Unveiling the Anti-Inflammatory Effects of Antidepressants: A Systematic Review of Human Studies over the Last Decade
Abstract
:1. Introduction
2. Relationship Between Inflammation and Depression
2.1. Mechanisms of Inflammation
2.2. Neuroinflammation
2.2.1. Microglia
2.2.2. Astrocytes
2.2.3. Lymphocyte Infiltration
2.2.4. Neuroplasticity
2.2.5. Oxidative Stress
2.2.6. Hypothalamic–Adrenal Axis
2.2.7. The Kynurenine Pathway
2.2.8. Gut–Brain Axis
3. Results
3.1. Anti-Inflammatory Effect of Antidepressants
3.1.1. IL-1β
3.1.2. IL-1ra
3.1.3. IL-2
3.1.4. IL-4
3.1.5. IL-5
3.1.6. IL-6
3.1.7. IL-7
3.1.8. IL-8
3.1.9. IL-9
3.1.10. IL-10
3.1.11. IL-12
3.1.12. IL-13
3.1.13. IL-15
3.1.14. IL-17
3.1.15. IFN-γ
3.1.16. TNF-α
3.1.17. CRP
Name | Class | Effect | Cytokines | Model | Citation |
---|---|---|---|---|---|
Escitalopram | SSRI | ↓ | IL-1β, IL-2, IL-5, IL-6, IL-7, IL-8, IL-9, IL-17, TNF-α, IFN-γ | Moderate depression, patients were their own control, serum, Luminex xMAP multiplexing technology, 26 weeks of antidepressant treatment, 90 participants (71% women) with a mean age of 38 years. | [191] |
↓ | IL-1ra, IL-4, IL-10, IL-13 | [191] | |||
↑ | IL-12, IL-15 | [191] | |||
↔ | IL-10, IL-1ra, IL-6, IL-8, TNF-α | Depression, randomized double-blinded trial, whole blood stimulated with LPS or PHA (in vitro), Luminex 100 platform, 4 weeks of antidepressant treatment, 44 participants (28 women), with a mean age of 32.7 years. | [198] | ||
↓ | IL-2, IL-6 and TNF-a | MDD, patients were their own control, cytokines were analyzed in serum by ELISA test, 6 weeks of antidepressant treatment, 65 participants (35 women), with a mean age of 36 years. | [203] | ||
↓ | IL-6 | MDD, open-label part-randomized multicenter pharmacogenetic study with two active pharmacological treatment arms, leukocyte mRNA levels were measured, 8 weeks of antidepressant treatment, 38 participants with a mean age of 38 years. | [215] | ||
Fluoxetine | ↔ | IL-1β, IL-6 | MDD, patients were their own control, cytokines were analyzed in serum by ELISA test, 8 weeks of study, 14 participants (10 women), with a mean age of 37 years. | [196] | |
↓ | IL-2, IL-6 and TNF-a | MDD, patients were their own control, cytokines were analyzed in serum by ELISA test, 6 weeks of study, 65 participants (36 women), with a mean age of 36 years. | [203] | ||
↑ | IL-10 | Crohn’s disease, presence of a separate control group that received a placebo, cytokines were analyzed by flow cytometry, 6 months of antidepressant treatment, 26 participants (12 women), with a mean age of 37 years. | [231] | ||
↓ | TNF-a | Depression, patients were their own control, cytokines were analyzed in serum by ELISA test, 12 weeks of antidepressant treatment, 30 participants (20 women), with a mean age of 36 years. | [252] | ||
↓ | IL-1β | Depression, the effect of fluoxetine was compared to the untreated group, cytokines were analyzed in serum by ELISA test, 12 weeks of antidepressant treatment, 32 participants (18 women), with a mean age of 34 years. | [192] | ||
↔ | IL-2, CRP | Depression | [205] | ||
↓ | IL-1ra | Depression, cytokine measurement in the 4th week of therapy, presence of a separate control group, cytokines were analyzed in serum by multiplex bead-based immunoassays, 8 weeks of antidepressant treatment, 22 participants (18 women), with a mean age of 17 years. | [193] | ||
↓ | IFN-γ, IL-1β, TNF-α, IL-6, IL-12, IL-15 | [193] | |||
↑ | IL-4 | Depression, cytokine measurement in the 8th week of therapy. | [193] | ||
↑ | IL-12 and IL-5 | [193] | |||
↔ | IL-10 and IL-13 | Depression | [193] | ||
