BRIEF REPORT
Tapering Clonazepam in Patients With Panic Disorder
After at Least 3 Years of Treatment
Antonio E. Nardi, MD, PhD, Rafael C. Freire, MD, MSc, Alexandre M. Valen0 a, MD, PhD,
Roman Amrein, MD, Ana Claudia R. de Cerqueira, MD, MSc, Fabiana L. Lopes, MD, PhD,
Isabella Nascimento, MD, PhD, Marco A. Mezzasalma, MD, PhD, André B. Veras, MD, MSc,
Aline Sardinha, Psy, MSc, Marcele R. de Carvalho, Psy, MSc, Rafael T. da Costa, Psy, MSc,
Michelle N. Levitan, Psy, MSc, Valfrido L. de-Melo-Neto, MD, MSc, Gastão L. Soares-Filho, MD, MSc,
and Marcio Versiani, MD, PhD
Abstract: High-potency benzodiazepines, such as clonazepam, are
frequently used in the treatment of panic disorder (PD) because of their
rapid onset of action and good tolerability. However, there is concern
about their potential to cause withdrawal symptoms. We aimed to
develop a protocol for safely tapering off clonazepam in patients with
PD who had been receiving treatment for at least 3 years. A specific scale
for judging withdrawal was also developed, the Composite Benzodiaz-
epine Discontinuation Symptom Scale. We selected 73 patients with
PD who had been asymptomatic for at least 1 year and who wished to
discontinue the medication. The trial consisted of a 4-month period of
tapering and an 8-month follow-up period. The dosage of clonazepam
was decreased by 0.5 mg per 2-week period until 1 mg per day was
reached, followed by a decrease of 0.25 mg per week. The mean dosage
at the start of tapering was 2.7 T 1.2 mg/d. In total, 51 (68.9%) of the
patients were free of the medication after the 4 months of tapering
according to the protocol, and 19 (26.0%) of the patients needed another
3 months to be free of medication. Clonazepam discontinuation symp-
toms were mostly mild and included mainly: anxiety, shaking/trembling/
tremor, nausea/vomiting, insomnia/nightmares, excessive sweating,
tachycardia/palpitations, headache, weakness, and muscle aches. The
improvement in PD and general well-being was maintained during both
the taper and follow-up phases. Clonazepam can be successfully
discontinued without any major withdrawal symptoms if the dose is
reduced gradually. We recommend reducing the dosage of clonazepam
after intermediate-term use by 0.25 mg/wk.
Key Words: panic disorder, benzodiazepine treatment, long-term
treatment, discontinuation schedule
(J Clin Psychopharmacol 2010;30: 290Y293)
P anic disorder (PD) is an incapacitating condition with long-
term negative consequences. Lifetime prevalence is esti-
mated between 1.5% and 5%.1 High-potency benzodiazepines,
such as clonazepam, usually lead to immediate relief of anxiety
From the Laboratory of Panic and Respiration, Institute of Psychiatry, Federal
University of Rio de Janeiro, INCT Translational Medicine (CNPq), Rio de
Janeiro, Brazil.
Received October 20, 2009; accepted after revision March 8, 2010.
Reprints: Antonio E. Nardi, MD, PhD, Laboratory of Panic and Respiration,
Institute of Psychiatry, Federal University of Rio de Janeiro, INCT
Translational Medicine (CNPq), R. Visconde de Pirajá 407/702, Rio de
Janeiro, 22410-003 Brazil (e-mail: antonionardi@terra.com.br).
The grant for this trial was from the Brazilian Council for Scientific
and Technological Development (CNPq) and INCT Translational
Medicine (CNPq).
