Original article 149
Do equivalent doses of escitalopram and citalopram have similar efficacy? A pooled analysis of two positive placebo-controlled studies in major depressive disorder Ulla Lepolaa,b, Alan Wadec and Henning Friis Andersend Escitalopram is the S-enantiomer of citalopram. In this study, we compared the efficacy of equivalent dosages of escitalopram and citalopram in the treatment of moderate to severe major depressive disorder (MDD), based on data from two, pooled, randomized, double-blind, placebo-controlled studies of escitalopram in which citalopram was the active reference. The primary efficacy parameter was the mean change from baseline in the Montgomery A˚sberg Depression Rating Scale (MADRS) total score. Significant differences in favour of escitalopram were observed for the MADRS [P < 0.05, observed cases (OC)/last observation carried forward (LOCF)] and Clinical Global Improvement–Severity of Illness scores (CGI-S; P < 0.05, OC/LOCF). Escitalopram separated from placebo at week 1 on the primary efficacy parameter, whereas citalopram first separated from placebo at week 6. An analysis of time to response showed that escitalopram-treated patients responded significantly faster to treatment than citalopram-treated patients (P < 0.01). More patients responded to and achieved remission with escitalopram than to citalopram (P < 0.05, OC). The HAMD scale was only used in the fixed-dose study, where escitalopram-treated patients had a significant reduction
Introduction Escitalopram and citalopram are effective antidepressants, with favourable tolerability profiles (Muldoon, 1996; Burke et al., 2002; Wade et al., 2002; Lepola et al., 2003). Citalopram is a racemate, which consists of equal amounts of an S- and an R-enantiomer. Pharmacological studies, performed both in vitro and in vivo, have shown that the selective serotonin reuptake inhibitor (SSRI) activity of citalopram resides almost exclusively in the Senantiomer, escitalopram (Hyttel et al., 1992), as does the antidepressant activity (Hogg and Sa´nchez, 1999). Of the currently available SSRIs, escitalopram has the highest selectivity for the human serotonin transporter relative to the noradrenaline or dopamine transporters (Owens et al., 2001). In the clinical development of escitalopram, it was assumed that the therapeutically active enantiomer would have the same efficacy as the racemate (citalopram), but at half the dose. However, recent biochemical, functional and behavioural experiments indicate that c 2004 Lippincott Williams & Wilkins 0268-1315
in HAMD-17 total score at week 8 compared to citalopram-treated patients (P < 0.05, OC/LOCF). In the pooled subpopulation of severely ill patients (MADRS Z 30), escitalopram-treated patients showed greater improvement than citalopram-treated patients (P < 0.05, LOCF/OC). Escitalopram showed consistently superior efficacy compared to citalopram in the treatment of moderate to severe MDD on all efficacy parameters, and was similarly well tolerated. Int Clin Psychopharmacol c 2004 Lippincott Williams & Wilkins. 19:149–155 International Clinical Psychopharmacology 2004, 19:149–155 Keywords: Antidepressant, CGI-S, citalopram, escitalopram, HAMD-17, MADRS, major depressive disorder, SSRI a Kuopion Psykiatripalvelu OY Psychiatric Research, Clinic of Kuopio, Kuopio, Finland, bDepartment of Psychiatry, Oulu and Helsinki University, Oulu, Helsinki, Finland, cCPS Ltd, Clinical Research Centre, Glasgow, UK and dH. Lundbeck A/S, International Clinical Research, Copenhagen, Denmark.
Correspondence and requests for reprints to Henning Friis Andersen, H. Lundbeck A/S, International Clinical Research, Ottiliavej 9, DK-2500 Copenhagen, Denmark. Fax: + 45 36306771; e-mail:
[email protected] Received 9 October 2003 Accepted 8 January 2004
escitalopram has greater efficacy and a faster onset of action than equivalent doses of citalopram in nonclinical studies (Mørk et al., 2003; Sa´nchez et al., 2003a, b). The lower serotonin reuptake inhibition by citalopram in these nonclinical studies is assumed to be due to the inhibition of the effect of escitalopram by R-citalopram, possibly via an allosteric effect in its interaction with the serotonin transporter. The tolerability profile of escitalopram is similar to that of citalopram, with placebo levels of patients withdrawing due to adverse events. Indeed, most adverse events reported by escitalopram-treated patients are mild and transient (Burke et al., 2002; Lepola et al., 2003), as is the case for citalopram. The results from three placebo-controlled clinical trials of escitalopram in the treatment of major depressive disorder (MDD) consistently favour escitalopram versus placebo both in primary care (Wade et al., 2002; Lepola et al., 2003) and in specialist settings (Burke et al., 2002). DOI: 10.1097/01.yic.0000122862.35081.cd
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Methods
In the two studies in which citalopram was the active reference, escitalopram separated significantly from placebo as early as week 1 or 2 on both the primary and secondary efficacy variables (Burke et al., 2002; Lepola et al., 2003). Statistically significant separation of citalopram from placebo did not occur until week 6, or later.
