Anti-Inflammatory Treatment Efficacy in Major Depressive Disorder: A Systematic Review of Meta-Analyses

Figures & data

Table 1 Study Characteristics of the Included Meta-Analyses

Study	Population	Treatment	Comparator	N with Treatment^a	Outcome Measures	RCT Only
Minocycline
Rosenblat et al, 2018^Citation43	MDD, one study with comorbid HIV	Monotherapy minocycline or TAU + minocycline 200mg/day	Placebo or TAU + placebo	80	HAMD MADRS	Yes
Zheng et al, 2019^Citation44	MDD	TAU + minocycline 200mg/day	TAU + placebo	57	HAMD MADRS	Yes
Köhler-Forsberg et al, 2019^Citation45	MDD, one study with comorbid HIV	TAU + minocycline 200mg/day	TAU + placebo	52	HAMD MADRS	Yes
Bai et al, 2020^Citation46	MDD, one study with comorbid HIV	Monotherapy minocycline or TAU + minocycline 200mg/day	Placebo or TAU + placebo	82	HAMD MADRS	Yes
Hang et al, 2021^Citation47	MDD, one study with comorbid HIV	Monotherapy minocycline or TAU + minocycline 200mg/day	Placebo or TAU + placebo	39	HAMD	Yes
Celecoxib
Faridhosseini et al, 2014^Citation48	MDD, one study only females	Antidepressants + celecoxib 200mg/day or 400mg/day	Antidepressants + placebo	160	HAMD	Yes
Na et al, 2014^Citation49/ Na et al, 2016^Citation50	MDD, one study only females	Antidepressants + celecoxib 200mg/day or 400mg/day	Antidepressants + placebo	75	HAMD	Yes
Köhler et al, 2014^Citation51	MDD, one study only females	Antidepressant + celecoxib 200mg/day or 400mg/day	Antidepressants + placebo	68	HAMD	Yes
Köhler-Forsberg et al, 2019^Citation45	MDD, one study only females	Antidepressant + celecoxib 200mg/day or 400mg/day	Antidepressants + placebo	68	HAMD	Yes
Bai et al, 2020^Citation46	MDD, one study only females	Antidepressants + celecoxib 400mg/days	Antidepressants + placebo	74	HAMD	Yes
Yuan et al, 2020^Citation52	MDD	Antidepressant + celecoxib 400mg/days	Antidepressant + placebo	50	HAMD	Yes
Hang et al, 2021^Citation47	MDD, one study only females	Antidepressant + celecoxib 200mg/day or 400mg/day	Antidepressants + placebo	52	HAMD	Yes
Omega3 fatty acids
Martins et al, 2012^Citation53 reanalysis	MDD^b, three studies only perinatal women, one study comorbid Parkinson’s disease	Monotherapy omega3 or antidepressants + omega3 multiple regimen^e	Placebo or antidepressants + placebo	265	HAMD MADRS EPDS	Yes
Martins et al, 2012^Citation53 updated analysis	MDD^b,c, three studies only perinatal women, each one study comorbid Parkinson’s disease, comorbid coronary heart disease, comorbid diabetes, only elderly women	Monotherapy omega3 or antidepressants + omega3 multiple regimen^f	Placebo or antidepressants + placebo	612	HAMD MADRS EPDS BDI-II GDS IDS-SR	Yes
Lin et al, 2012^Citation54	MDD^b, three studies only perinatal women, one study comorbid Parkinson’s disease	Monotherapy omega3 or antidepressants + omega3 multiple regimen^g	Placebo or antidepressants + placebo	254	HAMD BDI MADRS	Yes
Grosso et al, 2014^Citation55	MDD^c,d, three studies only elderly women	Monotherapy omega3 or antidepressants + omega3 multiple regimen^h	Placebo or antidepressants + placebo	229	HAMD MADRS GDS BDI-II	Yes
Appleton et al, 2015^Citation56	MDD^c, one study each with comorbid diabetes, coronary heart disease, Parkinson’s disease, renal disease, one study only elderly women	Monotherapy omega3 or antidepressants + omega3 multiple regimen^k	Placebo or antidepressants + placebo	727	HAMD MADRS GDS BDI-II	Yes
Mocking et al, 2016^Citation57	MDD, one study each with comorbid coronary heart disease and diabetes	Monotherapy omega3 or antidepressants + omega3 multiple regimen^j	Placebo or antidepressants + placebo	595	HAMD, MADRS	Yes
Sarris et al, 2016^Citation58	MDD, one study with comorbid diabetes	Antidepressants + omega3 multiple regimen^l	Antidepressants + placebo	226	HAMD BDI-II MADRS	Yes
Wei-Hong et al, 2017^Citation59	MDD (how diagnosis was obtained not clear)	Monotherapy omega3 multiple regimen^i	Placebo	62	HAMD	Yes
Schefft et al, 2017^Citation60	MDD, one study each with comorbid diabetes, coronary heart disease, Parkinson’s disease, Multiple sclerosis	Antidepressants + omega3 multiple regimen^m	Antidepressants + placebo	212	HAMD BDI MADRS	Yes
Bai et al, 2020^Citation46	MDD^b,c, three studies perinatal women, one study each with Parkinson’s disease, coronary heart disease, diabetes, Multiple sclerosis, one study only elderly women	Monotherapy omega3 or TAU/sertraline + omega3 multiple regimen^n	Placebo or TAU/sertraline + placebo	603	HAMD EPDS MADRS BDI-II GDS	Yes
Luo et al, 2020^Citation61	MDD	Monotherapy omega3 or antidepressants + omega3 multiple regimen^o	Placebo or antidepressants + placebo	493	HAMD MADRS IDS-SR	Yes
Jeremiah et al, 2020^Citation62	MDD	Antidepressants + omega3 multiple regimen^p	Antidepressants + placebo	160	HAMD BDI	Yes
Hang et al, 2021^Citation47	MDD, two studies with comorbid coronary heart disease, one study each with Multiple sclerosis and Parkinson’s disease	Monotherapy omega3 or antidepressants/ TAU + omega3 multiple regimen^q	Placebo or antidepressants/ TAU + placebo	406	BDI-II HAMD MADRS	Yes
Chambergo-Michilot et al, 2021^Citation63	MDD, two studies with coronary heart disease	Sertraline + omega3 multiple regimen^r	Sertraline + placebo	133	HAMD	Yes
Chambergo-Michilot et al, 2021^Citation63	MDD, two studies with coronary heart disease	Sertraline + omega3 multiple regimen^r	Sertraline + placebo	158	BDI	Yes
Multiple agents
Köhler et al, 2014^Citation51	MDD, one study only females	Antidepressants + celecoxib and monotherapy infliximab or TAU + infliximab multiple regimen^s	Placebo or antidepressants/TAU + placebo	98	HAMD	Yes