Copyright * 2010 by Lippincott Williams & Wilkins
ISSN: 0271-0749
DOI: 10.1097/JCP.0b013e3181dcb2f3
290 www.psychopharmacology.com Journal of Clinical Psychopharmacology
Copyright @ 2010 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
and panic attacks (PAs).2 However, the drawbacks of benzodi-
azepine therapy in PD are their potential for abuse or misuse
and physical dependence with long-term use, eventually re-
sulting in pronounced withdrawal and rebound symptoms when
treatment is discontinued. On the other hand, Moroz3 has shown
that discontinuation of clonazepam after intermediate-term use
is well tolerated if accomplished with a slow taper schedule.3
Compared with other benzodiazepines, clonazepam may allow
easier tapering and fewer withdrawal symptoms because of its
long half-life and higher potency.4
The present study describes the results of careful tapering
of clonazepam in patients with PD who had been receiving
clonazepam for at least 3 years. All patients were treated with
clonazepam at the Laboratory of Panic and Respiration in Rio
de Janeiro, Brazil. Most patients with PD seeking help at our
institute have a long history of PD, and nearly all of them suffer
from agoraphobia, which is moderate to severe in as many as
50% of cases. The main objectives of this study were to
investigate whether tapering off can be achieved without
major withdrawal symptoms and whether patients no longer
receiving clonazepam are asymptomatic for PD afterwards.
We also aim to develop a specific scale for the benzodiazepine
trials, the Composite Benzodiazepine Discontinuation Symptom
Scale (CBDSS).
METHODS
The scales most commonly used for judging the with-
drawal severity are the Benzodiazepine Withdrawal Symptom
Questionnaire,5 Clinical Institute Assessment of WithdrawalY
Benzodiazepines,6 Physician Withdrawal Checklist,7 Asthon
Withdrawal Symptoms Rating Scale,8 and Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition, Text
Revision (DSM-IV-TR) Symptom Checklist for Panic Disorder.
The 5 scales contain a total of 124 terms that we have con-
densed to the CBDSS. This was possible without loss of sig-
nificance because several items of the scales are identical or are
synonyms of an existing term of a higher ranking. Each symp-
tom was graded as follows: 0 = absent; 1 = mild; 2 = moderate;
and 3 = severe. None of the symptoms is specific for benzo-
diazepine withdrawal. Thus, we have summed up the severities
of all symptoms (CBDSS sum). A score sum of zero implies
that no symptom was present, whereas a sum of 150 would
indicate the most extreme state of withdrawal. The psychometric
properties of the CBDSS (reliability, concurrent validity, and
factorial study) will be addressed in future studies (Fig. 1).
At each visit, the investigators first queried for sponta-
neously reported adverse events (AEs) and afterwards for the
presence (and severity) of any symptom contained in the
CBDSS. The results of the CBDSS investigations summarized
& Volume 30, Number 3, June 2010
Journal of Clinical Psychopharmacology & Volume 30, Number 3, June 2010 Clonazepam Withdrawal After 3 Years

FIGURE 1. The Composite Benzodiazepine Discontinuation Symptom Scale (CBDSS). Encoding: 0 = absent; 1 = mild; 2 = moderate;
3 = severe.

the systematically queried AEs occurring within a period of
4 weeks. During the first month of drug tapering, the CBDSS
was applied twice, that is, at the end of the second and fourth
week. Symptoms occurring several times within a period were
recorded only once, using the highest degree of severity.
In total, 81 male and female patients (aged between 18 and
65 years) who met the DSM-IV criteria for PD, with or without
agoraphobia, as determined by the Structured Clinical Interview
for DSM-IV participated in the study. Patients who met the DSM-
IV criteria for other disorder were excluded. Patients with con-
current dysthymic or generalized anxiety disorders were allowed
to participate if PD was judged to be the principal diagnosis.
Patients invited to participate in this study had been free of PD
symptoms for at least 1 year and wished to discontinue clonaz-
epam therapy. Before entering the discontinuation study, patients
had participated in a specific 156-week treatment with clonaze-
pam,9 or they had received regular clonazepam monotherapy at
our clinic for 3 or more years.
This was a prospective, open study, planned to completely
taper off clonazepam within 4 months, followed by an 8-month
observation period. The clonazepam (manufactured by Roche,
São Paulo, Brazil) was bought with our research grant (CNPq)
and provided by our laboratory to the patients during this trial.
The patients were evaluated at the end of drug treatment
(baseline for withdrawal study) and afterwards during the
withdrawal period at the end of weeks 2 and 4 and then monthly
for a 1-year period. During the treatment period, tablets con-
taining 2 mg of clonazepam were used. For the discontinuation
protocol, this dose strength was supplemented with tablets
containing 0.5 and 0.25 mg. The patients were instructed to take
the tablets once daily after dinner.
