Prevention of relapse in generalized anxietydisorder by escitalopram treatment

Christer Allgulander1, Ioana Florea2 and Anna K. Trap Huusom2

1 Karolinska Institutet, Stockholm, Sweden2 H. Lundbeck A/S, Copenhagen, Denmark

Abstract

Escitalopram has demonstrated a robust and dose-dependent efficacy in the treatment of generalized

anxiety disorder (GAD) for up to 3 months. In the present study, the efficacy and tolerability of escitalo-

pram in the prevention of relapse in GAD was investigated. A total of 491 patients with a primary diag-

nosis of GAD and a Hamilton Anxiety (HAMA) total score o20 received 12 wk of open-label treatment

with a fixed dose of escitalopram (20 mg/d). Of these, 375 patients responded (HAMA total score f10)

and were randomized to double-blind treatment with 20 mg/d escitalopram (n=187) or placebo (n=188).

Treatment was continued for 24–76 wk unless the patient relapsed or was withdrawn for other reasons.

Relapse was defined as either an increase in HAMA total score too15, or lack of efficacy, as judged by the

investigator. The results of the primary analysis showed a clear beneficial effect of escitalopram relative to

placebo on the time to relapse of GAD (log-rank test, p<0.001). The risk of relapse was 4.04 times higher

for placebo-treated patients than for escitalopram-treated patients ; the proportion of patients who re-

lapsed was statistically significantly higher in the placebo group (56%) than in the escitalopram group (19

%) (p<0.001). Escitalopram was well tolerated and 7% of the escitalopram-treated patients withdrew due

to adverse events, vs. 8% of the placebo patients. The incidence of discontinuation symptoms with esci-

talopram during tapered withdrawal was low; the symptoms primarily being dizziness (10–12%), ner-

vousness (2–6%), and insomnia (2–6%). Escitalopram 20 mg/d significantly reduced the risk of relapse

and was well tolerated in patients with GAD.

Received 19 April 2005 ; Reviewed 13 June 2005 ; Revised 25 June 2005 ; Accepted 26 June 2005

Key words : Anxiety, clinical trial, escitalopram, placebo-controlled, relapse prevention.

Introduction

Generalized anxiety disorder (GAD) is characterized

by excessive anxiety and uncontrollable worry that

persist for more than 6 months. In order to fulfil the

GAD diagnosis according to the DSM-IV-TR criteria

(APA, 2000) patients, in addition to the excessive

anxiety and worry, must suffer from at least three of

the following symptoms: restlessness, fatigue, diffi-

culty in concentrating, irritability, muscle tension, and

impaired sleep cycle. Rates of GAD in primary-

care patients in Europe amount to 9% (Allgulander

and Nilsson, 2003 ; Weiller et al., 1998). GAD is asso-

ciated with significant psychosocial impairment and

increased somatic morbidity and mortality ; it there-

fore constitutes a public health problem (Kessler et al.,

2001).

Several placebo-controlled, double-blind studies

have evaluated SSRIs (selective serotonin reuptake

inhibitors) and SNRIs (serotonin noradrenaline re-

uptake inhibitors) as potential treatments for GAD.

For instance, both the SSRI paroxetine (Baldwin and

Polkinghorn, 2005; Pollack et al., 2001; Rocca et al.,

1997) and the SNRI venlafaxine (Allgulander et al.,

2001 ; Davidson et al., 1999) were efficacious and

achieved statistical superiority over placebo. SSRIs

and venlafaxine are currently the mainstays of treat-

ment for GAD and have replaced benzodiazepines

as the recommended first-line treatment (Uhlenhuth

et al., 1999). Data on the efficacy of various

psychotherapies in GAD are scarce and inconsistent

(Westen and Morrison, 2001).

The efficacy and tolerability of the serotonin re-

uptake inhibitor escitalopram (10 or 20 mg/d) in GAD

Address for correspondence : C. Allgulander, M.D., Karolinska

Institutet, Department of Clinical Neuroscience, Division of

Psychiatry at Karolinska University Hospital, SE-141 86 Stockholm,

Sweden.

Tel. : +468-585-85797

E-mail : christer.allgulander@neurotec.ki.se

International Journal of Neuropsychopharmacology (2005), 9, 1–11. Copyright f 2005 CINPdoi:10.1017/S1461145705005973

ARTIC

LE

was established in three 8-wk, placebo-controlled,

flexible-dose studies (Davidson et al., 2004; Goodman

et al., 2005). In addition, escitalopram has recently

shown robust efficacy in 3-month treatment of GAD

and significant superiority vs. paroxetine (Baldwin

et al., 2004 ; Bielski et al., 2005).

Although GAD is a chronic disorder, a major

clinical issue in the routine care of these patients is

how long should a patient be treated. Once a patient

has responded to treatment, and/or is in remission,

the issue of whether to continue treatment is on the

agenda of repeated subsequent consultations.

