Escitalopram versus other antidepressive agents for depression

Andrea Cipriani; Claudio Santilli; Toshi A Furukawa; Alessandra Signoretti; Atsuo Nakagawa; Hugh McGuire; Rachel Churchill; Corrado Barbui

doi:10.1002/14651858.CD006532.pub2

. Author manuscript; available in PMC: 2014 Sep 15.

Published in final edited form as: Cochrane Database Syst Rev. 2009 Apr 15;(2):CD006532. doi: 10.1002/14651858.CD006532.pub2

Escitalopram versus other antidepressive agents for depression

Andrea Cipriani ¹, Claudio Santilli ², Toshi A Furukawa ³, Alessandra Signoretti ¹, Atsuo Nakagawa ⁴, Hugh McGuire ⁵, Rachel Churchill ⁶, Corrado Barbui ¹

PMCID: PMC4164382 EMSID: EMS57800 PMID: 19370639

Abstract

Background

Although pharmacological and psychological interventions are both effective for major depression, antidepressant drugs remain the mainstay of treatment in primary and secondary care settings. During the last 20 years, antidepressant prescribing has risen dramatically in western countries, mainly because of the increasing consumption of selective serotonin reuptake inhibitors (SSRIs) and newer antidepressants, which have progressively become the most commonly prescribed antidepressants. Escitalopram is the pure S-enantiomer of the racemic citalopram.

Objectives

To assess the evidence for the efficacy, acceptability and tolerability of escitalopram in comparison with tricyclics, other SSRIs, heterocyclics and newer agents in the acute-phase treatment of major depression.

Search methods

Electronic databases were searched up to July 2008. Trial databases of drug-approving agencies were hand-searched for published, unpublished and ongoing controlled trials.

Selection criteria

All randomised controlled trials comparing escitalopram against any other antidepressant (including non-conventional agents such as hypericum) for patients with major depressive disorder (regardless of the diagnostic criteria used).

Data collection and analysis

Data were entered by two review authors (double data entry). Responders and remitters to treatment were calculated on an intention-to-treat basis. For dichotomous data, odds ratios (ORs) were calculated with 95% confidence intervals (CI). Continuous data were analysed using standardised mean differences (with 95% CI) using the random effects model.

Main results

Fourteen trials compared escitalopram with another SSRI and eight compared escitalopram with a newer antidepressive agent (venlafaxine, bupropion and duloxetine). Escitalopram was shown to be significantly more effective than citalopram in achieving acute response (OR 0.67, 95% CI 0.50 to 0.87). Escitalopram was also more effective than citalopram in terms of remission (OR 0.53, 95% CI 0.30 to 0.93). Significantly fewer patients allocated to escitalopram withdrew from trials compared with patients allocated to duloxetine, for discontinuation due to any cause (OR 0.62, 95% CI 0.38 to 0.99).

Authors’ conclusions

Some statistically significant differences favouring escitalopram over other antidepressive agents for the acute phase treatment of major depression were found, in terms of efficacy (citalopram and fluoxetine) and acceptability (duloxetine). There is insufficient evidence to detect a difference between escitalopram and other antidepressants in early response to treatment (after two weeks of treatment). Cost-effectiveness information is also needed in the field of antidepressant trials. Furthermore, as with most standard systematic reviews, the findings rely on evidence from direct comparisons. The potential for overestimation of treatment effect due to sponsorship bias should also be borne in mind.

Medical Subject Headings (MeSH): Antidepressive Agents [*therapeutic use], Citalopram [*therapeutic use], Depression [*drug therapy], Randomized Controlled Trials as Topic, Serotonin Uptake Inhibitors [*therapeutic use]

MeSH check words: Humans

BACKGROUND

Description of the condition

Major depression is generally diagnosed when a persistent and unreactive low mood and loss of all interest and pleasure are accompanied by a range of symptoms including appetite loss, insomnia, fatigue, loss of energy, poor concentration, psychomotor symptoms, inappropriate guilt and morbid thoughts of death (APA 1994). It was the third leading cause of burden among all diseases in the year 2002 and it is expected to show a rising trend during the coming 20 years (Murray 1997). This condition is associated with marked personal, social and economic morbidity, loss of functioning and productivity, and creates significant demands on service providers in terms of workload (NICE 2007).

Description of the intervention

Although pharmacological and psychological interventions are both effective for major depression, in primary and secondary care settings antidepressant drugs remain the mainstay of treatment (APA 2000; Ellis 2004; NICE 2007) (see below for other references to the relevant evidence). Amongst antidepressants many different agents are available, including tricyclics (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin re-uptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs, such as venlafaxine, duloxetine and milnacipran), and other newer agents (mirtazapine, reboxetine, bupropion). During the last 20 years, consumption of antidepressant has risen dramatically in western countries, mainly because of the increasing consumption of SSRIs and newer antidepressants, which have progressively become the most commonly prescribed antidepressants (Ciuna 2004; Guaiana 2005). SSRIs are generally better tolerated than TCAs (Barbui 2000), and there is evidence of similar efficacy (Anderson 2000; Geddes 2000; Williams 2000). However, head-to-head comparison have provided contrasting findings. Amitriptyline, for example, may have the edge over SSRIs in terms of efficacy (Guaiana 2003), and individual SSRIs and SNRIs may differ in terms of efficacy and tolerability (Puech 1997; Smith 2002; Hansen 2005; Cipriani 2006).

Escitalopram is the pure S-enantiomer of the racemic citalopram. As for all other antidepressants belonging to the SSRIs class, the mechanism of antidepressant action of escitalopram is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from its inhibition of neuronal re-uptake of serotonin. Escitalopram is at least 100 fold more potent than the R-enantiomer with respect to inhibition of 5-HT reuptake and inhibition of 5-HT neuronal firing rate. Escitalopram has no or very low affinity for other receptors (alpha- and beta-adrenergic, dopamine (D1-5), histamine (H1-3), muscarinic (M1-5), and benzodiazepine receptors). The single- and multiple-dose pharmacokinetics of escitalopram are linear and dose-proportional in a dose range of 10 to 30 mg/day. In vitro studies indicated that CYP3A4 and −2C19 are the primary enzymes involved in the metabolism of escitalopram, however these studies did not reveal an inhibitory effect of escitalopram on CYP2D6.

How the intervention might work

The efficacy of escitalopram as a treatment for major depressive disorder was established in three, 8-week, placebo-controlled studies conducted in outpatients between 18 and 65 years of age who met DSM-IV criteria for major depressive disorder (www.fda.gov). The primary outcome in all three studies was change from baseline to endpoint in the Montgomery Asberg Depression Rating Scale (MADRS) (Montgomery 1979). The 10 mg/day and 20 mg/day escitalopram treatment groups showed significantly greater mean improvement compared to placebo on the MADRS. Analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics. Among the 715 depressed patients who received escitalopram in placebo-controlled trials, 6% discontinued treatment due to an adverse event, compared to 2% of 592 patients receiving placebo. The rate of discontinuation for adverse events in patients assigned to a fixed dose of 20 mg/day escitalopram was 10%, which was significantly different from the rate of discontinuation for adverse events in patients receiving 10 mg/day escitalopram (4%) and placebo (3%). The most commonly observed adverse events in escitalopram patients (incidence of approximately 5% or greater and approximately twice the incidence as in placebo patients) were insomnia, ejaculation disorder (primarily ejaculatory delay), nausea, increased sweating, fatigue, and somnolence.

Why it is important to do this review

To shed light on the field of antidepressant trials and treatment of major depressive disorder, a group of researchers agreed to join forces under the rubric of the Meta-Analyses of New Generation Antidepressants Study Group (MANGA Study Group) to systematically review all available evidence for each specific newer antidepressant. As of October 2008, we have completed an individual review for fluoxetine (Cipriani 2005), and published the protocols for venlafaxine (Cipriani 2007a), sertraline (Malvini 2006), fluvoxamine (Omori 2006), citalopram (Imperadore 2007), duloxetine (Nose 2007), milnacipran (Nakagawa 2007), paroxetine (Cipriani 2007b) and mirtazapine (Watanabe 2006). Thus, the aim of the present review is to assess the evidence for the efficacy and tolerability of escitalopram in comparison with TCAs, heterocyclics, other SSRIs and newer antidepressants, including non-conventional agents such as herbal products like hypericum (Linde 2008), in the acute-phase treatment of major depression.

OBJECTIVES

To determine the efficacy of escitalopram in comparison with other antidepressive agents for depression in alleviating the acute symptoms of major depressive disorder.
To investigate the acceptability of escitalopram in comparison with other antidepressive agents for depression.
To investigate the adverse effects of escitalopram in comparison with other antidepressive agents for depression.

