Risks of Digestive System Side-Effects of Selective Serotonin Reuptake Inhibitors in Patients with Depression: A Network Meta-Analysis

Figures & data

Figure 1 Flow diagram of search.

Table 1 Characteristic of Included Studies

Study	Year	Length of RCT	Age	Diagnostic criteria	Recruitment	Intervention	Sample Size	Response
Yevtushenko VY^Citation24	2007	6	25--45	DSM-IV	Russia	Esc/Cia	108/108	2/8
Wade A^Citation25	2002	8	18--65	DSM-IV	NA	Esc/Pla	191/189	17/7
Moore N^Citation26	2005	8	18--65	DSM IV	France	Esc/Cia	142/152	6/11
Valle-Cabrera R^Citation27	2018	10	18--65	DSM-IV	Cuban	Ser/Pla	39/38	27/12
Mao PX^Citation28	2008	8	18--65	DSM-IV	China	Esc/Flu	123/117	15/16
Dunbar GC^Citation29	1993	6	18--65	DSM-III	US	Par/Pla	167/169	93/35
Wang YJ^Citation39	2016	6	20--65	CCMD-3	China	Esc/Cia	48/48	3/3
Zhu YH^Citation41	2015	8	19--64	ICD-10	China	Par/Esc	23/23	4/1
Liu R^Citation42	2013	6	18--60	CCMD-3	China	Esc/Cia	40/40	3/6
Xu Y^Citation43	2011	6	18--60	CCMD-3	China	Esc/Cia	35/35	9/7
Wang XF^Citation44	2010	6	18--55	CCMD-3	China	Esc/Flu	36/34	5/5
Zhang XX^Citation45	2010	6	18--62	CCMD-3	China	Esc/Ser	35/35	9/9
Hu MR^Citation46	2010	6	18--60	CCMD-3	China	Esc/Cia	25/23	3/5
Xun GL^Citation47	2009	6	18--65	CCMD-3	China	Esc/Cia	115/117	26/26
Liu XB^Citation48	2009	6	18--65	CCMD-3	China	Esc/Par	37/36	10/16
Xu FL^Citation52	2009	6	18--60	CCMD-3	China	Esc/Flu	39/38	12/8
Yang R^Citation49	2008	6	24--61	CCMD-3	China	Par/Cia	27/29	4/1
Hsu JW^Citation30	2011	6	20--65	DSM-IV	China	Ser/Cia	26/25	7/5
Ou JJ^Citation31	2011	6	18--65	DSM-IV	China	Esc/Cia	115/117	22/25
Woo YS^Citation32	2017	6	18--65	DSM-IV	Korean	Par/Esc	150/148	44/40
Detke MJ^Citation33	2004	8	≥18	DSM-IV	USA	Par/Pla	86/93	16/6
Perahia DG^Citation34	2006	8	≥18	DSM-IV	NA	Par/Pla	97/99	10/6
Jin XS^Citation50	2015	12	≥18	CCMD-3	China	Par/Esc	34/37	8/12
Croft H^Citation35	1999	8	≥18	DSM-IV	US	Ser/Pla	118/119	68/25
Rickels K^Citation36	1989	6	≥18	DSM-III	NA	Par/Pla	55/56	29/8
Goldstein DJ^Citation37	2004	8	≥18	DSM-IV	US	Par/Pla	87/89	26/5
Lepola UM^Citation38	2003	8	18--65	DSM-IV	Denmark	Esc/Cia/Pla	155/160/154	37/35/19
Zhou ZX^Citation40	2018	12	≥18	CCMD-3	China	Par/Esc	28/28	8/3
Cen LP^Citation53	2009	6	18--62	CCMD-3	China	Par/Esc	28/28	9/7
Nierenberg AA^Citation51	2007	8	≥18	DSM-IV	NA	Esc/Pla	274/137	88/32

Abbreviations: CCMD, Chinese Classification and the Diagnose Criterion of Mental Disorder; DSM, Diagnostic and Statistical Manual of Mental Disorders; ICD, International Classification of Diseases; RCT, random controlled trial; Esc, escitalopram; Cia, citalopram; Flu, fluoxetine; Par, paroxetine; Pla, placebo; Ser, sertraline; US, the United States; NA, not available.

