Neurobiology and Therapeutic Potential of Cyclooxygenase-2 (COX-2) Inhibitors for Inflammation in Neuropsychiatric Disorders

doi:10.3389/fpsyt.2019.00605

Review

. 2019 Sep 4:10:605.

doi: 10.3389/fpsyt.2019.00605. eCollection 2019.

Neurobiology and Therapeutic Potential of Cyclooxygenase-2 (COX-2) Inhibitors for Inflammation in Neuropsychiatric Disorders

Rickinder Sethi¹, Nieves Gómez-Coronado², Adam J Walker³, Oliver D'Arcy Robertson^{3

4}, Bruno Agustini³, Michael Berk^{3

4

5

6

7}, Seetal Dodd^{3

4

5

6}

Affiliations

¹ Department of Psychiatry, Western University, London, ON, Canada.
² Unidad de Gestión Clinica Salud Mental, Hospital Universitario Virgen del Rocio, Sevilla, Spain.
³ IMPACT Strategic Research Centre, Deakin University, Geelong, VIC, Australia.
⁴ University Hospital Geelong, Barwon Health, Geelong, VIC, Australia.
⁵ Department of Psychiatry, The University of Melbourne, Parkville, VIC, Australia.
⁶ Orygen, The National Centre of Excellence in Youth Mental Health, Parkville, VIC, Australia.
⁷ Department of Psychiatry, Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia.

PMID: 31551825
PMCID: PMC6738329
DOI: 10.3389/fpsyt.2019.00605

Review

Neurobiology and Therapeutic Potential of Cyclooxygenase-2 (COX-2) Inhibitors for Inflammation in Neuropsychiatric Disorders

Rickinder Sethi et al. Front Psychiatry. 2019.

. 2019 Sep 4:10:605.

doi: 10.3389/fpsyt.2019.00605. eCollection 2019.

Authors

Rickinder Sethi¹, Nieves Gómez-Coronado², Adam J Walker³, Oliver D'Arcy Robertson^{3

4}, Bruno Agustini³, Michael Berk^{3

4

5

6

7}, Seetal Dodd^{3

4

5

6}

Affiliations

¹ Department of Psychiatry, Western University, London, ON, Canada.
² Unidad de Gestión Clinica Salud Mental, Hospital Universitario Virgen del Rocio, Sevilla, Spain.
³ IMPACT Strategic Research Centre, Deakin University, Geelong, VIC, Australia.
⁴ University Hospital Geelong, Barwon Health, Geelong, VIC, Australia.
⁵ Department of Psychiatry, The University of Melbourne, Parkville, VIC, Australia.
⁶ Orygen, The National Centre of Excellence in Youth Mental Health, Parkville, VIC, Australia.
⁷ Department of Psychiatry, Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia.

PMID: 31551825
PMCID: PMC6738329
DOI: 10.3389/fpsyt.2019.00605

Abstract

Neuropsychiatric disorders, such as depression, bipolar disorder, schizophrenia, obsessive-compulsive disorder, and neurodevelopmental disorders such as autism spectrum disorder, are associated with significant illness burden. Accumulating evidence supports an association between these disorders and inflammation. Consequently, anti-inflammatory agents, such as the cyclooxygenase-2 inhibitors, represent a novel avenue to prevent and treat neuropsychiatric illness. In this paper, we first review the role of inflammation in psychiatric pathophysiology including inflammatory cytokines' influence on neurotransmitters, the hypothalamic-pituitary-adrenal axis, and microglial mechanisms. We then discuss how cyclooxygenase-2-inhibitors influence these pathways with potential therapeutic benefit, with a focus on celecoxib, due to its superior safety profile. A search was conducted in PubMed, Embase, and PsychINFO databases, in addition to Clinicaltrials.gov and the Stanley Medical Research Institute trial registries. The results were presented as a narrative review. Currently available outcomes for randomized controlled trials up to November 2017 are also discussed. The evidence reviewed here suggests cyclooxygenase-2 inhibitors, and in particular celecoxib, may indeed assist in treating the symptoms of neuropsychiatric disorders; however, further studies are required to assess appropriate illness stage-related indication.

Keywords: autism spectrum disorder; bipolar disorder; cyclooxygenase-2 inhibitors; depression; inflammation; obsessive compulsive disorder; psychiatry; schizophrenia.

