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Effect of Anti-inflammatory Treatment on Depression, Depressive Symptoms, and Adverse Effects: A Systematic Review and Meta-analysis of Randomized Clinical Trials
Open accessAbstract
IMPORTANCE: Several studies have reported antidepressant effects of anti-inflammatory treatment; however, the results have been conflicting and detrimental adverse effects may contraindicate the use of anti-inflammatory agents. OBJECTIVE: To systematically review the antidepressant and possible adverse effects of anti-inflammatory interventions. DATA SOURCES: Trials published prior to December, 31, 2013, were identified searching Cochrane Central Register of Controlled Trials, PubMed, EMBASE, PsychINFO, Clinicaltrials.gov, and relevant review articles. STUDY SELECTION: Randomized placebo-controlled trials assessing the efficacy and adverse effects of pharmacologic anti-inflammatory treatment in adults with depressive symptoms, including those who fulfilled the criteria for depression. DATA EXTRACTION AND SYNTHESIS: Data were extracted by 2 independent reviewers. Pooled standard mean difference (SMD) and odds ratios (ORs) were calculated. MAIN OUTCOMES AND MEASURES: Depression scores after treatment and adverse effects. RESULTS: Ten publications reporting on 14 trials (6262 participants) were included: 10 trials evaluated the use of nonsteroidal anti-inflammatory drugs (NSAIDs) (n=4,258) and 4 investigated cytokine inhibitors (n=2,004). The pooled effect estimate suggested that anti-inflammatory treatment reduced depressive symptoms (SMD, -0.34; 95% CI, -0.57 to -0.11; I2=90%) compared with placebo. This effect was observed in studies including patients with depression (SMD, -0.54; 95% CI, -1.08 to -0.01; I2=68%) and depressive symptoms (SMD, -0.27; 95% CI, -0.53 to -0.01; I2=68%). The heterogeneity of the studies was not explained by differences in inclusion of clinical depression vs depressive symptoms or use of NSAIDs vs cytokine inhibitors. Subanalyses emphasized the antidepressant properties of the selective cyclooxygenase 2 inhibitor celecoxib (SMD, -0.29; 95% CI, -0.49 to -0.08; I2=73%) on remission (OR, 7.89; 95% CI, 2.94 to 21.17; I2=0%) and response (OR, 6.59; 95% CI, 2.24 to 19.42; I2=0%). Among the 6 studies reporting on adverse effects, we found no evidence of an increased number of gastrointestinal or cardiovascular events after 6 weeks or infections after 12 weeks of anti-inflammatory treatment compared with placebo. All trials were associated with a high risk of bias owing to potentially compromised internal validity. CONCLUSIONS AND RELEVANCE: Our analysis suggests that anti-inflammatory treatment, in particular celecoxib, decreases depressive symptoms without increased risks of adverse effects. However, a high risk of bias and high heterogeneity made the mean estimate uncertain. This study supports a proof-of-concept concerning the use of anti-inflammatory treatment in depression. Identification of subgroups that could benefit from such treatment might be warranted.
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“Patients who receive cytokine treatments such as IL-2 or IFN γ as part of their treatment for hepatitis or cancer often develop depressive symptoms 82”
From Major depressive disorder (2016) · cites this paper as [82]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Similarly, Kohler and colleagues found that patients prescribed celecoxib compared to placebo were 7 times more likely to respond to an antidepressant with no increased risks of GI or CV effects (155).”
From Chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories (2023) · cites this paper as [155]
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“blockade of cytokines, such as TNF, or of inflammatory signalling pathway components, such as cyclooxygenase 2, has been shown to reduce depressive symptoms in patients with medical illnesses, including rheumatoid arthritis, psoriasis and cancer, as well as in patients with major depressive disorder27–29.”
From The role of inflammation in depression: from evolutionary imperative to modern treatment target (2016) · cites this paper as [29]
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In the citing paper
“Unfortunately, it appears that anti-inflammatory agents may only demonstrate effective antidepressant activity in subgroups of patients who show evidence of increased peripheral inflammation, for example individuals with medical conditions including osteoarthritis and psoriasis that are characterized by increased levels of peripheral inflammation and patients with depression with increased”
From The role of inflammation in depression: from evolutionary imperative to modern treatment target (2016) · cites this paper as [29]
Experimental — accuracy not yet measuredIn the citing paper
“depressive symptoms are more frequent in patients with conditions involving inflammation (e.g., autoimmune diseases) and can be reversed through the use of anti-inflammatory drugs (Kojima et al., 2009; Köhler et al., 2014).”
From The interplay between stress, inflammation, and emotional attention: relevance for depression (2019) · cites this paper as Köhler et al., 2014
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“There is also meta-analytic evidence that anti-inflammatory treatments can be effective means for treating depression (Köhler et al., 2014).”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Köhler et al., 2014
In the citing paper
“A meta-analysis of nonsteroidal anti-inflammatory drugs and cytokine inhibitors suggests that anti-inflammatory treatment, in particular celecoxib, decreases depressive symptoms in individuals with major depression or with clinically significant depressive symptoms198.”
From Mechanisms and treatment of late-life depression (2019) · cites this paper as [198]
In the citing paper
“There is particular interest in how inflammatory cell types in the brain cause depressive symptoms, as anti-inflammatory treatments reduce depressive symptoms in humans [173] and chronic stress enhances inflammation in animal models [174].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [173]
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Metadata
- Authors
- Köhler, O., Benros, M. E., Nordentoft, M., Farkouh, M. E., Iyengar, R. L., Mors, O., & Krogh, J.
- Affiliations
- Research Department P, Aarhus University Hospital, Risskov, Denmark2Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus University Hospital, Risskov, Denmark
- University of Copenhagen (DK)
- St. George's University (GD)
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2014-12-01
- Volume
- 71
- Issue
- 12
- Pages
- 1381
- ISSN
- 2168-622X (ISSN-L)
- OpenAlex
- W2156150528
- Semantic Scholar
- 04c60d39fcaf20a7ee393c91def9fcd0fd3f10fc
- Cited by
- 941
- References
- 56
- Citations by year
- 2026: 48 · 2025: 62 · 2024: 74 · 2023: 81 · 2022: 88 · 2021: 106 · 2020: 94 · 2019: 85 · 2018: 104 · 2017: 85 · 2016: 70 · 2015: 43 · 2014: 1
- FWCI
- 20.40
- Type
- journal article
- Language
- en
- Open access
- green
- pure.au.dk
- Locations
- JAMA Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- Funders
- Lundbeckfonden (R155-2014-1724)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- anti-inflammatory therapy, depression, depressive symptoms, nonsteroidal anti-inflammatory drugs, cytokine inhibitors, celecoxib, COX-2 inhibitors, antidepressant effects, adverse effects, remission, treatment response, adults with depression
- MeSH terms
- Anti-Inflammatory Agents, Depression, Humans, Randomized Controlled Trials as Topic
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