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Current Drug Targets, 2013, 14, 353-364 353

Clonazepam for the Treatment of Panic Disorder

Antonio E. Nardia, Sergio Machado

a,g,h,i, Leonardo Ferreira Almada

h, Flávia Paes

a,

Adriana Cardoso Silvaa, Ricardo José Marques

a,f, Roman Amrein

a, Rafael C. Freire

a,

Rocío Martin-Santosb, Fiammeta Cosci

c, Jaime E. Hallak

d, José A. Crippa

d and

Oscar Arias-Carrióne,*

aPanic and Respiration Laboratory, Institute of Psychiatry, Federal University of Rio de Janeiro, National Institute for Translational Medicine (INCT-TM), Rio de Janeiro, Brazil; bInstitute of Neuroscience, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), University of Barcelona, 08036 Barcelona, Spain; cDepartment of Psychology, University of Flor-ence, Florence, Italy; dDepartment of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, National Institute for Translational Medicine (INCT-TM), São Paulo, Brazil; Movement Disorders and Transcraneal Magnetic Stimulation Unit, Hospital General Dr. Manuel Gea González, Secretaría de Salud, México D.F., México; fFaculty of Psychology, Brazilian institute of Medicine and rehabilitation, Rio de Janeiro, Brazil; gQuiro-praxia Program of Faculty of Medical Sciences, Central University (UCEN), Santiago, Chile; hInstitute of Philosophy of Federal University of Uberlândia, Minas Gerais, Brazil; iPhysical Activity Neuroscience, Physical Activity Sciences Postgraduate Program - Salgado de Oliveira University, Niterói, Brazil

Abstract: Clonazepam was initially licensed as an anti-epileptic agent, but its use in a wide variety of psychiatric condi-

tions, including panic disorder (PD) has now been well established. This overview evaluates the current role of clonaze-

pam alone or in combination with antidepressants and/or behavioral therapy in the treatment of PD. We review the data

establishing the use of clonazepam in the treatment of PD as well as new information, particularly confirmation of long-

term efficacy and safety. We also discuss a regimen for safely tapered withdrawal of clonazepam, the characteristics of the

respiratory subtype of PD, and CO2-induced panic attacks as a diagnostic measure and predictor for therapeutic success. It

has been shown that panic attacks can more readily be induced by CO2 in PD patients with the respiratory subtype than

those with the non-respiratory subtype. More than 25 years after the first report of efficacy in PD in 1984, clonazepam,

alone or combined with selective serotonin reuptake inhibitors (SSRIs) and/or behavioral therapy, remains an important

therapeutic modality for the management of PD.

Keywords: Behavioral therapy, carbon dioxide test, clinical studies, clonazepam, panic disorder, selective serotonin reuptake

inhibitors, tapering.

INTRODUCTION

Clonazepam is a potent, long-acting nitrobenzodiazepine

derivative with anticonvulsant, muscle-relaxant, and

anxiolytic properties that has been used for years in the

treatment of PD [1-3]. In line with other benzodiazepines,

clonazepam increases the effects of aminobutyric acid

(GABA) via modulation of the GABA receptor, however, it

act only in GABAa receptor [4, 5]. Actually, clonazepam

potentiates the inhibitory effect of gamma-aminobutyric acid

(GABA) and reduces the use of serotonin, regulating 5HT1

5HT2 receptors and frontal cortex, distinguishing it from

other benzodiazepines [6], playing a relevant role in the anti-

panic effect [7]. Some years ago, clonazepam was used as an

alternative for PD patients resistant to antidepressants. Open

clinical controlled studies and the control of panic attacks

*Address correspondence to this author at the Movement Disorders and

Transcraneal Magnetic Stimulation Unit, Hospital General Dr. Manuel Gea

González. Calzada de Tlalpan 4 800, Col Sec. XVI, Delegación Tlalpan.

Código postal: 14080. México D.F. México; Tel: / Fax: +52 1 55-85438283;

E-mail: arias@ciencias.unam.mx

provocation in CO2 inhalation test justify the inclusion of

clonazepam in the pharmacotherapeutic modalities to PD [2].

The compound was originally developed for the treatment of

epilepsy but was subsequently shown to be effective in many

psychiatric indications, especially Panic Disorder (PD) [3, 8-

15]. Use of clonazepam in PD was approved by the Ameri-

can Food and Drug Administration (FDA) in 1996.

Today, a variety of drug treatments for PD are available.

These are mainly antidepressants such as SSRIs and tricyclic

antidepressants, as well as high-potency benzodiazepines

such as clonazepam and alprazolam [16-19]. In the past,

treatment recommendations differed considerably since they

had to be based mainly on short- and intermediate-term re-

sults. The advantages of high-potency benzodiazepines

shown in short-term studies (earlier onset of action and fewer

side effects) had to be balanced against the concerns regard-

ing discontinuation syndromes, recurrence, rebound, or

withdrawal [13, 20]. In recent years, long-term results for

treating PD with benzodiazepines have become available,

allowing a more fact-based choice of drug treatment for PD

[14, 15].

1873-5592/13 $58.00+.00 © 2013 Bentham Science Publishers

354 Current Drug Targets, 2013, Vol. 14, No. 3 Nardi et al.

This paper summarizes the main clinical studies with

clonazepam in PD, alone or in combination with SSRIs,

placing special emphasis on findings that have emerged dur-

ing the present decade, mainly long-term evidence, tapering

out, and the use of laboratory measures for diagnostic pur-

poses.

PD is a frequent and debilitating psychiatric condition

associated with reduced quality of life [21-24], and impaired

work performance [24, 25]. The condition is characterized

by discrete periods of intense fear or discomfort, often ac-

companied by somatic and/or cognitive symptoms. Genuine

physical signs such as chest pain, palpitations, and shortness

of breath resembling the known symptoms of acute cardiac

events are common [26, 27]. PD often remains undiagnosed

or untreated, although studies in patients with chest pain and

normal angiographic findings in the primary-care setting

revealed a large proportion (up to 47%) of patients meeting

the diagnostic criteria for PD [28, 29]. Moreover, it is esti-

mated that up to 40% of individuals with panic attacks never

seek treatment of any kind.