Notes: ^aAnalyzed if available, otherwise randomized. ^bOne study included patients with dysthymia since MDD was defined this way by the authors (Rees et al, 2008). ^cOne study included patients with dysthymia since MDD was defined this way by the authors (Rondanelli et al, 2010). ^dOne study included patients with dysthymia since MDD was defined this way by the authors (Rondanelli et al, 2011). ^eEPA 2g/day; DHA 2g/day; EPA 4.4g/day+DHA 2.2g/day; EPA 1.1g/day+DHA 0.8g/day; DHA 1.6g/day+EPA 0.4g/day; EPA 2.2g/day+DHA 1.2g/day; EPA 1g/day; EPA 1g/day / EPA 2g/day / EPA 4g/day; DHA 2.4g/day+EPA 0.6g/day; DHA 2.2g/day+EPA 0.6g/day; EPA 0.72g/day+DHA 0.48g/day. ^fEPA 2g/day; DHA 2g/day; EPA 4.4g/day+DHA 2.2g/day; EPA 1.1g/day+DHA 0.8g/day; DHA 1.6g/day+EPA 0.4g/day; EPA 2.2g/day+DHA 1.2g/day; EPA 930mg/day+DHA 750mg/day; EPA 1g/day; EPA 1.67g/day+DHA0.83g/day; EPA 0.9g/day; EPA 1g/day / EPA 2g/day / EPA 4g/day; DHA 2.4g/day+EPA 0.6g/day; DHA 2.2g/day+EPA 0.6g/day; EPA 0.72g/day+DHA 0.48g/day; EPA 1g/day; EPA 1.05g/day+DHA 0.15g/day. ^gEPA 2g/day; DHA 2g/day; EPA 4.4g/day+DHA 2.2g/day; EPA 1.1g/day+DHA 0.8g/day; DHA 1.6g/day+EPA 0.4g/day; EPA 2.2g/day+DHA 1.2g/day; EPA 1 g/day; EPA 1g/day / EPA 2g/day / EPA 4g/day; DHA 2.4g/day+EPA 0.6g/day; DHA 2.2g/day+EPA 0.6g/day; EPA 0.72g/day+DHA 0.48g/day; EPA 1.05g/day+DHA0.15g/day. ^hEPA 2g/day; DHA 2g/day; EPA 4.4g/day+DHA 2.2g/day; EPA 1g/day; EPA 1.67g/day+DHA 0.83g/day; DHA 2.2g/day+EPA 0.6g/day; EPA 1g/day; EPA 1.05g/day+DHA 0.15g/day; EPA 1.8g/day+DHA 0.4g/day; EPA 1.67g/day+DHA 0.83g/day; EPA+DHA 2.5g/day. ⁱEPA 1.1g/day+DHA 0.8g/day; DHA 1.6g/day+EPA 0.4g/day; EPA 2.2 g/day+DHA 1.2g/day. ^jEPA 2g/day; DHA 2g/day; EPA 4.4g/day+DHA 2.2g/day; EPA 930mg/day+DHA 750mg/day; EPA 1g/day; EPA 0.9g/day; EPA 1.06g/day+DHA 0.274g/day; EPA 0.18g/day+DHA 0.9g/day; DHA 1g/ / EPA 1g/day; DHA 2.2g/day+EPA 0.6g/day; EPA 1g/day; EPA 1.05g/day+DHA 0.15g/day; EPA 1.05g/day+DHA 0.15g/day; EPA 1.8g/day+DHA 0.4g/day. ^kEPA 0.9g/day; EPA 930mg/day+DHA 