METHODS

Criteria for considering studies for this review

Types of studies

Only randomised controlled trials were included. Quasi-randomised trials, such as those allocating by using alternate days of the week, were excluded.

Types of participants

Patients aged 18 or older, of both sexes, with a primary diagnosis of major depression. Studies adopting any standardised criteria to define patients suffering from unipolar major depression were included. Studies from the 1990s onwards were likely to have used DSM-IV (APA 1994) or ICD-10 (WHO 1992) criteria. Earlier studies may had used ICD-9 (WHO 1978), DSM-III (APA 1980) / DSM-III-R (APA 1987) or other diagnostic systems. ICD-9 is not operationalised criteria, because it has only disease names and no diagnostic criteria, so studies using ICD-9 were excluded. However, studies using Feighner criteria or Research Diagnostic Criteria were included. Studies in which less than 20% of the participants might be suffering from bipolar depression were included, but the validity of this decision was examined in a sensitivity analysis. A concurrent secondary diagnosis of another psychiatric disorder was not considered as an exclusion criterion. A concurrent primary diagnosis of Axis I or II disorders was an exclusion criterion. Antidepressant trials in depressive patients with a serious concomitant medical illness were also excluded.

Types of interventions

Experimental intervention

Escitalopram (as monotherapy). No restrictions on dose, frequency, intensity and duration were applied.

Comparator interventions

All other antidepressive agents in the treatment of acute depression, including:

conventional tricyclic ADs (TCAs)
heterocyclic antidepressants (e.g. maprotiline)
SSRIs (fluoxetine, fluvoxamine, citalopram, paroxetine, sertraline)
newer antidepressants (SNRIs such as venlafaxine, duloxetine, milnacipran; MAOIs or newer agents such as mirtazapine, bupropion, reboxetine; and non-conventional ADs, such as herbal products - e.g. hypericum).

No restrictions on dose, frequency, intensity and duration were applied.

Other types of psychopharmacological agent such as anxiolytics, anticonvulsants, antipsychotics or mood-stabilizers were excluded. Trials in which escitalopram was used as an augmentation strategy were also excluded

Types of outcome measures

Primary outcomes

Number of patients who responded to treatment, showing a reduction of at least 50% on the Hamilton Depression Scale (HAM-D) (Hamilton 1960) or MADRS (Montgomery 1979), or any other depression scale, or “much or very much improved” (score 1 or 2) on CGI-Improvement (Guy 1970). All response rates were calculated out of the total number of randomised patients. Where more than one criterion was provided, we preferred the HAM-D for judging response. We used the HAM-D whenever possible, even when we needed to impute SDs or response rates according to the procedures described in the Methods section below.

When studies reported response rates at various time points of the trial, we decided a priori to subdivide the treatment indices as follows:

Early response: between 1 and 4 weeks, the time point closest to 2 weeks was given preference.
Acute phase treatment response: between 6 and 12 weeks, the time point given in the original study as the study endpoint was given preference.
Follow-up response: between 4 and 6 months, the time point closest to 24 weeks was given preference.

The acute phase treatment response, i.e. between 6 and 12 weeks, was our primary outcome of interest.

Secondary outcomes

Number of patients who achieved remission. The cut-off point for remission was set a priori (i) at 7 or less on the 17-item HAM-D and at 8 or less for all the other longer versions of HAM-D, or (ii) at 12 or less on the MADRS (Zimmerman 2004), or (iii) “not ill or borderline mentally ill” (score 1 or 2) on CGI-Severity (Guy 1970). All remission rates was calculated out of the total number of randomised patients. Where two or more were provided, we preferred the HAM-D for judging remission.
Change scores from baseline to the time point in question (early response, acute phase response, or follow-up response as defined above) on HAM-D, or MADRS, or any other depression scale. We applied a looser form of ITT analysis, whereby all the patients with at least one post-baseline measurement were represented by their last observations carried forward.
Social adjustment, social functioning, including the Global Assessment of Function (Luborsky 1962) scores
Health-related quality of life: we limited ourselves to SF-12/SF-36 (Ware 1993), HoNOS (Wing 1994) and WHOQOL (WHOQOL Group 1998).
Costs to health care services
Acceptability
Acceptability was evaluated using the following outcome measures:
1. Number of patients who dropped out during the trial as a proportion of the total number of randomised patients - Total drop out rate
2. Number of patients who dropped out due to inefficacy during the trial as a proportion of the total number of randomised patients
  - -
    Drop out rates due to inefficacy
3. Number of patients who dropped out due to side effects during the trial as a proportion of the total number of randomised patients
  - -
    Drop out rates due to side effects.
Tolerability

Tolerability was evaluated using the following outcome measures:

Total number of patients experiencing at least some side effects.
Total number of patients experiencing the following specific side effects were sought for:
1. Agitation/anxiety
2. Constipation
3. Diarrhoea
4. Dry mouth
5. Hypotension
6. Insomnia
7. Nausea
8. Sleepiness/drowsiness
9. Urination problems
10. Vomiting
11. Deaths, suicide and suicidality

In order not to miss any relatively rare or unexpected yet important side effects, in the data extraction phase, we collected all side effects data reported in the literature and discussed ways to summarise them post hoc.

Search methods for identification of studies

Electronic searches

See: Cochrane Collaboration Depression, Anxiety and Neurosis Group (CCDAN) methods used in reviews.

Electronic Databases

CCDANCTR-Studies were searched using the following search strategy:

Diagnosis = Depress* or Dysthymi* or “Adjustment Disorder*” or “Mood Disorder*” or “Affective Disorder” or “Affective Symptoms” and Intervention = Escitalopram

CCDANCTR-References were searched using the following search strategy:

Keyword = Depress* or Dysthymi* or “Adjustment Disorder*” or “Mood Disorder*” or “Affective Disorder” or “Affective Symptoms” and Free-Text = Escitalopram

An additional Medline search was carried out (update: July 2008). Trial databases of the following drug-approving agencies - the Food and Drug Administration (FDA) in the USA, the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK, the European Medicines Agency (EMEA) in the EU, the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, the Therapeutic Goods Administration (TGA) in Australia) and ongoing trial registers (clinicaltrials.gov in the USA, ISRCTN and National Research Register in the UK, Nederlands Trial Register in the Netherlands, EUDRACT in the EU, UMIN-CTR in Japan and the Australian Clinical Trials Registry in Australia) were searched for published, unpublished and ongoing controlled trials (update: July 2008).

Searching other resources

1) Handsearches

Appropriate journals and conference proceedings relating to escitalopram treatment for depression were hand-searched and incorporated into the CCDANCTR databases.

2) Personal communication

Pharmaceutical companies and experts in this field were asked if they knew of any study which met the inclusion criteria of this review.

3) Reference checking

Reference lists of the included studies, previous systematic reviews and major textbooks of affective disorder written in English were checked for published reports and citations of unpublished research. The references of all included studies were checked via Science Citation Index for articles which had cited the included study.

Data collection and analysis

Selection of studies

Studies relating to escitalopram generated by the electronic search of CCDANCTR-Studies were scanned by one review author (HMG). Those studies that met the following criteria constituted the preliminary list and their full texts were retrieved:.

The rough inclusion criteria were:

Randomised trial
Comparing escitalopram against any other antidepressant
Patients with major depression, regardless of the diagnostic criteria used.

Studies relating to escitalopram generated by the search strategies of CCDANCTR-References and the other complementary searches were checked independently by the CCDAN Trials Search Coordinator (HMG), who is an author of this review, and another review author (AC, AS or CS) to see if they met the rough inclusion criteria, firstly based on the title and abstracts. All the studies rated as possible candidates by either of the two reviewers were added to the preliminary list and the full texts were retrieved. All the full text articles in this preliminary list was then assessed by two review authors (AC, AS or CS) independently to see if they met the strict inclusion criteria. If the raters disagreed, the final rating were made by consensus with the involvement (if necessary) of another member of the review group. Non-congruence in selection of trials was reported as percentage disagreement. Considerable care was taken to exclude duplicate publications.

Data extraction and management

One review author (CS) first extracted data concerning participant characteristics (age, sex, depression diagnosis, comorbidity, depression severity, antidepressant treatment history for the index episode, study setting), intervention details (intended dosage range, mean daily dosage actually prescribed, co-intervention if any, escitalopram as investigational drug or as comparator drug, sponsorship) and outcome measures of interest from the included studies. The results were compared with those in the completed reviews of individual antidepressants in the Cochrane Library. If there were any discrepancies, a second review author (AC) intervened and the agreed-upon results were used in the review as well as fed back to the authors of the completed reviews.