The study protocol was approved by our local ethics com-
mittee. The trial was conducted in accordance with the princi-
ples of the Declaration of Helsinki and its amendments. Before
any trial-specific procedures were performed, written informed
consent was obtained from each patient after explanation of the

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Nardi et al Journal of Clinical Psychopharmacology
aims, methods, benefits, and potential hazards of the trial. The
patients were free to withdraw from the study at any time and
without giving any reasons.
A physical examination, a 12-lead electrocardiogram, and
laboratory tests were performed on the first day of tapering
the drug and at the end of the withdrawal period or at study
discontinuation. Throughout the study, participants kept a daily
diary to record symptoms of PD and anticipatory anxiety, in-
cluding frequency of any PAs and duration of anticipatory anx-
iety, as well as any withdrawal symptoms.
All observed or spontaneously reported AEs were recorded,
detailing onset, duration, severity, relationship with the drug in
the investigator’s judgment, action taken, and outcome. Multiple
episodes of the same complaint were counted only once per
period, although rated at the greatest level of severity.
At each visit, the investigators rated the occurrence of with-
drawal symptoms (CBDSS), Clinical Global ImpressionYseverity
(CGI-S),10 CGI-improvement from baseline [at the end of the
treatment period],10 14 items of the Hamilton Anxiety Scale
(HAMA14),11 and frequency of PAs.
The success of the withdrawal procedure for each patient
was classified as follows: (1) Complete success: Dose reduction
as planned; few (if any) withdrawal complaints during the
tapering period; no recurrence of PAs; and drug-free at the end
of the follow-up period. (2) Delayed complete success: Dose
reduction slower than planned due to disturbing; no recurrence
of PAs after stopping clonazepam treatment; and drug-free at
the end of the observation period. (3) Partial success: Clo-
nazepam dose reduced down to 0.5 mg/d; in some instances,
additional treatment with mirtazapine at 30 mg/d; at the end
of the observation period, clonazepam dosage of 0.5 mg or
mirtazapine at 30 mg/d; and number of PAs maximally 1 per
month. (4) Failure: No essential reduction of daily clonazepam
dose achieved.
The dosage of clonazepam was decreased by increments
of 0.5 mg in 2-week intervals until reaching 1 mg/d. Subse-
quently, dose reduction was by 0.25 mg per week. If the patient
did not tolerate the tapering because of anxiety or withdrawal
symptoms, he/she was examined by 2 physicians and a study
nurse to determine the further procedure. The options were (1)
to slow down the tapering by increasing the intervals of dose
reduction; (2) to add another medication, such as mirtazapine
or carbamazepine; (3) to withdraw the patient from the discon-
tinuation protocol and to maintain clonazepam treatment.
During the year after the initiation of drug tapering, the patients
were observed in monthly intervals and were treated on a nat-
uralistic basis if necessary.
Patients who took at least one dose of clonazepam during
the withdrawal period and completed any additional assess-
ment were included in the analysis for safety and efficacy (in-
tention to treat analysis). Descriptive statistics including counts,
means, and SDs were used to summarize or describe the results.
RESULTS
Of the 81 patients with PD giving written informed consent
to participate, 73 patients (49 women, 24 men) entered the
discontinuation study. All patients suffered from some degree of
agoraphobia (mild: 33, moderate: 24, severe: 16). Our sample
was composed of 24 (32.9%) male and 49 (67.1%) female with
mean T SD age of 48.6 T 18.1 years. The psychiatric comor-
bidity was 15 (20.5%) patients with generalized anxiety disor-
der and 12 (16.4%) patients with dysthymia. The mean T SD
onset of PD was 18.8 T 9.4 years. In our sample, 26 (35.6%)
had a previous depressive episode. Before starting the clonaz-
epam discontinuation study, the patients had been free of PAs
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& Volume 30, Number 3, June 2010
for at least 1 year and received a daily clonazepam dosage of
2.7 T 1.2 mg on average. The withdrawal outcomes after 6 months
starting discontinuation of clonazepam were 51 (70.0%) patients
had a complete success; 14 (19.0%) had a delayed complete
success; 8 (11.0%) had a partial success; and we had no failure.
