# 2003 Taylor & Francis
International Journal of Psychiatry in Clinical Practice 2003
Volume 7
Pages 259 /268 259
Comparison of escitalopram and citalopram efficacy: A meta-analysis PASCAL AUQUIER1, STE´PHANE ROBITAIL1, PIERREMICHEL LLORCA2 AND BENOIˆT RIVE3 Int J Psych Clin Pract Downloaded from informahealthcare.com by University of Washington on 10/28/14 For personal use only.
1
De´partement de Sante´ Publique, Faculte´ de Me´decine, 27 Bd Jean Moulin, 13385 Marseille Cedex 5, France, 2Centre Medico-Psychologique B, Centre Hospitalier Universitaire, BP 69, 63003 Clermont-Ferrand, France and 3 Altipharm SA, 7 Rue de la Paix, 75002 Paris, France
OBJECTIVE: Escitalopram is a new selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of major depressive disorder (MDD) and panic disorder. Escitalopram is the therapeutically active enantiomer of citalopram. Its efficacy in the treatment of MDD was compared to that of citalopram. METHODS: A quantitative meta-analysis was applied to 1262 patients in four randomised clinical trials; the comparison was based on response rate and mean change from baseline in the Montgomery A˚sberg depression rating scale (MADRS) total score at week 8. Complementary analyses were performed on early MADRS change from baseline (week 1), in very severely depressed patients (baseline MADRS total score ] 35) and on the influence of the level of severity at baseline.
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Correspondence Address Pascal Auquier, De´partement de Sante´ Publique, Faculte´ de Me´decine, 27 Bd Jean Moulin, 13385 Marseille Cedex 5, France Tel: /(33) 491 384745 Fax: /(33) 491 797520 E-mail: [email protected]
Compared with citalopram, escitalopram-treated patients showed significantly higher response rates and increased mean change from baseline in MADRS at weeks 1 and 8. The superiority of escitalopram over citalopram was more pronounced in very severely depressed patients. This superiority was further shown to increase with degree of severity of the depression. The robustness of meta-analysis results was supported by sensitivity analyses. The clinical superiority of escitalopram versus citalopram is consistent with the results of preclinical pharmacological studies.
RESULTS:
Escitalopram was shown to be an effective therapeutic treatment for MDD, presenting significant advantages over citalopram. (Int J Psych Clin Pract 2003; 7: 259 268)
CONCLUSION:
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Received 24 July 2003; accepted for publication 2 September 2003
Keywords escitalopram meta-analysis depression
INTRODUCTION
E
scitalopram is a new selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of depression.1 It is the therapeutically active S -enantiomer of citalopram. Escitalopram has been shown to be an effective and welltolerated treatment for major depressive disorder (MDD) in primary care2 4 and specialist settings.5 Escitalopram at both 10 and 20 mg/day was more effective than placebo and at least as effective as citalopram 40 mg/day in alleviating the symptoms of depression in a study including 491 MDD patients.5 It has produced significant improvements in standard measurements of antidepressant effects, including
serotonin reuptake inhibitor efficacy
the Montgomery/A˚sberg Depression Rating Scale (MADRS),6 Hamilton Rating Scale for Depression (HAM-D),7 and Clinical Global Impression of Improvement and Severity (CGI-I and CGI-S) scales.8 Although not reaching systematically statistical significance, there was a trend for the 20mg escitalopram group to separate from the 40 mg citalopram group in terms of MADRS total score (P /0.07) and the HAM-D (P /0.06). Moreover, escitalopram 10 mg/ day was as effective as citalopram 40 mg/day on most assessments. In another placebo-controlled study,4 significantly more patients responded to treatment with escitalopram than with citalopram (P /0.021). Improvement of symptoms was rapid.9 Decrease in mean MADRS total score, the primary endpoint, was significantly DOI: 10.1080/13651500310003408
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greater with escitalopram than with placebo as soon as week 14 or week 2.2,5 Escitalopram showed an earlier separation from placebo than citalopram.4,5 These findings suggest that escitalopram is more efficacious than citalopram at equivalent doses. A pooled analysis by Gorman based on three randomised, placebo-controlled clinical trials (RCT) in which both escitalopram and citalopram were administered showed escitalopram to be statistically significantly superior to citalopram on mean change from baseline in MADRS total score at week 1 for the observed case (OC) and last-observation-carried-forward (LOCF) analyses and at week 8 for the OC analysis.10 The objective of the present analysis is to extend this comparison of escitalopram and citalopram using a quantitative meta-analysis coupled with a sensitivity analysis to ascertain the robustness of the results. Complementary analyses were performed to further investigate this comparison, on early mean MADRS change from baseline, on very severely depressed patients and on the influence of severity of depression.
METHODS TYPES
OF
STUDIES
This analysis considered all clinical trials that included both escitalopram and citalopram in patients with MDD. A priori criteria were established for selecting trials into the metaanalysis: (i) similar clinical inclusion criteria for patients with MDD defined by DSM-IV11, (ii) use of the mean change from baseline in MADRS total score as an efficacy measure and (iii) double-blind, randomised, treatment period of at least 8 weeks, with an assessment of MADRS at week 8. Four studies complied with these criteria, and no study was excluded. Studies were similar in design and inclusion/ exclusion criteria, primary endpoints and assessment schedules as described in Table 1. Eligible patients were male or female outpatients, aged between 18 and 65 years (or 80 in one study; Table 1). They met DSM-IV criteria for MDD, with a baseline MADRS total score ]/22. After a 1-week placebo run-in period, patients were randomised to a double-blind treatment phase of at least 8 weeks. MADRS scores were measured at baseline, and after 1, 2, 4, 6 and 8 weeks of treatment. Two studies were performed in the USA in specialist settings and two studies were performed in Europe (and Canada for one study) in primary care. One USA trial compared two fixed doses of escitalopram (ESC 10 and 20 mg/day) to placebo, with a single dose of citalopram (CIT 40 mg/day) as the active comparator.5 Patients in the ESC 20 mg and CIT 40 mg groups were force titrated to their final dose after 1 week of initial treatment at ESC 10 mg/day and CIT 20 mg/day. In two studies (one in the USA, one in Europe), flexible doses of both compounds were compared with placebo;
initial doses of ESC 10 mg/day or CIT 20 mg/day could be increased at week 3 (USA study) or at weeks 4 or 6 (European study) in case of unsatisfactory response to maximum doses of ESC 20 mg/day or CIT 40 mg/day.4,12. It should be noted that the USA flexible dose study12 failed to show a significant difference from placebo on the primary outcome for both escitalopram and citalopram (MADRS, LOCF), but demonstrated statistically significant efficacy on other parameters (MADRS OC, HAM-D, CGI-I). The fourth trial was a long-term study performed over a 6-month period, which compared ESC 10 mg/day to CIT 20 mg/day.3