Assessment of risk of bias in included studies

We used the Cochrane risk-of-bias tool as recommended in RevMan 5.0.0. This instrument consists of six items. Two of the items assess the strength of the randomisation process in preventing selection bias in the assignment of participants to interventions: adequacy of sequence generation and allocation concealment. The third item (blinding) assesses the influence of performance bias on the study results. The fourth item assesses the likelihood of incomplete outcome data, which raise the possibility of bias in effect estimates. The fifth item assesses selective reporting, the tendency to preferentially report statistically significant outcomes. It requires a comparison of published data with trial protocols, when such are available. The final item refers to other sources of bias that are relevant in certain circumstances, for example, in relation to trial design (methodologic issues such as those related to crossover designs and early trial termination) or setting.

Two review authors (AC, CB) assessed risk of bias in each trial independently, in accordance with the Cochrane Handbook (Higgins 2008). Where inadequate details of allocation concealment and other characteristics of trials were provided, the trial authors were contacted in order to obtain further information. If the raters disagreed the final rating was made by consensus with the involvement (if necessary) of another member of the review group. The ratings were also compared with those in the completed reviews of individual antidepressants in the Cochrane Library. If here were any discrepancies, they were fed back to the authors of the completed reviews.

Measures of treatment effect

Data were checked and entered into Review Manager 5 software by two review authors (AC, CS) (double data entry). For dichotomous, or event-like data, odds ratios (OR) were calculated with 95% confidence intervals. Continuous data were analysed using weighted mean differences (with 95% confidence intervals) or standardised mean differences (where different measurement scales are used) using the random effects model.

Unit of analysis issues

For trials which had a crossover design only results from the first randomisation period were considered. If the trial was a three (or more)-armed trial involving a placebo arm, the data were extracted from the placebo arm as well.

Dealing with missing data

Responders and remitters to treatment were calculated on the intention-to-treat (ITT) basis: drop-outs were always included in this analysis. Where participants had withdraw from the trial before the endpoint, it was assumed they would have experienced the negative outcome by the end of the trial (e.g. failure to respond to treatment). When there were missing data and the method of “last observation carried forward” (LOCF) had been used to do an ITT analysis, then the LOCF data were used, with due consideration of the potential bias and uncertainty introduced. When dichotomous or continuous outcomes were not reported, trial authors were asked to supply the data.

When only the SE or t-statistics or p values were reported, SDs were calculated according to Altman (Altman 1996). In the absence of supplemental data from the authors, the SDs of the HAM-D (or any other depression scale) and response/remission rates were calculated according to validated imputation methods (Furukawa 2005; Furukawa 2006). We examined the validity of these imputations in sensitivity analyses.

Assessment of heterogeneity

Skewed data and non-quantitative data were presented descriptively. An outcome whose minimum score is zero could be considered skewed when the mean was smaller than twice the SD. Heterogeneity between studies was investigated by the I-squared statistic (Higgins 2003) (I-squared equal to or more than 50% was considered indicative of heterogeneity) and by visual inspection of forest plots.

Assessment of reporting biases

Funnel plot analysis was performed to check for existence of small study effects, including publication bias.

Data synthesis

The primary analysis used a random effects model OR, which had the highest generalisability in our empirical examination of summary effect measures for meta-analyses (Furukawa 2002a). The robustness of this summary measure was routinely examined by checking the fixed effect model OR and the random effects model risk ratio (RR). Material differences between the models were reported. Fixed effect analyses were done routinely for the continuous outcomes as well, to investigate the effect of the choice of method on the estimates. Material differences between the models were reported.

Subgroup analysis and investigation of heterogeneity

Subgroup analyses were performed and interpreted with caution because multiple analyses can lead to false positive conclusions (Oxman 1992). However, we performed the following subgroup analyses, where possible, for the following a priori reasons:

Escitalopram dosing (fixed low dosage, fixed standard dosage, fixed high dosage; flexible low dosage, flexible standard dosage, flexible high dosage), because there was evidence to suspect that low dosage antidepressant might be associated with better outcomes both in terms of effectiveness and side effects than standard or high dosage antidepressants (Bollini 1999; Furukawa 2002b) and also because fixed versus flexible dosing schedule might affect estimates of treatment effectiveness (Khan 2003). In the case of escitalopram, based on the Defined Daily Dosage by World Health Organisation (WHO), low dosage referred to <10, standard dosage to >10 but <20, and high dosage to >20 mg/day.
Comparator dosing (low effective range, medium to high effective range), as it was easy to imagine that there were greater chances of completing the study on the experimental drug than on the comparator drug that was increased to the maximum dosage.
Depression severity (severe major depression, moderate/mild major depression).
Treatment settings (psychiatric inpatients, psychiatric outpatients, primary care).
Elderly patients (>65 years of age), separately from other adult patients.

Sensitivity analysis

The following sensitivity analyses were planned a priori. By limiting included studies to those with higher quality, we examined if the results changed, and checked for the robustness of the observed findings.

Excluding trials with unclear concealment of random allocation and/or unclear double blinding.
Excluding trials whose drop out rate was greater than 20%.
Performing the worst case scenario ITT (all the patients in the experimental group experience the negative outcome and all those allocated to the comparison group experience the positive outcome) and the best case scenario ITT (all the patients in the experimental group experience the positive outcome and all those allocated to the comparison group experience the negative outcome).
Excluding trials for which the response rates had to be calculated based on the imputation method (Furukawa 2005) and those for which the SD had to be borrowed from other trials (Furukawa 2006).
Examination of “wish bias” (also called “optimism bias”) by comparing escitalopram as investigational drug vs escitalopram as comparator, as there was evidence to suspect that a new antidepressant might perform worse when used as a comparator than when used as an experimental agent (Barbui 2004).
Excluding studies funded by the pharmaceutical company marketing escitalopram. This sensitivity analysis was particularly important in view of the recent repeated findings that funding strongly affects outcomes of research studies (Als-Nielsen 2003; Bhandari 2004; Lexchin 2003; Montgomery 2004; Perlis 2005; Procyshyn 2004) and because industry sponsorship and authorship of clinical trials were increasing over 20 years (Buchkowsky 2004).

If subgroups within any of the subgroup or sensitivity analyses turned out to be significantly different from one another, we ran meta-regression for exploratory analyses of additive or multiplicative influences of the variables in question. Our routine application of random effects and fixed effect models as well as our secondary outcomes of remission rates and continuous severity measures may be considered additional forms of sensitivity analyses.

RESULTS

Description of studies

See: Characteristics of included studies.

Results of the search

The search yielded 52 references of potentially eligible studies. After exclusion of papers that were not relevant (because they mainly were non-randomised studies or reviews), 19 randomised controlled trials were included in the present review. Three further randomised controlled trials were found in the web-based clinical trial register of the pharmaceutical industry manufacturing escitalopram and were included in the pool of included studies. Therefore, a total of 22 trials were included in the review.

In the presentation of the following analyses, a post-hoc decision was made to present all SSRIs (with sub-totals) together in one group, and SNRIs and newer antidepressant agents (without subtotals) together in a second group (see graphs). Fourteen trials (64%) compared escitalopram with another SSRI and eight (36%) compared escitalopram with a newer antidepressant (venlafaxine, bupropion and duloxetine). Neither trials comparing escitalopram with TCAs or MAOIs nor cross-over design studies were retrieved by the comprehensive search. In this review all studies were multicentre, randomised, double-blind trials (nine were three-arm, placebo-controlled trials).

Included studies

Design

Length of the studies

Escitalopram versus other SSRIs

In 11 studies the follow-up was 8 weeks (Alexopoulos 2004; Baldwin 2006; Burke 2002; Kasper 2005; Kennedy 2005; Lepola 2003; Mao 2008; Moore 2005; SCT-MD-02; SCT-MD-09; Ventura 2007). One study was a 6-week trial (Yevtushenko 2007) and in two studies the follow-up lasted up to 24 weeks (Boulenger 2006; Colonna 2005).

Escitalopram versus newer antidepressants

Seven studies were 8-week trials (Bielski 2004; Clayton (AK130926); Clayton (AK130927); Khan 2007; Montgomery 2004; Nierenberg 2007; SCT-MD-35) and one study was a 24-week trial (Wade 2007).

Sample size

Escitalopram versus other SSRIs

The mean of participants per study was 280.8 (SD 103.9), with a minimum sample size of 30 (SCT-MD-09) and a maximum of 459 (Boulenger 2006).

Escitalopram versus newer antidepressants

The mean of participants was 307.1 (SD 101.3), ranging between 202 (Bielski 2004) and 547 (Nierenberg 2007).

Setting

Escitalopram versus other SSRIs

In 11 studies the participants were outpatients (Alexopoulos 2004; Baldwin 2006; Boulenger 2006; Burke 2002; Colonna 2005; Kennedy 2005; Moore 2005; SCT-MD-02; SCT-MD-09; Ventura 2007; Yevtushenko 2007). In one study (Lepola 2003) participants were recruited in primary care. In two studies (Kasper 2005; Mao 2008) both outpatients and inpatients were eligible. In Kasper 2005, patients were recruited both in general practice and specialist settings.