Most patients (70%) succeeded in discontinuing clonazepam
within the foreseen period of 4 months and without recurrences
of PAs. As many as 89% of patients completely stopped intake
of any PA medication and were free of PAs within 6 months at
most. After 6 months, 8 patients still received 0.5 mg of clonaz-
epam per day. All were switched to mirtazapine, but 3 patients
asked to return to 0.5 mg/d of clonazepam because of recurrence
of anxiety symptoms.
The patients were then observed at regular monthly inter-
vals for a further 6 or 8 months and were treated naturalistically
if necessary. At this time, 80% of patients were free of PAs, 15%
had sporadic attacks (G1/month), and 5% had one PA/month. A
total of 68.5% of patients were free of PAs in the absence of any
treatment. Treatments taken by some of the patients were as
follows: 10 patients had a prescription for diazepam at 10 mg to
be taken as needed, and 5 patients took mirtazapine at 30 mg/d
because major depression (DSM-IV-TR) was diagnosed. The 3
patients returning to clonazepam at 0.5 mg/d after 6 months
were still taking the medication at the same dosage.
This positive outcome was achieved with little change in
the general well-being of the patients, as shown by CGI-change,
CGI-S, and HAMA. The CGI-S showed a slight, transient wors-
ening at the fourth week of the discontinuation study. The HAMA
was unchanged during clonazepam tapering and was slightly im-
proved at the end of the follow-up period (Table 1).
No severe or serious AEs occurred during the period of clo-
nazepam tapering. More than 95% of all reported symptoms
were mild. The mean CBDSS sum reached its maximum within
the first month of clonazepam tapering but was remarkably low
during the entire tapering period. Approximately 70% of patients
reported at least one CBDSS symptom during each month of
the discontinuation study; however, 38% of patients already had
one CBDSS symptom before starting the tapering protocol.
Sixteen of the 50 CBDSS symptoms were recorded for more than
10% of patients during the clonazepam discontinuation period,
whereby anxiety/irritability was by far the most frequent com-
plaint. The symptoms of CBDSS present in more than 10% of
patients with PD, n (%), during clonazepam discontinuation
were anxiety/irritability 42 (57.5); nausea/vomiting 32 (43.8);
insomnia/nightmares 29 (39.7); excessive sweating 27 (37.0);
tachycardia/palpitations 23 (31.5); headache 18 (24.7); weakness
18 (24.7); shaking/trembling tremor 13 (17.8); muscle aches/
stiffness 11 (15.1); overbreathing 10 (13.7); PAs 10 (13.7);
memory/concentration 9 (12.3); muscle fasciculation 9 (12.3);
TABLE 1. The CGI-Change and HAMA Scores During
Clonazepam Discontinuation
CGI-Change* CGI-Severity HAMA
N = 73 Mean SD Mean SD Mean SD
End of treatment 1.22 0.42 11 2.6
Withdrawal week 4 4.3 0.66 1.52† 0.63 11.5 2.9
Withdrawal week 16 4.1 0.73 1.42 0.71 11.2 3.1
Withdrawal week 52 4.1 0.62 1.27 0.45 10.3† 2.6
*Compared with end of treatment.
†
Significant change compared with end of treatment (P G 0.05
Bonferroni corrected).
* 2010 Lippincott Williams & Wilkins
Journal of Clinical Psychopharmacology & Volume 30, Number 3, June 2010
agoraphobia/phobias 8 (11.0); depersonalization 8 (11.0); and
depressive mood 8 (11.0). The following symptoms were reported
by less than 10% of patients: appetite/weight change (6.8%),
restlessness/agitation (6.8%), ataxia (5.5%), hypersensitivity
(5.5%), lethargy (5.5%), blurred/double vision (4.1%), dizziness/
light headiness (4.1%), dry mouth (4.1%), tinnitus (4.1%), dere-
alisation (2.7%), pain (2.7%), paresthesia (2.7%), perceptual
distortions (2.7%), stuffy noise/sinusitis (2.7%), and influenza-like
symptoms (1.4%). The following symptoms were never observed:
confusion, convulsions, craving, diarrhea/constipation, difficulty
in swallowing, frequency/pain on micturation/polyuria, halluci-
nations, incontinence, menorrhagia, metallic taste, obsessive
thoughts, orthostatic hypotension, paranoid thoughts, poor coor-
dination, skin rash/itching, sore eyes, speech difficulty, and thirst.
