Citalopram versus other anti-depressive agents for depression

  • Review
  • Intervention

Authors


Abstract

Background

Recent US and UK clinical practice guidelines recommend that second-generation antidepressants should be considered amongst the best first-line options when drug therapy is indicated for a depressive episode. Systematic reviews have already highlighted some differences in efficacy between second-generation antidepressants. Citalopram, one of the first selective serotonin reuptake inhibitors (SSRI) introduced in the market, is one of these antidepressant drugs that clinicians use for routine depression care.

Objectives

To assess the evidence for the efficacy, acceptability and tolerability of citalopram in comparison with tricyclics, heterocyclics, other SSRIs and other conventional and non-conventional antidepressants in the acute-phase treatment of major depression.

Search methods

We searched The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register and the Cochrane Central Register of Controlled Trials up to February 2012. No language restriction was applied. We contacted pharmaceutical companies and experts in this field for supplemental data.

Selection criteria

Randomised controlled trials allocating patients with major depression to citalopram versus any other antidepressants.

Data collection and analysis

Two reviewers independently extracted data. Information extracted included study characteristics, participant characteristics, intervention details and outcome measures in terms of efficacy (the number of patients who responded or remitted), patient acceptability (the number of patients who failed to complete the study) and tolerability (side-effects).

Main results

Thirty-seven trials compared citalopram with other antidepressants (such as tricyclics, heterocyclics, SSRIs and other antidepressants, either conventional ones, such as mirtazapine, venlafaxine and reboxetine, or non-conventional, like hypericum). Citalopram was shown to be significantly less effective than escitalopram in achieving acute response (odds ratio (OR) 1.47, 95% confidence interval (CI) 1.08 to 2.02), but more effective than paroxetine (OR 0.65, 95% CI 0.44 to 0.96) and reboxetine (OR 0.63, 95% CI 0.43 to 0.91). Significantly fewer patients allocated to citalopram withdrew from trials due to adverse events compared with patients allocated to tricyclics (OR 0.54, 95% CI 0.38 to 0.78) and fewer patients allocated to citalopram reported at least one side effect than reboxetine or venlafaxine (OR 0.64, 95% CI 0.42 to 0.97 and OR 0.46, 95% CI 0.24 to 0.88, respectively).

Authors' conclusions

Some statistically significant differences between citalopram and other antidepressants for the acute phase treatment of major depression were found in terms of efficacy, tolerability and acceptability. Citalopram was more efficacious than paroxetine and reboxetine and more acceptable than tricyclics, reboxetine and venlafaxine, however, it seemed to be less efficacious than escitalopram. As with most systematic reviews in psychopharmacology, the potential for overestimation of treatment effect due to sponsorship bias and publication bias should be borne in mind when interpreting review findings. Economic analyses were not reported in the included studies, however, cost effectiveness information is needed in the field of antidepressant trials.

アブストラクト

うつ病に対するシタロプラムと他の抗うつ薬との比較

背景

米国と英国の最近の臨床ガイドラインでは、うつ病エピソードに薬物療法を適用する場合、第2世代の抗うつ薬が第一選択肢の中でも最良であると推奨している。システマティック・レビューにより、第2世代の抗うつ薬の間にも有効性に差があることが既に明らかになっている。シタロプラムは、最初に市販された選択的セロトニン再取り込み阻害薬(SSRI)の一つで、臨床医がうつ病治療にルーチンに用いる抗うつ薬の一つである。

目的

大うつ病の急性期治療を対象に、三環系抗うつ薬、複数環系抗うつ薬、他のSSRI、他の既存または非既存の抗うつ薬と比較した、シタロプラムの有効性、許容性および忍容性に関するエビデンスを評価すること。

検索戦略

Cochrane Collaboration Depression、Anxiety and Neurosis Controlled Trials RegisterおよびCochrane Central Register of Controlled Trialsを、2012年2月まで検索した。言語による制約は設けなかった。加えて、製薬会社および本分野の専門家に連絡を取り、追加情報を得た。

選択基準

大うつ病患者をシタロプラムまたは他の抗うつ薬に割り付けているランダム化比較試験(RCT)。

データ収集と分析

2名のレビューアが別々にデータを抽出した。抽出した情報は、研究の特性、参加者背景、介入の詳細、有効性(反応または寛解した患者数)、患者の許容性(研究を終了できなかった患者数)、忍容性(副作用)というアウトカム指標であった。

主な結果

37件の試験がシタロプラムを他の抗うつ薬(三環系抗うつ薬、複数環系抗うつ薬、SSRI、ミルタザピン、ベンラファキシン、レボキセチンなどの既存抗うつ薬またはオトギリソウのような通常の抗うつ薬ではない薬剤)と比較していた。急性期の有効性において、シタロプラムはエスシタロプラムに比べて有意に有効性が低かった[オッズ比(OR)1.47、95%信頼区間(CI)1.08~2.02]が、パロキセチン(OR 0.65、95%CI 0.44~0.96)とレボキセチン(OR 0.63、95%CI 0.43~0.91)に比べて有効性が高かった。有害事象により試験を中止した患者は、三環系抗うつ薬群に比べてシタロプラム群の方が有意に少なく(OR 0.54、95% CI 0.38~0.78)、1つ以上の副作用が発現した患者は、レボキセチン群(OR 0.64、95%CI 0.42~0.97)とベンラファキシン群(OR 0.46、95%CI 0.24~0.88)に比べてシタロプラム群の方が少なかった。

著者の結論

有効性、忍容性および許容性の点で、大うつ病の急性期治療に対しシタロプラムと他の抗うつ薬との間にいくつかの統計学的有意差が認められた。シタロプラムは、パロキセチンとレボキセチンより有効で三環系抗うつ薬、レボキセチン、ベンラファキシンより許容性が高かったが、エスシタロプラムより有効性が低かった。精神薬理学における大半のシステマティック・レビューと同様に、レビュー所見を解釈する場合には、スポンサーバイアス及び出版バイアスによる投与効果の過大評価の可能性を念頭に置くべきである。選択した研究で経済学的分析の報告はなかったが、抗うつ薬試験の分野では費用対効果の情報が必要である。

Plain language summary

Citalopram versus other antidepressants for depression

Major depression is a severe mental illness characterised by a persistent and unreactive low mood and loss of all interest and pleasure, usually accompanied by a range of symptoms including appetite change, sleep disturbance, fatigue, loss of energy, poor concentration, psychomotor symptoms, inappropriate guilt and morbid thoughts of death. Antidepressant drugs remain the mainstay of treatment in moderate-to-severe major depression. During the last 20 years, selective serotonin reuptake inhibitors (SSRIs) have progressively become the most commonly prescribed antidepressants. Citalopram, one of the first SSRIs introduced in the market, is the racemic mixture of S- and R-enantiomer. In the present review we assessed the evidence for the efficacy, acceptability and tolerability of citalopram in comparison with all other antidepressants in the acute-phase treatment of major depression. Thirty-seven randomised controlled trials (more than 6000 participants) were included in the present review. In terms of efficacy, citalopram was more efficacious than other reference compounds like paroxetine or reboxetine, but worse than escitalopram. In terms of side effects, citalopram was more acceptable than older antidepressants, like tricyclics. Based on these findings, we conclude that clinicians should focus on practical or clinically relevant considerations including differences in efficacy and side-effect profiles.

平易な要約

うつ病に対するシタロプラムと他の抗うつ薬との比較

大うつ病は重症の精神疾患の一つで、持続的な非反応性の気分低下とあらゆる興味・喜びの消失を特徴とし、食欲変動、睡眠障害、疲労、活力消失、集中力不良、精神運動症状、不適切な罪悪感、死に対する病的思考を通常合併する。中等度~重度の大うつ病の治療の主流は依然として抗うつ薬である。ここ20年の間、選択的セロトニン再取り込み阻害薬(SSRI)が最もよく処方される抗うつ薬となっている。シタロプラムは最初に市販されたSSRIの一つでS-R-鏡像体のラセミ混合物である。今回のレビューで、大うつ病の急性期治療における他のすべての抗うつ薬と比較した、シタロプラムの有効性、許容性および忍容性に関するエビデンスを評価した。今回のレビューに37件のRCT(参加者6,000名超)を選択した。有効性の点で、シタロプラムはパロキセチンまたはレボキセチンのような他の対照薬より有効であったがエスシタロプラムに比べて有効性は低かった。副作用の点で、シタロプラムの許容性は三環系抗うつ薬のような古い抗うつ薬よりも高かった。これらの所見に基づき、有効性および副作用プロファイルにおける差などの実際的かつ臨床的に関連性のある点について臨床医は注目すべきと結論した。

訳注

監  訳: 三浦 智史,2012.11.14

実施組織: 厚生労働省委託事業によりMindsが実施した。

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Background

Description of the condition

Major depression is generally diagnosed when a persistent and unreactive low mood and/or loss of 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 2004 and it is expected to be the greatest cause in 2030 (WHO 2006). 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 (APA 2000; NICE 2010). Although pharmacological and psychological interventions are both effective for major depression, in primary and secondary care settings antidepressant (AD) drugs remain the mainstay of treatment in moderate to severe major depression (APA 2006; NICE 2010). Amongst ADs many different agents are available, including tricyclics (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs, such as venlafaxine, duloxetine and milnacipran), and other agents (mirtazapine, reboxetine, bupropion). During the last 20 years, ADs prescription has dramatically risen in western countries, mainly because of the increasing prescription of SSRIs which have progressively become the most commonly prescribed ADs (Ciuna 2004). SSRIs are generally more acceptable than TCAs, and there is evidence of similar efficacy (NICE 2010). However, head-to-head comparisons have provided contrasting findings (Cipriani 2006).

Description of the intervention

Citalopram hydrobromide is a selective serotonin reuptake inhibitor (SSRI) that has been available as an antidepressant since the 1980s in US and Europe. It is also available in many countries for anxiety disorders, including obsessive-compulsive disorder and social anxiety disorder. Citalopram is a racemic dicyclic phthalane derivative designated (±)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5carbonitrile (www.fda.gov). Citalopram has a chemical structure unrelated to that of other SSRIs or of tricyclic, tetracyclic, or other available antidepressant agents. Therefore, some differential clinical potency may be expected, not only between the drugs classes but also among the SSRIs.

How the intervention might work

Inhibition of the neuronal transporter for serotonin has long been established as one of the mechanisms of action of numerous antidepressants (Barker 1995). Citalopram is a dicyclic phthalide derivative and its effect is due to a specific inhibition of the re-uptake of serotonin in the brain (Stahl 1994). Citalopram is a highly selective and potent SSRI with minimal effects on the neuronal reuptake of norepinephrine (NE) and dopamine (DA). Citalopram has no or very low affinity for a series of receptors including serotonin 5-HT1A, 5-HT2, dopamine D1, and D2, a1-, a2-, b-adrenergic, histamine H1, muscarinic cholinergic, benzodiazepine, gamma aminobutyric acid (GABA) and opioid receptors (Stahl 1998). Citalopram has a pronounced tissue distribution and its binding to human plasma proteins is about 80%. Maximum concentration in blood is reached after one to six hours and the steady state concentration in blood is reached after one to two weeks. Protein binding is about 14L/k and the half-life is about 36 hours, (possibly longer for the elderly). The drug is metabolized before it is excreted. Citalopram is metabolized in the liver and the biotransformation of citalopram to its demethyl metabolites depends on both CYP2C19 and CYP3A4, with a small contribution from CYP2D6.

Why it is important to do this review

To shed light on the field of antidepressant trials and the treatment of major depression, 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. We have up to now completed some individual reviews about fluoxetine (Cipriani 2005a), sertraline (Cipriani 2009b), escitalopram (Cipriani 2009c), milnacipran (Nakagawa 2009), fluvoxamine (Omori 2010), and a number of other reviews are now underway. Thus, the aim of the present review is to assess the evidence for the efficacy and tolerability of citalopram in comparison with TCAs, heterocyclics, MAOIs, SSRIs, SNRIs and other antidepressants in the acute-phase treatment of major depression.

Objectives

(1) To determine the efficacy of citalopram in comparison with other antidepressants in alleviating the acute symptoms of major depressive disorder.
(2) To review acceptability of treatment with citalopram in comparison with other antidepressants.
(3) To investigate the adverse effects of citalopram in comparison with other antidepressants.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials that compared citalopram with all other active antidepressants as monotherapy in the acute phase treatment of depression. Quasi-randomised trials, such as those allocating by using alternate days of the week, were excluded. For trials which have a cross-over design, we only considered results from the first randomisation period.

Types of participants

The review included trials of patients 18 years or older, of both sexes, with a primary diagnosis of depression and studies adopting standardised criteria (DSM-III / DSM-III-R, DSM-IV (APA 2000), ICD-10 (WHO 1992), Feighner criteria (Feighner 1972) or Research Diagnostic Criteria (Spitzer 1972) to define patients suffering from unipolar major depression. We excluded studies using ICD-9, as it has only disease names and no diagnostic criteria. We included the following subtypes of depression: chronic, with catatonic features, with melancholic features, with atypical features, with postpartum onset, and with seasonal pattern. We also included studies in which up to 20% of patients presented depressive episodes in bipolar affective disorder. A concurrent secondary diagnosis of another psychiatric disorder was not considered an exclusion criterion. A concurrent primary diagnosis of Axis I or II disorders was an exclusion criterion. AD trials in depressive patients with a serious concomitant medical illness were excluded.

Types of interventions

We examined citalopram intervention in comparison with conventional treatment of acute depression. We also examined citalopram intervention in comparison with non-conventional antidepressants (herbal products or other non-conventional antidepressants. We excluded trials in which citalopram was compared with another type of psychopharmacological agent (i.e., anxiolytics, anticonvulsants, antipsychotics or mood-stabilizers). We also excluded trials in which citalopram was used as an augmentation strategy.

Eligible intervention:

1. Citalopram: any dose and pattern of administration.

Eligible comparators:

2. Conventional antidepressants: any dose and mode or pattern of administration.
2.1 TCAs
2.2 Heterocyclics
2.3 SSRIs
2.4 SNRIs
2.5 MAOIs or newer ADs
2.6 Other conventional psychotropic drugs

3. Non-conventional antidepressants
3.1 Herbal products
3.2 Other non-conventional antidepressants

Types of outcome measures

Primary outcomes

1. Response - acute phase

We examined trials regarding the number of patients (1) who responded to treatment by showing a reduction of at least 50% on the Hamilton Rating Scale for depression (HRSD) (Hamilton 1960), Montgomery Åsberg Depression Rating Scale (MADRS) (Montgomery 1979), or any other depression scale, depending on the study authors' definition or (2) who were "much or very much improved" (score 1 or 2) on the CGI-Improvement scale (Guy 1976) out of the total number of randomised patients. Where both were provided, we preferred the former criteria for judging response. The original authors' definitions of response and remission were not used in this review, to avoid possible outcome reporting bias (Furukawa 2007).

As studies report response rates at various time points throughout the trial period, we had determined a priori to subdivide the treatment indices - since one systematic review suggested that SSRIs begin to have observable beneficial effects in depression during the first week of treatment - as follows (Taylor 2006):

(i) Response - early phase: between one and four weeks, with the time point closest to two weeks given preference.
(ii) Response - acute phase: between six and 12 weeks, with preference given to the time point given in the original study as the study endpoint.
(iii) Response - follow-up phase: between four and six months, with the time point closest to 24 weeks given preference.

The acute phase treatment response rates were our primary outcome of interest.

Secondary outcomes

1. Response - early phase, and follow-up phase

2. Remission - early phase, acute phase, and follow-up phase

We were interested in the number of patients who achieved remission, (1) showing =< 7 on HRSD-17, =< 8 on for all the other longer versions of HRSD, and =< 11 on MADRS or (2) who were "not ill or borderline mentally ill" (score 1 or 2) on the CGI-Severity score out of the total number of randomised patients. Where both were provided, we preferred the former criterion for judging remission.

3. Group mean scores at the end of the trial and change score on depression scale

4. Social adjustment, social functioning, including the Global Assessment of Function (GAF) scores

(Hall 1995)

5. Health-related quality of life (QOL)

We limited ourselves to SF-12 (Ware 1998), SF-36 (Ware 1992), HoNOS (Wing 1998) and the WHO 2009-QOL (WHOQOL Group 1998).

6. Costs to healthcare services

7. Acceptability

7.1 Total dropout

Number of patients who dropped out during the trial as a proportion of the total number of randomised patients.

7.2 Dropout due to inefficacy

Number of patients who dropped out during the trial because the fluvoxamine was ineffective as a proportion of the total number of randomised patients.

7.3 Dropout due to side effects

Number of patients who dropped out during the trial due to side effects, as a proportion of the total number of randomised patients.

7.4 Number of patients experiencing at least one side effect

7.5 Number of patients experiencing the following specific side effects was sought:

  • sleepiness/drowsiness

  • insomnia

  • dry mouth

  • constipation

  • problems urinating

  • hypotension

  • agitation/anxiety

  • suicide wishes/gestures/attempts

  • completed suicide

  • vomiting/nausea

  • diarrhoea

To avoid missing any relatively rare or unexpected side effects in the data extraction phase, we collected all side effect data reported in the literature and discussed ways to summarize them post hoc. Descriptive data regarding side-effect profiles were extracted from all available studies. Only studies reporting the number of patients experiencing individual side effects were retained. Due to a lack of consistent reporting of side effects, which came primarily from the study authors' descriptions, we combined terms describing similar side effects; for example, we combined "dry mouth", "reduced salivation" and "thirst" into "dry mouth". All side-effect categories were then grouped by organ system, such as neuropsychiatric, gastrointestinal, respiratory, sensory, genitourinary, dermatological and cardiovascular, in accordance with the advice of a previous study (Mottram 2006).

Search methods for identification of studies

Electronic searches

We searched The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register and the Cochrane Central Register of Controlled Trials (CCDANCTR) up to February 2012, MEDLINE (1966 to 2012), EMBASE (1974 to 2012). We also searched trial databases of the following drug-approving agencies for published, unpublished and ongoing controlled trials: the Food and Drug Administration (FDA) in the USA, the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK, the European Medicines Agency (EMA) in the EU, the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan and the Therapeutic Goods Administration (TGA) in Australia.

In addition, we searched ongoing trial registers such as clinicaltrials.gov in the USA, International Standard Randomised Controlled Trial Number Register (ISRCTN) and the National Research Register in the UK, Nederland's Trial Register in the Netherlands, European Union Drug Regulating Authorities Clinical Trials (EudraCT) in the EU, UMIN-CTR in Japan, the Australian Clinical Trials Registry in Australia and the clinical trial register of Lundbeck and Forest (citalopram manufacturer): http://www.lundbecktrials.com/ and http://www.forestclinicaltrials.com/CTR/CTRController/CTRHome, respectively These searches were undertaken in November 2010 and replicated in February 2012.

No language restriction was applied.

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 = Citalopram

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 = Citalopram

Searching other resources

1. Handsearches
Appropriate journals and conference proceedings relating to citalopram treatment for depression have already been handsearched and incorporated into the CCDANCTR databases.

2. Personal communication

We asked pharmaceutical companies and experts in this field if they knew of any study that met the inclusion criteria of this review.

3. Reference checking

We checked reference lists of the included studies, previous systematic reviews and major textbooks of affective disorder written in English for published reports and citations of unpublished research (Trespidi 2011).

Data collection and analysis

Selection of studies

Two review authors independently checked to ensure that studies relating to duloxetine generated by the search strategies of the CCDANCTR-References and the other complementary searches met the rough inclusion criteria, firstly based on the title and abstracts. All of the studies that were rated as possible candidates by either of the two review authors were added to the preliminary list, and their full texts were retrieved. Review authors AC, GI, MP, AS and CT then assessed all of the full text articles in this preliminary list to see if they met the strict inclusion criteria. If the raters disagreed, the final rating was made by consensus with the involvement - if necessary - of another member of the review group (CB, NW or TAF). Considerable care was taken to exclude duplicate publications.

Data extraction and management

AC, GI, MP, AS and CT extracted data from the included studies. Again, any disagreement was discussed, and decisions were documented. If necessary, we contacted authors of studies for clarification. We extracted the following data:

(i) participant characteristics (age, sex, depression diagnosis, comorbidity, depression severity, antidepressant treatment history for the index episode, study setting);
(ii) intervention details (intended dosage range, mean daily dosage actually prescribed, co-intervention if any, duloxetine as investigational drug or as comparator drug, sponsorship);
(iii) 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 the trial was a three (or more)-armed trial involving a placebo arm, the data were extracted from the placebo arm as well.

Assessment of risk of bias in included studies

Two review authors independently assessed trial quality in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). This set of criteria is based on evidence of associations between effect overestimation and a high risk of bias in an article, such as sequence generation, allocation concealment, blinding, incomplete outcome data and selective reporting. The categories are defined as:

  • low risk of bias;

  • high risk of bias;

  • unclear risk of bias.