750mg/day; EPA 0.72g/day+DHA 0.48g/day; EPA 1.8g/day+DHA 0.4g/day; DHA 2.2g/day+EPA 0.6g/day; EPA 1g/day; EPA 1.05g/day+DHA 0.15g/day; EPA 1.05g/day+DHA 0.15g/day; DHA 2g/day; EPA 1.06g/day+DHA 0.274g/day / EPA 0.18g/day+DHA 0.9g/day; EPA 1g/day; EPA 2g/day; EPA 1g/day / EPA 2g/day / EPA 4g/day; EPA 1.67g/day+DHA 0.83g/day; DHA 2.4g/day+EPA 0.6g/day; EPA 4.4g/day+DHA 2.2g/day; EPA 740mg/d+DHA 400mg/d / EPA 1480 mg/d+ DHA 800 mg/d; EPA 1080mg/d+DHA 720mg/d; EPA 3g/day; EPA 3420mg/d+DHA 1800 mg/d. ^lEPA 4.4g/day+DHA 2.2g/day; EPA 930mg/day+DHA 750mg/day; EPA 1.8g/day+DHA 0.4g/day; EPA 1g/day / DHA 1g/day; EPA 2g/day; EPA 1g/day / 2g/day / 4g/day; EPA 1g/day; EPA 0.9g/day. ^mDHA 1g/day / EPA 1g/day; EPA 4.4g/day+DHA 2.2g/day; EPA 1.95g/day+DHA 1.35g/day; EPA 1.8g/day+DHA 0.4g/day; EPA 930mg/day+DHA 750mg/day; EPA 1.14g/day+DHA 0.6 g/day; EPA 1g/day; EPA 2g/day; EPA 0.9g/day; EPA 0.72g/day+DHA 0.48g/day. ⁿEPA 2g/day; DHA 2g/day; EPA 4.4g/day+DHA 2.2g/day; EPA 1.1g/day+DHA 0.8g/day; DHA 1.6g/day+EPA 0.4g/day; EPA 2.2g/day+DHA 1.2g/day; EPA 930mg/day+DHA 750mg/day; EPA 1g/day; EPA 1.67g/day+DHA0.83g/day; EPA 0.9g/day; EPA 1.06g/day+DHA 0.274g/day; EPA 0.18g/day+DHA 0.9g/day; EPA 1.06g/day+DHA0.26g/day; EPA 0.18g/day+DHA0.9g/day. ^oEPA 2g/day; DHA 2g/day; EPA 4.4g/day+DHA 2.2g/day; DHA 2,2g/day+EPA 0.6g/day; EPA 1g/day; EPA 1.05g/day+DHA 0.15g/day; DHA 1g/day / EPA 1g/day; EPA 1.06g/day+DHA 0.274g/day / EPA 0.18g/day+DHA 0.9g/day; EPA 1.8g/day+DHA 0.4g/day. ^pEPA 1.8g/day+DHA 0.4g/day; omega3 1g/day; EPA 1g/day; DHA 1g/day / EPA 1g/day; EPA 2g/day; EPA 1g/day / 2g/day / 4g/day. ^qEPA 930mg/day+DHA 750mg/day; EPA 2g/day; EPA 1.8g/day+DHA 0.4g/day; EPA 1g/day; DHA 2g/day; EPA 1g/day; EPA 1.06g/day+DHA 0.274g/day / EPA 0.18g/day+DHA 0.9g/day; EPA 2g/day; EPA 1.06g/day+DHA 0.26g/day / EPA 0.18g/day+DHA 0.9g/day; EPA 1.95g/day+DHA 1.35g/day; EPA 0.72g/day+DHA 0.48g/day. ^rEPA 930mg/day+DHA 750mg/day; omega3 1g/day; omega3 1g/day; EPA 2g/day. ^scelecoxib 200mg/day / 400mg/day; infliximab 5mg/kg.

