in this disorder.[10] Quetiapine showed anxiolytic properties in several studies and is used in mood disorders
with good results,[34,35] for this reason quetiapine is
also a promising agent for the treatment of PD and
treatmentresistant PD. The risks and benefits of atypical
antipsychotics should be weighted in treatmentresistant PD patients because these agents are associated
to increased appetite, weight gain, metabolic abnormalities, amenorrhea/galactorrhea, somnolence, sialorrhea,
sexual dysfunction, somnolence, blurred vision, headache, dizziness, akathisia, insomnia, tremor and other
side effects.[10,36] Increased appetite, weight gain,
metabolic abnormalities and sexual dysfunction are associated with both antidepressants and atypical antipsychotics, combining these two compounds could increase
the risk of the mentioned side effects.
According to the guidelines the best treatments for
PD are pharmacological, psychological or a combination of both.[2] Among psychological treatments for PD
and treatmentresistant PD, CBT has the highest level
of evidence. In most protocols, there are 8 12 sessions

EXPERT OPINION ON PHARMACOTHERAPY

once in a week, but shorter CBT programs with only five

sessions may also be effective if combined to the CBT
adjuvant D-cycloserine.[10] The CBT adjuvants are also
promising compounds for treatmentresistant PD.
The study of repetitive transcranial magnetic stimulation and transcranial direct current stimulation had
significant developments in the last decade,[37,38]
and in the future, they may become effective treatments for PD, including treatmentresistant PD.
Currently there are very few low quality studies
addressing the treatmentresistant PD, most of them
are open studies with very small samples of PD
patients. Well-designed, double-blind, randomized and
controlled studies with sufficient number of subjects
are needed to shed light on this subject.

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Declaration of interest
Funding for this study was provided by the Brazilian Council
for Scientific and Technological Development (CNPq). RC
Freire has received support from the Brazilian Council for
Scientific and Technological Development (CNPq). A Nardi
has received support from the Brazilian Council for Scientific
and Technological Development (CNPq). The authors have no
other relevant affiliations or financial involvement with any
other organization or entity with a financial interest in or
financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

ORCID
Rafael C. Freire

http://orcid.org/0000-0003-3875-4601

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