↓ | CRP | COVID-19; during a mid-hospital stay, a double-blind randomized, placebo-controlled clinical trial; 4 weeks of antidepressant treatment, 72 participants (35 women), with a mean age of 52 years. | [253] | ||
↓ | NLRP3, IL-1β, and IL-18 | First episode, moderate to severe MDD, patients were their own control, cytokines were analyzed in serum by ELISA test, 12 weeks of antidepressant treatment, 48 participants (30 women), with a mean age of 17 years. | [194] | ||
↑ | IL-4 | [194] | |||
Sertraline | ↔ | hsCRP, IL-6 | MDD and CKD, randomized, double-blind placebo-controlled trial, cytokines were analyzed in serum by ELISA test, 12 weeks of antidepressant treatment, 201 participants (61 women), with a mean age of 58 years. | [222] | |
↓ | IL-6 | Hemodialysis and depression, randomized double-blind, placebo-controlled clinical trial, cytokines were analyzed in serum by ELISA test, 12 weeks of antidepressant treatment, 43 participants (16 women), with a mean age of 63 years. | [216] | ||
↔ | TNF-α | [216] | |||
↔ | IL-10 | [216] | |||
↓ | IL-4, IL-10 | Unipolar depression, double-blind, placebo-controlled trial, blood cytokines were measured by flow cytometry, 6 weeks of antidepressant treatment, 120 participants (82 women), with a mean age of 42 years. | [204] | ||
↓ | IL-2, IL-6, IL-17a, IFN-γ | [204] | |||
↔ | TNF-α | [204] | |||
↔ | hsCRP, IL-6, and TNF-α | CHD and MDD, randomized, double-blind, placebo-controlled trial, cytokines were analyzed in serum by ELISA test, 10 weeks of antidepressant treatment, 122 participants (41 women), with a mean age of 59 years. | [223] | ||
↓ | CRP and IL-6 | CHD and MDD, randomized double-blind, placebo-controlled clinical trial, cytokines were analyzed in serum by ELISA test, 20 weeks of antidepressant treatment, 95 participants (48 women), with a mean age of 57 years. | [217] | ||
Paroxetine | ↑ | IL-10 | MDD, two randomized placebo-controlled clinical studies, cytokines were analyzed in serum by ELISA test, 10 weeks of antidepressant treatment, 106 participants (72 women), with a mean age of 46 years. | [220] | |
↑ | TNF-α, IL-6 and CRP | [220] | |||
Venlafaxine | SNRI | ↓ | CRP | MDD, two randomized placebo-controlled clinical studies, cytokines were analyzed in serum by ELISA test, 10 weeks of antidepressant treatment, 104 participants (64 women), with a mean age of 45 years. | [220] |
Ketamine | ↓ | CRP | Post-operative cognitive dysfunction, patients randomly received placebo or an i.v. bolus of ketamine (0.5 mg/kg) during anesthetic induction. Anesthesia was maintained with isoflurane and fentanyl. A nonsurgical group was also included as control, serum C-reactive protein (CRP) concentrations were determined before surgery and on the first post-operative day, 96 participants with a mean age of 66 years. | [251] | |
↓ | IL-8/IL-10 ratio | MDD, presence of a separate control group that received a placebo, plasma concentrations of cytokines were analyzed by ELISA test 24 h after ketamine infusion (0.5 mg/kg), 25 participants (7 women) with a mean age of 46 years. | [254] | ||
↓ | IL-4, and IL-10 | TRD, cytokines were analyzed in plasma by multiplex bead-based immunoassays on days 13 and 26, TRD patients received intravenous ketamine (0.5 mg/kg) three times weekly for 2 weeks, 66 participants (37 women) with a mean age of 36 years. | [195] | ||
↓ | IFN-γ, IL-17α, IL-1β, IL-2, IL-23, IL-5, IL-6, IL-7, and TNF-α | [195] | |||
↓ | IL-8 | Depression, presence of a separate control group that received a placebo, depressed patients (n = 46, female, n = 17), cytokines were analyzed in plasma by multiplex bead-based immunoassays 24 h after infusion of ketamine (0.5 mg/kg). | [226] | ||
