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

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 20 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 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 CSF and peripheral blood collection. Clinical
rating scales, cognitive tasks, MEG, CSF and 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 protocol 01-M-0254, "The
Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers".

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 protocol 01-M-0254, "The
Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers".

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.

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).