Neuropharmacologic Imaging and Biomarker Assessments of Response to Acute and Repeated-Dosed Ketamine Infusions in Major Depressive Disorder

• Status: Recruiting
• Trial end date: 2028-01-01
• Target enrollment: 0
• Participant gender: All

Summary

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

• Phase: Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: National Institute of Mental Health (NIMH)
• Treatments: Ketamine

Criteria

• INCLUSION CRITERIA:

Inclusion Criteria: All Subjects (Main Study)

1. 18 to 65 years of age.

2. Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.

3. 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").

4. Agree to be hospitalized

Additional Inclusion Criteria: Patients with MDD (Main Study)

1. At the initial study enrollment, subjects must have fulfilled DSM-IV or DSM-V criteria for Major Depression, single episode or recurrent. Subjects must be experiencing a current major depressive episode of at least 2 weeks duration.

2. At the initial screening and beginning of Phases II and III, subjects must have a baseline score on the MADRS greater than or equal to 20 and YMRS of < 12.

3. 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

1. 18 to 65 years of age.

2. Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.

3. 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").

4. Agree to be hospitalized.

EXCLUSION CRITERIA:

Additional Exclusion Criteria: Patients with MDD (Main Study)

1. Current diagnosis of Bipolar Disorder including Bipolar I, Bipolar II, or Bipolar NOS diagnoses.

2. Current psychotic features or a diagnosis of Schizophrenia or any other psychotic disorder as defined in the DSM-IV or DSM-V.

3. Subjects with a history of DSM-IV or DSM-V 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.

4. Treatment with a reversible MAOI within two weeks prior to Phase II.

5. Subjects who, in the investigator s judgment, pose a current serious suicidal or homicidal risk.

Exclusion Criteria: All Subjects (Main Study)

1. 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.

2. 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.

3. Clinically significant abnormal laboratory tests.

4. 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.

5. 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.

6. Any use of opioid medication in the past 3 months

7. Presence of metallic (ferromagnetic) implants (e.g, heart pacemaker, aneurysm clip) (for subjects doing imaging component of the study only).

8. Presence of any medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications.

9. Subjects who have hearing loss that has been clinically evaluated and diagnosed

10. 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).

11. Positive HIV test

12. Weight > 119 kg

13. A current NIMH employee/staff or their immediate family member

14. [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-V Axis I disorder based on clinical assessment and confirmed by a structured diagnostic interview (SCID).

Ketamine Metabolites Substudy Exclusion Criteria: Healthy Volunteers

1. Current or past history of any DSM-IV or DSM-V Axis I disorder based on clinical assessment and confirmed by a structured diagnostic interview (SCID).

2. Current (within the past 3 months) or past alcohol or substance abuse or dependence diagnosis (except for nicotine or caffeine)

3. 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.

4. 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.

5. Clinically significant abnormal laboratory tests.

6. Subjects with one or more seizures without a clear and resolved etiology or current use of medication known to lower seizure threshold.

7. Treatment with any other concomitant medication.

8. Any use of opioid medication in the past 3 months

9. Positive HIV test

10. Weight > 119 kg

11. A current NIMH employee/staff or their immediate family member

12. Presence of metallic (ferromagnetic) implants (e.g, heart pacemaker, aneurysm clip) (for subjects doing neuroimaging component of the study only).

13. 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).