Additional files

Section 1: selection criteria and search strategyIdentification and selection of reviews. Eligible reviews assessed the efficacy of citalopram or escitalopram

(any dosage) in adults (≥ 18 years old) with major depression via randomized controlled trials. Reviews that did not report efficacy assessment compared combination therapy or evaluated specific populations (eg, patients with concomitant chronic medical condition) and those in languages other than English were excluded.

First, we searched 4 electronic bibliographical databases (Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, MEDLINE via PubMed and EMBASE) for reviews published between January 2000 and March 2011. Search equations reflected Participants (major depression and synonyms) and Intervention (citalopram, escitalopram and their brand names) and included a filter to identify reviews in MEDLINE and EMBASE. The search strategies are reported below.

Second, we searched repositories of 4 national health technology agencies (UK National Institute for Health and Clinical Excellence, US Agency for Healthcare Research and Quality and the German Institute for Quality and Efficiency in Health Care). We also searched the repositories of the US Food and Drug Administration (Drugs@FDA database) and the French National Authority for Health (Haute Autorité de la Santé, Commission de la Transparence).

Identification and selection of randomized controlled trials. Eligible trials were randomized trials assessing the short-term efficacy (8-weeks) of escitalopram versus citalopram or escitalopram and/or citalopram versus placebo in patients with major depression. Fixed- and flexible dosage trials were eligible.

First, we screened reviews selected above and listed all included trials. Two reviewers read the corresponding report titles, abstracts and full texts, independently and in duplicate, to assess eligibility. In cases of disagreement at any step, consensus was reached by discussion.

Second, we searched for trial results published from March 2011 to February 2012 in MEDLINE via PubMed and EMBASE. Search equations reflected Participants (major depression and synonyms) and Intervention (citalopram, escitalopram and their brand names) and included the Cochrane Highly Sensitive Search filter for identifying randomized trials. The search strategies are reported below.

Finally, we searched for trial results in databases from the pharmaceutical companies commercializing citalopram and escitalopram (www.lundbecktrials.com, www.forestclinicaltrials.com). We also contacted Lundbeck France for a listing of clinical trials for the 2 medications.

Search equation for MEDLINEParticipants #1 ("Depressive Disorder"[Mesh] OR "Depressive Disorder, Major

"[Mesh] OR "major depression"[Text Word] OR "major depressive disorder"[Text Word])

Intervention #2 ("Citalopram"[Mesh] OR "citalopram"[Text Word] OR "desmethylcitalopram"[Text Word] OR "seropram"[Text Word] OR "seroplex"[Text Word] OR "cipramil"[Text Word] OR "celexa"[Text Word] OR "Lexapro"[Text Word] OR "cipralex"[Text Word])

Type of study #3 (“systematic”[sb]) #4 Cochrane Highly Sensitive Search Strategy for identifying

randomized trials in MEDLINESearch equation for reviews #1 AND #2 AND #3Search equation for trials #1 AND#2 AND #4

Search equation for EMBASE Participants #1 'major depression'/exp OR 'major depression' OR 'major

depressive'Intervention #2 'citalopram'/exp OR 'escitalopram'/exp OR citalopram OR

escitalopram OR seropram OR seroplex OR cipramil OR celexa OR lexapro OR cipralex OR lexamil OR lexam

Type of study #3 'meta-analysis':ti OR 'meta-analysis':ab OR 'meta-analysis':de OR 'search':ti OR 'search':ab OR 'review':pt

Search equation #1 AND #2 AND #3 Search equation for Cochrane and DARE

1

"major depression" OR "major depressive" OR "citalopram" OR " seropram" OR "seroplex" OR "escitalopram" in Title, Abstract, Keywords

Section 2: Methods and analysis detailsData extraction: For each trial report, we extracted the publication status, publication year, the compared

drugs, outcome assessment time, evaluated dosages (fixed or flexible), number of randomized patients, treatment responders, means and standard deviations for depression score at baseline and follow-up, change in depression score from baseline to follow-up, and age (mean, range) and sex proportion of subjects. This has been done by two independent reviewers; differences have been resolved by discussion.

Outcome measures: We assessed short-term treatment efficacy, that is, at the end of 8-week treatment. If 8-week assessment was not reported, we extracted outcome data for the closest time point reported. We extracted outcome data for the Montgomery-Åsberg depression rating scale (MADRS) and the Hamilton scale. When reports described results from both rating scales, we used the MADRS results. Efficacy was assessed by the proportion of responders in each treatment group, defined as patients with a decrease in depression score from baseline to follow-up of at least 50%. The numerator was the number of responders among the “efficacy” subset (ie, patients who received at least one dose of a drug and had at least one follow-up visit) and, when used, derived by the Last Observation Carried Forward (LOCF). The denominator was the number of randomly assigned participants. Subjects not included in the efficacy subset and drop-outs (when LOCF was not used) were assumed to be non-responders. In the absence of binary outcome data, we calculated the proportion of responders according to validated imputation methods. We computed the NNT from the combined ORs and by considering low and high response rates for the control group, defined as the lower and upper bounds of the 95% CI for the combined response rate across control groups in the meta-analysis.