There are limited data for the assessment of the risk

of relapse, although experienced clinicians experience

a substantial portion of relapses within months of

treatment discontinuation. To the best of our knowl-

edge, the effect of drug therapy on relapse prevention

in patients with GAD has been documented only in

one study of paroxetine (Stocchi et al., 2003) and in

one study of venlafaxine (Hackett et al., 2000). The

primary objective of the present study was thus to

evaluate the effect of escitalopram (20 mg/d) vs. that

of placebo on the prevention of relapse of GAD

in patients who had responded to treatment with

escitalopram.

Methods

Study design

The study was conducted in 59 centres in eight coun-

tries in accordance with the principles of Good Clinical

Practice (ICH, 1996) and the Declaration of Helsinki

(WMA, 2000) applicable at the time of the study. The

study was approved by the relevant local ethics com-

mittees and all patients gave their written informed

consent.

This relapse prevention study started with a 1-wk

screening period followed by a 12-wk open-label

period that was followed by a double-blind treat-

ment period (Figure 1). During the open-label

period, patients received 10 mg/d escitalopram

during the first week, and 20 mg/d during the

subsequent 11 wk. Responders to treatment were

defined as patients with a decrease in the Hamilton

Anxiety Scale (HAMA; Hamilton, 1959) total score

to f10. Non-responders left the study and were

treated at the physician’s discretion. Patients who

responded to treatment were randomized to double-

blind treatment in a 1 :1 ratio, using a computer-

generated randomization list, with either 20 mg/d

escitalopram or placebo. Patients were in the double-

blind period for a minimum of 24 wk and a maxi-

mum of 76 wk if they remained well, depending on

when in the recruitment period they entered the

study, as all patients completed the double-blind

period on the same date. This design optimized the

exposure time to treatment that enabled an estimate

of the risk of relapse based on a parsimonious

number of subjects. It also enabled the monitored

assessment of the utility of long-term treatment.

Patients randomized to placebo after the open-label

period had their escitalopram dose tapered from 20

to 10 mg/d one week before starting placebo. All

patients who relapsed were to be withdrawn from the

study and abruptly discontinued treatment without

taper. Patients who completed the double-blind

period, entered a 2-wk taper period where patients

on escitalopram received 10 mg/d for a week and

placebo for the second week, and patients on placebo

continued on placebo.

Study medications were tablets for oral adminis-

tration, of identical appearance, taste and smell.

Patients

Patients were recruited by general practitioners, by

psychiatrists ; some used media advertisements.

Patients eligible for this study were outpatients with

a primary diagnosis of GAD according to DSM-IV-

TR criteria (APA, 2000) who were otherwise healthy

and who had given informed consent. Patients aged

18–65 years were eligible if they had a HAMA total

score of o20 and a score of o2 on both HAMA

item 1 (anxious mood) and item 2 (tension) at

screening as well as at the start of the open-label

period.

To rule out comorbid depressive disorder, only pa-

tients who had a low level of depressive symptoms

were allowed in the study; a Montgomery – Asberg

Depression Rating Scale (MADRS; Montgomery and

Asberg, 1979) score of f16 at screening and at the

start of open-label period. Patients with any of the

following DSM-IV disorders elicited with the MINI

Open-label period

12 wk

Responders (HAMA �10)

At least 24 wk 2 wk

Tap

erin

g

Tap

erin

g

Randomized, double blind,placebo-controlled period

HAMA �20

Figure 1. Study design. &, 10 mg escitalopram; , 20 mg

escitalopram; %, placebo.

2 C. Allgulander et al.

(Sheehan et al., 1998) were excluded: major depressive

disorder, panic disorder, social anxiety disorder,

post-traumatic stress disorder, bipolar disorder,

obsessive–compulsive disorder, eating disorders,

substance use disorder, and any current or past

psychotic disorder. Patients were also excluded if

they had a body dysmorphic disorder or any person-

ality disorder, were at risk of suicide (elicited in

the MINI, or had >3 points on item 10 ‘suicidal

thoughts’ of the MADRS), or had made a suicide

attempt within the past year. Furthermore, patients

with an unstable serious somatic illness and/or

serious sequelae of liver or renal insufficiency were

also excluded. Pregnant or breastfeeding women were

excluded.

Assessments

Effectiveness and tolerability were assessed after 1, 2,

4, 8, and 12 wk of open-label treatment. For patients

randomized to double-blind treatment, efficacy and

tolerability parameters were assessed at 1, 2, and 4 wk,

and then every 4 wk until their last dose of double-

blind treatment. A safety follow-up was carried out

2 wk after completion or withdrawal.

The primary efficacy parameter was the time to

relapse during the double-blind treatment period.

