NMDA Receptor Function
Conditions
Keywords
Guanfacine, Ketamine, Functional Magnetic Resonance Imaging, Prefrontal Cortex Activity, Receptors, N-Methyl-D-Aspartate, Receptors, Adrenergic, alpha-2, Memory, Short-Term, Schizophrenia
Brief summary
The purpose of the study is 1. To establish the feasibility of fMRI studies of the interaction of guanfacine and ketamine. 2. To explore the possibility that guanfacine can ameliorate the negative effects of ketamine on task-related prefrontal activation. 3. To assess the strength of any interaction between guanfacine and ketamine.
Detailed description
Potential subjects will be interviewed over the phone and, if appropriate, will be scheduled for a screening session. Participants who meet study criteria will participate in two study sessions separated by at least two weeks. The sessions will be identical except on one day they will receive guanfacine and on the other, they will receive a placebo. This study was initially completed in 2014. Upon analysis of the collected data, it was decided to add additional subjects and gather additional data to verify results seen in the collected data. The study was reopened and new data was added beginning in September 2016. Information about the study beginning in 2016 is available in a separate record.
Interventions
DRUGGuanfacine
Subjects will be given 3mg of guanfacine before the fMRI scan. Then when in the scanner, a bolus of ketamine (0.23mg/kg over 1 min) will be given during the visual fixation scan. Immediately after completion of the 1 min bolus, the participant will receive a steady state ketamine infusion of 0.58 mg/kg/hour and brain activation will be measured during a spatial working memory task. The entire scan will last approximately two and a half hours and the ketamine infusion will be up to one hour and 15 minutes.
DRUGPlacebo
Subjects will be given a placebo before the fMRI scan. Then when in the scanner, a bolus of ketamine (0.23mg/kg over 1 min) will be given during the visual fixation scan. Immediately after completion of the 1 min bolus, the participant will receive a steady state ketamine infusion of 0.58 mg/kg/hour and brain activation will be measured during a spatial working memory task. The entire scan will last approximately two and a half hours and the ketamine infusion will be up to one hour and 15 minutes.
Sponsors
VA Office of Research and Development
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Age between 21 and 45, inclusive * Right-handed * Have at least a 12th grade education level or equivalent * Able to read and write English as a primary language * Willing to refrain from caffeine and alcohol use for one week prior to each MRI session.
Exclusion criteria
* Abnormality on physical examination * A 12 lead ECG at screening has clinically significant abnormalities as determined by the physician reading the ECG * A positive pre-study urine drug screen or, at the study physicians' discretion on any drug screens given before the scans * Abnormality on clinical chemistry or hematology examination at the pre-study medical screening. * History of positive HIV or Hepatitis B. * Has received either prescribed or over-the-counter (OTC) centrally active medicine or herbal supplements within the week prior to the MRI scan. * History of any substance abuse disorder meeting DSM-IV criteria with the exception of nicotine * Any history of DSM-IV Axis I psychiatric disorders, * Any history of major medical or neurological disorders * Any history indicating learning disability, mental retardation, or attention deficit disorder. * First-degree relative with Axis I DSM-IV disorder including substance abuse or dependence. * Any clinically significant abnormalities on screening electrocardiogram * Any history of head injury * Any evidence of psychosis-like symptoms, as indicated by elevated scores on the Perceptual Aberration-Magical Ideation (Chapman, Chapman et al. 1978; Eckblad, Chapman et al. 1983) and the revised Social Anhedonia scales(Eckblad, Chapman et al. unpublished) * A positive urine toxicology screen for illicit substance use or positive alcohol breathalyzer test conducted at screening interview and prior to each MRI session * Known sensitivity to ketamine. * Body circumference of 52 inches or greater. * History of claustrophobia * Any clinically significant impairment of color vision or visual acuity after correction available in the scanner. * Presence of cardiac pacemaker or other electronic device or ferromagnetic metal foreign bodies in vulnerable positions as assessed by a standard pre-MRI screening questionnaire * Pregnancy or breast-feeding would exclude potential participants and all female subjects will receive a urine pregnancy test at screening and before each MRI scan. * Donation of blood in excess of 500 mL within 56 days prior to dosing. * History of sensitivity to heparin or heparin-induced thrombocytopenia. * Blood pressure must be higher than 90/70. Pulse must be greater than 40 unless the participant is cleared by a study physician