Life-time and 12-month prevalence of PD, with or with-

out agoraphobia, is estimated to be 5.1% and 2.1% in the

United States of America (USA) [30, 31]. Similar figures

were recently reported for a nationally representative sample

of the United Kingdom (UK) population [32]. However,

prevalence rates differ considerably between racial groups,

with white Americans more likely to be diagnosed with PD

than African Americans [33]. Between 30% and 50% of in-

dividuals diagnosed with PD also suffer from agoraphobia

[34], but the prevalence of agoraphobia alone is considerably

higher [35]. Typically, onset of PD occurs between late ado-

lescence and the early twenties, but later onset up to the thir-

ties is not uncommon [30]. PD accompanied by agoraphobia

is twice as common in women as in men, while the fre-

quency of PD without agoraphobia is similar in men and

woman [36]. Currently, the diagnosis of PD is mainly based

on the Diagnostic and Statistical Manual of Mental Disorders

(DSM) which is the standard system to classify mental dis-

orders for clinical studies.

The most important risk factor for the development of PD

is a family history of anxiety disorders [37]. First-degree

relatives of subjects with PD have a four to seven times

greater risk of developing PD, and twin studies have indi-

cated a clear genetic relationship [37]. PD is now understood

as an inherited biochemical disturbance in the overall func-

tion or structure of the GABAergic, noradrenergic, sero-

toninergic, and/or dopaminergic systems [35]. It is also hy-

pothesized that disturbances of the acid-base balance in the

brainstem may play a role in the pathogenesis of PD [14, 31].

PD is a condition with many nuances, requiring a one-to-

one interaction between clinician and patient and an indi-

vidualized treatment approach. It is now generally agreed

that long-term treatment of PD, lasting minimally 1 year and

often 3 years or longer, is essential for a successful outcome.

Lasting drug-induced adverse events (AEs) are a major

handicap for successful long-term treatment leading to non-

compliance and dropouts [25]. Finding the best approach for

the individual patient is still very demanding. We hope that

the present review will facilitate this.

Fontaine and Chouinard [12] were the pioneers for using

clonazepam as antipanic agent. They anticipated that

clonazepam would be effective in the treatment of PD, based

on its pharmacodynamic and pharmacokinetic properties,

and reported the successful use of clonazepam in patients

with panic attacks for the first time. They expressed the opin-

ion that compared to the other benzodiazepine shown to be

effective in treating panic attacks (alprazolam), withdrawal

symptoms upon termination of treatment would be less prob-

lematic with clonazepam. They also thought that the longer

half-life of clonazepam would make dosing easier and more

flexible (once or twice daily vs. four times daily with alpra-

zolam). In addition, three years later, Herman et al. [38]

switched 48 PD patients to clonazepam after they had expe-

rienced interdose anxiety during treatment with alprazolam.

Overall, 82% of patients considered clonazepam to be supe-

rior to alprazolam. This supported the notion that the longer

half-life of clonazepam avoids interdose recurrence of symp-

toms. An additional advantage of clonazepam was the more

favorable side-effect profile anticipated and the lower risk of

overdose with clonazepam than with tricyclic antidepres-

sants.

The authors subsequently used clonazepam to treat se-

vere anxiety and agitation in both adolescents and adults and

found it to be well tolerated and efficacious at dosages of 6

to 12 mg/day [39]. In several cases, the use of clonazepam

enabled them to avoid using neuroleptics which could induce

tardive dyskinesia or Parkinsonian side effects. They con-

cluded that clonazepam is an efficacious antipanic and an-

tiphobic agent that provides an alternative treatment for pa-

tients suffering from severe anxiety with recurrent panic at-

tacks.

These pioneering studies created considerable interest in

the use of clonazepam for the treatment of PD because alpra-

zolam, the high-potency benzodiazepine used for the treat-

ment of PD at that time, has a short half-life with a short

duration of action, and patients who missed a dose frequently

reported worsening or re-emergence of symptoms [7, 38,

39]. Clonazepam showed promising efficacy in line with its

long half-life, high affinity for central benzodiazepine recep-

tors, lack of significant interaction with other drugs, and en-

hanced serotoninergic activity [40, 41].

The studies referred to here were retrieved from a Pub-

Med/MEDLINE and Excerpta medica English-literature

search using the search terms ‘clonazepam’ and ‘panic dis-

order’ and by review of references.

CLINICAL PHARMACOLOGY

Pharmacokinetics and Pharmacodynamics

Because clonazepam was initially developed as an anti-

convulsant, early clinical pharmacology studies focused on

both the oral and parenteral routes of administration. Kaplan

et al. [42] published data on the pharmacokinetics of

clonazepam in dogs and also included some data from stud-

ies in humans. The authors reported good absorption of a

micronized oral formulation (2 mg) with a relatively long

half-life. More extensive data on oral and intravenous (i.v.)

dosing in humans were reported by Berlin and Dahlström

[43]. The most recent pharmacokinetic evaluation was pub-

lished by Crevoisier et al. [44]. (Table 1) summarizes the

Clonazepam in Panic Disorder Current Drug Targets, 2013, Vol. 14, No. 3 355

pharmacokinetic parameters for a 2 mg dose reported in

these three studies. Its long half-life makes clonazepam

suited for once-daily or twice-daily dosing, and missed doses

would have little impact on the pharmacological effect. A

large volume of distribution assures good penetration into

the central nervous system (CNS).

Mechanistically, clonazepam is a partial benzodiazepine

agonist with some serotonergic activit [2, 20, 45]. These

pharmacodynamic properties, coupled with good oral ab-

sorption and a long half-life, seemed suited to the treatment

of PD and led to the studies that established clonazepam as a

useful contributor to the therapeutic armamentarium for this

illness [34, 41].

Clonazepam is metabolized to 7-acetamido clonazepam

(7-AM) by N-acetylation and 7-amino clonazepam (7-ACT)

by nitro reduction. Subjects with the slow acetylator pheno-

type excrete significantly less 7-ACT and more 7-AM than

do those with the rapid acetylator phenotype [34, 41, 46].

Interaction with Other Drugs

Several publications have focused on the beneficial inter-

action between clonazepam and anticonvulsants. The CNS-

depressant action of the benzodiazepines may be potentiated

by alcohol, narcotics, barbiturates, nonbarbiturate hypnotics,

anti-anxiety agents, certain antipsychotic agents, monoamine

oxidase inhibitors, tricyclic antidepressants, and other anti-

convulsant drugs.

No evidence of significant pharmacokinetic drug-drug

interactions of clonazepam in the context of PD treatment

with other drugs has emerged. Greenblatt et al. [47] reported

that fluoxetine impairs the clearance of alprazolam but not of

clonazepam. In a study in healthy volunteers receiving

clonazepam (1 mg/day) and sertraline (100 mg/day) for 10

days, there was no evidence of altered pharmacokinetics or

pharmacodynamics of clonazepam [47].

