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

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ClinicalTrials.gov Identifier: NCT04582916
Recruitment Status : Recruiting
First Posted : October 12, 2020
Last Update Posted : June 11, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )

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:

  1. the relationship between peripheral markers of inflammation and COX binding
  2. 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:

  1. Dynamic 3D PET brain scan on PET/CT.
  2. One venous line for radioligand injection.
  3. Arterial line for blood sampling.
  4. Transmission (CT) scan will be performed to measure and correct for attenuation.
  5. Injection of 20 mCi of [11C]MC1 or [11C]PS13.
  6. 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.
  7. 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.
  8. 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:

  1. Measurement of whole blood, plasma activity, and metabolite levels in all phases: MIB/NIMH.
  2. 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:

  1. 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).
  2. C-reactive protein (CRP) will be measured in the pre-PET blood sample to assess overall inflammatory status in periphery.
  3. 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).
  4. 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).
  5. 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.
  6. 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:

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

Study Population: 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.

Description of Sites/Facilities Enrolling Participants: Screening and PET imaging will be performed at the NIH Clinical Center.

Description of Study Intervention: Group A - Participants will be intravenously injected with 20 mCi of [11C]MC1 twice, once at baseline and once after blockade by celecoxib.

Group B - Subjects will be intravenously injected once with 20 mCi of [11C]PS13 and

For both groups, participants will also have a radial artery catheter(s) inserted to measure radioligand concentration before each scan. Participants will also have a brain MRI to provide anatomic orientation for the PET scans.

Study Duration: 36 months

Participant Duration: One to two weeks, depending on the participant's availability and investigators' overall access to MRI and PET cameras.

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Study Type : Interventional  (Clinical Trial)
Estimated 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)
Estimated Study Start Date : June 16, 2021
Estimated Primary Completion Date : May 29, 2023
Estimated Study Completion Date : August 29, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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




Primary Outcome Measures :
  1. Measure the concentration of radioligands [ Time Frame: 36 months ]
    Tracer binding level


Secondary Outcome Measures :
  1. measure peripheral markers of inflammation and COX binding [ Time Frame: 36 months ]
    Assess the severity of depression and/or anxiety

  2. measure clinical rating scales and COX binding [ Time Frame: 36 months ]
    Assess the severity of depression and/or anxiety



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION CRITERIA:

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

  1. Be male or female, aged 18 to 70 years old.
  2. Female participants of childbearing potential must be using a medically acceptable means of contraception.
  3. Participants must be in good general health as evidenced by medical history and physical examination.
  4. Each participant must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.
  5. 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' (PI: Carlos A. Zarate Jr).
  6. Participants must fulfill DSM-5 criteria for major depression (MDD) without psychoticfeatures, as based on clinical assessment and structured diagnostic interview (SCID-P).
  7. 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.
  8. Participants must be experiencing an MDE lasting at least four weeks.
  9. 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.
  10. Participants with stable medical conditions as assessed by their primary care provider (PCP) and/or in-house clinician are permitted to join the study.
  11. All MDD participants must have a PCP or psychiatrist in the community.
  12. 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.
  13. 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:

  1. Be male or female, aged 18 to 70 years old.
  2. Be able to understand the study and be willing to sign a written informed consent document.
  3. Be in good general health, as evidenced by medical history and physical examination, and have no cognitive impairment.
  4. Be enrolled in 01-M-0254, The Evaluation of Participants with Mood and Anxiety Disorders and Healthy Volunteers (PI: Dr. Carlos Zarate) or 17-M-0181, Recruitment and Characterization of Healthy Research Volunteers for NIMH Intramural Studies (PI: Dr. Joyce Chung).
  5. 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.
  6. 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:

  1. 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; and pregnancy test for women of childbearing potential.
  2. 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.
  3. 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.
  4. Current psychotic features or a diagnosis of schizophrenia or any other psychotic disorder as defined in the DSM-5.
  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.
  6. Participants who, in the investigator s judgment, pose a current serious suicidal or homicidal risk.
  7. Participants who have a history of aggressive behavior towards others.
  8. 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).
  9. Are unable to travel to the NIH.
  10. 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.
  11. 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.
  12. 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.
  13. 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:

  1. 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; and pregnancy test for women of childbearing potential.
  2. 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.
  3. 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.
  4. 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.
  5. 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).
  6. Are unable to travel to the NIH.
  7. 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.
  8. 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.
  9. 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.
  10. 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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04582916


Contacts
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Contact: Maria M Araneta (301) 443-6602 maria.araneta@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Institute of Mental Health (NIMH)
Investigators
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Principal Investigator: Robert B Innis, M.D. National Institute of Mental Health (NIMH)
Additional Information:
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Responsible Party: National Institute of Mental Health (NIMH)
ClinicalTrials.gov Identifier: NCT04582916    
Other Study ID Numbers: 200157
20-M-0157
First Posted: October 12, 2020    Key Record Dates
Last Update Posted: June 11, 2021
Last Verified: May 20, 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) ):
PET Imaging
Inflammation
Cyclooxygenase-2
Depression
Additional relevant MeSH terms:
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Depression
Depressive Disorder
Depressive Disorder, Major
Behavioral Symptoms
Mood Disorders
Mental Disorders