If the raters disagreed, the final rating was made by consensus with the involvement (if necessary) of another member of the review group. Non-congruence in quality assessment was reported as percentage disagreement. The ratings were also compared with those in the completed reviews of individual antidepressants in The Cochrane Library. If there were any discrepancies, these were fed back to the authors of the completed reviews.

Measures of treatment effect

All comparisons were performed between citalopram and comparator ADs as individual ADs. Citalopram was also compared with TCAs and heterocyclics as a class.

1. Dichotomous data

For dichotomous, or event-like, data, odds ratios (ORs) were calculated with 95% confidence intervals (CIs). For statistically significant results, we calculated the number needed to treat to provide benefit (NNTB) and the number needed to treat to induce harm (NNTH) as the inverse of the risk difference.

2. Continuous data

For continuous data, we calculated mean differences (MD), or standardised mean differences (SMD) where different measurement scales were used, with 95% CIs.

Unit of analysis issues

1. Cross-over trials

A major concern of cross-over trials is the carry-over effect. It occurs if an effect (e.g., pharmacological, physiological or psychological) of the treatment in the first phase is carried over to the second phase. As a consequence, on entry to the second phase, the participants can differ systematically from their initial state, despite a wash-out phase. For the same reason, cross-over trials are not appropriate if the condition of interest is unstable (Elbourne 2002). As both effects are very likely in major depression, we only used data from the first phase of the cross-over studies.

2. Cluster-randomised trials

No cluster-randomised trials were identified for this version of the review. Should they be identified in a future update, we plan to use the generic inverse variance technique, if such trials have been appropriately analysed taking into account intraclass correlation coefficients to adjust for cluster effects.

3. Multiple intervention groups

Studies that compared more than two intervention groups were included in meta-analysis by combining all relevant experimental intervention groups of the study into a single group, and all relevant control intervention groups into a single control group, as recommended in section 16.5 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Dealing with missing data

1. Dichotomous data

Responders and remitters to treatment were calculated on the strict intention-to-treat (ITT) basis: dropouts were included in this analysis. Where participants had been excluded from the trial before the endpoint, we assumed that they experienced a negative outcome by the end of the trial (e.g., failure to respond to treatment). We examined the validity of this decision in sensitivity analyses by applying worst- and best-case scenarios. We applied the loose ITT analyses for continuous variables, whereby all the patients with at least one post-baseline measurement were represented by their last observations carried forward (LOCF), with due consideration of the potential bias and uncertainty introduced.

When dichotomous outcomes were not reported but baseline mean, endpoint mean and the standard deviation (SD) of the HRSD (or other depression scale) were provided, we converted continuous outcome data expressed as mean and SD into the number of responding and remitted patients, according to the validated imputation method (Furukawa 2005). We examined the validity of this imputation in the sensitivity analyses. Where SDs were not reported, authors were asked to supply the data. When only the standard error (SE) or t-statistics or P values were reported, SDs were calculated according to Altman (Altman 1996). In the absence of data from the authors, we substituted SDs by those reported in other studies in the review (Furukawa 2006).

2. Continuous data

When there were missing data and the method of LOCF had been used to do an ITT analysis, then the LOCF data were used. When SDs were missing, we presented data descriptively.

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 I2 statistic (Higgins 2003) (an I2 equal to or more than 50% was considered indicative of heterogeneity) and by visual inspection of the forest plots. We performed subgroup analyses to investigate heterogeneity (see Subgroup analysis and investigation of heterogeneity).

Assessment of reporting biases

Data from included studies were entered into a funnel plot (trial effect against trial variance) to investigate small-study effects (Sterne 2000). We used the tests for funnel plot asymmetry only when there were at least 10 studies included in the meta-analysis, and results were interpreted cautiously, with visual inspection of the funnel plots (Higgins 2011). When evidence of small-study effects was identified, we investigated possible reasons for funnel plot asymmetry, including publication bias.

Data synthesis

For the primary analysis we 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. A P value of less than 0.05 and a 95% CI were considered statistically significant. Fixed-effect analyses were performed 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. Skewed data and non-quantitative data were presented descriptively. An outcome was considered skewed when the mean was smaller than twice the SD. In terms of change score, data were difficult to depict as skewed or not, as the possibility existed for negative values; therefore, we entered all of the results of this outcome into a meta-analysis.

Subgroup analysis and investigation of heterogeneity

We performed the following subgroup analyses for the primary outcome where possible, for the following a priori reasons. Results were interpreted with caution, since multiple comparisons could lead to false positive conclusions (Oxman 1992).

1. Citalopram dosing (fixed low dosage, fixed standard dosage, fixed high dosage; flexible low dosage, flexible standard dosage, flexible high dosage) Existing evidence implies that low dosage antidepressants may be associated with better outcomes - both in terms of efficacy and side effects - than standard or high dosage antidepressants (Bollini 1999; Furukawa 2002b). In addition, a fixed versus flexible dosing schedule may affect estimates of treatment effectiveness (Khan 2003). In the case of citalopram, based on the Defined Daily Dosage (DDD) by WHO (WHO 2009a), low dosage is referred to as < 20, standard dosage to >= 20 but < 40, and high dosage to >= 40 mg/day. We categorised studies by intended maximum dosage of citalopram.

2. Comparator dosing (low dosage, standard dosage, and high dosage) It is easy to imagine that people taking a comparator drug are less likely to complete a study if they are taking a high dosage of the comparator drug. We categorised studies by the intended maximum dose of the comparator based on the DDD.

3. Depression severity (severe major depression, moderate/mild major depression) "Severe major depression" was defined by a threshold baseline severity score for entry of 25 or more for HRSD and 31 or more for MADRS (Dozois 2004; Müller 2003).

4. Treatment settings (psychiatric in-patients, psychiatric outpatients, primary care) Because depressive disorder in primary care has a different profile than that of psychiatric in-patients or outpatients (Suh 1997), it is possible that results obtained from either of these settings may not be applicable to the other settings (Depression Guideline Panel 1993).

5. Elderly patients (>= 65 years of age), separately from other adult patients Older people may be more vulnerable to side effects associated with antidepressants and decreased dosage is often recommended for them (Depression Guideline Panel 1993).Because the number of a priori planned subgroup analyses now appears excessive in comparison with the identified studies, we will consider reducing the number of subgroup analyses or adjusting the level of significance to account for making multiple comparisons in the next update.

Sensitivity analysis

The following sensitivity analyses for primary outcome were planned a priori. By limiting the included studies to those with higher quality (analyses one to five) or to those free from some "bias" (analyses six to nine), we examined whether the results changed and we intended to check for the robustness of the observed findings.

  1. We excluded trials with unclear concealment of random allocation and/or unclear double blinding.

  2. We excluded trials with a dropout rate greater than 20%.

  3. We performed the worst-case scenario ITT: that all patients in the experimental group experienced the negative outcome and all those in the comparison group experienced the positive outcome.

  4. We performed the best-case scenario ITT: that all patients in the experimental group experienced the positive outcome and all those in the comparison group experienced the negative outcome.

  5. We excluded trials for which the response rates had to be calculated based on the imputation method (Furukawa 2005) and for which the SD had to be borrowed from other trials (Furukawa 2006).

  6. We examined a "wish bias" by comparing the trials where citalopram was used as an investigational drug, the drug that was used as a new compound, to the trials where citalopram was used as a comparator, since some evidence suggests that a new antidepressant might perform worse when used as a comparator than when used as an investigational agent (Barbui 2004).

  7. We excluded trials funded by, or with at least one author affiliated with, a pharmaceutical company marketing citalopram. This sensitivity analysis is particularly important in light 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 have increased over the past 20 years (Buchkowsky 2004).

  8. We excluded studies that included patients with bipolar depression.

  9. We excluded trials that included patients with psychotic features.

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.

If the CIs of ORs in the groups did not overlap, potential sources of heterogeneity were investigated.

Results

Description of studies

See:Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification.

Results of the search

Initially, we identified 303 references. After reading the abstracts, 265 references were considered relevant for our review and retrieved for more detailed evaluation. The search found 37 additional studies written in Chinese. We commissioned a professional translator for the full translation of these papers. The translation process is still ongoing, so in the present review we considered all Chinese studies as awaiting assessment studies (we will include them in the next update of the review, which is expected to be in a two years time). An additional four studies were considered as awaiting assessment because the papers reported insufficient information to decide about inclusion or exclusion (Ahlfors 1988; Galecki 2004; Moeller 1986; Thomas 2008). We contacted corresponding authors and at the time the review has been submitted we are still waiting for their reply and further information. We identified two ongoing studies. Although the search was thorough, it is still possible that there are still unpublished studies which have not been identified.

Included studies

A total of 37 studies were included in this systematic review. Of these, four trials were unpublished (29060/785; Lu 10-171, 83-01; Lu 10-171,79-01; SCT-MD-02). Attempts to contact authors for additional information were successful in seven cases (with additional data provided by authors) and unsuccessful in 13.

Sample Size

The mean sample size per arm was 107 participants (range 17-303). Sixteen studies recruited fewer than 100 participants overall.

Study design

The great majority of included studies were reported to be double-blind (28 out of 37 RCTs, that is 75.6%).

Country

The great majority of included studies had been carried out in Europe or in the US (29 out of 37 RCTs, that is 78.4%). Two studies randomised patients in China (Hsu 2011; Ou 2010), three in India (Khanzode 2003; Lalit 2004; Matreja 2007) and one in Russia (Yevtushenko 2007).

Age

Four studies randomised only elderly patients (Allard 2004; Karlsson 2000; Kyle 1998; Navarro 2001) and 22 studies only patients aged between 18 and 65 years (59.4%). The remaining studies randomised both adult and elderly patients or it was unclear.

Diagnosis

Only three studies (8.1%) included patients with bipolar disorder (Bougerol 1997a; Hosak 1999; Timmerman 1993). As per protocol, RCTs were included in the present review only if patients with bipolar disorder were less than 20% in each study.

Setting/participants

Twenty trials enrolled only out-patients, four studies only in-patients (Andersen 1986; de Wilde 1985; Hosak 1999; Lu 10-171,79-01), seven recruited both in- and out-patients (Bougerol 1997a; Gravem 1987; Karlsson 2000; Lu 10-171, 83-01; Navarro 2001; Ou 2010; Shaw 1986), three studies enrolled patients from general practice (Bougerol 1997b; Ekselius 1997; Lewis 2011). In the remaining three studies the setting was unclear. About two thirds of the participants were women. In 31 RCTs patients had a formal diagnosis of major depression (or major depressive disorder) according to DSM-III, DSM-III-R, DSM-IV or ICD-10 criteria. In six studies the diagnosis was based on different standardized research criteria (i.e., Feighner criteria).

Interventions and comparators

We found RCTs comparing citalopram with TCAs (amitriptyline, imipramine and nortriptyline), tetracycles (mianserin and maprotiline), other SSRIs (escitalopram, fluoxetine, sertraline, fluvoxamine and paroxetine), one SNRI (namely, venlafaxine), one MAOI (moclobemide), other conventional ADs (mirtazapine and reboxetine) and also only one non-conventional ADs (St John's wort, or hypericum). Hypericum, a member of the Hypericaceae family, has been used in folk medicine for a long time for a range of indications including depressive disorders. It is licensed and widely used in Germany for the treatment of depressive, anxiety and sleep disorders and in recent years it has also become increasingly popular in other European and non-European countries (Linde 2008).

Details on the included studies are as follows: nine studies (overall 1277 participants) comparing citalopram with TCAs (four studies versus amitriptyline, two versus imipramine and two studies versus nortriptyline and one study versus clomipramine, respectively); three studies (overall 477 participants) comparing citalopram with tetracyclics (two studies versus mianserin and one study versus maprotiline); 18 studies (overall 4200 participants) comparing citalopram with SSRIs (seven studies versus escitalopram, four studies versus fluoxetine), four studies versus sertraline, one study versus fluvoxamine, one study versus paroxetine and one study versus either escitalopram or sertraline); six studies (overall 1137 participants) comparing citalopram with SNRIs (one study versus each of the following drugs: venlafaxine and mirtazapine), comparing citalopram with MAOI (one study versus moclobemide), comparing citalopram with other conventional psychotropic drugs (two studies versus reboxetine), comparing citalopram with non-conventional antidepressants (one study versus hypericum).

There were four three-arm trials: one study comparing citalopram (20 mg/day) with escitalopram 20 mg/day or escitalopram 10 mg/day; one study comparing citalopram (20-60 mg/day) with amitriptyline (150-300 mg/day) or fluoxetine (20-60 mg/day); one study comparing citalopram 10-30 mg/day with citalopram 20-60 mg/day or imipramine (50-150 mg/day); one study compared citalopram (20 mg/day) with escitalopram 10 mg/day or citalopram 10 mg/day. One four-arm trial compared citalopram 20 mg/day with citalopram 40 mg/day or paroxetine controlled-release 12.5 mg/day or paroxetine controlled-release 25 mg/day.

Outcomes

Of the included 37 studies, one study (Andersen 1986) did not report efficacy data and one study reported split data according to different genotypes (Lewis 2011). We were not able to obtain further data for these trials because we could not contact the authors by any means and therefore, could not obtain extra information from these authors. By contrast, all 37 studies did report tolerability/acceptability data that could be entered into a meta-analysis The great majority of the identified studies (34 out of 37 RCTs) used the MADRS or HRSD as the rating scale of choice for primary or secondary outcome measures. Among the 35 studies reporting dropouts due to any reason, 31 reported dropouts due to side effects. Twenty-eight studies reported the number of patients experiencing individual side effects.

Excluded studies

Of the 265 references retrieved for more detailed evaluation, 214 articles did not meet our inclusion criteria and were excluded because of one of the following reasons: duplicate publications (eight articles), wrong diagnosis (24 articles), wrong population (51 articles), wrong comparison or intervention (63 articles) and non-randomised or wrong design (68 articles). Fourteen additional studies were considered as awaiting assessment (overall we found 51 awaiting assessment studies - see above).

Risk of bias in included studies

See: Included studies, Figure 1, Figure 2.

Figure 1.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

Figure 2.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Our judgment about the overall risk of bias in the individual studies is illustrated in Figure 1 and Figure 2. The methodological quality of these included studies was judged as poor, although judging articles from some time ago by today’s standard might be problematic (Begg 1996). Nevertheless, the reporting in these studies overall was not good. This type of reporting has been associated with an overestimate of the estimate of effect (Schulz 1995) and this should be considered when interpreting the results.

Allocation

The majority of studies reported the methods of generating random sequence, in which “a computer originated schedule” was used, however, only three studies reported enough details on allocation concealment (Colonna 2005; Lewis 2011; Ou 2010). We were not assured that bias was minimised during the allocation procedure in the other studies, yet the great majority of them reported that the participants allocated to each treatment group were “similar”, “the same”, “not significantly different”, “comparable” or “matched”.

Blinding

Thirty out of 37 RCTs (81.1%) described their design as “double-blind”; however, no tests were conducted to ensure successful blinding. In the review we have included one “single-blind” trial (Navarro 2001) which was rated as having a “high risk of bias” because it was unclear whether its outcome assessment was blinded to the medication. Four trials were open trials that did not seek blinding (Castanedo de Alba 1998; Hosak 1999; Lewis 2011; Matreja 2007) and in two studies the blinding was unclear (Moeller 2003; Ou 2010).

Incomplete outcome data

Total dropout rate was overall relatively high, ranging from 2% (Matreja 2007) to 56% (Stahl 2000). There were 23 studies (62.2%) where the total dropout rates were more than 20%.

Selective reporting

The study protocol was not available for almost all studies. Only six studies reported SDs of change scores (Burke 2002; Langworth 2006; Lepola 2003; Ou 2010; SCT-MD-02; Yevtushenko 2007); 10 studies (Allard 2004; Bouchard 1987; de Wilde 1985; Bougerol 1997a; Bougerol 1997b; Khanzode 2003; Lu 10-171, 83-01; Lu 10-171,79-01; Shaw 1986; Timmerman 1993) reported SDs of endpoint score of continuous efficacy variables.

Other potential sources of bias

Most of the included studies were funded by industry and only one study was clearly not funded by industry sponsor (Castanedo de Alba 1998). Among the trials comparing citalopram to TCAs or heterocyclics, the great majority (nine out of 11) were sponsored by, or had at least one author affiliated with, the pharmaceutical company marketing citalopram. Most of the studies comparing citalopram with other SSRIs (11 out of 16) were sponsored by the citalopram manufacturer, however, all the studies comparing citalopram with escitalopram (seven RCTs) were sponsored by their mutual manufacturer and in these studies citalopram was always considered as the reference drug. Among the six studies comparing citalopram with other ADs or non-conventional antidepressant agents, only one was sponsored by the citalopram manufacturer (Berlanga 2006).

Effects of interventions

The included studies did not report on all the outcomes that were pre-specified in the protocol of this review. Outcomes of clear relevance to patients and clinicians, in particular, patient's and their relatives' attitudes to treatment, their ability to return to work and resume normal social functioning, health-related quality of life measures and costs to healthcare services were not reported in the included studies. Overall, 6147 patients were available for assessing efficacy (3183 participants randomised to citalopram and 3023 to another antidepressant) and 6960 for examining acceptability of treatments (3538 participants allocated to citalopram and 3378 to another antidepressant). Evidence of differences in efficacy, acceptability and tolerability was found and details are listed below. To obtain missing response rates and remission, we used validated imputation methods from continuous outcomes. We imputed SDs for some continuous outcomes of the following studies: Castanedo de Alba 1998; Colonna 2005; Ekselius 1997; Hosak 1999; Leinonen 1999; Moore 2005; Rosenberg 1994; Stahl 2000.

The results of the present systematic review were reported comparison by comparison (grouping them into different drug classes according to review protocol, see Methods section - Types of interventions) and by outcome (following the review protocol - for details see Imperadore 2007). The forest plots were organised according to the relevance of outcomes, as reported in the review protocol. For adverse events, all the retrieved information about the adverse events specified in the review protocol were reported (either statistically or non-statistically significant). Remaining adverse events were only reported when statistically significant (non-statistically significant results about adverse events are presented in Table 1).