Relapse was defined as an increase in HAMA total

score to o15 (Montgomery and van Zwieten-Boot,

2002) or lack of efficacy as judged by the investigator.

Only 12 patients were withdrawn for lack of efficacy as

judged by the investigator.

The secondary efficacy parameters included change

in scores from the following scales : the HAMA total,

HAMA psychic anxiety subscale (items 1–6, 14) and

the HAMA somatic anxiety subscale (items 7–13),

MADRS, Hospital Anxiety and Depression Anxiety

(HADA) subscale scores (Zigmond and Snaith, 1983),

Clinical Global Impressions – Severity of illness

(CGI-S) and Improvement of illness (CGI-I ; Guy,

1976), and the Sheehan Disability Scale (SDS; Sheehan,

1983) scores (work, social life, and family life). Clinical

research staff were trained using videotaped inter-

views of GAD patients. Inter-rater agreement was

assessed, and if ratings fell outside acceptable

limits, further training was given. Only those subse-

quently approved as raters were allowed to rate

patients.

The tolerability and safety evaluations were based

on spontaneously reported adverse events (AEs), vital

signs, body weight, physical examinations, and clini-

cal safety laboratory tests. If AEs were contributory

to withdrawal from the study, they were regarded as

the primary reason for withdrawal. Discontinuation

symptoms were assessed by evaluation of AEs during

the 2-wk taper period (tapering of escitalopram for

patients randomized to the placebo arm) and during

the 2-wk taper period for patients who completed the

study.

Statistical analysis

The sample size and power calculations were based on

the analysis of time to relapse in the double-blind

period and assumed a length of accrual for the double-

blind period of 52 wk and a treatment duration of at

least 24 wk. A total of 250 patients (125 patients per

treatment group) randomized to the double-blind

period would provide 85% power to find a statistically

significant difference between escitalopram and pla-

cebo, using a two-tailed, log-rank test at the 5% level

of significance.

All efficacy analyses were conducted on the intent-

to-treat (ITT) population, consisting of all randomized

patients who took at least one dose of trial medication

in the double-blind treatment period.

The primary efficacy analysis used a two-tailed log-

rank test to compare the time to relapse for patients

treated with escitalopram vs. placebo, using statistical

software system SAS version 8.2 (SAS Institute Inc.,

Cary, NC, USA). In addition, Kaplan–Meier survival

curves were produced and the Cox proportional haz-

ard model for survival data was used to estimate

hazard ratios. A x2 test was used to compare the crude

proportions of relapsed patients.

The secondary efficacy parameters were analysed

based on ITT, and exploratory analyses investigated

the effect on the time to relapse of centre, country, sex,

age, and disease status.

Comparisons between escitalopram and placebo

with respect to the secondary efficacy parameters

(changes from the start of the double-blind period to

end-point in HAMA, CGI-S, HADA, and SDS scores)

and the changes in MADRS score were performed

using an additive analysis of covariance (ANCOVA)

model with treatment group and centre as factors and

with the score at the start of the double-blind period as

a covariate. The analyses were carried out using both

last observation carried forward (LOCF) and observed

cases (OC) approaches.

In order to exclude potentially confounding dis-

continuation effects, the influence of discontinua-

tion symptoms on the primary analysis was

investigated in two separate analyses, in which re-

lapses during the first 7 and 14 d after randomization

were censored.

Escitalopram in GAD relapse prevention 3

Results

Patient characteristics at inclusion and at

randomization

Of the 491 patients entering the open-label period, 375

patients (77%) were randomized to double-blind

treatment : 187 patients to 20 mg/d escitalopram and

188 patients to placebo. The ITT population comprised

373 patients, since two patients were randomized de-

spite being non-responders (Figure 2).

Patient demography at inclusion and at randomi-

zation is shown in Table 1. There were no significant

differences between patients treated with escitalopram

or placebo at randomization. The average age was

41 yr, the mean age of GAD onset was 36 yr, and the

mean duration since the GAD diagnosis was made

was 5.6 yr. There were no clinically relevant differ-

ences in efficacy parameters between patients treated

with escitalopram or placebo at the start of the double-

blind period. The patients had a mean baseline

MADRS total score of 11.1, which is below the usual

remission criterion for patients with major depressive

disorder (Table 2). Of the 375 patients continuing into

the double-blind period of the study, 168 (116 escita-

lopram-treated and 52 placebo-treated patients) re-

mained in the study until its completion.