We assessed treatment acceptability by the proportion of patients who did not drop out of the allocated treatment during the short-term treatment period (completers).

Section 3: Selected trials.Trial ID Reference Publication StatusCitalopram-placebo29060/785 [1] Unpublished89306 [2] Unpublished86141, Nyth 1992 [3, 4] Unpublished /Published85A, Mendels 1999 [5, 6] Unpublished /Published91206, Feighner 1999 [7, 8] Unpublished /Published89303, Montgomery 1992 [9, 10] Unpublished /PublishedCIT-MD-03, Roose 2004 [11, 12] Unpublished /PublishedEscitalopram-placeboAK130927, Clayton 2005 [13, 14] Unpublished /PublishedAK130926, Clayton 2005 [13, 14] Unpublished /Published99001, Wade 2002 [15, 16] Unpublished /Published99024,Kasper 2005 [17, 18] Unpublished /PublishedBose 2008 [19] PublishedF1J-US-HMCR,Pigott 2007, Nierenberg 2007 [20-22] Unpublished /PublishedSCT-MD-26 [23] UnpublishedSCT-MD-35 [24] UnpublishedSCT-MD-27 [25] UnpublishedEscitalopram -citalopram99022, Colonna 2005 [26, 27] Unpublished /PublishedMoore 2005 [28] PublishedOu 2011 [29] PublishedYevtushenko 2007 [30] PublishedEscitalopram-citalopram-placebo99003, Montgomery 2001, Lepola 2003 [31-33] Unpublished/PublishedSCT-MD-02 [34] UnpublishedSCT-MD-01, Burke 2002 [35, 36] Unpublished/Published

References

2

All provided links were accessed on April 11, 2012.

1. GSK Pharmaceuticals: 29060/785. In: Clinical trials registry. GSK 2001: http://www.gsk-clinicalstudyregister.com/result_detail.jsp;jsessionid=4EDCA4808236FF4808292B4808236B4808231B4429822C4808239A4808233?protocolId=4829060%4808232F4808785&studyId=5898670D-4808237AD4808235-4808240E4808236-B4808802-4808726A4808232A4808273CABD&compound=paroxetine

2. FDA: 89306. In: Statistical and Medical evaluation. 2001: http://www.accessdata.fda.gov/drugsatfda_docs/nda/98/020822a_medr_P020822.pdf.

3. Nyth AL, Gottfries CG, Lyby K, Smedegaard-Andersen L, Gylding-Sabroe J, Kristensen M, Refsum HE, Ofsti E, Eriksson S, Syversen S: A controlled multicenter clinical study of citalopram and placebo in elderly depressed patients with and without concomitant dementia. Acta Psychiatr Scand 1992, 86(2):138-145.

4. FDA: 86141 In: Medical evaluation2001: http://www.accessdata.fda.gov/drugsatfda_docs/nda/98/020822a_medr_P020821.pdf

5. Mendels J, Kiev A, Fabre LF: Double-blind comparison of citalopram and placebo in depressed outpatients with melancholia. Depress Anxiety 1999, 9(2):54-60.

6. FDA: 85A. In: Statistical evaluation. 2001: http://www.accessdata.fda.gov/drugsatfda_docs/nda/98/020822a_statr_P020823.pdf

7. Feighner JP, Overo K: Multicenter, placebo-controlled, fixed-dose study of citalopram in moderate-to-severe depression. J Clin Psychiatry 1999, 60(12):824-830.

8. FDA: 91206. In: Statistical Evaluation. 2001: http://www.accessdata.fda.gov/drugsatfda_docs/nda/98/020822a_medr_P020822.pdf

9. Montgomery SA, Rasmussen JG, Lyby K, Connor P, Tanghoj P: Dose response relationship of citalopram 20 mg, citalopram 40 mg and placebo in the treatment of moderate and severe depression. Int Clin Psychopharmacol 1992, 6 Suppl 5:65-70.

