Psychiatry and Clinical Neurosciences (2006), 60, 347–351doi:10.1111/j.1440-1819.2006.01512.x
Psychiatry, St Mary’s Hospital, Catholic University of Korea, College of Medicine, 62 Yoido-dong, Youngdeungpo-gu, Seoul 150-713,Korea. Email: alberto@catholic.ac.kr
Received 29 August 2005; revised 31 October 2005; accepted 13 Regular Article
Comparison of venlafaxine extended release versus
paroxetine for treatment of patients with generalized anxiety disorder
TAE-SUK KIM, md , 1 CHI-UN PAE, md, p h d , 1 SU-JUNG YOON, md , 2
WON-MYONG BAHK, md, p h d , 3 TAE-YOUN JUN, md, p h d , 3 WON-IHL RHEE, md, p h d 4 AND JEONG-HO CHAE, md, p h d 3
Department of Psychiatry, 1 Kangnam St Mary’s Hospital, 2 St Paul’s Hospital, and 3 St Mary’s Hospital, and
4
Department of Rehabilitation Medicine, Catholic University of Korea, College of Medicine, Seoul, Korea
Abstract
This trial was to evaluate the ef?cacy and tolerability of venlafaxine extended release (XR) and paroxetine for treatment of patients with generalized anxiety disorder (GAD). Sixty patients who met DSM-IV criteria for GAD were randomly assigned to either venlafaxine XR or paroxetine for 8 weeks. Ef?cacy was assessed with the Hamilton Rating Scale for Anxiety (HAM-A) and Clinical Global Impression-Severity of Illness (CGI-S) scale at the baseline, week 1, week 4, and week 8.The side-effects were collected with reported adverse events and laboratory tests throughout the study period. Repeated measures analysis of variance ( anova ) on the HAM-A and CGI-S scores showed a signi?cant decrease over time in both treatment groups without signi?cant group differ-ence or time × group interaction effect. There were no serious adverse events in both groups. This open trial demonstrated that either venlafaxine XR or paroxetine would be effective and tolerable for the treatment of patients with GAD. Double blind, placebo-controlled head-to-head compar-ison studies are needed to draw a de?nite conclusion.
Key words
ef?cacy, generalized anxiety disorder, paroxetine, tolerability, venlafaxine extended release.
INTRODUCTION
Generalized anxiety disorder (GAD) is a very com-mon, severe, chronic and distressing psychiatric disor-der needing long-term treatment, which is often under-recognized and under-treated in usual clinical prac-tice. 1 Benzodiazepines have traditionally been the mainstay of treatment for GAD, but they may not be the most appropriate treatment option. 2 I t has been found that approximately 25–30% of GAD patients fail to respond on this regimen, and there is also a risk that tolerance and dependence may occur. 3
A growing body of evidence suggests that antide-pressants, in particular those that affect serotonergic neurotransmission, are effective and tolerable in the treatment of GAD. 4,5
The serotonin norepinephrine re-uptake inhibitor (SNRI) venlafaxine extended release (XR) was the ?rst antidepressant to receive US Food and Drug Administration (FDA) approval for the treatment of GAD. Paroxetine is a selective serotonin reuptake inhibitor (SSRI ) with antidepressant and anxiolytic activity that may be considered as an appro-priate ?rst-line therapy for all ?ve anxiety disorders in DSM-IV categories including GAD.
However, there have been few comparisons of ven-lafaxine XR and paroxetine for the treatment of GAD.The present study was conducted to compare the ef?-cacy and tolerability of venlafaxine XR and paroxetine in patients with GAD. We hypothesized that both venlafaxine XR and paroxetine would be similarly effective and tolerable for the treatment of patients with GAD in spite of their different pharmacological
348T-S. Kim et al.
