Ketamine Plus Lithium in Treatment-Resistant Depression

Major Depressive Disorder (MDD) is a disabling medical illness and current monoaminergic
treatments are slow to act and possess only limited efficacy. In this context, the discovery
that the glutamate NMDA receptor antagonist ketamine is rapidly antidepressant (onset of
action within hours) -- even in patients suffering from treatment-resistant depression (TRD)
-- has ignited tremendous enthusiasm among clinicians, scientists and patients alike. A
critical obstacle to the translation of this discovery into a novel treatment, however, is
the limited duration of action following a course of ketamine (e.g. 1-2 weeks). The current
project will address this important gap in medical knowledge by testing a rational
neuropharmacological strategy designed to optimize and sustain the rapid antidepressant
effects of ketamine. Driven by the recent characterization of the molecular mechanisms
underpinning the antidepressant and neuroplasticity effects of ketamine, we will test the
combination of ketamine plus lithium in patients with TRD using a randomized, double blind,
placebo-controlled design. The primary aims of the project are (1) to test the efficacy of
lithium-plus-ketamine compared to placebo-plus-ketamine as an antidepressant combination
strategy in TRD and (2) to gather data on the safety and tolerability of the
lithium-plus-ketamine.

Inclusion Criteria:

- Male or female patients, 21-65 years of age;

- Female individuals who are not of childbearing potential (i.e., surgically sterile,
postmenopausal for at least one year) or using a medically accepted reliable means of
contraception. Women using oral contraceptive medication for birth control must also
be using a barrier contraceptive. Women of childbearing potential must also have a
negative serum B-HCG at screening and at pre-infusion;

- Participants must fulfill DSM-IV criteria for Major Depression without psychotic
features, based on clinical assessment by a study psychiatrist and confirmed by a
structured diagnostic interview, the Structured Clinical Interview for DSM-IV TR Axis
I Disorders, Patient Edition (SCID-P);

- Participants must have a history of at least one previous episode of depression prior
to the current episode (recurrent MDD) or have chronic MDD (of at least two years'
duration);

- Participants have not responded to two or more adequate trials of an antidepressant as
determined by Antidepressant Treatment History Form (ATHF) criteria (score >=3);

- Current Major Depressive Episode of at least moderate severity, defined as a QIDS-SR
score ≥ 14 and a CGI-S score of ≥ 4;Current major depressive episode is of at least 4
weeks duration;

- Each participant must have a level of understanding sufficient to agree to all tests
and examinations required by the protocol and must sign an informed consent document;

- Each participant must be able to identify a family member, physician, or friend who
will participate in the Treatment Contract.

Exclusion Criteria:

- Lifetime history of psychotic features, diagnosis of schizophrenia or any other
psychotic disorder, or diagnosis of bipolar disorder;

- Lifetime histories of autism, mental retardation, pervasive developmental disorders,
or Tourette's syndrome;

- Current diagnosis of OCD or eating disorder (bulimia nervosa or anorexia nervosa);

- Subjects with DSM-IV drug or alcohol abuse/dependence within the preceding 2 years;

- Patients with schizotypal or antisocial personality disorder, or any clinically
significant axis II disorder that would, in the investigator's judgment, preclude safe
study participation;

- Patients judged clinically to be at serious and imminent suicidal or homicidal risk;

- Women who are either pregnant or nursing;

- Serious, unstable medical illnesses including hepatic, renal impairment,
gastroenterologic (including gastro-esophageal reflux disease), respiratory (including
obstructive sleep apnea, or history of difficulty with airway management during
previous anesthetics), cardiovascular (including ischemic heart disease and
uncontrolled hypertension), endocrinologic, neurologic (including history of severe
head injury), immunologic, or hematologic disease;

- Clinically significant abnormal findings of laboratory parameters, physical
examination, or ECG;

- Patients who have a positive urine toxicology for illicit substances at screening and
within 24 hours of the infusion;

- Patients with one or more seizures without a clear and resolved etiology;

- Treatment with an irreversible MAOI within 2 weeks prior to randomization or
fluoxetine within 4 weeks prior to randomization;

- Treatment with other antidepressants within one week of randomization;

- Previous recreational use of PCP or ketamine;

- Hypertension (systolic BP >160 mm Hg or diastolic BP >90 mm Hg) not controlled by
diuretic or beta-blocker therapy alone or in combination;

- A blood pressure reading over 160/90 or two separate readings over 140/90 at screening
or baseline visits;

- Renal impairment, as reflected by a BUN > 20 mg/dL and/or creatinin clearance of >1.3
mg/dL;

- Thyroid impairment, as reflected by a TSH > 4.2 mU/L;

- Cardiac disease, as reflected by an EKG that is abnormal and of concern for cardiac
disease;

- Any anticipated change in medications that could affect fluid or salt balance,
including the following antihypertensive agents: ACE inhibitor, loop diuretics,
calcium channel blockers, thiazide diuretics, angiotensin II receptor blockers.