Department of Psychiatry, University of Ottawa, Ottawa, Ontario, Canada
Lääkärikeskus Mehiläinen, Helsinki, Finland
University of Stellenbosch, CapeTown, South Africa
Wyeth Research, Paris, France
Wyeth Research, Collegeville, Pennsylvania, USA
Correspondence: Dr Jacques Bradwejn, University of Ottawa Institute of Mental Health Research, Royal Ottawa Hospital, 1145 Carling Avenue, Ottawa, Ontario, Canada K1Z 7K4. Tel: +1-613-7226521, extension 6546; fax: +1-613-7982973; e-mail: jbradwej{at}rohcg.on.ca
Declaration of interest J.B. received funding for a clinical trial from Pfizer, and for consultation from GlaxoSmithKline, Wyeth Research and Servier. D.J.S. received research grants and/or consultancy honoraria from AstraZeneva, Eli-Lilly, GlaxoSmithKline, Lundbeck, Orion, Pfizer, Pharmacia, Roche, Solvay and Wyeth. E.S., G.E. and T.W. are employees of Wyeth.
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ABSTRACT |
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Aims To evaluate the efficacy, safety and tolerability of venlafaxine ER in treating panic disorder.
Method Adult out-patients (n=361) with panic disorder were randomly assigned to receive venlafaxine ER (75225 mg/day) or placebo for up to 10 weeks in a double-blind study.
Results Venlafaxine ER was not associated with a greater proportion of patients free from full-symptom panic attacks at the final on-therapy evaluation, but was associated with lower mean panic attack frequency and a higher proportion free from limited-symptom panic attacks, higher response and remission rates, and improvements in anticipatory anxiety, fear and avoidance. Adverse events were comparable with those of the drug in depression and anxiety disorders.
Conclusions Venlafaxine ER seems to be effective and well tolerated in the short-term treatment of panic disorder.
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INTRODUCTION |
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METHOD |
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Sample selection
Eligible out-patients were men and women at least 18 years of age who met
DSMIV criteria for panic disorder for at least 6 months before study
day 1. Confirmation of the primary diagnosis of panic disorder and exclusion
of other psychiatric diagnoses such as major depressive disorder and
generalised anxiety disorder was made using the DSMIV and the modified
Mini-International Neuropsychiatric Interview
(Sheehan et al,
1998). Participants were required to have a Clinical Global
Impression Severity (CGIS)
(Guy, 1976) score 4, a
minimum of four or more full-symptom panic attacks during the 4 weeks before
the screening visit, and at least two full-symptom panic attacks during the
14±3-day placebo lead-in period between the screening visit and
baseline (study day 1) to be eligible for the study. For the Panic and
Anticipatory Anxiety Scale (PAAS; Sheehan,
1983), participants were given diary cards to record daily details
regarding their panic attack frequency (including symptoms, situational or
unexpected) and anticipatory anxiety, and the investigator then completed the
scale after interview to verify the information in the diary.
Individuals were excluded if they met diagnostic criteria for any
clinically important Axis I or Axis II disorder, current or predominant,
within 6 months of study day 1, or if they had a history of alcohol dependence
or misuse (as defined in DSMIV) within 1 year of study day 1. Those
with a 17-item Hamilton Rating Scale for Depression (HRSD17;
Hamilton, 1960) total score
15, an HRSD17 item 1 (depressed mood) score >2, a Covi
Anxiety Scale (Lipman, 1982)
total score less than or equal to their Raskin Depression Scale
(Lipman, 1982) total score, or
a Raskin Depression Scale total score >9 or single-item score >3 at
screening were also excluded.
Individuals were excluded if they had received treatment with venlafaxine IR or ER within 6 months of study day 1, if they had taken investigational drugs, antipsychotics or fluoxetine, or had regularly used benzodiazepines or triptans within 30 days of study day 1; had taken other antidepressants, monoamine oxidase inhibitors, non-benzodiazepine anxiolytics, or other psychopharmacological drugs (including lithium, stimulants, or sedative-hypnotics or herbal products intended to treat anxiety or depression) within 14 days of study day 1; had undergone investigational procedures within 30 days of study day 1 or electroconvulsive therapy within 60 days; had taken non-psychopharmacological drugs with psychotropic effects unless they had been maintained at a stable dose for at least 3 months before study day 1 and the patient was expected to continue taking the drug without dose changes throughout the study; or had initiated or changed the intensity of formal psychotherapy or cognitivebehavioural therapy within 30 days of study day 1.
Other reasons for exclusion were the presence of clinically significant abnormal findings on laboratory tests, electrocardiogram (ECG), vital signs or physical examination; a history or presence of clinically important medical conditions; and, in women of childbearing potential, pregnancy, lactation or not using a medically acceptable form of contraception. A positive test result for any drug of misuse at the screening visit required either immediate exclusion or discussion with the medical monitor as to whether a negative result of a retest was acceptable for inclusion in the study. All concomitant treatments prohibited before study day 1 were also prohibited during the study.