In the open-label period, the total exposure to esci-

talopram was y103 patient years. In the double-blind

Patients included (n = 491)

Patients randomized (n = 375)

12 w

k o

pen

tre

atm

ent:

20

mg

esc

ital

op

ram

Min

imu

m o

f 24

wk

do

ub

le-b

lind

trea

tmen

t: 2

0 m

g e

scit

alo

pra

m o

r p

lace

bo

Week 12

Escitalopram (n = 187)(ITT n =186)

Completed (n =116) Completed (n = 52) Relapsed (n =105)Relapsed (n = 35)

Placebo (n =188)(ITT n =187)

Patients completed open-label period (n = 424)

Withdrawn (n = 67)Adverse events (n = 38)Lack of efficacy (n = 7)Lost to follow-up (n = 4)Consent withdrawn (n = 8)Protocol violation (n = 5)Non-compliance (n = 3)Other (n = 2)

Withdrawn (n = 49)Adverse events (n = 8)Lack of efficacy (n = 28)Consent withdrawn (n = 3)Non-compliance (n = 5)Other (n = 5)

Withdrawn (n = 71)Adverse events (n =13)Lack of efficacy (n = 32)Lost to follow-up (n = 8)Consent withdrawn (n = 8)Protocol violation (n =1)Non-compliance (n = 4)Other (n = 5)

Withdrawn (n =136)Adverse events (n =16)Lack of efficacy (n = 96)Lost to follow-up (n = 4)Consent withdrawn (n =10)Protocol violation (n =1)Non-compliance (n = 6)Other (n = 3)

Figure 2. Patient disposition for the open-label period and the randomized double-blind period of the study (weeks 24–76).

Patients who relapsed include all patients withdrawn due to lack of efficacy, plus other patients who fulfilled the relapse criteria.

4 C. Allgulander et al.

period, the total exposure was y120 patient years for

escitalopram and y71 patient years for placebo. The

difference in patient years of exposure was driven by

the difference in time to relapse between the two

groups : in the double-blind period, the mean treat-

ment time for the escitalopram group was 3 months

longer than that for the placebo group, and the median

treatment time was 6 months longer.

Efficacy

Open-label period

The effect of the 12-wk open-label treatment was re-

flected in a decrease from the start of the open-label

period in the mean HAMA total score (from 27.3 to

6.6) and subscale scores (psychic anxiety and somatic

anxiety), CGI-S, HADA score, SDS scores, and the

MADRS. Patients randomized to double-blind treat-

ment had mean HAMA total scores of 5.7 (escitalo-

pram) and 5.0 (placebo) at week 12 (Table 2).

Double-blind period

The results of the primary analysis showed a beneficial

effect of escitalopram relative to placebo on the time to

relapse of GAD (log-rank test, p<0.001) (Figure 3).

The proportion of patients who relapsed was signifi-

cantly higher in the placebo group (56%, 105 patients)

Table 1. Patient demography at the start of, and exposure to drug during, open-label treatment and randomization to

double-blind treatment

Open-label period Double-blind period

Escitalopram

(n=491)

Escitalopram

(n=187)

Placebo

(n=188)

Mean age in years (range) 41 (18–65) 41 (18–65) 42 (18–64)

Sex (% women) 59 60 60

Race (% Caucasian) 99 100 97

BMI (kg/m2) 25.5 25.5 25.3

Mean age at GAD onset in years (range) 36 (7–66) 37 (9–66) 37 (7–65)

Mean duration of GAD in years (range) 5.6 (0–56) 4.6 (0–47) 5.5 (0–56)

Mean exposure to drug (range) 78 (1–118) 236 (3–449) 139 (7–526)

Median exposure to drug 84 261 85

BMI, Body mass index ; GAD, generalized anxiety disorder.

Table 2. Secondary efficacy measures – change from randomization to week 24 of the double-blind period (ITT, OC)

Efficacy parameter

Start of open-

label period

(n=491)¡S.D.

Start of double-blind period Change after 24 wk double-blind treatmenta

Escitalopram

(n=186)¡S.D.

Placebo

(n=187)¡S.D.

Escitalopram

(n=133)

Placebo

(n=65)

Treatment difference

mean (95% CI)

HAMA total 27.3¡4.4 5.7¡2.9 5.0¡3.1 x0.83 +0.39 x1.22 (x2.28 to x0.17)*

HAMA psychic anxiety 14.5¡2.4 3.1¡2.0 2.8¡2.0 x0.30 +0.58 x0.88 (x1.57 to x0.20)*

HAMA somatic anxiety 12.8¡3.3 2.6¡1.9 2.3¡1.8 x0.54 x0.21 x0.33 (x0.88 to+0.23)

CGI-S 4.6¡0.7 1.9¡0.7 1.7¡0.7 x0.31 +0.02 x0.33 (x0.53 to x0.12)*

HADA 13.8¡3.4 5.5¡3.4 5.3¡3.5 x0.78 x0.14 x0.64 (x1.55 to+0.26)