STATISTICAL ANALYSIS The statistical analysis was performed on an intent-to-treat (ITT) basis, including all treated patients for whom at least one post-baseline assessment on the MADRS was measured. The efficacy criteria were (i) mean change from baseline to endpoint on the MADRS total score as well as (ii) response rate, defined as the percentage of patients achieving at least a 50% decrease in their baseline MADRS total score. For the long-term study, assessments measured after 8 weeks of treatment were not considered, and the 8-week evaluation was used as the endpoint measure. Further analysis of efficacy was determined by early change in mean MADRS total score (i.e., after 1 week of treatment), as well as analyses of the sub-group of very severely depressed patients characterised by a baseline MADRS total score ]/35. Results issued from individual studies were obtained for response rates by logistic regression with Centre and Treatment as factors. Estimates of treatment differences for each individual study are given as odds ratios with the corresponding 95% confidence interval. An odds ratio greater than one indicates superiority of escitalopram over citalopram. Analyses of change from baseline were performed by ANCOVA with Baseline Score as covariate and Centre and Treatment as factors. The only exception was the analysis of the very severely depressed sub-group (patients with a baseline MADRS total score ]/35) where the low number of patients did not allow Centre to be used as a factor. All analyses were performed using the LOCF method. A standard method was used for the meta-analysis: the combined effect was calculated as the weighted mean of the effects observed in each study, with the weight inversely proportional to the individual variances.13 The studies showing smaller inter-individual variations received the largest weight, resulting in a minimum variance for the pooled estimate. The presence of heterogeneity of treatment effect was tested using the Q statistic, which approximates the chisquare statistic with n /1 degrees of freedom.14 A fixed effect model was used as the primary analysis, unless substantial heterogeneity was detected (P B/0.05) in which case a random effect method was used as the primary
Reference Ref. 5
Country USA
Patient setting Specialist
Inclusion criteria DSM-IV EDM
Treatment duration
Treatment
8 weeks
Escitalopram
MADRS ]/22 Age 18 /65 years
1
Dosage /day (mean4)
Outcome measures
Citalopram Placebo
10 mg 20 mg 40 mg NA
118 123 125 119
MADRS1 CGI-S, CGI-I, Response2 Remission3 HAMD, HAMA
Ref. 4
Europe, Canada
Primary care
DSM-IV EDM MADRS ]/22 /40 Age 18 /65 years
8 weeks
Escitalopram Citalopram Placebo
10 /20 mg (11.7) 20 /40 mg (24.4) NA
155 159 154
MADRS1 CGI-S, CGI-I, Response2 Remission3
Ref. 12
USA
Specialist
DSM-IV EDM MADRS ]/22 Age 18 /80 years
8 weeks
Escitalopram Citalopram Placebo
10 /20 mg (13.4) 20 /40 mg (25.2) NA
124 119 125
MADRS CGI-S, CGI-I, Responses2 Remission3 HAMD, HAMA
Ref. 3
Europe
Primary care
DSM-IV EDM MADRS ]/22 Age 18 /65 years
24 weeks
Escitalopram Citalopram
10 mg 20 mg
165 174
MADRS1 CGI-S, HAMA, Response2 Remission3
Mean change from baseline in MADRS total score at week 8 was the main efficacy criteria. Response was defined as patients with ]/50% reduction of baseline MADRS total score at week 8. 3 Remission was defined as patients with MADRS 5/12 at week 8. 4 Mean daily dose corresponds to the average daily dose prescribed for the 8 weeks of treatments; it is indicated for flexible doses only. NA, not appropriate. 2
Patients (ITT)
Comparison of escitalopram and citalopram efficacy
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Table 1 Short summary of randomised clinical trials testing for escitalopram and citalopram included in the meta-analysis
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analysis since it gives more conservative results, but can deal with a certain amount of heterogeneity. Results for the individual studies and the meta-analysis (combined effect) were illustrated as Forrest plots presenting the estimated means (of the difference or odds ratio) with the corresponding 95% confidence intervals. The influence of the difference degree of severity of depression on the difference between escitalopram and citalopram efficacy was performed by ANOVA with Group of Severity as factor, and Treatment by Severity and Study by Centre as interactions. The efficacy criterion was the mean change from baseline in MADRS total score evaluated at endpoint on the ITT population for the three studies in which doses were appropriate for comparison of drugs in severe depression (i.e. the long-term study was excluded3). Four severity groups were defined a priori, based on the MADRS total score at baseline: B/25, ]/25 and B/30, ]/30 and B/35, and ]/35. The effect of treatment was evaluated from the Treatment by Severity interaction.
SENSITIVITY ANALYSES Various meta-analyses were performed as sensitivity analyses in order to test for the robustness of the results. This was performed by exclusion of some studies from the initial metaanalysis in order to test for their influence on the metaanalysis. Comparable results for the meta-analysis and the sensitivity analyses indicated studies of similar weight. The first sensitivity analysis (sensitivity 1 ) was performed after exclusion of the non-placebo-controlled study, i.e. the longterm study3, a second one (sensitivity 2 ) after exclusion of the inconclusive study12 and a third one (sensitivity 3 ) after concomitant exclusion of both studies. Analyses were performed as described for the initial meta-analysis.
RESULTS STUDY POPULATION A total of 1262 patients were included in the study population for the meta-analysis; 685 had received escitalo-
pram (83.9% of whom completed the study) and 577 had received citalopram (83% of whom completed the study). Patient demographics and other baseline characteristics are balanced between the two treatment groups, as summarised in Table 2. The mean MADRS total scores at baseline were 28.99/4.4 and 29.49/4.6 for the escitalopram and citalopram groups, respectively, signifying that patients were moderately to severely depressed. Among them, 157 were defined as very severely depressed (baseline MADRS ]/35), with 73 in the escitalopram group (MADRS of 37.09/1.9) and 84 in the citalopram group (MADRS of 37.19/2.2). Overall, patients received 12.6 mg/day of S -citalopram in the escitalopram group and 26.4 mg/day of R - and S-citalopram in the citalopram group.
CLINICAL OUTCOMES
IN
ALL PATIENTS
Figure 1 shows the main results of the clinical outcome measures of the meta-analysis, as well as the results of the sensitivity analyses. Response rates were 55.5% for escitalopram-treated patients and 50.8% for citalopram-treated patients; the corresponding meta-analysis odds ratio of 1.35 (CI 95% of 1.09 /1.70) reached statistical significance (P /0.01). Figure 1a illustrates that this trend was observed in the majority of individual studies. Testing for heterogeneity revealed no significant difference. The mean change from baseline in MADRS total score at endpoint was significantly greater after 8 weeks of escitalopram treatment than after citalopram treatment (estimate of 1.02; CI 95% of 0.09 /1.95; P /0.03). As shown in Figure 1b, this result was consistent with the majority of studies, in which numerically better results were observed for escitalopram-treated patients. Testing for heterogeneity of the individual results revealed no significant difference. Sensitivity analyses lead to similar results: odds ratios for response rates were comparable (with estimated values of 1.21, 1.51 and 1.40 for sensitivity 1, 2 and 3, respectively) and differences in mean change from baseline in MADRS total score were higher at week 8 (with estimated means of 1.12, 1.24 and 1.54 for sensitivity 1, 2 and 3, respectively). These results were close to significance for sensitivity 1 and
Table 2 Baseline characteristics of patients included in the meta-analysis No. of patients
Age (years) (mean9/SD)
% Women
MADRS (mean9/SD)
Mean dose (mg/day)
All patients (n /1262) Escitalopram Citalopram
685 577
429/12 439/12
68.2 65.5
28.99/4.4 29.49/4.6
12.6 26.4
Very severely depressed patients (n /157) Escitalopram Citalopram
73 84
449/11 439/13
64.4 71.4
37.09/1.9 37.19/2.2
12.7 24.9
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Figure 1 Main efficacy results of the meta-analysis and sensitivity analyses on the overall ITT population. (a) Odds ratios and 95% confidence intervals for response rates estimated for individual studies, meta-analysis and sensitivity analyses for the overall population (ITT analysis, LOCF approach). An odds ratio greater than 1 favours escitalopram; a confidence interval not including 1 indicates a statistically significant difference with PB/0.05. (b) Estimated differences and 95% confidence interval for MADRS score changes at week 8 for individual studies, meta-analysis and sensitivity analyses (ITT analysis, LOCF approach). A difference greater than 0 favours escitalopram; a confidence interval not including 0 indicates a statistically significant difference with P B/0.05. Sensitivity 1 is the meta-analysis performed without the long-term study,3 sensitivity 2 the meta-analysis performed without the inconclusive study12 and sensitivity 3 without both.
reached statistical significance for sensitivity 2 and 3 (P B/ 0.05).