Drug administration
After a 14±3-day single-blind, placebo lead-in period, participants
were randomly assigned to receive double-blind venlafaxine ER or placebo for
up to 10 weeks, followed by a taper period of up to 14 days (which could be
omitted or prolonged if clinically indicated). Participants returned for a
post-study evaluation 410 days after taking the last dose of study
medication. A 37.5 mg dose was used for the first 4 days of treatment and then
increased to 75 mg. If clinically indicated, the dose could be increased to
150 mg venlafaxine ER (or two placebo capsules) after day 14 and to a maximum
of 225 mg venlafaxine ER (or three placebo capsules) after day 21. Dosage
decreases were permitted at any time during the study to improve tolerance at
the discretion of the investigator, but after study day 7, the minimum daily
dose allowed was one capsule in the morning (75 mg venlafaxine ER or placebo).
Those unable to tolerate 75 mg venlafaxine ER were withdrawn from the
study.
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The primary outcome measure was the percentage of participants who were
free from full-symptom panic attacks (4 symptoms) at the on-therapy
evaluation. The post-baseline full-symptom panic attack frequency from the
PAAS was evaluated in 2-week (14-day) periods, and for the PAAS, the
on-therapy evaluation included the last 14 days of data collected during the
on-therapy period.
Secondary outcome measures comprised the change from baseline in fullsymptom panic attack frequency (based on the PAAS), response and remission. Response to treatment was defined as a CGII score of 1 (very much improved) or 2 (much improved). Remission was defined using the CGII and CGIS. Patients were considered to be in remission at a given evaluation evaluation using the CGII if they had zero full-symptom panic attacks on the PAAS and a CGII score of 1 (very much improved) at any 2-week evaluation and at the on-therapy evaluation. Using the CGIS, patients were considered to be in remission at a given evaluation if they had zero full-symptom panic attacks on the PAAS and a CGIS score of 1 or 2 (1=normal, not at all ill; 2=borderline mentally ill) at any 2-week evaluation and at the on-therapy evaluation. Other secondary efficacy measures analysed at each 2-week time point or at the time of discontinuation included anticipatory anxiety and limited-symptom panic attacks (both measures from the PAAS), the CGIS and CGII, the Phobia Scale fear and avoidance factors, and the Covi Anxiety Scale.
At baseline and on study day 70, participants were evaluated on the Quality of Life Enjoyment and Satisfaction Questionnaire (QLESQ; Endicott et al, 1993), the Sheehan Disability Scale (Sheehan, 1983) and an exploratory resource utilisation in panic disorder (RUPD) assessment comprising a series of single-item responses measuring unscheduled use of various healthcare services.
Safety and tolerability assessments
All treatment-emergent adverse events were reported,
including those not considered to be drug related and those that occurred
during the taper/post-study period. Safety assessments were based on reports
of adverse events and results of routine physical examinations, measurements
of vital signs, laboratory determinations, and ECG. Vital signs (supine and
standing blood pressure and supine pulse) were evaluated at screening and
baseline, at each visit during the double-blind period, and at the post-study
visit. Weight was evaluated at baseline (study day 1) and on study day
70. Electrocardiogram recordings were obtained at screening and on study day
70. Laboratory investigations were performed at screening and on study day 70,
and included haematology, blood chemistry, free thyroxine index (screening
visit only), urine drug screen, urinalysis and a serum beta-human chorionic
gonadotropin pregnancy test for women of childbearing potential (at the
screening visit and any time that pregnancy was suspected).
If a participant left the study before the end of the double-blind period (study day 70±3 days), all of the above assessments were performed on the last day on which the individual took the full dose of study medication (before taper) or as soon as possible thereafter. The post-study evaluations were performed 410 days after the participant took the last dose of double-blind or taper study medication.
Statistical analyses
Statistical analyses of efficacy measures were performed on the
intent-to-treat (ITT) population using last-observation-carried-forward (LOCF)
and final on-therapy values. The ITT population included participants who had
a baseline PAAS evaluation, took at least one dose of study medication and had
at least 7 days of PAAS data during the double-blind period, and had at least
one on-therapy double-blind evaluation for the primary efficacy variable
during visits on days 770 or within 3 days of stopping the study
medication, before taper. The safety population consisted of those who
completed the pre-study period and took at least one dose of randomly assigned
study medication under double-blind conditions.