Table 1. Adverse events
Adverse eventStudyCItalopramComparatorOdds Ratio, Random [95% CI]
EventsTotalEventsTotal
Citalopram versus TCAs
Citalopram vs amitriptyline
AstheniaShaw 19863275250.50 [0.11, 2.35]
ConfusionShaw 19862275250.32 [0.06, 1.83]
ConjunctivitisGravem 19871270242.77 [0.11, 71.35]
Dermatological problemsGravem 19871271240.88 [0.05, 14.96]
DizzinessGravem 1987; Kyle 1998; Shaw 198616233282350.47 [0.15, 1.44]
FatigueKyle 19986179111860.55 [0.20, 1.53]
GastrointestinalGravem 1987; Shaw 19863546490.45 [0.10, 2.07]
HeadacheGravem 1987; Hosak 1999; Kyle 1998; Shaw 198622262182661.25 [0.65, 2.42]
Loss of hairGravem 19871270242.77 [0.11, 71.35]
MeteorismGravem 19870271240.28 [0.01, 7.33]
PalpitationsGravem 1987; Shaw 19864549490.36 [0.10, 1.24]
RashShaw 19861271250.92 [0.05, 15.59]
RestlessnessGravem 1987; Shaw 19864545490.71 [0.18, 2.82]
SweatingGravem 19872273240.56 [0.09, 3.67]
SyncopeGravem 19870271240.28 [0.01, 7.33]
Taste abnormalitiesGravem 19870271240.28 [0.01, 7.33]
TremorGravem 19871271240.88 [0.05, 14.96]
Visual problemsGravem 19870273240.11 [0.01, 2.28]
Citalopram vs imipramine
AstheniaLu 10-171, 83-012223210.60 [0.09, 4.01]
DizzinessLu 10-171, 83-0172212210.35 [0.10, 1.22]
GastrointestinalLu 10-171, 83-016225211.20 [0.30, 4.74]
HeadacheLu 10-171, 83-016222213.56 [0.63, 20.15]
IrritabilityRosenberg 19942838012920.53 [0.26, 1.09]
RestlessnessLu 10-171, 83-013224210.67 [0.13, 3.44]
Citalopram vs maprotiline
Appetite increasedBouchard 19871481481.00 [0.06, 16.46]
Concentration decreaseBouchard 19871480483.06 [0.12, 77.09]
Craving for sweetsBouchard 19872480485.22 [0.24, 111.55]
Dermatological problemsBouchard 19871481481.00 [0.06, 16.46]
DizzinessBouchard 19877485481.47 [0.43, 5.00]
DyspepsiaBouchard 19872481482.04 [0.18, 23.32]
DyspneaBouchard 19870481480.33 [0.01, 8.22]
Feeling of numbnessBouchard 19872480485.22 [0.24, 111.55]
HeadacheBouchard 19876483482.14 [0.50, 9.12]
HypertoniaBouchard 19871481481.00 [0.06, 16.46]
Increased salivationBouchard 19871480483.06 [0.12, 77.09]
Nasal congestionBouchard 19871481481.00 [0.06, 16.46]
Orthostatic symptomsBouchard 19873483481.00 [0.19, 5.22]
RestlessnessBouchard 19871485480.18 [0.02, 1.63]
SweatingBouchard 19878484482.20 [0.62, 7.87]
TachycardiaBouchard 19873485480.57 [0.13, 2.55]
Taste abnormalitiesBouchard 19871480483.06 [0.12, 77.09]
TremorBouchard 19875488480.58 [0.18, 1.93]
Visual problemsBouchard 19871480483.06 [0.12, 77.09]
YawningBouchard 19871480483.06 [0.12, 77.09]
Citalopram vs nortriptyline
ConfusionLu 10-171,79-011170183.36 [0.13, 88.39]
HeadacheLu 10-171,79-015175181.08 [0.25, 4.70]
PalpitationsLu 10-171,79-014174181.08 [0.22, 5.22]
PruritusLu 10-171,79-015173182.08 [0.41, 10.53]
Citalopram versus heterocyclics
Citalopram vs mianserin
Back painKarlsson 20006163101730.62 [0.22, 1.75]
DizzinessKarlsson 20004163101730.41 [0.13, 1.33]
HeadacheKarlsson 200012163121731.07 [0.46, 2.45]
Pain (general)Karlsson 2000616391730.70 [0.24, 2.00]
Citalopram versus other SSRIs
Citalopram vs escitalopram
Abdominal painMoore 2005115201422.82 [0.11, 69.84]
Accidental injuryColonna 20054182101750.37 [0.11, 1.21]
Aggressive behaviourMoore 2005015211420.31 [0.01, 7.65]
AnorexiaOu 2010; Yevtushenko 2007222542230.64 [0.06, 7.29]
AstheniaMoore 2005215221420.93 [0.13, 6.72]
Back painColonna 2005; SCT-MD-0214305123001.36 [0.34, 5.51]
Breast surgeryMoore 2005115201422.82 [0.11, 69.84]
BronchitisColonna 20053182101750.28 [0.07, 1.02]
Chest painMoore 2005115201422.82 [0.11, 69.84]
Chicken poxMoore 2005015211420.31 [0.01, 7.65]
Dermatological problemsYevtushenko 2007211011092.00 [0.18, 22.38]
DizzinessMoore 2005; Ou 2010; SCT-MD-02; Yevtushenko 200711502174910.69 [0.28, 1.71]
DyspepsiaYevtushenko 2007111001093.00 [0.12, 74.45]
EnuresisMoore 2005015211420.31 [0.01, 7.65]
Exacerbation of depressionMoore 2005115201422.82 [0.11, 69.84]
GastrointestinalOu 201014117161150.84 [0.39, 1.81]
HeadacheColonna 2005; Moore 2005; SCT-MD-02; Yevtushenko 200745567465510.96 [0.49, 1.88]
Hot flashMoore 2005015211420.31 [0.01, 7.65]
Memory impairmentMoore 2005215201424.73 [0.23, 99.47]
PalpitationsMoore 2005015211420.31 [0.01, 7.65]
Panic attackMoore 2005115201422.82 [0.11, 69.84]
PharyngitisMoore 2005015211420.31 [0.01, 7.65]
PruritusMoore 2005115201422.82 [0.11, 69.84]
RashYevtushenko 2007111001093.00 [0.12, 74.45]
RhinitisColonna 2005; Lepola 2003; SCT-MD-0224466284560.87 [0.40, 1.87]
Sexual problems: erectile dysfunctionLepola 2003016121560.19 [0.01, 4.02]
Sexual problems: increased sexual desireSCT-MD-02912381251.15 [0.43, 3.10]
Sexual problems: otherBurke 2002; Moore 2005; SCT-MD-02; Yevtushenko 200716452315630.72 [0.36, 1.43]
SweatingLepola 2003; Moore 2005; SCT-MD-0213436154230.83 [0.39, 1.78]
TachycardiaSCT-MD-02012311250.34 [0.01, 8.33]
TremorMoore 2005015241420.10 [0.01, 1.89]
Upper respiratory tract infectionSCT-MD-028123121250.66 [0.26, 1.66]
Visual problemsMoore 2005115201422.82 [0.11, 69.84]
Weight gainColonna 2005; Moore 200515334123171.21 [0.55, 2.64]
Citalopram vs fluoxetine
Abdominal painBougerol 1997a; Bougerol 1997b16331103421.57 [0.55, 4.53]
Back painBougerol 1997b5173018412.04 [0.66, 219.46]
BronchitisBougerol 1997b517371840.75 [0.23, 2.42]
Decreased weightBougerol 1997a; Bougerol 1997b13331223420.62 [0.25, 1.50]
HeadacheBougerol 1997a; Bougerol 1997b; Hosak 199925360283720.90 [0.51, 1.60]
Influenza-like symptomsBougerol 1997b217361840.35 [0.07, 1.74]
NervousnessBougerol 1997a615851581.21 [0.36, 4.04]
PruritusBougerol 1997a215851580.39 [0.07, 2.05]
SweatingBougerol 1997a615821583.08 [0.61, 15.49]
TensionBougerol 1997a615861581.00 [0.32, 3.17]
VertigoBougerol 1997a715831582.40 [0.61, 9.43]
Citalopram vs paroxetine
Asthenia29060/78536207221991.69 [0.96, 3.00]
Headache29060/78554207441991.24 [0.79, 1.96]
Sexual problems: other29060/78513207111991.15 [0.50, 2.62]
Syncope29060/785120701992.90 [0.12, 71.57]
Citalopram vs sertraline
AstheniaEkselius 1997320062000.49 [0.12, 2.00]
Concentration decreaseEkselius 1997120022000.50 [0.04, 5.53]
Decreased weightEkselius 19971920092002.23 [0.98, 5.05]
Dermatological problemsEkselius 1997620052001.21 [0.36, 4.02]
DizzinessEkselius 199714200142001.00 [0.46, 2.16]
Emotional indifferenceEkselius 1997220012002.01 [0.18, 22.35]
ForgetfulnessEkselius 1997720042001.78 [0.51, 6.17]
GastrointestinalEkselius 19975200122000.40 [0.14, 1.16]
HeadacheEkselius 199713200182000.70 [0.33, 1.48]
Increased salivationEkselius 1997120002003.02 [0.12, 74.46]
PalpitationsEkselius 1997820062001.35 [0.46, 3.96]
Sexual problems: anorgasmiaEkselius 199724200132001.96 [0.97, 3.97]
Sexual problems: erectile dysfunctionEkselius 1997720032002.38 [0.61, 9.34]
Sexual problems: increased sexual desireEkselius 19971420072002.08 [0.82, 5.26]
Sexual problems: loss of sexual interestEkselius 199716200192000.83 [0.41, 1.66]
Sexual problems: otherEkselius 19971320082001.67 [0.68, 4.12]
SweatingEkselius 199734200262001.37 [0.79, 2.38]
TensionEkselius 1997720062001.17 [0.39, 3.55]
Visual problemsEkselius 19976200112000.53 [0.19, 1.47]
Weight gainEkselius 199726200302000.85 [0.48, 1.49]
Citalopram versus other antidepressants
Citalopram vs mirtazapine
DizzinessLeinonen 19996133121370.49 [0.18, 1.35]
FatigueLeinonen 199918133171371.10 [0.54, 2.25]
HeadacheLeinonen 199919133131371.59 [0.75, 3.37]
Influenza-like symptomsLeinonen 1999313371370.43 [0.11, 1.69]
Citalopram vs moclobemide
GastrointestinalCastanedo de Alba 19986225201.13 [0.28, 4.47]
HeadacheCastanedo de Alba 19980222200.16 [0.01, 3.64]
Sexual problems: loss of sexual interestCastanedo de Alba 19980221200.29 [0.01, 7.51]
TremorCastanedo de Alba 19982221201.90 [0.16, 22.72]
Citalopram vs reboxetine
Concentration decreaseLangworth 2006217631810.68 [0.11, 4.13]
ConfusionLangworth 2006117621810.51 [0.05, 5.69]
Decreased weightLangworth 2006117681810.12 [0.02, 1.00]
DizzinessBerlanga 2006135414470.75 [0.31, 1.81]
Emotional indifferenceLangworth 2006117641810.25 [0.03, 2.28]
HeadacheBerlanga 2006; Langworth 200617230272280.50 [0.25, 1.00]
Increased dream activityLangworth 20065176101810.50 [0.17, 1.49]
Increased salivationLangworth 2006017621810.20 [0.01, 4.27]
Influenza-like symptomsLangworth 2006917681811.17 [0.44, 3.09]
Memory impairmentLangworth 2006217631810.68 [0.11, 4.13]
Orthostatic symptomsLangworth 2006417691810.44 [0.13, 1.47]
ParaesthesiaLangworth 2006517651811.03 [0.29, 3.62]
RashLangworth 2006217641810.51 [0.09, 2.81]
Sexual problems: loss of sexual interestLangworth 2006517631811.73 [0.41, 7.37]
TachycardiaLangworth 2006317631811.03 [0.20, 5.17]
TensionLangworth 2006417631811.38 [0.30, 6.26]
TremorLangworth 2006217651810.40 [0.08, 2.11]
Upper respiratory tract infectionLangworth 2006817651811.68 [0.54, 5.23]
VertigoLangworth 20061017681811.30 [0.50, 3.38]
Visual problemsLangworth 2006117641810.25 [0.03, 2.28]
Weight gainBerlanga 2006; Langworth 20062123082282.37 [0.61, 9.19]
Citalopram vs venlafaxine XR
Common coldAllard 20042753760.67 [0.11, 4.11]
DizzinessAllard 20043754760.75 [0.16, 3.47]
Citalopram vs hypericum (St. John's wort)
Dermatological problemsGastpar 2006612741311.57 [0.43, 5.72]
InfectionGastpar 200617127201310.86 [0.43, 1.72]
Musculoskeletal and connective tissue disordersGastpar 2006512761310.85 [0.25, 2.87]

1. CITALOPRAM versus TCAs

PRIMARY OUTCOME
EFFICACY - Number of patients who responded to treatment (six to 12 weeks)

The analysis found no difference in terms of efficacy between citalopram and TCAs in total (OR 1.10, 95% CI 0.75 to 1.63, P = 0.62; 3 trials, 888 participants) nor in head-to-head comparisons (Analysis 1.1).

SECONDARY OUTCOMES
1) EFFICACY - Number of patients who responded to treatment
a) Early response (one to four weeks)

There was no evidence that citalopram was more effective than TCAs in total in terms of early response (OR 0.95, 95% CI 0.46 to 1.98, P = 0.90; 4 trials, 751 participants) (Analysis 2.1). In head-to-head comparisons citalopram was more efficacious than imipramine (OR 0.45, 95% CI 0.24 to 0.86, P = 0.01; one trial, 275 participants; NNTB 4, 95% CI 4 to 25) (Analysis 2.1).

b) Follow-up response (16 to 24 weeks)

There was no evidence that citalopram was more effective than imipramine (Analysis 3.1).

2) EFFICACY - Number of patients who remitted
a) Acute phase treatment (six to 12 weeks)

There was no difference between citalopram and TCAs, neither as a group (5 trials, 256 participants) nor as individual drugs in terms of remission (Analysis 5.1).

b) Early remission (one to four weeks)

There was no difference between citalopram and TCAs, neither as a group (3 trials, 225 participants) nor as individual drugs (see Analysis 4.1).

c) Follow-up remission (16 to 24 weeks)

No data available.

3) EFFICACY - Mean change from baseline
a) Acute phase treatment: between six and 12 weeks

Using rating scale scores, there was no evidence that citalopram was different from TCAs, neither as a group (5 trials, 402 participants) nor as individual drugs (see Analysis 8.1).

b) Early response (one to four weeks)

There was no difference between citalopram and TCAs neither individually nor as a class (see Analysis 7.1).

c) Follow-up response (16 to 24 weeks)

There was no evidence that citalopram was less effective than imipramine (Analysis 9.1).

4) EFFICACY- Social adjustment, social functioning, health-related quality of life, costs to healthcare services

No data available.

5) ACCEPTABILITY - Dropout rate

a) No statistically significant difference was found between citalopram and TCAs in terms of discontinuation due to any cause. However, even though not significant, we observed a trend in favour of citalopram (OR 0.81 95% CI 0.61 to 1.07, P = 0.14; 8 studies, 1209 participants) (Analysis 10.1).

b) No differences were found in terms of discontinuation due to inefficacy (Analysis 12.1).

c) Differences were found in terms of discontinuation due to side effects: patients allocated to citalopram were less likely to withdraw than patients allocated to amitriptyline (OR 0.54, 95% CI 0.34 to 0.87, P = 0.01; 3 studies, 484 participants; NNTH 10, 95% CI 6 to 34) and to TCAs as a group (OR 0.54, 95% CI 0.38 to 0.78, P = 0.001; 8 studies, 1216 participants; NNTH 15, 95% CI 9 to 25) (Analysis 11.1; Figure 3)

Figure 3.

Forest plot of comparison: 11 Failure to complete (side effects), outcome: 11.1 Citalopram versus TCAs.

6) TOLERABILITY

Total number of patients experiencing at least some side effects.

There was evidence that citalopram was associated with a lower rate of adverse events than amitriptyline (OR 0.43, 95% CI 0.28 to 0.65, P < 0.0001; 4 studies, 528 participants; NNTH 8, 95% CI 5 to 15 - Analysis 13.1) and with a higher rate of adverse events than imipramine (OR 1.82, 95% CI 1.14 to 2.89, P = 0.01; 2 studies 517 participants - Analysis 13.1). By contrast, there was no evidence that citalopram was associated with a smaller or higher rate of adverse events than nortriptyline (OR 0.94, 95% CI 0.20 to 4.39; 1 study 43 participants - Analysis 13.1).

Number of patients experiencing specific side effects (only figures for statistically significant differences were reported in the text)

a) Anxiety/agitation

There was no evidence that citalopram was associated with a lower rate of participants experiencing agitation/anxiety than nortriptyline (Analysis 18.1).

b) Constipation

There was evidence that citalopram was associated with a lower rate of participants experiencing constipation than TCAs (OR 0.36, 95% CI 0.24 to 0.55, P < 0.00001; 6 trials, 1018 participants; NNTH 10, 95% CI 6 to 34 - Analysis 30.1). In head-to-head comparison, the difference was statistically significant in favour of citalopram when compared with amitriptyline (OR 0.46, 95% CI 0.23 to 0.90, P = 0.02; 3 studies, 468 participants - Analysis 30.1) and imipramine (OR 0.31, 95% CI 0.18 to 0.53, P < 0.0001; 2 studies, 515 participants; NNTH 7, 95% CI 4 to 15 - Analysis 30.1), respectively.

c) Diarrohea

There was no evidence that citalopram was associated with a different rate of participants experiencing diarrhoea than amitriptyline or imipramine (Analysis 34.1).

d) Dry mouth

There was evidence that citalopram was associated with a lower rate of participants experiencing dry mouth than TCAs (OR 0.25, 95% CI 0.18 to 0.35, P < 0.00001; 7 trials, 1078 participants; NNTH 4, 95% CI 3 to 5 - Analysis 36.1). In head-to-head comparisons, the difference between citalopram and imipramine was statistically significant in favour of citalopram (OR 0.32, 95% CI 0.21 to 0.50, P < 0.00001; 2 trials, 515 participants; NNTH 4, 95% CI 3 to 7); furthermore, citalopram was associated with a lower rate of patients experiencing dry mouth than amitriptyline (OR 0.17, 95% CI 0.10 to 0.28, P < 0.00001; 4 trials, 528 participants; NNTH 4, 95% CI 3 to 5 - Analysis 36.1).

e) Hypotension

Citalopram was associated with lower rate of patients experiencing hypotension than imipramine (OR 0.38, 95% CI 0.19 to 0.75, P = 0.005; 1 trial, 472 participants - Analysis 49.1).

f) Insomnia

There was no evidence that citalopram was associated with a higher rate of participants experiencing insomnia than TCAs (Analysis 54.1).

g) Nausea/vomiting

There was evidence that citalopram was associated with a higher rate of participants experiencing nausea than amitriptyline (OR 2.44, 95% CI 1.27 to 4.66, P = 0.007; 3 trials, 477 participants - Analysis 61.1) and nortriptyline (OR 7.11, 95% CI 1.23 to 40.98; 1 trial, 35 participants - Analysis 61.1 ).

h) Sedation/drowsiness

In head-to-head comparisons, citalopram was associated with a lower rate of patients experiencing sedation/drowsiness than amitriptyline (OR 0.25, 95% CI 0.09 to 0.70, P = 0.009; 2 studies, 112 participants - Analysis 72.1).

i) Sleepiness/somnolence

There was evidence that citalopram was associated with a lower rate of participants experiencing sleepiness/somnolence than TCAs (OR 0.49, 95% CI 0.33 to 0.74, P = 0.0006; 5 trials, 966 participants - Analysis 76.1). In head-to-head comparisons, the difference between citalopram and amitriptyline was statistically significant in favour of citalopram (OR 0.45, 95% CI 0.24 to 0.85, P < 0.00001; 2 trials, 416 participants); furthermore, citalopram was associated with a lower rate of patients experiencing sleepiness than imipramine (OR 0.48, 95% CI 0.27 to 0.83, P = 0.009; 2 studies, 515 participants - Analysis 76.1).

j) Urination problems

There was no evidence that citalopram was associated with a lower rate of participants experiencing urination problems than TCAs (Analysis 83.1).

k) Suicide wishes/gestures/attempts

There was no difference between citalopram and TCAs, neither as a group nor as individual drugs (Analysis 89.1).

l) Deaths (all cause)/Completed suicide

There was no difference between citalopram and imipramine (Analysis 89.3; Analysis 89.4).

m) Other adverse events

Citalopram was associated with a lower rate of participants experiencing sweating (OR 0.50, 95% CI 0.30 to 0.83, P = 0.007; two studies, 515 participants - Analysis 77.1), tachycardia (OR 0.36, 95% CI 0.13 to 0.99, P = 0.05; 2 trials, 515 participants - Analysis 79.1), tremor (OR 0.45, 95% CI 0.25 to 0.80, P = 0.007; 2 studies, 515 participants - Analysis 82.1) and visual problems (OR 0.23, 95% CI 0.06 to 0.84, P = 0.03; 1 study, 43 participants - Analysis 86.1) than imipramine. Citalopram was associated with a lower rate of participants experiencing visual problems (OR 0.14, 95% CI 0.02 to 0.82, P = 0.03; 2 studies, 103 participants - Analysis 86.1) than amitriptyline.

2. CITALOPRAM versus HETEROCYCLICS

PRIMARY OUTCOME
EFFICACY - Number of patients who responded to treatment (six to 12 weeks)

The analysis found no difference in terms of efficacy between citalopram and heterocyclics in total (OR 1.05, 95% CI 0.56 to 1.96, P = 0.88; 2 trials, 432 participants) nor in head-to-head comparisons (Analysis 1.2).

SECONDARY OUTCOMES
1) EFFICACY - Number of patients who responded to treatment
a) Early response (one to four weeks)

No data available.

b) Follow-up response (16 to 24 weeks)

No data available.

2) EFFICACY - Number of patients who remitted
a) Acute phase treatment (six to 12 weeks)

There was no difference between citalopram and heterocyclics, neither as a group (5 trials, 256 participants) nor as individual drugs in terms of remission (Analysis 5.2).

b) Early remission (one to four weeks)

No data available.

c) Follow-up remission (16 to 24 weeks)

No data available.

3) EFFICACY - Mean change from baseline
a) Acute phase treatment: between 6 and 12 weeks

Using rating scale scores, there was no evidence that citalopram was different from heterocyclics, neither as a group (2 trials, 131 participants) nor as individual drugs (Analysis 8.2).

b) Early response (1 to 4 weeks)

There was evidence that citalopram was more effective than mianserin (SMD -0.55, 95% CI -1.07 to -0.02, P = 0.04, 1 trial, 58 participants) (see Analysis 7.2). There was no difference between citalopram and heterocyclics as a class.

c) Follow-up response (16 to 24 weeks)

No data available.

4) EFFICACY- Social adjustment, social functioning, health-related quality of life, costs to healthcare services

No data available.

5) ACCEPTABILITY - Dropout rate

a) No statistically significant difference was found between citalopram and heterocyclics in terms of discontinuation due to any cause (Analysis 10.2), due to inefficacy (Analysis 12.2) or due to side effects (Analysis 11.2)

6) TOLERABILITY

Total number of patients experiencing at least some side effects.

