PET Imaging of Cyclooxygenase in Participants With Major Depressive Disorder (MDD)

Sponsor

National Institute of Mental Health (NIMH) (NIH)

Overall Status

Recruiting

CT.gov ID

NCT04582916

Collaborator

(none)

Enrollment

Location

Arm

49.3

Anticipated Duration (Months)

1.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Purpose: To determine whether COX-1 and COX-2 are detectable in the brains of individuals with MDD experiencing a major depressive episode (MDE).

Endpoints:

Primary Endpoint:

Group A - Calculation of COX-2 density from [11C]MC1 PET scans, using baseline scans and scans after blockade with celecoxib.

Group B - Calculation of the density of COX-1 using [11C]PS13 in healthy volunteers and depressed subjects.

Secondary Endpoints:

the relationship between peripheral markers of inflammation and COX binding
the relationship between clinical rating scales and COX binding

Study Design: Group A Sixteen (16) medication-free participants with MDD; Group B Three groups of 16 subjects each will be studied: 1) Medicated MDD, 2) Unmedicated MDD and 3) healthy volunteers. Participants may be male or female. They must be between 18 and 70 years old. Individuals may be recruited from anywhere but, for those participating in the outpatient study, most are expected to come from the Washington DC metropolitan area. MDD participants must be in good medical health and provide informed consent.

Data acquisition of [11C]MC1 and [11C]PS13:

Dynamic 3D PET brain scan on PET/CT.
One venous line for radioligand injection.
Arterial line for blood sampling.
Transmission (CT) scan will be performed to measure and correct for attenuation.
Injection of 20 mCi of [11C]MC1 or [11C]PS13.
Emission scans on PET/CT or PET scanner. Emission scan for about 90 min (possibly up to 2h). Frame information: 6 frames 30 sec each, 3 frames 1 min each, 2 frames 2 min each, and remaining frames of 5 min each.
Vital signs (blood pressure, pulse, and respiratory rate) and ECG (either 3 or 12 lead) will be recorded within three hours of tracer injection, in the middle, and after the PET scan.
We will take the two [11C]MC1 scans preferably in same day. They should be separated by at least 2.5 hours

Blood analysis in [11C]MC1 and [11C]PS13:

Measurement of whole blood, plasma activity, and metabolite levels in all phases: MIB/NIMH.
Measurement of whole blood activity by PET Department is not required in any phase.

Administration of celecoxib: In these scans, specific binding of [11C]MC1 to COX-2 in the brain will be verified by a pre-blocking study using celecoxib (600 mg PO). Participants will be encouraged to have a light meal prior to PET studies with blockade by celecoxib. After oral administration, the plasma concentration peaks at about two hours (Paulson et al. 2001). Thus, we will administer celecoxib about two hours before the second PET scan.

Safety monitoring by MIB/NIMH:

Pre-scan labs within 24 hours prior to injection: Urine pregnancy test (woman of child bearing potential), CBC, acute care panel (Na, K, Cl, CO2, creatinine, glucose, urea nitrogen), hepatic panel (alkaline phosphatase, ALT, AST, bilirubin total, and bilirubin direct), glucose, mineral panel (albumin, calcium, magnesium, phosphorus).
C-reactive protein (CRP) will be measured in the pre-PET blood sample to assess overall inflammatory status in periphery.
Data for safety monitoring will be recorded at three timepoints: no more than three hours before injection, about the middle of the PET scan, and after the PET scan. Recorded data included: blood pressure, pulse, respiratory rate, and EKG (either 3- or 12-lead).
Post-scan labs: CBC, acute care panel (Na, K, Cl, CO2, creatinine, glucose, urea nitrogen), hepatic panel (alkaline phosphatase, ALT, AST, bilirubin total, and bilirubin direct), glucose, mineral panel (albumin, calcium, magnesium, phosphorus).
Pregnancy Tests: For women of childbearing potential, urine pregnancy testing will be done within the 24 hours prior to any MRI or PET scan. If the pregnancy test is positive, PET and MRI will not be done, and the subject will be taken off the protocol.
Follow-up Procedures: Subjects will be contacted one to three business days after each PET scan to determine whether they have had any untoward sequelae.

Condition or Disease	Intervention/Treatment	Phase
Depression	Drug: 11C-MCI Drug: 11CPS13	Phase 1

Detailed Description

Study Description: This study will examine whether cyclooxygenase 1 (COX-1) and cyclooxygenase-2 (COX-2) are detectable in the brain of individuals with major depressive disorder (MDD).

Objectives: Primary Objective: To determine whether COX-1 and COX-2 are detectable in the brains of individuals with MDD experiencing a major depressive episode (MDE).