Two randomized, multi-centre, placebo-controlled trials were conducted in outpatients with moderate to severe MDD in specialist settings in the USA (Burke et al., 2002) and in primary care in Europe and Canada (Lepola et al., 2003), and compared the effect of 8 weeks of doubleblind treatment with escitalopram with that of placebo, with citalopram as the active reference.
Although these studies were not powered to show differences between two active treatments, there were indications of advantages for escitalopram versus citalopram, apart from earlier separation from placebo (i.e. significantly more responders and remitters at endpoint and a faster time to response) (Lepola et al., 2003).
Eligible patients were male or female outpatients aged between 18 and 65 years, who met DSM-IV criteria for a major depressive episode (American Psychiatric Association, 1994), with a minimum score of 22 on the ˚ sberg Depression Rating Scale (MADRS) Montgomery A ˚sberg, 1979). The Hamilton Depression (Montgomery and A scale (HAMD-17) (Hamilton, 1960) was not used in the flexible-dose study (Lepola et al., 2003), whereas a minimum HAMD-17 score of 2 on item 1 (depressed mood) was an additional entry requirement in the fixeddose study (Burke et al., 2002).
A previous pooled analysis (Gorman et al., 2002) demonstrated a statistical superiority of escitalopram over citalopram. However, that analysis included multiple doses of both drugs without discriminating between doses. The present analysis was undertaken to compare equivalent doses of the two drugs. Thus, 20 mg/day escitalopram was compared with 40 mg/day of citalopram and 10–20 mg/day escitalopram was compared with 20– 40 mg/day citalopram. For this reason, the data from the 10 mg/day escitalopram fixed-dose arm were not included. Furthermore, data from a third trial were not included because neither active drug was statistically superior to placebo, based on the primary efficacy endpoint. Inclusion of such a trial is a potential source of bias because it lacked assay sensitivity (Klein, 2000).
Patients were excluded if there was evidence of active suicidal ideation (a score Z 5 on item 10 of the MADRS) or a recent suicide attempt, or if the patient had any DSM-IV Axis I disorder other than major depression. Both trials began with a 1-week single-blind placebo, lead-in period. At the end of the lead-in period, patients who still met the entry criteria were randomized to receive 8 weeks of double-blind treatment with active drug (escitalopram or citalopram) or placebo.
In addition, this study explores the efficacy of escitalopram versus that of citalopram in the larger cohort by pooling the data from two published clinical studies.
Burke et al. (2002) employed a fixed-dose design, with three active treatment groups: (i) 10 mg/day escitalopram; (ii) 20 mg/day escitalopram; and (iii) 40 mg/day
˚ sberg Depression Rating Scale (MADRS) total scores for the Table 1 Patient disposition, demographics, and mean baseline Montgomery A two studies Lepola et al. (2003) PBO
Disposition Patients randomized Patients treated Efficacy population (ITT) Patients completed (%)a Patients withdrawn (%)a Reason for withdrawal: Adverse event(s) (%) Lack of efficacy (%) Other (%) Demographics Men/women (%) Mean age, years Mean weight, kg Baseline MADRS, mean No. of severely ill patients (in ITT population)b
Burke et al. (2002)
ESC
CIT
10–20 mg
20–40 mg
154 154 154 139 (90) 15 (10)
156 155 155 146 (94) 9 (6)
161 160 159 152 (95) 8 (5)
4 (3) 5 (3) 6 (4)
4 (3) 0 (0) 5 (3)
6 (4) 1 (1) 1 (1)
28/72 43 76 28.7 58
25/75 43 71 29.0 69
31/69 44 74 29.2 69
PBO
ESC
CIT
10 mg
20 mg
40 mg
127 122 119 91 (75) 31 (25)
124 119 118 95 (80) 24 (20)
128 125 123 94 (75) 31 (25)
127 125 125 93 (74) 32 (26)
3 (3) 6 (5) 22 (18)
5 (4) 3 (3) 16 (13)
13 (10) 0 (0) 18 (14)
11 (9) 1 (1) 20 (16)
41/59 40 82 29.5 59
29/71 41 76 28.0 42
33/67 40 80 28.9 51
38/62 40 81 29.2 60
PBO, Placebo; CIT, citalopram; ESC, escitalopram. a Expressed as a percentage of patients treated; b MADRS Z 30 at baseline.