There was no evidence that citalopram was associated with a smaller or higher rate of adverse events than mianserin (OR 0.84, 95% CI 0.52 to 1.37; 1 study, 336 participants - Analysis 13.2).

Number of patients experiencing specific side effects (only figures for statistically significant differences were reported in the text)

a) Anxiety/agitation

There was no evidence that citalopram was associated with a lower rate of participants experiencing agitation/anxiety than heterocyclics (Analysis 18.2).

b) Constipation

There was no evidence that citalopram was associated with a lower rate of participants experiencing constipation than mianserin (Analysis 30.2)

c) Diarrohea

There was no evidence that citalopram was associated with a lower rate of participants experiencing diarrhoea than maprotiline (Analysis 34.1).

d) Dry mouth

There was no evidence that citalopram was associated with a lower rate of participants experiencing diarrhoea than maprotiline (Analysis 36.2).

e) Hypotension

No data available.

f) Insomnia

Citalopram was associated with higher rate of patients experiencing insomnia than mianserin (OR 2.94, 95% CI 1.20 to 7.25; 1 trial, 336 participants - Analysis 54.2).

g) Nausea/vomiting

There was no evidence that citalopram was associated with a higher rate of participants experiencing nausea than heterocyclics (Analysis 61.2).

h) Sedation/drowsiness

There was no evidence that citalopram was associated with a higher rate of participants experiencing nausea than maprotiline (Analysis 72.2).

i) Sleepiness/somnolence

Citalopram was associated with a lower rate of patients experiencing sleepiness than mianserin (OR 0.20, 95% CI 0.04 to 0.94; 1 trial, 336 participants - Analysis 76.2).

j) Urination problems

There was no evidence that citalopram was associated with a higher rate of participants experiencing urination problems than maprotiline (Analysis 83.2).

k) Suicide wishes/gestures/attempts

No data available

l) Deaths (all cause)/Completed suicide

There was no difference between citalopram and maprotiline (Analysis 89.3; Analysis 89.4).

m) Other adverse events

Citalopram was associated with a lower rate of participants experiencing fatigue than mianserin (OR 0.21, 95% CI 0.06 to 0.76, P = 0.02; 1 trial, 336 participants - Analysis 42.2).

3. CITALOPRAM versus other SSRIs

PRIMARY OUTCOME
EFFICACY - Number of patients who responded to treatment (six to 12 weeks)

The analysis found that citalopram was less effective than escitalopram (OR 1.47, 95% CI 1.08 to 2.02, P = 0.02, six trials, 1806 participants; NNTB 13, 95% CI 8 to 34) but more effective than paroxetine (OR 0.65, 95% CI 0.44 to 0.96, P = 0.03, 1 trial, 406 participants; NNTB 9, 95% CI 5 to 100) ( Analysis 1.3; Figure 4).

Figure 4.

Forest plot of comparison: 1 Failure to respond at endpoint (6-12 weeks), outcome: 1.3 Citalopram versus other SSRIs.

SECONDARY OUTCOMES
1) EFFICACY - Number of patients who responded to treatment
a) Early response (one to four weeks)

There was no evidence that citalopram was more effective than other SSRIs (Analysis 2.2).

b) Follow-up response (16 to 24 weeks)

There was no evidence that citalopram was more effective than other SSRIs (Analysis 3.2).

2) EFFICACY - Number of patients who remitted
a) Acute phase treatment (six to 12 weeks)

There was evidence that citalopram was less effective than escitalopram (OR 1.94, 95% CI 1.16 to 3.26, P = 0.01, 5 trials, 1427 participants) (Analysis 5.3).

b) Early remission (one to four weeks)

There was no evidence that citalopram was more effective than other SSRIs (Analysis 4.2).

c) Follow-up remission (16 to 24 weeks)

There was no evidence that citalopram was more effective than other SSRIs (Analysis 6.1).

3) EFFICACY - Mean change from baseline
a) Acute phase treatment: between six and 12 weeks

There was evidence that citalopram was less effective than escitalopram (SMD 0.16, 95% CI 0.05 to 0.27, P = 0.006, 7 trials, 1874 participants) (Analysis 8.3).

b) Early response (one to four weeks)

There was evidence that citalopram was more effective than fluoxetine (SMD -0.15, 95% CI -0.30 to -0.01, P = 0.04, 4 trials, 723 participants) (Analysis 7.3).

c) Follow-up response (16 to 24 weeks)

No data available.

4) EFFICACY- Social adjustment, social functioning, health-related quality of life, costs to healthcare services

No data available.

5) ACCEPTABILITY - Dropout rate

a) There was no difference between patients allocated to citalopram withdrawing from studies than those allocated to other SSRIs for discontinuation due to any cause (Analysis 10.3;).

b) No differences were found in terms of discontinuation due to inefficacy (Analysis 12.3).

c) No differences were found in terms of discontinuation due to side effects (Analysis 11.3).

6) TOLERABILITY

Total number of patients experiencing at least some side effects.

There was no evidence that citalopram was associated with a smaller or higher rate of adverse events than other SSRIs (Analysis 13.3).

Number of patients experiencing specific side effects is reported below.

a) Anxiety/agitation

There was no evidence that citalopram was associated with a lower rate of participants experiencing anxiety/agitation than other SSRIs (Analysis 18.3).

b) Constipation

There was no evidence that citalopram was associated with a lower rate of participants experiencing diarrhoea than other SSRIs (Analysis 30.3).

c) Diarrohea

There was no evidence that citalopram was associated with a lower rate of participants experiencing diarrhoea than other SSRIs (Analysis 34.3).

d) Dry mouth

There was no evidence that citalopram was associated with a lower rate of participants experiencing dry mouth than other SSRIs (Analysis 36.3).

e) Hypotension

There was no evidence that citalopram was associated with a lower rate of participants experiencing hypotension than escitalopram (OR 0.31, 95% CI 0.01 to 7.65; 1 trial, 294 participants) (Analysis 49.2).

f) Insomnia

There was no evidence that citalopram was associated with a lower rate of participants experiencing insomnia than other SSRIs (Analysis 54.3).

g) Nausea/vomiting

There was no evidence that citalopram was associated with a lower rate of participants experiencing nausea or vomiting than other SSRIs (Analysis 61.3).

h) Sedation/drowsiness

There was no evidence that citalopram was associated with a lower rate of participants experiencing sedation/drowsiness than other SSRIs (Analysis 72.3).

i) Sleepiness/somnolence

There was no evidence that citalopram was associated with a lower rate of participants experiencing somnolence than other SSRIs (Analysis 76.3).

j) Urination problems

There was no evidence that citalopram was associated with a higher rate of participants experiencing hypotension than sertraline (OR 1.52, 95% CI 0.42 to 5.45; 1 trial, 400 participants) (Analysis 83.3).

k) Suicide wishes/gestures/attempts

There was no difference between citalopram and other SSRIs (Analysis 89.1; Analysis 89.2).

l) Deaths (all cause)/Completed suicide

There was no difference in suicide rate between citalopram and other SSRIs (two patients committed suicide and both were in the citalopram group: one in a study that compared citalopram with fluvoxamine (Timmerman 1993) and one in a study comparing citalopram with escitalopram (Moore 2005) (Analysis 89.3; Analysis 89.4).

m) Other adverse events

Citalopram was associated with a lower rate of participants experiencing fatigue than escitalopram (OR 0.31, 95% CI 0.12 to 0.84, P = 0.02; 2 trials, 467 participants - Analysis 42.3) and a lower rate of participants experiencing headache than sertraline (OR 0.55, 95% CI 0.33 to 0.91, P = 0.02; 3 trials, 587 participants - Analysis 46.3)

4. CITALOPRAM versus SNRIs, MOAIs, other conventional ADs and non-conventional ADs

PRIMARY OUTCOME
EFFICACY - Number of patients who responded to treatment (six to 12 weeks)

The analysis of primary outcome found that citalopram is more effective than reboxetine (OR 0.63, 95% CI 0.43 to 0.91, P = 0.01, 2 trials, 458 participants; NNTB 9, 95% CI 5 to 50) (Analysis 1.5; Figure 5). No differences were found between citalopram and mirtazapine (Analysis 1.5), venlafaxine (Analysis 1.4) or hypericum (Analysis 1.6)

Figure 5.

Forest plot of comparison: 1 Failure to respond at endpoint (6-12 weeks), outcome: 1.4 Citalopram versus SNRI.

SECONDARY OUTCOMES
1) EFFICACY - Number of patients who responded to treatment
a) Early response (one to four weeks)

There was no evidence that citalopram is more effective than reboxetine (Analysis 2.3).

b) Follow-up response (16 to 24 weeks)

Citalopram is more effective than reboxetine (OR 0.46, 95% CI 0.30 to 0.70, P = 0.0003, 1 trial, 357 participants) (Analysis 3.4).

2) EFFICACY - Number of patients who remitted
a) Acute phase treatment (six to 12 weeks)

Citalopram was more effective than reboxetine (OR 0.59, 95% CI 0.38 to 0.92, P = 0.02, 1 trial, 357 participants; NNTB 9, 95% CI 5 to 50) (Analysis 5.5), but not than venlafaxine (Analysis 5.4).

b) Early remission (one to four weeks)

There was no evidence that citalopram was more effective than reboxetine (Analysis 4.3).

c) Follow-up remission (16 to 24 weeks)

Citalopram was more effective than reboxetine (OR 0.43, 95% CI 0.28 to 0.65, P < 0.0001, 1 trial, 357 participants) (Analysis 6.3), but not than venlafaxine (Analysis 6.2).

3) EFFICACY - Mean change from baseline
a) Acute phase treatment: between six and 12 weeks

There was evidence that citalopram was more efficacious than moclobemide (MD -4.60, 95% CI -8.28 to -0.92, P = 0.01, 1 trial, 40 participants) (Analysis 8.5). In term of efficacy, no difference was found between citalopram and venlafaxine (Analysis 8.4), and citalopram and reboxetine or mirtazapine (Analysis 8.6).

b) Early response (one to four weeks)

No data available.

c) Follow-up response (16 to 24 weeks)

We observed a trend in favour of citalopram compared with reboxetine in term of efficacy, although not statistically significant (MD -1.80, 95% CI -3.62 to 0.02, P < 0.05, 1 trial, 320 participants) (Analysis 9.3).

4) EFFICACY- Social adjustment, social functioning, health-related quality of life, costs to healthcare services

No data available.

5) ACCEPTABILITY - Dropout rate

a) There was no statistically significant difference between patients allocated to citalopram withdrawing from studies than those allocated to reboxetine or hypericum for discontinuation due to any cause (Analysis 10.4; Analysis 10.5). However, even though not significant, we observed a trend in favour of citalopram compared with mirtazapine (OR 0.42, 95% CI 0.18 to 1.01, P = 0.05; 1 study, 270 participants) (Analysis 10.4).

b) No differences were found in terms of discontinuation due to inefficacy between citalopram and mirtazapine or reboxetine (Analysis 12.4).

c) No differences were found in terms of discontinuation due to side effects between citalopram and venlafaxine (Analysis 11.4), mirtazapine or reboxetine (Analysis 11.5).

6) TOLERABILITY

Total number of patients experiencing at least some side effects.

We found that citalopram was associated with a lower rate of patients experiencing side effects than reboxetine (OR 0.64, 95% CI 0.42 to 0.97, P < 0.04; 1 trial, 357 participants) (Analysis 13.6) and than venlafaxine XR (OR 0.46, 95% CI 0.24 to 0.88, P < 0.02; 1 trial, 151 participants) (Analysis 13.4). By contrast, we found that citalopram was associated with a higher rate of patients experiencing side effects than hypericum (OR 1.69, 95% CI 1.01 to 2.83; 1 trial, 258 participants) (Analysis 13.7). No differences were found between citalopram and moclobemide (Analysis 13.5) or mirtazapine (Analysis 13.6).

Number of patients experiencing specific side effects is reported below.

a) Anxiety/agitation

No data available.

b) Constipation

There was evidence that citalopram was associated with a lower rate of participants experiencing constipation than reboxetine (OR 0.06, 95% CI 0.00 to 0.90, P < 0.04; 2 trials, 458 participants) (Analysis 30.5).

c) Diarrohea

There was no evidence that citalopram was associated with a lower rate of participants experiencing diarrhoea than mirtazapine or reboxetine (Analysis 34.4).

d) Dry mouth

There was no evidence that citalopram was associated with a lower rate of participants experiencing dry mouth than venlafaxine (Analysis 36.4) or mirtazapine (Analysis 36.5).

e) Hypotension

No data available.

f) Insomnia

There was no evidence that citalopram was associated with a lower rate of participants experiencing insomnia than moclobemide (Analysis 54.4) or reboxetine (Analysis 54.5).

g) Nausea/vomiting

There was evidence that citalopram was associated with a higher rate of participants experiencing nausea than mirtazapine (OR 2.24, 95% CI 1.12 to 4.49, P = 0.02; 1 trial, 270 participants), but not than reboxetine (Analysis 61.4).

h) Sedation/drowsiness

There was no evidence that citalopram was associated with a lower rate of participants experiencing somnolence than mirtazapine or reboxetine (Analysis 72.4).

i) Sleepiness/somnolence

There was no evidence that citalopram was associated with a lower rate of participants experiencing sedation/drowsiness than moclobemide (Analysis 76.4) or reboxetine (Analysis 76.5).

j) Urination problems

There was no evidence that citalopram was associated with a lower rate of subjects experiencing urination problems than reboxetine (Analysis 83.4.

k) Suicide wishes/gestures/attempts

No data available.

l) Deaths (all cause)/Completed suicide

No data available.

l) Other adverse events

In comparison with hypericum, citalopram was associated with a higher rate of patients experiencing gastrointestinal problems (OR 2.41, 95% CI 1.12 to 5.18, P = 0.02; 1 trial, 258 participants) (Analysis 45.4) and vertigo (OR 6.12, 95% CI 1.33 to 28.17, P = 0.02; 1 trial, 258 participants) (Analysis 85.3). Citalopram was associated with a lower rate of participants experiencing appetite increase (OR 0.16, 95% CI 0.03 to 0.72, P = 0.02; 1 trial, 270 participants) (Analysis 19.2) and weight gain (OR 0.26, 95% CI 0.10 to 0.67, P = 0.005; 1 trial, 270 participants) (Analysis 87.2) than mirtazapine, but it was associated with a higher rate of participants experiencing sweating (OR 7.91, 95% CI 2.29 to 27.29, P = 0.001; 1 trial, 270 participants) (Analysis 77.4). Citalopram was associated with a lower rate of participants experiencing reduced salivation (OR 0.31, 95% CI 0.14 to 0.67, P = 0.003; 1 trial, 357 participants) (Analysis 71.1) and sweating (OR 0.38, 95% CI 0.16 to 0.90, P = 0.03; 1 trial, 357 participants) (Analysis 77.4) than reboxetine, but it was associated with a higher rate of participants with orgastic dysfunction (OR 3.74, 95% CI 1.56 to 8.95, P = 0.003; 1 trial, 357 participants) (Analysis 75.5), and with other sexual problems (OR 8.65, 95% CI 1.86 to 40.22, P = 0.006; 1 trial, 101 participants) (Analysis 75.6).

SUBGROUP ANALYSES

1) Citalopram dosing
All studies used citalopram within the standard therapeutic range (20 to 60 mg/day). Only in one study were investigators allowed to use citalopram up to 80 mg/day, but the mean dose was below 60 mg/day (de Wilde 1985). Therefore, it was not meaningful to carry out this pre-planned subgroup analysis.

2) Comparator dosing
All comparator doses were within the therapeutic range. Due to the small number of trials outside the therapeutic range, it was not considered meaningful to carry out this pre-planned subgroup analysis.

3) Depression severity
The great majority of studies reported a mean baseline score corresponding to moderate to severe major depression. Therefore, it was not meaningful to carry out this pre-planned subgroup analysis.

4) Treatment settings
Only three studies selectively recruited patients in general practice (Bougerol 1997b; Ekselius 1997; Lewis 2011) and only three studies enrolled only in-patients (Andersen 1986; de Wilde 1985; Hosak 1999), therefore, it was not considered meaningful to carry out this pre-planned subgroup analysis.

5) Elderly patients
As only three studies specifically recruited elderly patients (Karlsson 2000; Kyle 1998; Navarro 2001), it was not meaningful to carry out this pre-planned subgroup analysis.

FUNNEL PLOT ANALYSIS

Where available, the funnel plot analyses did not suggest evidence of publication bias, however, for many comparisons the presence of publication bias was not examined because there were insufficient trials to allow meaningful formal assessment using funnel plots.

SENSITIVITY ANALYSES

1) Excluding trials with unclear concealment of random allocation and/or unclear double blinding
Although technically possible to carry out these sensitivity analyses, they were not performed, because they would not have contributed useful information due to the small number of studies (only two trials) reporting clear details on concealment of random allocation (Colonna 2005; Ou 2010). About 20% of studies were not double-blind (about one fifth), however they compared many different compounds with citalopram, so a sensitivity analysis excluding those studies from the analysis was not meaningful because it would not have been informative.

2) Excluding trials whose dropout rate was greater than 20%
Overall, in 16 studies dropout rate was less than 20% in each arm (Bougerol 1997b; de Wilde 1985; Gastpar 2006; Gravem 1987; Hosak 1999; Hsu 2011; Karlsson 2000; Khanzode 2003; Lalit 2004; Leinonen 1999; Lepola 2003; Lewis 2011; Matreja 2007; Moore 2005; Ou 2010; Yevtushenko 2007). However, excluding trials whose dropout rate was greater than 20% from the analysis did not materially change the results.

3) Performing the worst- and best-case scenario analysis
Results from these sensitivity analyses did not materially change the main findings (full details available on request from authors).

4) Excluding trials for which imputation methods were used
a) Imputed response rate

Excluding trials for which the response rate had to be calculated based on the imputation method, results for all comparisons did not materially change.
b) Imputed remission rate
We did not impute remission rates.
c) Borrowed SDs
Excluding trials for which the SDs had to be borrowed from other trials, results for all comparisons did not materially change.

5) Examination of “wish bias” and exclusion of studies funded by the pharmaceutical company marketing citalopram
These pre-planned sensitivity analyses were not carried out because we found only a few studies per comparison.

6) Excluding studies that included patients with bipolar depression or psychotic features

After discussion within the review group, we decided not to carry out these two pre-planned subgroup analyses, because only three studies included bipolar patients (Bougerol 1997a; Hosak 1999; Timmerman 1993) and only one study patients with psychotic symptoms (Navarro 2001).

Discussion

Summary of main results

This systematic review and meta-analysis included 37 trials that compared citalopram versus other antidepressants in terms of efficacy and tolerability. The included studies did not report on all the outcomes that were pre-specified in the protocol of this review and only a small number of trials per comparison was found for most ADs (with the exception of escitalopram). The present review showed that citalopram should be considered for treating depression because it was significantly more effective than other ADs (reboxetine and paroxetine) and appeared to be more acceptable than other AD, like tricyclics. The finding that citalopram was less effective than escitalopram should be carefully interpreted considering that all trials included in this comparison were sponsored by the manufacturer of both drugs, and therefore, the possibility of wish bias cannot be ruled out (Barbui 2004). The dataset of the present review collected insufficient randomised evidence to detect a difference in early response to treatment (within four weeks of treatment). Looking at the data reported in the trials included in this systematic review, the question on comparative efficacy of early onset response has yet to be proven and remains a matter of ongoing debate (Gourion 2008).

Overall completeness and applicability of evidence

It has long been argued that placebo controlled trials are required to adequately demonstrate the efficacy of novel antidepressant drugs (Cipriani 2009a), however, in the present review we focused only on the comparison between citalopram and other active treatments. Retrieved randomised evidence compared citalopram with a selection of possible comparator antidepressants but only a few studies per comparison were found. Although the search was thorough, it is still possible that there are unpublished studies that have not been identified but the small number of trials identified per comparison hinders the detection of any publication bias. Although we did our very best to retrieve as much data as possible, through asking pharmaceutical companies and study authors to supply all available information, we can assume that data from some trials are still lacking, most of which are likely to be studies with negative findings. We are also aware of the possibility that a number of additional randomised controlled trials (RCTs) comparing citalopram with other antidepressant drugs are currently being conducted and will be included in future updates of the review.

Quality of the evidence

All included studies were RCTs and were very similar in design and conduct. Using high-quality research evidence is relevant to review results and to speed translation of research in a way that really responds to clinically relevant questions. However, the quality of RCTs is not easy to assess and the problem of study quality is relevant for interpreting results and for usefulness of results in practice. Despite the fact that RCTs are the best methodological standards for clinical research, included studies failed to report key methodological issues. For example, the majority of trials still do not report adequate information about methods of randomisation and allocation concealment. The reporting of the outcomes in the included studies was often unclear or incomplete and the figures used for the analyses not immediately understandable. The scant information about randomisation and allocation concealment may be a matter of reporting in the text rather than real defects in study design. However, sometimes there were some discrepancies between published reports and unpublished data available on the websites of the pharmaceutical industries. When dealing with summary statistics, the quality of information is important. Meta-analyses of poor quality studies may be seriously misleading (Ioannidis 2005), because the bias associated with defects in the conduct of primary studies (randomised trials) can seriously affect overall estimates of intervention. Systematic reviewers (not only within The Cochrane Collaboration) should routinely assess the risk of bias in the results of trials, and should report meta-analyses restricted to trials at low risk of bias (Wood 2008).

