Neuropharmacologic Imaging and Biomarker Assessments of Response to Acute and Repeated-Dosed Ketamine Infusions in Major Depressive Disorder
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 150
- 试验地点
- 1
- 主要终点
- To demonstrate more robust neuropharmacodynamic effects measured by neuropharmacodynamic imaging (fMRI+EEG and MEG) of ketamine 0.5 mg/kg as compared to placebo administered over 40 minutes.
研究概览
简要总结
Background:
Most medications that treat depression take weeks or months to work. Researchers want to develop fast-acting treatments. One dose of ketamine has a rapid antidepressant effect. For most people, this lasts a week or less. Repeated doses of ketamine may help maintain this effect.
Objective:
Main Study: To study the effects of ketamine in treating depression.
Ketamine Metabolites Substudy: To study how ketamine effects brain chemistry.
To study how ketamine effects the brain. This is done by looking at metabolites, which are created when a drug is broken down.
Eligibility:
Main Study: People ages 18-65 with major depressive disorder and healthy volunteers
Ketamine Metabolites Substudy: Healthy volunteers ages 18-65
Design:
Main Study:
Participants will be screened in another study, with:
- Medical and psychiatric history
- Psychiatric and physical exam
- Blood, urine, and heart tests
Participants will be inpatients at NIH for 4 phases totaling 14-20 weeks.
Phase I (2-7 weeks):
- Gradually stop current medications
- MRI: Participants lie and perform tasks in a machine that takes pictures of the body.
- Mood and thinking tests
- Blood and urine tests
- Sleep test: Monitors on the skin record brain waves, breathing, heart rate, and movement during sleep.
- Transcranial magnetic stimulation: A coil on the scalp gives an electrical current that affects brain activity.
- Stress tests: Electrodes on the skin measure reactions to loud noises or electric shocks.
Phase I tests are repeated in Phases II and III and in the final visit.
Phase II (4-5 weeks):
- 4 weekly IV infusions of ketamine or a placebo during an MRI or MEG. For the MEG, a cone over the head records brain activity.
Phase III (optional):
- 8 infusions of ketamine over 4 weeks
Phase IV (optional):
- Symptoms monitoring for 4 weeks
- Participants will have a final visit. They will be offered standard treatment at NIH for up to 2 months.
Ketamine Metabolites Substudy:
Participants will be screened in another study, with:
- Medical and psychiatric history
- Psychiatric and physical exam
- Blood, urine, and heart tests
Participants will be inpatients at NIH for 4 days.
Study Procedures:
Mood and thinking tests
Blood and urine tests
1 infusion of ketamine
Spinal tap and spinal catheter: Used to get samples of cerebrospinal fluid (CSF). This is a fluid that moves around and within the brain and spinal cord. Studying CSF will help us learn how ketamine effects brain chemistry
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详细描述
Objective
The current protocol has a two-fold purpose. In the pharmacodynamic imaging phase, we will investigate the neuropharmacodynamics of acute intravenous ketamine administration in patients with major depressive disorder (MDD) and healthy volunteers (HV) using functional MRI (fMRI) and electrophysiological modalities [electroencephalography (EEG) and magnetoencephalography (MEG)]. We will also investigate if specific signatures from functional neuroimaging, transcranial magnetic stimulation (TMS) associated evoked potentials (TMS-EP), sleep EEG (S-EEG), and psychophysiologic responses can be used to classify specific subpopulations of patients with MDD; preliminary findings from such an approach may be important in forging further studies identifying those who will respond to ketamine infusions. In the repeat-dosing phase, we will expand upon our previous findings of the immediate efficacy of glutamatergic modulators by investigating the safety and efficacy of repeated dose administrations of ketamine in MDD patients. We will include all MDD patients regardless of antidepressant response to single infusions of ketamine to allow for potential identification of patients who are able to attain and/or maintain a response over a series of infusions. To reduce any potential biases due to partial blinding, all patients will be randomized into groups to receive ketamine at either 0.5 mg/kg or 0.1 mg/kg (an active comparator).
Study Population
The study consists of 50 patients with treatment-resistant MDD between 18 and 65 years old and 50 age/gender matched HVs. Within the MDD group, 25 patients will be enrolled into each group in the repeat-dosing phase. An addition 50 HVs will participate in the Ketamine Metabolites Substudy.
