Neurotec/Psychiatry, Huddinge University Hospital, Huddinge, Sweden
Wyeth-Ayerst Research, CNS Department, Puteaux, Paris, France
Correspondence: Dr C. Allgulander, Neurotec/Psychiatry, M57 Huddinge University Hospital, S-14186 Huddinge, Sweden
Declaration of interest This study was funded by Wyeth-Ayerst Research, of which D.H. and E.S. are employees. C. A. is an employee of the Karolinska Institutet, Stockholm, and was an investigator for one study centre.
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ABSTRACT |
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Aims To assess the efficacy and safety of venlafaxine extended release (ER) in patients with GAD.
Method A total of 541 out-patients, 18-86 years old, were recruited to this 24-week, placebo-controlled, double-blind study of three fixed doses (37.5, 75 and 150 mg/day) of venlafaxine ER.
Results All doses of venlafaxine ER showed efficacy superior to placebo, apparent from week 2, that was sustained throughout the 24-week study for the two higher doses. The discontinuation rate did not differ significantly among the treatment groups.
Conclusions Venlafaxine ER is an effective and safe treatment for GAD for up to 6 months.
Clinical characteristics
The American Psychiatric Association in 1980 first defined generalised
anxiety disorder (GAD) as a condition characterised by worry combined with
somatised anxiety. Subsequent revisions of the DSM nosology have focused on a
chronic state of worry combined with muscular tension, cognitive dysfunction
and poor sleep. Large-scale epidemiological studies indicate a lifetime
prevalence of 5-6% (Wittchen et
al, 1994). It is often comorbid with other disorders,
particularly major depression, panic disorder, phobic states and substance
misuse (Merikangas et al,
1996; Judd et al,
1998). It is associated with psychosocial impairment, increased
morbidity and mortality and therefore constitutes a public health problem
(Kessler & Wittchen,
2001).
Current treatments
Although the benzodiazepines are used as anxiolytics in many conditions,
they have not been indicated specifically for GAD. In the 1980s, buspirone was
introduced for treating GAD-related symptoms
(Goa & Ward, 1986).
Supportive therapy, muscle relaxation and cognitivebehavioural
techniques have some evidence of effectiveness for up to 6 months
(Fisher & Durham,
1999).
Study rationale
The efficacy in panic anxiety of clomipramine, enhancing both serotonergic
and noradrenergic transmission, and the efficacy of imipramine and trazodone
in GAD called for a study of venlafaxine in patients with anxiety disorder
(Modigh et al, 1992;
Rickels et al, 1993). This study was designed to compare the short- and long-term efficacy and
safety of three fixed doses of the serotonergic and noradrenergic reuptake
inhibitor (SNRI) venlafaxine extended release (ER) with placebo in
out-patients with GAD.
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METHOD |
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Patients were excluded from the study if they had had a major depressive disorder in the previous 6 months or exhibited clinically significant depressive symptomatology. In addition, they were excluded if they had any clinically important medical disease or abnormality on physical examination as well as other psychiatric disorders, excessive consumption of caffeine-containing food and drink and use of pharmacological or non-pharmacological drugs with psychotropic effects as checked with a drug screen. Maintenance medications that were not psychopharmacological but had psychotropic effects, such as beta-blockers for hypertension, were permitted.
Study design
After a 4-10-day single-blind placebo washout period, the study consisted
of a 24-week double-blind treatment period followed by a 1-week single-blind
placebo discontinuation period. The patients were assigned randomly to receive
one of the three non-titrated fixed doses of venlafaxine ER (37.5, 75 or 150
mg) or placebo once daily in the morning for up to 24 weeks. A randomisation
schedule in blocks of four was generated for packaging and labelling by the
Biostatistics Section of Wyeth-Ayerst Research. The 75-mg and 150-mg dosages
of venlafaxine ER were chosen on the basis of the usual dosage recommendations
for the treatment of depression. The lower dose of 37.5 mg of venlafaxine ER
was included to evaluate the dose-response relationship and the minimal
effective dose in anxiety.
Assessments
The following rating scales were completed at baseline and at each visit
(weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 and 25): the HRSA; the Hospital
Anxiety and Depression (HAD; Zigmond &
Snaith, 1983) scale (a 14-item self-administered measure); the
Brief Scale for Anxiety (BSA; Tyrer et
al, 1984); and the Clinical Global Impression of Improvement
(CGI-I; Guy, 1976). Changes in
social functioning were assessed using the Self-Rated Social Adjustment Scale
(SAS-SR; Weissman & Bothwell,
1976) at baseline and at weeks 8 and 24. Tolerability was assessed
by spontaneous replies to an open question at each visit. Safety was assessed
by means of a physical examination at screening, by monitoring weight, blood
chemistry and blood pressure and by assessments of the resting
electrocardiogram (ECG). The Physician Withdrawal Checklist (PWC;
Rickels et al, 1990)
was administered at screening, baseline and weeks 24 and 25. An assessment of
compliance was made by counts of returned medication at each visit.
