Depression
Conditions
Keywords
PET Imaging, Inflammation, Ketamine, Depression
Brief summary
Background: Major depressive disorder (MDD) may have many underlying causes. One theory is that brain cells with low levels of a molecule called cyclic AMP (cAMP) may cause depression. A drug called ketamine may increase the levels of cAMP in a person's brain cells. Objective: To find out if administering ketamine to people with depression affects cAMP levels in their brains. Eligibility: People aged 18 to 70 with MDD who are enrolled in another NIH study that uses ketamine. Design: Participants will visit the NIH clinic 5 times in up to 6 weeks. Some of the visits may be spread out over more than 1 day. Participants will be screened. They will have a physical exam with blood and urine tests. They will have a test of their heart function. They will have a psychiatric evaluation. They will answer questions about their family history and mental health. Participants will have a positron emission tomography (PET) scan. A small amount of a radioactive drug will be injected into a vein in their arm. Participants will lie on a bed that slides in and out of a doughnut-shaped machine that records images of their brains. They will have their heads in a holder to prevent movement. Each scan will last up to 2 hours. After their first PET scan, participants will receive ketamine in a different study they are enrolled in. Then they will come back for another PET scan with the radioactive drug. Participants will also have another scan called an MRI. They will lie on a table that slides into a metal tube. They will lie still for up to an hour....
Detailed description
Study Description: This study will test the effects of ketamine infusion on the cAMP system in human brain to determine if ketamine mediates its antidepressant effects at least in part due to modulation of cAMP signaling. Objectives: Primary Objective: To determine if ketamine infusions in depression causes increases in cAMP signaling as measured by \[11C\](R)-rolipram binding. Secondary Objectives: To determine if increases in \[11C\](R)-rolipram correlate with symptomatic improvement in major depressive symptoms. Endpoints: Primary Endpoint: measurement of PDE4 density (volume of distribution VT) in brains of individuals with major depressive disorder (MDD) before and after administration of ketamine. Secondary Endpoints: Clinical rating scales of depression, including MADRS, HAM-D.
Interventions
DRUG11(R)-rolipram
Injected IV followed by PET scanning
Sponsors
National Institute of Mental Health (NIMH)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: Patients: 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'. 6. Participants must be enrolled in the ketamine arms of protocols 19-M-0107 'Ketamine and AMPA', 17-M-0060 'Neuropharmacology of Ketamine', or 15-M-0188 'Neurobiology of Suicide'. 7. Participants must fulfill DSM-5 criteria for major depression (MDD) without psychotic features, as based on clinical assessment and structured diagnostic interview (SCID-P). 8. Participants must have an initial score on the MADRS \>= 18 or HAM-D \>= 15 within two weeks of study entry. 9. Participants with stable medical conditions as assessed by their primary care provider (PCP) and/or in-house clinician are permitted to join the study. 10. Patients must qualify for ketamine administration, usually defined as lack of response to two adequate lifetime antidepressant trials, with \[at least\] one in the current major depressive episode, operationally defined using the Antidepressant Treatment History Form (ATHF); a failed adequate trial of ECT \[or TMS\] would count as an adequate antidepressant trial. 11. 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. 12. Participants must 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, alanine transaminase (ALT), aspartate aminotransferase (\[AST), bilirubin total, and bilirubin direct\]; mineral panel (albumin, calcium, magnesium, phosphorus); glucose; prothrombin and partial prothrombin tests. 2. Current psychotic features, a diagnosis of schizophrenia or any other psychotic disorder as defined in the DSM-5. 3. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Whole Brain Total Distribution Volume (VT) | 90 minutes after injection of 11C-R-Rolipram | Participants received 11C-R-Rolipram during PET scan and were scanned for 90 minutes with arterial blood sampling. Volume of distribution was calculated using two-tissue compartmental modeling. Participants had one PET scan pre-Ketamine and a second PET scan post-Ketamine administration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Measure of Level of Depression Using Montgomery-Åsberg Depression Rating Scale (MADRS) | Within two weeks of start of study (Pre) and within 7 days of Ketamine infusion (Post) | Participants rated level of depression using Montgomery-Åsberg Depression Rating Scale (MADRS). MADRS is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. Each item yields a score of 0 to 6 with overall score ranging from 0 to 60. Higher MADRS score indicates more severe depression. Scores were measured at two visits, pre-Ketamine administration and a second visit post-Ketamine administration. |
