Efficacy, Effectiveness and Efficiency of Escitalopram in the Treatment of Major Depressive and Anxiety Disorders

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Efficacy, Effectiveness and Efficiency of
            Escitalopram in the Treatment of Major
               Depressive and Anxiety Disorders
 Raymond W. Lam, Lieven Annemans

 Expert Rev Pharmacoeconomics Outcomes Res. 2007;9(6):559-576.

Abstract and Introduction
Abstract

In addition to the large personal challenge that depression and anxiety present, these disorders are
associated with a substantial burden of disability and lost productivity, and are responsible for
considerable strain on healthcare resources and on society. Escitalopram is recommended as first-line
therapy for the treatment of major depressive disorder and severe depression, and is indicated in anxiety
disorders. Compared with other antidepressants, escitalopram has equal or superior efficacy, as proven
in clinical trial settings, equal or superior real-life effectiveness, established in both clinical and
observational studies, and a better tolerability profile. While drug acquisition costs are higher for
escitalopram than for generic drugs such as fluoxetine and citalopram, numerous prospective and
modeled economic analyses show that associated direct and indirect costs of treatment are lower with
escitalopram than with citalopram, fluoxetine, sertraline and venlafaxine. Thus, escitalopram appears to
be more economically efficient than many antidepressants currently available. Escitalopram has a
prominent role in the treatment of major depressive disorder and anxiety disorders, and may also prove
to be important in the treatment of mixed depressive anxiety disorder.

Introduction

Major depressive disorder (MDD) and anxiety disorders are common forms of affective disorder. MDD
has a lifetime prevalence of approximately 16%, and is associated with substantial symptoms and role
impairment.[1] The prevalence of anxiety disorders is 25%, which includes generalized anxiety disorder
(GAD), panic disorder, social anxiety disorder (SAD) and obsessive-compulsive disorder (OCD).[2]

Depression and anxiety are commonly concomitant, with 35-60% of patients with depression also having
an anxiety disorder.[1,3,4] Similarly, the proportion of patients with anxiety disorders who experience at
least one depressive episode can be as high as 70%.[5] Presence of both disorders is linked to poorer
outcome, greater disability, poorer quality of life (QoL) and greater costs compared with either MDD or
anxiety disorder alone.[6-8]
Severe depression accounts for approximately one third of all outpatients diagnosed with depression and
all hospitalized patients with depression.[9] Severe depression can be defined as a high score on a
depression rating scale (e.g., scores of ≥28-30 on the Montgomery-Åsberg Depression Rating Scale
[MADRS], of ≥25-28 on the 17-item Hamilton Depression Rating Scale [HAM-D-17] or ≥28 on the 21-item
HAM-D).[10] On average, patients with more severe depression have worse clinical outcomes, poorer
QoL, take more sick leave and cost more to treat than patients with mild-to-moderate depression.[10]

Depression and anxiety also impose a substantial disease and economic burden on patients, caregivers
and healthcare providers and services. In Europe, depression accounts for 6% of the burden of all
diseases and 30% of the burden of all neuropsychiatric diseases, based on disability adjusted life-
years;[11] the cost of treatment, including direct and indirect costs, is estimated to be €118 billion per year
(€253 per inhabitant).[12] A breakdown of direct and indirect costs involved in the treatment of MDD and
anxiety disorders is shown in Box 1. Drug acquisition costs alone have increased many times over in the
last 20 years, mainly owing to increased prescribing and use, and higher cost products. [13] However, drug
costs represent only 4-8% of total treatment costs, while 61-65% is accounted for by indirect costs, such
as loss of productivity (e.g., sick leave, absenteeism or loss of productivity at work) or premature
death.[12,14] The main cost drivers in depression and anxiety disorders are hospitalization, which is
influenced by treatment efficacy (lower response and remission rates) and tolerability (side effects and
treatment adherence), and work productivity.[15] Differences in antidepressant effectiveness can translate
into economic savings: increased response and remission rates can lead to reduced healthcare resource
use, including fewer physician visits, fewer referrals for specialist care, a reduced need for dose
modification, switching and adjunctive medications, fewer sick days and lower hospitalization rates. [16]
Overall cost per patient per year in Europe ranges from €1200 to €8000, of which indirect costs comprise
approximately €750-6000.[12]

A major aim of treatment for MDD and anxiety disorders is complete sustained remission and the
prevention of relapse. Patients with depression who achieve remission (a maintained period of minimal
depressive symptoms) have better prognosis, function and a more stable enduring state compared with
patients who do not remit.[17] In addition, achieving remission leads to significantly reduced healthcare
costs and improved QoL.[18]

Selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI)
antidepressants are the preferred first-line therapy for MDD and anxiety disorders.[8] Escitalopram
(Cipralex®, Lexapro®) is the therapeutically active S-isomer of the antidepressant citalopram.[19] It is a
second-generation SSRI with activity on only one allosteric site and can, therefore, be classed as an
allosteric serotonin reuptake inhibitor. It is the most selective serotonin-specific antidepressant marketed
to date.[19,20] The R-enantiomer is not only inactive but appears to somewhat counteract the
antidepressant activity displayed by the S-enantiomer.[21,22] Escitalopram is approved for MDD and anxiety
disorders (GAD, SAD, OCD and panic disorder).[23] Dose-ranging placebo-controlled trials showed
escitalopram 10 mg/day to be the dose recommended for treatment of depression, titrating to 20 mg/day
if required.[24-27]

With many of the current pharmacological options being available in generic form (fluoxetine, citalopram,
sertraline and paroxetine) in Europe or the USA, proof of value for branded drugs such as escitalopram,
venlafaxine extended release (XR) or duloxetine is demanded, in order to justify the additional drug
acquisition costs. Most economic studies focus on the overall burden of depression, making it difficult to
identify the specific healthcare costs that could be affected by clinical differences between treatments.
However, some studies specifically examine the extra cost of not achieving remission, allowing for
greater understanding of the specific costs associated with pharmacological treatment. Several economic
studies based on success (remission) rates as the main outcome have shown that nonremission is a
major driver of the cost of treating MDD. For example, studies by François et al. and Demyttenaere et al.
have demonstrated that the cost associated with nonremission is significantly higher than that of
remission, mainly owing to additional costs for secondary care required.[28-30] Results from the Health
Economics of Depression in Sweden (HEADIS) study, a naturalistic observational study in 426 patients
with depression, showed that, over a 6-month observation period, remitting patients had significantly
fewer outpatient visits and fewer sick-leave days (leading to €2700 lower total cost per patient; p < 0.01)
and significantly improved health-related QoL scores compared with nonremitting patients (p < 0.01).[18]

This article is the first to review published literature relating to the clinical efficacy, real-life effectiveness
and economic efficiency of escitalopram for the treatment of MDD and anxiety disorders. The manner in
which the headings efficacy, effectiveness and efficiency will be used in this review is represented briefly
in Figure 1 and further defined below. Efficacy relates to the ability of a treatment or intervention to
produce a therapeutic effect, as measured using strict scales (often the primary end point), in a clinical
trial setting, in other words, where strict inclusion and exclusion criteria, scheduling, dosing and
monitoring processes are applied. Effectiveness is the ability of a treatment or intervention to produce a
therapeutic effect, either in a clinical trial setting (but assessed with more real-life clinical practice
measures such as remission, patient-reported outcomes (PROs) and productivity - often secondary end
points) or in observational studies, where physicians, other allied healthcare professionals and patients
are not necessarily required to adhere to strict selection criteria, treatment regimes, or monitoring
processes. Efficiency is defined as the cost-effectiveness of a treatment or intervention relative to other
treatments or interventions for a given indication.
Figure 1.