10. FDA: 89303. In: Statistical evaluation. FDA; 1992: http://www.accessdata.fda.gov/drugsatfda_docs/nda/98/020822a_medr_P020822.pdf?bcsi_scan_CBA020824F020892DB020823F020863E020822=020820&bcsi_scan_filename=020822a_medr_P020822.pdf

11. Roose SP, Sackeim HA, Krishnan KR, Pollock BG, Alexopoulos G, Lavretsky H, Katz IR, Hakkarainen H: Antidepressant pharmacotherapy in the treatment of depression in the very old: a randomized, placebo-controlled trial. Am J Psychiatry 2004, 161(11):2050-2059.

12. Forest Laboratories: CIT-MD-03. In: Clinical Trial Registry. http://www.forestclinicaltrials.com/CTR/CTRController/CTRViewPdf?_file_id=scsr/SCSR_CIT-MD-03_final.pdf

13. Clayton AH, Croft HA, Horrigan JP, Wightman DS, Krishen A, Richard NE, Modell JG: Bupropion extended release compared with escitalopram: effects on sexual functioning and antidepressant efficacy in 2 randomized, double-blind, placebo-controlled studies. J Clin Psychiatry 2006, 67(5):736-746.

14. GSK Pharmaceuticals: WELL_AK130926. In: Clinical Trial Registry. 2005: http://www.google.fr/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&cts=1331652480045&sqi=1331652480042&ved=1331652480040CCcQFjAA&url=http%1331652480043A%1331652480042F%1331652480042Fdownload.gsk-clinicalstudyregister.com%1331652480042Ffiles

3

%1331652480042F1331652420466.pdf&ei=ymZfT1331652480044jmCILrOZ-WiOYH&usg=AFQjCNE1331652480048VD-Qj1331652480045h_J-vTUoG1331652480042OpTrlpy1331652480042Qg&sig1331652480042=-Hds1331652480040_HmXy1331652480043NpPN1331652480047ydqfvg.

15. Wade A, Michael Lemming O, Bang Hedegaard K: Escitalopram 10 mg/day is effective and well tolerated in a placebo-controlled study in depression in primary care. Int Clin Psychopharmacol 2002, 17(3):95-102.

16. FDA: 99001. In: Statistical Evaluation. FDA; 2000: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/021323_S021007&021365_S021001_LEXAPRO_TABS.pdf

17. Kasper S, de Swart H, Friis Andersen H: Escitalopram in the treatment of depressed elderly patients. Am J Geriatr Psychiatry 2005, 13(10):884-891.

18. Lundbeck Pharmaceutical: 99024. In: Clinical Trial registry. 2001: http://www.lundbecktrials.com/Data/PDFs/99024_CTRS_final_99030Dec92005.pdf

19. Bose A, Li D, Gandhi C: Escitalopram in the acute treatment of depressed patients aged 60 years or older. Am J Geriatr Psychiatry 2008, 16(1):14-20.

20. Pigott TA, Prakash A, Arnold LM, Aaronson ST, Mallinckrodt CH, Wohlreich MM: Duloxetine versus escitalopram and placebo: an 8-month, double-blind trial in patients with major depressive disorder. Curr Med Res Opin 2007, 23(6):1303-1318.

21. Nierenberg AA, Greist JH, Mallinckrodt CH, Prakash A, Sambunaris A, Tollefson GD, Wohlreich MM: Duloxetine versus escitalopram and placebo in the treatment of patients with major depressive disorder: onset of antidepressant action, a non-inferiority study. Curr Med Res Opin 2007, 23(2):401-416.

22. lilly E: F1J-US-HMCR. In: Clinical Trial Registry. 2007.23. Forest Laboratories: SCT-MD-26. In: Clinical Trial Registry. 2002:

http://www.forestclinicaltrials.com/CTR/CTRController/CTRViewPdf?_file_id=scsr/SCSR_SCT-MD-26_final.pdf

24. Forest Laboratories: SCT-MD-35. In: Clinical Trial Registry. 2007: http://www.forestclinicaltrials.com/CTR/CTRController/CTRViewPdf?_file_id=scsr/SCSR_SCT-MD-35_final.pdf

25. Forest Laboratories: SCT-MD-27. In: Clinical Trial Registry. 2005: http://www.forestclinicaltrials.com/CTR/CTRController/CTRViewPdf?_file_id=scsr/SCSR_SCT-MD-27_final.pdf

26. Colonna L, Andersen HF, Reines EH: A randomized, double-blind, 24-week study of escitalopram (10 mg/day) versus citalopram (20 mg/day) in primary care patients with major depressive disorder. Curr Med Res Opin 2005, 21(10):1659-1668.