Symptoms were rated as mild in 84% and as moderate in
16% of events. None of the symptoms was severe. Anxiety
was recorded for 57.5% of patients during the tapering period,
but this was not associated with any increase in HAMA. Most
symptoms recorded at the systematic CBDSS inquiries dur-
ing the 4-month withdrawal period had already been reported
spontaneously at similar frequencies before initiation of clo-
nazepam treatment. All patients suffered before the start of
the drug treatment from at least one symptom contained in the
CBDSS (mean T SD, 3.1 T 0.9): in percentage, anxiety (79.5);
insomnia/nightmares (47.9); headache (19.2), excessive sweat-
ing (15.1); hypochondria (13.7), memory/concentration (13.7),
nausea/vomiting (13.7), appetite/weight change (12.3), dizziness
(12.3), tachycardia/palpitations (12.3), and weakness (12.3).
No laboratory abnormalities were observed at the end of
the trial, and no clinically significant electrocardiogram abnor-
malities were noted.
DISCUSSION
This is the first study investigating the phasing out of
clonazepam after treatment lasting at least 3 years. As proposed
by Ballenger,12 we decided to slow down the tapering (0.5 mg
every second week) and to protract the clonazepam discontin-
uation period in case patients did not tolerate the foreseen
procedure. The primary goal, that is, to phase out clonazepam
completely within 16 weeks at most without any PAs emerging,
was achieved in 70% of patients. For 19% of patients, more time
was needed to discontinue clonazepam therapy. These patients
received mirtazapine before they became asymptomatic in the
absence of any medication.13,14 Three patients continued to take
clonazepam, albeit at a much reduced dosage (0.5 mg/d), mainly
because they still had infrequent PAs. A further 8 patients
received mirtazapine (30 mg/d) for the same reason.14 During
the follow-up period (typically 8 months), the clinical situation
was essentially unchanged: No patient had to go back to the
original treatment, 82.2% of patients remained free of PAs, and
all others had one PA/month at most. A total of 10 (13.6%)
patients experiencing PAs during the follow-up period received
a prescription for diazepam (10 mg as needed) to be taken on
demand. Based on our data, we recommend reducing the dosage
of clonazepam after intermediate-term use by 0.125 mg twice a
day every 3 days (0.5 mg/wk).
Several factors may have contributed to this very positive
result: Clonazepam has a relatively long elimination half-life
(39.0 T 8.3 h).15 It was suggested that withdrawal symptoms are
less frequent with clonazepam than with other benzodiazepines
with short to intermediate elimination half-lives.15 Moreover, the
slow and protracted tapering protocol and the fact that patients
were asymptomatic for at least 1 year before the study started
and wished to discontinue clonazepam treatment may also have
helped to minimize treatment discontinuation symptoms.
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Clonazepam Withdrawal After 3 Years
Rebound symptoms, defined as a the transient return of
severe and even more intense symptoms for which the ben-
zodiazepine was prescribed, were not observed in this study.
Withdrawal syndrome, defined as the development of new signs
and symptoms in response to drug discontinuation that were
not part of the disorder for which the drug was originally
prescribed, did not occur. In exceptional cases, PAs did break
through but were managed by further slowing down the clo-
nazepam discontinuation scheme or by providing mirtazapine
(30 mg/d) for a limited period of time.
In the present study, the slow tapering of clonazepam, after
treatment for at least 3 years, was investigated. Discontinuation
was well tolerated without relapse, rebound, or withdrawal
syndrome. At the end of the follow-up period (1 year after start
of clonazepam discontinuation), most of the patients were free
of PAs.
AUTHOR DISCLOSURE INFORMATION
The authors have no conflicts of interest related to the topic
of this trial.
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