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Do escitalopram and citalopram have similar efficacy? Lepola et al. 151
Evaluations were conducted after 1, 2, 4, 6 and 8 weeks (Burke et al., 2002) or after 1, 2, 3, 4, 6 and 8 weeks of double-blind treatment (Lepola et al., 2003). Efficacy assessments included the MADRS and the Clinical Global Impression–Improvement and Severity of Illness scales (CGI-I and CGI-S) (Guy, 1976). In the fixed-dose study, HAMD-24 was also rated (Burke et al., 2002). The primary efficacy outcome measure in both trials was the change from baseline in MADRS total score at endpoint using the last observation carried forward (LOCF). The efficacy analyses were based upon the pooled intent-to-treat (ITT) population, which comprised all patients from both studies who received at least one dose of double-blind study product and who had at least one valid post-baseline MADRS assessment, with the exception of those in the 10 mg/day escitalopram fixed-dose arm (Burke et al., 2002), to compare equivalent doses of escitalopram and citalopram [20 versus 40 mg/ day for Burke et al. (2002) and 10–20 versus 20–40 mg/day for Lepola et al. (2003)]. The rating scale scores were analysed using analyses of covariance, while the remission and response rates were analysed using logistic regression. In both types of analyses, treatment group and centre were used as factors and baseline efficacy score as a covariate. For all variables, analyses were conducted using both LOCF and observed cases (OC). Time to response was analysed using parametric survival analysis, including factors for centre and treatment.
Results Patient demographics
Table 1 presents the patient disposition, demographics, and mean baseline MADRS total score for the two studies. There were no significant differences between treatment groups in sex, mean age and weight, or mean MADRS total score at baseline.
Table 2 Adjusted mean changes from baseline in Montgomery A˚sberg Depression Rating Scale (MADRS) total score and Clinical Global Improvement–Severity of Illness (CGI-S) score after 8 weeks of treatment with placebo, citalopram, or escitalopram in each study and in the pooled analysis (OC and LOCF) MADRS n Lepola et al. (2003) PBO CIT ESC Burke et al. (2002) PBO CIT40 ESC10 ESC20 Pooled analysis PBO CIT ESC
OC
CGI-S LOCF
OC
LOCF
– 12.2 – 13.7 – 15.1**
– 1.56 – 1.68 – 1.90*
– 1.42 – 1.58 – 1.80*,w
– 0.98 – 1.38* – 1.58*** – 1.66***
– 0.86 – 1.18* – 1.40*** – 1.42***,w
154 159 155
– 13.6 – 14.6 – 15.9**
119 125 118 123
– 10.4 – 9.4 – 12.1* – 13.8** – 14.9*** – 13.4*** – 16.2***,w – 14.1***,w
273 284 278
– 12.6 – 11.3 – 1.39 – 1.25 – 13.4** – 1.61* – 1.48* – 14.5** ***,z ***,z ***,z – 16.2 – 15.0 – 1.86 – 1.71***,z
OC, Observed cases; LOCF, last observation carried forward; PBO, placebo; CIT, citalopram; ESC, escitalopram. * P < 0.05; **P < 0.01; ***P < 0.001 versus placebo; wP < 0.10; zP < 0.05 versus citalopram.
Fig. 1
30 Estimated Mean MADRS Total Score
citalopram. Patients in the 20 mg/day escitalopram group and in the 40 mg/day citalopram group were titrated to their final dose after 1 week of treatment at half the assigned dose. No further adjustment of dosage was permitted. Lepola et al. (2003) employed a flexible-dose design, with initial doses of 10 mg/day for escitalopram and 20 mg/day for citalopram. Based on clinical response, as measured by CGI-S, the dose could be increased to a maximum of 20 mg/day escitalopram or 40 mg/day citalopram. Increases in dose were allowed at week 4 or week 6 and the dose could subsequently be returned to the initial dose if adverse events emerged.