Carbon Dioxide and Breath-Holding Challenge Tests with Clonazepam in Panic Disorder

Induction of panic attacks by carbonic acid (CO2) inhala-

tion in PD patients can be used as a trait marker for PD [48,

49] or as a pharmacodynamic marker to evaluate antipanic

agents [10, 50-52]. Clonazepam inhibits CO2-induced panic

attacks in PD patients [51-53]. This blockade was found not

only after several weeks of treatment [54] but already after

the intake of a single acute dose [50].

EFFICACY

Early studies (Case Reports and Open-Label Studies)

In 1984, Fontaine and Chouinard were the first to re-

ported the successful use of clonazepam in patients (10 of

12) with panic attacks [7]. Beaudry et al. [9] successfully

treated 8 patients with recurrent panic attacks with clonaze-

pam. Biederman [55] reported the successful use of clonaze-

pam in the treatment of three prepubertal children who suf-

fered severe, incapacitating anxiety with panic-like symp-

toms. At follow-up after 5 months to 3 years, the children

had remained symptom-free. Fifty patients with PD or ago-

raphobia with panic attacks were treated with clonazepam by

Pollack et al. [56]. The authors reported on the outcome of

these patients after an average follow-up period of 1 year,

suggesting that clonazepam is a safe and effective drug that

is easy to administer in a treatment-refractory population of

non-depressed patients with PD and agoraphobia. Spier et al. [11] observed that 78% of 50 patients with PD or agorapho-

bia with panic attacks responded to an average clonazepam

dose of 1.9 mg/day. Similar results were reported with a

clonazepam dose of 2.1 ± 0.66 mg/day [57]. Tesar and

Rosenbaum [58] reported that 7 of 10 treatment-resistant PD

patients with or without agoraphobia achieved cessation of

their attacks while 3 patients had mild to moderate symptom

persistence.

Placebo-Controlled Studies

(Table 2) summarizes the placebo-controlled studies

without active comparator. The four studies comprising a

total of 904 patients with PD consistently showed superiority

of clonazepam over placebo with respect to the efficacy end-

points [58-63]. Beauclair et al. [59] observed an antipanic

effect already during the first week of treatment, and 11 of

the 13 patients treated with clonazepam were classified as

responders compared with only 1 of 10 placebo-treated pa-

tients [59]. In the multicenter dose-finding study published

by Rosenbaum et al., 413 patients suffering from panic at-

tacks with or without agoraphobia were randomly assigned

to receive placebo or one of five fixed daily doses (0.5 mg,

1.0 mg, 2.0 mg, 3.0 mg, or 4.0 mg) of clonazepam [60].

Doses of 1 mg and above were all more efficacious than pla-

cebo or 0.5 mg of clonazepam. Within the dose range of 1 to

4 mg, no clear-cut dose effect for efficacy was apparent but

the 3.0 mg and 4.0 mg dose groups had the highest AE rates.

In the four higher dose groups, 69% of patients on average

were free of panic attacks at the end of the study. Moroz and

Rosenbaum reported the treatment of 438 PD patients over 6

Table 1. Pharmacokinetic Parameters of Clonazepam After an Oral Dose (2 mg) in Healthy Volunteers

Authors Subjects (n) T1/2 (h) Cmax (ng/mL) Tmax (h) AUCinf (ng·h·mL-1

) Vd (i.v. dose)

Kaplan et al., 1974 8 18.7-39 6.5 to 131-2 (6 subjects)

6-8 (2 subjects)- -

Berlin and Dahlström, 1975 8 19-42 7.1-23.6 1-4 231-841 1.5-4.4 (L/kg)

Crevoisier et al., 2003 12 39.0 ± 8.3 SD 14.9 ± 3.9 SD 1.7 ± 0.9 SD 561 ± 105 SD 180 ± 50 (L)

AUCinf = area under the curve extrapolated to infinity, Cmax = maximum concentration, i.v. = intravenous, SD = standard deviation, T1/2 = half-life, Tmax = time to maximum concen-

tration, Vd = volume of distribution

356 Current Drug Targets, 2013, Vol. 14, No. 3 Nardi et al.

Table 2. Placebo-Controlled Studies with Clonazepam in Panic Disorder

Patients (n) Diagnosis Active Treatment

and Duration Outcome Adverse Events Authors

29

DSM-III

PD or agoraphobia

with panic attacks

Clonazepam, dose titrated

for 2 weeks (average 2.2

mg/day). Total treatment 4

weeks.

Clonazepam significantly

better than placebo for CGI-

S, HAM-A, and GAS. Num-

ber, intensity, and duration

of situational attacks, antici-

patory attacks, and sponta-

neous attacks.

Drowsiness in 9/13 patients.

Other AEs with clonazepam

but not placebo: mem-

ory/concentration, sexual

problems

Beauclair et al.,

1994

413 DSM-III PD

Clonazepam, fixed daily

doses up-titrated over 3

weeks to 0.5 mg, 1.0 mg, 2.0

mg, 3.0 mg, and 4.0 mg.

Maintained for 6 weeks and

then tapered for 7 weeks.

Clonazepam (dose of 1 mg

and above) significantly

better than placebo for CGI-

S, PGI-C, and HAM-A.

Doses of 1-2 mg considered

to have the best benefit/risk

ratio.

Somnolence, ataxia, depres-

sion, dizziness, fatigue, and

irritability more frequent

with clonazepam than with

placebo.

Rosenbaum et

al., 1997

438

DSM-III

PD with or without

agoraphobia

Clonazepam, uptitrated for 3

weeks, maintained for 3

weeks (total 6-week thera-

peutic phase) at a daily dose

of 0.25 to 4.0 mg/day. Doses

tapered gradually to zero for

7 weeks.

Clonazepam clinically and

statistically superior to pla-

cebo in change in the num-

ber of panic attacks and

CGI-S, CGI-C, and PGI-C.

Gradual withdrawal not

associated with withdrawal

symptoms. No evidence of

rebound. Main AE associ-

ated with clonazepam ther-

apy: somnolence.

Moroz and

Rosenbaum.

1999

72 PD

Clonazepam, 2.5 mg/day

(average), alprazolam, 5.4

mg/day (average) for 6

weeks.

Statistically significantly

better effect with clonaze-

pam and alprazolam than

placebo. No differences

between the two active

treatments.

Main AEs associated with

clonazepam therapy: seda-

tion and ataxia.

Tesar et al., 1991

40 PD Clonazepam, 2 mg/day for 4

weeks.

Significantly higher response

of clonazepam than placebo

(84% vs. 35%).

Main AEs associated with

clonazepam therapy: somno-

lence/drowsiness, vertigo,

unsteadiness of gait.