Potential biases in the review process

Some possible limitations of this review should be noted.

  • We had to impute the response rate, our primary outcome, for some of the included trials. However, we consider that imputation of response and remission rates by a validated statistical method (Furukawa 2006) in our review should minimize the risk of bias. Nevertheless, we regret that we were unable to do a sensitivity analysis excluding trials with imputed response rates. As we update this review and assemble more trials involving citalopram, we hope to conduct such a sensitivity analysis and be able to examine if our conclusions are robust.

  • By making multiple comparisons we might have committed a type 1 error, that is, identifying and reporting a spurious association. As stated in the review protocol, we did not carry out a Bonferroni correction. As many statistical tests have been used in the review, the findings from this review are better thought of as hypothesis forming rather than hypothesis testing and it would be very comforting to see the conclusions replicated in future trials.

  • Pharmaceutical industry sponsor. Most of included studies were sponsored by the drug industry, and these have been shown to be more than four times likely to demonstrate positive effects of the sponsors' drug as independent studies (Lexchin 2003). The sponsorship bias may play a role also in the issue related to the comparison between citalopram and escitalopram (Leonard 2010). Citalopram is the racemic mixture of S-citalopram and R-citalopram and escitalopram is the S-enantiomer of the racemate citalopram (Sanchez 2004). As for all other new investigational compounds, the potential for overestimation of treatment effect due to sponsorship bias should be borne in mind, as we found marked heterogeneity for the escitalopram comparisons. So, results reported for comparative efficacy favouring escitalopram have therefore to be viewed with caution because a possible inflation of efficacy in favour of escitalopram cannot be ruled out. We asked Lundbeck to have access to individual patient data and we are still waiting for a reply (last contact via e-mail correspondence: June 2010)

  • Economic evaluation. In the present review only one RCT reported economic outcomes (Hosak 1999). The authors concluded that limitation of prescription of SSRIs in Czech Republic by health insurance companies did not appear to lead to cost savings, while it may have led to unnecessary patients' suffering due to adverse events of TCAs. Given that several SSRIs and the great majority of antidepressants are now available as generic formulation (only escitalopram and duloxetine are still on patent), more comprehensive economic estimates of antidepressant treatment effect should be considered to better inform healthcare policy.

  • In this review we decided to focus on treatment response because it is one of the main goals for the treatment of major depressive disorder. The term “treatment response” describes a state of improvement in the patient’s condition of sufficient quality to result in treating the physician’s impression of at least a moderate degree of global improvement, conventionally defined as a reduction of at least 50% in depressive symptomatology. However, from a clinical point of view, the ultimate goal of the acute treatment phase of major depressive disorder may well be to achieve remission. Full remission from depression correlates with better longer-term functional recovery, lower risk of relapse and higher level of patients satisfaction than partial response (without remission). Thus, one important limitation of the included trials (and consequently of the present review) is that only a few studies reported remission rates, underpowering the analysis and undermining the possibility to find significant differences between comparisons. Moreover, outcomes of clear relevance to patients and clinicians, in particular, patients’ and their carers’ attitudes to treatment, their ability to return to work and resume normal social functioning, were not reported in the included studies.

  • In this review we included only RCTs. As debate in the scientific literature, one of the main limitations of efficacy trials is to include patients far from “real world” (Rothwell 2005). When drafting the systematic review protocol, we did our best to include as much evidence as possible to inform clinical practice, balancing internal with external validity (Cipriani 2009d). This is the reason why we included single-blind or non-blind randomised studies, but on the other hand, decided to exclude patients with medical comorbidity.

  • As expected, in this review only a few studies reported data about suicide and deliberate self-harm (Geddes 2004). Deliberate self-harm, particularly suicide, is often thought to be a relatively “hard” outcome in studies of antidepressants, but enormous scope exists for ascertainment bias. Observational evidence offers insights into long-term and real-world outcomes for large groups of people, but it can rarely show a convincing causal relation between two events (Cipriani 2007). Systematic reviews of randomised controlled trials may increase statistical power, but absolute numbers of patients having rare adverse events such as completed or attempted suicide are low. Thus, reporting or not reporting a few cases can completely change the overall outcome (Cipriani 2005b).

Agreements and disagreements with other studies or reviews

Even though it is matter of ongoing discussion in the scientific literature (Gartlehner 2010; Gartlehner 2011), there is now robust evidence that there are statistically and clinically significant differences among antidepressants (Cipriani 2009a). Results from this review are consistent with this interpretation and might contribute to developing and keeping up to date an evidence-based hierarchy of antidepressants to be used by clinicians (both specialists and general practitioners) (Barbui 2011). Even though citalopram was not among the best treatments in terms of efficacy, it scored well in terms of acceptability and remains an important option for physicians when an AD is to be prescribed for moderate-to-severe major depression.

Authors' conclusions

Implications for practice

Citalopram appears to be a suitable option to be used for moderate-to-severe acute major depression because it showed to be more effective than other antidepressants (namely, paroxetine and reboxetine) and it was overall well tolerated.

Implications for research

Results described in this systematic review come from a set of randomised studies that are in many cases financially supported by pharmaceutical industries. Industry-sponsored trials tend to follow a standard design which involves short-term, double-blind, parallel-group studies of patients with acute episodes or exacerbations of chronic illness. Moreover, it is known that economic support by drug manufacturer can strongly influence progress of research and its results. Consequently, there is a risk that these studies do not provide sufficient and adequate information to clinicians in real-world settings. Studies should be conducted with the intent of provide clinicians with useful practical data regarding the comparative effectiveness of marketed medications, and consider rating scale but also pragmatic outcome measures (for example hospitalisations, return to work, social functioning and so on). Considering the methodological limitation of standard systematic reviews that rely only on evidence from direct comparisons and given the wide spectrum of available comparisons for the treatment of major depression, the use of the methodology of multiple treatments meta-analysis (MTM) may provide a more informative and clinically useful summary of the results that can be used to guide treatment decisions.

Acknowledgements

The authors would like to thank Julian Higgins and Georgia Salanti for their helpful comments and feedback on the review protocol. We also would like to thank all authors that provided additional data to be used in the present report and especially Drs. Ladislav Hosak, Sidney Kennedy, Sven Langworth, Glyn Lewis, Stephen Stahl and Thomas Werge. We are grateful to the Fondazione Cariverona, who provided a three-year Grant to the WHO Collaborating Centre for Research and Training in Mental Health and Service Organisation at the University of Verona, directed by Professor Michele Tansella. The authors would also like to acknowledge and thank Hugh McGuire for his excellent editorial input on this and other MANGA reviews.

Data and analyses

Download statistical data

Comparison 1. Failure to respond at endpoint (6-12 weeks)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs3888Odds Ratio (M-H, Random, 95% CI)1.10 [0.75, 1.63]
1.1 Versus Amitriptyline2416Odds Ratio (M-H, Random, 95% CI)1.44 [0.54, 3.87]
1.2 Versus Imipramine1472Odds Ratio (M-H, Random, 95% CI)1.00 [0.64, 1.58]
2 Citalopram versus heterocyclics2432Odds Ratio (M-H, Random, 95% CI)1.05 [0.56, 1.96]
2.1 Versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)0.67 [0.27, 1.62]
2.2 Versus Mianserin1336Odds Ratio (M-H, Random, 95% CI)1.31 [0.85, 2.04]
3 Citalopram versus other SSRIs13 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Versus Escitalopram61806Odds Ratio (M-H, Random, 95% CI)1.47 [1.08, 2.02]
3.2 Versus Fluoxetine2673Odds Ratio (M-H, Random, 95% CI)1.03 [0.75, 1.43]
3.3 Versus Fluvoxamine1217Odds Ratio (M-H, Random, 95% CI)0.90 [0.50, 1.62]
3.4 Versus Paroxetine1406Odds Ratio (M-H, Random, 95% CI)0.65 [0.44, 0.96]
3.5 Versus Sertraline3551Odds Ratio (M-H, Random, 95% CI)0.53 [0.20, 1.42]
4 Citalopram versus SNRI1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 Versus Venlafaxine XR1151Odds Ratio (M-H, Random, 95% CI)0.91 [0.46, 1.78]
5 Citalopram versus other conventional ADs3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
5.1 Versus Mirtazapine1270Odds Ratio (M-H, Random, 95% CI)0.76 [0.38, 1.52]
5.2 Versus Reboxetine2458Odds Ratio (M-H, Random, 95% CI)0.63 [0.43, 0.91]
6 Citalopram versus non-conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
6.1 Versus Hypericum (St. John's wort)1258Odds Ratio (M-H, Random, 95% CI)0.93 [0.57, 1.52]
Analysis 1.1.

Comparison 1 Failure to respond at endpoint (6-12 weeks), Outcome 1 Citalopram versus TCAs.

Analysis 1.2.

Comparison 1 Failure to respond at endpoint (6-12 weeks), Outcome 2 Citalopram versus heterocyclics.

Analysis 1.3.

Comparison 1 Failure to respond at endpoint (6-12 weeks), Outcome 3 Citalopram versus other SSRIs.

Analysis 1.4.

Comparison 1 Failure to respond at endpoint (6-12 weeks), Outcome 4 Citalopram versus SNRI.

Analysis 1.5.

Comparison 1 Failure to respond at endpoint (6-12 weeks), Outcome 5 Citalopram versus other conventional ADs.

Analysis 1.6.

Comparison 1 Failure to respond at endpoint (6-12 weeks), Outcome 6 Citalopram versus non-conventional ADs.

Comparison 2. Failure to respond (1-4 weeks)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs4751Odds Ratio (M-H, Random, 95% CI)0.95 [0.46, 1.98]
1.1 versus Amitriptyline3476Odds Ratio (M-H, Random, 95% CI)1.33 [0.76, 2.31]
1.2 versus Imipramine1275Odds Ratio (M-H, Random, 95% CI)0.45 [0.24, 0.86]
2 Citalopram versus other SSRIs4 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Versus Escitalopram1143Odds Ratio (M-H, Random, 95% CI)1.46 [0.75, 2.82]
2.2 Versus Fluoxetine2416Odds Ratio (M-H, Random, 95% CI)0.89 [0.34, 2.34]
2.3 Versus Sertraline2245Odds Ratio (M-H, Random, 95% CI)1.14 [0.60, 2.15]
3 Citalopram versus other conventional antidepressants2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus Reboxetine2458Odds Ratio (M-H, Random, 95% CI)0.87 [0.27, 2.75]
Analysis 2.1.

Comparison 2 Failure to respond (1-4 weeks), Outcome 1 Citalopram versus TCAs.

Analysis 2.2.

Comparison 2 Failure to respond (1-4 weeks), Outcome 2 Citalopram versus other SSRIs.

Analysis 2.3.

Comparison 2 Failure to respond (1-4 weeks), Outcome 3 Citalopram versus other conventional antidepressants.

Comparison 3. Failure to respond (16-24 weeks)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus Imipramine1472Odds Ratio (M-H, Random, 95% CI)1.09 [0.69, 1.72]
2 Citalopram versus other SSRIs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Versus Escitalopram1357Odds Ratio (M-H, Random, 95% CI)1.04 [0.64, 1.68]
2.2 Versus Sertraline1400Odds Ratio (M-H, Random, 95% CI)0.72 [0.45, 1.17]
3 Citalopram versus SNRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Versus Venlafaxine XR1151Odds Ratio (M-H, Random, 95% CI)0.89 [0.44, 1.82]
4 Citalopram versus other conventional antidepressants1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 versus Reboxetine1357Odds Ratio (M-H, Random, 95% CI)0.46 [0.30, 0.70]
Analysis 3.1.

Comparison 3 Failure to respond (16-24 weeks), Outcome 1 Citalopram versus TCAs.

Analysis 3.2.

Comparison 3 Failure to respond (16-24 weeks), Outcome 2 Citalopram versus other SSRIs.

Analysis 3.3.

Comparison 3 Failure to respond (16-24 weeks), Outcome 3 Citalopram versus SNRIs.

Analysis 3.4.

Comparison 3 Failure to respond (16-24 weeks), Outcome 4 Citalopram versus other conventional antidepressants.

Comparison 4. Failure to remission (1-4 weeks)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs3225Odds Ratio (M-H, Random, 95% CI)2.13 [0.98, 4.63]
1.1 versus Amitriptyline2111Odds Ratio (M-H, Random, 95% CI)2.29 [0.81, 6.48]
1.2 versus Clomipramine1114Odds Ratio (M-H, Random, 95% CI)1.95 [0.61, 6.23]
2 Citalopram versus other SSRIs4 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Versus Escitalopram1143Odds Ratio (M-H, Random, 95% CI)1.53 [0.75, 3.15]
2.2 Versus Fluoxetine3732Odds Ratio (M-H, Random, 95% CI)0.78 [0.56, 1.10]
2.3 Versus Sertraline1145Odds Ratio (M-H, Random, 95% CI)1.86 [0.89, 3.88]
3 Citalopram versus other conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus Reboxetine1357Odds Ratio (M-H, Random, 95% CI)0.75 [0.27, 2.05]
Analysis 4.1.

Comparison 4 Failure to remission (1-4 weeks), Outcome 1 Citalopram versus TCAs.

Analysis 4.2.

Comparison 4 Failure to remission (1-4 weeks), Outcome 2 Citalopram versus other SSRIs.

Analysis 4.3.

Comparison 4 Failure to remission (1-4 weeks), Outcome 3 Citalopram versus other conventional ADs.

Comparison 5. Failure to remission (6-12 weeks)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs5256Odds Ratio (M-H, Random, 95% CI)1.32 [0.77, 2.26]
1.1 versus Amitriptyline2110Odds Ratio (M-H, Random, 95% CI)1.05 [0.48, 2.32]
1.2 versus Nortriptyline2101Odds Ratio (M-H, Random, 95% CI)2.06 [0.81, 5.29]
1.3 versus Imipramine145Odds Ratio (M-H, Random, 95% CI)1.09 [0.34, 3.51]
2 Citalopram versus heterocyclics2156Odds Ratio (M-H, Random, 95% CI)0.66 [0.35, 1.24]
2.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)0.71 [0.31, 1.60]
2.2 versus Mianserin160Odds Ratio (M-H, Random, 95% CI)0.58 [0.21, 1.62]
3 Citalopram versus other SSRIs10 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Versus Escitalopram51427Odds Ratio (M-H, Random, 95% CI)1.94 [1.16, 3.26]
3.2 Versus Fluoxetine2673Odds Ratio (M-H, Random, 95% CI)0.94 [0.63, 1.42]
3.3 Versus Fluvoxamine1217Odds Ratio (M-H, Random, 95% CI)0.56 [0.23, 1.34]
3.4 Versus Sertraline2151Odds Ratio (M-H, Random, 95% CI)0.56 [0.29, 1.08]
4 Citalopram versus SNRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 Versus Venlafaxine XR1151Odds Ratio (M-H, Random, 95% CI)0.66 [0.34, 1.26]
5 Citalopram versus other conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
5.1 versus Reboxetine1357Odds Ratio (M-H, Random, 95% CI)0.59 [0.38, 0.92]
Analysis 5.1.

Comparison 5 Failure to remission (6-12 weeks), Outcome 1 Citalopram versus TCAs.

Analysis 5.2.

Comparison 5 Failure to remission (6-12 weeks), Outcome 2 Citalopram versus heterocyclics.

Analysis 5.3.

Comparison 5 Failure to remission (6-12 weeks), Outcome 3 Citalopram versus other SSRIs.

Analysis 5.4.

Comparison 5 Failure to remission (6-12 weeks), Outcome 4 Citalopram versus SNRIs.

Analysis 5.5.

Comparison 5 Failure to remission (6-12 weeks), Outcome 5 Citalopram versus other conventional ADs.

Comparison 6. Failure to remission (16-24 weeks)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Versus Escitalopram1357Odds Ratio (M-H, Random, 95% CI)1.17 [0.74, 1.84]
2 Citalopram versus SNRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Versus Venlafaxine XR1151Odds Ratio (M-H, Random, 95% CI)0.77 [0.35, 1.70]
3 Citalopram versus other conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus Reboxetine1357Odds Ratio (M-H, Random, 95% CI)0.43 [0.28, 0.65]
Analysis 6.1.

Comparison 6 Failure to remission (16-24 weeks), Outcome 1 Citalopram versus other SSRIs.

Analysis 6.2.

Comparison 6 Failure to remission (16-24 weeks), Outcome 2 Citalopram versus SNRIs.

Analysis 6.3.

Comparison 6 Failure to remission (16-24 weeks), Outcome 3 Citalopram versus other conventional ADs.

Comparison 7. Standardised mean difference (1-4 weeks)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs4174Std. Mean Difference (IV, Random, 95% CI)0.10 [-0.20, 0.40]
1.1 versus Amitriptyline291Std. Mean Difference (IV, Random, 95% CI)0.03 [-0.38, 0.44]
1.2 versus Nortriptyline283Std. Mean Difference (IV, Random, 95% CI)0.22 [-0.35, 0.79]
2 Citalopram versus heterocyclics2150Std. Mean Difference (IV, Random, 95% CI)-0.22 [-0.81, 0.37]
2.1 versus Maprotiline192Std. Mean Difference (IV, Random, 95% CI)0.06 [-0.35, 0.47]
2.2 versus Mianserin158Std. Mean Difference (IV, Random, 95% CI)-0.55 [-1.07, -0.02]
3 Citalopram versus other SSRIs9 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
3.1 versus Escitalopram3657Std. Mean Difference (IV, Random, 95% CI)0.09 [-0.07, 0.24]
3.2 versus Fluoxetine4723Std. Mean Difference (IV, Random, 95% CI)-0.15 [-0.30, -0.01]
3.3 versus Sertraline3287Std. Mean Difference (IV, Random, 95% CI)-0.25 [-0.76, 0.25]
4 Citalopram versus other conventional ADs1 Mean Difference (IV, Random, 95% CI)Subtotals only
4.1 versus Reboxetine1317Mean Difference (IV, Random, 95% CI)-1.5 [-2.76, -0.24]
Analysis 7.1.

Comparison 7 Standardised mean difference (1-4 weeks), Outcome 1 Citalopram versus TCAs.

Analysis 7.2.

Comparison 7 Standardised mean difference (1-4 weeks), Outcome 2 Citalopram versus heterocyclics.

Analysis 7.3.

Comparison 7 Standardised mean difference (1-4 weeks), Outcome 3 Citalopram versus other SSRIs.

Analysis 7.4.

Comparison 7 Standardised mean difference (1-4 weeks), Outcome 4 Citalopram versus other conventional ADs.

Comparison 8. Standardised mean difference at endpoint (6-12 weeks)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs5402Std. Mean Difference (IV, Random, 95% CI)0.06 [-0.15, 0.26]
1.1 versus Amitriptyline144Std. Mean Difference (IV, Random, 95% CI)-0.07 [-0.66, 0.53]
1.2 versus Imipramine2289Std. Mean Difference (IV, Random, 95% CI)-0.03 [-0.27, 0.22]
1.3 versus Nortriptyline269Std. Mean Difference (IV, Random, 95% CI)0.46 [-0.02, 0.94]
2 Citalopram versus heterocyclics2131Std. Mean Difference (IV, Random, 95% CI)-0.18 [-0.65, 0.29]
2.1 versus Maprotiline173Std. Mean Difference (IV, Random, 95% CI)0.04 [-0.42, 0.50]
2.2 versus Mianserin158Std. Mean Difference (IV, Random, 95% CI)-0.44 [-0.96, 0.09]
3 Citalopram versus other SSRIs163610Std. Mean Difference (IV, Random, 95% CI)-.00 [-0.11, 0.10]
3.1 versus Escitalopram71872Std. Mean Difference (IV, Random, 95% CI)0.16 [0.05, 0.27]
3.2 versus Fluoxetine3672Std. Mean Difference (IV, Random, 95% CI)-0.17 [-0.46, 0.11]
3.3 versus Fluvoxamine1162Std. Mean Difference (IV, Random, 95% CI)-0.19 [-0.50, 0.12]
3.4 versus Paroxetine1201Std. Mean Difference (IV, Random, 95% CI)-0.11 [-0.39, 0.16]
3.5 versus Sertraline4703Std. Mean Difference (IV, Random, 95% CI)-0.13 [-0.31, 0.04]
4 Citalopram versus SNRIs1 Mean Difference (IV, Random, 95% CI)Subtotals only
4.1 versus Venlafaxine XR1148Mean Difference (IV, Random, 95% CI)-0.5 [-2.93, 1.93]
5 Citalopram versus MAOIs or newer ADs1 Mean Difference (IV, Random, 95% CI)Subtotals only
5.1 versus Moclobemide140Mean Difference (IV, Random, 95% CI)-4.6 [-8.28, -0.92]
6 Citalopram versus other conventional ADs3 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
6.1 versus Mirtazapine1269Std. Mean Difference (IV, Random, 95% CI)-0.02 [-0.26, 0.22]
6.2 versus Reboxetine2866Std. Mean Difference (IV, Random, 95% CI)-0.15 [-0.33, 0.04]
Analysis 8.1.