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Figures

**Figure 1**
COX-2 contributes to inflammation through PGE₂ and IL-6 and is selectively inhibited by celecoxib and rofecoxib. Activated by inflammatory cytokines including PGE₂ and IL-6, AA (the precursor substrate of the COX-2 pathway) is extracted from phospholipid membranes by phospholipases such as cPLA2. COX-2 then drives production of prostaglandins including prostaglandin H₂ (PGH₂), which in turn is converted to PGE₂ *via* PGE synthase. An accumulation of PGE₂ leads to increased IL-6 (along with other cytokines) contributing to the inflammatory milieu, further potentiation of the pathway and neurotoxicity contributing to psychopathology. Celecoxib and rofecoxib exert selective inhibition of COX-2 reducing this pathway’s contribution to inflammation mediated neurotoxicity (→ = activates/increases, ⊥ = inhibits).

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Comment in

Commentary: Neurobiology and Therapeutic Potential of Cyclooxygenase-2 (COX-2) Inhibitors for Inflammation in Neuropsychiatric Disorders.
Westwell-Roper C, Stewart SE. Westwell-Roper C, et al. Front Psychiatry. 2020 Apr 22;11:264. doi: 10.3389/fpsyt.2020.00264. eCollection 2020. Front Psychiatry. 2020. PMID: 32425818 Free PMC article. No abstract available.

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References

1. Kohler CA, Freitas TH, Maes M, de Andrade NQ, Liu CS, Fernandes BS, et al. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr Scand (2017) 135(5):373–87. 10.1111/acps.12698 - DOI - PubMed
1. Berk M, Williams LJ, Jacka FN, O’Neil A, Pasco JA, Moylan S, et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med (2013) 11(1):200. 10.1186/1741-7015-11-200 - DOI - PMC - PubMed
1. Huynh NN, McIntyre RS. What are the implications of the STAR*D trial for primary care? A review and synthesis. Prim Care Companion J Clin Psychiatry (2008) 10(2):91–6. 10.4088/PCC.v10n0201 - DOI - PMC - PubMed
1. Muller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Muller B, et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry (2006) 11(7):680–4. 10.1038/sj.mp.4001805 - DOI - PubMed
1. Akhondzadeh S, Jafari S, Raisi F, Nasehi AA, Ghoreishi A, Salehi B, et al. Clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial. Depress Anxiety (2009) 26(7):607–11. 10.1002/da.20589 - DOI - PubMed

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[1] Kohler CA, Freitas TH, Maes M, de Andrade NQ, Liu CS, Fernandes BS, et al. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr Scand (2017) 135(5):373–87. 10.1111/acps.12698 - DOI - PubMed

[2] Kohler CA, Freitas TH, Maes M, de Andrade NQ, Liu CS, Fernandes BS, et al. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr Scand (2017) 135(5):373–87. 10.1111/acps.12698 - DOI - PubMed

[3] Berk M, Williams LJ, Jacka FN, O’Neil A, Pasco JA, Moylan S, et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med (2013) 11(1):200. 10.1186/1741-7015-11-200 - DOI - PMC - PubMed

[4] Berk M, Williams LJ, Jacka FN, O’Neil A, Pasco JA, Moylan S, et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med (2013) 11(1):200. 10.1186/1741-7015-11-200 - DOI - PMC - PubMed

[5] Huynh NN, McIntyre RS. What are the implications of the STAR*D trial for primary care? A review and synthesis. Prim Care Companion J Clin Psychiatry (2008) 10(2):91–6. 10.4088/PCC.v10n0201 - DOI - PMC - PubMed

[6] Huynh NN, McIntyre RS. What are the implications of the STAR*D trial for primary care? A review and synthesis. Prim Care Companion J Clin Psychiatry (2008) 10(2):91–6. 10.4088/PCC.v10n0201 - DOI - PMC - PubMed

[7] Muller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Muller B, et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry (2006) 11(7):680–4. 10.1038/sj.mp.4001805 - DOI - PubMed

[8] Muller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Muller B, et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry (2006) 11(7):680–4. 10.1038/sj.mp.4001805 - DOI - PubMed

[9] Akhondzadeh S, Jafari S, Raisi F, Nasehi AA, Ghoreishi A, Salehi B, et al. Clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial. Depress Anxiety (2009) 26(7):607–11. 10.1002/da.20589 - DOI - PubMed

[10] Akhondzadeh S, Jafari S, Raisi F, Nasehi AA, Ghoreishi A, Salehi B, et al. Clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial. Depress Anxiety (2009) 26(7):607–11. 10.1002/da.20589 - DOI - PubMed

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Neurobiology and Therapeutic Potential of Cyclooxygenase-2 (COX-2) Inhibitors for Inflammation in Neuropsychiatric Disorders

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Neurobiology and Therapeutic Potential of Cyclooxygenase-2 (COX-2) Inhibitors for Inflammation in Neuropsychiatric Disorders

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