Dyukova et al.,

1991

144 PD

Clonazepam, uptitrated for 3

weeks, maintained for 3

weeks (6-week therapeutic

phase) at a daily dose of 0.25

to 4.0 mg/day. Doses tapered

gradually to zero for 7

weeks.

Improvement on the SF-36

MCS scale was more than

twice as great with clonaze-

pam as with placebo

(p=0.03), with highest im-

provement in “general men-

tal health” in MCS and

“freedom from bodily pain”

in the PHCS.

See Moroz and Rosenbaum.

1999

Jacobs et

al.,1997

(Data obtained in

conjunction with

study Moroz and

Rosenbaum.

1999)

27 Chest pain. PD with

normal angiography

Clonazepam, 1-4 mg/day for

6 weeks.

Reduction of panic attacks

>50%; clonazepam 67%;

placebo 47%. Reduction in

HAM-A score >50%;

clonazepam 58%; placebo

14%.

Safety not reported. Wulsin et al.,

1999

24 PD with agorapho-

bia

Clonazepam, 2 mg/day for 6

weeks.

Clonazepam superior to

placebo for CGI (p=0.031).

Main AEs associated with

clonazepam therapy: somno-

lence, ataxia, dizziness.

Valença et al.,

2000

AE = adverse event, CGI-S = Clinical Global Impression of Severity, CGI-C = Clinical Global Impression of Change, GAS = Global Assessment Score,

HAM-A = Hamilton Anxiety rating, MCS = Mental Health Component Summary, PD = panic disorder, PHCS = Physical Health Component Summary, PGI-C = Patient Global

Impression of Change

Clonazepam in Panic Disorder Current Drug Targets, 2013, Vol. 14, No. 3 357

weeks with either placebo or clonazepam at individually

adjusted doses [61]. The mean optimized clonazepam dose

was 2.3 mg/day. Clonazepam was superior to placebo in

reducing the number of panic attacks, extent of fear and

avoidance, and duration of anticipatory anxiety, and in im-

proving the different items on the Clinical Global Impression

(CGI) scales. The gradual tapering of clonazepam was not

associated with symptoms suggestive of withdrawal syn-

drome.

Quality of life and work productivity were examined in a

proportion of the population in the study by Moroz and

Rosenbaum, and the findings were reported by Jacobs [21].

Improvement on the SF-36 Mental Health Component

Summary (MCS) scale was more than twice as great with

clonazepam than with placebo (p=0.03), with highest im-

provement in the items ‘general mental health of MCS’ and

‘freedom from bodily pain’ in the Physical Health Compo-

nent Summary. Between-group differences in mental and

emotional work productivity measures favored clonazepam

(p=0.04).

In a double-blind study, Wulsin et al. [63] compared

clonazepam with placebo in 27 chest-pain patients with

panic disorder and normal coronary arteries. The treatment

lasted 4 weeks and used a flexible clonazepam dose (1 to 4

mg). Patients were followed up for 2 weeks after discon-

tinuation of the study medication. Overall, 66% of patients

receiving clonazepam and 47% patients receiving placebo

showed a reduction in the frequency of panic attacks. Pa-

tients were classified as responders if they had a reduction in

the Hamilton Anxiety rating (HAM-A) of 50% or more. On

this basis, the responder rate was 58% for clonazepam and

14% for placebo. The small sample size, high placebo-

response rate, and unbalanced baseline values were men-

tioned as limitations of the study.

Valença et al. [62] tested a fixed dose of clonazepam (2

mg/day) versus placebo in 24 PD patients with agoraphobia.

After 6 weeks, the response rate (reducing anticipatory anxi-

ety, scores of phobia, and CGI) was 61% with clonazepam

and 1% with placebo. Three years later, Valença et al. [64]

compared 34 PD patients with agoraphobia regarding the

clinical efficacy of clonazepam in a fixed dosage (2 mg/day)

versus placebo. The patients were divided in respiratory and

non-respiratory subtypes. After 6 weeks, there was a statisti-

cally significant clinical improvement in favor of the group

that received clonazepam, showing remission of panic at-

tacks (p < 0.001) and decrease in anxiety (p = 0.024). While

in the placebo group there was no significant difference be-

tween the respiratory and non-respiratory subtypes of PD.

However, with respect to clinical efficacy of clonazepam, the

findings show there is no difference in the therapeutic re-

sponse between PD subtypes.

Studies of Clonazepam Versus Active Drug

In a 6-week, double-blind, randomized study, Tesar et al. [65] compared clonazepam with alprazolam and placebo in

72 patients with PD in a standardized but flexible dosing

schedule. Medication was taken four times a day. At week 3,

the mean (± SD) dosages of alprazolam and clonazepam

were 4.34 ± 1.43 mg/day and 2.18 ± 0.46 mg/day, respec-

tively. Both clonazepam and alprazolam were superior to

placebo for the treatment of PD as reflected by changes in

the number of panic attacks, overall phobic distress, social

and work disability, and global assessments of severity of

illness and improvement. In all groups, side effects (mostly

sedation and ataxia) were most frequent through week 3 and

were virtually absent by the end of the study. There was no

difference in efficacy and tolerability when comparing

clonazepam with alprazolam. This study had two shortcom-

ings: 64% of patients in the placebo group dropped out be-

fore week 6, and clonazepam had to be taken four times a

day instead of once or twice a day. Herman et al. [38]

switched 48 consecutive patients treated for PD with alpra-

zolam to clonazepam, and 82% rated clonazepam better be-

cause of decreased frequency of administration and lack of

interdose anxiety.

Nardi et al. [14] randomized 120 patients to receive ei-

ther clonazepam (0.5 to 2 mg/day) or paroxetine (10 to 40

mg/day), taken after dinner. Patients with a history of drug or

alcohol abuse were excluded from the study. Maintenance

doses (2 mg clonazepam and 40 mg paroxetine) were

reached at the end of the second treatment week. During the

first weeks of treatment, weekly panic attacks decreased in

both treatment groups. At week 4, patients in the clonazepam

group had significantly fewer panic attacks (0.1 ± 0.5 per

week) than those in the paroxetine group (0.5 ± 0.9 per

week; p<0.01), but at week 8, patients experienced similarly

low numbers of panic attacks with clonazepam and paroxet-

ine (0.2 ± 0.6 vs. 0.2 ± 0.4 per week). Overall, clonazepam-

treated patients had a faster onset of action (reduction of

panic attacks, CGI-I, and HAM-A) and fewer lasting AEs.

Long-term results of this study are described below.

Co-Therapy with SSRIs or Augmentation Therapy

SSRIs are effective in the treatment of PD and are re-

garded by many clinicians as first-choice treatment [66].