EARLY CHANGE
FROM
BASELINE
The mean change from baseline in MADRS total score was significantly greater for escitalopram-treated patients than for citalopram-treated patients as early as week 1 of treatment (estimated difference of 0.63; CI95% of 0.08 /1.17; P / 0.02). This early numerical superiority of escitalopram was observed in all individual studies although these differences did not reach statistical significance. Testing for heterogeneity revealed no significant difference. Sensitivity analyses gave similar results with estimated means of 0.85 (P /0.02), 0.63 (P /0.07) and 0.77 (P / 0.06) for sensitivity 1, 2 and 3, respectively.
increased to 1.83 (CI95% of 0.95 /3.51) and the difference in the mean change from baseline in MADRS total score at endpoint increased to 3.48 (CI95% of /0.28 /7.24). Both these differences between treatments were close to statistical significance (P /0.07 in both cases) and reflect trends observed in all individual studies. Meta-analyses performed for sensitivity 2 (exclusion of the inconclusive study) led to similar results as the meta-analysis (cf. Figure 2a and 2b), while sensitivity 1 and 3 (i.e. those excluding long-term/low dose study) led to greater differences: for sensitivity 1, the odds ratio for response rate was 2.34 (P /0.04) and the difference in MADRS at endpoint was 7.33 (P /0.008), and for sensitivity 3, results were 2.06 for response rate (P / 0.13) and 8.05 for the difference in MADRS at endpoint (P / 0.009).
VERY SEVERELY DEPRESSED PATIENTS
INFLUENCE OF BASELINE SEVERITY DEPRESSION
For the sub-group of very severely depressed patients (i.e. patients with a baseline MADRS ]/35), the difference between escitalopram- and citalopram-treated patients was more pronounced. The estimated odds ratio for response rate
Figure 3 illustrates the influence of the degree of severity of the depression of patients measured at baseline on the mean change from baseline in MADRS total score at week 8, in the placebo-controlled studies. The overall analysis showed
OF
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Figure 2 Main efficacy results of the meta-analysis and sensitivity analyses on the very severely depressed patient sub-group. (a) Odds ratios and 95% confidence intervals for response rates estimated for individual studies, meta-analysis and sensitivity analyses for the very severely depressed patients with baseline MADRS ]/35 (ITT analysis, LOCF approach). An odds ratio greater than 1 favours escitalopram; a confidence interval not including 1 indicates a statistically significant difference with P B/0.05. (b) Estimated differences and 95% confidence interval for MADRS score changes at week 8 for individual studies, meta-analysis and sensitivity analyses (ITT analysis, LOCF approach). A difference greater than 0 favours escitalopram, and a confidence interval not including 0 indicates a statistically significant difference, with P B/0.05. Sensitivity 1 is the meta-analysis performed without the long-term study,3 sensitivity 2 the meta-analysis performed without the inconclusive study12 and sensitivity 3 without both.
statistically significant differences between the two groups of patients with baseline MADRS ]/30 and MADRS ]/35, with respective mean differences of 1.91 and 5.10 in favour of escitalopram (P /0.02 in both cases).
Figure 3 Mean change from baseline in MADRS total score to endpoint as a function of severity of depression at baseline with patients a priori categorised into four groups of severity. *P B/0.05 for the difference between escitalopram and citalopram in the two most severely depressed patients sub-groups.
DISCUSSION METHODOLOGY Meta-analysis is a useful approach to compare active treatments, and provides balanced evidence of differences, or lack thereof, observed in individual randomised clinical trials. For consensus statements and development of treatment guidelines, meta-analyses today are regarded as A1 evidence. The quality of meta-analyses depends on the methodology applied, which by and large relies on the selection of studies.15 As suggested by the Cochrane group, the present analysis selected trials based on the robustness of their methodology (properly randomised and blinded trials), similarity of design, outcome measures and therapeutic issue addressed; studies selection remained independent of efficacy outcomes (inclusion of inconclusive study was possible). The main criteria for selecting studies led to the inclusion of all existing randomised double-blind studies that included both escitalopram and citalopram. The four studies were similar in terms of inclusion criteria for patients, outcome measures and design. Differences in the dosage schedules between studies (different levels of doses, flexible versus fixed doses) could have introduced heterogeneity, as the efficacy outcome may vary
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Comparison of escitalopram and citalopram efficacy
according to dose, and the possibility of increasing the dose in flexible-dose studies is often associated with a renewed response that can alter the endpoint outcome compared to fixed-dose studies. These differences were considered to be limited, since individual comparisons were balanced in terms of dose equivalence between escitalopram and citalopram (see Table 1), except for the fixed-dose USA study,5 which included escitalopram (10 mg) without an equivalent citalopram dose (20 mg). This resulted in comparison of a slightly lower overall dose of escitalopram (12.6 mg/day) than of citalopram (26.4 mg/day). The inclusion of some of the studies may have implied choices that could be methodologically questionable. In order to test the approach used, and to measure its robustness, a sensitivity analysis was performed. A potential bias could have resulted from inclusion of a non-placebo-controlled study with the placebo-controlled studies, as this could affect the level of therapeutic response. Non-placebo-controlled studies are known to induce higher treatment response than placebo-controlled studies, since patients and physicians have a greater expectation of effective treatment.16 This potential bias was circumvented by exclusion of the non-placebo-controlled study from the metaanalysis (sensitivity 1 ). A second potential bias might have resulted from the inclusion of an inconclusive study, as such results might not give useful information about efficacy. This potential impact was tested in the second sensitivity analysis (sensitivity 2). The impact of both potential biases was further tested in sensitivity 3 . Results of these sensitivity analyses supported the superiority of escitalopram over citalopram observed in the initial meta-analysis; the changes observed in either the magnitude of the estimated difference or the degree of statistical significance were not relevant with the exception of the very severely depressed patient sub-group analysis after exclusion of the long-term study (i.e. sensitivity 1 and 3 , discussed below). They lead to similar conclusions as those drawn from the meta-analysis, showing the robustness of the approach. The meta-analysis was therefore optimal in that it was exhaustive and robust.
CLINICAL RESPONSE
TO
265
in the present analysis, as it is of direct clinical significance although it sacrifices statistical power. In our present comparison, at least half of the patients who received either escitalopram or citalopram responded to treatment. The meta-analysis estimated the difference to reach statistical significance with an odds ratio of response rates of 1.35. For a translation into a meaningful outcome, it is interesting to convert these results into the number of patients needed to treat (NNT) to realise a difference. In our initial metaanalysis, 20 patients would be needed to be treated by escitalopram in order to obtain an extra responder compared with citalopram. When excluding results of both the inconclusive study and the non-placebo-controlled study (sensitivity 3 ), this NNT decreased to 15, while in the 6month non-placebo-controlled fixed-dose study3 comparing ESC 10 mg to CIT 20 mg the NNT was 11 at week 8. When considering the comparison in terms of mean change from baseline in MADRS total score, the estimated difference was statistically significant although not numerically important. This difference is not unexpected as (i) we used a worst-case scenario comparing lower doses of escitalopram than of citalopram, (ii) we included an inconclusive study in the meta-analysis (the magnitude of MADRS difference is increased when this study is excluded in sensitivity 2) and (iii) a high placebo response rate is usually observed in RCT where drug effect is confounded by extensive and iterative patient interviews and valuation that contributes to their improvement. As illustrated from our data, the more severely depressed the patient is, the lower the response to placebo (see Figure 4). An analysis focused on very severely depressed patients allows us to minimise the impact of this placebo effect, and is therefore better evidence of the real difference between treatments. The assessment of treatment differences in relationship with the severity of the depression may then be a useful means to identify the real difference between treatments. When focusing on very severely depressed patients, the superiority of escitalopram over citalopram was greater, in
ESCITALOPRAM
Results of the meta-analysis supported indications from individual studies of the superiority of escitalopram over citalopram based on response rate and mean change from baseline in MADRS total score at endpoint. Escitalopram differentiated from citalopram as early as the first week of treatment. These results confirmed those from the pooled analysis of Gorman.10 The individual studies used the mean change from baseline in MADRS total score change as the primary outcome measure as it is a direct measure of improvement of depressive symptomatology. As it is difficult to establish a translation from a difference in two MADRS scores into a clinical meaning, the response rate, defined as a 50% reduction in the baseline MADRS score, was also considered
Figure 4 Response rates measured for the placebo group as a function of severity. Response rates were calculated from a meta-analysis of the three placebo-controlled studies.