PBO n=273 CIT n=284 ESC n=278
25 * 20
**
LOCF
*** 15
** *** #
**
** *** #
*** # 0 0
2
4
6
8
Week
Estimated mean MADRS total scores during 8 weeks of treatment with placebo, citalopram, or escitalopram. Pooled results from both studies [ITT, OC and LOCF (endpoint)]. *P r 0.05; **P r 0.01; ***P r 0.001 versus placebo; #P r 0.05 versus citalopram.
8 weeks of treatment with placebo, escitalopram, or citalopram for the two studies separately and for the pooled analysis (OC and LOCF). Escitalopram was statistically superior to placebo in both studies. The escitalopram group had a consistently numerically greater decrease in MADRS total score and CGI-S score compared to the citalopram group, with the difference approaching significance (P < 0.10) in one or both studies (Table 2).
Efficacy
Table 2 presents the adjusted mean changes from baseline in MADRS total score and CGI-S score after
When the data from both studies were pooled (Fig. 1), the mean decrease from baseline in MADRS total score
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152 International Clinical Psychopharmacology 2004, Vol 19 No 3
Fig. 2
Fig. 3
0.6
*** #
*** #
CIT n=284
3
2
**
**
1
Estimated Difference from Placebo in Mean CGI-S Score
Estimated Difference from Placebo in Mean MADRS Total Score
ESC n=278
4
ESC n=278 CIT n=284
*** #
*** #
0.4
*
* 0.2
0 0
LOCF
OC
OC
LOCF
Estimated difference from placebo in mean MADRS total scores after 8 weeks of treatment with either citalopram or escitalopram. Pooled results from two studies (ITT, OC and LOCF). **P < 0.01; ***P < 0.001 versus placebo; #P < 0.05 versus citalopram.
after 8 weeks of treatment was statistically significantly greater in the escitalopram group than in the citalopram group, yielding estimated differences of 1.77 and 1.62 (OC and LOCF, P = 0.015 and P = 0.026, respectively) (Table 2 and Fig. 2). Escitalopram showed statistically significant separation from placebo at week 1 and every visit thereafter, whereas citalopram first showed statistically significant separation from placebo at week 6 (Fig. 1). The clinical relevance of the decrease in MADRS total score was reflected in the change from baseline in the CGI-S scores for the pooled population. Patients in the escitalopram group had a significant decrease in mean CGI-S score compared to those in the citalopram group, in both the OC and LOCF data sets (P = 0.013 and P = 0.015, respectively) (Table 2 and Fig. 3). A statistically significantly greater proportion of patients responded to escitalopram than to citalopram (defined as Z 50% decrease from baseline in MADRS total score) (P = 0.009, OC; P = 0.033, LOCF). An analysis of time to response showed that escitalopram-treated patients responded significantly faster than citalopram-treated patients (P = 0.0057). In addition, a significantly greater proportion of escitalopram-treated patients than citalopram-treated patients achieved remission (MADRS total score r12) (P = 0.044, OC; P = 0.123, LOCF) (Table 3 and Fig. 4). Based on the LOCF data, 7.9% more patients were responders to escitalopram than to citalopram at week 8, while 5.6% more patients were in remission. This means that for every 13 patients treated with escitalopram or citalopram, one more patient will be a responder if treated with escitalopram whereas, for remission, it is
Estimated difference from placebo in mean CGI-S scores after 8 weeks of treatment with either citalopram, or escitalopram. Pooled results from both studies (ITT, OC and LOCF). *P < 0.05; ***P < 0.001 versus placebo; #P < 0.05 versus citalopram.
Table 3 Patients responding [ Z 50% decrease in Montgomery A˚sberg Depression Rating Scale (MADRS) total score] or in remission (MADRS total score r12) at week 8: pooled analysis of the two studies
Responders (%) OC LOCF Remitters (%) OC LOCF
Placebo
Escitalopram
Citalopram
40.7 36.6
63.6***,z 56.8***,w
53.6** 48.9**
37.2 33.7
51.6***,w 46.4***
44.3 40.8*
OC, Observed cases; LOCF, last observation carried forward. * P < 0.05; **P < 0.01; ***P < 0.001 versus placebo; wP < 0.05; zP < 0.01 versus citalopram.