Figure 2 Risk of bias.

Figure 3 Network of evidence.

Notes: Width of the lines was proportional to the number of trials comparing every pair of treatments. Size of every circle was proportional to the number of randomly assigned participants.

Abbreviations: Cia, citalopram; Esc, escitalopram; Flu, fluoxetine; Ser, sertraline; Par, paroxetine; Pla, placebo.

Table 2 Results of SSRIs for the Incidence of Induced-Digestive System Side-Effects from Network Meta-Analysis

Esc
0.86 (0.61, 1.19)	Cia
0.56 (0.32, 0.99)	0.66 (0.36, 1.21)	Ser
1.07 (0.58, 2.04)	1.24 (0.63, 2.61)	1.9 (0.82, 4.47)	Flu
0.62 (0.43, 0.87)	0.72 (0.45, 1.14)	1.1 (0.61, 1.97)	0.58 (0.28, 1.15)	Par
2.47 (1.75, 3.51)	2.87 (1.85, 4.5)	4.39 (2.64, 7.31)	2.31 (1.12, 4.61)	3.97 (2.85, 5.68)	Pla

Note: Bold values indicate P<0.05, data presented as OR (95% CI).

Abbreviations: Esc, escitalopram; Cia, citalopram; Flu, fluoxetine; Ser, sertraline; Par, paroxetine; Pla, placebo.

Figure 4 Forest plots of network meta-analysis of all trials for acceptability. (A) Forest plots for the outcomes compared with Escitalopram. (B) Forest plots for the outcomes compared with Citalopram. (C) Forest plots for the outcomes compared with Sertraline. (D) Forest plots for the outcomes compared with Fluoxetine. (E) Forest plots for the outcomes compared with Paroxetine. (F) Forest plots for the outcomes compared with Placebo.

Abbreviations: Cia, citalopram; CrI, confidence intervals; Esc, escitalopram; Flu, fluoxetine; Ser, sertraline; Par, paroxetine; Pla, placebo.

Table 3 Rank Probability of Caused Digestive System Side Effects Among SSRIs

	1	2	3	4	5	6
Esc	0.0005	0.00375	0.1189	0.54815	0.32915	0
Cia	0.0209	0.0962	0.54315	0.24135	0.0984	0
Ser	0.61095	0.282	0.07395	0.0219	0.0112	0
Flu	0.02965	0.05195	0.18205	0.17665	0.54715	0.01255
Par	0.33845	0.5661	0.08195	0.0119	0.0016	0
Pla	0	0	0	0.0005	0.0125	0.98745

Abbreviations: Esc, escitalopram; Cia, citalopram; Flu, fluoxetine; Ser, sertraline; Par, paroxetine; Pla, placebo; Rank probability, preferred direction=1.

Figure 5 Rank probability of caused digestive system side effects among SSRIs.

Abbreviations: Cia, citalopram; Esc, escitalopram; Flu, fluoxetine; Ser, sertraline; Par, paroxetine; Pla, placebo.

Figure 6 The heterogeneity of the included studies.

Abbreviations: Cia, citalopram; Esc, escitalopram; Flu, fluoxetine; Ser, sertraline; Par, paroxetine; Pla, placebo.

Figure 7 Summarized results of direct and indirect comparisons between different SSRI.

Abbreviations: Cia, citalopram; Esc, escitalopram; Flu, fluoxetine; Ser, sertraline; Par, paroxetine; Pla, placebo.

Figure 8 Comparison-adjusted funnel plots.

Notes: The red line suggests the null hypothesis that the study-specific effect sizes do not differ from the respective comparison-specific pooled effect estimates. Different colors represent different comparisons.