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spite of the low number of patients included in the metaanalysis (73 and 84 for escitalopram and citalopram, respectively). This was particularly evident in the sensitivity analyses, in which the long-term study (i.e. where fixed low doses were administered) was excluded: odds ratios greater than 2 and differences in MADRS scores at endpoint around 7 /8 were estimated. In the long-term study, the administration of low doses did not allow the drugs to be differentiated in severely depressed patients; this finding is consistent with results reported for this study indicating that escitalopram 10 mg/day had similar efficacy to citalopram 20 mg/day in the total population but greater efficacy in the sub-group of moderately depressed patients (MADRS ]/22 and 5/29), which represent about half the population.3 Results of the meta-analysis are in line with those of the influence of the severity of depression on the difference between escitalopram and citalopram. Both drugs presented non-significantly different results on mildly depressed patients (baseline MADRS B/25), while the differences gradually increased when baseline MADRS score increased, with mean differences change from baseline in MADRS scores of 1.9 (P /0.02) and 5.1 (P /0.02) for the 30 /35 and ]/35 sub-groups, respectively. The more severely depressed the patient, the greater the difference between escitalopram and citalopram. Statistical significance with such a small number of patients indicates that the difference between escitalopram and citalopram reflects a clinically relevant improvement.
UNDERLYING MECHANISMS The superior efficacy profile of escitalopram over citalopram may be explained by the different pharmacological profiles of the two enantiomers of citalopram. The antidepressant activity of citalopram resides in its S -enantiomer, which was found to mediate its serotonin uptake inhibitory and antidepressant effects, whereas R -citalopram produced no or minor effects.17,18 In the rat chronic mild stress model of depression, escitalopram produced a shorter time to effect than citalopram.19 Moreover, a series of recent studies comparing serotonin levels in the frontal cortex of freely moving rats after single doses20 have demonstrated that Rcitalopram counteracts the serotonin-enhancing properties of escitalopram. Serotonin levels in the frontal cortex of the rats were more than 2-fold increased after administration of escitalopram than an equivalent dose of the racemate. No change in serotonin levels was observed with R -citalopram alone, and administration of R -citalopram prior to escitalopram inhibited the effects of the latter. The mechanism involved in these differences is unknown at the moment but may help explain the improved clinical antidepressant activity seen with escitalopram in comparison with citalopram. Although rare, antagonistic activity between two enantiomers of a racemate is well established and has been described for other compounds: (/) and ( /)-picenadol,21 R -1methyl-5-phenyl-5-propylbarbituric acid (R-MPPB) and S-
MPPB22 and S-2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl) propionic acid (S -APPA) and R -APPA.23
COMPARISON
WITH
OTHER META-ANALYSES
A conventional belief is that the available antidepressant drugs are equally effective. This might be based on results issued from conventional trials that are not powered to discriminate between effective drugs and consequently are relatively insensitive to modest but potentially clinically relevant differences between active treatments.24 Meta-analyses have been developed to determine whether a ‘nonstatistically different’ finding issued from a single study reflects a true therapeutic equivalence or is a false negative. They have been increasingly used to compare various antidepressant strategies. Several meta-analyses have shown that SSRIs have a comparable efficacy profile to that of the tricyclic antidepressants (TCA).25 29 There have been relatively few publications comparing individual SSRIs. When compared together, SSRIs have not been demonstrated to differ statistically in head-to-head comparison in well-designed comparative studies.30 In fact, a meta-analytic approach has shown an overall ‘within group’ comparability in terms of efficacy, whereas fluoxetine had a slower onset of action, suggesting that some heterogeneity exists within the class of the SSRIs.31 By showing superior efficacy compared with citalopram, escitalopram substantiates this heterogeneity of therapeutic efficacy within the class of SSRIs.
CONCLUSION The meta-analysis applied in the present report is based on high quality studies using similar designs; sensitivity analyses were performed to assess the robustness of results. The results from the present meta-analysis, strengthened by sensitivity analyses, support the superiority of escitalopram compared to citalopram in terms of onset of response, magnitude of antidepressant effect and response to treatment. The superiority of escitalopram increased with the degree of severity of depression: the more severely depressed the patient, the greater the difference between escitalopram and citalopram. As a confounding factor, placebo response hides the real difference between active antidepressants and an analysis focused on very severely depressed patients allows minimising the impact of this placebo effect and therefore brings a better evidence of the real difference between treatments. This analysis illustrates the interest of performing such exhaustive approaches when considering sub-populations, mostly under-represented in standard randomised clinical trials. Escitalopram was shown to be a useful therapeutic alternative in the treatment of major depressive disorder.
Comparison of escitalopram and citalopram efficacy
ACKNOWLEDGEMENTS
KEY POINTS
Preparation of this manuscript was supported by an unrestricted grant from H. Lundbeck A/S.
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. A meta-analysis of four randomised clinical trials supported superior efficacy of escitalopram compared to citalopram . The superiority was observed in terms of onset of response, magnitude of antidepressant effect and response to treatment . The more severely depressed the patient, the greater the difference between escitalopram and citalopram . Escitalopram was shown to be an effective therapeutic treatment for MDD . Escitalopram presents significant advantages over citalopram
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Waugh J, Goa K (2003) Escitalopram: a review of its use in the management of major depressive and anxiety disorders. CNS Drugs 17: 343 /62. Wade A, Lemming OM, Hedegaard KB (2002) Escitalopram 10 mg/day is effective and well tolerated in a placebo-controlled study in depression in primary care. Int Clin Psychopharmacol 17: 95 / 102. Colonna L, Reines EH, Andersen HF (2002) Escitalopram is well tolerated and more efficacious than citalopram in long-term treatment of moderately depressed patients [Abstracts from the 3rd International Forum on Mood and Anxiety Disorders, 27 /30 November 2002, Monte-Carlo]. Int J Psych Clin Pract 6: 243 /4. Lepola UM, Loft H, Reines EH (2003) Escitalopram (10 /20 mg/ day) is effective and well tolerated in a placebo-controlled study in depression in primary care. Int Clin Psychopharmacol 18: 211 /7. Burke WJ, Gergel I, Bose A (2002) Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry 63: 331 /6. Montgomery SA, Asberg M (1979) A new depression scale designed to be sensitive to change. Br J Psychiatry 134: 382 /9. Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23: 56 /62. Guy W (ed) (1976) Early Clinical Drug Evaluation Unit (ECDEU) Assessment Manual for Psychopharmacology. Revised edition. US Department of Health, Education and Welfare Publication ADM 76-338. Rockville, MD: US Department of Health, Education and Welfare. Montgomery SA, Loft H, Sanchez C et al (2001) Escitalopram (S enantiomer of citalopram): clinical efficacy and onset of action predicted from a rat model. Pharmacol Toxicol 88: 282 /6. Gorman JM, Korotzer A, Su G (2002) Efficacy comparison of escitalopram and citalopram in the treatment of major depressive disorder: pooled analysis of placebo-controlled trials. CNS Spectrums 7: 40 /4. American Psychiatric Association (eds) (1994) Diagnostic and Statistical Manual of Mental Disorders , Fourth edition. Washington, DC: American Psychiatric Association. Forrest Laboratories Inc., unpublished data. Hasselblad V, McCrory DC (1995) Meta-analytic tools for medical decision making: a practical guide. Med Decis Making 15: 81 /96. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7: 177 /88.