Overview of the terms efficacy, effectiveness and efficiency.

Efficacy
A common primary efficacy goal or end point in clinical trials of depression is change from baseline in
scores on clinical scales. These scales include the MADRS, which comprises ten items rated from 0
(best) to 6 (worst),[31] and the HAM-D, which can contain varying numbers of items (e.g., 6, 12, 17, 21 or
24).[32] Remission and response to interventions are often additional objectives that can be measured in a
clinical trial or clinical practice setting; however, remission as an outcome is the focus of the next section
(Effectiveness) and, therefore, will not be discussed here. For anxiety disorders, the 24-item Liebowitz
Social Anxiety Scale (LSAS) and the 14-item Hamilton Anxiety Scale (HAM-A) are commonly used
investigator-reported measures in a clinical trial setting.[33]

Escitalopram in Major Depressive Disorder

Escitalopram is an efficacious and well-tolerated treatment for MDD.[24-27] Randomized controlled trials
have shown that escitalopram is associated with significantly greater efficacy than placebo in
MDD.[24,26,27,34]

Escitalopram Versus SSRIs & SNRIs. Randomized controlled trials have also demonstrated
escitalopram to be significantly more effective than citalopram in patients with MDD. [35,36] A meta-analysis
of four trials (n = 1262) confirmed the superiority of escitalopram to citalopram, and showed the
difference to be particularly marked in severely depressed patients.[37] The meta-analysis was recently
updated[38] to include a head-to-head trial of escitalopram versus citalopram.[35] In the updated analysis,
which included 1971 patients, mean changes in MADRS scores from baseline to end point were
significantly higher for escitalopram versus citalopram (estimated mean difference, 1.20; 95% confidence
interval [CI]: 0.35-2.05; p = 0.006).[38] Escitalopram produced a significantly greater response rate
(defined as the proportion of patients with a

≥50% reduction in the MADRS score from baseline), with a response rate of 59.0% compared with
52.9% for citalopram (odds ratio [OR]: 1.44; 95% CI: 1.17-1.77; p = 0.001).[38]

The efficacy of escitalopram has also been compared with conventional SSRIs and SNRIs. In a meta-
analysis of ten studies of antidepressant treatment for MDD, escitalopram (10-20 mg/day; n = 1345) was
superior in reducing MADRS score compared with conventional SSRIs (citalopram, 20-40 mg/day;
fluoxetine, 20-40 mg/day; paroxetine, 20-40 mg/day; sertraline, 50-200 mg/day; n = 1102) and the SNRI
venlafaxine XR (75-225 mg/day; n = 240), with an estimated difference in treatment score of 1.07 (95%
CI: 0.42-1.73; p
57.8%; OR: 1.93; 95% CI: 1.41-2.64; p < 0.001) and a higher remission rate (53.8 vs 45.9%; OR: 1.59;
95% CI: 1.16-2.16; p < 0.01) than comparators (citalopram, fluoxetine, paroxetine, sertraline or
venlafaxine).[39]

The results from these pooled and meta-analyses were supported by data from two randomized, double-
blind clinical trials. In patients with severe depression at baseline (MADRS score ≥30), escitalopram 20
mg was found to be statistically significantly superior to citalopram (40 mg/day)[35] and paroxetine (40
mg/day).[36]

Escitalopram in Anxiety Disorders

Escitalopram is also approved for the treatment of anxiety disorders.[46] Its efficacy has been
demonstrated in randomized, placebo- and active comparator-controlled trials in patients with GAD,[47-52]
SAD,[53-55] panic disorder[56] and OCD.[57,58]

Several trials have evaluated escitalopram for anxiety disorders; there are three trials for which economic
analyses are also available, and these are discussed briefly here.[50-52] The data from two of these
trials[50,51] were used to develop economic models for escitalopram in GAD[59-61] and one trial evaluated
escitalopram for SAD,[52] alongside which a health economic study was conducted.[62]

Allgulander et al. evaluated the efficacy and tolerability of escitalopram versus placebo for preventing
relapse (following initial open-label escitalopram treatment) in GAD.[51] Time to relapse was longer (p <
0.001) and the proportion of patients who relapsed was lower (p < 0.001), with a 4.04-fold lower risk of
relapse (p
negative impact of poor tolerability on adherence to treatment. In MDD, the overall adverse event
frequency and the rate of premature discontinuation due to adverse events with escitalopram 10 mg/day
do not differ from placebo.[24] A 24-week study showed that escitalopram and citalopram had similar
adverse event profiles, but withdrawal rates were significantly higher with citalopram from weeks 9 to 24
(4.0 vs 11.2%; p < 0.05), suggesting that long-term tolerability was better with escitalopram.[63]
Escitalopram is better tolerated than the SNRIs venlafaxine and duloxetine; trial withdrawal rates owing
to adverse events for escitalopram were significantly lower than venlafaxine (p < 0.05)[39] or duloxetine (p
< 0.05).[40-42]

Escitalopram tolerability in patients with anxiety disorders is similar to that seen in MDD.[47,53,56] While most
of the anxiety studies were 8-12 weeks in duration, and there are no comparative data available in this
patient group,[20] escitalopram was also shown to be well tolerated in 24-week studies in SAD[55] and
OCD.[57] Long-term tolerability is particularly important in patients with panic disorders owing to the
recommended 12-month minimum duration of treatment.[64]

Effectiveness
The effectiveness of antidepressant treatments can be evaluated using various validated outcomes that
are closer to real-life efficacy than those commonly used as primary end points in clinical trials. These
include remission rates, QoL measures, PROs and productivity (i.e., how effective a treatment is at
reducing the number of sick leave days/absenteeism). In addition to clinical trials, outcomes reported in
observational studies can be valuable measures of effectiveness in a real-world setting.

Remission

Remission has been recognized as a valid and clinically relevant end point for both investigators and
practitioners, and is the desired goal of both acute and long-term treatment.[65] Remission can be defined
as the absence of (or presence of minimal) major depressive symptoms (sadness and reduced
interest/pleasure) plus the presence of less than three of the remaining Diagnostic and Statistical Manual
of Mental Disorders, 4th Edition (DSM-IV) criteria for three or more consecutive weeks.[17] Remission may
also be defined as a score within the normal range on a rating scale (e.g., MADRS score of

≤12 or HAM-D-17 score of ≤7).[31]

The effectiveness of escitalopram versus citalopram was evaluated in a double-blind trial, in which
outpatients with baseline MADRS scores of 30 or more received fixed doses of escitalopram (20 mg/day;
n = 138) or citalopram (40 mg/day; n = 142) for 8 weeks.[35] A secondary end point of the trial was
remission rate (where remission was prospectively defined as MADRS total score ≤12). The remission
rate was significantly higher in the escitalopram group versus citalopram group (56.1 and 43.6%,
respectively; p = 0.04). The corresponding adjusted number of patients needed to treat for remission was
nine (95% CI: 4-117).[35]

In the meta-analysis comparing five trials of escitalopram versus citalopram, the remission rates were
47.1 versus 43.3% (OR: 1.27; 95% CI: 1.03-1.57; p = 0.023).[38]

Patient-reported Outcomes

PRO is a measurement of any aspect of a patient's health status that comes directly from the patient.[66]
Measuring PRO in clinical trials can provide evidence of a treatment benefit from the patient perspective.
PRO instruments (such as questionnaires) can measure a range of aspects of treatment, from single
symptoms to broader concepts, such as QoL. Beyond clinical trials, researchers are also investigating
how PROs can be used in clinical practice to improve the treatment of patients.[66]

The MADRS-S is a PRO based on the MADRS.[67] This instrument was used to assess treatment
effectiveness in the head-to-head study of escitalopram versus citalopram.[35] The mean change from
baseline to end point in MADRS-S score was in favor of escitalopram (-9.9 vs -8.6 for citalopram) and the
treatment difference of 1.3 was statistically significant (p < 0.05).[35] This difference was also clinically
relevant, as it has been suggested that an improvement of 5% on a PRO is meaningful;[67] the MADRS-S
range is 0 to 27,[68] therefore, an improvement of 1.3 can be considered clinically relevant.