Abbreviations: MDD, major depressive disorder; HIV, human immunodeficiency virus; TAU, treatment as usual; HAMD, Hamilton Depression Rating Scale; MADRS, Montgomery Asberg Depression Rating Scale; EPDS, Edinburgh Postnatal Depression Scale; BDI, Beck Depression Inventory; GDS, Geriatric Depression Scale; IDS-SR, Inventory of Depressive Symptomatology self-rating; RCT, randomized controlled trial.

Figure 1 PRISMA 2020 flow diagram of the study selection process.

Notes: PRISMA figure adapted from Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. Creative Commons.³⁹

Abbreviations: n, number of studies; MDD, major depressive disorder.

Table 2 R-AMSTAR Quality Rating of Meta-Analyses Ranked in Descending Order and Quality Ratings by the Meta-Analyses of the Included Single Studies

Study	R-AMSTAR Total Score (Max. Score 44)	Overall Quality Estimation of Single Studies in Meta-Analyses
Appleton et al, 2015^Citation56	39	Very low to low
Chambergo-Michilot et al, 2021^Citation63	36	Moderate to high
Hang et al, 2021^Citation47	34	Moderate to high
Mocking et al, 2016^Citation57	33	High
Zheng et al, 2019^Citation44	35, corrected 33^a	Moderate to high
Faridhosseini et al, 2014^Citation48	32	Moderate to high
Bai et al, 2020^Citation46	31	Moderate to high
Grosso et al, 2014^Citation55	31	Range from 4–13 points out of 13 points
Jeremiah et al, 2020^Citation62	31	Low to moderate
Rosenblat et al, 2018^Citation43	31	Low
Köhler-Forsberg et al, 2019^Citation45	30	Low
Wei-Hong et al, 2017^Citation59	30	High
Yuan et al, 2020^Citation52	33, corrected 30^b	High, but only assessed for non-randomized studies which were not studies of interest for this meta-analysis
Na et al, 2014^Citation49	29	Low to high
Köhler et al, 2014^Citation51	28	Low
Luo et al, 2020^Citation61	28	Moderate
Schefft et al, 2017^Citation60	27	Moderate to high
Sarris et al, 2016^Citation58	26	Was not assessed
Lin et al, 2012^Citation54	Not assessable – letter to the editor with selected reanalysis
Martins et al, 2012^Citation53	Not fully assessable – selected reanalysis

