The Effect of Celecoxib on Neuroinflammation in MDD
Status:
Recruiting
Trial end date:
2023-07-31
Target enrollment:
Participant gender:
Summary
Major depressive disorder (MDD) affects an estimated 350 million people worldwide and is a
leading contributor to global disease burden. Commonly used monoamine reuptake-inhibiting
treatments for depression are suboptimal, resulting in only 30% of patients achieving
remission. This may be because monoamine dysfunction is not the primary pathophysiology in
all MDD patients. One avenue for the development of novel MDD treatments is through
anti-inflammatory drugs; MDD is linked to a pro-inflammatory phenotype characterized by
microglial activation, leading to the release of pro-inflammatory cytokines and upregulation
of cellular markers including cyclooxygenase-2 (COX-2) and translocator protein (TSPO; a
protein located on the outer membrane of microglia). Relevant to this proposal, TSPO can
serve as an in vivo marker of neuroinflammation using the newly developed positron emission
tomography (PET) tracer for TSPO, [18F]FEPPA. In support of this, a recent [18F]FEPPA PET
study found that MDD patients in a current major depressive episode (MDE) had significantly
higher TSPO binding in the prefrontal cortex (PFC), anterior cingulate cortex (ACC) and
insula, relative to healthy controls. The prefrontal cortex and ACC are both implicated in
mood regulation whereas the insula is involved in interoceptive signaling, which is known to
be abnormal in MDD. Celecoxib, a selective COX-2 nonsteroidal anti-inflammatory drug (NSAID),
is a promising new treatment for neuroinflammation in MDD. Clinical studies have observed
that, in a subset of depressed patients, celecoxib treatment reduced depression severity as
assessed by the Hamilton Depression Rating Scale (HDRS). While these findings demonstrate
that celecoxib reduces symptom severity, PET imaging technology is critical for understanding
how celecoxib affects the underlying pathophysiology of depression. Here, the team will
investigate neuroinflammation as an underlying pathology in depression and test whether
neuroinflammation is reduced by celecoxib in MDD patients. Specifically, in the proposed
pilot study, MDD patients in a current MDE will receive [18F]FEPPA PET scans prior to and
following 8 weeks of treatment with 800mg/day of celecoxib, with HDRS scores obtained at each
time point. The investigators hypothesize that following celecoxib treatment, patients will
show a significant reduction in neuroinflammation in the PFC, ACC and insula, which will
correlate positively with the reduction in depressive symptoms, as measured by the HDRS. The
proposed study will use novel imaging technology, [18F]FEPPA PET, to measure the effects of
celecoxib on neuroinflammation in MDD patients. Our results will help to 1) identify
neuroinflammation as an underlying pathology in MDD and 2) test whether reduction of
inflammation is the mechanism of action of celecoxib. As such, the results of this study will
aid in the development of targeted clinical treatments to improve remission rates in MDD
patients.