This is also reflected in the American Psychiatric Associa-

tion (APA) guidelines for the treatment of PD. However,

SSRIs have a number of disadvantages including a slow on-

set of action (several weeks) and unpleasant side effects,

such as worsening of anxiety in the initial treatment phase,

sexual and cognitive disturbances, insomnia, agitation, and

weight gain [67]. As suggested by Eppel [68], adding

clonazepam for the initial 6 to 8 weeks is effective in bridg-

ing the time until the desired SSRI effect is achieved. This

helps to prevent the occurrence of anxiety states, insomnia,

and agitation during the initial phase of treatment.

In a double-blind trial, Goddard et al. [69] treated 50 PD

patients with open-label sertraline for 12 weeks. In addition,

the patients were randomly assigned to either clonazepam

(1.5 mg/day) or placebo for 4 weeks. The clonazepam dose

was then tapered during 3 weeks and finally discontinued.

There were significantly more responders in the ser-

traline/clonazepam group than the sertraline/placebo group at

the end of week 1 of the trial (41% vs. 4%, p=0.003).

Moreover, there was a significant between-group difference

in the percentage of responders at the end of week 3 (63% of

the sertraline/clonazepam group vs. 32% of the ser-

traline/placebo group, p=0.05). The authors concluded that

stabilization of panic symptoms can be safely achieved with

a sertraline/clonazepam combination, demonstrating the

358 Current Drug Targets, 2013, Vol. 14, No. 3 Nardi et al.

clinical value of the combination for facilitating early im-

provement of panic symptoms relative to sertraline alone.

In a randomized study in 60 PD patients, Pollack et al. [70] compared the efficacy and safety of paroxetine and pla-

cebo vs. paroxetine co-administered with clonazepam. The

initial treatment phase was followed by a tapered benzodi-

azepine discontinuation phase or ongoing combination

treatment. All treatment groups demonstrated marked im-

provement. There was a significant advantage for combined

treatment early on but subsequently, the outcome in all three

groups was similar. The authors concluded that combined

treatment with paroxetine and clonazepam resulted in a more

rapid initial response than selective serotonin reuptake in-

hibitors (SSRI) treatment alone, but there was no difference

beyond the initial few weeks of therapy. Initiating combined

treatment, followed by benzodiazepine taper after a few

weeks, may provide fast benefit while avoiding the potential

adverse consequences of long-term combination therapy.

Published studies suggest that between 30% and 60% of

patients receiving antidepressants including SSRIs may ex-

perience some form of treatment-induced sexual dysfunction

[71-73]. In an opinion survey among 439 psychiatrists, most

psychiatrists appeared to favor switching to clonazepam

monotherapy if major AEs occurred with SSRIs, rather than

continuing with combination therapy [74].

Treatment of Subpopulations: Respiratory Subtype

During the Cross-National Panic Study, Briggs et al. [75]

found that patients could be divided into two groups, charac-

terized by the presence or absence of prominent respiratory

symptoms. The two groups differed with respect to psycho-

pathology on study entry as well as treatment outcome. Pa-

tients with the respiratory subtype have more pronounced

CO2 sensitivity [62, 76]. PD patients of the non-respiratory

subtype have a more marked family history of PD, lower

comorbidity with depression, longer duration of illness,

lower neuroticism scores, and higher scores in severity scales

than PD patients of the respiratory subtype [77]. In a 6-week

study, Valença et al. [64] found that clonazepam is equally

effective in both the respiratory and non-respiratory subtypes

of PD, but we subsequently demonstrated that, based on the

Sheenan panic and anticipatory scale, the respiratory sub-

group responds more rapidly [78]. However, long-term

treatment outcome (3-year follow-up) was the same in the

two groups, while the therapeutic effect was sustained. The

DSM-IV diagnostic criteria do not specify the respiratory

subtypes of PD.

Long-Term Treatment

Pollack et al. [56] were the first to report on the long-

term outcome of treatment with clonazepam in larger patient

populations. At 1 year after initiation of treatment, 31 of 50

patients with PD or agoraphobia with panic attacks were still

attending their clinic, and 20 of these patients were still re-

ceiving clonazepam at an average dose of 2.3 mg/day. In this

cohort, 2 patients were judged to have had a poor therapeutic

response, while 18 patients had had a good response. Eight

patients each had a constant dose or small dose increase, and

4 patients had a dose decrease.

The same group [79] also did a long-term follow-up as-

sessment of the Tesar study [66]. After a mean period of 1.5

years after the end of the study, 78% of the 59 patients still

received medication. The mean daily dose of alprazolam (1.9

mg) or clonazepam (2.0 mg) had not increased. The authors

concluded that most patients maintain benefit from long-term

pharmacotherapy, but that residual symptoms may require

more intensive or additional treatment strategies. A positive

outcome at the end of the acute trial was significantly corre-

lated with the clinical global impression of severity (GCI-S)

score at baseline and the presence of dysthymia. Poor out-

come at follow-up was associated with total duration of the

disorder, agoraphobic subtype, and the presence of co-

morbid social phobia.

The Massachusetts General Hospital (MGH) performed a

naturalistic longitudinal study in 204 PD patients over a 2-

year period. Overall, 46% of patients received clonazepam

alone or in combination with an antidepressant. All treatment

groups tended to improve over time without significant dif-

ferences in outcome between groups. Clonazepam doses

remained stable over time. Results of this study suggest that

treatment of PD with clonazepam achieved and maintained a

therapeutic benefit similar to that obtained with alternative

pharmacologic treatments, without the development of toler-

ance as manifested by dose escalation or worsening of clini-

cal status [80].

In a 3-year, open study, we followed 67 patients with the

respiratory or non-respiratory subtype of PD [78]. Clonaze-

pam had a sustained therapeutic effect on all efficacy vari-

ables over the entire treatment period. The patients who par-

ticipated in the acute treatment comparison of clonazepam

(n=63) with paroxetine (n=57) in PD were invited to enter a

prospective long-term study. Patients with a good primary

outcome were allowed to continue treatment with either

clonazepam or paroxetine, and patients with insufficient

primary outcome were offered combination therapy with

clonazepam (2 mg/day) plus paroxetine (40 mg/day). A total

of 47 clonazepam patients and 37 paroxetine patients re-

ceived long-term monotherapy whereas the combination-

therapy group consisted of 21 patients (10 patients originally

taking clonazepam and 11 patients originally taking paroxet-

ine). Overall, 95.7% of patients receiving clonazepam,

89.2% of those receiving paroxetine, and 76.1% of those

taking the drug combination finished the foreseen 3-year

long-term treatment. In both monotherapy groups, the initial

positive effect was maintained or increased without change

in the daily dose (clonazepam 1.9 ± 0.29 mg/day and par-

oxetine 38.2 ± 3.87 mg/day). The mean (± SD) number of

panic attacks at month 34 was 0.11 ± 0.31 with clonazepam

and 0.16 ± 0.50 with paroxetine. The mean CGI-I during

long-term treatment was 1.06 ± 0.16 for clonazepam-treated

patients and was significantly better than that for paroxetine-

treated patients (1.11 ± 0.14, p=0.04). Anxiety severity,

measured on the HAM-A scale, was reduced with both

treatments over the study period. In the combination group,

there was an early improvement in efficacy outcomes which

was maintained throughout the duration of the long-term

study. After a maximum of 6 months of total treatment dura-

tion, the patients in the combination-group had reached the

same favorable treatment results as the other two groups.