The percentage of those free from PAAS full-symptom panic attacks was analysed using logistic regression with treatment group and site as factors (sites with five or fewer patients were combined). The median change in panic attack frequency and anticipatory anxiety data from the PAAS were analysed with the MannWhitney U-test (Wilcoxon rank sum test). The remission and CGII responder data were analysed by the Fisher exact test. The Phobia Scale, CoviRaskin, HRSD, CGII and CGIS data were analysed by analysis of covariance (ANCOVA) with treatment and site as the factors and the baseline scores as covariates.
The sample size computation was based on estimates from the literature: the percentage of those free from panic attacks was expected to be roughly 50% in the venlafaxine-treated group compared with 30% in the placebo-treated group. It was also estimated that 140 ITT participants per treatment arm would be needed to provide a 90% power for a two-sided test at the 0.05 significance level. To compensate for about 15% of participants expected not to qualify for the ITT criteria, the planned enrolment was 165 per treatment group.
Improvement on each domain of the Sheehan Disability Scale was defined as
reduction from baseline and analysed using ANCOVA with treatment as the main
effect and centre and baseline score as covariates. The QLESQ
was evaluated as improvement (increase) from baseline on each domain using
ANCOVA with treatment as the main effect and the baseline score and centre as
covariates. The RUPD data were analysed using a 2-test with
treatment group as the exposure variable and any use of a specific type of
healthcare service versus no use of that healthcare service as the dichotomous
outcome variable.
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RESULTS |
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Efficacy
At the final on-therapy evaluation, the primary end point, 55.0% of
venlafaxine ER- and 52.4% of placebo-treated participants were free from
full-symptom panic attacks, a statistically non-significant difference
(Fig. 2). The median reduction
from baseline in full-symptom panic frequency was significantly greater for
the venlafaxine ER group (Fig.
3). A significantly higher proportion of the venlafaxine ER group
responded to treatment (CGII score of 1 or 2), beginning at week 3
(Fig. 4) and experienced
CGII remission, beginning at week 6
(Fig. 5). Improvement in fear
and avoidance factors of the Phobia Scale was significantly greater for the
venlafaxine ER group than for the placebo group, beginning at week 6 and
continuing through the remainder of the study, with the exception of week 8
for the avoidance factor (Fig.
6). Venlafaxine ER was associated with significantly greater
improvement than placebo in observed scores for the work and
social life/leisure activities domains of the Sheehan Disability
Scale, but not family life and home responsibilities
(Fig. 7). A significantly
greater proportion of venlafaxine ER-treated participants were free from
limited-symptom panic attacks at the final on-therapy evaluation compared with
those who received placebo, and the venlafaxine ER group showed significantly
greater improvement in adjusted mean CGIS scores, CGII total
scores and Covi Anxiety Scale scores, median time spent experiencing
anticipatory anxiety, and QLESQ overall life
satisfaction (Table
2).
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Significant differences in favour of venlafaxine on the QLESQ were also demonstrated in subjective feelings of well-being (0.63 v 0.36, respectively; P<0.001), general activities (0.58 v. 0.36, respectively; P=0.002), satisfaction with medication (0.85v. 0.45, respectively; P=0.001), physical health/activities (0.65 v. 0.45, respectively; P=0.021), work (0.39 v. 0.18, respectively; P=0.041), and social relations (0.46 v. 0.31; P=0.026). No significant differences were observed between the venlafaxine ER group and the placebo group for the remaining three domains (household duties, school/coursework and leisure time activities). No significant between-group differences in healthcare utilisation were observed.
Safety and tolerability
Overall, treatment-emergent adverse events were reported by 138 (78%) of
the placebo-treated group and 152 (86%) of the venlafaxine ER-treated group
(Table 3). Eleven individuals
had events that precipitated withdrawal from the trial: 5 in the placebo group
(1 each with unintended pregnancy, infection, vascular purpura, myocardial
infarction and anxiety) and 6 in the venlafaxine ER group (1 each with
accidental overdose, unintended pregnancy, deep thrombophlebitis, colitis,
panic attack and metrorrhagia). The treatment-emergent adverse events that
most frequently caused discontinuation of treatment in the venlafaxine ER
group (reported by 2%) were anorexia, nausea, insomnia and sweating.
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Venlafaxine ER treatment was associated with few clinically important changes in laboratory tests, vital sign results or ECG assessments. Mean changes in laboratory values at final on-therapy evaluation included significant increases from baseline in total cholesterol (0.18 mmol/l, P<0.01) and low-density lipoprotein (LDL) cholesterol (0.12 mmol/l, P<0.05) in the venlafaxine ER group, and nonsignificant decreases in the placebo group (0.05 mmol/l and 0.07 mmol/l, respectively). Between-group comparisons were significant for both variables (total cholesterol, P=0.032; LDL, P=0.017).