27. Lundbeck Pharmaceutical: 99022. In: Clinical Trial registry. Lundbeck Pharmaceutical; 2002: http://www.lundbecktrials.com/Data/PDFs/99022_CTRS_final_99030Dec92005.pdf

28. Moore N, Verdoux H, Fantino B: Prospective, multicentre, randomized, double-blind study of the efficacy of escitalopram versus citalopram in outpatient treatment of major depressive disorder. Int Clin Psychopharmacol 2005, 20(3):131-137.

29. Ou JJ, Xun GL, Wu RR, Li LH, Fang MS, Zhang HG, Xie SP, Shi JG, Du B, Yuan XQ et al: Efficacy and safety of escitalopram versus citalopram in major depressive disorder: a 6-week, multicenter, randomized, double-blind, flexible-dose study. Psychopharmacology (Berl) 2011, 213(2-3):639-646.

30. Yevtushenko VY, Belous AI, Yevtushenko YG, Gusinin SE, Buzik OJ, Agibalova TV: Efficacy and tolerability of escitalopram versus citalopram in major depressive disorder: a

4

6-week, multicenter, prospective, randomized, double-blind, active-controlled study in adult outpatients. Clin Ther 2007, 29(11):2319-2332.

31. Montgomery SA, Loft H, Sanchez C, Reines EH, Papp M: Escitalopram (S-enantiomer of citalopram): clinical efficacy and onset of action predicted from a rat model. Pharmacol Toxicol 2001, 88(5):282-286.

32. Lepola UM, Loft H, Reines EH: Escitalopram (10-20 mg/day) is effective and well tolerated in a placebo-controlled study in depression in primary care. Int Clin Psychopharmacol 2003, 18(4):211-217.

33. Center of Drug Evaluation and Research: 99003. In: Statistical and medical evaluation. FDA; 2001: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/2021-2323.pdf_Lexapro_Medr_P2001.pdf.

34. Forest Laboratories: SCT-MD-02. In: Clinical Trial Registry. 2005: http://www.forestclinicaltrials.com/CTR/CTRController/CTRViewPdf?_file_id=scsr/SCSR_SCT-MD-02_final.pdf

35. Burke WJ, Gergel I, Bose A: Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry 2002, 63(4):331-336.

36. Center of Drug Evaluation and Research: SCT-MD-01. In: Statistical evaluation. FDA; 2002: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/2021-2323.pdf_Lexapro_Statr.pdf.

5

Section 4: Network analysis of trials for direct and indirect comparison and the number of trials in each comparison.

Section 5: Characteristics of trials.Trial ID Age,

mean (yr)

Male, %

Scale used in the

analysis

Baseline depression severity, mean

Setting Elderly specific

population

Dosage Outcome measurement delay (weeks)

Funder

Citalopram-placebo89306 42.7 32 MADRS 32.1 In- and

outpatientsNo Fixed 6 Forest Lab

29060/785 39.4 43 MADRS 31.4 NC No Fixed 6 GSK85A, Mendles 1999 43 66 HAMD 33.7 Outpatients No Flexible 4 Pfizer86141, Nyth 1992 77.2 29 MADRS 25.2 In- and

outpatientsYes Flexible 6 Lundbeck

6

Trial ID Age, mean (yr)

Male, %

Scale used in the

analysis

Baseline depression severity, mean

Setting Elderly specific

population

Dosage Outcome measurement delay (weeks)

Funder

89303, Montgomery 1992 43.2 30 MADRS 24.7 In- and outpatients

No Fixed 6 Lundbeck

91206, Feighner 1999 39.5 40 MADRS 27.3 Outpatients No Fixed 6 LundbeckCIT-MD-03, Roose 2004 79.5 42 MADRS 24.7 NC Yes Flexible 8 Forest LabEscitalopram-placeboAK130926, Clayton 2005 36.5 35 HAMD 24.1 Outpatients No Flexible 8 GSKAK130927, Clayton 2005 35 38 HAMD 24.1 Outpatients No Flexible 8 GSK99001, Wade 2002 40.5 24 MADRS 28.9 Outpatients No Fixed 8 Forest lab99024, Kasper 2005 75 24 MADRS 28.4 In- and

outpatientsYes Fixed 8 Lundbeck

Bose 2008 68.3 40 MADRS 28.9 NC Yes Flexible 12 Forest LabF1J-US-HMCR, Pigott 2007, Nieremberg 2007