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Amelioration of Ketamine-related Task Activation as Measured by Functional Magnetic Resonance Imaging in Inferior Parietal Lobule | Within 4 hours of dose administration, after up to 1.25 hours of ketamine infusion | Scans will be analyzed for task-related prefrontal activation Difference Score: Percent Signal Change in Regions of Interest (ketamine - saline) |
| Percent Change in Amelioration of Ketamine-related Task Activation as Measured by Functional Magnetic Resonance Imaging in Middle Frontal Gyrus | Within 4 hours of dose administration, after up to 1.25 hours of ketamine infusion | Difference Score: Percent Signal Change in Regions of Interest (ketamine - saline) |
| Percent Change in Amelioration of Ketamine-related Task Activation as Measured by Functional Magnetic Resonance Imaging in Superior Frontal Gyrus | Within 4 hours of dose administration, after up to 1.25 hours of ketamine infusion | Difference Score: Percent Signal Change in Regions of Interest (ketamine - saline) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Overall Study This 'arm' consists of all study participants who started the first Study Period. This Study Period consisted of an initial screening visit in which it was determined whether participants met the inclusion/exclusion criteria for further participation in this study. | 19 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Period | Adverse Event | 1 | 1 |
| First Period | moved out of area | 1 | 0 |
Baseline characteristics
| Characteristic | Overall Study |
|---|---|
| Age, Continuous | 30 years STANDARD_DEVIATION 6.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 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 | 2 Participants |
| Race (NIH/OMB) White | 13 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 19 |
| other Total, other adverse events | 0 / 19 | 0 / 19 |
| serious Total, serious adverse events | 0 / 19 | 0 / 19 |
Outcome results
Primary
Percent Change in Amelioration of Ketamine-related Task Activation as Measured by Functional Magnetic Resonance Imaging in Inferior Parietal Lobule
Scans will be analyzed for task-related prefrontal activation Difference Score: Percent Signal Change in Regions of Interest (ketamine - saline)
Time frame: Within 4 hours of dose administration, after up to 1.25 hours of ketamine infusion
Population: ALL SUBJECTS WHO COMPLETED THE STUDY WERE INCLUDED IN ANALYSIS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine | Percent Change in Amelioration of Ketamine-related Task Activation as Measured by Functional Magnetic Resonance Imaging in Inferior Parietal Lobule | -0.17 percent change in saline signal | Standard Error 0.046 |
| Placebo | Percent Change in Amelioration of Ketamine-related Task Activation as Measured by Functional Magnetic Resonance Imaging in Inferior Parietal Lobule | -0.094 percent change in saline signal | Standard Error 0.054 |
Primary
Percent Change in Amelioration of Ketamine-related Task Activation as Measured by Functional Magnetic Resonance Imaging in Middle Frontal Gyrus
Difference Score: Percent Signal Change in Regions of Interest (ketamine - saline)
Time frame: Within 4 hours of dose administration, after up to 1.25 hours of ketamine infusion
Population: ALL SUBJECTS WHO COMPLETED THE STUDY WERE INCLUDED IN ANALYSIS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine | Percent Change in Amelioration of Ketamine-related Task Activation as Measured by Functional Magnetic Resonance Imaging in Middle Frontal Gyrus | -0.1 percent change in saline signal | Standard Error 0.052 |
| Placebo | Percent Change in Amelioration of Ketamine-related Task Activation as Measured by Functional Magnetic Resonance Imaging in Middle Frontal Gyrus | 0.052 percent change in saline signal | Standard Error 0.0652 |
Primary
Percent Change in Amelioration of Ketamine-related Task Activation as Measured by Functional Magnetic Resonance Imaging in Superior Frontal Gyrus
Difference Score: Percent Signal Change in Regions of Interest (ketamine - saline)
Time frame: Within 4 hours of dose administration, after up to 1.25 hours of ketamine infusion
Population: ALL SUBJECTS WHO COMPLETED THE STUDY WERE INCLUDED IN ANALYSIS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine | Percent Change in Amelioration of Ketamine-related Task Activation as Measured by Functional Magnetic Resonance Imaging in Superior Frontal Gyrus | -0.134 percent change in saline signal | Standard Error 0.0413 |
| Placebo | Percent Change in Amelioration of Ketamine-related Task Activation as Measured by Functional Magnetic Resonance Imaging in Superior Frontal Gyrus | -0.086 percent change in saline signal | Standard Error 0.0365 |