Another PRO instrument, which specifically evaluated the QoL during treatment with escitalopram, is the
15-item Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q15).[69] A secondary analysis
of data from the randomized, double-blind, placebo-controlled parallel group trial performed by Burke and
colleagues included results of Q-LES-Q15.[24] In this trial, in which citalopram (40 mg/day) was an active
reference to two dose levels of escitalopram (10 and 20 mg/day), 20 mg escitalopram was superior on
the Q-LES-Q15 to both escitalopram 10 mg and citalopram 40 mg (p ≤ 0.01).[70]

The effect of escitalopram on Health Related Quality of Life (HRQoL) in anxiety disorders has been
assessed. In an HRQoL evaluation conducted alongside an escitalopram-relapse prevention trial during
the 12-week open-label escitalopram treatment period, patients reported significant improvements in
HRQoL on all dimensions of the SF-36 health survey (p < 0.001).[71] In a 24-week relapse prevention
study in patients with SAD, escitalopram-treated patients reported significant improvement versus
placebo on the following SF-36 dimensions: mental health (p < 0.001), social functioning (p = 0.001), role
emotional and vitality (p < 0.05).[62] In panic disorders, escitalopram was significantly better than placebo
in improving QoL (measured by the Q-LES-Q total score).[72]

Productivity

Work productivity is often decreased in patients with depression because they take sick days more often
and for a longer duration (increased absenteeism from work), and have reduced productivity during days
at work (known as presenteeism).[73]

An economic comparison of escitalopram versus citalopram was conducted [74] alongside the head-to-
head trial.[35] The percentage of patients taking sick leave days (25.4 and 26.8%) and the average
number of sick leave days taken (9.46 and 9.28 days) were similar for both escitalopram and citalopram
in the 2-month pre-study period. However, both measures increased slightly in the 2-month study period;
the increase was greater in the citalopram group (31.7 and 12.18 days) than the escitalopram group
(26.8% and 11.56 days); the difference in number of sick leave days between the two drugs was
statistically significant (p < 0.01).[74] The observed increase in sick leave from pre-study period to
treatment period may have been due to recall bias (i.e., patients being unable to remember accurately
the number of sick days they took in the pre-study period); since the trial was randomized, however, the
bias should be equal for both treatment groups.

The randomized, double-blind trial comparing 24 weeks of escitalopram with duloxetine treatment[40]
incorporated a parallel economic analysis.[75] Escitalopram was associated with 58% shorter duration of
sick leave over the 24 weeks compared with duloxetine (p < 0.001).[75]

Escitalopram Effectiveness in Observational Studies

Results from observational and naturalistic studies support those from randomized clinical trial settings
with regards to the effectiveness of escitalopram.

In a prospective, naturalistic, 8-week study comparing escitalopram (n = 67) with citalopram (n = 60) for
severe MDD (baseline MADRS score ≥30), significantly greater improvements were observed in MADRS
score (p < 0.001), response rate (according to Clinical Global Impression of Severity [CGI-S] and
Improvement [CGI-I] scales; p < 0.001), and remission rate (MADRS score ≤12; p < 0.001) in patients
who received escitalopram versus citalopram.[76]

A large (11,760 patients) multicenter German study, evaluating the effectiveness of escitalopram for
MDD (all severities), was conducted in private practice clinics.[77] Of the 10,477 patients who completed 8
weeks of escitalopram treatment, 66% were treated in a general practitioner setting, and 33% were
treated by specialists. The response rate was 70% (≥50% decrease in score according to the short
version of the MADRS [svMADRS]) and the remission rate was 56.8% (svMADRS score ≤12) at week
8.[77] Similar to results from clinical trials, a higher response was observed in patients suffering from
severe depression (baseline svMADRS ≥30).

Escitalopram significantly reduced the number of (patient reported) sick leave days (11.0 vs 5.4 days for
the 3-month pre-study period vs the 3-month study period; p < 0.001) in an observational study of 2378
outpatients with mood or anxiety disorders in Austria.[78] CGI-S scores were also significantly improved
between baseline and 3 months of treatment with escitalopram (p < 0.001).[78]

A 12-month study of 590 patients with MDD treated with open-label escitalopram following participation
in double-blind acute trials found a favorable safety and tolerability profile with low withdrawal rates.[79]
Clinical response also steadily increased during the study period, with 86% of patients achieving
remission (MADRS score ≤12) by the end of 52 weeks. Response rates of 68% (measured as score ≤2
on the clinician assessed CGI-I) or 66% (≤2 on the patient global evaluation score) were observed in an
8-week open-label trial of escitalopram in 5433 patients with MDD treated in primary, psychiatric or other
speciality practices.[80]

Efficiency
Given the efficacy and effectiveness of escitalopram in the treatment of MDD and anxiety disorders, its
cost-effectiveness compared with other treatments is an important consideration.

Pharmacoeconomic Analyses of Escitalopram

Economic evaluations of escitalopram for the treatment of depression include three prospective studies,
conducted alongside clinical trials comparing escitalopram with citalopram,[74] venlafaxine[81] or
duloxetine,[40] and ten studies using decision analytical models comparing escitalopram with citalopram
and/or venlafaxine in various countries.[82] summarizes the studies comparing the pharmacoeconomics of
escitalopram with other antidepressants in the treatment of MDD.

Table 1. Summary of Escitalopram Pharmacoeconomic Studies in Patients With Major Depressive

