Principal Investigator moved to Jacksonville, FL campus.

The purpose of this research study is to compare the antidepressant effect of lithium versus placebo in adults receiving ketamine. Lithium is available commercially for depression; ketamine is available commercially and can help the symptoms of depression; however, it has not been approved by the U.S. Food and Drug Administration (FDA) for this use. The FDA has allowed the use of this drug in this research study.

This is a randomized clinical trial in adults with Treatment-Resistant Depression. All participants will receive three intravenous (IV) Ketamine (KET) infusions over 7 days. Before receiving the first KET infusion, subjects will be randomized to 2 weeks of pre-KET treatment with either Lithium or matching placebo. Pre-treatment medications will then be continued in a double-blind manner during the acute phase administration of ketamine. Questionnaires will be administered at baseline, prior to each KET infusion, and at 40, 100, and 120 minutes after each infusion, and again at weekly intervals following the third (final) KET infusion for 4 weeks, using standardized rating scales. Those who achieve positive response (>50% decrease in questionnaire total score from baseline) will be given 4 additional once-weekly KET infusions (same dose and infusion rate).

Inclusion Criteria:

• Ability to provide informed consent;
• Current psychiatric inpatient (voluntary only) or outpatient treatment;
• Meets Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) diagnostic criteria for major depressive disorder, bipolar I disorder, or bipolar II disorder;
• 9-item Patient Health Questionnaire (PHQ-9) total score > 15 at screening and at baseline (just prior to first acute phase ketamine infusion);
• Treatment-resistant depression, as defined by failure of at least two previous antidepressant or mood stabilizing treatments within the current depressive episode. Failed antidepressant or mood stabilizing treatments can include pharmacotherapy for depression at an adequate dose for at least 8 weeks, or an acute series of at least 6 administrations of electroconvulsive therapy (ECT);
• Adequate social support, defined as having at least one individual identified who is committed to function as support, including providing transportation to and from outpatient ketamine infusion visits;
• Ability to pass a comprehension assessment test related to effects of ketamine and trial objectives and criteria.

Exclusion Criteria:

• Diagnosis of schizophrenia, schizoaffective disorder, or active psychotic symptoms;
• On active lithium treatment;
• Serious risk for suicide, as assessed by the evaluating study clinician; a serious suicide risk will be considered: (a) an inability to control suicide impulses or imminent or unacceptably high risk of suicide in the investigator's judgment; or (b) a recent history of suicidal behavior, which is defined as either one or more suicide attempts (or interrupted suicide attempts) in the 12 months before study entry; or (c) history of serious suicidal behavior, defined as one or more suicide attempts (or interrupted attempts) in the last 3 years with a potential lethality judged by the evaluating study clinician to have possibly resulted in serious injury or death;
• Ongoing prescription of > 4 mg lorazepam equivalents (total) daily, or morning dosing of any benzodiazepine at the time of assessment;
• Currently undergoing ECT, transcranial magnetic stimulation, vagal nerve stimulation, or deep brain stimulation as either an acute or maintenance treatment of depression;
• Any active or unstable medical condition judged by the study psychiatrist as conferring too great a level of medical risk to allow inclusion in the study;
• Use or abuse of methamphetamine, cocaine, cannabis, or stimulants (prescribed and illicit) within the past 12 months;
• Any current abuse or dependence of alcohol or drugs (excluding nicotine and caffeine). Note: Persons will be allowed to enroll in this study if their drug or alcohol abuse/dependence is in complete (not partial) and sustained (> 1 year) remission;
• History of traumatic brain injury that resulted in loss of consciousness;
• Developmental delay, mental retardation, or intellectual disorder;
• Clinical or self-reported diagnosis of delirium, encephalopathy, or related clinical diagnosis within the prior 12 months;
• Cognitive disorder (mild and major categories, per DSM-5);
• Prior participation in another study of ketamine for depression within the prior 6 months;
• History of either poor antidepressive response to or poor tolerability of ketamine (any route of administration) when previously administered for treating symptoms of depression;
• History of hypothyroidism unless taking a stable dose of thyroid medication and asymptomatic for 6 months;
• Significant unstable medical condition
• Hepatic insufficiency (2.5 X Upper Limit of Normal (ULN) for Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT)) within 1 year of consent, past liver transplant recipient, and/or clinical diagnosis of cirrhosis of the liver;
• History of either poor antidepressive response to or poor tolerability of ketamine (any route of administration) when previously administered for treating symptoms of depression;
• History of medical condition(s) which are not recommended to be taken concurrently with lithium; Current anti-depressive pharmacotherapies will not be allowed during the acute phase KET infusions.
• Pregnancy, or nursing;
• Prisoners;
• Involuntary psychiatric hospitalization.

Triple blinded study. The staff accessible to the blind includes pharmacy staff and one assigned investigator.