METHODS
The present study was a prospective, open, randomized comparison of the ef?cacy and tolerability of venlafax-ine XR versus paroxetine in patients with GAD. The diagnosis was made on the consensus between two board-certi?ed psychiatrists (CUP; JHC), according to the DSM-IV criteria of GAD.6 The Structured Clinical I nterview, DSM-I V Axis I Disorders-Clinician Ver-sion,7was assigned to all subjects, aged from 18 to 65 years. Subject inclusion required a Hamilton Rating Scale for Anxiety (HAM-A)8symptom score of ≥18 and a Clinical Global I mpression-Severity of I llness (CGI-S)9 scale score of ≥4.
Subjects having a 17-item Hamilton Rating Scale for Depression (HAM-D)10 score >17 at baseline, any other current diagnosis of DSM-IV axis I disorder,
a history of substance abuse or dependence within
6 months prior to baseline, current use of any psycho-tropic medication including benzodiazepines and bus-pirone, any clinically signi?cant medical conditions or laboratory abnormality, history of organic brain dis-eases or who were pregnant or breast-feeding, were excluded from the study.
Written informed consent was obtained from each subject prior to study enrollment. The protocol of the present study was critically reviewed and approved by an institutional review board.
The study period was 8 weeks with ?exible dosing schedules. Subjects who met study criteria were assigned to either the venlafaxine XR treatment group (VTG) or the paroxetine treatment group (PTG) by simple randomization. Starting doses were 37.5 mg/day for venlafaxine XR and 10 mg/day for paroxetine. Daily dose could be titrated upward to a maximum of 225 mg/day for venlafaxine XR or 40 mg/day for par-oxetine by clinician’s decision after the second visit. Subjects were assessed at baseline, week 1, week 4 and week 8 (end-point). The only other allowed psychotro-pic was zolpidem for sleep control during the study. Ef?cacy and tolerability of the treatments were assessed at every visit. The primary ef?cacy measure was the HAM-A total score and CGI-S score. The sec-ondary ef?cacy measures included responder (≥50% reduction in the HAM-A score compared to baseline) and remission (HAM-A score ≤7 at end-point) analy-ses. To assess tolerability, blood pressure, heart rate, and reported adverse events were obtained at each visit.
To measure effectiveness throughout the study, the HAM-A and CGI-S scores were tested by a repeated measure analysis of variance (anova) in terms of within-subject factor and between-subject factor.(T) and treatment group (G). Descriptive statistics and χ2 test were performed for the group difference in the frequencies of side-effects. Odds ratio (OR) and 95% con?dence interval (CI) were presented where appro-priate. P< 0.05 (two-tailed) was considered statistically signi?cant. For α= 0.05 (two-tailed), the power of our sample was 80% for detecting an effect size (d) of 0.85, which corresponds to a difference in the HAM-A of approximately 4.3 points between the two groups.
RESULTS
Baseline characteristics
A total of 60 subjects were enrolled into the present study. Each 30 subjects were randomly assigned to receive venlafaxine XR or paroxetine. Eight subjects did not return for scheduled visits and could not be contacted, six subjects discontinued the medication for personal reasons without medical consultation. There-fore, 21 subjects (70%) in the VTG and 25 (83%) in the PTG completed the study. There was no statistically signi?cant difference between the two groups in base-line demographic data (Table 1). The daily mean dose throughout the present study was 127.5 ± 38.2 mg/day in the VTG and 33.8 ±5.4 mg/day in the PTG. The average exit dose was 114.6 ± 44.8 mg/day in the VTG and 36.8 ± 4.8 mg/day in the PTG.