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Smith ML, Glass GV (1977) Meta-analysis of psychotherapy outcome studies. Am Psychol 32: 752 /60. Khan A, Detke M, Khan SR et al (2003) Placebo response and antidepressant clinical trial outcome. J Nerv Ment Dis 191: 211 /8. Hyttel J, Bogeso KP, Perregaard J et al (1992) The pharmacological effect of citalopram residues in the (S )-(/)-enantiomer. J Neural Transm Gen Sect 88: 157 /60. Sa´nchez C (2003) R -Citalopram attenuates anxiolytic effects of escitalopram in a rat ultrasonic vocalisation model. Eur J Pharmacol 464: 155 /8. Sa´nchez C, Bergqvist PB, Brennum LT et al (2003) Escitalopram, the S -(/)-enantiomer of citalopram, is a selective serotonin reuptake inhibitor with potent effects in animal models predictive of antidepressant and anxiolytic activities. Psychopharmacology (Berlin) 167: 353 /62. Mørk A, Kreilgaard M, Sa´nchez C (2003) The R -enantiomer of citalopram counteracts escitalopram-induced increase in extracellular 5-HT in the frontal cortex of freely moving rats. Neuropharmacology 45: 167 /73. Leander JD, Zimmerman DM (1983) Effects of picenadol and its agonist and antagonist isomers on schedule-controlled behavior. J Pharmacol Exp Ther 227: 671 /5. Ticku MK, Rastogi SK, Thyagarajan R (1985) Separate site(s) of action of optical isomers of 1-methyl-5-phenyl-5-propylbarbituric acid with opposite pharmacological activities at the GABA receptor complex. Eur J Pharmacol 112: 1 /9. Ebert B, Lenz S, Brehm L et al (1994) Resolution, absolute stereochemistry, and pharmacology of the S -(/)- and R -( /)isomers of the apparent partial AMPA receptor agonist (R ,S )-2amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid [(R ,S )APPA]. J Med Chem 37: 878 /84. Thase ME (2002) Comparing the methods used to compare antidepressants. Psychopharmacol Bull 36: 24 /35. Anderson IM, Tomenson BM (1994) The efficacy of selective serotonin reuptake inhibitors in depression: a meta-analysis of studies against tricyclic antidepressants. J Psychopharmacol 8: 238 /49. Anderson IM (2000) Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. J Affect Disord 58: 19 /36. MacGillivray S, Arroll B, Hatcher S et al (2003) Efficacy and tolerability of selective serotonin reuptake inhibitors compared
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with tricyclic antidepressants in depression treated in primary care: systematic review and meta-analysis. Br Med J 326: 1014. Hotopf M, Hardy R, Lewis G (1997) Discontinuation rates of SSRIs and tricyclic antidepressants: a meta- analysis and investigation of heterogeneity. Br J Psychiatry 170: 120 /7. Geddes JR, Freemantle N, Mason J, Eccles MP, Boynton J (2002) Selective Serotonin reuptake inhibitors (SSRIs) for depression
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International Journal of Psychiatry in Clinical Practice 2003
Volume 7
Pages 259 /268 259
Comparison of escitalopram and citalopram efficacy: A meta-analysis PASCAL AUQUIER1, STE´PHANE ROBITAIL1, PIERREMICHEL LLORCA2 AND BENOIˆT RIVE3 Int J Psych Clin Pract Downloaded from informahealthcare.com by University of Washington on 10/28/14 For personal use only.
1
De´partement de Sante´ Publique, Faculte´ de Me´decine, 27 Bd Jean Moulin, 13385 Marseille Cedex 5, France, 2Centre Medico-Psychologique B, Centre Hospitalier Universitaire, BP 69, 63003 Clermont-Ferrand, France and 3 Altipharm SA, 7 Rue de la Paix, 75002 Paris, France
OBJECTIVE: Escitalopram is a new selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of major depressive disorder (MDD) and panic disorder. Escitalopram is the therapeutically active enantiomer of citalopram. Its efficacy in the treatment of MDD was compared to that of citalopram. METHODS: A quantitative meta-analysis was applied to 1262 patients in four randomised clinical trials; the comparison was based on response rate and mean change from baseline in the Montgomery A˚sberg depression rating scale (MADRS) total score at week 8. Complementary analyses were performed on early MADRS change from baseline (week 1), in very severely depressed patients (baseline MADRS total score ] 35) and on the influence of the level of severity at baseline.
/
/
Correspondence Address Pascal Auquier, De´partement de Sante´ Publique, Faculte´ de Me´decine, 27 Bd Jean Moulin, 13385 Marseille Cedex 5, France Tel: /(33) 491 384745 Fax: /(33) 491 797520 E-mail: [email protected]
Compared with citalopram, escitalopram-treated patients showed significantly higher response rates and increased mean change from baseline in MADRS at weeks 1 and 8. The superiority of escitalopram over citalopram was more pronounced in very severely depressed patients. This superiority was further shown to increase with degree of severity of the depression. The robustness of meta-analysis results was supported by sensitivity analyses. The clinical superiority of escitalopram versus citalopram is consistent with the results of preclinical pharmacological studies.
RESULTS:
Escitalopram was shown to be an effective therapeutic treatment for MDD, presenting significant advantages over citalopram. (Int J Psych Clin Pract 2003; 7: 259 268)
CONCLUSION:
/
Received 24 July 2003; accepted for publication 2 September 2003
Keywords escitalopram meta-analysis depression
INTRODUCTION
E
scitalopram is a new selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of depression.1 It is the therapeutically active S -enantiomer of citalopram. Escitalopram has been shown to be an effective and welltolerated treatment for major depressive disorder (MDD) in primary care2 4 and specialist settings.5 Escitalopram at both 10 and 20 mg/day was more effective than placebo and at least as effective as citalopram 40 mg/day in alleviating the symptoms of depression in a study including 491 MDD patients.5 It has produced significant improvements in standard measurements of antidepressant effects, including
serotonin reuptake inhibitor efficacy
the Montgomery/A˚sberg Depression Rating Scale (MADRS),6 Hamilton Rating Scale for Depression (HAM-D),7 and Clinical Global Impression of Improvement and Severity (CGI-I and CGI-S) scales.8 Although not reaching systematically statistical significance, there was a trend for the 20mg escitalopram group to separate from the 40 mg citalopram group in terms of MADRS total score (P /0.07) and the HAM-D (P /0.06). Moreover, escitalopram 10 mg/ day was as effective as citalopram 40 mg/day on most assessments. In another placebo-controlled study,4 significantly more patients responded to treatment with escitalopram than with citalopram (P /0.021). Improvement of symptoms was rapid.9 Decrease in mean MADRS total score, the primary endpoint, was significantly DOI: 10.1080/13651500310003408
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greater with escitalopram than with placebo as soon as week 14 or week 2.2,5 Escitalopram showed an earlier separation from placebo than citalopram.4,5 These findings suggest that escitalopram is more efficacious than citalopram at equivalent doses. A pooled analysis by Gorman based on three randomised, placebo-controlled clinical trials (RCT) in which both escitalopram and citalopram were administered showed escitalopram to be statistically significantly superior to citalopram on mean change from baseline in MADRS total score at week 1 for the observed case (OC) and last-observation-carried-forward (LOCF) analyses and at week 8 for the OC analysis.10 The objective of the present analysis is to extend this comparison of escitalopram and citalopram using a quantitative meta-analysis coupled with a sensitivity analysis to ascertain the robustness of the results. Complementary analyses were performed to further investigate this comparison, on early mean MADRS change from baseline, on very severely depressed patients and on the influence of severity of depression.