Notes: Quality assessment was judged based on what authors reported in the manuscript and Supplemental Material. ^aPublication bias was considered and analyzed but not for the major depression sample that is of interest for this review (only N=2 studies). Thus, two points must be subtracted when only accounting for the major depressed sample. ^bPoints for scientific quality items were only rated for non-randomized studies that were not studies of interest for this review. Thus, three points must be subtracted when only accounting for randomized controlled trials.

Figure 2 Quality of included meta-analysis by R-AMSTAR domain.

Notes: Per item, the relative frequencies (percentage) of studies that were rated by the respective point category is displayed; green represents 4 points, yellow represents three points, orange represents two points, red represents one point. The corrected scores were considered.

Table 3 Parameters Extracted from the Meta-Analyses Indicative of Pooled Efficacy of Anti-Inflammatory Agents

Study	Number of Studies Included^a	Effect Size Mean Difference / Response Yes-No	p	95% CI	Heterogeneity
Minocycline
Rosenblat et al, 2018^Citation43	3	SMD = −0.78	0.005	[−1.33;-0.24]	I^2 = 62%
Zheng et al, 2019^Citation44	2	SMD = −0.81	0.08	[−1.73;0.10]	I^2 = 75%
Köhler-Forsberg et al, 2019^Citation45	2^b	SMD = −0.81	0.08	[−1.72;0.10]	I^2 = 77%
	3^c	SMD = −0.87	0.003	[−1.45;-0.29]	I^2 = 63%
Bai et al, 2020^Citation46	3	SMD = −0.79	0.002	[−1.29;-0.28]	I^2 = 53%
Hang et al, 2021^Citation47	2	RR = 2.83 response rates	0.02	[1.14;6.98]	I^2 = 0%
Celecoxib
Faridhosseini et al, 2014^Citation48	3	SMD = 3.3 (week 4)	0.002	[1.2;5.3]	I^2 = 33%
		SMD = 3.43 (week 6)	<0.001	[1.9;4.9]	I^2 = 0%
Faridhosseini et al, 2014^Citation48	3	OR = 6.6 response rates	<0.001	[2.5;17]	I^2 = 0%
Faridhosseini et al, 2014^Citation48	4	OR = 6.6 remission rates	<0.001	[2.7;15.9]	I^2 = 0%
Na et al, 2014^Citation49/ Na et al, 2016^Citation50	4	WMD = 3.26	<0.001	[1.81;4.71]	I^2 = 0%
Na et al, 2014^Citation49	4	OR = 6.49 response rates	<0.001	[2.89;14.55]	I^2 = 0%
Na et al, 2014^Citation49	4	OR = 6.58 remission rates	<0.001	[2.55;17.00]	I^2 = 0%
Köhler et al, 2014^Citation51	4	SMD = −0.82	<0.001	[−1.17;-0.46]	I^2 = 0%
Köhler et al, 2014^Citation51	3	OR = 6.59 response rates	<0.001	[2.24;19.42]	I^2 = 0%
Köhler et al, 2014^Citation51	4	OR = 7.89 remission rates	<0.001	[2.94;21.17]	I^2 = 0%
Köhler-Forsberg et al, 2019^Citation45	4	SMD = −0.82	<0.001	[−1.17;-0.46]	I^2 = 0%
Köhler-Forsberg et al, 2019^Citation45	4	RR = 1.88 response rates	<0.001	[1.45;2.45]	I^2 = 0%
Köhler-Forsberg et al, 2019^Citation45	4	RR = 4.11 remission rates	<0.001	[1.86;9.11]	I^2 = 0%
Bai et al, 2020^Citation46	4	SMD = −0.76	<0.001	[−1.14;-0.39]	I^2 = 0%
Yuan et al, 2020^Citation52	3	OR = 9.23 response rates	<0.001	[3.07;27.75]	I^2 = 0%
Yuan et al, 2020^Citation52	3	OR = 6.47 remission rates	0.003	[1.88;22.29]	I^2 = 0%