one patient for every 18 patients treated. Based on OC data, 10.0% more patients were responders to escitalopram than to citalopram at week 8, while 7.3% more patients were in remission. These numbers correspond to one additional responder for every 10 patients treated, and one additional patient achieving remission for every 14 patients treated with escitalopram. In the fixed-dose study, escitalopram-treated patients had a significant reduction in HAMD-17 total score compared to the citalopram-treated patients (estimated differences 1.90; P = 0.024, OC; 1.62; P = 0.034, LOCF) (Fig. 5). The analysis of the pooled results in the severely ill patients (baseline MADRS Z 30) revealed a significantly greater decrease in MADRS total score in the escitalopram group than the citalopram group (estimated difference 2.92; P = 0.029, OC; estimated difference 2.67; P = 0.043, LOCF) (Fig. 6). The difference between escitalopram and citalopram in the severely ill was so
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Do escitalopram and citalopram have similar efficacy? Lepola et al. 153
Fig. 4
Fig. 6
ESC n=278 CIT n=284
Percent Difference from Placebo
25
*** ##
20
*** #
15
**
10
Estimated Mean MADRS Total Score
30
PBO n=117 CIT n=129 ESC n=120
30 **#
25
LOCF
*
20
* **
15
***# ***#
0
0
5
2
4
6
8
Week
0 Response
Remission
Difference from placebo in the proportions of patients responding ( Z 50% decrease in MADRS total score) and in remission (MADRS total score r 12) after 8 weeks of treatment with either citalopram or escitalopram. Pooled results from both studies (ITT, OC). **P < 0.01; ***P < 0.001 versus placebo; #P < 0.05; ##P < 0.01 versus citalopram.
Estimated mean MADRS total scores for severely ill patients (MADRS Z 30 at baseline) during 8 weeks of treatment with placebo, citalopram, or escitalopram. Pooled results from both studies [ITT, OC and LOCF (endpoint)]. *P r 0.05; **P r 0.01; ***P r 0.001 versus placebo; #P r 0.05 versus citalopram.
Tolerability
Fig. 5
Estimated Difference from Placebo in Mean HAMD-17 Score
ESC n=123
4
CIT n=125
*** # *** #
3
2
*
1
0 OC
LOCF
Estimated difference from placebo in mean HAMD-17 scores after 8 weeks of treatment with either citalopram or escitalopram in the fixeddose study (ITT; OC and LOCF). *P r 0.05; ***P r 0.001 versus placebo; #P r 0.05 versus citalopram.
great that it was also statistically significant for the fixeddose study alone (estimated difference 4.24, 20 mg/day escitalopram versus 40 mg/day citalopram; P = 0.045, OC; P = 0.125, LOCF).
Both citalopram and escitalopram were well tolerated, with similar adverse event profiles. Only headache (placebo 20%, escitalopram 16% and citalopram 19%) and nausea [placebo 8%, escitalopram 16% (P < 0.05 versus placebo) and citalopram 18% (P < 0.05 versus placebo)] were reported by Z 10% of the patients in any treatment group in the pooled analysis. The overall rates of withdrawal were similar between treatment groups within the two studies, although they were generally higher in Burke et al. (2002) than in Lepola et al. (2003) (Table 1). For patients in the flexible-dose study, the withdrawal rate due to adverse events was similar between the treatment groups and at the same level as that of the placebo group (Table 1) (Lepola et al., 2003). For patients in the fixed-dose study, the withdrawal rates due to adverse events were similar in the 20 mg/day escitalopram group and the 40 mg/ day citalopram group (10% and 9%, respectively) (Burke et al., 2002).
Discussion The results of the present pooled analyses demonstrated a clinically relevant superiority of escitalopram over citalopram. This difference was supported by the higher response and remission rates and CGI scores for escitalopram. These findings are particularly noteworthy in light of the current literature showing not only difficulties in separating efficacy between antidepressants, but also between established antidepressants and placebo (Khan et al., 2002).