SDS – work 6.0¡2.1 1.5¡1.6 1.4¡1.6 x0.46 +0.02 x0.48 (x0.91 to x0.05)*

SDS – social life 6.0¡2.2 1.6¡1.7 1.3¡1.6 x0.19 +0.44 x0.63 (x1.08 to x0.17)*

SDS – family life 5.6¡2.1 1.4¡1.5 1.3¡1.7 x0.33 +0.12 x0.45 (x0.84 to x0.06)*

MADRS total score 11.1¡3.2 3.5¡2.7 3.3¡ 2.7 x0.37 +0.38 x0.75 (x1.61 to+0.11)

ITT, Intent to treat ; OC, observed cases ; S.D., standard deviation; CI, confidence interval ; HAMA, Hamilton Anxiety Scale ;

CGI-S, Clinical Global Impressions – Severity of illness ; HADA, Hospital Anxiety and Depression Anxiety ; SDS, Sheehan

Disability Scale ; MADRS, Montgomery – Asberg Depression Rating Scale.a Change relative to score at the start of double-blind period ; * p<0.05 ANCOVA.

Escitalopram in GAD relapse prevention 5

than in the escitalopram group (19%, 35 patients) (x2

test, p<0.001). The proportion of patients who re-

lapsed within 24 wk was significantly higher in the

placebo group (52%, 98 patients) than in the escitalo-

pram group (18%, 34 patients) (x2 test, p<0.001). The

decrease in patient numbers after week 24 results not

only from patients withdrawn from the study but also

from the lower number of patients treated for longer

periods. After 24 wk of double-blind treatment, there

were still 133 patients in the escitalopram group and

65 patients in the placebo group (Table 3). Only one

escitalopram-treated patient relapsed after day 143

(Figure 3).

In the secondary analysis of time to relapse, based

on the Cox proportional hazard model, the hazard ra-

tio was 4.04 (95% CI 2.75–5.94), that is, the risk of re-

lapse was 4.04 times higher with placebo than with

escitalopram (x2 test, p<0.001) (Table 4).

In order to determine the robustness of the ITT data,

analyses were performed excluding all relapses that

occurred within the first 7 or 14 d after randomization

to discount the possible effect of discontinuation

symptoms. Escitalopram was also statistically signifi-

cantly superior to placebo in preventing relapse of

GAD in these analyses (log-rank test, p<0.001 in all

analyses) (Table 4). In all analyses, the Cox pro-

portional hazard model gave estimated hazard ratios

of >4; that is, the risk of relapse of GAD was consist-

ently more than four times higher for placebo-treated

patients than for escitalopram-treated patients.

Analyses with covariates [sex, age, weight or body

mass index (BMI), HAMA score at randomization,

duration of GAD, age of GAD onset] revealed no in-

teractions with treatment or any noteworthy change in

the estimated relapse risk.

The effect of long-term treatment as measured by

the HAMA total score (ITT, OC) was stable over time

for the escitalopram group and showed a slight

deterioration in the placebo group during the

double-blind period. A similar pattern was seen for

all secondary measures (HAMA subscales, CGI-S,

HADA, SDS, and MADRS) (Table 2). Based on an

LOCF analysis, these differences in favour of escitalo-

pram were statistically significant for both primary

and all secondary measures.

Tolerability

Open-label period

A total of 67 out of 491 patients (24%) withdrew dur-

ing the 12-wk open-label period, 38 due to AEs

(Figure 2). Prior to randomization a further 49 patients

withdrew (Figure 2). AEs that occurred during the

open-label period are shown in Table 5. In almost all

cases reported, AEsweremild tomoderate. The overall

incidence of severe adverse events (SAEs) was low: 10

patients had a total of 15 SAEs. During the open-label

period, three patients had three SAEs, one of which

(syncope) was considered to be possibly related to

treatment. During the double-blind period, three

patients in the escitalopram group had three SAEs and

four patients in the placebo group had nine SAEs. One

patient was hospitalized with six SAEs (worsening

of insomnia, worsening of dyspnoea, worsening of

1

0.8

0.6

0.4

0.2

00 28 56 84 112 140 168 196

Time (d)

Kap

lan

–Mei

er e

stim

ate

224 252 280 308 336 364 392 420 448 476 504 532

Figure 3. Kaplan–Meier survival analysis of relapse over

76 wk. Time to relapse showed a significant advantage for

patients treated with escitalopram ( ) compared to

patients treated with placebo ( ) (p<0.001, log-rank

test).

Table 3. Patient numbers during the double-blind perioda

Day Week Escitalopram Placebo

0 0 186 187

56 8 154 111

112 16 143 80

168 24 125 64

224 32 99 46

336 48 43 18

392 56 24 7

448 64 6 4

504 72 0 1

a The decrease in the number of patients during the study is

due to the decreasing number of patients randomized to

double-blind treatment at earlier dates, together with patients

withdrawn due to relapse. The number of patients at a given

time point is based on days since first dose in double-blind

treatment.