Hang et al, 2021^Citation47	3	RR = 1.55 response rates	<0.001	[1.23;1.95]	I^2 = 0%
Omega3 fatty acids
Martins et al, 2012^Citation53 reanalysis	11^d	SMD = 0.242	0.014	[0.048;0.436]	Q = 38.135 p < 0.001
Martins et al, 2012^Citation53 updated analysis	16^d	SMD = 0.363	0.005	[0.120;0.605]	Q = 55.293 p < 0.001
Lin et al, 2012^Citation54	12	SMD = 0.23	0.01	[0.05;0.42]	I^2 = 73%
Grosso et al, 2014^Citation55	12	SMD = 0.560	0.002	[0.20;0.92]	I^2 = 71%
Appleton et al, 2015^Citation56	25	SMD = −0.30	0.003	[−0.50;-0.10]	I^2 = 59%
Appleton et al, 2015^Citation56	15	OR = 1.39 response rates	0.09	[0.905;2.04]	I^2 = 6%
Appleton et al, 2015^Citation56	6	OR = 1.38 remission rates	0.17	[0.87;2.20]	I^2 = 7%
Mocking et al, 2016^Citation57	13	SMD = 0.398	0.006	[0.114;0.682]	I^2 = 73.36
Sarris et al, 2016^Citation58	11	Hedges’ g = 0.608	0.009	[0.15;1.06]	I^2 = 82%
Wei-Hong et al, 2017^Citation59	3	SMD = 0.63	<0.001	[0.27;1.00]	I^2 = 0%
Schefft et al, 2017^Citation60	10	SMD = −0.48	0.01	[−0.84;-0.11]	I^2 = 64%
Bai et al, 2020^Citation46	12	SMD = −0.35	0.008	[−0.60;-0.09]	I^2 = 61%
Luo et al, 2020^Citation61	9^e	SMD = −0.71^Citation5	Not stated	[−1.13;−0.28]^Citation5	I^2 = 87.4%
	10^f	SMD = 1.243^Citation6		[0.060;2.414]^Citation6
Jeremiah et al, 2020^Citation62	9	SMD = −0.91	<0.001	[−1.44;-0.38]	I^2 = 80%
Hang et al, 2021^Citation47	12	RR = 1.10 response rates	0.33	[0.91;1.34]	I^2 = 30%
Chambergo-Michilot et al, 2021^Citation63	2^g	Pooled MD = 0.42	n.s.	[−1.44;2.29]	I^2 = 35.7%
Chambergo-Michilot et al, 2021^Citation63	3^h	SMD = 0.50	n.s.	[−0.51;1.50]	I^2 = 94.1%
Multiple agents
Köhler et al, 2014^Citation51	5	SMD = −0.54	0.05	[−1.08;-0.01]	I^2 = 68%

Notes: ^aStudies included more than once due to multiple arms counting as multiple studies; ^bconsidered as MDD by authors; ^cconsidered as MDD and depressive symptoms, but Emadi-Kouchak et al, 2016 is considered MDD by other authors; ^dlikely studies with multiple arms only counted once/paper does not provide appropriate information; ^eas per results section; ^fas per abstract; ^goutcome HAMD; ^houtcome BDI.

Abbreviations: CI, confidence interval; SMD, standard mean differences; WMD, weighted mean differences; OR, pooled odds ratios; RR, relative risk; pooled MD, pooled mean difference.

Figure 3 Continued.

Figure 3 (A) Positive mean differences from meta-analyses by agent and effect size parameter. (B) Negative mean differences from meta-analyses by agent and effect size parameter.

Abbreviations: RCTs, randomized controlled trials; SMD, standard mean difference; BDI, Beck Depression Inventory; WMD, weighted mean difference; MD, mean difference; HAMD, Hamilton Depression Rating Scale.

Figure 4 Risk ratios and odds ratios from meta-analyses by agent for response and remission.

Abbreviations: RCTs, randomized controlled trials; RR, risk ratio; OR, odds ratio.

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