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

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.

Cyclooxygenase Inhibition Safety and Efficacy in Inflammation-Based Psychiatric Disorders

“…A significant difference was observed in the change in YMRS scores on day 42 compared to baseline in the two groups. Celecoxib revealed to be an effective adjuvant therapy in the treatment of manic episodes (without psychotic features) of bipolar mood disorder [101,166]. Table 3 data clearly shown that the use of celecoxib powers up anti-BD drugs, improving patients' symptomatology.…”

“…Several studies argue that celecoxib is effective in the management of depressive symptoms [98][99][100][101]. According to Eyre et al [102], celecoxib is clinically inadequate.…”

“…In the brain, they are involved in regulating the activity of various neurotransmitters, such as serotonin, noradrenaline, dopamine, and glutamate [113]. In particular, pro-inflammatory cytokines such as IL-1β and IL-6 can affect the neuronal development of the dopaminergic and serotonergic systems [101,[145][146][147][148]. Cytokines also show effects on the regulation of neuroplasticity, cell resilience, and apoptosis control [113].…”

“…TNF-α inhibits the release of the neurotrophin BDNF, thus compromising its protective effect [113]. Furthermore, a correlation between cytokine levels and negative symptoms, cognitive deficits, and psychomotor retardation was reported [101,[149][150][151].…”

Curcumin in antidepressant treatments: An overview of potential mechanisms, pre‐clinical/clinical trials and ongoing challenges

“…In recent years, increasing evidence has uncovered that inflammation is closely related to the pathophysiology of depression. 35,36 Notably, the resistance to antidepressant treatment may be probably attributed to the increasing of inflammatory markers in depressed patients. 37 There are a number of meta-analyses proving that depression is highly relevant to the up-regulation of certain pro-inflammatory cytokines levels such as interleukin-1 (IL-1), interleukin-6 (IL-6) and other inflammatory mediators such as C-reactive protein (CRP).…”