A Study to Investigate Evoked Potentials as Markers of Ketamine-induced Cortical Plasticity in Patients With Major Depressive Disorder

This study will be conducted in patients with Major Depressive Disorder (MDD) and divided
into 2 sequential cohorts. Cohort 1 will be conducted in 12 patients at a single center. For
each patient, there will be up to 4 sequential phases: a screening phase of up to 6 weeks,
an open-label treatment phase of up to 4 weeks, an optional open-label treatment phase of up
to 1 week, and a follow-up phase of up to 1 week (if applicable). Cohort 2 will be conducted
in 20 patients and will be a multicenter, double-blind (neither physician nor patient knows
the treatment that the patient receives), randomized (the study drug is assigned by chance),
placebo-controlled (an inactive substance that is compared with a drug to test whether the
drug has a real effect in a clinical trial) design. For each patient, there will be up to 4
sequential phases: a screening phase of up to 6 weeks, a double-blind treatment phase of up
to 4 weeks, an optional open-label treatment phase of up to 1 week, and a follow-up phase of
up to 1 week (if applicable). The total study duration for each patient will be maximally
about 12 weeks. Participant safety will be monitored throughout the study.

Inclusion Criteria:

- Patient must be medically stable

- Patient must meet Diagnostic and Statistical Manual of Mental Disorders - Fourth
Edition (DSM-IV) diagnostic criteria for Major Depressive Disorder (MDD), without
psychotic features, based upon clinical assessment and confirmed by the Mini
International Psychiatric Interview (MINI)

- Patient must have had an inadequate response to at least 2 antidepressants, one of
which is in the current episode of depression

- Patient must have an Inventory of Depressive Symptomatology 30-item Clinician-rated
(IDS-C30) total score ≥ 34 at Screening and Day -1

- Women must be postmenopausal, surgically sterile, or, if heterosexually active,
practicing a highly effective method of birth control

- Men who are heterosexually active with a woman of childbearing potential must agree
to use a double barrier method of birth control and to not donate sperm during the
study and for 3 months after receiving the last dose of study drug

Exclusion Criteria:

- Patient has current signs and/or symptoms of liver or renal insufficiency;
significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic,
hematologic, rheumatologic, or metabolic disturbances

- Patient has a primary DSM-IV diagnosis of current (active) generalized anxiety
disorder (GAD), panic disorder, obsessive compulsive disorder (OCD), posttraumatic
stress disorder (PTSD), anorexia nervosa, or bulimia nervosa

- Patient has a current diagnosis of bipolar disorder, mental retardation, or cluster b
personality disorder (e.g., borderline personality disorders, antisocial personality
disorder, etc)

- Patient has a current or prior diagnosis of a psychotic disorder or MDD with
psychosis

- Patient has not responded to treatment with electroconvulsive therapy (ECT) in the
current episode of depression

- Patient has suicidal ideation with intent to act, or has homicidal ideation/intent,
during Screening phase per Investigator's clinical judgment

- Patient has any significant primary sleep disorder