Comparison 8 Standardised mean difference at endpoint (6-12 weeks), Outcome 1 Citalopram versus TCAs.

Analysis 8.2.

Comparison 8 Standardised mean difference at endpoint (6-12 weeks), Outcome 2 Citalopram versus heterocyclics.

Analysis 8.3.

Comparison 8 Standardised mean difference at endpoint (6-12 weeks), Outcome 3 Citalopram versus other SSRIs.

Analysis 8.4.

Comparison 8 Standardised mean difference at endpoint (6-12 weeks), Outcome 4 Citalopram versus SNRIs.

Analysis 8.5.

Comparison 8 Standardised mean difference at endpoint (6-12 weeks), Outcome 5 Citalopram versus MAOIs or newer ADs.

Analysis 8.6.

Comparison 8 Standardised mean difference at endpoint (6-12 weeks), Outcome 6 Citalopram versus other conventional ADs.

Comparison 9. Standardised mean difference (16-24 weeks)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs1 Mean Difference (IV, Random, 95% CI)Subtotals only
1.1 versus Imipramine1168Mean Difference (IV, Random, 95% CI)0.90 [-1.02, 2.82]
2 Citalopram versus SNRIs1 Mean Difference (IV, Random, 95% CI)Subtotals only
2.1 versus Venlafaxine XR1148Mean Difference (IV, Random, 95% CI)0.0 [-2.61, 2.61]
3 Citalopram versus other conventional ADs1 Mean Difference (IV, Random, 95% CI)Subtotals only
3.1 versus Reboxetine1320Mean Difference (IV, Random, 95% CI)-1.80 [-3.62, 0.02]
Analysis 9.1.

Comparison 9 Standardised mean difference (16-24 weeks), Outcome 1 Citalopram versus TCAs.

Analysis 9.2.

Comparison 9 Standardised mean difference (16-24 weeks), Outcome 2 Citalopram versus SNRIs.

Analysis 9.3.

Comparison 9 Standardised mean difference (16-24 weeks), Outcome 3 Citalopram versus other conventional ADs.

Comparison 10. Failure to complete (any cause)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs81209Odds Ratio (M-H, Random, 95% CI)0.81 [0.61, 1.07]
1.1 versus Amitriptyline4535Odds Ratio (M-H, Random, 95% CI)0.70 [0.47, 1.04]
1.2 versus Clomipramine1114Odds Ratio (M-H, Random, 95% CI)1.63 [0.61, 4.36]
1.3 versus Imipramine2517Odds Ratio (M-H, Random, 95% CI)0.88 [0.55, 1.41]
1.4 versus Nortriptyline143Odds Ratio (M-H, Random, 95% CI)0.63 [0.19, 2.08]
2 Citalopram versus heterocyclics3492Odds Ratio (M-H, Random, 95% CI)0.75 [0.46, 1.22]
2.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)0.82 [0.35, 1.96]
2.2 versus Mianserin2396Odds Ratio (M-H, Random, 95% CI)0.72 [0.40, 1.29]
3 Citalopram versus other SSRIs18 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Versus Escitalopram82206Odds Ratio (M-H, Random, 95% CI)0.92 [0.64, 1.31]
3.2 Versus Fluoxetine4799Odds Ratio (M-H, Random, 95% CI)1.16 [0.81, 1.67]
3.3 Versus Fluvoxamine1217Odds Ratio (M-H, Random, 95% CI)0.71 [0.37, 1.33]
3.4 Versus Paroxetine1406Odds Ratio (M-H, Random, 95% CI)1.01 [0.62, 1.63]
3.5 Versus Sertraline5911Odds Ratio (M-H, Random, 95% CI)0.74 [0.51, 1.08]
4 Citalopram versus other conventional ADs5 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 versus Reboxetine41095Odds Ratio (M-H, Random, 95% CI)0.71 [0.42, 1.21]
4.2 versus Mirtazapine1270Odds Ratio (M-H, Random, 95% CI)0.42 [0.18, 1.01]
5 Citalopram versus non-conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
5.1 versus Hypericum (St. John's wort)1258Odds Ratio (M-H, Random, 95% CI)3.01 [0.93, 9.72]
Analysis 10.1.

Comparison 10 Failure to complete (any cause), Outcome 1 Citalopram versus TCAs.

Analysis 10.2.

Comparison 10 Failure to complete (any cause), Outcome 2 Citalopram versus heterocyclics.

Analysis 10.3.

Comparison 10 Failure to complete (any cause), Outcome 3 Citalopram versus other SSRIs.

Analysis 10.4.

Comparison 10 Failure to complete (any cause), Outcome 4 Citalopram versus other conventional ADs.

Analysis 10.5.

Comparison 10 Failure to complete (any cause), Outcome 5 Citalopram versus non-conventional ADs.

Comparison 11. Failure to complete (side effects)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs81216Odds Ratio (M-H, Random, 95% CI)0.54 [0.38, 0.78]
1.1 versus Amitriptyline3484Odds Ratio (M-H, Random, 95% CI)0.54 [0.34, 0.87]
1.2 versus Clomipramine1114Odds Ratio (M-H, Random, 95% CI)0.10 [0.01, 1.97]
1.3 versus Imipramine2517Odds Ratio (M-H, Random, 95% CI)0.65 [0.36, 1.19]
1.4 versus Nortriptyline2101Odds Ratio (M-H, Random, 95% CI)0.15 [0.02, 1.34]
2 Citalopram versus heterocyclics2432Odds Ratio (M-H, Random, 95% CI)0.50 [0.21, 1.18]
2.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)0.19 [0.01, 4.10]
2.2 versus Mianserin1336Odds Ratio (M-H, Random, 95% CI)0.54 [0.22, 1.32]
3 Citalopram versus other SSRIs15 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Versus Escitalopram71989Odds Ratio (M-H, Random, 95% CI)1.09 [0.65, 1.82]
3.2 Versus Fluoxetine3732Odds Ratio (M-H, Random, 95% CI)1.46 [0.80, 2.67]
3.3 Versus Fluvoxamine1217Odds Ratio (M-H, Random, 95% CI)0.56 [0.28, 1.11]
3.4 Versus Paroxetine1406Odds Ratio (M-H, Random, 95% CI)0.87 [0.36, 2.09]
3.5 Versus Sertraline4860Odds Ratio (M-H, Random, 95% CI)0.69 [0.43, 1.09]
4 Citalopram versus SNRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 Versus Venlafaxine XR1151Odds Ratio (M-H, Random, 95% CI)0.49 [0.12, 2.02]
5 Citalopram versus other conventional ADs4 Odds Ratio (M-H, Random, 95% CI)Subtotals only
5.1 versus Mirtazapine1270Odds Ratio (M-H, Random, 95% CI)0.82 [0.21, 3.12]
5.2 versus Reboxetine3494Odds Ratio (M-H, Random, 95% CI)0.40 [0.13, 1.27]
Analysis 11.1.

Comparison 11 Failure to complete (side effects), Outcome 1 Citalopram versus TCAs.

Analysis 11.2.

Comparison 11 Failure to complete (side effects), Outcome 2 Citalopram versus heterocyclics.

Analysis 11.3.

Comparison 11 Failure to complete (side effects), Outcome 3 Citalopram versus other SSRIs.

Analysis 11.4.

Comparison 11 Failure to complete (side effects), Outcome 4 Citalopram versus SNRIs.

Analysis 11.5.

Comparison 11 Failure to complete (side effects), Outcome 5 Citalopram versus other conventional ADs.

Comparison 12. Failure to complete (inefficacy)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs91267Odds Ratio (M-H, Random, 95% CI)1.47 [0.84, 2.57]
1.1 versus Amitriptyline4535Odds Ratio (M-H, Random, 95% CI)0.83 [0.33, 2.09]
1.2 versus Clomipramine1114Odds Ratio (M-H, Random, 95% CI)2.48 [0.72, 8.59]
1.3 versus Imipramine2517Odds Ratio (M-H, Random, 95% CI)1.64 [0.24, 11.24]
1.4 versus Nortriptyline2101Odds Ratio (M-H, Random, 95% CI)2.55 [0.76, 8.53]
2 Citalopram versus heterocyclics2432Odds Ratio (M-H, Random, 95% CI)0.63 [0.24, 1.69]
2.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)0.64 [0.17, 2.42]
2.2 versus Mianserin1336Odds Ratio (M-H, Random, 95% CI)0.63 [0.15, 2.68]
3 Citalopram versus other SSRIs14 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Versus Escitalopram82206Odds Ratio (M-H, Random, 95% CI)0.80 [0.38, 1.66]
3.2 Versus Fluoxetine3732Odds Ratio (M-H, Random, 95% CI)1.15 [0.64, 2.08]
3.3 Versus Paroxetine1406Odds Ratio (M-H, Random, 95% CI)0.57 [0.13, 2.42]
3.4 Versus Sertraline3760Odds Ratio (M-H, Random, 95% CI)0.73 [0.34, 1.60]
4 Citalopram versus other conventional ADs3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 versus Mirtazapine1270Odds Ratio (M-H, Random, 95% CI)0.25 [0.03, 2.28]
4.2 versus Reboxetine2458Odds Ratio (M-H, Random, 95% CI)0.66 [0.17, 2.57]
Analysis 12.1.

Comparison 12 Failure to complete (inefficacy), Outcome 1 Citalopram versus TCAs.

Analysis 12.2.

Comparison 12 Failure to complete (inefficacy), Outcome 2 Citalopram versus heterocyclics.

Analysis 12.3.

Comparison 12 Failure to complete (inefficacy), Outcome 3 Citalopram versus other SSRIs.

Analysis 12.4.

Comparison 12 Failure to complete (inefficacy), Outcome 4 Citalopram versus other conventional ADs.

Comparison 13. SE - Subjects with at least one TEAEs
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs71088Odds Ratio (M-H, Random, 95% CI)0.65 [0.30, 1.41]
1.1 versus Amitriptyline4528Odds Ratio (M-H, Random, 95% CI)0.43 [0.28, 0.65]
1.2 versus Imipramine2517Odds Ratio (M-H, Random, 95% CI)1.82 [1.14, 2.89]
1.3 versus Nortriptyline143Odds Ratio (M-H, Random, 95% CI)0.94 [0.20, 4.39]
2 Citalopram versus heterocyclics1336Odds Ratio (M-H, Random, 95% CI)0.84 [0.52, 1.37]
2.1 versus Mianserin1336Odds Ratio (M-H, Random, 95% CI)0.84 [0.52, 1.37]
3 Citalopram versus other SSRIs15 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Versus Escitalopram71979Odds Ratio (M-H, Random, 95% CI)1.20 [0.97, 1.47]
3.2 Versus Fluoxetine3732Odds Ratio (M-H, Random, 95% CI)1.10 [0.81, 1.47]
3.3 Versus Paroxetine1406Odds Ratio (M-H, Random, 95% CI)1.34 [0.83, 2.18]
3.4 Versus Sertraline5902Odds Ratio (M-H, Random, 95% CI)0.67 [0.39, 1.16]
4 Citalopram versus SNRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 Versus Venlafaxine XR1151Odds Ratio (M-H, Random, 95% CI)0.46 [0.24, 0.88]
5 Citalopram versus MAOIs or newer ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
5.1 versus Moclobemide142Odds Ratio (M-H, Random, 95% CI)0.69 [0.20, 2.35]
6 Citalopram versus other conventional ADs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
6.1 versus Mirtazapine1270Odds Ratio (M-H, Random, 95% CI)1.22 [0.73, 2.04]
6.2 versus Reboxetine1357Odds Ratio (M-H, Random, 95% CI)0.64 [0.42, 0.97]
7 Citalopram versus non-conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
7.1 versus Hypericum (St. John's wort)1258Odds Ratio (M-H, Random, 95% CI)1.69 [1.01, 2.83]
Analysis 13.1.

Comparison 13 SE - Subjects with at least one TEAEs, Outcome 1 Citalopram versus TCAs.

Analysis 13.2.

Comparison 13 SE - Subjects with at least one TEAEs, Outcome 2 Citalopram versus heterocyclics.

Analysis 13.3.

Comparison 13 SE - Subjects with at least one TEAEs, Outcome 3 Citalopram versus other SSRIs.

Analysis 13.4.

Comparison 13 SE - Subjects with at least one TEAEs, Outcome 4 Citalopram versus SNRIs.

Analysis 13.5.

Comparison 13 SE - Subjects with at least one TEAEs, Outcome 5 Citalopram versus MAOIs or newer ADs.

Analysis 13.6.

Comparison 13 SE - Subjects with at least one TEAEs, Outcome 6 Citalopram versus other conventional ADs.

Analysis 13.7.

Comparison 13 SE - Subjects with at least one TEAEs, Outcome 7 Citalopram versus non-conventional ADs.

Comparison 14. SE - Abdominal pain
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other SSRIs3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Versus Escitalopram1294Odds Ratio (M-H, Random, 95% CI)2.82 [0.11, 69.84]
1.2 Versus Fluoxetine2673Odds Ratio (M-H, Random, 95% CI)1.57 [0.55, 4.53]
Analysis 14.1.

Comparison 14 SE - Abdominal pain, Outcome 1 Citalopram versus other SSRIs.

Comparison 15. SE - Accidental injury
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Versus Escitalopram1357Odds Ratio (M-H, Random, 95% CI)0.37 [0.11, 1.21]
Analysis 15.1.

Comparison 15 SE - Accidental injury, Outcome 1 Citalopram versus other SSRIs.

Comparison 16. SE - Aggressive behaviour
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Versus Escitalopram1294Odds Ratio (M-H, Random, 95% CI)0.31 [0.01, 7.65]
Analysis 16.1.

Comparison 16 SE - Aggressive behaviour, Outcome 1 Citalopram versus other SSRIs.

Comparison 17. SE - Anorexia
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other SSRIs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Versus Escitalopram2448Odds Ratio (M-H, Random, 95% CI)0.64 [0.06, 7.29]
Analysis 17.1.

Comparison 17 SE - Anorexia, Outcome 1 Citalopram versus other SSRIs.

Comparison 18. SE - Anxiety/agitation
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs135Odds Ratio (M-H, Random, 95% CI)1.4 [0.35, 5.54]
1.1 versus Nortriptyline135Odds Ratio (M-H, Random, 95% CI)1.4 [0.35, 5.54]
2 Citalopram versus heterocyclics2432Odds Ratio (M-H, Random, 95% CI)0.91 [0.16, 5.16]
2.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)0.19 [0.01, 4.10]
2.2 versus Mianserin1336Odds Ratio (M-H, Random, 95% CI)1.49 [0.58, 3.81]
3 Citalopram versus other SSRIs4 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Versus Escitalopram2437Odds Ratio (M-H, Random, 95% CI)0.79 [0.07, 9.51]
3.2 Versus Fluoxetine2673Odds Ratio (M-H, Random, 95% CI)1.04 [0.50, 2.16]
3.3 Versus Sertraline1145Odds Ratio (M-H, Random, 95% CI)2.96 [0.30, 29.12]
Analysis 18.1.

Comparison 18 SE - Anxiety/agitation, Outcome 1 Citalopram versus TCAs.

Analysis 18.2.

Comparison 18 SE - Anxiety/agitation, Outcome 2 Citalopram versus heterocyclics.

Analysis 18.3.

Comparison 18 SE - Anxiety/agitation, Outcome 3 Citalopram versus other SSRIs.

Comparison 19. SE - Appetite increased
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus heterocyclics196Odds Ratio (M-H, Random, 95% CI)1.0 [0.06, 16.46]
1.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)1.0 [0.06, 16.46]
2 Citalopram versus other conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus Mirtazapine1270Odds Ratio (M-H, Random, 95% CI)0.16 [0.03, 0.72]
Analysis 19.1.

Comparison 19 SE - Appetite increased, Outcome 1 Citalopram versus heterocyclics.

Analysis 19.2.

Comparison 19 SE - Appetite increased, Outcome 2 Citalopram versus other conventional ADs.

Comparison 20. SE - Asthenia
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus Amitriptyline152Odds Ratio (M-H, Random, 95% CI)0.50 [0.11, 2.35]
1.2 Versus Imipramine143Odds Ratio (M-H, Random, 95% CI)0.6 [0.09, 4.01]
2 Citalopram versus other SSRIs4 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Versus Escitalopram1294Odds Ratio (M-H, Random, 95% CI)0.93 [0.13, 6.72]
2.2 Versus Paroxetine1406Odds Ratio (M-H, Random, 95% CI)1.69 [0.96, 3.00]
2.3 Versus Sertraline2442Odds Ratio (M-H, Random, 95% CI)0.39 [0.11, 1.37]
Analysis 20.1.

Comparison 20 SE - Asthenia, Outcome 1 Citalopram versus TCAs.

Analysis 20.2.

Comparison 20 SE - Asthenia, Outcome 2 Citalopram versus other SSRIs.

Comparison 21. SE - Back pain
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus heterocyclics1336Odds Ratio (M-H, Random, 95% CI)0.62 [0.22, 1.75]
1.1 versus Mianserin1336Odds Ratio (M-H, Random, 95% CI)0.62 [0.22, 1.75]
2 Citalopram versus other SSRIs3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Versus Escitalopram2605Odds Ratio (M-H, Random, 95% CI)1.36 [0.34, 5.51]
2.2 Versus Fluoxetine1357Odds Ratio (M-H, Random, 95% CI)12.04 [0.66, 219.46]
Analysis 21.1.

Comparison 21 SE - Back pain, Outcome 1 Citalopram versus heterocyclics.

Analysis 21.2.

Comparison 21 SE - Back pain, Outcome 2 Citalopram versus other SSRIs.

Comparison 22. SE - Brest surgery
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Versus Escitalopram1294Odds Ratio (M-H, Random, 95% CI)2.82 [0.11, 69.84]
Analysis 22.1.

Comparison 22 SE - Brest surgery, Outcome 1 Citalopram versus other SSRIs.

Comparison 23. SE - Bronchitis
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other SSRIs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Versus Escitalopram1357Odds Ratio (M-H, Random, 95% CI)0.28 [0.07, 1.02]
1.2 Versus Fluoxetine1357Odds Ratio (M-H, Random, 95% CI)0.75 [0.23, 2.42]
Analysis 23.1.

Comparison 23 SE - Bronchitis, Outcome 1 Citalopram versus other SSRIs.

Comparison 24. SE - Chest pain
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Versus Escitalopram1294Odds Ratio (M-H, Random, 95% CI)2.82 [0.11, 69.84]
Analysis 24.1.

Comparison 24 SE - Chest pain, Outcome 1 Citalopram versus other SSRIs.

Comparison 25. SE - Chicken pox
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Versus Escitalopram1294Odds Ratio (M-H, Random, 95% CI)0.31 [0.01, 7.65]
Analysis 25.1.

Comparison 25 SE - Chicken pox, Outcome 1 Citalopram versus other SSRIs.

Comparison 26. SE - Common cold
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus SNRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Versus Venlafaxine XR1151Odds Ratio (M-H, Random, 95% CI)0.67 [0.11, 4.11]
Analysis 26.1.

Comparison 26 SE - Common cold, Outcome 1 Citalopram versus SNRIs.

Comparison 27. SE - Concentration decrease
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus heterocyclics196Odds Ratio (M-H, Random, 95% CI)3.06 [0.12, 77.09]
1.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)3.06 [0.12, 77.09]
2 Citalopram versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Versus Sertraline1400Odds Ratio (M-H, Random, 95% CI)0.50 [0.04, 5.53]
3 Citalopram versus other conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus Reboxetine1357Odds Ratio (M-H, Random, 95% CI)0.68 [0.11, 4.13]
Analysis 27.1.

Comparison 27 SE - Concentration decrease, Outcome 1 Citalopram versus heterocyclics.

Analysis 27.2.

Comparison 27 SE - Concentration decrease, Outcome 2 Citalopram versus other SSRIs.

Analysis 27.3.

Comparison 27 SE - Concentration decrease, Outcome 3 Citalopram versus other conventional ADs.

