Table 1.
Published Clinical Studies on Anti-inflammatory Treatment Strategies for Depression.
| Study | Agent Studied and Site of Action | Total Number of Patients | Subjects | Depression Diagnosis | Comorbidities | Treatment | Outcomes |
|---|---|---|---|---|---|---|---|
| NSAID Monotherapy | |||||||
| Almeida et al. (2010) | Aspirin, COX-1 and COX-2 | 5556 | All males age 69–87. | GDS-15 | Smoking, cardiovascular disease, arthritis, cognitive impairment | Aspirin exposure in previous 5 years | Aspirin use not associated with lower odds of depression |
| Pasco et al. (2010) | Aspirin, COX-1 and COX-2 | 345 | All females above age 50. Twenty-two MDD and 323 controls | Structured Clinical Interview for DSM-IV-TR, research version, non-patient edition | Smoking, hyperlipidemia | Previous statin and aspirin exposure | Exposure to statins and aspirin associated with reduced MDD risk |
| Almeida et al. (2012) | Aspirin, COX-1 and COX-2 | 3687 | All males age 69–87 with increased homocysteine plasma levels | GDS-15 ≥ 7 | Smoking, others based on Charlson index | Aspirin exposure in previous 5 years | Aspirin use is associated with lower depression risk |
| Fields et al. (2012) | Celecoxib, COX-2; naproxen, COX-1 and COX-2 | 2312 | Age > 70. Depressive (449), controls (2079) | 30-item GDS score > 5 to | Family history of dementia | 12 months placebo (1,038) vs. celecoxib 400 mg (7 2 6) vs. naproxen 440 mg (7 1 9) daily | Celecoxib or naproxen did not improve depressive symptoms |
| Iyengar et al. (2013) | Celecoxib, COX-2; ibuprofen or naproxen, COX-1 and COX-2 | 1497 | Median age 61 in all treatment groups | PHQ-9 ≥ 10 | Active osteoarthritis | 6 weeks placebo (297) vs. ibuprofen 2400 mg or naproxen 1000 mg (593) vs. celecoxib200 mg (607) | All treatments superior to placebo |
| NSAID Augmentation Therapy | |||||||
| Muller et al. (2006) | Celecoxib, COX-2; reboxetine, noradrenaline reuptake | 40 | Mean age 44 in both treatment groups | HAMD 15–38 | None | 6 weeks reboxetine + placebo (20) vs. 400 mg (20) | Celecoxib group superior to reboxetine alone |
| Akhondzadeh et al. (2009) | Celecoxib, COX-2; fluoxetine, selective serotonin reuptake | 40 | Mean age 34 in both treatment groups | HAMD ≥ 18 | None | 6 weeks fluoxetine + placebo (20) vs. fluoxetine + celecoxib 400 mg (20) | Celecoxib group superior to fluoxetine alone |
| Abbasi et al. (2012) | Celecoxib, COX-2; sertraline, selective serotonin reuptake | 40 | Mean age of 35 in celecoxib group, 34 in placebo group | HAMD ≥ 18 | None | 6 weeks sertraline + placebo (20) vs. sertraline + celecoxib 400 mg (20) | Celecoxib group superior to sertraline alone. Baseline serum IL-6 predicted response |
| Majd et al. (2015) | Celecoxib, COX-2; fluoxetine, selective serotonin reuptake | 30 | Mean age 34 in celecoxib group, 36 in placebo group | HAMD ≥ 18 | None | 8 weeks fluoxetine + placebo (20) vs. fluoxetine + celecoxib 200 mg (20) | Celecoxib group superior to fluoxetine alone after 4 weeks but no difference after 8 weeks |
| Cytokine Inhibition | |||||||
| Tyring et al. (2006) | Etanercept, TNF-α | 618 | Mean age 45 in both treatment groups | HAMD, BDI | Psoriasis | 12 weeks placebo (309) vs. etanercept 50 mg (311) injections twice weekly | Etanercept superior to placebo for depression and fatigue |
| Menter et al. (2010) | Adalimumab, TNF-α | 96 | Mean age 45 in adalimumab group, 43 in placebo group | ZDS | Psoriasis | 12 weeks placebo (52) vs. adalimumab 40 mg (44) injectionsevery other week | Adalimumab superior in reducing depressive symptoms and improving QOL |
| Langley et al. (2010) | Ustekinumab, IL-12 and IL-23 | 1230 | Mean age 46 in ustekinumab group, 47 in placebo group | HADS-D | Psoriasis | 24 weeks placebo (410) vs. ustekinumab 45 mg (409) vs. ustekinumab 90 mg (411) | Both ustekinumab groups were superior to placebo in improving depressive symptoms and QOL |