METHODS TYPES
OF
STUDIES
This analysis considered all clinical trials that included both escitalopram and citalopram in patients with MDD. A priori criteria were established for selecting trials into the metaanalysis: (i) similar clinical inclusion criteria for patients with MDD defined by DSM-IV11, (ii) use of the mean change from baseline in MADRS total score as an efficacy measure and (iii) double-blind, randomised, treatment period of at least 8 weeks, with an assessment of MADRS at week 8. Four studies complied with these criteria, and no study was excluded. Studies were similar in design and inclusion/ exclusion criteria, primary endpoints and assessment schedules as described in Table 1. Eligible patients were male or female outpatients, aged between 18 and 65 years (or 80 in one study; Table 1). They met DSM-IV criteria for MDD, with a baseline MADRS total score ]/22. After a 1-week placebo run-in period, patients were randomised to a double-blind treatment phase of at least 8 weeks. MADRS scores were measured at baseline, and after 1, 2, 4, 6 and 8 weeks of treatment. Two studies were performed in the USA in specialist settings and two studies were performed in Europe (and Canada for one study) in primary care. One USA trial compared two fixed doses of escitalopram (ESC 10 and 20 mg/day) to placebo, with a single dose of citalopram (CIT 40 mg/day) as the active comparator.5 Patients in the ESC 20 mg and CIT 40 mg groups were force titrated to their final dose after 1 week of initial treatment at ESC 10 mg/day and CIT 20 mg/day. In two studies (one in the USA, one in Europe), flexible doses of both compounds were compared with placebo;
initial doses of ESC 10 mg/day or CIT 20 mg/day could be increased at week 3 (USA study) or at weeks 4 or 6 (European study) in case of unsatisfactory response to maximum doses of ESC 20 mg/day or CIT 40 mg/day.4,12. It should be noted that the USA flexible dose study12 failed to show a significant difference from placebo on the primary outcome for both escitalopram and citalopram (MADRS, LOCF), but demonstrated statistically significant efficacy on other parameters (MADRS OC, HAM-D, CGI-I). The fourth trial was a long-term study performed over a 6-month period, which compared ESC 10 mg/day to CIT 20 mg/day.3
STATISTICAL ANALYSIS The statistical analysis was performed on an intent-to-treat (ITT) basis, including all treated patients for whom at least one post-baseline assessment on the MADRS was measured. The efficacy criteria were (i) mean change from baseline to endpoint on the MADRS total score as well as (ii) response rate, defined as the percentage of patients achieving at least a 50% decrease in their baseline MADRS total score. For the long-term study, assessments measured after 8 weeks of treatment were not considered, and the 8-week evaluation was used as the endpoint measure. Further analysis of efficacy was determined by early change in mean MADRS total score (i.e., after 1 week of treatment), as well as analyses of the sub-group of very severely depressed patients characterised by a baseline MADRS total score ]/35. Results issued from individual studies were obtained for response rates by logistic regression with Centre and Treatment as factors. Estimates of treatment differences for each individual study are given as odds ratios with the corresponding 95% confidence interval. An odds ratio greater than one indicates superiority of escitalopram over citalopram. Analyses of change from baseline were performed by ANCOVA with Baseline Score as covariate and Centre and Treatment as factors. The only exception was the analysis of the very severely depressed sub-group (patients with a baseline MADRS total score ]/35) where the low number of patients did not allow Centre to be used as a factor. All analyses were performed using the LOCF method. A standard method was used for the meta-analysis: the combined effect was calculated as the weighted mean of the effects observed in each study, with the weight inversely proportional to the individual variances.13 The studies showing smaller inter-individual variations received the largest weight, resulting in a minimum variance for the pooled estimate. The presence of heterogeneity of treatment effect was tested using the Q statistic, which approximates the chisquare statistic with n /1 degrees of freedom.14 A fixed effect model was used as the primary analysis, unless substantial heterogeneity was detected (P B/0.05) in which case a random effect method was used as the primary
Reference Ref. 5
Country USA
Patient setting Specialist
Inclusion criteria DSM-IV EDM
Treatment duration
Treatment
8 weeks
Escitalopram
MADRS ]/22 Age 18 /65 years
1
Dosage /day (mean4)
Outcome measures
Citalopram Placebo
10 mg 20 mg 40 mg NA
118 123 125 119
MADRS1 CGI-S, CGI-I, Response2 Remission3 HAMD, HAMA
Ref. 4
Europe, Canada
Primary care
DSM-IV EDM MADRS ]/22 /40 Age 18 /65 years
8 weeks
Escitalopram Citalopram Placebo
10 /20 mg (11.7) 20 /40 mg (24.4) NA
155 159 154
MADRS1 CGI-S, CGI-I, Response2 Remission3
Ref. 12
USA
Specialist
DSM-IV EDM MADRS ]/22 Age 18 /80 years
8 weeks
Escitalopram Citalopram Placebo
10 /20 mg (13.4) 20 /40 mg (25.2) NA
124 119 125
MADRS CGI-S, CGI-I, Responses2 Remission3 HAMD, HAMA
Ref. 3
Europe
Primary care
DSM-IV EDM MADRS ]/22 Age 18 /65 years
24 weeks
Escitalopram Citalopram
10 mg 20 mg
165 174
MADRS1 CGI-S, HAMA, Response2 Remission3
Mean change from baseline in MADRS total score at week 8 was the main efficacy criteria. Response was defined as patients with ]/50% reduction of baseline MADRS total score at week 8. 3 Remission was defined as patients with MADRS 5/12 at week 8. 4 Mean daily dose corresponds to the average daily dose prescribed for the 8 weeks of treatments; it is indicated for flexible doses only. NA, not appropriate. 2
Patients (ITT)
Comparison of escitalopram and citalopram efficacy
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Table 1 Short summary of randomised clinical trials testing for escitalopram and citalopram included in the meta-analysis
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analysis since it gives more conservative results, but can deal with a certain amount of heterogeneity. Results for the individual studies and the meta-analysis (combined effect) were illustrated as Forrest plots presenting the estimated means (of the difference or odds ratio) with the corresponding 95% confidence intervals. The influence of the difference degree of severity of depression on the difference between escitalopram and citalopram efficacy was performed by ANOVA with Group of Severity as factor, and Treatment by Severity and Study by Centre as interactions. The efficacy criterion was the mean change from baseline in MADRS total score evaluated at endpoint on the ITT population for the three studies in which doses were appropriate for comparison of drugs in severe depression (i.e. the long-term study was excluded3). Four severity groups were defined a priori, based on the MADRS total score at baseline: B/25, ]/25 and B/30, ]/30 and B/35, and ]/35. The effect of treatment was evaluated from the Treatment by Severity interaction.
SENSITIVITY ANALYSES Various meta-analyses were performed as sensitivity analyses in order to test for the robustness of the results. This was performed by exclusion of some studies from the initial metaanalysis in order to test for their influence on the metaanalysis. Comparable results for the meta-analysis and the sensitivity analyses indicated studies of similar weight. The first sensitivity analysis (sensitivity 1 ) was performed after exclusion of the non-placebo-controlled study, i.e. the longterm study3, a second one (sensitivity 2 ) after exclusion of the inconclusive study12 and a third one (sensitivity 3 ) after concomitant exclusion of both studies. Analyses were performed as described for the initial meta-analysis.
RESULTS STUDY POPULATION A total of 1262 patients were included in the study population for the meta-analysis; 685 had received escitalo-
pram (83.9% of whom completed the study) and 577 had received citalopram (83% of whom completed the study). Patient demographics and other baseline characteristics are balanced between the two treatment groups, as summarised in Table 2. The mean MADRS total scores at baseline were 28.99/4.4 and 29.49/4.6 for the escitalopram and citalopram groups, respectively, signifying that patients were moderately to severely depressed. Among them, 157 were defined as very severely depressed (baseline MADRS ]/35), with 73 in the escitalopram group (MADRS of 37.09/1.9) and 84 in the citalopram group (MADRS of 37.19/2.2). Overall, patients received 12.6 mg/day of S -citalopram in the escitalopram group and 26.4 mg/day of R - and S-citalopram in the citalopram group.