Escitalopram versus other antidepressants

In 7 studies the participants were outpatients (Bielski 2004; Clayton (AK130926); Clayton (AK130927); Khan 2007; Nierenberg 2007; SCT-MD-35; Wade 2007). In Montgomery 2004 patients were recruited in primary care.

Participants

Age

Escitalopram versus other SSRIs

In eight studies patients over 65 years were excluded (Alexopoulos 2004; Baldwin 2006; Burke 2002; Colonna 2005; Lepola 2003; Mao 2008; SCT-MD-09; Yevtushenko 2007). Five studies included patients over 65 years (Boulenger 2006; Kennedy 2005; Moore 2005; SCT-MD-02; Ventura 2007). One study (Kasper 2005) included only elderly patients (over 65 years).

Escitalopram versus newer antidepressants

In two studies patients over 65 years were excluded (Bielski 2004; Wade 2007). Four studies included patients over 65 years (Khan 2007; Montgomery 2004; Nierenberg 2007; SCT-MD-35). In two studies age range was not specified (Clayton (AK130926); Clayton (AK130927)).

Diagnosis

All the studies enrolled patients suffering from DSM-IV criteria for major depressive disorder.

Interventions

Escitalopram versus other SSRIs

In six studies escitalopram was compared with citalopram (Burke 2002; Colonna 2005; Lepola 2003; Moore 2005; SCT-MD-02; Yevtushenko 2007), in four with fluoxetine (Kasper 2005; Kennedy 2005; Mao 2008; SCT-MD-09), in two with paroxetine (Baldwin 2006; Boulenger 2006) and in the remaining two with sertraline (Alexopoulos 2004; Ventura 2007). Five studies included a placebo arm (Alexopoulos 2004; Burke 2002; Kasper 2005; Lepola 2003; SCT-MD-02). One study (Burke 2002) presented a comparison between four arms: escitalopram 10mg/day, escitalopram 20mg/day, citalopram and placebo.

Escitalopram versus newer antidepressants

Three studies compared escitalopram with bupropion XR (Clayton (AK130926); Clayton (AK130927); SCT-MD-35), three with duloxetine (Khan 2007; Nierenberg 2007; Wade 2007) and two with venlafaxine XR (Bielski 2004; Montgomery 2004). Four studies included a placebo arm (Clayton (AK130926); Clayton (AK130927); Nierenberg 2007; SCT-MD-35). One study (SCT-MD-35) presented a comparison between four arms: escitalopram 4mg/day, bupropion XR 150mg/day, placebo and a combination of escitalopram 4mg/day and bupropion XR 150mg/day.

Dosage of study drugs

In 21 out of 22 studies the dosage of escitalopram was within the therapeutic dosage (10 to 20 mg/day). In one study (SCT-MD-35) the escitalopram dosage was set at 4 mg/day (fixed dose). Eleven trials used a fixed- and the remaining eleven a flexible-dosage regimen. The use of a fixed- or a flexible-dose regimen was consistent among comparisons within the same study in the great majority of included trials. However, in three out of 22 studies one of the two compounds used a fixed-dose while the other used a flexible-dose design (Burke 2002; Khan 2007; Ventura 2007).

Primary Outcomes

Escitalopram versus other SSRIs

The primary outcome used in the great majority of studies was change from baseline on MADRS. One study (Mao 2008) used the change on the HAM-D-17 total score and another trial (SCT-MD-09) evaluated the effects of escitalopram and fluoxetine on sleep in depressed patients using the number of awakenings (polysomnogram) as the primary outcome. The latter study lasted only five weeks, did not evaluate efficacy and has been included in the present review only for early discontinuation and tolerability outcomes (side-effect profile).

Escitalopram versus other antidepressants

Five studies used the change from baseline on MADRS (Bielski 2004; Khan 2007; Montgomery 2004; SCT-MD-35; Wade 2007) as the primary outcome and one used change on HAMD-17 (Nierenberg 2007). In studies by Clayton (Clayton (AK130926); Clayton (AK130927)) sexual functioning was considered the primary outcome and depression was rated as mean change on HAMD-17.

Response Rate

Escitalopram versus other SSRIs

In nine studies a decrease from baseline to endpoint of at least 50% in rating scale total score (either on MADRS or on HAM-D) was used to define “response” (Baldwin 2006; Boulenger 2006; Burke 2002; Colonna 2005; Kasper 2005; Lepola 2003; Mao 2008; Moore 2005; Ventura 2007). The four remaining studies (Alexopoulos 2004; Kennedy 2005; SCT-MD-02; SCT-MD-09) provided only continuous data and therefore response rates were imputed (see Methods).

Escitalopram versus newer antidepressants

In four studies, a decrease from baseline to endpoint of at least 50% in MADRS total score was used to define “response” (Bielski 2004; Khan 2007; Montgomery 2004; Wade 2007). In three studies a decrease from baseline to endpoint of at least 50% in HAMD-17 total score was used for defining “response” (Clayton (AK130926); Clayton (AK130927); Nierenberg 2007). In one study (SCT-MD-35) only continuous data were available and therefore response rate was imputed (see Methods).

Remission Rate

Escitalopram versus other SSRIs

Six studies used MADRS to assess remission rate (Baldwin 2006; Boulenger 2006; Colonna 2005; Kasper 2005; Lepola 2003; Moore 2005). One study used HAMD-17 (Ventura 2007). Five studies did not report remission rate (Alexopoulos 2004; Burke 2002; Kennedy 2005; SCT-MD-02; SCT-MD-09). However, considering that continuous outcomes were available, remission rates were imputed (see Methods)

Escitalopram versus newer antidepressants

Six studies used HAMD-17 (Bielski 2004; Clayton (AK130926); Clayton (AK130927); Khan 2007; Nierenberg 2007; Wade 2007) and one used MADRS (Montgomery 2004) to assess remission rate. One study (SCT-MD-35) did not report dichotomous data remission rate, so remission rate was imputed using continuous outcomes (see Methods)

Sponsorship

Escitalopram versus other SSRIs

All the studies were sponsored by the drug company marketing escitalopram.

Escitalopram versus newer antidepressants

Five studies were sponsored by the drug company marketing escitalopram (Bielski 2004; Khan 2007; Montgomery 2004; SCT-MD-35; Wade 2007). Two studies were sponsored by the drug company marketing bupropion XR (Clayton (AK130926); Clayton (AK130927)). One study was sponsored by the drug company marketing duloxetine (Nierenberg 2007).

Excluded studies

Thirty-three references of potentially eligible studies were excluded after checking titles and abstracts. Of those, 21 were reviews, nine were non-randomised studies and three were duplicates.

Risk of bias in included studies

See Figure 1 and Figure 2 for a graphical summary of methodological quality for the 22 included studies, based on the six risk of bias domains.

Allocation

Only four studies reported sufficient details on allocation concealment (Baldwin 2006; Boulenger 2006; Colonna 2005; Wade 2007).

Blinding

All studies were reported to be double-blind trials, however only five studies reported sufficient details on blinding (Baldwin 2006; Boulenger 2006; Colonna 2005; Wade 2007; Yevtushenko 2007)

Incomplete outcome data

Only three studies reported incomplete outcome data (Clayton (AK130926); Clayton (AK130927); SCT-MD-09).

Selective reporting

Only eight studies were indicated to be free from selective reporting (Alexopoulos 2004; Bielski 2004; Boulenger 2006; Clayton (AK130926); Clayton (AK130927); Khan 2007; Ventura 2007; Yevtushenko 2007).

Other potential sources of bias

The large majority of included studies were sponsored by the manufacturer of escitalopram.

Effects of interventions

Some statistically significant differences in efficacy, acceptability and tolerability were found and details are listed below. The results are reported comparison by comparison (dividing SSRIs from newer antidepressants) and the forest plots are organised according to the relevance of outcomes, as reported in the review protocol. For adverse events, all the information about adverse events specified in the review protocol are reported (either statistically or non-statistically significant). However, remaining adverse events are only reported when statistically significant (non-statistically significant results about adverse events are presented in Table 1).

Table 1. Adverse events.