6 C. Allgulander et al.

anxiety, mouth dry, fatigue, and concentration im-

paired) 17 d after randomization to placebo.

Double-blind period

During the 24–76 wk double-blind period, the overall

withdrawal rate, excluding relapses, was comparable

for both treatments : 20.9% for patients treated with

escitalopram (39 patients), and 21.3% for patients

treated with placebo (40 patients). Reasons for with-

drawal other than relapse were largely the same in the

two treatment groups and are shown in Figure 2.

During the double-blind period, 8.5% of the patients

in the placebo group and 7.0% of the patients in the

Table 4. Analysis of time to relapse in the double-blind period (ITT)

Relapses

x2

Hazard ratio (Cox)

(95% CI)

Escitalopram

(N=186)

Placebo

(N=187)

All

(N=373)

n (%) n (%) n (%)

Entire period 35 (19%) 105 (56%) 140 (38%) 59.5* 4.04 (2.75–5.94)

7-d cut-off 32 (17%) 102 (54%) 134 (36%) 52.1* 4.35 (2.92–6.49)

14-d cut-off 27 (14%) 80 (43%) 107 (29%) 42.6* 4.31 (2.78–6.68)

* p<0.001 vs. placebo.

Table 5. Adverse events (AEs) with an incidence o5% in any treatment group

Preferred term

Open-label

period

Escitalopram

(n=491)

103 PYE

Double-blind period (up to 76 wk)

Taper after

randomization

(weeks 0–2)

From week 2 until

completion Taper after completion

Escitalopram

(n=187)

7.0 PYE

Placeboa

(n=188)

6.6 PYE

Escitalopram

(n=187)

112.3 PYE

Placebo

(n=188)

63.0 PYE

Escitaloprama

(n=116)

4.4 PYE

Placebo

(n=52)

2.0 PYE

Patients with AEs 382 (77.8%) 57 (30.5%) 63 (33.5%) 105 (56.1%) 61 (32.4%) 33 (28.4%) 6 (11.5%)

Nausea 119 (24.2%) 4 (2.1%) 6 (3.2%) 4 (2.1%) 1 (0.5%) 5 (4.3%) 0

Headache 82 (16.7%) 9 (4.8%) 9 (4.8%) 21 (11.2%)* 7 (3.7%) 2 (1.7%) 1 (1.9%)

Ejaculation failure (men) 24 (11.8%) <1% <1% 0 0 <1% <1%

Dizziness 57 (11.6%) 4 (2.3%) 23 (12.2%)* 7 (3.7%) 6 (3.2%) 11 (9.5%)* 0

Fatigue 55 (11.2%) 1 (0.5%) 3 (1.6%) 9 (4.8%) 5 (2.7%) 4 (3.4%) 1 (1.9%)

Insomnia 54 (11.0%) 4 (2.1%) 12 (6.4%) 7 (3.7%) 7 (3.7%) 2 (1.7%) 0

Dry mouth 53 (10.8%) <1% <1% 3 (1.6%) 2 (1.1%) <1% <1%

Somnolence 48 (9.8%) <1% <1% 0 0 <1% <1%

Diarrhoea 47 (9.6%) 0 3 (1.6%) 7 (3.7%) 5 (2.7%) <1% <1%

Increased sweating 39 (7.9%) 2 (1.1%) 0 3 (1.6%) 0 3 (2.6%) 0

Decreased libido 31 (6.3%) <1% <1% 1 (0.5%) 1 (0.5%) <1% <1%

Anorexia 29 (5.9%) <1% <1% 1 (0.5%) 2 (1.1%) <1% <1%

Rhinitis 27 (5.5%) 9 (4.8%)* 2 (1.1%) 26 (13.9%)* 11 (5.9%) 2 (1.7%) 0

Upper resp. tract infection 19 (3.9%) 2 (1.1%) 1 (0.5%) 13 (7.0%) 5 (2.7%) <1% <1%

Back pain 13 (2.6%) 2 (1.1%) 2 (1.1%) 11 (5.9%) 8 (4.3%) <1% <1%

Nervousness 7 (1.4%) 2 (1.1%) 3 (1.6%) 1 (0.5%) 2 (1.1%) 7 (6.0%) 0

PYE, patient years of exposure.

* p<0.05, not adjusted for differences in PYE.a Patients tapering from escitalopram to placebo.

Escitalopram in GAD relapse prevention 7

escitalopram group withdrew due to AEs. In both

groups, the majority of the AEs reported during the

double-blind period (excluding both taper periods)

were mild to moderate, and the incidence of AEs was

higher in the escitalopram group (56.1%) than in the

placebo group (32.4%) (Table 5). The large difference

in the extent of patient exposure during the double-

blind period should be considered when interpreting

these results.