Comparison 28. SE - Confusion
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus Amitriptyline152Odds Ratio (M-H, Random, 95% CI)0.32 [0.06, 1.83]
1.2 versus Nortriptyline135Odds Ratio (M-H, Random, 95% CI)3.36 [0.13, 88.39]
2 Citalopram versus other conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus Reboxetine1357Odds Ratio (M-H, Random, 95% CI)0.51 [0.05, 5.69]
Analysis 28.1.

Comparison 28 SE - Confusion, Outcome 1 Citalopram versus TCAs.

Analysis 28.2.

Comparison 28 SE - Confusion, Outcome 2 Citalopram versus other conventional ADs.

Comparison 29. SE - Conjunctivitis
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs151Odds Ratio (M-H, Random, 95% CI)2.77 [0.11, 71.35]
1.1 versus Amitriptyline151Odds Ratio (M-H, Random, 95% CI)2.77 [0.11, 71.35]
Analysis 29.1.

Comparison 29 SE - Conjunctivitis, Outcome 1 Citalopram versus TCAs.

Comparison 30. SE - Constipation
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs61018Odds Ratio (M-H, Random, 95% CI)0.36 [0.24, 0.55]
1.1 versus Amitriptyline3468Odds Ratio (M-H, Random, 95% CI)0.46 [0.23, 0.90]
1.2 versus Imipramine2515Odds Ratio (M-H, Random, 95% CI)0.31 [0.18, 0.53]
1.3 versus Nortriptyline135Odds Ratio (M-H, Random, 95% CI)0.43 [0.09, 2.09]
2 Citalopram versus heterocyclics1336Odds Ratio (M-H, Random, 95% CI)0.70 [0.24, 2.00]
2.1 versus Mianserin1336Odds Ratio (M-H, Random, 95% CI)0.70 [0.24, 2.00]
3 Citalopram versus other SSRIs4 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Versus Escitalopram1294Odds Ratio (M-H, Random, 95% CI)2.82 [0.11, 69.84]
3.2 Versus Fluoxetine1357Odds Ratio (M-H, Random, 95% CI)0.35 [0.07, 1.74]
3.3 Versus Sertraline2442Odds Ratio (M-H, Random, 95% CI)0.65 [0.23, 1.88]
4 Citalopram versus SNRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 Versus Venlafaxine XR1151Odds Ratio (M-H, Random, 95% CI)2.64 [0.50, 14.07]
5 Citalopram versus other conventional ADs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
5.1 versus Reboxetine2458Odds Ratio (M-H, Random, 95% CI)0.06 [0.00, 0.90]
Analysis 30.1.

Comparison 30 SE - Constipation, Outcome 1 Citalopram versus TCAs.

Analysis 30.2.

Comparison 30 SE - Constipation, Outcome 2 Citalopram versus heterocyclics.

Analysis 30.3.

Comparison 30 SE - Constipation, Outcome 3 Citalopram versus other SSRIs.

Analysis 30.4.

Comparison 30 SE - Constipation, Outcome 4 Citalopram versus SNRIs.

Analysis 30.5.

Comparison 30 SE - Constipation, Outcome 5 Citalopram versus other conventional ADs.

Comparison 31. SE - Craving for sweets
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus heterocyclics196Odds Ratio (M-H, Random, 95% CI)5.22 [0.24, 111.55]
1.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)5.22 [0.24, 111.55]
Analysis 31.1.

Comparison 31 SE - Craving for sweets, Outcome 1 Citalopram versus heterocyclics.

Comparison 32. SE - Decreased weight
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other SSRIs3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Versus Fluoxetine2673Odds Ratio (M-H, Random, 95% CI)0.62 [0.25, 1.50]
1.2 Versus Sertraline1400Odds Ratio (M-H, Random, 95% CI)2.23 [0.98, 5.05]
2 Citalopram versus other conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus Reboxetine1357Odds Ratio (M-H, Random, 95% CI)0.12 [0.02, 1.00]
Analysis 32.1.

Comparison 32 SE - Decreased weight, Outcome 1 Citalopram versus other SSRIs.

Analysis 32.2.

Comparison 32 SE - Decreased weight, Outcome 2 Citalopram versus other conventional ADs.

Comparison 33. SE - Dermatological problems
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs151Odds Ratio (M-H, Random, 95% CI)0.88 [0.05, 14.96]
1.1 versus Amitriptyline151Odds Ratio (M-H, Random, 95% CI)0.88 [0.05, 14.96]
2 Citalopram versus heterocyclics196Odds Ratio (M-H, Random, 95% CI)1.0 [0.06, 16.46]
2.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)1.0 [0.06, 16.46]
3 Citalopram versus other SSRIs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Versus Escitalopram1219Odds Ratio (M-H, Random, 95% CI)2.0 [0.18, 22.38]
3.2 Versus Sertraline1400Odds Ratio (M-H, Random, 95% CI)1.21 [0.36, 4.02]
4 Citalopram versus non-conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 versus Hypericum (St. John's wort)1258Odds Ratio (M-H, Random, 95% CI)1.57 [0.43, 5.72]
Analysis 33.1.

Comparison 33 SE - Dermatological problems, Outcome 1 Citalopram versus TCAs.

Analysis 33.2.

Comparison 33 SE - Dermatological problems, Outcome 2 Citalopram versus heterocyclics.

Analysis 33.3.

Comparison 33 SE - Dermatological problems, Outcome 3 Citalopram versus other SSRIs.

Analysis 33.4.

Comparison 33 SE - Dermatological problems, Outcome 4 Citalopram versus non-conventional ADs.

Comparison 34. SE - Diarrhoea
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs295Odds Ratio (M-H, Random, 95% CI)1.27 [0.26, 6.16]
1.1 versus Amitriptyline152Odds Ratio (M-H, Random, 95% CI)1.92 [0.16, 22.58]
1.2 versus Imipramine143Odds Ratio (M-H, Random, 95% CI)0.95 [0.12, 7.44]
2 Citalopram versus heterocyclics196Odds Ratio (M-H, Random, 95% CI)1.0 [0.14, 7.40]
2.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)1.0 [0.14, 7.40]
3 Citalopram versus other SSRIs8 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Versus Escitalopram41247Odds Ratio (M-H, Random, 95% CI)1.22 [0.78, 1.92]
3.2 Versus Fluoxetine2673Odds Ratio (M-H, Random, 95% CI)2.11 [0.34, 13.22]
3.3 Versus Paroxetine1406Odds Ratio (M-H, Random, 95% CI)0.73 [0.41, 1.32]
3.4 Versus Sertraline1400Odds Ratio (M-H, Random, 95% CI)0.63 [0.29, 1.37]
4 Citalopram versus other conventional ADs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 versus Mirtazapine1270Odds Ratio (M-H, Random, 95% CI)2.13 [0.63, 7.24]
4.2 versus Reboxetine1357Odds Ratio (M-H, Random, 95% CI)1.03 [0.20, 5.17]
Analysis 34.1.

Comparison 34 SE - Diarrhoea, Outcome 1 Citalopram versus TCAs.

Analysis 34.2.

Comparison 34 SE - Diarrhoea, Outcome 2 Citalopram versus heterocyclics.

Analysis 34.3.

Comparison 34 SE - Diarrhoea, Outcome 3 Citalopram versus other SSRIs.

Analysis 34.4.

Comparison 34 SE - Diarrhoea, Outcome 4 Citalopram versus other conventional ADs.

Comparison 35. SE - Dizziness
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs5546Odds Ratio (M-H, Random, 95% CI)0.59 [0.27, 1.27]
1.1 versus Amitriptyline3468Odds Ratio (M-H, Random, 95% CI)0.47 [0.15, 1.44]
1.2 versus Imipramine143Odds Ratio (M-H, Random, 95% CI)0.35 [0.10, 1.22]
1.3 versus Nortriptyline135Odds Ratio (M-H, Random, 95% CI)1.82 [0.44, 7.48]
2 Citalopram versus heterocyclics2432Odds Ratio (M-H, Random, 95% CI)0.77 [0.22, 2.68]
2.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)1.47 [0.43, 5.00]
2.2 versus Mianserin1336Odds Ratio (M-H, Random, 95% CI)0.41 [0.13, 1.33]
3 Citalopram versus other SSRIs6 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Versus Escitalopram51136Odds Ratio (M-H, Random, 95% CI)0.88 [0.43, 1.81]
3.2 Versus Sertraline2545Odds Ratio (M-H, Random, 95% CI)0.76 [0.41, 1.39]
4 Citalopram versus SNRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 Versus Venlafaxine XR1151Odds Ratio (M-H, Random, 95% CI)0.75 [0.16, 3.47]
5 Citalopram versus other conventional ADs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
5.1 versus Mirtazapine1270Odds Ratio (M-H, Random, 95% CI)0.49 [0.18, 1.35]
5.2 versus Reboxetine1101Odds Ratio (M-H, Random, 95% CI)0.75 [0.31, 1.81]
Analysis 35.1.

Comparison 35 SE - Dizziness, Outcome 1 Citalopram versus TCAs.

Analysis 35.2.

Comparison 35 SE - Dizziness, Outcome 2 Citalopram versus heterocyclics.

Analysis 35.3.

Comparison 35 SE - Dizziness, Outcome 3 Citalopram versus other SSRIs.

Analysis 35.4.

Comparison 35 SE - Dizziness, Outcome 4 Citalopram versus SNRIs.

Analysis 35.5.

Comparison 35 SE - Dizziness, Outcome 5 Citalopram versus other conventional ADs.

Comparison 36. SE - Dry mouth
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs71078Odds Ratio (M-H, Random, 95% CI)0.25 [0.18, 0.35]
1.1 versus Amitriptyline4528Odds Ratio (M-H, Random, 95% CI)0.17 [0.10, 0.28]
1.2 versus Imipramine2515Odds Ratio (M-H, Random, 95% CI)0.32 [0.21, 0.50]
1.3 versus Nortriptyline135Odds Ratio (M-H, Random, 95% CI)0.44 [0.11, 1.70]
2 Citalopram versus heterocyclics196Odds Ratio (M-H, Random, 95% CI)0.73 [0.30, 1.79]
2.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)0.73 [0.30, 1.79]
3 Citalopram versus other SSRIs10 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Versus Escitalopram51457Odds Ratio (M-H, Random, 95% CI)0.98 [0.60, 1.62]
3.2 Versus Fluoxetine2416Odds Ratio (M-H, Random, 95% CI)0.49 [0.02, 11.57]
3.3 Versus Paroxetine1406Odds Ratio (M-H, Random, 95% CI)1.03 [0.60, 1.79]
3.4 Versus Sertraline2442Odds Ratio (M-H, Random, 95% CI)0.65 [0.35, 1.20]
4 Citalopram versus SNRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 Versus Venlafaxine XR1151Odds Ratio (M-H, Random, 95% CI)1.16 [0.42, 3.18]
5 Citalopram versus other conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
5.1 versus Mirtazapine1270Odds Ratio (M-H, Random, 95% CI)0.52 [0.25, 1.10]
Analysis 36.1.

Comparison 36 SE - Dry mouth, Outcome 1 Citalopram versus TCAs.

Analysis 36.2.

Comparison 36 SE - Dry mouth, Outcome 2 Citalopram versus heterocyclics.

Analysis 36.3.

Comparison 36 SE - Dry mouth, Outcome 3 Citalopram versus other SSRIs.

Analysis 36.4.

Comparison 36 SE - Dry mouth, Outcome 4 Citalopram versus SNRIs.

Analysis 36.5.

Comparison 36 SE - Dry mouth, Outcome 5 Citalopram versus other conventional ADs.

Comparison 37. SE - Dyspepsia
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus heterocyclics196Odds Ratio (M-H, Random, 95% CI)2.04 [0.18, 23.32]
1.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)2.04 [0.18, 23.32]
2 Citalopram versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Versus Escitalopram1219Odds Ratio (M-H, Random, 95% CI)3.0 [0.12, 74.45]
Analysis 37.1.

Comparison 37 SE - Dyspepsia, Outcome 1 Citalopram versus heterocyclics.

Analysis 37.2.

Comparison 37 SE - Dyspepsia, Outcome 2 Citalopram versus other SSRIs.

Comparison 38. SE - Dyspnea
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus heterocyclics196Odds Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.22]
1.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.22]
Analysis 38.1.

Comparison 38 SE - Dyspnea, Outcome 1 Citalopram versus heterocyclics.

Comparison 39. SE - Emotional indifference
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Versus Sertraline1400Odds Ratio (M-H, Random, 95% CI)2.01 [0.18, 22.35]
2 Citalopram versus other conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus Reboxetine1357Odds Ratio (M-H, Random, 95% CI)0.25 [0.03, 2.28]
Analysis 39.1.

Comparison 39 SE - Emotional indifference, Outcome 1 Citalopram versus other SSRIs.

Analysis 39.2.

Comparison 39 SE - Emotional indifference, Outcome 2 Citalopram versus other conventional ADs.

Comparison 40. SE - Enuresis
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Versus Escitalopram1294Odds Ratio (M-H, Random, 95% CI)0.31 [0.01, 7.65]
Analysis 40.1.

Comparison 40 SE - Enuresis, Outcome 1 Citalopram versus other SSRIs.

Comparison 41. SE - Exacerbation of depressive disorder
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Versus Escitalopram1294Odds Ratio (M-H, Random, 95% CI)2.82 [0.11, 69.84]
Analysis 41.1.

Comparison 41 SE - Exacerbation of depressive disorder, Outcome 1 Citalopram versus other SSRIs.

Comparison 42. SE - Fatigue
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs1365Odds Ratio (M-H, Random, 95% CI)0.55 [0.20, 1.53]
1.1 versus Amitriptyline1365Odds Ratio (M-H, Random, 95% CI)0.55 [0.20, 1.53]
2 Citalopram versus heterocyclics1336Odds Ratio (M-H, Random, 95% CI)0.21 [0.06, 0.76]
2.1 versus Mianserin1336Odds Ratio (M-H, Random, 95% CI)0.21 [0.06, 0.76]
3 Citalopram versus other SSRIs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Versus Escitalopram2467Odds Ratio (M-H, Random, 95% CI)0.31 [0.12, 0.84]
4 Citalopram versus other conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 versus Mirtazapine1270Odds Ratio (M-H, Random, 95% CI)1.10 [0.54, 2.25]
Analysis 42.1.

Comparison 42 SE - Fatigue, Outcome 1 Citalopram versus TCAs.

Analysis 42.2.

Comparison 42 SE - Fatigue, Outcome 2 Citalopram versus heterocyclics.

Analysis 42.3.

Comparison 42 SE - Fatigue, Outcome 3 Citalopram versus other SSRIs.

Analysis 42.4.

Comparison 42 SE - Fatigue, Outcome 4 Citalopram versus other conventional ADs.

Comparison 43. SE - Feeling of numbness
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus heterocyclics196Odds Ratio (M-H, Random, 95% CI)5.22 [0.24, 111.55]
1.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)5.22 [0.24, 111.55]
Analysis 43.1.

Comparison 43 SE - Feeling of numbness, Outcome 1 Citalopram versus heterocyclics.

Comparison 44. SE - Forgetfulness
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Versus Sertraline1400Odds Ratio (M-H, Random, 95% CI)1.78 [0.51, 6.17]
Analysis 44.1.

Comparison 44 SE - Forgetfulness, Outcome 1 Citalopram versus other SSRIs.

Comparison 45. SE - Gastrointestinal
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs3146Odds Ratio (M-H, Random, 95% CI)0.77 [0.28, 2.15]
1.1 versus Amitriptyline2103Odds Ratio (M-H, Random, 95% CI)0.45 [0.10, 2.07]
1.2 versus Imipramine143Odds Ratio (M-H, Random, 95% CI)1.2 [0.30, 4.74]
2 Citalopram versus other SSRIs3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Versus Escitalopram2375Odds Ratio (M-H, Random, 95% CI)1.14 [0.54, 2.40]
2.2 Versus Sertraline2545Odds Ratio (M-H, Random, 95% CI)0.62 [0.30, 1.30]
3 Citalopram versus MAOIs or newer ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus Moclobemide142Odds Ratio (M-H, Random, 95% CI)1.13 [0.28, 4.47]
4 Citalopram versus non-conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 versus Hypericum (St. John's wort)1258Odds Ratio (M-H, Random, 95% CI)2.41 [1.12, 5.18]
Analysis 45.1.

Comparison 45 SE - Gastrointestinal, Outcome 1 Citalopram versus TCAs.

Analysis 45.2.

Comparison 45 SE - Gastrointestinal, Outcome 2 Citalopram versus other SSRIs.

Analysis 45.3.

Comparison 45 SE - Gastrointestinal, Outcome 3 Citalopram versus MAOIs or newer ADs.

Analysis 45.4.

Comparison 45 SE - Gastrointestinal, Outcome 4 Citalopram versus non-conventional ADs.

Comparison 46. SE - Headache
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs6606Odds Ratio (M-H, Random, 95% CI)1.37 [0.78, 2.42]
1.1 versus Amitriptyline4528Odds Ratio (M-H, Random, 95% CI)1.25 [0.65, 2.42]
1.2 versus Imipramine143Odds Ratio (M-H, Random, 95% CI)3.56 [0.63, 20.15]
1.3 versus Nortriptyline135Odds Ratio (M-H, Random, 95% CI)1.08 [0.25, 4.70]
2 Citalopram versus heterocyclics2432Odds Ratio (M-H, Random, 95% CI)1.27 [0.62, 2.60]
2.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)2.14 [0.50, 9.12]
2.2 versus Mianserin1336Odds Ratio (M-H, Random, 95% CI)1.07 [0.46, 2.45]
3 Citalopram versus other SSRIs11 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Versus Escitalopram51261Odds Ratio (M-H, Random, 95% CI)1.08 [0.64, 1.81]
3.2 Versus Fluoxetine3732Odds Ratio (M-H, Random, 95% CI)0.90 [0.51, 1.60]
3.3 Versus Paroxetine1406Odds Ratio (M-H, Random, 95% CI)1.24 [0.79, 1.96]
3.4 Versus Sertraline3587Odds Ratio (M-H, Random, 95% CI)0.55 [0.33, 0.91]
4 Citalopram versus IMAOs or newer ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 versus Moclobemide142Odds Ratio (M-H, Random, 95% CI)0.16 [0.01, 3.64]
5 Citalopram versusother conventional ADs3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
5.1 versus Mirtazapine1270Odds Ratio (M-H, Random, 95% CI)1.59 [0.75, 3.37]
5.2 versus Reboxetine2458Odds Ratio (M-H, Random, 95% CI)0.50 [0.25, 1.00]
Analysis 46.1.

Comparison 46 SE - Headache, Outcome 1 Citalopram versus TCAs.

Analysis 46.2.

Comparison 46 SE - Headache, Outcome 2 Citalopram versus heterocyclics.

Analysis 46.3.

Comparison 46 SE - Headache, Outcome 3 Citalopram versus other SSRIs.

Analysis 46.4.

Comparison 46 SE - Headache, Outcome 4 Citalopram versus IMAOs or newer ADs.

Analysis 46.5.

Comparison 46 SE - Headache, Outcome 5 Citalopram versusother conventional ADs.

Comparison 47. SE - Hot flush
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Versus Escitalopram1294Odds Ratio (M-H, Random, 95% CI)0.31 [0.01, 7.65]
Analysis 47.1.

Comparison 47 SE - Hot flush, Outcome 1 Citalopram versus other SSRIs.

Comparison 48. SE - Hypertonia
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus heterocyclics196Odds Ratio (M-H, Random, 95% CI)1.0 [0.06, 16.46]
1.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)1.0 [0.06, 16.46]
Analysis 48.1.

Comparison 48 SE - Hypertonia, Outcome 1 Citalopram versus heterocyclics.

Comparison 49. SE - Hypotension
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus Imipramine1472Odds Ratio (M-H, Random, 95% CI)0.38 [0.19, 0.75]
2 Citalopram versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Versus Escitalopram1294Odds Ratio (M-H, Random, 95% CI)0.31 [0.01, 7.65]
Analysis 49.1.

Comparison 49 SE - Hypotension, Outcome 1 Citalopram versus TCAs.

Analysis 49.2.

Comparison 49 SE - Hypotension, Outcome 2 Citalopram versus other SSRIs.

Comparison 50. SE - Increased dream activity
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus Reboxetine1357Odds Ratio (M-H, Random, 95% CI)0.5 [0.17, 1.49]
Analysis 50.1.

Comparison 50 SE - Increased dream activity, Outcome 1 Citalopram versus other conventional ADs.

Comparison 51. SE - Increased salivation
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus older ADs196Odds Ratio (M-H, Random, 95% CI)3.06 [0.12, 77.09]
1.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)3.06 [0.12, 77.09]
2 Citalopram versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Versus Sertraline1400Odds Ratio (M-H, Random, 95% CI)3.02 [0.12, 74.46]
3 Citalopram versus newer ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus Reboxetine1357Odds Ratio (M-H, Random, 95% CI)0.20 [0.01, 4.27]
Analysis 51.1.

