This study will examine the effects of Intravenous (IV) ketamine both in an outpatient population and with subjects on the inpatient unit with suicidal ideation (SI).

Depression is a debilitating disorder that affects 12-20% of population and is among the top five leading causes of burden of disease worldwide (Kruijshaar ME 2005). Suicide associated with depression and other psychiatric disorders is a pervasive public health problem and results in almost one million deaths per year. Unfortunately, current treatments for severe depression have limited efficacy for suicidality, specifically due to the slow time course of change in suicidal thoughts. Recently ketamine, a glutamate-modulating agent, was shown to have antidepressant and anti-suicidal effect in outpatient depressed patients. The proposed study will test the ability of a single sub-anesthetic intravenous (IV) dose of the glutamate NMDA receptor antagonist, ketamine, to provide rapid decrease in suicidal ideation (SI) in patients hospitalized with SI. In this randomized parallel-arm placebo controlled trial, ketamine is compared to midazolam, which is expected to mimic some of the acute subjective effects of ketamine but not have any sustained antidepressant effects.

Specific Aim 1: To determine feasibility and tolerability of a single low-dose IV infusion of ketamine in patients with prominent SI and elevated risk for suicide.

Hypothesis 1: Ketamine administration will be feasible and well tolerated in patients admitted to a psychiatric hospital with SI.

Specific Aim 2: To test the efficacy of a single IV dose of ketamine, compared to an anesthetic control condition (midazolam), to rapidly reduce SI in a controlled hospital setting.

Hypothesis 2: Ketamine will be associated with significant and rapid reductions in SI and depressive symptoms within 24 hours.

This study will test the rapid anti-suicidal effect of a single IV dose of the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine in suicidality compared with the clinical response to a single IV dose of the short-acting benzodiazepine midazolam. Midazolam is able to induce transient neuropsychiatric effects mimicking ketamine and therefore is expected to protect the integrity of the blind. Participants will continue to receive standard treatment for their psychiatric condition throughout the trial. This unique "proof-of-concept" study in suicidal patients will be conducted over three-year period.

Inclusion Criteria:

• English speaking Male or female patients, 18-80 years
• Patients have voluntarily admitted themselves to an inpatient psychiatric unit at MSH or, regarding the outpatient population, have clinically significant suicidal ideation without intent to harm themselves
• Women of childbearing potential must have a negative pregnancy test
• Clinically significant suicidal ideation and score of ≥4 on MADRS item 10 for suicidality
• Each subject 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

Exclusion Criteria:

• Lifetime history of schizophrenia or other primary psychotic disorder
• Current presence of psychotic symptoms
• Lifetime history of a clearly established psychotic episode
• Established diagnosis of Schizoid, Schizotypal or Paranoid personality disorder
• Urine toxicology screen positive for drugs of abuse on admission
• Substance abuse or dependence within the preceding 1 month
• Anticipated discharge within 7 days of study enrollment (for patients in the inpatient arm)
• Women who plan to become pregnant, are pregnant or are breast-feeding
• Concurrent course of electroconvulsive therapy (ECT)
• Any unstable medical illness including hepatic, renal, gastro-enterologic, respiratory, cardiovascular, endocrinologic, neurologic, immunologic, or hematologic disease
• Clinically significant abnormal findings of laboratory parameters, physical examination, or ECG
• The presence of any known or suspected contraindications to midazolam or ketamine including, but not limited to, known allergic reactions to these agents or acute intermittent porphyria
• Uncontrolled hypertension, defined as BP systolic >160 or BP diastolic >100 on medications
• Arrhythmia requiring medication
• Severe coronary artery disease, defined as Canadian Cardiovascular Status III or IV

Sample size is small, increasing the likelihood of a false negative finding due to limited power. Unknown if the lack of significant separation between the treatment and control conditions at 24 h represents a true null finding or a false negative.