Ef?cacy
Repeated measures anova run on the HAM-A scores showed a signi?cant decrease over time (F= 168.5, P< 0.0001), but no differences between the two groups (F= 0.428, P=0.517), and no signi?cant effect of the interaction between T and G (F= 0.116, P= 0.920; Fig. 1). With respect to the CGI-S scores, we found a similar trend: a signi?cant improvement over time
Table 1.Baseline characteristics of GAD patients (mean ± SD)
Characteristics VTG (n= 21)PTG (n= 25) Age (years)41.9 ± 8.246.4 ± 8.8 Female, n (%)14 (66.7)14 (56.0) Body weight (kg)58.1 ± 8.760.0 ± 9.0 Baseline scores
HAM-A28.7 ± 4.730.0 ± 6.0 CGI-S 4.3 ± 0.7 4.6 ± 0.8
CG-S, Clinical Global mpression-Severity of llness; GAD, generalized anxiety disorder; HAM-A, Hamilton Rating Scale for Anxiety; PTG, paroxetine treatment group;
Venlafaxine XR vs paroxetine for GAD349
(F=130.3, P<0.0001) but no effect of G (F= 0.878, P= 0.354) or T × G interaction (F= 0.299, P= 0.826). The number of patients with a ≥50% reduction in the HAM-A scores at the end-point was 19 (90.5%) in the VTG and 23 (92.0%) in the PTG, indicating no group difference (P= 0.855). The number entering remission (HAM-A ≤ 7) at the end-point was seven (33.3%) and nine (36.0%) in the VTG and PTG, respectively, indi-cating no group difference (P= 0.850).
Tolerability
No patients reported serious adverse events. Both treatments were generally well-tolerated, as shown in Table 2. Three patients (14.3%) in the VTG and three
(12.0%) in the PTG discontinued therapy because of
gastrointestinal discomfort and somnolence, respec-
tively. The most common adverse experiences occur-
ring during the 8-week treatment were nausea,
headache, somnolence, sweating, and dizziness.
Regarding weight change, 12 patients (57.1%) in
the VTG and 21 (84.0%) in the PTG had weight
gain at the end-point, indicating a marginally signi?-
cant group difference (P= 0.044). Three patients (14.3%) in the VTG had weight loss at the end-
point. The weight increased signi?cantly by 1.5% and
2.7% from baseline to end-point in the VTG
(P=0.008) and the PTG (P< 0.0001), respectively.
ancova(covariates: baseline weight, age, and sex)
showed signi?cant group difference in terms of mean
change in weight (F= 5.90, P=0.020) from the base-
line and end-point.
As for blood pressure, the systolic blood pressure
decreased by 1.5% and 0.7% from the baseline to the
end-point with no signi?cant difference in the VTG
(P=0.078) and the PTG (P= 0.167), respectively.
ancova(covariates: baseline systolic blood pressure,
age, and sex) showed signi?cant group difference in
terms of mean change in systolic blood pressure (F=
6.35, P= 0.016) from the baseline to the end-point. The
diastolic blood pressure increased signi?cantly by 3.8%
from the baseline to the end-point in the VTG (P=
0.009), while it decreased by 0.4% with no signi?cant
difference in the PTG (P= 0.507). ancova (covariates:
baseline diastolic blood pressure, age, and sex) showed
signi?cant group difference in terms of mean change in
diastolic blood pressure (F= 12.76, P= 0.001) from the
baseline to the end-point.
Figure 1.Time course of changes for mean Hamilton Rat-
ing Scale for Anxiety (HAM-A) score during the study in the
(?) venlafaxine XR treatment group and the (?) paroxetine
treatment group. Bars indicate SD.
Table 2.Adverse events (n, %)
VTG (n= 21)PTG (n= 25)OR95% CI Nausea 4 (19.0) 4 (16.0) 1.2350.291–5.224 Vomiting 3 (14.3) 2 (8.0) 1.9170.340–10.643 Somnolence 2 (9.5) 6 (24.0)0.3330.069–1.671 Dry mouth 2 (9.5) 4 (16.0)0.5330.106–2.946 Anorexia 4 (19.0) 3 (12.0) 1.7250.374–7.887 Yawning 2 (9.5) 5 (20.0)0.4210.084–2.166 Sweating 6 (28.6) 2 (8.0) 4.6000.910–22.463 Sexual dysfunction 4 (19.0) 4 (16.0) 1.2350.291–5.254 Insomnia 2 (9.5) 1 (4.0) 2.1260.302–20.261 Constipation 2 (9.5) 4 (16.0)0.5530.106–2.946 Dizziness7 (33.3) 3 (12.0) 3.6670.864–15.241 Headache 4 (19.0) 1 (4.0) 5.6470.753–40.265 CI, con?dence interval; OR, odds ratio; PTG, paroxetine treatment group; VTG, venlafaxine extended-release treatment
350T-S. Kim et al.