| Raison et al. (2013) | Infliximab, TNF-α | 60 | Mean age 42 in infliximab group, 44 in placebo group | HAMD | None | 12 weeks three infusions placebo (30) vs. infliximab 5 mg/kg (30) | Infliximab superior if baseline CRP > 5mg/L |
| McIntyre et al. (2019) | Infliximab, TNF-α | 60 | Mean age 45 in infliximab group, 47 in placebo group | MADRS | History of childhood trauma (physical and/or sexual abuse) | 12 weeks three infusions placebo (31) vs. infliximab 5 mg/kg (29) | Infliximab superior only in pts with childhood trauma |
| Sun et al. (2017) | Sirukumab and siltuximab, IL-6 | 176 in sirukumab study, 65 in siltuximab study | Mean age 51 in sirukumab study, 44 in siltuximab study | PDMA criteria derived from SF-36 Health Survey | RA in sirukumab study, MCD in siltuximab study | Depressive symptoms assessed after 12 weeks of varying sirukumab doses and 15 weeks of siltuximab (11 mg/kg) intravenous infusion every 3 weeks | Siltuximab superior to placebo in improving depressive symptoms. Increased baseline IL-6R levels predicted sirukumab response |
| NMDA Receptor Antagonism | |||||||
| Yang et al. (2015) | Ketamine, NMDA receptor | 40 | 16 inpatient individuals, 24 healthy controls | HAMD and MADRS | None | Single intravenous infusion of ketamine 0.5 mg/kg over 40 min. | Baseline serum levels of IL-6 in the responder group were significantly higher than those in the nonresponder group. |
| Kiraly et al. (2017) | Ketamine, NMDA receptor | 59 | Mean age 45 in depressed group, 39 in control group | MADRS | Three patients had stable hypertension, two with hyperlipidemia, and one with mild type II diabetes. | Single intravenous infusion of ketamine 0.5 mg/Ag | Low pretreatment levels of fibroblast growth factor 2 were associated with ketamine treatment response. |
| Kynurenine Pathway Modulation | |||||||
| Miyaoka et al. (2012) | Minocycline, kynurenine pathway | 25 | Mean age 46.9 | HAMD | None | Non-placebo controlled, Open-label. 6 weeks SSRI + 150 mg minocycline | Minocycline add-on treatment showed significant and safe improvements in depressive symptoms |
| Dean et al. (2017) | Minocycline, kynurenine pathway | 71 | Mean age of 51 in minocycline group, 47.8 in placebo group | MADRS | Several, anxiety being the highest in both groups | 12 weeks of regular treatment + minocycline 200 mg/day or regular treatment + placebo | Minocycline add on treatment did not show significant improvements in depression scores |
| Husain et al. (2017) | Minocycline, kynurenine pathway | 41 | Mean age of 40 in minocycline group, 35 in placebo group | HAMD | None | 12 weeks of regular treatment + minocycline (100 mg/day, then 200 mg/day) or regular treatment + placebo | Minocycline add on treatment superior to placebo in improving depressive symptoms. |
| Emadi-Kouchak et al. (2016) | Minocycline, kynurenine pathway | 50 | Mean age of 34.7 in minocycline group, 36.4 in placebo group | HAMD | HIV (receiving HAART) | 6 weeks of minocycline 100 mg twice daily monotherapy or placebo | Minocycline monotherapy superior to placebo in decreasing depressive symptoms |
Abbreviations: NSAID, non-steroidal anti-inflammatory drug; COX, cyclooxygenase; GDS-15, 15-item geriatric depression scale; MDD, major depressive disorder; PHQ, patient health questionnaire-9; HAMD, hamilton depression scale; TNF-α, tumor necrosis factor-α; BDI, beck depression inventory; ZDS=zung self-rating depression scale; QOL, quality of life; HADS-D, hospital anxiety and depression scale for depression; CRP, c-reactive protein; IL-6, interleukin 6; PDMA, prevalent depressed mood and anhedonia; NMDA, N-methyl-d-aspartate; SF-36, short form survey; MCD, multicentric castleman’s disease; IL-6R, interleukin 6 receptor; NMDA, N-methyl-D-aspartate. GABAA, gamma-Aminobutyric acid-A.