Disorder, Severe Depression and Anxiety Disorders

                                       Escitalo
                                        pram
                                         dose
             Country/cu     Clinical     and      Patie               Main
               rrency        data      compara     nt     Study     outcome                  Commen
Study          (year)       source        tor     type    design    measure      Results        t           Ref.
Prospective studies
Fantino   France/€    RCT    ESC: 20   MDD     Prospe Remissio      Mean         Lower      [35,74]
                             mg/day;   OP (n   ctive    n           cost per     ADR with
                             CIT: 40   =       societal             patients     escitalop
                             mg/day    294)    perspec              were         ram due
                                               tive                 41%          to lower
                                               (direct              lower        hospitaliz
                                               healthc              with ESC     ation
                                               are                  vs CIT       rate;
                                               costs                (€96 vs      ICER
                                               plus                 163; p <     showed
                                               cost of              0.05)        ESC to
                                               sick                              be more
                                               leave)                            cost
                                                                                 effective
                                                                                 than CIT
Fernand   European    RCT    ESC:      MDD     Prospe EQ-5D         Total        ICER      [90,102
ez        (UK,               10-20     OP (n   ctive                costs        showed    ]
          Denmark,           mg/day;   =       CE                   significan   ESC to
          Finland,           VEN XR:   251)    payer                tly lower    be at
          France,            75-150            perspec              with ESC     least as
          Germany,           mg/day            tive                 after        cost
          Spain)/€                             (societa             adjustme     effective
          (2001)                               l                    nt for       as VEN if
                                               perspec              other        not more
                                               tive in              cost
                                               sensitivi            drivers (p
                                               ty                   = 0.007)
                                               analysis
                                               include
                                               d
                                               estimat
                                               ed
                                               costs of
                                               lost
                                               producti
                                               vity)
Modeled analyses
Armstron US/$         Two    ESC:      MDD     6-        Cost per   Total        ICER     [24,85,
g        (2005)       RCTs   10-20     OP      month     QALY       direct       showed   102]
                             mg/day;           CUA       gained     costs:       ESC
                             SER:              model                $919 for     dominate
                             50-200            (direct              ESC and      d SER
                             mg/day            costs                $1351 for
                                               only)                SER;
                                                                    QALYs
                                                                    gained:
                                                                    0.403 for
                                                                    ESC and
                                                                    0.393 for
                                                                    SER;
                                                                    Differenc
                                                                    e mainly
                                                                    due to
                                                                    drug
                                                                    titration
costs and
                                                                        adverse
                                                                        events;
                                                                        Cost/QA
                                                                        LY:
                                                                        $2280 for
                                                                        ESC and
                                                                        $3440 for
                                                                        SER
Demytte    Belgium/€   One       ESC:     MDD    6-         Remissio    Success                [16,28]
naere      (2003)      MA, ad    10-20    OP     month      n           rates
                       hoc       mg/day;         two-       (success)   (remissio
                       survey    CIT: 20-        path       rates       n at week
                       and       40              decisio                8
                       expert    mg/day;         n                      sustained
                       panel     VEN XR:         analytic               at week
                                 75-150          model;                 24):
                                 mg/day          two                    62.3%
                                                 parallel               with ESC
                                                 analyse                vs 57.2%
                                                 s: ESC                 with CIT;
                                                 vs CIT;                66.6%
                                                 ESC vs                 with ESC
                                                 VEN                    vs 67.0%
                                                                        with
                                                                        VEN;
                                                                        Total
                                                                        costs
                                                                        were
                                                                        lower for
                                                                        ESC than
                                                                        CIT from
                                                                        payer
                                                                        (€390 vs
                                                                        411) or
                                                                        societal
                                                                        (€1162
                                                                        vs 1276)
                                                                        perspecti
                                                                        ve; Total
                                                                        costs
                                                                        were
                                                                        lower for
                                                                        ESC than
                                                                        VEN
                                                                        from
                                                                        payer
                                                                        (€333 vs
                                                                        350) or
                                                                        societal
                                                                        (€1002
                                                                        vs 1036)
                                                                        perspecti
                                                                        ve
François   Finland/€   Data      ESC:      MDD   6-         Remissio Overall        Sensitivit [29]
           (2000)      from      10-20     OP    month      n         success       y
                       several   mg/day;         two-       (success) rate          analysis
RCTs,       CIT: 20-       path       rates       higher for   showed
                     literatur   40             decisio    (CE,        ESC vs       that ESC
                     e review    mg/day;        n          QALY,       other        was
                     and         FLU: 20-       analytic   CU)         ADs;         associate
                     expert      40             model;                 Average      d with
                     panel       mg/day;        CE and                 expected     lower
                                 VEN:           CU                     total        costs
                                 75-150         analyse                costs        and
                                 mg/day         s                      were         higher
                                                                       similar      success
                                                                       for ESC      rate than
                                                                       and VEN      CIT or
                                                                       (€857        FLU;
                                                                       and 876),    ESC
                                                                       and          more
                                                                       higher for   cost
                                                                       CIT and      effective
                                                                       FLU          than
                                                                       (€990        VEN due
                                                                       and 959);    to lower
                                                                       Cost/suc     costs
                                                                       cess         and
                                                                       higher       similar
                                                                       with ESC     success
                                                                       than         rates
                                                                       other
                                                                       ADs;
                                                                       Cost/QA
                                                                       LY higher
                                                                       than with
                                                                       other
                                                                       ADs
François   Norway/   Data        ESC:     MDD   6-         Remissio    Success      Sensitivit [30]
           NOK       from        10-20    OP    month      n           rates        y
           (2000)    several     mg/day;        two-       (success)   highest      analysis:
                     RCTs,       CIT: 20-       path       rates       with ESC     ESC
                     literatur   40             decisio                (64.2 vs     remained
                     e review    mg/day;        n                      58.7,        more
                     and         FLU: 20-       analytic               58.7 and     cost
                     expert      40             model                  62.1%        effective
                     panel       mg/day;        CE                     with CIT,    than FLU
                                 VEN:           (direct                FLU and      and CIT
                                 75-150         costs                  VEN,         even at
                                 mg/day         only)                  respectiv    the
                                                                       ely);        extremes
                                                                       Total        of values
                                                                       costs        and likely
                                                                       similar      to be
                                                                       for ESC      more
                                                                       and VEN      cost
                                                                       and          effective
                                                                       higher for   than
                                                                       CIT and      VEN
                                                                       FLU;
                                                                       Total
                                                                       cost per
                                                                       success:
                                                                       ESC
30,600N
                                                                          OK; CIT
                                                                          38,000N
                                                                          OK; FLU
                                                                          38,400N
                                                                          OK; and
                                                                          VEN
                                                                          33,800N
                                                                          OK
François   Sweden/    Compar ESC;            MDD   6-         Remissio    Success    Increase [83]
           SEK (2000) ative     CIT;         OP    month      n           rates:     drug
                      trial     FLU;               two-       (success)   ESC        costs
                      data,     VEN                path       rates       63.5%;     more
                      publishe                     decisio                CIT        than
                      d                            n                      57.2%;     offset by
                      literatur                    analytic               FLU        decrease
                      e and                        model;                 57.0%;     in other
                      expert                       CE                     VEN        healthcar
                      opinion                      (payer                 61.1%;     e costs
                                                   perspec                Cost per
                                                   tive)                  patient:
                                                                          ESC
                                                                          SEK15,6
                                                                          70; CIT
                                                                          SEK18,8
                                                                          60; FLU
                                                                          SEK19,0
                                                                          50; VEN
                                                                          16,580
Hemels     Austria/€   One        ESC:       MDD   6-         Remissio    Success    Sensitivit [26,86]
           (2002)      RCT,       10-20      OP    month      n           rates:     y
                       current    mg/day           two-       (success)   ESC        analysis:
                       practice   CIT: 20-         path       rates       64.5%;     ESC
                       and        40               decisio                CIT        remained
                       expert     mg/day           n                      59.1%;     dominant
                       opinion                     analytic               Cost per   even
                                                   model;                 success:   when
                                                   CE                     Payer:     CIT drug
                                                   (payer                 €608 vs    cost = 0
                                                   and                    723;
                                                   societal               Society:
                                                   perspec                €3034 vs
                                                   tive)                  3670
Hemels     Austria/€   RCT        ESC:     MDD     6-         Remissio    Success    Sensitivit [90,103
           (2002)                 10-20    OP      month      n           rates:     y          ]
                                  mg/day;          two-       (success)   ESC        analysis:
                                  CIT: 20-         path       rates       64.5%;     ESC
                                  40               decisio                CIT        remained
                                  mg/day;          n                      59.1%;     dominant
                                  VEN XR:          analytic               VEN        in both
                                  75-150           model;                 62.2%;     payer
                                  mg/day           CE                     Cost per   and
                                                   (payer                 success    societal
                                                   and                    (ESC vs    perspecti
                                                   societal               CIT and    ve
                                                   perspec                VEN):      analyses
tive)                  Payer:
                                                                       €608 vs
                                                                       723 and
                                                                       650;
                                                                       Society:
                                                                       €3034 vs
                                                                       3670 and
