Conditions: Major Depressive Disorder
Keywords: Ketamine Major Depressive Disorder Treatment Depression
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 38
Healthy volunteers: yes

Brief summary:
Depressed patients will be offered experimental treatment with a new, potentially fast-acting antidepressant called ketamine while being scanned by magnetic resonance imaging (MRI) to measure the chemical effect of the drug. Ketamine will be given in a dose of 0.0 (placebo), 0.1, 0.2, 0.3, 0.4, or 0.5 mg/kg. If a patient does not respond to ketamine after the first infusion, it may be because s/he received ketamine placebo or the dose of ketamine was too low. In that case, an optional second scan and infusion of active ketamine (0.5 mg/kg) will be offered. This second scan will occur no later than weeks after the first scan/infusion (as scheduling permits). There is no guarantee that the patient will respond to the second ketamine infusion. Patients enrolled in the study are eligible for up to 6 months treatment with their study psychiatrist after the ketamine infusion(s).

Healthy Volunteers: Healthy controls will receive an infusion of ketamine at a single dose (0.5 mg/kg). Volunteers will only receive one MRI scan and infusion.

Detailed description:
Major depressive disorder (MDD) is a common illness, affecting over 14 million American adults each year. MDD is a leading cause of disability worldwide, and is responsible for huge workplace and healthcare costs. The several week delay between onset of treatment and improvement in MDD symptoms with currently available treatments further increases the burden of the disorder. Shortening this delay is a major unmet challenge in the treatment of MDD. Studies report that a single intravenous low dose of a drug called ketamine can bring about substantial improvement in depression in hours, even in patients that have not improved with other antidepressant treatments. Certain aspects of ketamine's drug action are fairly well understood, but the question remains of how these properties relate to antidepressant effect. The investigator's preliminary data support the rapid antidepressant benefit from ketamine. The investigators have used a scanner to measure the effects of ketamine on two major brain chemical transmitters and found that it causes a significant increase (more than 60%) in glutamate (Glu) and gamma aminobutyric acid (GABA) levels in the front of the brain. The investigators hypothesize that this increase in Glu and GABA levels, is responsible for the antidepressant action of the medication. Knowing how ketamine works could help to develop better medications that can be used orally and used for maintenance of the improvement seen with ketamine. The objective of the proposed dose finding study is to examine the relationship between the ketamine-induced improvement of MDD and the Glu and GABA responses to ketamine and to compare the Glu and GABA responses to ketamine in MDD and healthy subjects to better understand the pathophysiology of MDD. To achieve these aims this the investigators propose a randomized, placebo-controlled, double blind study with several different doses of ketamine. The investigators will conduct MRI scans to measure Glu and GABA before and during the ketamine treatment.

Arms:
arm 1: 0.1 mg/kg, IV (in the vein) of Ketamine and MRI scan arm 2: 0.2 mg/kg, IV (in the vein) of Ketamine and MRI scan arm 3: 0.3 mg/kg, IV (in the vein) of Ketamine and MRI scan arm 4: 0.4 mg/kg, IV (in the vein) of Ketamine and MRI scan arm 5: 0.5 mg/kg, IV (in the vein) of Ketamine and MRI scan arm 6: Saline infused over 40 minutes and MRI scan

Interventions: intervention 1: Ketamine intervention 2: Saline intervention 3: Magnetic Resonance Imaging (MRI)
Intervention descriptions: intervention 1: Single dose of 0.1, 0.2, 0.3, 0.4 or 0.5 mg/kg of ketamine given intravenously over 40 minutes. intervention 2: Single infusion of saline given intravenously over 40 minutes. intervention 3: 90-minute scan during the 40-minute infusion.

Protocol document: