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Treatment–resistant panic disorder: a systematicreview

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Treatment–resistant panic disorder: a systematicreview

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): Treatment–resistant panic disorder: a systematic review, Expert Opinion onPharmacotherapy, DOI: 10.1517/14656566.2016.1109628

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REVIEW

Treatment–resistant panic disorder: a systematic review

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

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

ABSTRACT

Introduction: The prevalence of panic disorder (PD) in the population is high and these patientshave work impairment, high unemployment rates, seek medical treatment more frequently andhave more hospitalizations than people without panic symptoms. Despite the availability of pharmacological, psychological and combined treatments, approximately one-third of all PDpatients have persistent panic attacks and other PD symptoms after treatment.

Areas covered : MEDLINE/Pubmed, CENTRAL, PsycINFO and Web of Science databases weresearched for clinical trials in treatment–resistant PD. Only studies published between 1980 and2015, in English, with human subjects, considered “ journal articles” and clinical trial wereincluded. We included trials recruiting only adult subjects with treatment–resistant PD, consistentwith criteria from DSM-III to DSM5. We included all prospective experimental studies. Case, caseseries, retrospective studies or studies with


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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 andafter 2 years of treatment more than one-third of the

patients still have PD symptoms.[16]

The objective of this systematic review is to summar-

ize and discuss the evidences regarding the treatment

of patients with treatment–resistant PD.

2. Methods

Articles were identified by a search of electronic

records, including the databases from MEDLINE/

Pubmed, the Cochrane Collaboration’s Clinical Trials

Register (CENTRAL), PsycINFO and Thomson Reuters’s

Web of Science. The search terms used were: “Panic

disorder” AND (“ Treatment–resistant” 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 “ jour-

nal articles” and clinical trial were included. We

included trials recruiting only adult subjects with treat-

ment–resistant PD, consistent with criteria from DSM-III

to DSM5.[17–20] All definitions of treatment–resistance

were accepted. We included all prospective experimen-

tal studies including randomized-controlled trials,

quasi-random trials, crossover designs, and single arm

studies, blinded or open label. Case, case series, retro-

spective studies or studies with


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

clinical trials, phases I, II and III. Phase I was not with

treatment–resistant PD and was not included in the

review, phases II and III were treated as independent

trials.

The studied drugs were divalproex sodium, reboxe-

tine, pindolol, aripiprazole, olanzapine, sertraline, esci-

talopram and clonazepam. Among the 12 clinical trials,

the studied treatment was an augmentation of another

treatment in nine of them. The trial duration rangedfrom 4 to 16 weeks. There were no significant differ-

ences between low and high dose of sertraline or esci-

talopram,[22] otherwise all studied treatments were

considered effective.

There were several limitations regarding the ade-

quacy of treatment including doses and duration of

trials. There were trials with no augmentation, augmen-

tation 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 pindololand fluoxetine had significant improvements in the

Panic Self-questionnaire (PSQ) (Cohen’s d = 2.72) and

Clinical Global Impression – Improvement scale (CGI-I)

(Cohen’s d = 4.00), compared to patients taking fluox-

etine 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.

Records identified through database

searching

(n = 306)

S c r e e n i n g

I n c l u d e d

E l i g

i b i l i t y

I d e n t i f i c a t i o n

Additional records identified through

other sources

(n = 0)

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

Not clinical trial 09

Less than 10 PDpatients

07

Not treatment-

resistant patients

07

Retrospective study 02

Full-text not found 01

Not PD patients 01

Total

(n = 27)

Studies included in

qualitative synthesis

(n = 11)

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

EXPERT OPINION ON PHARMACOTHERAPY 3


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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 differ-

ences 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 con-

current 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 disorderand self-reported “mood instability” were included.

Besides the improvement of anxiety and panic symp-

toms, 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 inhi-

bitor (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 [29–32] did not include comparisons to

placebo, wait list or other treatments. In one rando-

mized trial,[22] CBT and clonazepam were compared

as augmentation to SSRI and both treatments were

equally effective. All studies had limitations regarding

the treatment–

resistance criteria and concurrent use of multiple pharmacological agents such as antidepres-

sants, benzodiazepines and lithium. ( Table 1)

All protocols [22,29–32] 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 symp-

toms, 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 treatment–resistant

PD were scant, quality studies regarding this subject

were exiguous. Regarding the pharmacological treat-

ment there was preliminary evidence of efficacy in

treatment–resistant PD for monotherapy with reboxe-

tine and olanzapine. The augmentation of antidepres-

sants, anxiolytics and other drugs with CBT, pindolol,

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

Trial TRPD criteria

Number of patients

(completed) Drug Dose

Trialduration

(in weeks) Outcome Other information

Hirschmann et al . 2000 [23] Previous treatmentwith at least twoantidepressantsand no responseafter a 8-week trialwith fluoxetine