CLINICAL OUTCOMES
IN
ALL PATIENTS
Figure 1 shows the main results of the clinical outcome measures of the meta-analysis, as well as the results of the sensitivity analyses. Response rates were 55.5% for escitalopram-treated patients and 50.8% for citalopram-treated patients; the corresponding meta-analysis odds ratio of 1.35 (CI 95% of 1.09 /1.70) reached statistical significance (P /0.01). Figure 1a illustrates that this trend was observed in the majority of individual studies. Testing for heterogeneity revealed no significant difference. The mean change from baseline in MADRS total score at endpoint was significantly greater after 8 weeks of escitalopram treatment than after citalopram treatment (estimate of 1.02; CI 95% of 0.09 /1.95; P /0.03). As shown in Figure 1b, this result was consistent with the majority of studies, in which numerically better results were observed for escitalopram-treated patients. Testing for heterogeneity of the individual results revealed no significant difference. Sensitivity analyses lead to similar results: odds ratios for response rates were comparable (with estimated values of 1.21, 1.51 and 1.40 for sensitivity 1, 2 and 3, respectively) and differences in mean change from baseline in MADRS total score were higher at week 8 (with estimated means of 1.12, 1.24 and 1.54 for sensitivity 1, 2 and 3, respectively). These results were close to significance for sensitivity 1 and
Table 2 Baseline characteristics of patients included in the meta-analysis No. of patients
Age (years) (mean9/SD)
% Women
MADRS (mean9/SD)
Mean dose (mg/day)
All patients (n /1262) Escitalopram Citalopram
685 577
429/12 439/12
68.2 65.5
28.99/4.4 29.49/4.6
12.6 26.4
Very severely depressed patients (n /157) Escitalopram Citalopram
73 84
449/11 439/13
64.4 71.4
37.09/1.9 37.19/2.2
12.7 24.9
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Figure 1 Main efficacy results of the meta-analysis and sensitivity analyses on the overall ITT population. (a) Odds ratios and 95% confidence intervals for response rates estimated for individual studies, meta-analysis and sensitivity analyses for the overall population (ITT analysis, LOCF approach). An odds ratio greater than 1 favours escitalopram; a confidence interval not including 1 indicates a statistically significant difference with PB/0.05. (b) Estimated differences and 95% confidence interval for MADRS score changes at week 8 for individual studies, meta-analysis and sensitivity analyses (ITT analysis, LOCF approach). A difference greater than 0 favours escitalopram; a confidence interval not including 0 indicates a statistically significant difference with P B/0.05. Sensitivity 1 is the meta-analysis performed without the long-term study,3 sensitivity 2 the meta-analysis performed without the inconclusive study12 and sensitivity 3 without both.
reached statistical significance for sensitivity 2 and 3 (P B/ 0.05).
EARLY CHANGE
FROM
BASELINE
The mean change from baseline in MADRS total score was significantly greater for escitalopram-treated patients than for citalopram-treated patients as early as week 1 of treatment (estimated difference of 0.63; CI95% of 0.08 /1.17; P / 0.02). This early numerical superiority of escitalopram was observed in all individual studies although these differences did not reach statistical significance. Testing for heterogeneity revealed no significant difference. Sensitivity analyses gave similar results with estimated means of 0.85 (P /0.02), 0.63 (P /0.07) and 0.77 (P / 0.06) for sensitivity 1, 2 and 3, respectively.
increased to 1.83 (CI95% of 0.95 /3.51) and the difference in the mean change from baseline in MADRS total score at endpoint increased to 3.48 (CI95% of /0.28 /7.24). Both these differences between treatments were close to statistical significance (P /0.07 in both cases) and reflect trends observed in all individual studies. Meta-analyses performed for sensitivity 2 (exclusion of the inconclusive study) led to similar results as the meta-analysis (cf. Figure 2a and 2b), while sensitivity 1 and 3 (i.e. those excluding long-term/low dose study) led to greater differences: for sensitivity 1, the odds ratio for response rate was 2.34 (P /0.04) and the difference in MADRS at endpoint was 7.33 (P /0.008), and for sensitivity 3, results were 2.06 for response rate (P / 0.13) and 8.05 for the difference in MADRS at endpoint (P / 0.009).
VERY SEVERELY DEPRESSED PATIENTS
INFLUENCE OF BASELINE SEVERITY DEPRESSION
For the sub-group of very severely depressed patients (i.e. patients with a baseline MADRS ]/35), the difference between escitalopram- and citalopram-treated patients was more pronounced. The estimated odds ratio for response rate
Figure 3 illustrates the influence of the degree of severity of the depression of patients measured at baseline on the mean change from baseline in MADRS total score at week 8, in the placebo-controlled studies. The overall analysis showed
OF
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Figure 2 Main efficacy results of the meta-analysis and sensitivity analyses on the very severely depressed patient sub-group. (a) Odds ratios and 95% confidence intervals for response rates estimated for individual studies, meta-analysis and sensitivity analyses for the very severely depressed patients with baseline MADRS ]/35 (ITT analysis, LOCF approach). An odds ratio greater than 1 favours escitalopram; a confidence interval not including 1 indicates a statistically significant difference with P B/0.05. (b) Estimated differences and 95% confidence interval for MADRS score changes at week 8 for individual studies, meta-analysis and sensitivity analyses (ITT analysis, LOCF approach). A difference greater than 0 favours escitalopram, and a confidence interval not including 0 indicates a statistically significant difference, with P B/0.05. Sensitivity 1 is the meta-analysis performed without the long-term study,3 sensitivity 2 the meta-analysis performed without the inconclusive study12 and sensitivity 3 without both.
statistically significant differences between the two groups of patients with baseline MADRS ]/30 and MADRS ]/35, with respective mean differences of 1.91 and 5.10 in favour of escitalopram (P /0.02 in both cases).
Figure 3 Mean change from baseline in MADRS total score to endpoint as a function of severity of depression at baseline with patients a priori categorised into four groups of severity. *P B/0.05 for the difference between escitalopram and citalopram in the two most severely depressed patients sub-groups.
DISCUSSION METHODOLOGY Meta-analysis is a useful approach to compare active treatments, and provides balanced evidence of differences, or lack thereof, observed in individual randomised clinical trials. For consensus statements and development of treatment guidelines, meta-analyses today are regarded as A1 evidence. The quality of meta-analyses depends on the methodology applied, which by and large relies on the selection of studies.15 As suggested by the Cochrane group, the present analysis selected trials based on the robustness of their methodology (properly randomised and blinded trials), similarity of design, outcome measures and therapeutic issue addressed; studies selection remained independent of efficacy outcomes (inclusion of inconclusive study was possible). The main criteria for selecting studies led to the inclusion of all existing randomised double-blind studies that included both escitalopram and citalopram. The four studies were similar in terms of inclusion criteria for patients, outcome measures and design. Differences in the dosage schedules between studies (different levels of doses, flexible versus fixed doses) could have introduced heterogeneity, as the efficacy outcome may vary
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Comparison of escitalopram and citalopram efficacy
according to dose, and the possibility of increasing the dose in flexible-dose studies is often associated with a renewed response that can alter the endpoint outcome compared to fixed-dose studies. These differences were considered to be limited, since individual comparisons were balanced in terms of dose equivalence between escitalopram and citalopram (see Table 1), except for the fixed-dose USA study,5 which included escitalopram (10 mg) without an equivalent citalopram dose (20 mg). This resulted in comparison of a slightly lower overall dose of escitalopram (12.6 mg/day) than of citalopram (26.4 mg/day). The inclusion of some of the studies may have implied choices that could be methodologically questionable. In order to test the approach used, and to measure its robustness, a sensitivity analysis was performed. A potential bias could have resulted from inclusion of a non-placebo-controlled study with the placebo-controlled studies, as this could affect the level of therapeutic response. Non-placebo-controlled studies are known to induce higher treatment response than placebo-controlled studies, since patients and physicians have a greater expectation of effective treatment.16 This potential bias was circumvented by exclusion of the non-placebo-controlled study from the metaanalysis (sensitivity 1 ). A second potential bias might have resulted from the inclusion of an inconclusive study, as such results might not give useful information about efficacy. This potential impact was tested in the second sensitivity analysis (sensitivity 2). The impact of both potential biases was further tested in sensitivity 3 . Results of these sensitivity analyses supported the superiority of escitalopram over citalopram observed in the initial meta-analysis; the changes observed in either the magnitude of the estimated difference or the degree of statistical significance were not relevant with the exception of the very severely depressed patient sub-group analysis after exclusion of the long-term study (i.e. sensitivity 1 and 3 , discussed below). They lead to similar conclusions as those drawn from the meta-analysis, showing the robustness of the approach. The meta-analysis was therefore optimal in that it was exhaustive and robust.