DISCUSSION
The present study compared the ef?cacy and tolerabil-
ity over 8 weeks in patients with GAD who received
venlafaxine XR and paroxetine. After an 8-week trial
the HAM-A and CGI-S scores signi?cantly decreased
in both groups. The response rate in the HAM-A was
90.5% in the VTG and 92.0% in the PTG at the
end-point, respectively. Furthermore, remission rate
(HAM-A score ≤7) was 33.3% in the VTG and 36.0%
in the PTG at the end-point, respectively. These posi-
tive results for ef?cacy in both groups are in accor-
dance with other previous studies.11–14Overall, the
response rates and remission rates in the VTG and
PTG were higher than in those of the placebo treat-
ment group in the previous controlled studies with
venlafaxine XR and paroxetine, respectively,12,14sug-
gesting that both agents may be effective and tolerable
for the treatment of GAD.
Except for weight and blood pressure changes, the
common adverse events were dizziness, sweating, nau-
sea, and headache in the VTG, which are similar to
those of previous studies.13,15 In contrast, somnolence,
yawning, constipation, and nausea were reported in the
PTG, which are consistent with those of previous stud-
ies.14,16However, most adverse events were mild to
moderate in severity and more likely to occur at the
onset of treatment and to diminish over time. Only
three patients (14.3%) in the VTG and three (12.0%)
in the PTG discontinued therapy because of gas-
trointestinal discomfort and somnolence, respectively.
In the present study a signi?cant different effect on
weight between venlafaxine XR and paroxetine was
observed, indicating a superior pro?le in the VTG. The
PTG had a signi?cant increase in mean change of
weight compared to the VTG. However, there was no
patient who had signi?cant weight gain (increase of ≥7% in baseline body weight) among the 33 patients with weight gain at the end-point in both groups. How-
ever, the VTG had a trend to increase blood pressure
at the end-point compared with the PTG. In terms of
mean change in systolic and diastolic blood pressure
from the baseline to the end-point, the VTG had sig-
ni?cant increase compared to the PTG. Venlafaxine
can cause both transient and sustained elevated supine
diastolic blood pressure, probably the result of norad-
renergic potentiation.17However, the effects of
venlafaxine on blood pressure were strongly dose-
dependent and the incidence of elevated supine dias-
tolic blood pressure was statistically and clinically sig-
ni?cant at dosages >300 mg/day, especially in acute
phase therapy.18I n the present study the daily mean
dose and the average exit dose in the VTG was tively. Thus, to evaluate the effect of venlafaxine on blood pressure precisely, long-term treatment with venlafaxine on GAD will be needed.
We should bear in mind the limitations of the present study. Because the sample size was relatively small, any de?nite conclusions are limited. The present study did not include a placebo control group so that the reduction in the HAM-A and CGI-S scores may simply be due to the natural course of the disease. We were also unable to exclude the observer bias.
I n summary, the present open study demonstrated that either venlafaxine XR or paroxetine is effective and tolerable for the treatment of GAD. Double-blind, placebo-controlled, head-to-head comparison studies are needed to draw de?nite conclusions. ACKNOWLEDGMENT
This study was supported by a grant from the Korean Health 21 R&D Project, Ministry of Health and Wel-fare, Republic of Korea (A050047). REFERENCES
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