Yevtushenko VY, Belous AI, Yevtushenko YG, Gusinin SE, Buzik OJ, Agibalova TV. Efficacy and tolerability of escitalopram versus citalopram in major depressive disorder: a 6-week, multicenter, prospective, randomized, double-blind, active-controlled study in adult outpatients. Clin Ther. 2007;29(11):2319–2332. doi:10.1016/j.clinthera.2007.11.014

 PubMed Web of Science ®Google Scholar

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. doi:10.1097/00004850-200205000-00001

 PubMed Web of Science ®Google Scholar

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. doi:10.1097/00004850-200505000-00002

 PubMed Web of Science ®Google Scholar

Valle-Cabrera R, Mendoza-Rodríguez Y, Robaina-García M, et al. Efficacy of sertraline in patients with major depressive disorder naive to selective serotonin reuptake inhibitors: a 10-week randomized, Multicenter, Placebo-Controlled, Double-Blind, Academic Clinical Trial. J Clin Psychopharmacol. 2018;38(5):454–459. doi:10.1097/JCP.0000000000000950

 PubMed Web of Science ®Google Scholar

Mao PX, Tang YL, Jiang F, et al. Escitalopram in major depressive disorder: a multicenter, randomized, double-blind, fixed-dose, parallel trial in a Chinese population. Depress Anxiety. 2008;25(1):46–54. doi:10.1002/da.20222

 PubMed Web of Science ®Google Scholar

Dunbar GC, Claghorn JL, Kiev A, Rickels K, Smith WT. A comparison of paroxetine and placebo in depressed outpatients. Acta Psychiatr Scand. 1993;87(5):302–305. doi:10.1111/j.1600-0447.1993.tb03376.x

 PubMed Web of Science ®Google Scholar

Wang Y. Comparison of the effects of escitalopram and citalopram in the treatment of depression. Strait Pharma J. 2016;28(12):119–120.

 Google Scholar

Zhu Y. Analysis of the therapeutic effect of escitalopram oxalate and paroxetine hydrochloride on 46 patients with depression. Contemp Med. 2015;21(05):150–151.

 Google Scholar

Liu R, Yu Z. Wu X. The efficacy and side effects of escitalopram in the treatment of depression. Jilin med j. 2013;34(24):4871–4872.

 Google Scholar

Xu Y, Pan X, Pan X, Hao C, Deng Y. A controlled study of escitalopram and citalopram in the treatment of depression. J Clin psychiatry. 2011;21(01):42.

 Google Scholar

Wang X, Han D, Wang L. Escitalopram vs. Fluoxetine in the Treatment of Depression: A Control Study. Eval Anal Drug-Use Hospital China. 2010;10(07):620–622.

 Google Scholar

Zhang X, Xu X. Comparison of the treatment of Escitalopram and Sertraline for depression. Med j Chinese People’s Health. 2010;22(17):2205–2206+2209.

 Google Scholar

Hu M, Li Y, Lu X, Xu G, Chen J. Escitalopram vs citalopram for depression: a randomized, double-blind, double-dummy, multicenter parallel controlled study. Central South Pharmacy. 2010;8(01):67–69.

 Google Scholar

Xun G, Li Y, Zhao J, et al. Escitalopram vs citalopram in treatment of depression: a randomized, double-blind, double-dummy, multicenter parallel controlled study. Chin J New Drugs Clin Rem. 2009;28(04):263–267.

 Google Scholar

Liu X, Zhang Y, Tan Q, Chen Y, Wang Z, Nie D. A controlled study in the treatment of depression with escitalopram and paroxetine. J Clin psychiatr. 2009;19(03):177–178.

 Google Scholar

Xu F, Xu L. Escitalopram vs. Fluoxetine for Depression: A Control Study. China Pharm. 2009;20(14):1084–1086.

 Google Scholar

Yang R. A comparative study of citalopram and paroxetine in the treatment of depression. Shanxi Med j. 2008;37(06):563.