Data management and statistics
The statistical analyses were based on the pooled data from all study
sites. Data from centres with small sample sizes were combined with other
centres before the study blind was broken, reducing it to 14 centre groups:
seven in the UK, three in France, two in Sweden and one each in Belgium and
Finland. The main efficacy analyses considered the intention-to-treat
population, which included all patients who had received at least one dose of
study medication and who had a baseline and at least one on-therapy efficacy
assessment.
Outcome variables
The end of week 8 was considered the primary time point for short-term
treatment and the end of week 24 for long-term treatment, but data for
assessments at other weeks are also described. The primary outcome variables
for the assessment of efficacy were defined a priori as the HRSA
total, the HRSA psychic anxiety factor, the HAD anxiety sub-scale and the
CGI-I rating. The comparisons of principal interest were between each dose of
venlafaxine ER and placebo for these variables. All other comparisons and all
other variables were considered secondary. Data were analysed using both the
last observation carried forward (LOCF) method and the observed data at each
time point. Response to treatment was defined as a decrease of
at least 50% in the HRSA total score from baseline or a CGI-I score of 1 or 2
(much or very much improved).
Statistical analyses
For the primary variables of interest, a Bonferroni correction for multiple
testing was made. Differences were considered significant for primary pairwise
comparisons when P values were 0.05 for the global
F-test and
0.017 for the pairwise comparison. All other
comparisons were considered significant if the P value of a pairwise
comparison was
0.05 for both the global F-test and the pairwise
comparison. All hypothesis testing was two-sided. The HRSA total and factor
scores and the HAD sub-scales were analysed with a two-way analysis of
covariance (ANCOVA), with treatment, centre and their interaction as factors
in the model and with the baseline value as covariate. The CGI-I was analysed
by using a two-way analysis of variance (ANOVA), with treatment, centre and
their interaction as factors. Because of the low numbers of patients in some
treatment groups at the later time points for the observed case analyses and
because no evidence of a treatment by centre interaction was found in the LOCF
analysis, the interaction term was dropped from the model to allow the
adjusted means to be estimated for the observed case analysis only. The
results described used adjusted means derived from ANOVA/ANCOVA.
Visit-minus-baseline change scores were used in the appropriate
statistical model in all cases except the CGI-I, where the actual scores were
used. Responder rates at each time point were compared by means of Fisher's
exact test. Withdrawal was assessed by means of ANCOVA on the PWC total score
at the withdrawal assessment.
Safety
All patients assigned to double-blind treatment were included in the
evaluation of safety and tolerability. Adverse events were coded using COSTART
(Food and Drug Administration,
1989), by body system and preferred term. Laboratory data and
vital signs were assessed using group mean changes and criteria for
potentially clinically important change that identified values
or changes that fell outside predetermined limits.
Protocol violations
By convention, the ITT population includes patients who are found to
violate the inclusion criteria. In this study, 25 subjects reported a current
illness duration of less than 6 months, although they met all the other
diagnostic criteria for GAD. The results remained unchanged when these
subjects were excluded from the analysis.
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RESULTS |
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Nearly three-quarters of patients in all groups (74%; 399/541) had received prior treatment for anxiety, mostly benzodiazepines and antidepressants. Other prior treatments for anxiety that had been used by at least 10% of patients in each group included hypnotics (mostly benzodiazepines) and ß-adrenergic receptor blocking agents. Eighty-five per cent (461/541) of patients received some type of non-anxiolytic concomitant therapy during the study (26 patients had beta-blocker maintenance therapy and 52 patients used zolpidem or chloral hydrate occasionally for sleep). There were no marked differences among the treatment groups in terms of the classes of concomitant medications given.
Discontinuations
A total of 147 (36%) patients discontinued treatment over the 24-week
treatment period (Table 2). The
number of patients who discontinued did not differ significantly among the
treatment groups, but there were relatively fewer discontinuations among
patients receiving the higher doses of venlafaxine ER (75 or 150 mg/day).
Patients who received placebo were significantly more likely to discontinue
because of lack of efficacy than patients receiving venlafaxine ER (P
<0.001). The most common reason for discontinuation among patients
receiving placebo or the lowest dose of venlafaxine ER (37.5 mg) was
unsatisfactory response/efficacy. Among patients receiving the
higher dose of venlafaxine ER, adverse events were the most common reason for
discontinuation. Discontinuations due to adverse events were as common among
patients receiving placebo as among those receiving any of the doses of
venlafaxine ER, although there were more discontinuations on venlafaxine ER
during the early weeks of treatment.
