The Effect of Celecoxib on Neuroinflammation in MDD

The Effect of Celecoxib on Neuroinflammation in MDD: PET Imaging of a Novel Treatment Target With [18F]FEPPA

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 400mg/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.

Study Overview

• Status: Recruiting
• Conditions: Major Depressive Disorder; Neuroinflammation
• Intervention / Treatment: Drug: Celecoxib 400 mg

• Study Type: Interventional
• Enrollment (Estimated): 42
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Alexandra Checkers, MBA; Phone Number: 631-638-0291; Email: alexandra.checkers@stonybrookmedicine.edu

Study Locations

• United States
  • New York
    • Stony Brook, New York, United States, 11794-8101
      • Recruiting
      • Psychiatry Department at Stony Brook University
      • Contact: Alexandra Checkers, MBA; Phone Number: 631-638-0291; Email: alexandra.checkers@stonybrookmedicine.edu
      • Contact: Christine DeLorenzo, PhD; Phone Number: 631-638-1523; Email: christine.delorenzo@stonybrookmedicine.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

• Age: 18-65
• Diagnosis of MDD and currently in a major depressive episode
• Capacity to give informed consent
• Score of at least 29 on the MADRS

Exclusion Criteria

• Low affinity binders (LABs) for TSPO Genotype
• Hypersensitivity to celecoxib, sulfonamides, aspirin, other NSAIDs, or any component of the formulation; previous asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs
• Heptic impairment, heart failure, severe renal impairment, recent GI bleed, history of peptic ulcer disease, anemia or any other contraindication for celecoxib
• Poor CYP2C9 metabolizer
• Currently taking medications that interact with celecoxib (digoxin, antihypertensives, diuretics, anticoagulant or anti-platelet treatment, including aspirin)
• Use of herbs, drugs, or medications with anti-inflammatory or immunomodulatory properties (within 5 half-lives of starting celecoxib treatment)
• Unlikely to tolerate medication washout or the medication-free period following washout
• Participant considered at significant risk for suicide
• ECT within 1 month
• High potential for excessive drug/alcohol use during the treatment period (excluding nicotine or cannabis)
• Significant active physical illness or neurological deficit that may affect brain functioning or imaging
• Any PET contraindications, including if study imaging will result in the participant receiving greater exposure than the research limit, or if participant is currently pregnant, breastfeeding, or planning to conceive during the course of study participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Celecoxib 400 mg; Patients will receive 400 mg/day of celecoxib for 8 weeks.	Drug: Celecoxib 400 mg; Patients will receive 400 mg/day of celecoxib for 8 weeks.; Other Names: celebrex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in neuroinflammation as measured by [18F]FEPPA PET.	Change in [18F]FEPPA VT (VT; volume of distribution: ratio of the concentration of radioligand in tissue to that in plasma at equilibrium)	Before and after 8 weeks of treatment with celecoxib.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Hamilton Depression Rating Scale-17 (HAMD) score.	Comparison of Hamilton Depression Rating Scale-17 score at pretreatment and post-treatment. Minimum score 0, maximum possible score 52, with remission defined as <=7. The higher the score on the scale, the more severe the degree of depression.	Before and after 8 weeks of treatment with celecoxib.

Collaborators and Investigators

• Sponsor: Stony Brook University
• Collaborators: Brain & Behavior Research Foundation
• Investigators: Principal Investigator: Christine DeLorenzo, PhD, Stony Brook University

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2018
• Primary Completion (Estimated): July 31, 2024
• Study Completion (Estimated): July 31, 2024

Study Registration Dates

• First Submitted: March 22, 2021
• First Submitted That Met QC Criteria: March 22, 2021
• First Posted (Actual): March 24, 2021

Study Record Updates

• Last Update Posted (Estimated): November 22, 2023
• Last Update Submitted That Met QC Criteria: November 20, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: PET; Neuroinflammation; Major Depressive Disorder
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Pathologic Processes; Nervous System Diseases; Mood Disorders; Inflammation; Depression; Depressive Disorder; Depressive Disorder, Major; Neuroinflammatory Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Cyclooxygenase 2 Inhibitors; Celecoxib
• Other Study ID Numbers: 81741

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No