Clonazepam in Panic Disorder Current Drug Targets, 2013, Vol. 14, No. 3 359

One year later, in a randomized, naturalistic study, Nardi

et al. [53] treated PD patients with or without agoraphobia in

order to compare the efficacy and safety of clonazepam (n =

47) and paroxetine (n = 37) over a 3-year total treatment

duration. Patients with a good primary outcome during acute

treatment continued monotherapy with clonazepam or par-

oxetine, while patients with partial primary treatment success

were switched to a combined therapy with clonazepam (2

mg/day) and paroxetine (40 mg/day). The mean doses of

clonazepam and paroxetine at the beginning of the study

were 1.9 (SD = 0.30) and 38.4 (SD = 3.74) mg/d, respec-

tively. The doses were maintained up to month 36 (clonaze-

pam 1.9 [SD, 0.29] mg/d and paroxetine 38.2 [SD, 3.87]

mg/d). Long-term treatment with clonazepam led to a small

but significantly better CGI Improvement rating than treat-

ment with paroxetine (mean difference: CGI-Severity scale

3.48 vs 3.24, respectively, p = 0.02; CGI-Improvement scale

1.06 vs 1.11, respectively, p = 0.04). Both treatments simi-

larly reduced the number of panic attacks and severity of

anxiety. Patients treated with clonazepam had significantly

fewer adverse events than those treated with paroxetine

(28.9% vs 70.6%, p = 0.001). The efficacy of clonazepam

and paroxetine for the treatment of panic disorder was main-

tained over the long-term course, showing a significant ad-

vantage with clonazepam over paroxetine with respect to the

frequency and nature of adverse events.

SAFETY AND TOLERABILITY

Tolerability in Short/Intermediate-Term Studies

The most comprehensive information on the safety of

short- and intermediate-term treatment with clonazepam in

PD comes from the large placebo-controlled studies involv-

ing 850 PD patients with or without agoraphobia [46, 76].

During controlled clinical studies in which 574 patients re-

ceived clonazepam at doses of 0.5 to 4 mg, the drug was well

tolerated. Side effects were usually mild and transient. (Ta-

ble 3) shows the treatment-emergent adverse events (AEs)

occurring in 2% of patients or more in these studies.

The AE profile shown there is consistent with the general

features of benzodiazepines as a class and data presented in

other studies. In all published studies, clonazepam was safe

and nontoxic in the dose range used. AEs cited by various

authors include drowsiness, ataxia, sedation, derealization,

incontinence, irritability, vertigo, faintness, tachycardia,

dysthymia, rebound lethargy, facial flushing, mild anxiety,

and tinnitus. While no paper reported any serious AEs asso-

ciated with clonazepam, there were a few reports of patients

discontinuing clonazepam therapy due to tolerability prob-

lems, such as sedation, sleep disturbances, and/or nausea [62,

64, 71]. In placebo-controlled short-term studies, somno-

lence/drowsiness was the most frequent AE associated with

clonazepam [59, 80].

Tolerability in Long-Term Studies

It is now generally accepted that the majority of PD pa-

tients need treatment for at least 1 year and in many in-

stances for up to 3 years. Nevertheless, there is limited in-

formation on the safety and tolerability during prolonged

treatment for most antipanic drugs.

In their longitudinal study conducted at the MGH, Wor-

thington et al. [80] stated that there were no spontaneous

reports of significant AEs during the 2-year observation pe-

riod in 204 PD patients treated with clonazepam. The authors

did, however, point out that safety information was not col-

lected systematically.

In our study in patients with the respiratory subtype of

PD, we treated 67 PD outpatients with clonazepam for 3

years and followed them up for another 3 years [78]. The

patients had previously been classified as belonging to the

respiratory (n=35) or non-respiratory (n=32) subgroup. Dur-

ing the study, no serious AEs occurred, and the withdrawal

rate because of AEs was low and did not differ significantly

between the groups. The most frequent AEs were somno-

lence, fatigue, memory complaints, dry mouth, decreased

libido, ataxia, constipation, and lightheadedness.

In our 3-year study [53] comparing clonazepam (n=47)

with paroxetine (n=37), we found that already at baseline,

before treatment initiation, most patients reported AEs,

mainly anxiety/agitation (53%), insomnia/nightmares (48%),

shaking/trembling/tremor (42%), paresthesia (34%), head-

ache (30%), memory/concentration problems (28%), and

weakness (26%). After 2 months of treatment, the number of

AEs associated with clonazepam had decreased while those

associated with paroxetine had increased, reaching 47% and

84%, respectively (p<0.001). After 3 years of clonazepam

treatment, the number of AEs had dropped further to 28.9%.

A significantly larger number of patients treated with par-

oxetine experienced AEs (70.6%; p<0.0001). At this time

point, the most common AEs were drowsiness/fatigue

(24.4%), memory/concentration problems (15.6%), and sex-

ual dysfunction (11.1%) in the clonazepam group, and appe-

tite/weight changes (48.6%), sexual dysfunction (55.9%),

drowsiness (50.0%), dry mouth (35.3%), diarrhea/

constipation (35.3%), memory/concentration problems

(26.5%), nausea/vomiting (17.6%), and shaking/trem-

bling/tremor (11.8%) in the paroxetine group. During long-

term treatment, significantly more patients in the paroxetine

group than the clonazepam group experienced sexual dys-

function, drowsiness/fatigue, diarrhea/ constipation, dry

mouth, excessive sweating, shaking/ trembling/tremor, and

nausea/vomiting (all p<0.0001), memory/concentration prob-

lems (p<0.005), insomnia/nightmares, headache (both

p<0.01), and paresthesia (p<0.05). Patients taking the drug

combination suffered most frequently from AEs, with sexual

dysfunction, drowsiness, memory/concentration problems,

and fluctuations in appetite/weight being the most frequent

ones.