Two participants, both in the venlafaxine ER group, experienced clinically important changes in vital signs (one with tachycardia and one with increased blood pressure). The venlafaxine ER and placebo groups differed significantly in mean changes from baseline in supine pulse rate (2.18 beats/min v. 0.12 beats/min, respectively; P=0.007) and weight (0.72 kg v. 0.21 kg, respectively; P=0.002).
Individual clinically important ECG results were observed for four
participants, all in the placebo group. No participant had a QTc interval
greater than 500 ms. Mean changes from baseline in ECG variables at the final
on-therapy evaluation included, for the venlafaxine ER group, a decrease in PR
interval (4.58 ms, P0.01) and increases in QTc interval
(4.02 ms, P=NS) and ECG-measured heart rate (3.38 beats/min,
P<0.001), and for the placebo group, a non-significant increase in
PR interval (1.72 ms) and non-significant decreases in QTc interval (-4.32 ms)
and ECG- measured heart rate (-1.45 beats/min). Between-group comparisons were
significant for all three variables (PR interval, P=0.01; QTc
interval, P= 0.035; ECG-measured heart rate, P<0.001).
None of the participants had any clinically important findings on physical
examination, and no other statistically significant changes from baseline or
differences between groups were deemed clinically important by the medical
monitor.
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DISCUSSION |
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Methodological issues
Assessment of panic attack frequency, and in particular panic-free status,
in clinical trials is difficult and correlates poorly with global measures of
efficacy (Bandelow et al,
1995), as was the case here in the medication group (55%
panic-free v. 68% responders). Panic attacks are known to be sporadic
and highly variable in frequency and it is not uncommon for there to be a
period of several weeks when no panic attacks occur
(Shear et al, 1998).
In fact, up to 50% of those receiving placebo in short-term clinical studies
are panic-free at end point
(den Boer, 1998), which is
similar to the proportion in this study (i.e. 52%). A meta-analysis by Otto
et al (2001) found
that more recently reported trials of selective serotonin reuptake inhibitors
in panic disorder that included larger sample sizes were associated with
smaller panic frequency effect sizes compared with earlier trials with small
sample sizes. If both published and unpublished studies were available, it is
likely that even higher panic-free rates for placebo-treated individuals would
be observed (Otto et al,
2001). Thus, failure to detect differences between active
treatment and placebo groups in panic-free status is not uncommon, even with
agents that are known to be highly effective in the treatment of panic
disorder.
Multidimensional assessment
Multidimensional assessment of therapeutic interventions for panic disorder
is therefore considered appropriate
(Ballenger et al,
1998). In addition to panic attack frequency, four key domains
have been identified as relevant for the assessment and treatment of panic
disorder: anticipatory anxiety; panic-related phobias; well-being and overall
severity of illness; and effect on work, social life, the family and quality
of life (Ballenger et al,
1998). Global measures by clinicians are also clinically important
in assessing how the individual has responded to treatment over time
(Pollack et al,
2002). Our study showed that the venlafaxine ER group had
significant response (CGII of 1, very much improved, or 2, much
improved) and remission (panic-free and CGII of 1) rates based on
global measures of improvement compared with placebo, and significantly
greater improvement in global severity and in symptoms of anticipatory anxiety
and fear/avoidance. Finally, improvement in a majority of domains representing
quality of life and functionality was observed.
Tolerability and safety
The increases in total plasma cholesterol and LDL levels observed in the
venlafaxine ER group relative to the placebo group in this report are
consistent with studies of healthy volunteers that show an increase in LDL
after treatment with the selective serotonin reuptake inhibitor paroxetine
(Lara et al, 2003)
and an increase in total plasma cholesterol with mirtazapine, an agent that
has both serotonergic and noradrenergic properties
(Lara et al, 2003;
Nicholas et al,
2003). Other studies have reported increased total plasma
cholesterol levels in individuals with anxiety disorders
(Peter et al, 2002).
The metabolic basis of such results and their clinical significance merits
further investigation. Heart rate and QT interval variability in those with
panic disorder relative to controls has been attributed to abnormal
2-adrenergic function
(Yeragani et al,
2003). Further investigation of the differences in heart rate and
QTc interval changes from baseline between treatment and placebo groups, as in
the present study, is desirable.
Summary
Venlafaxine ER was generally safe and well tolerated in this study. The
type and frequency of adverse events and discontinuation rate attributable to
adverse events in the venlafaxine ER group was similar to that seen in
individuals with depression, generalised anxiety disorder and social anxiety
disorder, indicating no additional risk of adverse events in those with panic
disorder. Together with its superior efficacy relative to placebo across most
outcome measures, the favourable safety and tolerability profile of
venlafaxine ER suggests that it is a viable treatment option for panic
disorder.
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Clinical Implications and Limitations |
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LIMITATIONS
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Received for publication May 6, 2004. Revision received December 13, 2004. Accepted for publication December 21, 2004.
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