Study Design
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •INCLUSION CRITERIA:
- •Inclusion Criteria: All Subjects (Main Study)
- •18 to 65 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 either protocol 01-M-0254, "The Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers" or protocol 17-M-0181 ("Recruitment and Characterization of Research Volunteers for NIMH Intramural Studies").
- •Agree to be hospitalized
- •Additional Inclusion Criteria: Patients with MDD (Main Study)
- •At the initial study enrollment, subjects must have fulfilled DSM-IV or DSM-5 criteria for Major Depression, single episode or recurrent. Subjects must be experiencing a current major depressive episode of at least 2 weeks duration.
- •At the initial screening and beginning of Phases II and III, subjects must have a baseline score on the MADRS >= 20 and YMRS of <
- •Current or past history of lack of response to one adequate antidepressant trial, operationally defined using the Antidepressant Treatment History Form (ATHF); a failed adequate trial of ECT would count as an adequate antidepressant trial.
- •Ketamine Metabolites Substudy Inclusion Criteria: Healthy Volunteers
- •18 to 65 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 either protocol 01-M-0254 "The Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers") or 17-M-0181 ("Recruitment and Characterization of Research Volunteers for NIMH Intramural Studies").
- •Agree to be hospitalized.
排除标准
- •Additional Exclusion Criteria: Patients with MDD (Main Study)
- •Current diagnosis of Bipolar Disorder including Bipolar I, Bipolar II, or Bipolar NOS diagnoses.
- •Current psychotic features or a diagnosis of Schizophrenia or any other psychotic disorder as defined in the DSM-IV or DSM-
- •Subjects with a history of DSM-IV or DSM-5 drug or alcohol dependency or abuse (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 screen and must have a negative alcohol and drug urine test (except for prescribed benzodiazepines or stimulants) urine test at screening.
- •Treatment with a reversible MAOI within two weeks prior to Phase II.
- •Subjects who, in the investigator s judgment, pose a current serious suicidal or homicidal risk.
- •Exclusion Criteria: All Subjects (Main Study)
- •Pregnant or nursing women or women who plan to become pregnant. Women who are able to get pregnant must be willing to use at least one form of effective birth control during the entire period of study participation (or until last clinical labs and rating) and have a negative pregnancy test that was obtained no more than 24 hours prior to MRI and infusion of ketamine.
- •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.
- •Clinically significant abnormal laboratory tests.
- •Subjects with one or more seizures without a clear and resolved etiology or current use of medication known to lower seizure threshold. History of seizure (regardless of age or etiology), history of epilepsy in self or first-degree relatives, stroke, brain surgery, head injury, or known structural brain lesion will be excluded from the TMS procedures.
- •Treatment with any other concomitant medication 14 days prior to Phase II. An exception of this would be necessary for those who are taking Fluoxetine or Aripiprazole. Prior to Phase II, treatment with Fluoxetine must be discontinued for at least 5 weeks and treatment with Aripiprazole must be discontinued for at least 3 weeks.
- •Any use of opioid medication in the past 3 months
- •Presence of metallic (ferromagnetic) implants (e.g, heart pacemaker, aneurysm clip) (for subjects doing imaging component of the study only).
- •Presence of any medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications.
- •Subjects who have hearing loss that has been clinically evaluated and diagnosed
- •Participants who are uncomfortable in small closed spaces (have claustrophobia), unable to lie comfortably supine for up to 90 minutes, and would feel uncomfortable in the MRI machine (for subjects doing imaging component of the study only).
- •Positive HIV test
- •Weight > 119 kg
- •[for participants undergoing NPU Threat Test with Auditory Startle] Known history of hearing loss
- •Additional Exclusion Criteria: Healthy Volunteers (Main Study)
- •1. Current or past history of any DSM-IV or DSM-5 Axis I disorder based on clinical assessment and confirmed by a structured diagnostic interview (SCID).
- •Ketamine Metabolites Substudy Exclusion Criteria: Healthy Volunteers
- •Current or past history of any DSM-IV or DSM-5 Axis I disorder based on clinical assessment and confirmed by a structured diagnostic interview (SCID).
- •Current (within the past 3 months) or past alcohol or substance abuse or dependence diagnosis (except for nicotine or caffeine)
- •Pregnant or nursing women or women who plan to become pregnant. Women who are able to get pregnant must be willing to use at least one form of effective birth control during the 4-days of the study participation (or until last clinical labs and rating) and have a negative pregnancy test that was obtained no more than 24 hours prior to infusion of ketamine.
