Background:
Most drugs that treat mood disorders take a long time to work. Ketamine works within hours. A dose can last for a week or more. Certain receptors in the brain might help ketamine work. A drug that blocks these receptors might affect how it works.
Objective:
To see if the antidepressant response of ketamine is linked to AMPA receptors.
Eligibility:
Adults ages 18-70 with major depression disorder without psychotic features
Design:
Participants will be screened under protocol 01-M-0254. They will have blood tests and a physical exam.
Participants will stay at the NIH Clinical Center for 5 weeks.
Phase 1 lasts 4 weeks. For 2 weeks, participants will taper off their psychiatric medicine. Then they will have the following tests:
* Blood draws * Psychological tests * MRI: Participants will lie in a machine that takes pictures of their brain. * MEG: Participants will lie down and do tasks. A cone lowered on their head will record brain activity. * Optional sleep tests: Electrodes on the scalp and body and belts around the body will monitor participants while they sleep. * Optional TMS: Participants will do tasks while a wire coil is held on their scalp. An electrical current will pass through the coil that affects brain activity.
For phase 2, on day 0 participants will take the study drug or a placebo orally. While having a MEG, they will get ketamine infused into a vein in one arm while blood is drawn from a vein in the other arm. On day 1, participants will again take the study drug or a placebo orally. On days 3-7, they will repeat many of the phase 1 tests. Days 8 and 9 are optional and include an open label ketamine treatment and many of the phase 1 tests.
18 to 70 years of age.
Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.
All subjects must have undergone a screening assessment under protocol 01-M-0254, "The Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers".
Subjects must fulfill DSM-IV or -5criteria for Major Depression (Major Depressive Disorder) without psychotic features, based on clinical assessment and informed by a structured diagnostic interview (SCID-P).
Current psychotic features or a diagnosis of schizophrenia or any other psychotic disorder as defined in the DSM-IV or DSM-5.
Subjects with a history of substance abuse or dependence diagnosis (DSM-IV) or substance use disorder (DSM-5 equivalent) (except for caffeine or nicotine dependence) within the preceding 3 months. In addition, subjects who currently are using drugs (except for caffeine or nicotine) must not have used illicit substances or known drugs of abuse in the 2 weeks prior to screening and must have a negative alcohol and drug urine test (except for prescribed benzodiazepines or stimulants) at screening.
Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease, coronary artery disease, atherosclerotic ischemic stroke, and atrial fibrillation), endocrinologic, neurologic, immunologic, or hematologic disease.
Pregnant or nursing individuals or those who are physically able to become pregnant. Participants who are physically able to become pregnant or cause a pregnancy must use at least one form of effective birth control or remain completely abstinent from sexual intercourse during the entire period of study participation (or until the last clinical labs and ratings). Participants able to become pregnant must have negative urine pregnancy tests no more than 24 hours prior to receiving the study drugs and undergoing imaging procedures.
Parallel
Arm 1, 2, 3 device interventions
DeviceMagPro 100 TMS Therapy System
Arm 2 Interventions
Other interventionPlacebo
Arm 1, 2, 3 drug Interventions
DrugKetamine
Arm 1 and 2 Interventions
DrugPerampanel
Acute Antidepressant Efficacy: Change from baseline Montgomery Asberg Depression Rating Scale (MADRS) score post ketamine infusion
Clinical rating scale of depression
Continued Antidepressant Efficacy: Change from baseline MADRS score post treatment with ketamine with perampanel versus placebo.
Clinical rating scale of depression
Acute Antidepressant Efficacy: Change in slow wave activity/slope post ketamine infusion
Polysomnography (PSG)/Electroencephalography (EEG) data
Acute Antidepressant Efficacy: Change in synaptic plasticity post ketamine infusion
Transcranial Magnetic Stimulation (TMS) data
Continued Antidepressant Efficacy: Gamma power change from baseline post treatment with ketamine with perampanel versus placebo
Magnetoencephalography (MEG) data
Continued Antidepressant Efficacy: Change in slow wave activity/slope from baseline post treatment with ketamine with perampanel versus placebo
PSG/EEG data
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