Adverse event	Study	Escitalopram		Comparator		Odds Ratio, Random [95% CI]
Adverse event	Study	Events	Total	Events	Total	Odds Ratio, Random [95% CI]
Escitalopram versus citalopram
Accidental overdose	Burke 2002	0	244	1	125	0.17 [0.01, 4.20]
Aggressive behaviour	Moore 2005	1	142	0	152	3.23 [0.13, 80.02]
Anaphylaxis	Burke 2002	1	244	0	125	1.55 [0.06, 38.23]
Anorexia	Yevtushenko 2007	0	108	1	108	0.33 [0.01, 8.20]
Asthenia	Moore 2005	2	142	2	152	1.07 [0.15, 7.71]
Bronchitis	Colonna 2005, Lepola 2003	13	330	11	342	1.24 [0.54, 2.83]
Coma	Burke 2002	0	244	1	125	0.17 [0.01, 4.20]
Concentration decrease	Moore 2005	0	142	1	152	0.35 [0.01, 8.77]
Death fetal	Lepola 2003	0	116	1	111	0.32 [0.01, 7.84]
Dehydration	SCT-MD-02	0	125	1	123	0.33 [0.01, 8.06]
Depression	Moore 2005	0	142	1	152	0.35 [0.01, 8.77]
Dermatological problems	Moore 2005, Yevtushenko 2007	1	250	3	260	0.44 [0.06, 3.02]
Disease Of Liver And Hepatic Duct	SCT-MD-02	0	125	1	123	0.33 [0.01, 8.06]
Dizziness	Burke 2002, Moore 2005, SCT-MD-02	31	511	15	400	1.43 [0.58, 3.49]
Dyspepsia	Yevtushenko 2007	0	108	1	108	0.33 [0.01, 8.20]
Enuresis	Moore 2005	1	142	0	152	3.23 [0.13, 80.02]
Forgetfulness	Moore 2005	0	142	2	152	0.21 [0.01, 4.44]
Hot flashes	Moore 2005	1	142	0	152	3.23 [0.13, 80.02]
Inflicted injury	Burke 2002	8	244	3	125	1.38 [0.36, 5.29]
Non-accidental overdose	SCT-MD-02	1	125	0	123	2.98 [0.12, 73.76]
Ophtalmological problems	Moore 2005	0	142	2	152	0.21 [0.01, 4.44]
Oppression	Moore 2005	0	142	1	152	0.35 [0.01, 8.77]
Palpitation	Moore 2005	1	142	0	152	3.23 [0.13, 80.02]
Panic attack	Moore 2005	0	142	1	152	0.35 [0.01, 8.77]
Pelvic inflammation	Lepola 2003	1	116	0	111	2.90 [0.12, 71.85]
Pharyngitis	Burke 2002, Lepola 2003, Moore 2005	18	541	12	437	0.92 [0.41, 2.06]
Pregnancy unintended	Lepola 2003	1	116	0	111	2.90 [0.12, 71.85]
Rhinitis	Burke 2002, Colonna 2005, Lepola 2003, SCT-MD-02	46	699	33	590	1.19 [0.73, 1.91]
Sexual problems	Burke 2002, Lepola 2003, SCT-MD-02, Yevtushenko 2007	19	283	15	267	1.14 [0.53, 2.44]
Sinusitis	Lepola 2003	6	155	4	160	1.57 [0.43, 5.68]
Subjects with non-fatal severe adverse events	Burke 2002, Lepola 2003, SCT-MD-02	6	524	4	408	1.12 [0.31, 4.08]
Tachycardia	SCT-MD-02	1	125	0	123	2.98 [0.12, 73.76]
Tinnitus	Moore 2005	0	142	1	152	0.35 [0.01, 8.77]
Tremor	Moore 2005	3	142	0	152	7.65 [0.39, 149.47]
Trismus	Moore 2005	0	142	1	152	0.35 [0.01, 8.77]
Upper respiratory tract infection	Burke 2002, Lepola 2003, SCT-MD-02	31	524	16	408	1.59 [0.85, 2.98]
Weight gain	Colonna 2005, Moore 2005	4	317	14	334	0.38 [0.06, 2.37]
Escitalopram versus bupropion XR
Accidental overdose	Clayton (AK130926)	0	143	1	135	0.31 [0.01, 7.74]
Decreased appetite	Clayton (AK130927)	13	138	9	141	1.53 [0.63, 3.69]
Disease Of Liver And Hepatic Duct	Clayton (AK130927) , SCT-MD-35	2	269	0	275	3.09 [0.32, 29.89]
DIzziness	Clayton (AK130926) , Clayton (AK130927)	15	281	18	276	0.84 [0.33, 2.12]
Dyspepsia	Clayton (AK130926)	5	143	5	135	0.94 [0.27, 3.33]
Flatulence	Clayton (AK130926)	8	143	4	135	1.94 [0.57, 6.60]
Irritability	Clayton (AK130926) , Clayton (AK130927)	3	281	14	276	0.26 [0.06, 1.04]
Musculoskeletal disorder	SCT-MD-35	10	131	9	134	1.15 [0.45, 2.92]
Nasal congestion	Clayton (AK130926), Clayton (AK130927)	11	281	6	276	1.86 [0.68, 5.11]
Non-accidental overdose	Clayton (AK130927)	1	138	0	141	3.09 [0.12, 76.44]
Palpitation	Clayton (AK130926)	3	143	4	135	0.70 [0.15, 3.20]
Pharyngitis	Clayton (AK130927)	7	138	9	141	0.78 [0.28, 2.17]
Subjects with non-fatal severe adverse events	Clayton (AK130926) , Clayton (AK130927) , SCT-MD-35	5	410	5	412	0.95 [0.24, 3.72]
Tooth ache	Clayton (AK130926)	3	143	2	135	1.43 [0.23, 8.66]
Tremor	Clayton (AK130926)	3	143	6	135	0.46 [0.11, 1.88]
Upper respiratory tract infection	Clayton (AK130926) , SCT-MD-35	20	274	14	269	1.45 [0.68, 3.08]
Escitalopram versus duloxetine
Accidental overdose	Khan 2007	0	137	1	133	0.32 [0.01, 7.96]
Chest pressure	Khan 2007	0	137	1	133	0.32 [0.01, 7.96]
Decreased appetite	Nierenberg 2007	13	274	22	273	0.57 [0.28, 1.15]
Depression	Khan 2007	0	137	2	133	0.19 [0.01, 4.02]
Dizziness	Khan 2007, Nierenberg 2007, Wade 2007	39	554	64	557	0.59 [0.39, 0.90]
Dyspepsia	Wade 2007	9	143	4	151	2.47 [0.74, 8.20]
Hypertension	Khan 2007	0	137	1	133	0.32 [0.01, 7.96]
Musculoskeletal disorder	Khan 2007	18	137	12	133	1.53 [0.70, 3.30]
Pharyngitis	Wade 2007	15	143	11	151	1.49 [0.66, 3.37]
Sexual problems	Khan 2007	5	56	7	48	0.57 [0.17, 1.94]
Subjects with non-fatal severe adverse events	Khan 2007, Nierenberg 2007	4	411	9	406	0.45 [0.07, 2.80]
Upper respiratory tract infection	Khan 2007, Nierenberg 2007	57	411	48	406	1.21 [0.79, 1.85]
Escitalopram versus fluoxetine
Anorexia	Kasper 2005	2	173	4	164	0.47 [0.08, 2.59]
Depression	Kasper 2005	2	173	4	164	0.47 [0.08, 2.59]
Dermatological problems	SCT-MD-09	3	16	2	14	1.38 [0.20, 9.77]
Disease Of Liver And Hepatic Duct	Mao 2008	2	123	6	117	0.31 [0.06, 1.55]
DIzziness	Kasper 2005, Kennedy 2005, Mao 2008	20	394	22	380	0.88 [0.46, 1.67]
Dyspepsia	Kasper 2005	4	173	7	164	0.53 [0.15, 1.85]
Hypertension	Kasper 2005	4	173	4	164	0.95 [0.23, 3.85]
Indigestion	Kennedy 2005	2	98	6	99	0.32 [0.06, 1.64]
Orthostatic symptoms	Kasper 2005	2	173	1	164	1.91 [0.17, 21.23]
Rhinitis	SCT-MD-09	1	16	3	14	0.24 [0.02, 2.68]
Sexual problems	Kennedy 2005	4	37	1	32	3.76 [0.40, 35.49]
Subjects with non-fatal severe ad-verse events	Kasper 2005, Kennedy 2005, Mao 2008	8	394	16	380	0.48 [0.20, 1.14]
Tooth ache	SCT-MD-09	1	16	2	14	0.40 [0.03, 4.96]
Vertigo	Kasper 2005	3	173	7	164	0.40 [0.10, 1.56]
Escitalopram versus paroxetine
DIzziness	Boulenger 2006	21	229	20	225	1.03 [0.54, 1.97]
Erectile dysfunction	Boulenger 2006	4	75	4	68	0.90 [0.22, 3.75]
Sexual problems	Boulenger 2006	2	75	6	68	0.28 [0.06, 1.45]
Subjects with non-fatal severe adverse events	Boulenger 2006	7	229	3	225	2.33 [0.60, 9.14]
Escitalopram versus sertraline
Decreased appetite	Ventura 2007	8	104	6	108	1.42 [0.47, 4.23]
Depression	Alexopoulos 2004	1	134	0	137	3.09 [0.12, 76.52]
Flatulence	Alexopoulos 2004	6	134	6	137	1.02 [0.32, 3.26]
Indigestion	Alexopoulos 2004	3	134	7	137	0.43 [0.11, 1.68]
Rhinitis	Alexopoulos 2004	6	134	7	137	0.87 [0.28, 2.66]
Sexual problems	Alexopoulos 2004, Ventura 2007	23	162	23	172	0.91 [0.48, 1.72]
Subjects with non-fatal severe adverse events	Alexopoulos 2004	3	134	1	137	3.11 [0.32, 30.32]
Upper respiratory tract infection	Alexopoulos 2004, Ventura 2007	21	238	26	245	0.82 [0.44, 1.50]
Escitalopram versus venlafaxine
Cardiac failure	Montgomery 2004	0	146	1	143	0.32 [0.01, 8.03]
Colon Obstruction	Bielski 2004	1	98	0	100	3.09 [0.12, 76.83]
Decreased weight	Montgomery 2004	5	146	10	143	0.47 [0.16, 1.42]
Dermatological problems	Montgomery 2004	0	146	1	143	0.32 [0.01, 8.03]
Dizziness	Montgomery 2004	7	146	8	143	0.85 [0.30, 2.41]
Gastritis	Montgomery 2004	0	146	3	143	0.14 [0.01, 2.68]
Inflicted injury	Bielski 2004	0	98	1	100	0.34 [0.01, 8.37]
Non-accidental overdose	Bielski 2004	0	98	1	100	0.34 [0.01, 8.37]
Sexual problems	Bielski 2004	2	30	12	53	0.24 [0.05, 1.18]
Subjects with non-fatal severe adverse events	Bielski 2004, Montgomery 2004	4	244	8	243	0.51 [0.14, 1.77]
Transitory Ischaemic Attack	Montgomery 2004	0	146	1	143	0.32 [0.01, 8.03]
Vertigo	Montgomery 2004	7	146	6	143	1.15 [0.38, 3.51]

