Celecoxib for Major Depressive Disorder

Overseen By Alexandra Checkers, MBA

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Stony Brook University

Must not be taking: Digoxin, Antihypertensives, Diuretics, others

Disqualifiers: Low TSPO binders, Celecoxib allergy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 8 weeks

42 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

Yes, you will need to stop taking certain medications before joining the trial. Specifically, you cannot take medications that interact with celecoxib or have anti-inflammatory or immune-modulating effects. There is also a required period without these medications before starting celecoxib.

What data supports the effectiveness of the drug Celecoxib for treating Major Depressive Disorder?

Research shows that adding Celecoxib to standard antidepressant treatment can lead to greater improvement in depression symptoms compared to antidepressants alone. This suggests that Celecoxib, which reduces inflammation, may help treat depression by addressing inflammation-related aspects of the disorder. ^{1 2 3 4 5}

Is Celecoxib safe for use in humans?

Celecoxib, also known as Celebrex, is generally considered safe for humans when used at the lowest effective dose for the shortest time. It has fewer stomach-related side effects compared to other similar drugs, but it may increase the risk of heart problems, especially at higher doses. People with heart issues or allergies to sulfonamides should be cautious, and it's important to discuss potential risks and benefits with a doctor. ^{6 7 8 9 10}

How does the drug celecoxib work differently for major depressive disorder?

Celecoxib is unique for treating major depressive disorder because it works by reducing inflammation in the body, specifically by inhibiting pro-inflammatory substances like interleukin-6 (IL-6). This anti-inflammatory action is different from traditional antidepressants, which typically target neurotransmitters in the brain. ^{1 3 5 11 12}

Research Team

Christine DeLorenzo, PhD

Principal Investigator

Stony Brook University

Eligibility Criteria

This trial is for adults aged 18-65 with Major Depressive Disorder (MDD) currently experiencing a major depressive episode. Participants must score at least 29 on the MADRS, which measures depression severity. People who are pregnant, breastfeeding, or planning to conceive during the study; have certain genetic traits affecting drug metabolism; severe allergies to celecoxib or similar drugs; heart, liver, kidney issues; recent GI bleeding or peptic ulcers can't join.

Inclusion Criteria

I am currently experiencing a major depressive episode.

Your depression severity score on the MADRS (Montgomery-Åsberg Depression Rating Scale) is 29 or higher.

I understand the details of the trial and can consent to participate.

Exclusion Criteria

I haven't taken any anti-inflammatory or immune-modifying drugs recently.

You are allergic to celecoxib, sulfonamides, aspirin, or other medications like NSAIDs. You have had asthma, hives, or allergic reactions when taking aspirin or other NSAIDs in the past.

I am on medications that could interact with celecoxib.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 400 mg/day of celecoxib for 8 weeks, with PET scans and HDRS scores obtained at each time point

8 weeks

2 visits (in-person) for PET scans

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Celecoxib

Trial Overview The trial tests if Celecoxib (400 mg daily), an anti-inflammatory drug, reduces neuroinflammation and eases symptoms in MDD patients. It involves PET scans using [18F]FEPPA tracer before and after an 8-week treatment period to measure changes in brain inflammation and correlate these with symptom improvement as per HDRS scores.

Participant Groups

Group I: Celecoxib 400 mg Experimental Treatment 1 Intervention

Patients will receive 400 mg/day of celecoxib for 8 weeks.

Celecoxib is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Celebrex for:

• Pain relief
• Inflammation
• Osteoarthritis
• Rheumatoid arthritis
• Menstrual cramps
• Colorectal polyps prevention

Approved in European Union as Celebrex for:

• Symptomatic relief in osteoarthritis
• Symptomatic relief in rheumatoid arthritis
• Ankylosing spondylitis
• Acute pain
• Primary dysmenorrhea
• Adenomatous polyposis coli

Approved in Canada as Celebrex for:

• Symptomatic relief of osteoarthritis
• Symptomatic relief of rheumatoid arthritis
• Ankylosing spondylitis
• Acute pain
• Primary dysmenorrhea

Who Is Running the Clinical Trial?

Stony Brook University

Lead Sponsor

Trials

225

Recruited

41,700+

Brain & Behavior Research Foundation

Collaborator

Trials

63

Recruited

2,900+

Findings from Research

In a study involving 40 patients with major depression, the addition of the COX-2 inhibitor celecoxib to reboxetine treatment resulted in significantly greater improvements in depressive symptoms compared to reboxetine alone over a 6-week period.

The positive effects of celecoxib suggest a link between inflammation and major depression, indicating that targeting inflammatory processes may enhance the effectiveness of traditional antidepressant therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Müller, N., Schwarz, MJ., Dehning, S., et al.[2022]

Celecoxib, when added to standard treatment, significantly reduces depressive symptoms in patients with unipolar depression, as shown by a decrease in Hamilton Depression Rating Scale scores at both 4 and 6 weeks.

Patients receiving celecoxib also had much higher rates of treatment response and remission compared to those on placebo, indicating its potential effectiveness as an add-on therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Celecoxib: a new augmentation strategy for depressive mood episodes. A systematic review and meta-analysis of randomized placebo-controlled trials. Faridhosseini, F., Sadeghi, R., Farid, L., et al.[2018]

A meta-analysis of 29 randomized controlled studies involving 847 patients with depression found that celecoxib, a selective COX2 inhibitor, has a significant anti-depressant effect, suggesting it could be a viable treatment option.

Despite the overall positive findings, there was considerable heterogeneity in the results, likely due to differences in depression types and scales used, indicating that further research is needed to clarify its efficacy across various depression subtypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of celecoxib on improving depression: A systematic review and meta-analysis. Wang, Z., Wu, Q., Wang, Q.[2022]

Celecoxib, an NSAID, may improve outcomes in patients with major depressive disorder when used alongside antidepressants, based on four small randomized controlled trials involving a total of 160 participants.