CLINICAL RESPONSE
TO
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in the present analysis, as it is of direct clinical significance although it sacrifices statistical power. In our present comparison, at least half of the patients who received either escitalopram or citalopram responded to treatment. The meta-analysis estimated the difference to reach statistical significance with an odds ratio of response rates of 1.35. For a translation into a meaningful outcome, it is interesting to convert these results into the number of patients needed to treat (NNT) to realise a difference. In our initial metaanalysis, 20 patients would be needed to be treated by escitalopram in order to obtain an extra responder compared with citalopram. When excluding results of both the inconclusive study and the non-placebo-controlled study (sensitivity 3 ), this NNT decreased to 15, while in the 6month non-placebo-controlled fixed-dose study3 comparing ESC 10 mg to CIT 20 mg the NNT was 11 at week 8. When considering the comparison in terms of mean change from baseline in MADRS total score, the estimated difference was statistically significant although not numerically important. This difference is not unexpected as (i) we used a worst-case scenario comparing lower doses of escitalopram than of citalopram, (ii) we included an inconclusive study in the meta-analysis (the magnitude of MADRS difference is increased when this study is excluded in sensitivity 2) and (iii) a high placebo response rate is usually observed in RCT where drug effect is confounded by extensive and iterative patient interviews and valuation that contributes to their improvement. As illustrated from our data, the more severely depressed the patient is, the lower the response to placebo (see Figure 4). An analysis focused on very severely depressed patients allows us to minimise the impact of this placebo effect, and is therefore better evidence of the real difference between treatments. The assessment of treatment differences in relationship with the severity of the depression may then be a useful means to identify the real difference between treatments. When focusing on very severely depressed patients, the superiority of escitalopram over citalopram was greater, in
ESCITALOPRAM
Results of the meta-analysis supported indications from individual studies of the superiority of escitalopram over citalopram based on response rate and mean change from baseline in MADRS total score at endpoint. Escitalopram differentiated from citalopram as early as the first week of treatment. These results confirmed those from the pooled analysis of Gorman.10 The individual studies used the mean change from baseline in MADRS total score change as the primary outcome measure as it is a direct measure of improvement of depressive symptomatology. As it is difficult to establish a translation from a difference in two MADRS scores into a clinical meaning, the response rate, defined as a 50% reduction in the baseline MADRS score, was also considered
Figure 4 Response rates measured for the placebo group as a function of severity. Response rates were calculated from a meta-analysis of the three placebo-controlled studies.
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spite of the low number of patients included in the metaanalysis (73 and 84 for escitalopram and citalopram, respectively). This was particularly evident in the sensitivity analyses, in which the long-term study (i.e. where fixed low doses were administered) was excluded: odds ratios greater than 2 and differences in MADRS scores at endpoint around 7 /8 were estimated. In the long-term study, the administration of low doses did not allow the drugs to be differentiated in severely depressed patients; this finding is consistent with results reported for this study indicating that escitalopram 10 mg/day had similar efficacy to citalopram 20 mg/day in the total population but greater efficacy in the sub-group of moderately depressed patients (MADRS ]/22 and 5/29), which represent about half the population.3 Results of the meta-analysis are in line with those of the influence of the severity of depression on the difference between escitalopram and citalopram. Both drugs presented non-significantly different results on mildly depressed patients (baseline MADRS B/25), while the differences gradually increased when baseline MADRS score increased, with mean differences change from baseline in MADRS scores of 1.9 (P /0.02) and 5.1 (P /0.02) for the 30 /35 and ]/35 sub-groups, respectively. The more severely depressed the patient, the greater the difference between escitalopram and citalopram. Statistical significance with such a small number of patients indicates that the difference between escitalopram and citalopram reflects a clinically relevant improvement.
UNDERLYING MECHANISMS The superior efficacy profile of escitalopram over citalopram may be explained by the different pharmacological profiles of the two enantiomers of citalopram. The antidepressant activity of citalopram resides in its S -enantiomer, which was found to mediate its serotonin uptake inhibitory and antidepressant effects, whereas R -citalopram produced no or minor effects.17,18 In the rat chronic mild stress model of depression, escitalopram produced a shorter time to effect than citalopram.19 Moreover, a series of recent studies comparing serotonin levels in the frontal cortex of freely moving rats after single doses20 have demonstrated that Rcitalopram counteracts the serotonin-enhancing properties of escitalopram. Serotonin levels in the frontal cortex of the rats were more than 2-fold increased after administration of escitalopram than an equivalent dose of the racemate. No change in serotonin levels was observed with R -citalopram alone, and administration of R -citalopram prior to escitalopram inhibited the effects of the latter. The mechanism involved in these differences is unknown at the moment but may help explain the improved clinical antidepressant activity seen with escitalopram in comparison with citalopram. Although rare, antagonistic activity between two enantiomers of a racemate is well established and has been described for other compounds: (/) and ( /)-picenadol,21 R -1methyl-5-phenyl-5-propylbarbituric acid (R-MPPB) and S-
MPPB22 and S-2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl) propionic acid (S -APPA) and R -APPA.23
COMPARISON
WITH
OTHER META-ANALYSES
A conventional belief is that the available antidepressant drugs are equally effective. This might be based on results issued from conventional trials that are not powered to discriminate between effective drugs and consequently are relatively insensitive to modest but potentially clinically relevant differences between active treatments.24 Meta-analyses have been developed to determine whether a ‘nonstatistically different’ finding issued from a single study reflects a true therapeutic equivalence or is a false negative. They have been increasingly used to compare various antidepressant strategies. Several meta-analyses have shown that SSRIs have a comparable efficacy profile to that of the tricyclic antidepressants (TCA).25 29 There have been relatively few publications comparing individual SSRIs. When compared together, SSRIs have not been demonstrated to differ statistically in head-to-head comparison in well-designed comparative studies.30 In fact, a meta-analytic approach has shown an overall ‘within group’ comparability in terms of efficacy, whereas fluoxetine had a slower onset of action, suggesting that some heterogeneity exists within the class of the SSRIs.31 By showing superior efficacy compared with citalopram, escitalopram substantiates this heterogeneity of therapeutic efficacy within the class of SSRIs.
CONCLUSION The meta-analysis applied in the present report is based on high quality studies using similar designs; sensitivity analyses were performed to assess the robustness of results. The results from the present meta-analysis, strengthened by sensitivity analyses, support the superiority of escitalopram compared to citalopram in terms of onset of response, magnitude of antidepressant effect and response to treatment. The superiority of escitalopram increased with the degree of severity of depression: the more severely depressed the patient, the greater the difference between escitalopram and citalopram. As a confounding factor, placebo response hides the real difference between active antidepressants and an analysis focused on very severely depressed patients allows minimising the impact of this placebo effect and therefore brings a better evidence of the real difference between treatments. This analysis illustrates the interest of performing such exhaustive approaches when considering sub-populations, mostly under-represented in standard randomised clinical trials. Escitalopram was shown to be a useful therapeutic alternative in the treatment of major depressive disorder.
Comparison of escitalopram and citalopram efficacy
ACKNOWLEDGEMENTS
KEY POINTS
Preparation of this manuscript was supported by an unrestricted grant from H. Lundbeck A/S.
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. A meta-analysis of four randomised clinical trials supported superior efficacy of escitalopram compared to citalopram . The superiority was observed in terms of onset of response, magnitude of antidepressant effect and response to treatment . The more severely depressed the patient, the greater the difference between escitalopram and citalopram . Escitalopram was shown to be an effective therapeutic treatment for MDD . Escitalopram presents significant advantages over citalopram
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