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Efficacy evaluation
For evaluation of efficacy, the primary comparisons of interest for both
the short-and long-term evaluations (up to weeks 8 and 24, respectively) are
summarised in Table 3 for the
LOCF analysis. In the short term, both of the higher venlafaxine ER dose
groups (75 and 150 mg) showed significant differences from the placebo group
on all of the primary efficacy variables. A significant difference between
37.5 mg of venlafaxine and placebo was seen only for the HAD anxiety sub-scale
at week 8. The highest dose of 150 mg of venlafaxine ER also showed
significantly greater efficacy than 37.5 mg of venlafaxine ER on three of the
four primary efficacy variables (HRSA psychic anxiety factor, HAD anxiety,
CGI-I scores) in the short term. Results after 24 weeks of treatment showed
that the greater efficacy seen for the higher venlafaxine ER doses was
maintained during the long term, as was the superiority over low-dose
venlafaxine ER (37.5 mg). A graphic presentation of both the short- and the
long-term results for the HRSA total and psychic anxiety factor is shown in
Fig. 1. It is of note that
similar results for 75 and 150 mg of venlafaxine ER were seen in the observed
case analysis, which considers only those patients who have remained in
treatment. Thus, in the observed case analysis of patients who completed the
6-month treatment, the differences from placebo in the adjusted mean change
from baseline of the 75 and 150 mg doses of venlafaxine ER in the HRSA total
score were 3.9 and 4.7, respectively.
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The secondary outcome variables, including social impairment, also showed a more consistent picture of efficacy in comparison with placebo for 75 and 150 mg of venlafaxine ER than for 37.5 mg of venlafaxine ER during both short- and long-term treatment (Table 4). In addition, the 150 mg dose of venlafaxine showed consistent superiority over 37.5 mg of venlafaxine ER on all secondary outcome variables except the HRSA somatic factor.
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Onset of effect
For most variables, onset of anxiolytic effect was seen at weeks 1 and 2
with 150 mg of venlafaxine ER and at weeks 2 and 3 with 75 and 37.5 mg
(Table 5). There was a tendency
for more parameters to show onset of effect at week 3 with the lowest dose of
venlafaxine ER. Onset of effect on the somatic factors of the BSA and the HRSA
appeared later in the treatment - at weeks 4 and 8, respectively.
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Dose and response
All doses of venlafaxine ER showed significantly higher treatment response
rates compared with placebo on both the HRSA and CGI-I as early as week 2.
This effect was maintained until week 24 (except for the 37.5 mg venlafaxine
ER group at week 8). Responder rates for the CGI-I scores showed a significant
difference from placebo and a dose response with respect to onset: 150 mg of
venlafaxine ER at week 1, 75 mg of venlafaxine ER at week 2 and 37.5 mg of
venlafaxine ER at week 4 (Fig.
2).
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Adverse events
There was no difference with respect to the overall frequency of
treatment-emerging adverse events (TEAEs) reported during either short- (82%,
87%, 93%, 88%) or long-term treatment (56%, 62%, 69%, 65%) for the placebo and
37.5-, 75- and 150-mg venlafaxine ER groups, respectively. The most frequent
events were nausea, dizziness, sweating, dry mouth and constipation; the
incidence of these events appeared to be dose-related and subsided within a
short time (Table 6). With
respect to sexual dysfunction, the incidence of TEAEs reported on venlafaxine
ER was less than 10% at any dose compared with 0% on placebo. The need for
concomitant medication or temporary cessation of treatment to manage TEAEs was
similar for the placebo and all active treatment groups.
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There were no differences between the treatment groups in the percentage of patients who discontinued and gave adverse events as either a primary or a secondary reason: 22%, 14%, 21% and 19% for placebo, 37.5-, 75- and 150-mg treatment groups, respectively. The most common adverse event leading to discontinuation in the venlafaxine ER treatment groups was nausea: 4%, 6% and 7% for 37.5-, 75- and 150-mg groups, respectively, compared with 2% for placebo. Dizziness was the most frequent cause of discontinuation in the placebo group: 5% compared with <1%, 5% and 4% in the 37.5-, 75- and 150-mg venlafaxine ER treatment groups respectively. Other adverse events associated with discontinuation, but with no apparent association with either placebo or venlafaxine ER, were headache (2% in each group), sweating (<1%, 1%, 4% and 2%) and insomnia (<1%, 1%, 3% and 2%) for placebo and 37.5, 75 and 150 mg of venlafaxine ER respectively. Changes in laboratory parameters, ECG, weight and vital signs, including blood pressure readings, were generally small and sporadic and were not judged to be clinically important.