 Google Scholar

Hsu JW, Su TP, Huang CY, Chen YS, Chou YH. Faster onset of antidepressant effects of citalopram compared with sertraline in drug-naïve first-episode major depressive disorder in a Chinese population: a 6-week double-blind, randomized comparative study. J Clin Psychopharmacol. 2011;31(5):577–581. doi:10.1097/JCP.0b013e31822c091a

 PubMed Web of Science ®Google Scholar

Ou JJ, Xun GL, Wu RR, et al. Efficacy and safety of escitalopram versus citalopram in major depressive disorder: a 6-week, multicenter, randomized, double-blind, flexible-dose study. Psychopharmacology. 2011;213(2–3):639–646. doi:10.1007/s00213-010-1822-y

 PubMed Web of Science ®Google Scholar

Woo YS, McIntyre RS, Kim JB, et al. Paroxetine versus venlafaxine and escitalopram in Korean patients with major depressive disorder: a randomized, rater-blinded, six-week study. Clin Psychopharmacol Neurosci. 2017;15(4):391–401. doi:10.9758/cpn.2017.15.4.391

 PubMed Web of Science ®Google Scholar

Detke MJ, Wiltse CG, Mallinckrodt CH, McNamara RK, Demitrack MA, Bitter I. Duloxetine in the acute and long-term treatment of major depressive disorder: a placebo- and paroxetine-controlled trial. Eur neuropsychopharmacol. 2004;14(6):457–470. doi:10.1016/j.euroneuro.2004.01.002

 PubMed Web of Science ®Google Scholar

Perahia DG, Wang F, Mallinckrodt CH, Walker DJ, Detke MJ. Duloxetine in the treatment of major depressive disorder: a placebo- and paroxetine-controlled trial. Eur psychiatr. 2006;21(6):367–378. doi:10.1016/j.eurpsy.2006.03.004

 PubMed Web of Science ®Google Scholar

Jin X, Xu X, Xu D, Yy C. Clinical efficacy and safety of escitalopram oxalate versus paroxetine in the treatment of unipolar depression. Chin J Clin Pharmacol. 2015;31(10):812–814.

 Google Scholar

Croft H, Settle E Jr, Houser T, Batey SR, Donahue RM, Ascher JA. A placebo-controlled comparison of the antidepressant efficacy and effects on sexual functioning of sustained-release bupropion and sertraline. Clin Ther. 1999;21(4):643–658. doi:10.1016/S0149-2918(00)88317-4

 PubMed Web of Science ®Google Scholar

Rickels K, Amsterdam J, Clary C, Fox I, Schweizer E, Weise C. A placebo-controlled, double-blind, clinical trial of paroxetine in depressed outpatients. Acta Psychiatr Scand Suppl. 1989;350:117–123. doi:10.1111/j.1600-0447.1989.tb07188.x

 PubMedGoogle Scholar

Goldstein DJ, Lu Y, Detke MJ, Wiltse C, Mallinckrodt C, Demitrack MA. Duloxetine in the treatment of depression: a double-blind placebo-controlled comparison with paroxetine. J Clin Psychopharmacol. 2004;24(4):389–399. doi:10.1097/01.jcp.0000132448.65972.d9

 PubMed Web of Science ®Google Scholar

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. doi:10.1097/00004850-200307000-00003

 PubMed Web of Science ®Google Scholar

Zhou Z. Clinical efficacy and adverse reactions of escitalopram and paroxetine in the treatment of single depression. Contemp Med. 2018;24(22):152–153.

 Google Scholar

Cen L, Zou J, Tong J. Comparative study  on escitalopram and paroxetine in the treatment of depression. Shanghai arch psychiatr. 2009;21(01):41–42.

 Google Scholar

Nierenberg AA, Greist JH, Mallinckrodt CH, et al. 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. doi:10.1185/030079906X167453

 PubMed Web of Science ®Google Scholar