| Measure of Level of Depression Using the Hamilton Depression (HAM-D) Rating Scale | Within two weeks of start of study (Pre) and within 7 days of Ketamine infusion (Post) | Participants rated level of depression using the Hamilton Depression (HAM-D) Rating Scale. The HAM-D is a clinician-administered depression assessment scale which contains 17 items pertaining to symptoms of depression experienced over the past week. Eight items are rated 0-4 and nine items are rated 0-2 for a minimum score of zero and a maximum score of 50. Higher value indicates worsening depression. Scores were measured at two visits, prior to PET scan pre-Ketamine and a second visit post-Ketamine administration. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Subjects With Major Depression Disorder (MDD) Participants with major depressive disorder received 20 mCi of \[11C\](R)-rolipram intravenously for two positron emission tomography (PET) scans, prior to and after ketamine infusion as well as brain MRI | 1 |
| Total | 1 |
Baseline characteristics
| Characteristic | Subjects With Major Depression Disorder (MDD) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment United States | 1 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 1 |
| other Total, other adverse events | 0 / 1 |
| serious Total, serious adverse events | 0 / 1 |
Outcome results
Primary
Whole Brain Total Distribution Volume (VT)
Participants received 11C-R-Rolipram during PET scan and were scanned for 90 minutes with arterial blood sampling. Volume of distribution was calculated using two-tissue compartmental modeling. Participants had one PET scan pre-Ketamine and a second PET scan post-Ketamine administration.
Time frame: 90 minutes after injection of 11C-R-Rolipram
Population: Analysis included participant who completed the study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Subjects With Major Depression Disorder (MDD) | Whole Brain Total Distribution Volume (VT) | Pre-Ketamine | 0.512639 mL x cm^3 |
| Subjects With Major Depression Disorder (MDD) | Whole Brain Total Distribution Volume (VT) | Post-Ketamine | 0.443411 mL x cm^3 |
Secondary
Measure of Level of Depression Using Montgomery-Åsberg Depression Rating Scale (MADRS)
Participants rated level of depression using Montgomery-Åsberg Depression Rating Scale (MADRS). MADRS is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. Each item yields a score of 0 to 6 with overall score ranging from 0 to 60. Higher MADRS score indicates more severe depression. Scores were measured at two visits, pre-Ketamine administration and a second visit post-Ketamine administration.
Time frame: Within two weeks of start of study (Pre) and within 7 days of Ketamine infusion (Post)
Population: Analysis included participant who completed the study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Subjects With Major Depression Disorder (MDD) | Measure of Level of Depression Using Montgomery-Åsberg Depression Rating Scale (MADRS) | Pre-Ketamine | 28 score on a scale |
| Subjects With Major Depression Disorder (MDD) | Measure of Level of Depression Using Montgomery-Åsberg Depression Rating Scale (MADRS) | Post-Ketamine | 25 score on a scale |
Secondary
Measure of Level of Depression Using the Hamilton Depression (HAM-D) Rating Scale
Participants rated level of depression using the Hamilton Depression (HAM-D) Rating Scale. The HAM-D is a clinician-administered depression assessment scale which contains 17 items pertaining to symptoms of depression experienced over the past week. Eight items are rated 0-4 and nine items are rated 0-2 for a minimum score of zero and a maximum score of 50. Higher value indicates worsening depression. Scores were measured at two visits, prior to PET scan pre-Ketamine and a second visit post-Ketamine administration.
Time frame: Within two weeks of start of study (Pre) and within 7 days of Ketamine infusion (Post)
Population: Analysis included participant who completed the study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Subjects With Major Depression Disorder (MDD) | Measure of Level of Depression Using the Hamilton Depression (HAM-D) Rating Scale | Pre-Ketamine | 17 score on a scale |
| Subjects With Major Depression Disorder (MDD) | Measure of Level of Depression Using the Hamilton Depression (HAM-D) Rating Scale | Post-Ketamine | 16 score on a scale |