The potential effects of abrupt discontinuation of venlafaxine ER were
evaluated in 83% (297/359) of patients during a 1-week, single-blind placebo
discontinuation phase. The proportion of patients reporting at least three new
symptoms during the discontinuation phase was similar in the 37.5- and 75-mg
venlafaxine ER groups, where the most frequent symptoms were dizziness and/or
light- headedness. Discontinuation symptoms with an incidence of 10% and
double the incidence on placebo were highest with 150 mg of venlafaxine ER,
where the most frequent events were dizziness, light- headedness, tinnitus,
nausea, vomiting and loss of appetite
(Table 7). Discontinuation
symptoms began 24-72 h after the last dose of active treatment and usually
lasted 3-7 days. There were no differences between treatment groups in the
potential for rebound anxiety (defined as a greater HRSA total score during
the discontinuation phase than at baseline in patients who had shown a
response).
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DISCUSSION |
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Efficacy
Efficacy for the two higher doses of venlafaxine ER (75 and 150 mg daily)
was evident across all the primary comparisons. These effects were maintained
during treatment for up to 6 months. Results for 37.5 mg venlafaxine ER were
not as robust or consistent. Corroborating evidence for efficacy is found in
the results of the secondary efficacy measures, including improvement of
impairment in social functioning. The improved social functioning associated
with treatment with venlafaxine ER will be reported in detail in a separate
paper.
These assessments of efficacy indicated a dose-response relationship, with the highest dose of venlafaxine ER (150 mg) showing the greatest improvements and highest responder rates. This was significant compared with the lowest dose (37.5 mg) at weeks 8 and 24. The dose-response relationship was also apparent for onset of the anxiolytic effect. Onset was seen from weeks 1 or 2 with 150 mg of venlafaxine ER, from weeks 2 or 3 with the 75-mg dose and from weeks 2-4 with the 37.5-mg dose for all variables apart from somatic anxiety. The delay in improvement of somatic anxiety symptoms may reflect the natural course of improvement in anxiety, the side-effects seen during the first 2 weeks of venlafaxine ER treatment or the differences in response to either venlafaxine Er or placebo for psychic and somatic anxiety.
Tolerance
In any chronic condition where long-term treatment is the norm, it is
important that the intervention is not only safe and well tolerated but also
that there is good patient acceptability. The similar overall discontinuation
rates for all treatment groups, including placebo, and the similar
discontinuation rates where adverse events were cited either as a primary or
secondary reason suggest good patient acceptability of venlafaxine ER in the
management of GAD. The benign safety profile (laboratory, blood pressure,
weight and ECG variables) of venlafaxine ER in the dose range up to 150 mg
daily also was apparent in this population.
Discontinuation
The experimental design employed here included an evaluation of the extent
of discontinuation symptoms following abrupt discontinuation of all three
fixed doses of venlafaxine ER. The findings of dose-related symptoms during
the discontinuation phase are consistent with the current understanding and
experience with venlafaxine and the wording of the labelling for the
depression indication, where it is recommended that doses above 75 mg of
venlafaxine ER should be tapered before discontinuation.
Similar recommendations are valid for all of the selective serotonin reuptake inhibitors. Importantly, there was no evidence for the occurrence of rebound anxiety with any of the doses of venlafaxine ER when treatment was discontinued, as is the case with benzodiazepines (Rickels et al, 1990). Physical discontinuation symptoms are known to be associated with a number of commonly used psychoactive compounds, including the serotonin reuptake inhibitors (Rosenbaum et al, 1998).
Dose
The current study provides evidence for the efficacy of venlafaxine ER in
both the short- and long-term treatment of GAD and the efficacy is
dose-related over the range studied. The optimal clinical dose of venlafaxine
ER is 75 mg daily in most cases requiring the management of symptoms of
anxiety. In some patients, and when clinically indicated, it may be necessary
to increase the dose of venlafaxine ER to 150 mg daily.
Venlafaxine in vitro inhibits the reuptake of both serotonin and noradrenaline, although the relative potencies at the sites and the interpretation of the clinical meaning of these findings have been discussed. It has been suggested that noradrenaline effects in humans only become apparent at higher doses. In recent studies, however, enhancement of noradrenaline activity was found at either 75 or 150 mg (Abdelmawal et al, 1999, Bitsios et al, 1999). Melichar et al (2001) demonstrated that 1 mg/kg venlafaxine displaced the noradrenaline ligand MHED. These data suggest that venlafaxine inhibits the reuptake of both monoamines at the lower end of the dose range, but that the full effect on noradrenaline may require 150 mg or more.
Bearing in mind the chronicity of GAD and the frequent likely comorbidity with other Axis I disorders, further studies extending beyond 6 months evaluating the effect of venlafaxine ER and studies in comorbid populations are also recommended.
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Clinical Implications and Limitations |
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LIMITATIONS
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APPENDIX |
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Received for publication June 15, 2000. Revision received December 21, 2000. Accepted for publication December 22, 2000.