                                                                       3269
Hemels    Denmark/D One          ESC:     MDD   6-         Remissio    Success     Sensitivit [16,93]
          KK (2004) RCT          10-20    OP    month      n           rates:      y
                    current      mg/day;        two-       (success)   ESC         analysis:
                    practice     CIT: 20-       path       rates       61.1% vs    ESC
                    and          40             decisio                CIT         remained
                    expert       mg/day;        n                      58.9%;      dominant
                    opinion      VEN XR:        analytic               ESC         in both
                                 75-150         model;                 69.1% vs    payer
                                 mg/day         two                    VEN         and
                                                parallel               68.6%;      societal
                                                analyse                Cost per    perspecti
                                                s: ESC                 success:    ve
                                                vs CIT;                ESC vs      analyses
                                                ESC vs                 CIT;
                                                VEN;                   Payer:
                                                CE                     23,535D
                                                (payer                 KK vs
                                                and                    25,943D
                                                societal               KK;
                                                perspec                Society:
                                                tive)                  75,991D
                                                                       KK vs
                                                                       87,926D
                                                                       KK; ESC
                                                                       vs VEN;
                                                                       Payer:
                                                                       16,767D
                                                                       KK vs
                                                                       17,847D
                                                                       KK;
                                                                       Society:
                                                                       56,782D
                                                                       KK vs
                                                                       58,717D
                                                                       KK
Kulp      Germany/€   Clinical   ESC: 10 MDD    70-day     Remissio    ESC was     ICER       [91]
                      data       mg/day; OP     CE         n           associate   favored
                      and        VEN XR:        Markov     (success)   d with      ESC
                      physicia   75             model      rate        similar     over
                      ns         mg/day                                success     VEN XR
                      survey                                           rates and
                                                                       lower
                                                                       costs
                                                                       than VEN
                                                                       XR
                                                                       (€7446
                                                                       vs 9836)
Sørense   Denmark/D System       ESC:    MDD    6-         Remissio    ESC had     Sensitivit [87]
n          KK (2004)   atic        10-20    OP    month    n              a lower      y
                       literatur   mg/day;        three-   (success)      cost per     analysis
                       e           CIT: 20-       path     rate           success      showed
                       review,     40             decisio                 than CIT:    ESC to
                       ad hoc      mg/day;        n                       Payer:       be more
                       survey      VEN XR:        analytic                22,323D      cost
                       and         75-150         model;                  KK vs        effective
                       expert      mg/day         Payer                   25,778D      than CIT
                       opinion                    and                     KK;          and
                                                  societal                Societal:    similar in
                                                  perspec                 72,399D      cost-
                                                  tive                    KK vs        effective
                                                                          87,786D      ness to
                                                                          KK;          VEN
                                                                          Success
                                                                          rates and
                                                                          costs
                                                                          were
                                                                          similar
                                                                          for ESC
                                                                          and VEN
Sullivan   USA/$       Literatur All      MDD     6-         EQ-5D-       ESC was      Sensitivit [84]
           (2003)      e review currently OP      month      based        the least    y
                                 markete          two-       QALY         costly of    analysis
                                 d SSRIs:         path       (including   all SSRIs    showed
                                 ESC,             decisio    relative     and had      that ESC
                                 CIT,             n          rates of     the          was the
                                 FLU,             analytic   ADRs)        highest      most
                                 PAR,             model;                  effectiven   likely to
                                 PAR              CE and                  ess          be cost
                                 CR,              CU                                   effective
                                 SER,
                                 VEN and
                                 VEN XR
Wade       UK/£        Meta-       ESC:     MDD   6-         Remissio     ESC vs       ESC        [16,92]
           (2003)      analysis    10-20    OP    month      n rates,     CIT:         dominate
                       of RCTs     mg/day;        two-       relapse      costs        d CIT;
                       and         CIT: 24-       path       rates and    were         ESC had
                       GPRD        40             decisio    adverse      lower        lower
                       data,       mg/day;        n          events       and          cost per
                       publishe    VEN XR:        analytic                success      success
                       d           75-150         model;                  rate         than
                       literatur   mg/day         Payer                   higher       VEN but
                       e and                      and                     with         differenc
                       expert                     societal                ESC.         e was
                       opinion                    perspec                 Costs per    not
                                                  tive                    success      significan
                                                                          were 732     t
                                                                          vs 933
                                                                          (payer)
                                                                          and 3635
                                                                          vs 4519
                                                                          (societal)
                                                                          ; ESC vs
                                                                          VEN:
                                                                          costs
                                                                          were
lower
                                                                           with ESC
                                                                           and
                                                                           success
                                                                           rates
                                                                           similar.
                                                                           Costs per
                                                                           success
                                                                           were 546
                                                                           vs 607
                                                                           (payer)
                                                                           and 2640
                                                                           vs 2693
                                                                           (societal)
Severe depression
Danchen Norway/NO Data          ESC:       SD       12-      Remissio      ESC vs       Results   [96]
ko      K (2006)  from          10-20      OP       month    n rates       CIT:         robust to
                  several       mg/day;    (MAD     two-                   higher       changes
                  RCTs,         CIT: 20-   RS       path                   effectiven   but
                  literatur     40         ≥30      decisio                ess and      model
                  e             mg/day;    at       n                      lower        substanti
                  review,       VEN:       baseli   analytic               costs        ally
                  national      75-225     ne)      model;                 (cost per    depende
                  sources       mg/day              societal               success:     nt on
                  and                               perspec                113,213      productiv
                  expert                            tive                   NOK vs       ity loss
                  panel                                                    123,971      inputs
                                                                           NOK);
                                                                           ESC vs
                                                                           VEN:
                                                                           higher
                                                                           effectiven
                                                                           ess (1st
                                                                           line) and
                                                                           QALYs
                                                                           (cost per
                                                                           success:
                                                                           106,733
                                                                           NOK vs
                                                                           115,548
                                                                           NOK)
Wade      UK/ £     Meta-       ESC:       SD       6-         Remissio    ESC          Sensitivit [44,94]
          (2003)    analysis    10-20      (MAD     month      n,          costs        y
                    of RCTs     mg/day;    RS       two-       discontin   were         analysis
                    and         CIT: 24-   ≥30      path       uation      lower        showed
                    GPRD        40         at       decisio    and         and          that ESC
                    data,       mg/day     baseli   n          response    success      dominate
                    publishe               ne)      analytic   rates       rate         d CIT
                    d                               model;                 higher
                    literatur                       payer                  with ESC
                    e and                           and                    vs CIT;
                    expert                          societal               Total
                    opinion                         perspec                cost per
                                                    tive                   success:
                                                                           ESC
                                                                           £786 vs
CIT £932
                                                                              (payer)
                                                                              and
                                                                              £1283 vs
                                                                              £1521
                                                                              (societal)
Hemels    Austria/€   Pooled      ESC:       SD       6-       Remissio       ESC vs       Sensitivit [43,104
          (2002)      analysis    10-20      (MAD     month    n rates        CIT          y          ]
                      of three    mg/day;    RS       two-                    success      analysis
                      RCTs        CIT: 20-   ≥30      path                    rates        showed
                                  40         at       decisio                 53.7 vs      that ESC
                                  mg/day     baseli   n                       48.7%;       dominate
                                             ne)      analytic                Total        d CIT
                                                      model;                  cost per     even if
                                                      Payer                   success:     CIT drug
                                                      and                     ESC          cost = 0
                                                      societal                €2879 vs
                                                      perspec                 CIT
                                                      tive                    €3803
                                                                              (payer);
                                                                              €5610 vs
                                                                              €6979
                                                                              (societal)
Anxiety disorders
Jørgense UK/£         RCT,        ESC:       GAD      9-         Success      Success      Sensitivit [50,59,
n        (2005)       epidemi     10-20               month      (response    rates        y          105]
                      o-          mg/day;             two-       at 12        were         analysis
                      logical     PAR:                path       weeks        higher       demonstr
                      study,      20-50               decisio    and no       and costs    ated
                      publishe    mg/day              n          relapse      lower        ESC
                      d                               analytic   after        with ESC     dominan
                      literatur                       model      further 24   vs PAR       ce over
                      e and                           based      weeks)       (lower       PAR
                      expert                          on                      costs due    even
                      opinion                         NICE                    to lower     when
                                                      treatme                 rates of     PAR
                                                      nt                      sick         drug cost
                                                      guidanc                 leave,       =0
                                                      e;                      secondar
                                                      societal                y care
                                                      perspec                 and
                                                      tive                    switch
                                                                              rates);
                                                                              Total 9-
                                                                              month
                                                                              costs:
                                                                              ESC
                                                                              £8434 for
                                                                              ESC vs
                                                                              £9843
                                                                              PAR
Servant   European/€ RCT          ESC:       SAD      Prospe     Relapse      Improved     Higher     [52,62]
          (2005)                  10-20               ctive      preventio    PRO with     efficacy
                                  mg/day              societal   n and        ESC (p <     and
                                                      perspec    PRO          0.05);       lower
                                                      tive                    2.8-fold     costs vs
(direct               reduced     placebo;
                                                        costs                 risk of     Costs
                                                        and                   relapse     with
                                                        sick                  with ESC    ESC, but
                                                        leave                 (p <        not
                                                        costs)                0.0001);    placebo,
                                                                              Cost per    decrease
                                                                              relapse     d over
                                                                              with ESC    study
                                                                              prevente    period
                                                                              d €400