Endpoints: Primary Endpoints: Group A - Calculation of COX-2 density from [11C]MC1 PET scans, using baseline scans and scans after blockade with celecoxib. Group B - Calculation of the density of COX-1 using [11C]PS13

Secondary Endpoints, common to both groups:

the relationship between peripheral markers of inflammation and COX binding;
the relationship between clinical rating scales and COX binding

Study Design

Study Type:

Interventional

Anticipated Enrollment :

64 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Diagnostic

Official Title:

PET Imaging of Cyclooxygenase in Participants With Major Depressive Disorder (MDD)

Actual Study Start Date :

Jul 20, 2021

Anticipated Primary Completion Date :

May 29, 2025

Anticipated Study Completion Date :

Aug 29, 2025

Arms and Interventions

Arm	Intervention/Treatment
Other: One Arm All subject receive the same tests	Drug: 11C-MCI Injected IV followed by PET scanning Drug: 11CPS13 Injected IV followed by PET scanning

Arm

Intervention/Treatment

Other: One Arm

All subject receive the same tests

Drug: 11C-MCI

Injected IV followed by PET scanning

Drug: 11CPS13

Injected IV followed by PET scanning

Outcome Measures

Primary Outcome Measures

Measure the concentration of radioligands [36 months]
Tracer binding level

Secondary Outcome Measures

measure peripheral markers of inflammation and COX binding [36 months]
Assess the severity of depression and/or anxiety
measure clinical rating scales and COX binding [36 months]
Assess the severity of depression and/or anxiety

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

INCLUSION CRITERIA:

In order to be eligible for this study, MDD participants must meet all of the following criteria:

Be male or female, aged 18 to 70 years old.
Female participants of childbearing potential must be using a medically acceptable means of contraception.
Participants must be in good general health as evidenced by medical history and physical examination.
Each participant must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.
All participants must have undergone a screening assessment under protocol 01-M-0254, 'The Evaluation of Patients with Mood and Anxiety Disorders and Healthy Participants.
Participants must fulfill DSM-5 criteria for major depression (MDD) without psychoticfeatures, as based on clinical assessment and structured diagnostic interview (SCID-P).
Participants must have an initial score on the MADRS greater than or equal to 18 or HAM-D greater than or equal to 15 within one week of study entry.
Participants must be experiencing an MDE lasting at least four weeks.
Unmedicated participants in both Groups must be medication-free for at least two weeks (5 weeks for aripirazole, brexpiprazole, fluoxetine) prior to first screen visit. Medications will not be discontinued for the purpose of this study.
Participants with stable medical conditions as assessed by their primary care provider (PCP) and/or in-house clinician are permitted to join the study.
Participants must have their radial artery pulse checked for the presence of adequate ulnar collateral flow and the absence of any metal or foreign objects in both wrists.
Participants must agree to adhere to the lifestyle considerations.

Healthy Controls: In order to be eligible to participate in this study, control subjects must meet all of the following criteria:

Be male or female, aged 18 to 70 years old.
Be able to understand the study and be willing to sign a written informed consent document.
Be in good general health, as evidenced by medical history and physical examination, and have no cognitive impairment.
Be enrolled in 01-M-0254, The Evaluation of Participants with Mood and Anxiety Disorders and Healthy Volunteers or 17-M-0181, Recruitment and Characterization of Healthy Research Volunteers for NIMH Intramural Studies .
Have their radial artery pulse checked for the presence of adequate ulnar collateral flow and the absence of any metal or foreign objects in both wrists.
Agree to adhere to the lifestyle considerations.

EXCLUSION CRITERIA:

Participants with MDD who meet any of the following criteria will be excluded from participation in this study:

Clinically significant abnormalities on EKG or laboratory testing. This includes CBC; acute care panel (Na, K, Cl, CO2, creatinine, glucose, urea nitrogen); hepatic panel (alkaline phosphatase, ALT, AST, bilirubin total, and bilirubin direct); mineral panel (albumin, calcium, magnesium, phosphorus); glucose; prothrombin and partial prothrombin tests; HIV blood test.
Participants must be free of all prohibited medications or at least two weeks (5 weeks for aripiprazole, brexpiprazole, fluoxetine) prior to screen visit. These medications include antidepressants, anti-inflammatory drugs (except for study medication celecoxib), antipsychotics, anxiolytics, psychotropic drugs not otherwise specified (including herbal products), and sedatives/hypnotics. Medicated participants in Group B may continue their therapy.
Participants should not have taken NSAIDs for two weeks prior to the PET scan. Aspirin, corticosteroids (with the exception of topical steriods), or immunosuppressants (e.g. methotrexate) must not have been taken in the prior month.
Current psychotic features or a diagnosis of schizophrenia or any other psychotic disorder as defined in the DSM-5.
Participants with a history of DSM-5 substance use disorder (except for caffeine or nicotine dependence) within the preceding three months. In addition, participants must not have substance use disorder or alcohol use disorder. However, alcohol or cannabis use by themselves are not exclusion criteria, unless that use impairs function.
Participants who, in the investigator s judgment, pose a current serious suicidal or homicidal risk.
Participants who have a history of aggressive behavior towards others.
Participants who have an unstable medical condition that, in the opinion of the investigators, makes participation unsafe (e.g., an active infection or untreated malignancy).
Participants seeking treatment or a change in treatment and may be referred to the community or to another research study.
Are unable to travel to the NIH.
Have recent exposure to radiation related to research (e.g., PET from other research) that, when combined with this study, would be above the allowable limits.
Have an inability to lie flat and/or lie still on the camera bed for at least two hours, including claustrophobia, overweight greater than the maximum for the scanner, and uncontrollable behavioral symptoms, which will be screened by an interview with the participant during the screening visit.
Are unable to have an MRI scan (e.g., because of pacemakers or other implanted electrical devices, brain stimulators, dental implants, aneurysm clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins and rods, heart valves, and cochlear implants), permanent eyeliner, implanted delivery pumps, shrapnel fragments, or metal fragments in the eye.
Pregnancy
HIV Infection
Be NIMH staff or an NIH employee who is a subordinate/relative/co-worker of the investigators.

Healthy controls who meet any of the following criteria will be excluded from participation in this study:

Clinically significant abnormalities on EKG or laboratory testing. This includes CBC; acute care panel (Na, K, Cl, CO2, creatinine, glucose, urea nitrogen); hepatic panel (alkaline phosphatase, ALT, AST, bilirubin total, and bilirubin direct); mineral panel (albumin, calcium, magnesium, phosphorus); glucose; prothrombin and partial prothrombin tests.
Participants must be free of all prohibited medications or at least two weeks (5 weeks for aripiprazole, brexpiprazole, fluoxetine) prior to screen visit. These medications include antidepressants, anti-inflammatory drugs (except for study medication celecoxib), antipsychotics, anxiolytics, psychotropic drugs not otherwise specified (including herbal products), and sedatives/hypnotics.
Participants should not have taken NSAIDs for two weeks prior to the PET scan. Aspirin, corticosteroids, or immunosuppressants (e.g. methotrexate) must not have been taken in the prior month.
Participants with a history of DSM-5 substance use disorder (except for caffeine or nicotine dependence) within the preceding three months. In addition, participants must not have substance use disorder or alcohol use disorder. However, alcohol or cannabis use by themselves are not exclusion criteria, unless that use impairs function.
Participants who have an unstable medical condition that, in the opinion of the investigators, makes participation unsafe (e.g., an active infection or untreated malignancy).
Are unable to travel to the NIH.
Have recent exposure to radiation related to research (e.g., PET from other research) that, when combined with this study, would be above the allowable limits.
Have an inability to lie flat and/or lie still on the camera bed for at least two hours, including claustrophobia, overweight greater than the maximum for the scanner, and uncontrollable behavioral symptoms, which will be screened by an interview with the participant during the screening visit.
Are unable to have an MRI scan (e.g., because of pacemakers or other implanted electrical devices, brain stimulators, dental implants, aneurysm clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins and rods, heart valves, and cochlear implants), permanent eyeliner, implanted delivery pumps, shrapnel fragments, or metal fragments in the eye.
Pregnancy
HIV Infection
Be NIMH staff or an NIH employee who is a subordinate/relative/co-worker of the investigators.

EXCLUSION OF CHILDREN:

Because this protocol has more than minimal risk from radiation exposure without possibility of direct benefit, inclusion of children is not appropriate.

EXCLUSION OF PREGNANT OR BREASTFEEDING WOMEN:

Pregnant women will be excluded because this protocol involves exposure to ionizing radiation. Lactating women will be excluded because radioisotopes may be excreted in milk.

EXCLUSION OF PARTICIPANTS WHO ARE HIV POSITIVE:

Persons with HIV infection are excluded because HIV infection itself may cause neuroinflammation, and we wish to specifically study the effect of depression on neuroinflammation.

EXCLUSION OF NON ENGLISH SPEAKING PARTICIPANTS:

Non-English-speaking participants will be excluded from participation in this study because neuropsychological testing is required by this protocol. This testing, which is critical for interpreting study results, has not been validated in other languages or when using a translator.