Methods	Eight-week, double-blind, randomised, multicentre study.
Participants	Outpatients meeting DSM-IV criteria for Major Depressive Disorder and having a minimum score of 22 on Montgomery-Asberg Depression Ration Scale. Age range: 18-65 years.
Interventions	Escitalopram: 136 participants. Sertraline: 138 participants. Escitalopram dose range: 10-20 mg/day. Sertraline dose range: 50-200 mg/day.
Outcomes	Primary Outcome: Change from baseline to week 8 in Montgomery-Asberg Depression Ration Scale. Secondary Outcomes: Hamilton Depression Rating Scale - 24 Item, Clinical Global Impression - Improvement, Clinical Global Impression - Severity
Notes	Only unpublished data. This study was funded by escitalopram manufacturer
*Risk of bias*
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	Quote: “randomized”. Probably done.
Allocation concealment?	Unclear	No information provided.
Blinding? All outcomes	Unclear	No information provided.
Incomplete outcome data addressed? All outcomes	Yes	Quote: “ITT population, which included patients who had at least one post-baseline assessment of MADRS”
Free of selective reporting?	Yes

Methods	24-week, double-blind, randomised, multicentre study.
Participants	Outpatients meeting DSM-IV criteria for Major Depressive Disorder and having a minimum score of 30 on Montgomery-Asberg Depression Rating Scale (MADRS) . Age range: 18-75 years. Exclusion criteria: bipolar disorder, psychotic disorder or features, obsessive-compulsive disorder, current eating disorders, mental retardation, any pervasive developmental disorder or cognitive disorder, or alcohol or drug abuse-related disorders within the past 12 months, a serious risk of suicide (a minimum score of 5 on item 10 of the MADRS) , concomitant behaviour therapy or systematic psychotherapy, pregnancy or breastfeeding, a history of lactose intolerance, a history of hypersensitivity or non-response to citalopram or escitalopram or duloxetine or with increased intra-ocular pressure, risk of acute narrow-angle glaucoma, use within the past 2 weeks of MAOI or RIMA, SSRIs (fluoxetine within 5 weeks), SNRIs, tricyclic antidepressants, tryptophan, psychoactive herbal remedies, any drug used for augmentation of antidepressant action or any other antidepressant drugs, oral antipsychotics and anti-manic drugs, dopamine antagonists, anxiolytics, any anticonvulsant drug, serotoninergic agonists, narcotic analgesics, cardiac glycosides, type 1c anti-arrythmics, oral anticoagulants, cimetidine, potent inhibitors of CYP2C19, CYP1A2, or medicinal products with a narrow therapeutic index predominantly metabolised by CYP2D6, use of ECT within the past 6 months
Interventions	Escitalopram: 232 participants. Paroxetine: 227 participants. Escitalopram dose: 20 mg/day. Paroxetine dose: 40 mg/day. Zolpidem, zolpiclone or zaleplon used episodically for insomnia were allowed
Outcomes	Primary Outcome: Change from baseline to week 24 in Montgomery-Asberg Depression Rating Scale Secondary Outcomes: Hamilton Depression Scale - 24 and 17 item, Hamilton Anxiety Scale, Clinical Global Impression - Improvement, Clinical Global Impression - Severity
Notes	Remission: a score equal or less than 12 on MADRS. This study was funded by escitalopram manufacturer
*Risk of bias*
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	Quote: “Patients …. were assigned to 24 weeks of double-blind treatment in a 1:1 ratio … according to a computer-generated randomisation list.”
Allocation concealment?	Yes	Quote: “The details of the randomisation series were unknown to any of the investigators and were contained in a set of sealed opaque envelopes. At each study centre, sequentially enrolled patients were assigned the lowest randomisation number available in blocks of 4.”
Blinding? All outcomes	Yes	Quote: “The medication was given as capsules of identical appearance, taste and smell. All study personnel and participants were blinded to treatment assignment for the duration of the entire study.”
Incomplete outcome data addressed? All outcomes	Yes	The prospectively defined primary end-point was the adjusted mean change in MADRS total score from baseline to Week 24, based on the intent-to-treat set (ITT) and using last-observation-carried-forward (LOCF) analysis
Free of selective reporting?	Yes

Methods	Eight-week, double-blind, double-dummy, randomised, multicentre study
Participants	Outpatients meeting DSM-IV criteria for Major Depressive Disorder, having a minimum score of 19 on a 17-item Hamilton Rating Scale for Depression, with normal orgasm function, engaging in sexual activity leading to orgasm at least once every 2 weeks. Age range: 18 years or older. Exclusion criteria: any sexual dysfunction except sexual desire disorder related to depression, history of anorexia nervosa, bulimia, seizure disorder, brain injury, diagnosis of panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder or acute stress disorder within the past 12 months, diagnosis of bipolar I or II disorder, schizophrenia or other psychotic disorders, history of attempted suicide within the past 6 months, use of medications that might affect sexual functioning
Interventions	Escitalopram: 138. Bupropion XR: 141. Escitalopram dose range: 10-20 mg/day. Bupropion XR dose range: 300-450 mg/day.
Outcomes	Primary Outcome: Percentage of subjects with orgasm dysfunction and change from baseline to week 8 in 17-item Hamilton Depression Rating Scale. Secondary Outcomes: Percentage of subjects with worsened sexual function, percentage of subjects satisfied with their sexual functioning, 17-item Hamilton Depression Scale
Notes	This study was funded by burpopion manufacturer.
*Risk of bias*
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	Quote: “randomised”. Probably done
Allocation concealment?	Unclear	No information reported
Blinding? All outcomes	Unclear	No information reported
Incomplete outcome data addressed? All outcomes	No	ITT population defined as all randomised patients who took at least 1 dose of study medication, had no orgasm dysfunction reported from the sexual functioning assessment at rendomization, had a HAM-D assessment completed at randomization and provided at least 1 post-randomization HAMD-17 and orgasm function assessment
Free of selective reporting?	Yes