Some AEs observed during treatment were already pre-

sent before treatment. Thus, they are more likely to be caus-

ally related to PD, especially since they diminished in paral-

lel with improvement of PD. Drowsiness/day time sedation

was the only treatment-related AE observed in the clonaze-

pam group also during long-term use. Thus, long-term use of

clonazepam does not appear to impose any additional toler-

ability risks and essentially represents the safety profile

known from studies of shorter duration.

Tolerability of Clonazepam Co-Administered for up to 8

Weeks with SSRIs

Despite the widespread use of combined SSRI and ben-

zodiazepine treatment in PD, systematic assessment of the

360 Current Drug Targets, 2013, Vol. 14, No. 3 Nardi et al.

Table 3. Incidence of Treatment-Emergent Adverse Events in Placebo-Controlled Clinical Trials Lasting 6 to 9 Weeks (Rosenbaum

et al., 1997; Moroz and Rosenbaum, 1999)

Adverse Events by Body System (%) Clonazepam (0.5 – 4 mg) n=574 Placebo n=294

Central and peripheral nervous system

Somnolence 37 10

Dizziness 8 4

Coordination abnormal 6 0

Ataxia 5 0

Dysarthria 2 0

Psychiatric

Depression 7 1

Memory disturbance 4 2

Nervousness 3 2

Intellectual ability reduced 2 0

Respiratory system

Upper respiratory tract 8 4

Infection

Sinusitis 4 3

Rhinitis 2 1

Coughing 2 0

Pharyngitis 2 1

Gastrointestinal system

Constipation 2 2

Body as a whole

Fatigue 7 4

Allergic reaction 2 1

safety and efficacy of this therapeutic strategy has rarely

been done. In PD, the safety and tolerability of clonazepam

comedication was systematically addressed in 2 studies [69,

70]. In the Pollack study, tolerability of paroxetine alone or

combined with clonazepam was similar with respect to the

type and frequency of AEs and the number of AEs leading to

withdrawal from the study. Most AEs were mild to moderate

and occurred early in the course of treatment; most of them

subsided with ongoing therapy.

In a placebo-controlled study, Goddard et al. [69] treated

50 PD patients with clonazepam (1.5 mg/day) or placebo

combined with sertraline (target dose 100 mg/day) for 4

weeks, followed by a 3-week clonazepam taper. AEs and the

number of patients withdrawing from the study because of

AEs did not differ significantly between the groups, and the

rate of clinical worsening as the reason to withdraw was

similar in the two groups. During the clonazepam tapering

phase, a few patients experienced diarrhea which did not

occur in the group receiving sertraline/placebo.

When clonazepam was combined with paroxetine or ser-

traline, the AE profile was typical for SSRIs, and the addi-

tion of clonazepam had no significant influence on the fre-

quency, nature, or severity of the observed AEs.

Tolerability of Clonazepam in Children and Elderly Pa-

tients

Clonazepam is approved for use in children with epi-

lepsy, but the safety and efficacy in PD patients below the

age of 18 years have not been studied systematically. Some

information on the use of clonazepam in children comes

from Biederman [8], who successfully treated three prepu-

bertal children with severe anxiety disorder and panic-like

symptoms. The patients received clonazepam at daily doses

between 0.5 mg and 3 mg for up to 3 years. No AEs of note

Clonazepam in Panic Disorder Current Drug Targets, 2013, Vol. 14, No. 3 361

were reported, indicating that pediatric patients do not seem to be exposed to a higher safety risk than adults. Graae et al. [82] conducted a crossover study with clonazepam and pla-cebo in 15 children (aged 7 to 13 years) with anxiety disor-ders. Drowsiness, irritability, and/or oppositional behavior occurred in 10 children during the clonazepam phase and in 5 children during the placebo phase.

Similarly, no clinical studies in PD patients older than 65 years have been published. However, in a 21-month study conducted at a veterans’ affairs medical center, clonazepam (mean dose of 1.2 mg for a minimum of 2 weeks) was well tolerated in 24 demented and nondemented geriatric patients suffering from various psychiatric illnesses [82]. Only one patient had to discontinue clonazepam treatment because of sedation and confusion.

Discontinuation of Clonazepam Therapy

The safety and tolerability profile of clonazepam essen-tially reflects the known properties of benzodiazepines [2]. A major concern of benzodiazepine therapy is the development of dependence with long-term use. Thus, a significant safety concern in connection with clonazepam is treatment discon-tinuation and the handling of withdrawal symptoms. Since PD patients tend to be highly sensitive to bodily symptoms and somatic stress, treatment discontinuation may be particu-larly challenging [83]. Dependence and withdrawal problems in connection with prolonged use of benzodiazepines are influenced by a number of factors, such as the underlying diagnosis, the specific benzodiazepine used, and the rate of drug discontinuation [2]. Treatment cessation may be further complicated by comorbidities such as other anxiety disorders or drug dependence [47]. The available studies, however, point to the fact that gradual withdrawal of clonazepam over prolonged periods of time is safe and effective [80].

Recently, we developed a protocol for safely tapering off clonazepam dosage [3]. We studied 73 PD patients who had been receiving clonazepam for at least 3 years. All patients had been asymptomatic for at least 1 year and wished to dis-continue the medication. Tapering took place during a 4-month period, and follow-up observation lasted for 8 months. The clonazepam dose was decreased by 0.5 mg per 2-week period until 1 mg/day was reached, followed by a decrease of 0.25 mg/week. Most (70%) patients succeeded in discontinuing clonazepam within the foreseen period of 4 months and without recurrences of panic attacks. As many as 89% of patients completely stopped intake of any medication for panic attacks and were free of anxiety symptoms within 6 months at most. After 6 months, 8 patients still received clonazepam (0.5 mg/day). All were switched to mirtazapine, but 3 patients asked to return to clonazepam (0.5 mg/day) because of recurrence of anxiety symptoms. The most fre-quent clonazepam discontinuation symptoms included anxi-ety, shaking/tremor, nausea/vomiting, insomnia/nightmares, excessive sweating, tachycardia/palpitations, headache, weakness, and muscle aches, but most symptoms were of a mild nature. We concluded that in most patients, clonazepam can be successfully discontinued with few AEs and without any major withdrawal symptoms if the dose is reduced gradually [3].