AD = Antidepressant; ADR = Adverse drug reaction; CE = Cost-effectiveness; CIT = Citalopram; CR =
Controlled release; CU = Cost-utility analysis; EQ-5D = 5-item EuroQoL questionnaire; ESC =
Escitalopram; FLU = Fluoxetine; GAD = Generalized anxiety disorder; ICER = Incremental cost-
effectiveness ratio; MA = Meta-analysis; MADRS = Montgomery-Åsberg Depression Rating Scale; MDD
= Major depressive disorder; NICE = National Institute for Clinical Excellence; OP = Outpatients; PAR =
Paroxetine; PRO = patient-reported outcome; QALY = Quality-adjusted life years; RCT = Randomized
controlled trial; Remission rate = Proportion of patients with MADRS ≤12 at end point; SAD = Social
anxiety disorder; SD = Severe depression; SER = Sertraline; SSRI = Selective serotonin reuptake
inhibitor; VEN = Venlafaxine; XR = Extended release

Escitalopram Versus SSRIs in Major Depressive Disorder

Several studies have shown escitalopram to be cost effective compared with standard SSRIs. [29,30,74,82-85]
The cost-effectiveness of escitalopram versus citalopram has been assessed extensively.

Escitalopram Versus Citalopram

The economic evidence for escitalopram versus citalopram has been generated using three different
methodologies:

       A prospective cost-effectiveness analysis[74]

       Nine country-specific economic modeled analyses[82]

       Simple model based on the evaluation of cost of remission versus nonremission [18]
A prospective cost-effectiveness analysis of escitalopram versus citalopram, based on the double-blind
randomized clinical trial performed by Moore and colleagues[35] in 294 outpatients with MDD, showed that
escitalopram was dominant over citalopram (i.e., that escitalopram was more effective and associated
with significant cost-savings).[74] Patients receiving escitalopram were significantly more likely to achieve
remission (55 vs 44%; p < 0.05). Mean per-patient costs were 41% lower (€96 vs €163; p < 0.05) for the
escitalopram group compared with the citalopram group, mainly accounted for by differences in
hospitalization costs.[74] In the cost-effectiveness analysis, bootstrapped CIs on the difference in costs
and effectiveness were significantly in favor of escitalopram.[74]

The prospective data generated by Fantino et al. are consistent with data from modeled analyses. A
qualitative review of eight country-specific economic modeled analyses (seven European countries and
Canada), using best practice according to the healthcare system in each country, concluded that
escitalopram is cost effective compared with citalopram and may provide cost-savings from both
healthcare payer and societal perspectives. Effectiveness measures included remission rates or PRO,
and cost-effectiveness was expressed as cost per successfully treated patient. Savings were mainly
attributed to lower rates of referral for specialist care and hospitalization.[82] Economic analyses in
Finland, Sweden and Norway using a 6-month, two-path decision analysis model developed by François
et al. found that escitalopram was cost effective compared with citalopram when used as first-line
therapy for MDD.[29,30,83] In the Finnish study, escitalopram dominated citalopram, in other words,
escitalopram was associated with lower costs and more quality-adjusted life years (QALYs) gained.[29]

Economic studies in Austria[86] and Belgium[28] produced similar results with an adapted 6-month two-path
decision analytic model using remission rates as the main outcome. Hemels et al. showed that
escitalopram was cost effective compared with citalopram from the perspective of the healthcare
insurance system and society.[86] Data from the economic analysis by Demyttenaere et al. also showed
that escitalopram was dominant (less costly with more patients in remission) over citalopram. The main
cost driver was the difference in remission rates between the two treatments.[28] A recent Danish study
also showed significant dominance of escitalopram over citalopram owing to greater clinical benefit and
reduced costs for both payers and society.[87]

A simple modeling approach to compare the cost-effectiveness of escitalopram with citalopram is to
perform a cost analysis of remission. Using the remission rates observed in the meta-analysis by Lançon
et al. (escitalopram, 47.1%; citalopram, 43.3%) and the 6-month costs of remission and nonremission
estimated in the HEADIS study (cost of remission: €4221 and cost of nonremission: €6894 per patient
treated),[18,38] the 6 month cost per 100 patients can be estimated at €563,502 for escitalopram-treated
patients versus €573,659 for citalopram-treated patients (a net saving of €10,157 with escitalopram).
Escitalopram Versus SNRIs in Major Depressive Disorder

Escitalopram Versus Venlafaxine. A review of clinical and economic studies suggests that, given the
fact that escitalopram is at least as effective and better tolerated than venlafaxine XR, it may be more
cost effective.[88] A prospective economic study found that escitalopram was at least as cost effective as
venlafaxine XR.[81] These results contradict the perception that venlafaxine is superior (in cost-
effectiveness terms) to SSRIs, which was possibly gained from data from earlier studies comparing
venlafaxine with older SSRIs.[89] Doyle and colleagues performed a multinational (ten countries)
pharmacoeconomic analysis comparing venlafaxine immediate release (IR) with SSRIs and tricyclic
antidepressants for MDD using a decision analytic model.[89] Venlafaxine IR was less costly per patient
success (50% reduction in HAM-D or MADRS score) than SSRIs (each country analysis including at
least two of citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline), except in Poland (inpatient
setting) and Italy (outpatient setting).[89]