Methods	Eight-week, double-blind, randomisation, multicentre study.
Participants	Outpatients meeting DSM-IV criteria for Major Depressive Disorder, having a minimum score of 22 on Montgomery-Asberg Depression Rating Scale (MADRS) and a minimum score of 4 on Clinical Global Impression - Severity. Age range: 18 years and over. Exclusion criteria: pregnancy, lactation, primary Axis I disorder other than MDD, an Axis II disorder considered likely to interfere with compliance to the study protocol, substance dependence (excluding nicotine and caffeine) within the past 6 months, a significant risk of suicide, clinically significant laboratory abnormalities or co-morbid medical conditions if would likely require intervention, hospitalisation or use of an excluded medication during the course of the study, a lack of response to two or more courses of antidepressant medication in the current episode with each trial at least 4 weeks in duration and at a clinically appropriate dose, a history of non-response in association with a previous adequate trial of duloxetine, escitalopram or citalopram therapy, use of monoamine oxidase inhibitor within 14 days or of fluoxetine within the past 30 days, electroconvulsive treatment (ECT) or transcranial magnetic stimulation within the past year
Interventions	Escitalopram: 274 participants. Duloxetine: 273 participants. Escitalopram dose: 10 mg/day. Duloxetine dose : 60 mg/day. Episodic use of benzodiazepines and certain hypnotics or sedatives (e.g., chloral hydrate or zolpidem) was allowed, provided that use occurred on no more than 50% of the total days between visits. Psychotherapy was permitted but initiating, stopping or changing frequency or modality after study entry was prohibited
Outcomes	Primary Outcome: Decrease from baseline in the Hamilton Rating Scale for Depression (17-item) Maier subscale (includes HAMD17 Items 1, 2, 7, 8, 9 and 10). Secondary Outcomes: Hamilton Rating Scale for Depression (17-item) total scores, HAMD17 subscales (core, anxiety/somatization, retardation/somatization, sleep), Hamilton Rating Scale for Anxiety total score, Clinical Global Impression - Severity, Patient Global Impression of Improvement
Notes	This study was funded by duloxetine manufacturer
*Risk of bias*
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	Quote: “randomized”. Probably done
Allocation concealment?	Yes	Quote: “..via the Interactive Voice Response System”. Probably done
Incomplete outcome data addressed? All outcomes	Yes
Free of selective reporting?	No	Many graphs and some unclear reporting (i.e. re. sexual functioning)

Methods	Five-week, double-blind, randomised, forced-titration, single-centre study
Participants	Outpatients meeting DSM-IV criteria for Major Depressive Disorder and having a minimum score of 18 on the Hamilton Depression Rating Scale (HAMD) with a score of at least 1 on the HAMD sleep disturbance subscale. Age range: 18-55 years.
Interventions	Escitalopram: 16 participants. Fluoxetine: 14 participants. Escitalopram dose range: 10-20 mg/day. Fluoxetine dose range: 20-40 mg/day.
Outcomes	Primary Outcome: Change from baseline to day 1 and to endpoint (mean of days 33 and 34) in the number of awakenings (Polysomnogram) Secondary Outcomes: Polysomnogram (Percent Time Awake, Sleep Efficiency, Percent REM Sleep, REM Latency, REM Epochs with Eye Movements, non-REM Epochs with Eye Movements), Sleep Diary, Pittsburgh Sleep Quality Index
Notes	Only unpublished data. This study was funded by escitalopram manufacturer.
*Risk of bias*
Item	Authors’ judgement	Description
Adequate sequence generation?	Unclear	Quote: “randomized”. Probably done
Blinding? All outcomes	Unclear	Quote:“double-blind”
Incomplete outcome data addressed? All outcomes	No
Free of other bias?	No

Methods	6-week, prospective, randomised, double-blind, active-controlled trial was conducted at 8 psychiatric outpatient clinics across the Federation of Russia
Participants	Outpatients, aged 25 (this minimum age limit was a requirement of one of the ethics committees) to 45 years, with a diagnosis of major depressive disorder, as defined in the DSM-IV and a total score more than or equal to 25 on MADRS. Patients were not eligible if they met DSM-IV criteria for mania or any bipolar disorder, schizophrenia, or any psychotic disorder, or displayed any psychotic features, obsessive-compulsive disorder, mental retardation or any pervasive developmental disorder, eating disorder (anorexia nervosa or bulimia nervosa), dementia, or alcohol or drug abuse within the previous12 months, a history of severe drug allergy or hypersensitivity, other serious illness or sequela of serious illness, citalopram or escitalopram treatment within 60 days prior to inclusion. Patients were also excluded if they had received an oral antipsychotic drug or monoamine oxidase inhibitor within 2 weeks prior to inclusion; a depot antipsychotic preparation within 6 months prior to inclusion; an SSRI (except fluoxetine), a serotonin-noradrenaline reuptake inhibitor, or a TCA within 1 week prior to inclusion; or fluoxetine within 5 weeks before inclusion; an antiparkinsonian compound, barbiturate, chloral hydrate, lithium, anticonvulsant, or hypnotic and anxiolytic (except for benzodiazepines used for insomnia at a stable dose for the previous 6 months or used episodically at a lower recommended dose). Women who were pregnant or breast feeding were also excluded from the study
Interventions	Using equal (~110 patients per group) block randomization, patients were assigned to receive a once-daily fixed dose of escitalopram 10 mg (109 participants), citalopram10 mg (111 participants), or citalopram 20 mg (110 participants) for 6 weeks
Outcomes	The primary efficacy measure was the change in the MADRS total score from baseline to end of study. Secondary efficacy measures were changes from baseline in MADRS total score in a subgroup of severely depressed patients (MADRS total score more than or equal to 35), MADRS core depression subscale score (in the overall population and severely depressed subgroup), CGI-S, andCGI-I. In addition, the proportions of patients classified a priori as responders (decrease in MADRS total score by at least 50% of the baseline value) or remitters (primary definition, MADRS total score less than or equal to 12; secondary definition, less than or equal to 10) were analysed
Notes	The present study was part of the S-citalopram development program for approval in some European countries through a bridging procedure using results from studies of the racemate, citalopram. Care and medication were free of charge for the patients enrolled in the trial. This study was specifically designed a priori as a superiority study. The sample size was calculated using Singer’s method. The largest between-group difference was estimated at 5 points, with an SD of 12. Given this assumption, and with an a level of 5% (2-tailed) and a b level of 20%, it was calculated that 100 patients per arm would be needed to achieve sufficient power. Assuming a 10% withdrawal rate, 10 additional patients per arm were included in the design to ensure sufficient power, giving 110 patients per arm (330 patients in total). This research was sponsored by OOO ARBACOM (Moscow, Federation of Russia) (it’s unclear the relationship with the escitalopram manufacturer)
*Risk of bias*
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	Quote: “…Eight block randomizations were generated, 1 per center.” Probably done
Blinding? All outcomes	Yes	Quote: “To maintain blinding, all study medication was provided in capsules (tablets were encapsulated in a lactose powder) that were identical in appearance, taste, and odor.Investigators and patients were blinded to treatment.”
Incomplete outcome data addressed? All outcomes	Yes	LOCF method of replacing missing values
Free of selective reporting?	Yes