Comparison 51 SE - Increased salivation, Outcome 1 Citalopram versus older ADs.

Analysis 51.2.

Comparison 51 SE - Increased salivation, Outcome 2 Citalopram versus other SSRIs.

Analysis 51.3.

Comparison 51 SE - Increased salivation, Outcome 3 Citalopram versus newer ADs.

Comparison 52. SE - Infection
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus non-conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus Hypericum (St. John's wort)1258Odds Ratio (M-H, Random, 95% CI)0.86 [0.43, 1.72]
Analysis 52.1.

Comparison 52 SE - Infection, Outcome 1 Citalopram versus non-conventional ADs.

Comparison 53. SE - Influenza-like symptoms
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Versus Fluoxetine1357Odds Ratio (M-H, Random, 95% CI)0.35 [0.07, 1.74]
2 Citalopram versus other conventional ADs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus Mirtazapine1270Odds Ratio (M-H, Random, 95% CI)0.43 [0.11, 1.69]
2.2 versus Reboxetine1357Odds Ratio (M-H, Random, 95% CI)1.17 [0.44, 3.09]
Analysis 53.1.

Comparison 53 SE - Influenza-like symptoms, Outcome 1 Citalopram versus other SSRIs.

Analysis 53.2.

Comparison 53 SE - Influenza-like symptoms, Outcome 2 Citalopram versus other conventional ADs.

Comparison 54. SE - Insomnia
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs2532Odds Ratio (M-H, Random, 95% CI)1.64 [0.58, 4.69]
1.1 versus Amitriptyline160Odds Ratio (M-H, Random, 95% CI)3.78 [0.70, 20.53]
1.2 versus Imipramine1472Odds Ratio (M-H, Random, 95% CI)1.17 [0.52, 2.59]
2 Citalopram versus heterocyclics1336Odds Ratio (M-H, Random, 95% CI)2.94 [1.20, 7.25]
2.1 versus Mianserin1336Odds Ratio (M-H, Random, 95% CI)2.94 [1.20, 7.25]
3 Citalopram versus other SSRIs12 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Versus Escitalopram61613Odds Ratio (M-H, Random, 95% CI)0.88 [0.60, 1.30]
3.2 Versus Fluoxetine3732Odds Ratio (M-H, Random, 95% CI)1.16 [0.60, 2.23]
3.3 Versus Paroxetine1406Odds Ratio (M-H, Random, 95% CI)0.92 [0.53, 1.59]
3.4 Versus Sertraline3587Odds Ratio (M-H, Random, 95% CI)1.54 [0.82, 2.91]
4 Citalopram versus MAOIs or newer ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 versus Moclobemide142Odds Ratio (M-H, Random, 95% CI)0.29 [0.01, 7.51]
5 Citalopram versus other conventional ADs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
5.1 versus Reboxetine2458Odds Ratio (M-H, Random, 95% CI)0.31 [0.05, 1.99]
Analysis 54.1.

Comparison 54 SE - Insomnia, Outcome 1 Citalopram versus TCAs.

Analysis 54.2.

Comparison 54 SE - Insomnia, Outcome 2 Citalopram versus heterocyclics.

Analysis 54.3.

Comparison 54 SE - Insomnia, Outcome 3 Citalopram versus other SSRIs.

Analysis 54.4.

Comparison 54 SE - Insomnia, Outcome 4 Citalopram versus MAOIs or newer ADs.

Analysis 54.5.

Comparison 54 SE - Insomnia, Outcome 5 Citalopram versus other conventional ADs.

Comparison 55. SE - Irritability
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs1472Odds Ratio (M-H, Random, 95% CI)0.53 [0.26, 1.09]
1.1 versus Imipramine1472Odds Ratio (M-H, Random, 95% CI)0.53 [0.26, 1.09]
Analysis 55.1.

Comparison 55 SE - Irritability, Outcome 1 Citalopram versus TCAs.

Comparison 56. SE - Loss of hair
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs151Odds Ratio (M-H, Random, 95% CI)2.77 [0.11, 71.35]
1.1 versus Amitriptyline151Odds Ratio (M-H, Random, 95% CI)2.77 [0.11, 71.35]
Analysis 56.1.

Comparison 56 SE - Loss of hair, Outcome 1 Citalopram versus TCAs.

Comparison 57. SE - Memory impairment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Versus Escitalopram1294Odds Ratio (M-H, Random, 95% CI)4.73 [0.23, 99.47]
2 Citalopram versus other conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus Reboxetine1357Odds Ratio (M-H, Random, 95% CI)0.68 [0.11, 4.13]
Analysis 57.1.

Comparison 57 SE - Memory impairment, Outcome 1 Citalopram versus other SSRIs.

Analysis 57.2.

Comparison 57 SE - Memory impairment, Outcome 2 Citalopram versus other conventional ADs.

Comparison 58. SE - Meteorism
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs151Odds Ratio (M-H, Random, 95% CI)0.28 [0.01, 7.33]
1.1 versus Amitriptyline151Odds Ratio (M-H, Random, 95% CI)0.28 [0.01, 7.33]
Analysis 58.1.

Comparison 58 SE - Meteorism, Outcome 1 Citalopram versus TCAs.

Comparison 59. SE - Musculoskeletal and connective tissue disorders
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus non-conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus Hypericum (St. John's wort)1258Odds Ratio (M-H, Random, 95% CI)0.85 [0.25, 2.87]
Analysis 59.1.

Comparison 59 SE - Musculoskeletal and connective tissue disorders, Outcome 1 Citalopram versus non-conventional ADs.

Comparison 60. SE - Nasal congestion
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus heterocyclics196Odds Ratio (M-H, Random, 95% CI)1.0 [0.06, 16.46]
1.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)1.0 [0.06, 16.46]
Analysis 60.1.

Comparison 60 SE - Nasal congestion, Outcome 1 Citalopram versus heterocyclics.

Comparison 61. SE - Nausea/vomiting
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs61027Odds Ratio (M-H, Random, 95% CI)1.78 [0.96, 3.30]
1.1 versus Amitriptyline3477Odds Ratio (M-H, Random, 95% CI)2.44 [1.27, 4.66]
1.2 versus Imipramine2515Odds Ratio (M-H, Random, 95% CI)0.98 [0.55, 1.73]
1.3 versus Nortriptyline135Odds Ratio (M-H, Random, 95% CI)7.11 [1.23, 40.98]
2 Citalopram versus heterocyclics2432Odds Ratio (M-H, Random, 95% CI)2.82 [0.60, 13.23]
2.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)12.26 [0.66, 228.27]
2.2 versus Mianserin1336Odds Ratio (M-H, Random, 95% CI)1.88 [0.89, 3.97]
3 Citalopram versus other SSRIs12 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Versus Escitalopram72055Odds Ratio (M-H, Random, 95% CI)0.92 [0.49, 1.74]
3.2 Versus Fluoxetine3732Odds Ratio (M-H, Random, 95% CI)1.46 [0.91, 2.35]
3.3 Versus Paroxetine1406Odds Ratio (M-H, Random, 95% CI)1.15 [0.67, 1.95]
3.4 Versus Sertraline142Odds Ratio (M-H, Random, 95% CI)0.71 [0.14, 3.64]
4 Citalopram versus other conventional ADs3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 versus Mirtazapine1270Odds Ratio (M-H, Random, 95% CI)2.24 [1.12, 4.49]
4.2 versus Reboxetine2458Odds Ratio (M-H, Random, 95% CI)3.46 [0.40, 29.92]
Analysis 61.1.

Comparison 61 SE - Nausea/vomiting, Outcome 1 Citalopram versus TCAs.

Analysis 61.2.

Comparison 61 SE - Nausea/vomiting, Outcome 2 Citalopram versus heterocyclics.

Analysis 61.3.

Comparison 61 SE - Nausea/vomiting, Outcome 3 Citalopram versus other SSRIs.

Analysis 61.4.

Comparison 61 SE - Nausea/vomiting, Outcome 4 Citalopram versus other conventional ADs.

Comparison 62. SE - Nervousness
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Versus Fluoxetine1316Odds Ratio (M-H, Random, 95% CI)1.21 [0.36, 4.04]
Analysis 62.1.

Comparison 62 SE - Nervousness, Outcome 1 Citalopram versus other SSRIs.

Comparison 63. SE - Orthostatic symptoms
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus heterocyclics196Odds Ratio (M-H, Random, 95% CI)1.0 [0.19, 5.22]
1.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)1.0 [0.19, 5.22]
2 Citalopram versus newer ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus Reboxetine1357Odds Ratio (M-H, Random, 95% CI)0.44 [0.13, 1.47]
Analysis 63.1.

Comparison 63 SE - Orthostatic symptoms, Outcome 1 Citalopram versus heterocyclics.

Analysis 63.2.

Comparison 63 SE - Orthostatic symptoms, Outcome 2 Citalopram versus newer ADs.

Comparison 64. SE - Pain (general)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus heterocyclics1336Odds Ratio (M-H, Random, 95% CI)0.70 [0.24, 2.00]
1.1 versus Mianserin1336Odds Ratio (M-H, Random, 95% CI)0.70 [0.24, 2.00]
Analysis 64.1.

Comparison 64 SE - Pain (general), Outcome 1 Citalopram versus heterocyclics.

Comparison 65. SE - Palpitations
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs3138Odds Ratio (M-H, Fixed, 95% CI)0.54 [0.21, 1.41]
1.1 versus Amitriptyline2103Odds Ratio (M-H, Fixed, 95% CI)0.36 [0.10, 1.24]
1.2 versus Nortriptyline135Odds Ratio (M-H, Fixed, 95% CI)1.08 [0.22, 5.22]
2 Citalopram versus other SSRIs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Versus Escitalopram1294Odds Ratio (M-H, Random, 95% CI)0.31 [0.01, 7.65]
2.2 Versus Sertraline1400Odds Ratio (M-H, Random, 95% CI)1.35 [0.46, 3.96]
Analysis 65.1.

Comparison 65 SE - Palpitations, Outcome 1 Citalopram versus TCAs.

Analysis 65.2.

Comparison 65 SE - Palpitations, Outcome 2 Citalopram versus other SSRIs.

Comparison 66. SE - Panic attack
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Versus Escitalopram1294Odds Ratio (M-H, Random, 95% CI)2.82 [0.11, 69.84]
Analysis 66.1.

Comparison 66 SE - Panic attack, Outcome 1 Citalopram versus other SSRIs.

Comparison 67. SE - Paraesthesia
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus Reboxetine1357Odds Ratio (M-H, Random, 95% CI)1.03 [0.29, 3.62]
Analysis 67.1.

Comparison 67 SE - Paraesthesia, Outcome 1 Citalopram versus other conventional ADs.

Comparison 68. SE - Pharyngitis
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Versus Escitalopram1294Odds Ratio (M-H, Random, 95% CI)0.31 [0.01, 7.65]
Analysis 68.1.

Comparison 68 SE - Pharyngitis, Outcome 1 Citalopram versus other SSRIs.

Comparison 69. SE - Pruritus
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus Nortriptyline135Odds Ratio (M-H, Random, 95% CI)2.08 [0.41, 10.53]
2 Citalopram versus other SSRIs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Versus Escitalopram1294Odds Ratio (M-H, Random, 95% CI)2.82 [0.11, 69.84]
2.2 Versus Fluoxetine1316Odds Ratio (M-H, Random, 95% CI)0.39 [0.07, 2.05]
Analysis 69.1.

Comparison 69 SE - Pruritus, Outcome 1 Citalopram versus TCAs.

Analysis 69.2.

Comparison 69 SE - Pruritus, Outcome 2 Citalopram versus other SSRIs.

Comparison 70. SE - Rash
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus Amitriptyline152Odds Ratio (M-H, Random, 95% CI)0.92 [0.05, 15.59]
2 Citalopram versus other SSRIs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Versus Escitalopram1219Odds Ratio (M-H, Random, 95% CI)3.0 [0.12, 74.45]
3 Citalopram versus other conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus Reboxetine1357Odds Ratio (M-H, Random, 95% CI)0.51 [0.09, 2.81]
Analysis 70.1.

Comparison 70 SE - Rash, Outcome 1 Citalopram versus TCAs.

Analysis 70.2.

Comparison 70 SE - Rash, Outcome 2 Citalopram versus other SSRIs.

Analysis 70.3.

Comparison 70 SE - Rash, Outcome 3 Citalopram versus other conventional ADs.

Comparison 71. SE - Reduced salivation
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other conventional ADs1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus Reboxetine1357Odds Ratio (M-H, Random, 95% CI)0.31 [0.14, 0.67]
Analysis 71.1.

Comparison 71 SE - Reduced salivation, Outcome 1 Citalopram versus other conventional ADs.

Comparison 72. SE - Sedation/drowsiness
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs2112Odds Ratio (M-H, Random, 95% CI)0.25 [0.09, 0.70]
1.1 versus Amitriptyline2112Odds Ratio (M-H, Random, 95% CI)0.25 [0.09, 0.70]
2 Citalopram versus heterocyclics196Odds Ratio (M-H, Random, 95% CI)0.62 [0.20, 1.90]
2.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)0.62 [0.20, 1.90]
3 Citalopram versus other SSRIs3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Versus Escitalopram1294Odds Ratio (M-H, Random, 95% CI)0.31 [0.01, 7.65]
3.2 Versus Fluoxetine159Odds Ratio (M-H, Random, 95% CI)1.04 [0.14, 7.90]
3.3 Versus Sertraline1400Odds Ratio (M-H, Random, 95% CI)0.90 [0.36, 2.25]
4 Citalopram versus other conventional ADs2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 versus Mirtazapine1270Odds Ratio (M-H, Random, 95% CI)0.73 [0.29, 1.88]
4.2 versus Reboxetine1357Odds Ratio (M-H, Random, 95% CI)0.91 [0.34, 2.41]
Analysis 72.1.

Comparison 72 SE - Sedation/drowsiness, Outcome 1 Citalopram versus TCAs.

Analysis 72.2.

Comparison 72 SE - Sedation/drowsiness, Outcome 2 Citalopram versus heterocyclics.

Analysis 72.3.

Comparison 72 SE - Sedation/drowsiness, Outcome 3 Citalopram versus other SSRIs.

Analysis 72.4.

Comparison 72 SE - Sedation/drowsiness, Outcome 4 Citalopram versus other conventional ADs.

Comparison 73. SE - Rhinitis
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus other SSRIs3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Versus Escitalopram3922Odds Ratio (M-H, Random, 95% CI)0.87 [0.40, 1.87]
Analysis 73.1.

Comparison 73 SE - Rhinitis, Outcome 1 Citalopram versus other SSRIs.

Comparison 74. SE - Restlessness
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs3146Odds Ratio (M-H, Random, 95% CI)0.69 [0.24, 1.99]
1.1 versus Amitriptyline2103Odds Ratio (M-H, Random, 95% CI)0.71 [0.18, 2.82]
1.2 versus Imipramine143Odds Ratio (M-H, Random, 95% CI)0.67 [0.13, 3.44]
2 Citalopram versus heterocyclics196Odds Ratio (M-H, Random, 95% CI)0.18 [0.02, 1.63]
2.1 versus Maprotiline196Odds Ratio (M-H, Random, 95% CI)0.18 [0.02, 1.63]
Analysis 74.1.

Comparison 74 SE - Restlessness, Outcome 1 Citalopram versus TCAs.

Analysis 74.2.

Comparison 74 SE - Restlessness, Outcome 2 Citalopram versus heterocyclics.

Comparison 75. SE - Sexual problems
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Anorgasmia1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
1.1 versus Sertraline1400Odds Ratio (M-H, Random, 95% CI)1.96 [0.97, 3.97]
2 Erectile dysfunction2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
2.1 versus Escitalopram1317Odds Ratio (M-H, Random, 95% CI)0.19 [0.01, 4.02]
2.2 versus Sertraline1400Odds Ratio (M-H, Random, 95% CI)2.38 [0.61, 9.34]
3 Increased sexual desire2 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 versus Escitalopram1248Odds Ratio (M-H, Random, 95% CI)1.15 [0.43, 3.10]
3.2 versus Sertraline1400Odds Ratio (M-H, Random, 95% CI)2.08 [0.82, 5.26]
4 Loss of sexual interest3 Odds Ratio (M-H, Random, 95% CI)Subtotals only
4.1 versus Moclobemide142Odds Ratio (M-H, Random, 95% CI)0.29 [0.01, 7.51]
4.2 versus Reboxetine1357Odds Ratio (M-H, Random, 95% CI)1.73 [0.41, 7.37]
4.3 versus Sertraline1400Odds Ratio (M-H, Random, 95% CI)0.83 [0.41, 1.66]
5 Orgastic dysfunction1 Odds Ratio (M-H, Random, 95% CI)Subtotals only
5.1 versus Reboxetine1357Odds Ratio (M-H, Random, 95% CI)3.74 [1.56, 8.95]
6 Other sexual problems7 Odds Ratio (M-H, Random, 95% CI)Subtotals only
6.1 versus Escitalopram41015Odds Ratio (M-H, Random, 95% CI)0.72 [0.36, 1.43]
6.2 versus Paroxetine1406Odds Ratio (M-H, Random, 95% CI)1.15 [0.50, 2.62]
6.3 versus Reboxetine1101Odds Ratio (M-H, Random, 95% CI)8.65 [1.86, 40.22]
6.4 versus Sertraline1400Odds Ratio (M-H, Random, 95% CI)1.67 [0.68, 4.12]
Analysis 75.1.

Comparison 75 SE - Sexual problems, Outcome 1 Anorgasmia.

Analysis 75.2.

Comparison 75 SE - Sexual problems, Outcome 2 Erectile dysfunction.

Analysis 75.3.

Comparison 75 SE - Sexual problems, Outcome 3 Increased sexual desire.

Analysis 75.4.

Comparison 75 SE - Sexual problems, Outcome 4 Loss of sexual interest.

Analysis 75.5.

Comparison 75 SE - Sexual problems, Outcome 5 Orgastic dysfunction.

Analysis 75.6.

Comparison 75 SE - Sexual problems, Outcome 6 Other sexual problems.

Comparison 76. SE - Sleepiness/somnolence
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs5966Odds Ratio (M-H, Random, 95% CI)0.49 [0.33, 0.74]
1.1 versus Amitriptyline2416Odds Ratio (M-H, Random, 95% CI)0.45 [0.24, 0.85]
1.2 versus Imipramine2515Odds Ratio (M-H, Random, 95% CI)0.48 [0.27, 0.83]
1.3 versus Nortriptyline135Odds Ratio (M-H, Random, 95% CI)0.9 [0.24, 3.41]
2 Citalopram versus heterocyclics1336Odds Ratio (M-H, Random, 95% CI)0.20 [0.04, 0.94]
2.1 versus Mianserin1336Odds Ratio (M-H, Random, 95% CI)0.20 [0.04, 0.94]
3 Citalopram versus other SSRIs7 Odds Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Versus Escitalopram3859Odds Ratio (M-H, Random, 95% CI)0.75 [0.34, 1.64]
3.2 Versus Fluoxetine1316Odds Ratio (M-H, Random, 95% CI)1.42 [0.44, 4.57]
3.3 Versus Paroxetine1406Odds Ratio (M-H, Random, 95% CI)1.64 [0.92, 2.90]
3.4 Versus Sertraline2442Odds Ratio (M-H, Random, 95% CI)0.68 [0.31, 1.51]
4 Citalopram versus MAOIs or newer ADs142Odds Ratio (M-H, Random, 95% CI)2.86 [0.11, 74.31]
4.1 versus Moclobemide142Odds Ratio (M-H, Random, 95% CI)2.86 [0.11, 74.31]
5 Citalopram versus other conventional ADs1357Odds Ratio (M-H, Random, 95% CI)2.46 [0.63, 9.66]
5.1 versus Reboxetine1357Odds Ratio (M-H, Random, 95% CI)2.46 [0.63, 9.66]
Analysis 76.1.

Comparison 76 SE - Sleepiness/somnolence, Outcome 1 Citalopram versus TCAs.

Analysis 76.2.

Comparison 76 SE - Sleepiness/somnolence, Outcome 2 Citalopram versus heterocyclics.

Analysis 76.3.

Comparison 76 SE - Sleepiness/somnolence, Outcome 3 Citalopram versus other SSRIs.

Analysis 76.4.

Comparison 76 SE - Sleepiness/somnolence, Outcome 4 Citalopram versus MAOIs or newer ADs.

Analysis 76.5.

Comparison 76 SE - Sleepiness/somnolence, Outcome 5 Citalopram versus other conventional ADs.

<
Comparison 77. SE - Sweating
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Citalopram versus TCAs5653Odds Ratio (M-H, Random, 95% CI)0.49 [0.31, 0.77]
1.1 versus Amitriptyline2103Odds Ratio (M-H, Random, 95% CI)0.41 [0.12, 1.49]