Since the early nineties, it is known that discontinuation symptoms are not limited to the withdrawal of benzodiazepi-

nes. Discontinuation of antidepressants can induce similar symptoms [89]. We therefore examined if slow discontinua-tion of clonazepam or paroxetine after 3 years of treatment [13] would show the same course. AEs were frequent during the withdrawal period in both treatment groups, whereby anxiety/irritability, insomnia/nightmare, and agorapho-bia/phobias were most frequently observed. Most AEs were mild, and many of them were of a transient nature. The AE profile was similar for the two treatment groups during and in the months after discontinuation, although shaking/tremor was more frequently observed in the clonazepam group whereas dizziness/lightheadness, weakness, appetite/weight change, nausea/vomiting, and hypersomnia were more fre-quent during and after paroxetine withdrawal. Withdrawal success was higher in the clonazepam group, with 58% of clonazepam patients (vs. 21% of paroxetine patients) com-pletely stopping clonazepam after 2 months at most. Subse-quently, the patients were in remission with minimal (if any) complaints and without requiring other antipanic drugs. An additional 13% (paroxetine 12%) of patients reached the same target some weeks later (at month 6, latest).

A much shorter discontinuation period (7 weeks) was employed in two large placebo-controlled studies in PD pa-tients receiving clonazepam for 4 or 6 weeks. No major tol-erability issues emerged, and there was minimal clinical de-terioration without evidence of a significant rebound phe-nomenon [48, 83].

Patients with depression receiving clonazepam/fluoxetine cotherapy for 3 months experienced no major withdrawal AEs when clonazepam was tapered over 3 weeks [84]. Simi-larly, clonazepam tapering for 3 weeks was well tolerated in PD patients who had received clonazepam in combination with sertraline [69] or paroxetine [56] for 3 or 4 weeks.

We recommend reducing the dosage of clonazepam after intermediate or long-term use by 0.25 mg/week. These find-ings are in agreement with the opinion of Susman and Klee [41] who stated: “Judicious use of high-potency benzodi-azepines followed by a cautious taper and discontinuation may optimize the benefits and minimize any potential risk associated with this class of drugs”.

CONCLUSIONS

Clonazepam is a potent partial benzodiazepine agonist with a half-life of about 40 h. The compound also has some serotonergic activity and was originally developed for sev-eral forms of epilepsy in children and adults. Fontaine and Chouinard [7] anticipated that the pharmacodynamic and pharmacokinetic properties of clonazepam would make it suitable for the treatment of PD and reported the first posi-tive results. After a series of promising open studies of clonazepam in panic attacks, its efficacy in this indication was finally established in 8 placebo-controlled short-term studies comprising a total of 1187 patients. Clonazepam was superior to placebo in all studies and was well tolerated. On-set of the antipanic effect was rapid, often observed as early as during the first week of treatment. Discontinuation with slow dose reduction was uneventful. Panic attacks provoked by CO2 inhalation can be blocked with a single, acute clonazepam dose. The long elimination half-life renders clonazepam suitable for once-daily or twice-daily dosing without inter-dose anxiety symptoms.

362 Current Drug Targets, 2013, Vol. 14, No. 3 Nardi et al.

Because of the potential of benzodiazepines to induce

dependence, several organizations have proposed SSRIs as

the first choice for treating panic attacks, although long-term

results were missing. SSRIs have a slow onset of action

(several weeks). In several placebo-controlled studies, add-

ing clonazepam for the initial 4 to 8 weeks was shown to be

effective in bridging the time until the desired SSRI effect

was achieved.

Three studies including more than 300 patients investi-

gated the long-term use of clonazepam in PD. Clonazepam

was well tolerated and the initial early efficacy was main-

tained or increased over time without dose escalation. In one

of these studies, clonazepam was compared with paroxetine.

Earlier onset of antipanic effects and similar efficacy during

long-term treatment were seen, while there were fewer AE,

mainly less frequent sexual dysfunction, drowsiness/fatigue,

diarrhea/constipation, dry mouth, excessive sweating, shak-

ing/trembling/tremor, nausea/vomiting, memory/concen-

tration problems insomnia/nightmares, headache, and pares-

thesia. Slow down-titration after intermediate and long-term

treatment resulted in slight initial AEs but a panic-free state

was achieved in most patients without the need of further

pharmacological treatment. During long-term treatment or

drug discontinuation, no signs of drug abuse or drug depend-

ence were observed. This is in line with the observation that

recreational abuse appears to occur principally in persons

who also abuse other drugs or alcohol [85]. These patients

were excluded from studies.

More than 25 years after the first report of efficacy in PD

[7], clonazepam, alone or combined with SSRIs and/or be-

havioral therapy, has remained an important therapeutic mo-

dality for the management of PD. Because its safe and effec-

tive long-term use is now well documented and drug with-

drawal turned out to be at least no more difficult than with

SSRIs, the primary choice of medication should be guided

by the patient’s case history and preferences. Patients with

comorbid depression or a history of drug or alcohol abuse

should be guided towards SSRIs, eventually combined with

short-term clonazepam augmentation. Patients in need of an

early antipanic effect or those worrying about side effects,

such as worsening of anxiety in the initial treatment phase,

sexual disturbances, insomnia, agitation, and weight gain and

therefore at risk of non-compliance and early dropout can

safely and efficiently be treated with clonazepam, usually

with a once-daily dose (1-2 mg) to be taken at bedtime.

CONFLICT OF INTEREST

The authors confirm that this article content has no con-

flicts of interest.

ACKNOWLEDGEMENTS

A.E. Nardi, J.E. Hallak, and J.A. Crippa are recipients of

CNPq Productivity fellowship awards. R.C. Freire is recipi-

ent of a CAPES post-graduating fellowship. The authors

received editorial/writing support in the preparation of this

manuscript, which was funded by F. Hoffmann-La Roche

Ltd., Basel, Switzerland. The funding source had no role in

the review design and collection, analysis, and interpretation

of data, or in the decision to submit the paper for publication.

ABBREVIATIONS

AEs = Adverse events

APA = American Psychiatric Association

CNS = Central nervous system

CGI = Clinical Global Impression

CGI-S = Clinical global impression of severity

CO2 = Carbonic acid

DSM = Diagnostic and Statistical Manual of Mental

Disorders

FDA = Food and Drug Administration

GABA = -aminobutyric acid

HAM-A = Hamilton Anxiety rating

MCS = Mental Health Component Summary

MGH = Massachusetts General Hospital

PD = Panic Disorder

PSQ = Panic Self-Questionnaire

SSRIs = Selective serotonin reuptake inhibitors

UK = United Kingdom

USA = United States of America

7-AM = 7-acetamido clonazepam

7-ACT = N-acetylation and 7-amino clonazepam

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Received: April 19, 2012 Revised: December 10, 2012 Accepted: December 11, 2012

PMID: 23256724