42.9 33 HAMD 17.8 Outpatients No Flexible 8 Eli Lilly

SCT-MD-26 38.4 37 MADRS 30.4 NC No Flexible 8 Forest LabSCT-MD-27 40 47 MADRS 30.6 NC No Flexible 8 Forest LabSCT-MD-35 41.4 45 MADRS 30.1 Outpatients No Fixed 8 Forest LabEscitalopram-Citalopram99022, Colonna 2005 46 25 MADRS 29.9 Outpatients No Fixed 8 LundbeckMoore 2005 45.1 33 MADRS 36 Outpatients No Fixed 8 LundbeckOu 2011 36.5 43 HAMD 23.2 In- and

outpatientsNo Flexible 6 Chinese

National Institute of

Pharmaceutical Research and Development

Yevtushenko 2007 34.9 41 MADRS 35.2 Outpatients No Fixed 6 ArbacomEscitalopram-Citalopram-Placebo99003, Montgomery 2001, Lepola 2003 43.3 27 MADRS 28.9 Outpatients No Flexible 8 Forest LabSCT-MD-01, Burke 2002 40.1 34 MADRS 28.6 Outpatients No Fixed 8 Forest LabSCT-MD-02 41.9 48 MADRS 28.6 Outpatients No Flexible 8 Forest Lab

7

MADRS= Montgomery–Åsberg Depression Rating ScaleHAMD= Hamilton Rating Scale for DepressionNC= unclear

8

Section 6: Characteristics of trials by different comparisons.Age, mean (yrs)

Male, %

Baseline depression severity (MADRS)*, mean

Fixed dosage regimen

8-week outcome assessment

Citalopram vs placebo (10 trials)

45.6 40% 28.9 5 trials (50%) 4 trials (40%)

Escitalopram vs placebo (12 trials)

45.9 36% 29.2 4 trials (33%) 11 trials (91.6%)

Escitalopram vs citalopram (7 trials)

41.2 34% 31.2 4 trials (57%) 5 trials (71%)

*MADRS, Montgomery-Åsberg depression rating scale

9

Section 7: Consumption and cost analyses for the citalopram, its generic forms, and escitalopram from the French national health insurance information system.

Number of reimbursements DDD* units(in thousands)

Annual reimbursement cost(in millions of euros)†

YearCitalopram Citalopram

generic drugs

Escitalopram

Citalopram Citalopram generic drugs

Escitalopram

Citalopram Citalopram generic drugs

Escitalopram

2003 2,634,520 9,215 – 89,166 342 – 60.9 0.1 –

2004 2,184,828 87,2903 – 73,905 30,348 – 50.8 14.1 –

2005 1,335,787 160,4962 457,355 45,126 55,210 15,732 31.5 25.6 8.6

2006 757,861 1,676,548 1,709,140 25,200 57,179 62,095 16.0 24.4 33.4

2007 431,068 1,813,318 2,626,081 14,004 61,264 98,888 8.6 24.6 50.7

2008 263,646 1,851,633 3,460,475 8,705 61,769 125,788 5.3 23.0 63.0

2009 247,447 1,735,815 4,273,723 7,801 57,533 149,165 4.6 20.2 75.4

2010 237,262 1,739,404 5,486,320 7,607 58,567 193,839 4.4 20.3 96.8

*DDD, defined daily dosage: For a given reimbursement, the corresponding number of DDD units was the number of pills × the dosage × the number of boxes reimbursed divided by the DDD. For instance, the reimbursement of 2 boxes of 28 pills of escitalopram, 20 mg, would be 112 DDD units (28×20×2/10).

† For a given reimbursement, the corresponding cost was the number of boxes reimbursed × the direct unit price × the amount of reimbursement coverage.

10

Section 8: Meta-analysis of efficacy data for head-to-head trials.

NOTE: Weights are from random effec ts analys is

. (0.39, 6.62)with es timated predic tive interval

D+L Overal l (I-squared = 80.0%, p = 0.000)

Ou 2011

I-V Overal l

Study

Moore 2005

ID

SCT-MD-01, Burke 2002

99003, Montgomery 2001, Lepola 2003

Yevtushenko 2007

99022, Colonna 2005

SCT-MD-02

1.60 (1.05, 2.46)

0.85 (0.49, 1.49)

1.44 (1.19, 1.73)

2.12 (1.29, 3.47)

OR (95% CI)

1.15 (0.75, 1.77)

1.62 (1.03, 2.52)

10.53 (4.42, 25.04)

1.31 (0.86, 2.00)

1.02 (0.62, 1.67)

667/1083

83/120

Events ,

105/142

Treatment

122/252

95/156

103/109

104/175

55/129

597/1091

87/120

Events ,

87/152

Control

57/127

79/161

137/221

96/182

54/128

100.00

%

13.94

Weight

14.70

(D+L)

15.46

15.25

10.40

15.56

14.69

1.60 (1.05, 2.46)

0.85 (0.49, 1.49)

1.44 (1.19, 1.73)