Despite some potential benefits, there are concerns about adverse effects and drug interactions with NSAIDs, making their use in treating depression a cautious and tentative approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antidepressant augmentation with anti-inflammatory agents. Andrade, C.[2022]

In the PREDDICT study involving 122 participants, switching to vortioxetine from other antidepressants was found to be safe and well-tolerated, with mild side effects reported during the transition.

Participants experienced a significant reduction in depression symptoms, as indicated by a decrease in the Montgomery-Åsberg Depression Rating Scale scores over the first four weeks of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Switching Strategies of Various Antidepressants to Vortioxetine in the PREDDICT Trial. Mills, NT., Sampson, E., Fourrier, C., et al.[2022]

Celecoxib, a selective COX-2 inhibitor, offers the benefit of fewer gastrointestinal side effects compared to traditional nonsteroidal anti-inflammatory drugs (NSAIDs), making it a safer option for managing musculoskeletal symptoms and pain.

While higher doses of celecoxib do increase cardiovascular risk, this risk is similar to that associated with nonselective NSAIDs, highlighting the need for careful consideration of individual patient risks and benefits when prescribing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Celecoxib in arthritis: relative risk management profile and implications for patients. McKellar, G., Singh, G.[2021]

Celecoxib is an effective treatment for various types of arthritis and pain management, offering improved gastrointestinal tolerability compared to nonselective NSAIDs, making it a safer option for patients at risk of GI issues.

While there is some inconsistency regarding its cardiovascular risk, any potential increase is likely small and comparable to that of nonselective NSAIDs, suggesting celecoxib is a reasonable choice for patients with low cardiovascular risk who need NSAID therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Celecoxib: a review of its use in the management of arthritis and acute pain. Frampton, JE., Keating, GM.[2021]

A postmarketing analysis of 31,024 adverse event reports linked to rofecoxib revealed a significant incidence of serious adverse events, particularly hemorrhage, thrombosis, and embolism, with a notable risk increase in patients using anticoagulants or NSAIDs.

The data suggests that rofecoxib users face heightened risks for cardiovascular issues and hemorrhagic events, especially among older males and those taking blood thinners, indicating a need for careful monitoring in these populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postmarketing surveillance of serious adverse events associated with the use of rofecoxib from 1999-2002. Bottone, FG., Barry, WT.[2019]

Celecoxib is effective for treating osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, showing significant efficacy compared to placebo and similar effectiveness to other pain relievers like paracetamol and nonselective NSAIDs.

Celecoxib has a lower incidence of upper gastrointestinal complications compared to nonselective NSAIDs, making it a safer option for patients at risk of GI toxicity, although caution is advised when used with low-dose aspirin due to potential cardiovascular risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Celecoxib: a review of its use for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. McCormack, PL.[2021]

Celecoxib is a selective COX-2 inhibitor that offers similar pain relief as traditional NSAIDs but has a safer gastrointestinal profile, making it a preferable option for patients at risk of GI complications.

Despite its GI safety, celecoxib carries similar risks of other adverse effects as NSAIDs, and caution is advised for certain populations, including the elderly and those with cardiovascular issues, as it does not provide antithrombotic benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety of celecoxib administration]. Babić-Naglić, D.[2017]

In a study of 40 patients with major depressive disorder, celecoxib significantly reduced serum IL-6 levels and depressive symptoms compared to a placebo, suggesting its antidepressant effect may be linked to its anti-inflammatory properties.

Patients taking celecoxib experienced higher rates of response (95%) and remission (35%) compared to those on placebo (50% and 5%), indicating that celecoxib is both effective and safe as an adjunct treatment for depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of celecoxib add-on treatment on symptoms and serum IL-6 concentrations in patients with major depressive disorder: randomized double-blind placebo-controlled study. Abbasi, SH., Hosseini, F., Modabbernia, A., et al.[2022]

In a study involving 32 patients with major depressive disorder (MDD) and 20 healthy controls, the COX-2 inhibitor celecoxib significantly reduced depression symptoms when added to reboxetine treatment, as measured by the Hamilton Depression Scale.

The study found elevated levels of macrophage migration inhibitory factor (MIF) and reduced levels of transforming growth factor-β (TGF-β) in depressed patients, suggesting a link between immune response and depressive symptoms, although the sample size was small.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elevated macrophage migration inhibitory factor and decreased transforming growth factor-beta levels in major depression--no influence of celecoxib treatment. Musil, R., Schwarz, MJ., Riedel, M., et al.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

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. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Celecoxib: a new augmentation strategy for depressive mood episodes. A systematic review and meta-analysis of randomized placebo-controlled trials. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Effect of celecoxib on improving depression: A systematic review and meta-analysis. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Antidepressant augmentation with anti-inflammatory agents. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Clinical Switching Strategies of Various Antidepressants to Vortioxetine in the PREDDICT Trial. [2022]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Celecoxib in arthritis: relative risk management profile and implications for patients. [2021]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Celecoxib: a review of its use in the management of arthritis and acute pain. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Postmarketing surveillance of serious adverse events associated with the use of rofecoxib from 1999-2002. [2019]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Celecoxib: a review of its use for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. [2021]

10. Croatia pubmed.ncbi.nlm.nih.gov

[Safety of celecoxib administration]. [2017]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Effect of celecoxib add-on treatment on symptoms and serum IL-6 concentrations in patients with major depressive disorder: randomized double-blind placebo-controlled study. [2022]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Elevated macrophage migration inhibitory factor and decreased transforming growth factor-beta levels in major depression--no influence of celecoxib treatment. [2018]