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The results from the individual studies demonstrate the robust and consistent performance of escitalopram compared to placebo on all efficacy parameters assessed. The difference in adjusted mean change from baseline in MADRS total scores between placebo groups in the two studies is approximately 3 points and is probably due to differences in study settings (Montgomery, 1999). Citalopram was included as the active reference in both studies, and neither study was powered to assess differences between the active treatments. At the outset, it was assumed that escitalopram would have the same clinical efficacy as citalopram, but at half the dose. In spite of this, escitalopram-treated patients had a significant reduction in HAMD-17 total score (OC and LOCF) compared to citalopram-treated patients in the fixed-dose study. In addition, 20 mg/day escitalopram was statistically significantly superior to an equivalent dose of citalopram (40 mg/day) for severely ill patients (MADRS total score Z 30) after 8 weeks of treatment (OC and LOCF). In patients in the flexible-dose study, there were significantly more responders and remitters at endpoint, and a faster time to response, for escitalopram than for citalopram (Lepola et al., 2003). The LOCF approach is generally considered more conservative in handling data from patients who are withdrawn from a clinical study. However, if the number and timing of patient withdrawals are similar between treatment arms, the OC approach is often more clinically relevant, particularly for long-term studies. In the present analyses, we have presented both the OC and LOCF results because the primary efficacy endpoint for each study was prospectively defined as LOCF, but similar patterns of patient withdrawals between treatment groups justify the use of OC results (ICH, 1998). The individual studies showed strong trends in favour of escitalopram on the secondary efficacy measures. For example, 20 mg/day escitalopram was borderline significantly superior to 40 mg/day citalopram on several parameters, such as CGI-I (Burke et al., 2002) and HAMD-17 (Fig. 5) after 8 weeks of treatment. Flexible doses of 10–20 mg/day escitalopram were borderline significant compared to 20–40 mg/day citalopram based on CGI-S (LOCF). Finding a direct advantage of one antidepressant over another in a placebo-controlled trial, such as that observed in the present study, is a rare phenomenon; an example is provided by Rudolph and Feiger (1999). When pooling the two studies, the 10 mg/day escitalopram group (Burke et al., 2002) was excluded from the analysis to avoid bias, because no relevant comparator group (i.e. 20 mg/day citalopram) was included in the study. Thus, the pooled analysis was performed on comparable dose groups, namely, 20 mg/day escitalopram
versus 40 mg/day citalopram, and 10–20 mg/day escitalopram versus 20–40 mg/day citalopram. The pooled analysis of the two studies revealed escitalopram to be significantly more efficacious than citalopram after 8 weeks of treatment. The clinical relevance of the statistically significant difference between escitalopram and citalopram treatment based on MADRS total score (OC and LOCF) is supported by the results obtained on CGI-S (OC and LOCF). Furthermore, a significantly larger proportion of patients responded to escitalopram than to citalopram, as measured by a Z 50% reduction in the MADRS total score (OC and LOCF). The results obtained for the proportion of patients in remission may be even more relevant than the proportion responding because patients failing to achieve remission are more prone to relapse and recurrence of the disorder (Farvolden et al., 2003). Escitalopram was numerically (LOCF) and significantly superior to citalopram (OC), as measured by a MADRS total score r 12 at endpoint. Pooled analysis of the subgroup of severely ill patients (baseline MADRS Z 30) demonstrated that the efficacy of escitalopram was superior to citalopram (OC and LOCF), and suggests that there could be a distinct clinical advantage in using escitalopram in this patient population. The clinical efficacy of citalopram in the treatment of MDD has been previously demonstrated (Montgomery et al., 1993, 1994). The biochemical rationale for the greater efficacy of escitalopram may be related to higher serotonergic activity in the brain in response to escitalopram than to citalopram (Mørk et al., 2003). This may be because escitalopram apparently enhances its own binding to the serotonin transporter, by its action at an allosteric binding site, thereby inhibiting serotonin reuptake. This effect is not seen with R-citalopram, which appears to decrease the affinity of escitalopram for the serotonin transporter. As a self-enhancing effect is not seen with other SSRIs, the superior clinical efficacy of escitalopram may be associated with this property. The early onset of effect of escitalopram versus citalopram has been seen in the rat chronic mild stress model (Montgomery et al., 2001; Sa´nchez et al., 2003b) and the rat resident-intruder paradigm (Mitchell and Hogg, 2002). In clinical settings, this is seen as a separation from placebo at a significantly earlier time for escitalopram (week 1) than for citalopram (week 6). Early onset of symptom improvement may increase patient adherence to treatment and reduce progression to chronic major depression (Stahl et al., 2001). The estimated worldwide exposure to citalopram is now over 90 million patients and the estimated worldwide
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Do escitalopram and citalopram have similar efficacy? Lepola et al. 155
exposure to escitalopram is greater than 7 million patients, with a similarly favourable safety profile. In the pooled analysis, only nausea, a well-known adverse drug reaction to SSRIs, had a significantly higher incidence in the active treatment groups compared to the placebo group, and this was generally mild and transient. The small differences in withdrawal rates between the two antidepressants and placebo support their suitability for a wide spectrum of patients suffering from MDD. In conclusion, there is good evidence that escitalopram offers superior efficacy to citalopram in the treatment of moderate to severe MDD, while being similarly well tolerated.
Acknowledgements The authors gratefully acknowledge Helle Harder Birkeslund for assistance in preparing this manuscript.
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