↓ | TNF-α | TRD, randomized, double-blind control study, patients were randomized into three groups according to the treatment received: 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, and normal saline infusion, cytokines were analyzed in plasma by ELISA test at baseline and at 40 min, 240 min, day 3, and day 7 post-infusion, 71 participants (53 women), with a mean age of 46 years. | [246] | ||
↑ | IL-6 | MDD, double-blind, placebo-controlled studies, cytokines were analyzed in plasma by multiplex bead-based immunoassays, blood samples were received at 60 min before ketamine infusion and at 230 min, one day, and three days post-infusion ketamine (0.5 mg/kg) or saline placebo, 80 participants (61 women), with a mean age of 45 years. | [221] | ||
↑ | TNF-α | TRD, randomized placebo-controlled and open-label trials, cytokines were analyzed in plasma by ELISA test, 78 patients were allocated to receive two ketamine infusions (n = 30, days 1 and 4), a single ketamine (0.5 mg/kg) infusion (n = 24, only day 1), or normal saline placebo infusion (n = 24, only day 1). | [247] | ||
Esketamine | ↓ | IL-6 and CRP | Labor and postpartum depression, a randomized, double-blinded controlled trial, cytokines were analyzed in plasma by ELISA test, a total of 120 women who underwent labor analgesia by epidural analgesia pump were enrolled and divided into two groups randomly. Esketamine at a dose of 0.2 mg/kg was intravenously injected after fetal disengagement in the test group and placebo was administered in the control group. | [218] | |
↑ | IL-10 | [218] | |||
↓ | IL-6 | Elective non-cardiac thoracic surgery under general anesthesia, randomized controlled trial. During the operation, patients received 0.2 mg/kg (low-esketamine group) or 0.5 mg/kg esketamine (high-esketamine group) vs. placebo, cytokines were analyzed in plasma by ELISA test before surgery, post-operative day 1 and day 3, 129 participants (56 women), with a mean age of 65 years. | [219] |
4. Discussion
4.1. Mechanisms of Anti-Inflammatory Action
4.1.1. NF-κB
4.1.2. NLRP3 Inflammasome Complex
4.1.3. SSRIs
Fluoxetine
Escitalopram
Sertraline
Paroxetine
4.1.4. SNRIs: Venlafaxine
4.1.5. SSRIs vs. SNRIs
4.1.6. Ketamine/Esketamine
4.2. Limitations of Evidence
5. Materials and Methods
5.1. Literature Search
5.2. Eligibility Criteria
6. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Bleibel, L.; Sokołowska, P.; Henrykowska, G.; Owczarek, J.; Wiktorowska-Owczarek, A. Unveiling the Anti-Inflammatory Effects of Antidepressants: A Systematic Review of Human Studies over the Last Decade. Pharmaceuticals 2025, 18, 867. https://doi.org/10.3390/ph18060867
Bleibel L, Sokołowska P, Henrykowska G, Owczarek J, Wiktorowska-Owczarek A. Unveiling the Anti-Inflammatory Effects of Antidepressants: A Systematic Review of Human Studies over the Last Decade. Pharmaceuticals. 2025; 18(6):867. https://doi.org/10.3390/ph18060867
Chicago/Turabian StyleBleibel, Layla, Paulina Sokołowska, Gabriela Henrykowska, Jacek Owczarek, and Anna Wiktorowska-Owczarek. 2025. "Unveiling the Anti-Inflammatory Effects of Antidepressants: A Systematic Review of Human Studies over the Last Decade" Pharmaceuticals 18, no. 6: 867. https://doi.org/10.3390/ph18060867
APA StyleBleibel, L., Sokołowska, P., Henrykowska, G., Owczarek, J., & Wiktorowska-Owczarek, A. (2025). Unveiling the Anti-Inflammatory Effects of Antidepressants: A Systematic Review of Human Studies over the Last Decade. Pharmaceuticals, 18(6), 867. https://doi.org/10.3390/ph18060867