The Effects of Ketamine and Guanfacine on Working Memory in Healthy Subjects

Study Overview
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Brief Summary
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The purpose of the study is To establish the feasibility of fMRI studies of the interaction of guanfacine and ketamine. To explore the possibility that guanfacine can ameliorate the negative effects of ketamine on task-related prefrontal activation. To assess the strength of any interaction between guanfacine and ketamine.

Detailed Description
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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.

Official Title
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The Effects of Ketamine and Guanfacine on Working Memory in Healthy Subjects

Conditions
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NMDA Receptor Function

Intervention / Treatment
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* Drug: Guanfacine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Guanfacine then Placebo<br>During the first study session, the participant will receive guanfacine before undergoing a ketamine-infusion fMRI. During the second study session, at least two weeks later, the participant will receive a placebo before undergoing a ketamine-infusion fMRI. | Drug: Guanfacine<br>* 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.<br>Drug: Placebo<br>* 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.<br>|
| Active Comparator: Placebo then Guanfacine<br>During the first study session, the participant will receive a placebo before undergoing a ketamine-infusion fMRI. During the second study session, at least two weeks later, the participant will receive guanfacine before undergoing a ketamine-infusion fMRI. | Drug: Guanfacine<br>* 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.<br>Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | Within 4 hours of dose administration, after up to 1.25 hours of ketamine infusion | 
| 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) | Within 4 hours of dose administration, after up to 1.25 hours of ketamine infusion | 
| 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) | Within 4 hours of dose administration, after up to 1.25 hours of ketamine infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Receptors, Adrenergic, alpha-2, Memory, Short-Term, Schizophrenia, Guanfacine, Ketamine, Functional Magnetic Resonance Imaging, Prefrontal Cortex Activity, Receptors, N-Methyl-D-Aspartate