Taper periods

The incidence of AEs was similar in the escitalopram

group (30.5%) and in the placebo group (33.5%) dur-

ing the first 2 wk after randomization to double-blind

treatment. During taper at the end of double-blind

treatment, more escitalopram patients (28.4%) than

placebo patients (11.5%) reported AEs, particularly

dizziness (9.5%) and nervousness (6.0%) (Table 5).

There were no clinically relevant changes from

baseline to the end of the study or differences between

treatment groups in laboratory values or vital signs.

Discussion

A relevant and common question in the management

of stabilized patients with GAD is what risk a patient

assumes when discontinuing pharmacotherapy. This

study provides a robust answer: the risk of relapsing

is four times higher on placebo than on continued

maintenance treatment with escitalopram. In brief,

there was no loss of efficacy during long-term main-

tenance therapy. The side-effect burden was minimal

and did not constitute a clinical issue. This is the first

reported controlled study that goes beyond 6 months

of GAD treatment ; in fact patients were monitored for

up to 76 wk. An indirect measure of the satisfaction of

the participating patients is that two-thirds (116/187)

of the patients randomized to continued escitalopram

remained in the study until its completion ; in spite of

the discipline required and life events of all sorts. The

design of this study is similar to that with paroxetine,

in which responders to 8 wk of open-label treatment

were randomized to treatment with paroxetine or

placebo (Stocchi et al., 2003) or venlafaxine (Hackett

et al., 2000). The relapse rates in these studies were

11% for paroxetine vs. 40% for placebo, and 12% for

venlafaxine vs. only 16% for placebo. In the present

study, the 24-wk relapse rates were 18% for escitalo-

pram vs. 52% for placebo.

Since the care of patients in a controlled clinical trial

is substantially more comprehensive than in routine

outpatient settings, the risk of relapse is probably even

higher in routine settings. The subjects studied were

representative of European and Canadian patients

with primary and disabling GAD, and with symptom

severity at baseline that unquestionably justified

treatment intervention. Not only did many patients

attain remission of symptoms, but also a restoration of

their capacity for occupational performance, leisure

activities, and family relations.

One of the problems associated with a study design

that randomizes patients from active treatment to

placebo is the risk that possible discontinuation

symptoms might be misinterpreted as relapses. These

symptoms appear to be relatively minor with escita-

lopram, but to make sure, a secondary relapse analysis

was carried out excluding the first 7–14 d after rando-

mization, since SSRI discontinuation symptoms

usually peak in that period (Montgomery et al., 2003).

The hazard ratio remained essentially unchanged in

these secondary analyses, due to the low rate of dis-

continuation symptoms on switching from escitalo-

pram to placebo.

In the initial open-label period, the overall incidence

and pattern of AEs was similar to that previously seen

with escitalopram in GAD. In the entire double-blind

period, the incidence of AEs was slightly higher in the

escitalopram group than in the placebo group (56% vs.

32%). The large differences in drug exposure during

the double-blind period should be kept in mind when

interpreting these findings. Nevertheless, the inci-

dence of withdrawals from the study due to AEs was

actually lower in the escitalopram group than in the

placebo group.

There was a low level of discontinuation symptoms

with escitalopram observed in the two taper periods.

This was also seen in previous escitalopram trials

(Baldwin et al., 2004). The triad of dizziness, par-

esthesias, and nausea that has been called ‘dis-

equilibrium syndrome’ when some SSRIs and SNRIs

are abruptly withdrawn in some patients (Haddad,

2001 ; Rosenbaum et al., 1998) did not appear as a

clinical issue in this study. As with many classes of

medications, it may yet be advisable to taper the esci-

talopram dose over a 1–2 wk period.

The results of this study are also of interest in terms

of public policy. Increasingly, regulatory bodies re-

quire evidence to justify long-term pharmacotherapy

of a range of different disorders. Since GAD is a com-

mon disorder both in the general population and in

health-care settings, it is a public health priority

(Davidson, 2004 ; Stein, 2004). It is known that patients

with GAD have an increased risk of alcohol and to-

bacco misuse, cardiovascular disease, and suicide. In a

UK population survey, only 24 out of 300 (8%) GAD

8 C. Allgulander et al.

cases in the community received any kind of therapy

(Bebbington et al., 2000), indicative of the need for in-

forming policy makers and the public of the potential

benefits of treatment.

There are some limitations to consider in this study.

Patients with comorbid disorders were excluded from

the study. There is a shared diathesis for GAD and

major depression, particularly in women (Hettema

et al., 2005). In routine health services, patients with

GAD tend to seek treatment when they develop a co-

morbid depressive episode, and they are more readily

identified by the physician at that time (Weiller et al.,

1998). Thus, the results of this study cannot automati-

cally be generalized to routine health-care settings.