2.12 (1.29, 3.47)

OR (95% CI)

1.15 (0.75, 1.77)

1.62 (1.03, 2.52)

10.53 (4.42, 25.04)

1.31 (0.86, 2.00)

1.02 (0.62, 1.67)

667/1083

83/120

Events ,

105/142

Treatment

122/252

95/156

103/109

104/175

55/129

1.1 .2 .5 1 2 5 10

Odds ratio > 1 favours escitalopram over citalopram- I-V : Inverse-variance fixed effect model.   - D+L: random effect dersimonian.- For the efficacy analysis: The 95% prediction interval was 0.39–6.62, which overlapped 1 and so in

some settings, escitalopram may not have been superior to citalopram. - Heterogeneity was considerable across trials (I²=80%; τ²=0.26), but mainly because of one trial,

Yevtushenko 2007, which showed outlying results. After excluding this trial, the heterogeneity was moderate (I²=39% and τ²=0.04) and the meta-analysis showed significant superiority of escitalopram over citalopram (random-effects OR 1.30 [1.02–1.66]).

11

Section 9: Funnel plot of efficacy data for head-to-head trials.0

.1

.2

.3

.4

.5

Sta

ndar

d er

ror

-1 0 1 2 3Effect estimate

St udies

1%

5%

10%

- Criteria to apply asymmetry tests were not met, because of fewer than 10 trials, the considerable heterogeneity and an insufficiently large difference in precision of the largest and smallest study.

- The funnel plot of the 7 comparisons did not reveal asymmetry, although Yevtushenko 2007 had the largest standard error and showed the largest outlying treatment effect.

12

Section 10: Meta-analysis of acceptability data for head-to-head trials

NOTE: Weights are from random effec ts analys is

. (0.65, 2.47)with es timated predic tive interval

D+L Overal l (I-squared = 26.0%, p = 0.230)

Yevtushenko 2007

SCT-MD-02

Moore 2005

I-V Overal l

Study

99003, Montgomery 2001, Lepola 2003

99022, Colonna 2005

ID

Ou 2011

SCT-MD-01, Burke 2002

1.27 (0.93, 1.72)

3.53 (0.43, 29.08)

0.85 (0.48, 1.51)

2.60 (1.20, 5.63)

1.25 (0.98, 1.61)

0.86 (0.34, 2.19)

1.62 (0.97, 2.69)

OR (95% CI)

1.08 (0.50, 2.35)

1.10 (0.68, 1.78)

921/1083

108/109

96/129

132/142

Events ,

146/156

144/175

Treatment

106/120

189/252

925/1091

214/221

99/128

127/152

Events ,

152/161

135/182

Control

105/120

93/127

100.00

2.03

19.01

12.29

Weight

9.11

21.99

(D+L)

12.19

23.38

%

1.27 (0.93, 1.72)

3.53 (0.43, 29.08)

0.85 (0.48, 1.51)

2.60 (1.20, 5.63)

1.25 (0.98, 1.61)

0.86 (0.34, 2.19)

1.62 (0.97, 2.69)

OR (95% CI)

1.08 (0.50, 2.35)

1.10 (0.68, 1.78)

921/1083

108/109

96/129

132/142

Events ,

146/156

144/175

Treatment

106/120

189/252

1.1 .2 .5 1 2 5 10

Odds ratio > 1 favours escitalopram over citalopram

13

Section 11: Meta-analysis of efficacy data for placebo-controlled trials.

NOTE : W eights are from random effects analysis

. (1.24, 1.83)

. (1.08, 2.24)

with estimated predictive interval

with estimated predictive interval

.

.

.

.

citalopram86141, Nyth 1992

89303, Montgomery 1992

91206, Feighner 1999

99003, Montgomery 2001, Lepola 2003S CT-MD-01, B urke 2002CIT-MD-03, Roose 200489306

29060/785S CT-MD-02

85A , Mendles 1999

D+L S ubtotal (I-squared = 0.0% , p = 0.648)

I-V S ubtotal

escitalopram99003, Montgomery 2001, Lepola 2003

99001, W ade 2002

S CT-MD-01, B urke 2002

99024, K asper 2005B ose 2008S CT-MD-02

S CT-MD-26

S CT-MD-27S CT-MD-35

A K 130926, C layton 2006

A K 130927, C layton 2006F1J-US -HMCR, P igott 2007, N ieremberg 2007

D+L S ubtotal (I-squared = 27.4% , p = 0.176)

I-V S ubtotal

ID

S tudy

1.25 (0.60, 2.59)

1.77 (0.92, 3.40)

1.51 (1.01, 2.28)

