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

 This study is a Phase I Clinical Trial that comprises four phases.

 Phase I includes screening, medication taper (as needed), medication-free period, and
 baseline assessments, including optional TMS-EP, S-EEG, the None, Predictive, Unpredictive
 (NPU)-threat test, and blood samples for plasma neurochemicals and peripheral blood
 biomarkers.

 In Phase II, all subjects will receive an alternating series of placebo and ketamine
 infusions, once per week, for a total of 4 infusions (2 ketamine, 2 placebo). Concurrently
 with each infusion, subjects will be administered either resting-state fMRI with simultaneous
 EEG, or resting state MEG recording, thus each subject receives fMRI+EEG and MEG for both a
 placebo and ketamine infusion. Participants may also undergo optional sEEG, TMS-EP, and NPU.

 Phase III involves MDD patients whose depression symptoms relapsed after the final infusion
 in Phase II. Patients whose symptoms did not relapse may receive an additional one-week
 washout. Subjects will be randomized to receive ketamine at 0.5 or 0.1 mg/kg twice weekly for
 4 weeks (total of 8 infusions). Participants may undergo optional fMRI S-EEG, TMS-EP, and NPU
 at time points between infusions. Clinical rating scales will assess depression symptomology
 and blood will be drawn for pharmacokinetics testing and biomarker analyses.

 Phase IV includes patients who completed Phase III and who are responders . These patients
 will be followed up for an additional 4 weeks, or until relapse, to determine durability of
 response. The final study day will include rating scales, medical evaluations, blood tests,
 and an additional sMRI to assess structural changes that may have occurred due to repeated
 ketamine infusions.

 The protocol includes a substudy evaluating ketamine metabolites in (Ketamine Metabolites
 Substudy). Only HVs will be enrolled in this substudy. Subjects will undergo a single
 infusion of ketamine concurrently with serial peripheral blood collection. Some participants
 may also undergo serial CSF collection during the ketamine infusion. Clinical rating scales,
 cognitive tasks, MEG, S-EEGCSF and/or blood draws for pharmacokinetics testing and biomarker
 analyses will be done.

 Outcome Measures:

 The primary outcome measure of Phase II is the pharmacodynamic fMRI and MEG responses to
 ketamine compared to placebo. Secondary outcome measures include the difference in
 Montgomery-Asberg Depression Rating Scale (MADRS) score from baseline to 24 hours between the
 placebo and ketamine infusion, correlations between an antidepressant response and TMS-EP,
 S-EEG, neuroimaging, and NPU measures. In Phase II, the HVs acts as another level of control
 to identify a potential neuropharmacodynamic signature associated with an antidepressant
 response to ketamine.

 The primary outcome measure for Phase III is the difference or change in MADRS from baseline
 to the end of 4 weeks of twice-weekly infusions. Secondary outcome measures include TMS-EP,
 S-EEG, and NPU-threat test measures.

 Other outcome measures for both Phase II and III include clinical rating scales,
 neurocognitive tests, ketamine levels, plasma neurochemicals, and peripheral blood
 biomarkers. Additional outcomes in Phase III are baseline and post-repeated dose infusion MRI
 scans, and neurocognitive test results. Rating scales are the outcomes measures of Phase IV.
 Subjects will continue Phase IV for 4 weeks or until relapse
-  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).