That being said, the efficacy of escitalopram compared

to placebo in relapse prevention in major depression

(Rapaport et al., 2004) and social anxiety disorder

(Montgomery et al., 2003) has been demonstrated and

escitalopram has been shown to be effective in GAD

(Bielski et al., 2005 ; Goodman et al., 2005). SSRIs

are recommended in treatment guidelines as first-line

medication also for patients with GAD and comorbid

conditions (Baldwin and Polkinghorn, 2005 ; Ballenger

et al., 2001).

In conclusion, 20 mg/d escitalopram showed a clear

beneficial effect relative to placebo on the time to re-

lapse of GAD. Maintenance treatment of GAD with

escitalopram produced substantial reduction of

symptoms and improved function. Patients switched

to placebo were four times more likely to suffer a re-

lapse.

Acknowledgements

The authors gratefully acknowledge the contribution

of the investigators in each of the centres in this study:

Canada : Roumen Milev, Gebrehiwot Abraham,

Emorphea Voutsilakos, Nicholas Delva, Francis John

Jarrett, Angelo Fallu, Manon Therrien, Marie-Josee

Queenton, Claude Robillard, Francisco Jose Pinero-

Medina, Anthony Levitt, Ayal Schaffer, Sue Hershkop,

Stephen Sokolov, Jacques Plamondon, Jean-Pierre

Fournier, Pratap Chokka, Lorne Warneke, Michael

Demas, Robin Reesal, Linda Dianne Hames, Badri

Ganesh Rickhi, Louis Theriault, Etienne Marquis,

Alain Maurin, Christian Calvy, Saibal Nandy,

Anthony Frank Jeraj, Jeffres Bratvold, David Bakish,

Spence A. Tighe, Hamilton Sequeira, Mark

Ujjainwalla, Rami Habib, Russell Jay Deutsch, Jean-

Michel Le Melledo, Nicholas Coupland, Philip

Tibbo, Pierre Chue, Yves Chaput, Andre Gamache,

Denis Lacroix, Pierre Bleau, Pierre Assalian; France :

Frederic Delamotte, Fabrice Lanvin, Eric Tanneau,

Francois-Xavier Poudat, Catherine Thevenon, Francis

Gheysen, Joel Langeard, Jean-Claude Petit, Pierre Le

Goubey, Dominique Servant, Jerome Prizac, Bruno

Scottez, Mocrane Abbar, Yves Caer, Fabrice Boulet,

Pierre-Henri Bondon; Germany : Cornelia Hirsch,

Andreas Fiedler, Andreas Hause, ThomasMaier, Peter

Donat, Marianne Pusskailer, Klaus Zitzmann, Utta

Thurmulla, Hans-Joarchim Schietsch, Ute Pleimes,

Klaus Sallach, Ullrich Rausch; Hungary : Erika

Szadozky, Zsuzanna Torok, Gabriella Agoston, Judit

Herr, Gyorgy Bartko, Hedvig Varadi, Eniko Gugan,

Janos Vizi, Eva Madarasz, Laszlo Tringer, Katalin

Sujto, Csilla Bolyos, Csaba M. Banki, Csaba More ;

Ireland : Eamonn Shanahan, Derek Forde, Mary

Belton, Tom Dennehy; Poland : Mariusz A. Perucki,

Bartosz Krzewinski, Witold Rembalsk, Mariusz K.

Perucki, Majciej Czerwınski, Agnieszka Nowakowska-

Rudzka, Dariusz M. Myszka, Iwona Furman, Tadeusz

Piotrowski, Mieczyslaw Janiszewski, Ewa Kordyjak

Starczewska, Wlozimierz Chrzanowski, Anna A.

Tomczak, Dariusz Juchnowicz ; Sweden : Christer

Allgulander, Sergej Andreewitch, Anna Lowenstein,

Elisabeth Tengelin, Christer Wendestam, Per Ekdal,

Leif Ostling, Kurt Wahlstedt, Christer Engstrom, Curt

Rolleri ; Switzerland : Andreas Mohl, Christian

Dietrich, Ceasar Spisla, Thomas Roost, Hanspeter

Bosshard, Isaack Biyoung, Farshid Sadeghi, Blagoje

Radosavac, Majid A. Shalchi, Liong-Seng Liem, Gerda

Mastronardi.

We also acknowledge Ross S. Baird for his assistance

in preparing the manuscript. This study was spon-

sored by H. Lundbeck A/S.

Statement of Interest

Christer Allgulander has received honoraria from,

and has conducted clinical research supported by

H. Lundbeck A/S. Ioana Florea and Anna K. Trap

Huusom are full-time employees of H. Lundbeck A/S.

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