1.25 (0.80, 1.95)2.32 (1.37, 3.94)1.08 (0.59, 1.97)1.32 (0.79, 2.19)

1.86 (1.14, 3.03)1.27 (0.77, 2.10)

1.98 (0.96, 4.07)

1.50 (1.27, 1.78)

1.50 (1.27, 1.78)

2.02 (1.29, 3.18)

1.63 (1.09, 2.44)

2.67 (1.68, 4.27)

0.91 (0.60, 1.38)1.33 (0.82, 2.17)1.30 (0.79, 2.14)

1.46 (0.91, 2.34)

1.70 (1.05, 2.75)1.57 (0.95, 2.58)

1.40 (0.88, 2.22)

1.96 (1.21, 3.17)1.44 (0.94, 2.23)

1.55 (1.33, 1.82)

1.55 (1.36, 1.77)

OR (95% CI)

70/98

51/134

220/521

79/16157/12734/87100/185

102/20754/128

25/89

792/1737

95/156

103/191

122/252

78/17459/13255/129

61/154

69/13656/138

82/149

90/138109/274

979/2023

Treatment

E vents,

34/51

17/66

42/129

67/15433/12734/9142/89

36/10547/129

15/91

367/1032

67/154

79/189

33/127

85/18051/13547/129

48/155

51/13541/135

64/137

69/14143/137

678/1754

Control

E vents,

5.28

6.58

16.91

14.2410.037.6610.92

11.8511.14

5.39

100.00

8.59

10.00

8.20

9.607.677.41

8.15

7.797.41

8.24

7.859.10

100.00

(D+L)

W eight%

1.25 (0.60, 2.59)

1.77 (0.92, 3.40)

1.51 (1.01, 2.28)

1.25 (0.80, 1.95)2.32 (1.37, 3.94)1.08 (0.59, 1.97)1.32 (0.79, 2.19)

1.86 (1.14, 3.03)1.27 (0.77, 2.10)

1.98 (0.96, 4.07)

1.50 (1.27, 1.78)

1.50 (1.27, 1.78)

2.02 (1.29, 3.18)

1.63 (1.09, 2.44)

2.67 (1.68, 4.27)

0.91 (0.60, 1.38)1.33 (0.82, 2.17)1.30 (0.79, 2.14)

1.46 (0.91, 2.34)

1.70 (1.05, 2.75)1.57 (0.95, 2.58)

1.40 (0.88, 2.22)

1.96 (1.21, 3.17)1.44 (0.94, 2.23)

1.55 (1.33, 1.82)

1.55 (1.36, 1.77)

OR (95% CI)

70/98

51/134

220/521

79/16157/12734/87100/185

102/20754/128

25/89

792/1737

95/156

103/191

122/252

78/17459/13255/129

61/154

69/13656/138

82/149

90/138109/274

979/2023

Treatment

E vents,

1.2 .5 1 2 5

Odds ratio > 1 favours escitalopram or citalopram over placebo

Section 12: Funnel plot for efficacy data for placebo-controlled trials.0

.1

.2

.3

Stand

ard error

-1 -.5 0 .5 1Effect estimate

St udies

1%

5%

10%

0

.1

.2

.3

.4

Stand

ard error

-1 -.5 0 .5 1Effect estimate

St udies

1%

5%

10%

14

Section 13: Meta-analysis for acceptability data for placebo-controlled trials.

NOTE: Weights are from random effects analysis

. (0.73, 1.14)

. (0.58, 1.36)

with estimated predictive interval

with estimated predictive interval

.

.

.

.

citalopram

86141, Nyth 1992

89303, Montgomery 1992

91206, Feighner 1999

99003, Montgomery 2001, Lepola 2003

SCT-MD-01, Burke 2002

CIT-MD-03, Roose 2004

89306

29060/785

SCT-MD-02

85A, Mendles 1999

D+L Subtotal (I-squared = 0.0%, p = 0.482)

I-V Subtotal

escitalopram

99003, Montgomery 2001, Lepola 2003

99001, Wade 2002

SCT-MD-01, Burke 2002

99024, Kasper 2005

Bose 2008

SCT-MD-02

SCT-MD-26

SCT-MD-27

SCT-MD-35

AK130926, Clayton 2006

AK130927, Clayton 2006

F1J-US-HMCR, Pigott 2007, Nieremberg 2007

D+L Subtotal (I-squared = 24.7%, p = 0.202)

I-V Subtotal

ID

Study

0.64 (0.30, 1.37)

1.28 (0.67, 2.46)

1.01 (0.67, 1.53)

1.82 (0.77, 4.30)

1.08 (0.62, 1.88)

0.48 (0.22, 1.04)