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Escitalopram versus other SSRIs	13		Odds Ratio (M-H, Random, 95% CI)	Subtotals only
1.1 Versus Citalopram	6	1823	Odds Ratio (M-H, Random, 95% CI)	0.67 [0.50, 0.89]
1.2 Versus Fluoxetine	3	783	Odds Ratio (M-H, Random, 95% CI)	0.81 [0.60, 1.10]
1.3 Versus Paroxetine	2	784	Odds Ratio (M-H, Random, 95% CI)	0.89 [0.61, 1.32]
1.4 Versus Sertraline	2	489	Odds Ratio (M-H, Random, 95% CI)	1.06 [0.73, 1.53]
2 Escitalopram versus newer ADs	8		Odds Ratio (M-H, Random, 95% CI)	Subtotals only
2.1 Versus Bupropion XR	3	842	Odds Ratio (M-H, Random, 95% CI)	0.91 [0.69, 1.20]
2.2 Versus Duloxetine	3	1120	Odds Ratio (M-H, Random, 95% CI)	0.72 [0.43, 1.20]
2.3 Versus Venlafaxine XR	2	495	Odds Ratio (M-H, Random, 95% CI)	0.86 [0.53, 1.39]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Escitalopram versus other SSRIs	1	240	Odds Ratio (M-H, Random, 95% CI)	1.15 [0.52, 2.56]
1.1 Versus Fluoxetine	1	240	Odds Ratio (M-H, Random, 95% CI)	1.15 [0.52, 2.56]
2 Escitalopram versus newer ADs	1		Odds Ratio (M-H, Random, 95% CI)	Subtotals only
2.1 Versus Venlafaxine XR	1	293	Odds Ratio (M-H, Random, 95% CI)	0.85 [0.47, 1.55]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Escitalopram versus newer ADs	1		Odds Ratio (M-H, Random, 95% CI)	Subtotals only
1.1 Versus Duloxetine	1	295	Odds Ratio (M-H, Random, 95% CI)	0.72 [0.45, 1.16]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Escitalopram versus other SSRIs	12		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only’
1.1 Versus Citalopram	5	1392	Std. Mean Difference (IV, Random, 95% CI)	−0.17 [−0.30, −0.04]
1.2 Versus Fluoxetine	3	759	Std. Mean Difference (IV, Random, 95% CI)	−0.17 [−0.32, −0.03]
1.3 Versus Paroxetine	2	772	Std. Mean Difference (IV, Random, 95% CI)	−0.05 [−0.36, 0.26]
1.4 Versus Setraline	2	477	Std. Mean Difference (IV, Random, 95% CI)	0.02 [−0.16, 0.20]
2 Escitalopram versus newer ADs	8		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only
2.1 Versus Bupropion XR	3	793	Std. Mean Difference (IV, Random, 95% CI)	−0.08 [−0.22, 0.05]
2.2 Versus Duloxetine	3	1096	Std. Mean Difference (IV, Random, 95% CI)	−0.10 [−0.30, 0.09]
2.3 Versus Venlafaxine XR	2	483	Std. Mean Difference (IV, Random, 95% CI)	−0.07 [−0.38, 0.25]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Escitalopram vs. other SSRIs	14		Odds Ratio (M-H, Random, 95% CI)	Subtotals only
1.1 Versus Citalopram	6	1823	Odds Ratio (M-H, Random, 95% CI)	0.78 [0.56, 1.10]
1.2 Versus Fluoxetine	4	813	Odds Ratio (M-H, Random, 95% CI)	0.89 [0.51, 1.55]
1.3 Versus Paroxetine	2	784	Odds Ratio (M-H, Random, 95% CI)	0.68 [0.36, 1.29]
1.4 Versus Sertraline	2	489	Odds Ratio (M-H, Random, 95% CI)	1.24 [0.78, 1.97]
2 Escitalopram versus newer ADs	8		Odds Ratio (M-H, Random, 95% CI)	Subtotals only
2.1 Versus Bupropion XR	3	842	Odds Ratio (M-H, Random, 95% CI)	1.02 [0.75, 1.39]
2.2 Versus Duloxetine	3	1120	Odds Ratio (M-H, Random, 95% CI)	0.62 [0.38, 0.99]
2.3 Versus Venlafaxine XR	2	495	Odds Ratio (M-H, Random, 95% CI)	0.90 [0.58, 1.39]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Abdominal Pain	4		Odds Ratio (M-H, Random, 95% CI)	Subtotals only
1.1 Versus Bupropion XR	1	278	Odds Ratio (M-H, Random, 95% CI)	0.78 [0.23, 2.61]
1.2 Versus Citalopram	1	294	Odds Ratio (M-H, Random, 95% CI)	0.35 [0.01, 8.77]
1.3 Versus Fluoxetine	1	337	Odds Ratio (M-H, Random, 95% CI)	1.05 [0.43, 2.53]
1.4 Versus Venlafaxine XR	1	289	Odds Ratio (M-H, Random, 95% CI)	1.39 [0.43, 4.49]
2 Back Pain	8		Odds Ratio (M-H, Random, 95% CI)	Subtotals only
2.1 Versus Bupropion XR	1	278	Odds Ratio (M-H, Random, 95% CI)	2.91 [0.58, 14.69]
2.2 Versus Citalopram	4	1289	Odds Ratio (M-H, Random, 95% CI)	0.84 [0.38, 1.83]
2.3 Versus Duloxetine	1	270	Odds Ratio (M-H, Random, 95% CI)	2.93 [0.12, 72.67]
2.4 Versus Fluoxetine	1	337	Odds Ratio (M-H, Random, 95% CI)	1.94 [0.57, 6.57]
2.5 Versus Venlafaxine XR	1	289	Odds Ratio (M-H, Random, 95% CI)	0.98 [0.38, 2.54]
3 Chest Pain			Odds Ratio (M-H, Random, 95% CI)	Subtotals only
3.1 Versus Bupropion XR	1	265	Odds Ratio (M-H, Random, 95% CI)	0.34 [0.01, 8.38]
3.2 Versus Citalopram	1	294	Odds Ratio (M-H, Random, 95% CI)	0.35 [0.01, 8.77]
4 Pain In Extremity	1		Odds Ratio (M-H, Random, 95% CI)	Subtotals only
4.1 Versus Bupropion XR	1	278	Odds Ratio (M-H, Random, 95% CI)	4.79 [0.23, 100.64]
5 Pharyngolaryngeal Pain	1		Odds Ratio (M-H, Random, 95% CI)	Subtotals only

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Suicide - Tendency/Ideation	3		Odds Ratio (M-H, Random, 95% CI)	Subtotals only
1.1 Versus Citalopram	1	248	Odds Ratio (M-H, Random, 95% CI)	2.98 [0.12, 73.76]
1.2 Versus Bupropion XR	1	279	Odds Ratio (M-H, Random, 95% CI)	5.18 [0.25, 108.95]
1.3 Versus Venlafaxine XR	1	198	Odds Ratio (M-H, Random, 95% CI)	3.09 [0.12, 76.83]
2 Suicide - Attempted	6		Odds Ratio (M-H, Random, 95% CI)	Subtotals only
2.1 Versus Citalopram	3	974	Odds Ratio (M-H, Random, 95% CI)	1.48 [0.40, 5.45]
2.2 Versus Fluoxetine	2	437	Odds Ratio (M-H, Random, 95% CI)	0.98 [0.10, 9.50]
2.3 Versus Venlafaxine XR	1	289	Odds Ratio (M-H, Random, 95% CI)	4.97 [0.24, 104.34]
3 Suicide - Completed	3		Odds Ratio (M-H, Random, 95% CI)	Subtotals only
3.1 Versus Citalopram	1	294	Odds Ratio (M-H, Random, 95% CI)	0.35 [0.01, 8.77]
3.2 Versus Fluoxetine	1	337	Odds Ratio (M-H, Random, 95% CI)	2.86 [0.12, 70.73]
3.3 Versus Duloxetine	1	294	Odds Ratio (M-H, Random, 95% CI)	0.35 [0.01, 8.65]
4 Deaths	5		Odds Ratio (M-H, Random, 95% CI)	Subtotals only
4.1 Versus Citalopram	1	294	Odds Ratio (M-H, Random, 95% CI)	0.35 [0.01, 8.77]
4.2 Versus Fluoxetine	1	337	Odds Ratio (M-H, Random, 95% CI)	1.91 [0.17, 21.23]
4.3 Versus Duloxetine	2	841	Odds Ratio (M-H, Random, 95% CI)	1.03 [0.11, 9.90]
4.4 Versus Venlafaxine XR	1	293	Odds Ratio (M-H, Random, 95% CI)	0.32 [0.01, 8.03]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Escitalopram versus other SSRIs (dropout rate greater than 20% in both arms)	6		Odds Ratio (M-H, Random, 95% CI)	Subtotals only
1.1 Versus Citalopram	4	1187	Odds Ratio (M-H, Random, 95% CI)	0.56 [0.40, 0.79]
1.2 Versus Fluoxetine	2	578	Odds Ratio (M-H, Random, 95% CI)	0.80 [0.56, 1.13]
2 Escitalopram versus other SSRIs (dropout rate greater than 20% in only one arm)	3		Odds Ratio (M-H, Random, 95% CI)	Subtotals only
2.1 Versus Citalopram	3	830	Odds Ratio (M-H, Random, 95% CI)	0.49 [0.34, 0.72]

Date	Event	Description
10 July 2008	Amended	Converted to new review format and last update of the search
13 March 2007	New citation required and conclusions have changed	Substantive amendment

PERMALINK

Escitalopram versus other antidepressive agents for depression

Andrea Cipriani

Claudio Santilli

Toshi A Furukawa

Alessandra Signoretti

Atsuo Nakagawa

Hugh McGuire

Rachel Churchill

Corrado Barbui

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors’ conclusions

BACKGROUND

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

OBJECTIVES

METHODS

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Experimental intervention

Comparator interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Electronic Databases

Searching other resources

1) Handsearches

2) Personal communication

3) Reference checking

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

RESULTS

Description of studies

Results of the search

Included studies

Design

Length of the studies

Escitalopram versus other SSRIs

Escitalopram versus newer antidepressants

Sample size

Escitalopram versus other SSRIs

Escitalopram versus newer antidepressants

Setting

Escitalopram versus other SSRIs

Escitalopram versus other antidepressants

Participants

Age

Escitalopram versus other SSRIs

Escitalopram versus newer antidepressants

Diagnosis

Interventions

Escitalopram versus other SSRIs

Escitalopram versus newer antidepressants

Dosage of study drugs

Primary Outcomes

Escitalopram versus other SSRIs

Escitalopram versus other antidepressants

Response Rate