20 mg/day

26 (25) Fluoxetine +pindolol orfluoxetine +PBO

Fluoxetine20 mg/day;pindolol7.5 mg/day

4 Superior to PBO;significant differencesin PSQ (ES: 2.72),CGI-I (ES: 4.00),HAM-A, CAS+PA andNIMH Anxiety Scale *

The clinical changesnoted with pindololwere evident by thesecond week of thestudy

Simon et al . 2009 – phase II[22]

No response after6-week trial withsertraline (up to100 mg/day) orescitalopram (upto 15 mg/day)

24 (19) Sertraline orescitalopramhigh dose orPBO (no doseincrease)

High dose –sertraline 150– 200 mg/day;escitalopram20 – 30 mg/day

6 Not superior to PBO,no significantdifferences in CGI-S(ES: 0.16) and PDSS(ES: 0.01); significantimprovement in PDSSin both groups **

CAS + PA: Clinical Anxiety Scale with panic attacks; CGI-I: Clinical Global Impression – Improvement; ES: effect size compared to placebo, Cohen’s d; HAM-A:Hamilton Rating Scale for Anxiety; NIMH: National Institute of Mental Health; PBO: Placebo; PDSS: Panic Disorder Severity Scale; PSQ: Panic Self-Questionnaire; TRPD: Treatment–resistant 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.



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divalproex sodium, aripiprazole and olanzapine demon-

strated 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 treatment–resistant PD.

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 pharmacologi-

cal 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 treat-

ment–resistant PD and currently there are no opera-

tional criteria for classifying these patients. We opted

to accept all criteria for treatment–resistance, otherwisevery 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 recog-

nized 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 sec-

ond 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 treatment–resistant.

Treatment–resistance 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 anti-

psychotics. Switching the antidepressant – including

tricyclic antidepressants (TCA) and monoamine oxidase

inhibitors (MAOI) in the treatment options – or combin-

ing two antidepressants should be a good strategy for

patients with comorbid major depressive disorder.

Psychotherapy would probably be the best augmenta-

tion strategy for patients with treatment–resistant PD

and comorbid avoidant or dependent personality dis-

orders, 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, desi-

pramine, 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 withantidepressants for treatment–resistant PD patients and it

showed that these patients may benefit from augmenta-

tion with reboxetine.[26] Other strategies for treatment–

resistant PD with antidepressants such as switching the

antidepressant to TCA or MAOI, or combining two anti-

depressants 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

treatment–resistant PD, but there are still no clinical trialswith these drugs for treatment–resistant PD.

The benzodiazepines alprazolam, clonazepam, diaze-

pam 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 benzodiaze-

pines are frequently combined to antidepressants in clin-

ical practice, there are no trials with benzodiazepines as

monotherapy or augmentation for treatment–resistant 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, ris-

peridone and sulpiride have demonstrated some efficacy

in this disorder.[10] Quetiapine showed anxiolytic prop-

erties 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

treatment–resistant PD. The risks and benefits of atypical

antipsychotics should be weighted in treatment–resis-

tant PD patients because these agents are associated

to increased appetite, weight gain, metabolic abnormal-

ities, amenorrhea/galactorrhea, somnolence, sialorrhea,

sexual dysfunction, somnolence, blurred vision, head-

ache, dizziness, akathisia, insomnia, tremor and other

side effects.[10,36] Increased appetite, weight gain,

metabolic abnormalities and sexual dysfunction are asso-

ciated with both antidepressants and atypical antipsy-

chotics, 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 combina-

tion of both.[2] Among psychological treatments for PD

and treatment–resistant PD, CBT has the highest level

of evidence. In most protocols, there are 8 – 12 sessions

8 R. C. FREIRE ET AL.


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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 treatment–resistant PD.

The study of repetitive transcranial magnetic stimu-

lation and transcranial direct current stimulation had

significant developments in the last decade,[37,38]

and in the future, they may become effective treat-ments for PD, including treatment–resistant PD.

Currently there are very few low quality studies

addressing the treatment–resistant 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.

Declaration of interest

Funding for this study was provided by the Brazilian Council

for Scientific and Technological Development (CNPq). RCFreire 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 dis-

cussed in the manuscript apart from those disclosed.

ORCID

Rafael C. Freire http://orcid.org/0000-0003-3875-4601

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Papers of special note have been highlighted as either of

interest (*) or of considerable interest (**) to readers.

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** One of the two randomized controlled double-blind

clinical trials for treatment–resistant panic disorder

(phase II). Also includes the only head-to-head rando-

mized clinical trial for treatment resistant panic dis-

order (phase III).

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


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* One of the two randomized controlled double-blind

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Freire 2015 - Treatment-resistant PD Review