0.93 (0.52, 1.69)

0.77 (0.42, 1.41)

0.78 (0.43, 1.43)

0.77 (0.42, 1.38)

0.91 (0.75, 1.10)

0.91 (0.75, 1.10)

1.58 (0.68, 3.62)

0.94 (0.54, 1.62)

1.19 (0.73, 1.92)

0.60 (0.33, 1.10)

0.64 (0.36, 1.13)

0.79 (0.43, 1.45)

0.59 (0.33, 1.03)

0.67 (0.36, 1.26)

0.95 (0.54, 1.67)

0.69 (0.40, 1.18)

1.22 (0.71, 2.08)

1.38 (0.86, 2.22)

0.89 (0.73, 1.07)

0.89 (0.76, 1.05)

OR (95% CI)

64/98

100/134

349/521

152/161

93/127

66/87

139/185

163/207

99/128

48/89

1273/1737

146/156

160/191

189/252

144/174

96/132

100/129

116/154

108/136

106/138

106/149

105/138

216/274

1592/2023

Treatment

Events,

38/51

46/66

86/129

139/154

91/127

79/91

68/89

87/105

105/129

55/91

794/1032

139/154

160/189

91/127

160/180

109/135

105/129

130/155

115/135

105/135

107/137

102/141

100/137

1423/1754

Control

Events,

6.38

8.51

21.72

4.94

11.99

5.96

10.37

9.87

9.88

10.38

100.00

4.47

8.73

10.66

7.51

8.22

7.56

8.46

7.10

8.39

9.06

9.06

10.79

100.00

(D+L)

Weight

%

0.64 (0.30, 1.37)

1.28 (0.67, 2.46)

1.01 (0.67, 1.53)

1.82 (0.77, 4.30)

1.08 (0.62, 1.88)

0.48 (0.22, 1.04)

0.93 (0.52, 1.69)

0.77 (0.42, 1.41)

0.78 (0.43, 1.43)

0.77 (0.42, 1.38)

0.91 (0.75, 1.10)

0.91 (0.75, 1.10)

1.58 (0.68, 3.62)

0.94 (0.54, 1.62)

1.19 (0.73, 1.92)

0.60 (0.33, 1.10)

0.64 (0.36, 1.13)

0.79 (0.43, 1.45)

0.59 (0.33, 1.03)

0.67 (0.36, 1.26)

0.95 (0.54, 1.67)

0.69 (0.40, 1.18)

1.22 (0.71, 2.08)

1.38 (0.86, 2.22)

0.89 (0.73, 1.07)

0.89 (0.76, 1.05)

OR (95% CI)

64/98

100/134

349/521

152/161

93/127

66/87

139/185

163/207

99/128

48/89

1273/1737

146/156

160/191

189/252

144/174

96/132

100/129

116/154

108/136

106/138

106/149

105/138

216/274

1592/2023

Treatment

Events,

1.2 .5 1 2 5

Odds ratio > 1 favours escitalopram or citalopram over placebo

15

Section 14: Consumption levels (monthly no. of prescriptions) between 2003 and 2011 in France.

Num

ber o

f rei

mbu

rsem

ents

0

100000

200000

300000

400000

500000

600000

700000

800000

900000

Year

Jan 2003 Jan 2004 Jan 2005 Jan 2006 Jan 2007 Jan 2008 Jan 2009 Jan 2010 Jan 2011

CITALOPRAM CITALOPRAM GENERIC DRUGS ESCITALOPRAM

Section 15: Consumption levels (monthly defined daily dosage [DDD] units) between 2003 and 2011 in France.

DD

D c

onsu

mpt

ion

0

5000000

10000000

15000000

20000000

25000000

30000000

Year

Jan 2003 Jan 2004 Jan 2005 Jan 2006 Jan 2007 Jan 2008 Jan 2009 Jan 2010 Jan 2011

CITALOPRAM CITALOPRAM GENERIC DRUG ESCITALOPRAM

16

Section 16: Monthly consumption levels for escitalopram versus citalopram and its generic forms combined.

Num

ber o

f rei

mbu

rsem

ents

0

100000

200000

300000

400000

500000

600000

700000

800000

900000

Year

Jan 2003 Jan 2004 Jan 2005 Jan 2006 Jan 2007 Jan 2008 Jan 2009 Jan 2010 Jan 2011

CITALOPRAM (AND GENERIC DRUGS) ESCITALOPRAM

Section 17: Total monthly consumption of escitalopram, citalopram and its generic forms combined.

Num

ber o

f rei

mbu

rsem

ents

0

100000

200000

300000

400000

500000

600000

700000

800000

900000

Year

17