- •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.
- •Clinically significant abnormal laboratory tests.
- •Subjects with one or more seizures without a clear and resolved etiology or current use of medication known to lower seizure threshold.
- •Treatment with any other concomitant medication.
- •Any use of opioid medication in the past 3 months
- •Positive HIV test
- •Weight > 119 kg
- •Presence of metallic (ferromagnetic) implants (e.g, heart pacemaker, aneurysm clip) (for subjects doing neuroimaging component of the study only).
- •Participants who are uncomfortable in small closed spaces (have claustrophobia), unable to lie comfortably supine for up to 90 minutes, and would feel uncomfortable in the MRI machine (for subjects requiring clinical MRI scans for safety and/or structural MRI scans for MEG coregistration).
研究组 & 干预措施
Phase II, Arm 1b
Double-blind, single dose of 0.5 mg/kg IV ketamine, concurrently with fMRI+EEG or MEG
干预措施: Cobot TS MV robotic arm for TMS (Device)
Phase II, Arm 2b
Double-blind, single dose of 0.5 mg/kg IV saline, concurrently with fMRI+EEG or MEG.
干预措施: Cobot TS MV robotic arm for TMS (Device)
Phase IV
Follow-up evaluations
Phase II, Arm 2
Double-blind, single dose of 0.5 mg/kg IV saline
干预措施: Cobot TS MV robotic arm for TMS (Device)
Phase II, Arm 2b
Double-blind, single dose of 0.5 mg/kg IV saline, concurrently with fMRI+EEG or MEG.
干预措施: Placebo (Other)
Phase II, Arm 2
Double-blind, single dose of 0.5 mg/kg IV saline
干预措施: Placebo (Other)
Phase II, Arm 1b
Double-blind, single dose of 0.5 mg/kg IV ketamine, concurrently with fMRI+EEG or MEG
干预措施: Ketamine (Drug)
Phase III
Double-blind, repeated dose of 0.5 mg/kg or 0.1 mg/kg IV ketamine
干预措施: Ketamine (Drug)
Metabolites Substudy
Open-label, single dose of 0.5 mg/kg IV ketamine
干预措施: Ketamine (Drug)
Phase II, Arm 1
Double-blind, single dose of 0.5 mg/kg IV ketamine
干预措施: Ketamine (Drug)
Phase II, Arm 1
Double-blind, single dose of 0.5 mg/kg IV ketamine
干预措施: Cobot TS MV robotic arm for TMS (Device)
Phase III
Double-blind, repeated dose of 0.5 mg/kg or 0.1 mg/kg IV ketamine
干预措施: NeurOptics PLRTM-30000 Pupillometer (Device)
Phase I
Medication taper, drug-free period, and baseline assessments
干预措施: Cobot TS MV robotic arm for TMS (Device)
结局指标
主要结局
To demonstrate more robust neuropharmacodynamic effects measured by neuropharmacodynamic imaging (fMRI+EEG and MEG) of ketamine 0.5 mg/kg as compared to placebo administered over 40 minutes.
时间窗: Multiple
Magnetoencephalography (MEG) data
Ketamine Metabolites Substudy: To determine if ketamine metabolites cross the blood brain barrier and enter the brain during ketamine IV administration.
时间窗: Multiple
Data from peripheral blood and CSF (in some participants)
次要结局
- To identify baseline peripheral measures associated with response to the administration of ketamine 0.5 mg/kg, as potential biomarkers of acute (24 hour) treatment response.(Baseline to 24-hours post-ketamine infusion)
- To demonstrate enhanced efficacy, as measured by the MADRS, of IV ketamine 0.5 mg/kg in participants with MDD using a psychophysiological technique (i.e. NPU-threat test).(Multiple)
- To profile ketamine s opioid action based on the PLR using video pupillometry.(Multiple)
- To determine if increases in synaptic plasticity, using electrophysiological measures in response to TMS and in association with sleep (i.e. slow wave sleep EEG activity) are associated with better antidepressant response to 0.5 mg/kg ketamine.(Multiple)
- Ketamine Metabolites Substudy: To correlate metabolite levels in periphery and CSF with changes in clinical rating scales.(Multiple)