The prospective cost-effectiveness analysis of escitalopram versus venlafaxine XR mentioned
previously[81] was conducted in tandem with an 8-week, randomized, double-blind, clinical trial that
compared escitalopram (10-20 mg/day) with venlafaxine XR (75-150 mg/day) in patients with MDD.[90]
The analysis, using the 5-dimension EuroQoL questionnaire (EQ-5D) as the primary efficacy measure,
was performed from the perspective of the healthcare payer and included 251 patients from several
European countries.[81] Both treatment groups achieved a significant and similar improvement in QoL.
Total treatment costs per patient were 32% lower with escitalopram compared with venlafaxine XR (€110
vs 161), as a result of lower drug acquisition costs (€62 vs 84) and fewer hospitalizations (inpatient care
costs, €0 vs 46), but this difference was not statistically significant. A multivariate analysis was
performed, adjusting for factors associated with healthcare costs (receiving escitalopram, being from
French or British sample, male sex, age ≥60 years, living alone or in an urban area, being unemployed or
a nonworking spouse, and having at least some problems on EQ-5D self-care, usual activities or pain
dimensions); escitalopram was associated with significantly lower costs than venlafaxine XR (40% lower
for the average patient; p = 0.007). Both drugs were effective and an analysis of the EQ-5D scores
showed no difference between the drugs. Hence, although escitalopram was not found to be dominant
(i.e., more effective and less costly), it was associated with lower costs and equal effectiveness
compared with venlafaxine XR.[81]

The qualitative review of country-specific economic modeled analyses discussed previously (comparing
escitalopram with citalopram) also included studies comparing escitalopram with venlafaxine XR.[82]
These analyses have indicated that escitalopram treatment is associated with lower total costs than
venlafaxine XR treatment in MDD.[28-30,83,91] In Danish and UK modeled analyses of escitalopram- and
venlafaxine-related costs, escitalopram was associated with higher success (remission) rates, and lower
total, direct and indirect costs compared with venlafaxine.[92,93] In addition, a US modeled analysis showed
that escitalopram was likely to be more cost effective than venlafaxine XR, from the perspective of a US-
managed care payer, owing mainly to the lower costs associated with fewer adverse drug reactions. [84] Of
the published economic analyses comparing escitalopram with venlafaxine, one report (a country-
specific modeled analysis conducted in Denmark) showed that escitalopram was associated with a
slightly higher 6-month remission rate and was slightly less expensive than venlafaxine;[87] the other
studies showed larger differences in effects and costs.

A recent review of head-to-head clinical studies and economic analyses comparing escitalopram and
venlafaxine XR concluded that escitalopram is at least as effective as venlafaxine XR in terms of
improvements in MADRS score from baseline, response and remission rates and health-related QoL,
and may have advantages in terms of tolerability, time to remission and cost-effectiveness. Greater cost-
effectiveness has been demonstrated from both a payer and a societal perspective. [88]

Escitalopram Versus Duloxetine. The cost-effectiveness analysis conducted alongside the clinical trial
comparing 24 weeks of escitalopram with duloxetine in outpatients with MDD[40] revealed that
escitalopram appeared to be more effective on the Sheehan Disability Scale and less costly than
duloxetine.[75] Among patients who completed 24 weeks of treatment, patients receiving escitalopram had
significantly lower total cost (over £1000) compared with duloxetine (p = 0.002), and a 58% reduction of
sick-leave duration (p
versus £933 (21.5% lower) from a UK National Health Service perspective, and £3635 versus £4519
(19.6% lower) from a societal perspective.[92] Similarly, in the severe depression study of patients with
baseline MADRS score of 30 or more, success (remission) rates were higher and costs were lower with
escitalopram compared with citalopram: success rates were 53.7 versus 48.7% and total costs were
£422 versus £454 (NHS perspective) and £690 versus £740 (societal perspective). Again, average cost
per success for escitalopram versus citalopram were £786 versus £932 (15.7% lower) from an NHS
perspective, and £1283 versus £1521 (15.6% lower) from a societal perspective.[94] Multivariate analysis
showed that escitalopram was the more effective therapy from both perspectives and, even with
citalopram costs given as zero, escitalopram remained the more cost-effective therapy from a societal
perspective.

Two Norwegian analyses compared the cost-effectiveness of escitalopram with other antidepressants,
one in MDD and one in severe depression.[95,96] Both models were probabilistic, two-path decision analytic
models, using remission as the outcome and head-to-head clinical trial data, published data, national
sources and expert panel estimations for costs and utilization. In the MDD study, escitalopram was
compared with citalopram, fluoxetine and venlafaxine: overall success (remission) rates were 64.2, 58.7,
58.7 and 62.1%, respectively. Escitalopram was dominant over all comparators, being more effective and
less costly when total, direct or indirect costs were taken into consideration; 6-month cost per success
was 6700NOK, 8400NOK, 8550NOK and 8200NOK, respectively, from the payer perspective, and
30,600NOK, 38,000NOK, 38,400NOK and 33,800NOK, respectively, from a societal perspective. [95] In the
study of patients with severe depression (baseline MADRS score ≥30), escitalopram was compared with
citalopram and venlafaxine from a societal perspective over a 12-month period. Again, escitalopram was
more effective and less costly than both citalopram and venlafaxine. For escitalopram versus citalopram,
success (remission) rates were 53.6 versus 49.0% and costs per patient were 113,213 versus
123,971NOK. For escitalopram versus venlafaxine, costs per patient were 106,733NOK versus
115,548NOK.[96]

Cost-effectiveness of Escitalopram in Anxiety Disorders

There have been fewer economic analyses of escitalopram in the treatment of anxiety disorders than for
MDD. Results from three analyses of escitalopram for GAD are available; two for escitalopram versus
paroxetine (one UK[59] and one US[60,61]), and one for escitalopram versus venlafaxine (US).[97] For SAD,
the cost-effectiveness of escitalopram compared with placebo for the prevention of relapse has been
analyzed.[98,99] No economic analyses of escitalopram for OCD have been published to date.

Generalized Anxiety Disorder. In the UK study comparing the cost-effectiveness of escitalopram and
paroxetine in the treatment of GAD, the analysis was performed from a societal perspective using a 9-
month decision analytic model, adapted to the UK setting based on treatment success (defined as
response after 12 weeks of treatment and no relapse during the following 24 weeks) as the main
outcome measure.[59] The first-line success rate was higher in escitalopram recipients (49.6 vs 35.2%)
and discontinuation rates due to adverse events were significantly lower than with paroxetine.
Escitalopram was associated with lower total costs and resource use, resulting from lower rates of
switching drugs and lower use of secondary care owing to increased work productivity.[59]

Erder and colleagues evaluated both escitalopram versus paroxetine and escitalopram versus
venlafaxine for GAD in a US setting.[60,61,97] Both studies used cost-minimization models from a US
managed-care perspective, and were based on outcomes and costs from randomized, parallel-group,
fixed dose, multicenter trials.[50,100] A 13% lower cost was associated with escitalopram versus paroxetine,
primarily owing to fewer hospitalization days, a result that was robust, as determined through sensitivity
analysis.[60,61] Cost-savings (60%; cost per patient, US$136 vs US$334) were also observed with
escitalopram versus venlafaxine XR.[97]

Social Anxiety Disorder. In a double-blind, placebo-controlled trial of escitalopram for SAD, there were
significant improvements in PRO (SF-36 scores) in the escitalopram group compared with placebo
group.[62] The total costs (from a societal perspective) in the escitalopram group decreased significantly
from baseline to end of study (p = 0.02), while those in the placebo group remained constant. The
incremental cost per relapse prevented with escitalopram was estimated to be €400. [62]

Expert Commentary
The clinical efficacy of escitalopram is superior to placebo, and equal or superior to the SSRIs and
SNRIs currently available, and has a better tolerability profile. The real-life effectiveness of escitalopram,
as shown through clinical and observational studies, is also well founded.

In terms of economic efficiency, the cost-effectiveness and cost-utility advantages of escitalopram
compared with other SSRIs and the SNRI duloxetine has been demonstrated in prospective
studies,[62,74,75,81] modeled analyses[28-30,59-61,83,86,87,94,96] and meta-analyses/systematic reviews.[82,88] The cost
advantages of escitalopram were independent of the geographical area studied, specific outcomes and
sources of costs employed in the analyses, perspective used (payer or societal) and indication or
comparator agents investigated. All retrospective modeled analyses were country specific since valid
models, using data from more than one country, are difficult to construct, although not impossible. [89]
Simple models employing remission data as the primary outcome showed similar results to those using
more complex decision trees. Most studies utilized methods of validating the data whether by sensitivity
analyses, data adjustment for baseline factors other than treatment known to impact cost and/or
calculation of incremental cost-effectiveness ratios.

In both the modeled and the prospective analyses, the main reason for the reduction in overall direct
costs with escitalopram therapy was the reduced need for secondary care, particularly hospitalization,
and lower product costs than other branded antidepressants. The relative cost-effectiveness of
escitalopram was more pronounced when productivity-related costs (sick leave) were included in the
model.

When the costs of nonremission versus remission are taken into consideration, escitalopram, based on
its superior ability to improve remission rates, provides more cost savings relative to other treatments;
these cost-savings outweigh cost-savings made through the use of generic versions of drugs.

These findings show that escitalopram is more cost effective than other SSRIs and at least as cost
effective as venlafaxine in MDD; the single study comparing escitalopram with duloxetine suggests that
escitalopram is more cost effective, although further studies are required to confirm this. What is also
significant is that many of the analyses included comparisons with generic agents (fluoxetine and
citalopram). Compared with these agents, escitalopram was shown to be more cost effective, even when
some analyses set the generic drug acquisition cost as zero, suggesting that the drug acquisition cost is
not the primary driver of cost of treatment in these disorders.

Most cost analyses used a 6-month time frame. Therefore, longer-term prospective economic studies or
prolonged modeling analyses are needed to investigate whether the cost benefits achieved with
escitalopram are maintained over the longer term. This is important owing to the chronic nature of these
disorders and the likelihood of the need for long-term treatment. Another potential limitation is that all
these studies (as with most economic analyses of medications) were sponsored by the manufacturer of
escitalopram; although the studies were randomized and double-blind, sponsor bias cannot be ruled out
entirely.

Escitalopram has clearly demonstrated cost-effectiveness benefits for MDD, severe depression and
anxiety disorders. This, together with the fact that the majority of patients with depression also have
comorbid anxiety, suggest that escitalopram has the potential to provide similar clinical benefits in
patients with mixed depressive anxiety disorder and these benefits may translate into greater cost-
effectiveness compared with other agents. However, this needs to be formally demonstrated in robust
cost analyses in this population. MDD and anxiety disorders are difficult to differentially diagnose in many
patients in the primary care setting, therefore a single, effective and well-tolerated drug for first-line
therapy of individual disorders or comorbid disorders is attractive.

As has been shown in these analyses, one of the main drivers for the lower costs with escitalopram
therapy is its benign tolerability profile. This, together with less titration required compared with sertraline
and the SNRIs, facilitates the management of patients with depression and comorbidities.

In conclusion, extensive evidence from clinical and economic studies and meta-analyses shows that
escitalopram is good value for money. It is effective in reducing symptoms of depression and anxiety, in
preventing relapse and improving remission rates, and this can typically be achieved without
compromising safety and at lower overall costs of treatment compared with several agents.

Five-year View
The WHO predicts that by 2020 MDD is expected to move from fourth to second place in terms of
greatest global disease burden, therefore increasing attention to the health burden of MDD and anxiety
disorders is expected in the next 5 years.[101] Recent improvements in the understanding of the precise
distinctions between the different depressive and anxiety disorders should lead to improvement in
differential diagnosis based on revised International Classification of Disease classification and revised
diagnostic criteria in DSM, particularly in anxiety disorders and mixed depressive-anxiety disorder.

Healthcare funding in many countries is coming under increasing pressure, therefore recognition of the
main drivers of cost of treatment may need to improve. For example, healthcare payers need to be
aware of the relatively low impact of drug cost on total disease costs (direct and indirect) and the high
rate and costs of absenteeism and presenteeism in inadequately treated patients. In addition, payers
should appreciate the impact of treatments to reduce total health costs rather than the current 'one-eyed'
focus on lower drug acquisition costs. More consistent use in economic analyses of clinical outcomes
that have been shown to affect total cost, in other words, remission rate, time to remission and
tolerability, should give a better overall view of the real costs and benefits of treatments.

Evidence of important differences between antidepressant medications in terms of clinical efficacy and
tolerability profiles will increase. This, in addition to further recognition of the problems posed by poor
treatment adherence and the benefits of a simple dosing regimen, should result in further use of the
more effective and better tolerated agents as first-line therapy, leading to a greater potential to reduce
total costs in MDD and anxiety disorders. The publication of additional clinical evidence on optimal
treatment regimens, including more aggressive treatment for longer durations, may also result in lower
overall costs of disease.
Sidebar: Key Issues
     The burden of major depressive disorder (MDD) and anxiety disorders on healthcare resources
      and society is increasing.

     Escitalopram, compared with some selective serotonin reuptake inhibitors (SSRIs), is associated
      with greater improvements in Montgomery-Åsberg Depression Rating Scale score, and greater
      response and remission rates in MDD; escitalopram is at least as effective as venlafaxine and
      duloxetine.

     Escitalopram is better tolerated than citalopram, sertraline, fluoxetine, paroxetine, venlafaxine
      and duloxetine.

     Owing to its beneficial efficacy and tolerability profile, escitalopram may be more cost effective
      than other SSRIs and venlafaxine and duloxetine in MDD (including severe depression), mainly
      because of savings resulting from lower need for secondary care and fewer sick leave days. The
      cost-effectiveness of escitalopram relative to other antidepressants has been demonstrated
      using pharmacoeconomic models and prospective analyses using total, direct and indirect costs,
      from both a payer and a societal perspective.

     Escitalopram has also been shown to be more cost effective than paroxetine in generalized
      anxiety disorder.

     Further economic studies with robust methodology, particularly prospective randomized studies
      or those based on real-life data from registries, are required to confirm the cost-effectiveness
      advantages of escitalopram over serotonin-norepinephrine reuptake inhibitors in MDD, and to
      provide further evidence for the relative cost-effectiveness of escitalopram in anxiety disorders
      and mixed depressive anxiety disorder.
Acknowledgments

Writing assistance was utilized in the production of this manuscript. The authors would like to thank
Natalie Barker, a medical writer funded by H Lundbeck A/S, for writing assistance provided in the
preparation of this manuscript.

Reprint Address

Raymond W Lam, Professor of Psychiatry, University of British Columbia, 2255 Wesbrook Mall,
Vancouver, BC, V6T 2A1, Canada. Email: r.lam@ubc.ca

Expert Rev Pharmacoeconomics Outcomes Res. 2007;9(6):559-576. © 2007 Future Drugs Ltd.
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