This study is designed to compare the effectiveness of two medications, Ketamine and Midazolam, for rapidly relieving suicidal thoughts in people suffering from bipolar depression.

The first drug, ketamine, is an experimental antidepressant that early studies have shown may quickly reduce suicidal thoughts, but we are not sure how well it may work. Midazolam, the comparison drug, is not thought to reduce depression or suicidal thoughts.

Patients currently taking psychiatric medications may continue them during the study. However, if a patient is taking a benzodiazepine (such as Ativan, Klonopin, or Xanax), they will be able to take up to 2mg per day of Lorazepam during the week before the infusion, but none will be permitted in the 24 hours pre-infusion. Also, Zolpidem (Ambien) will not be permitted in the 24 hours pre-infusion. If a person chooses to participate, their dose of benzodiazepine may need to be reduced so that they can do without it during the 24 hours pre-infusion.

Participants are randomly assigned to receive a single dose of Ketamine (0.5 mg/kg) or Midazolam (0.02 mg/kg), which is given slowly, in a vein, over about 40 minutes. The study is "double-blind," meaning patients and study staff will not know which medication is in the infusion.

If a patient does not respond to the first infusion, and s/he received Midazolam, then s/he will be offered the option of a second infusion, this time with Ketamine (0.5 mg/kg). After the infusion(s), participants will have weekly research interviews for 6 weeks to monitor response.

After post-infusion research measures are completed, all subjects will receive open clinical treatment. During open clinical treatment, medication will be changed for those patients who don't respond or whose response is transient.

Participation in this study requires a brief inpatient stay, at no cost, at the New York State Psychiatric Institute (NYSPI).

Eligible participants enrolled in this study will be offered medication management visits at no cost for a total of up to 6 months combining inpatient and outpatient treatment. At the end of the 6 months of treatment patients will be referred for ongoing care.

INCLUSION CRITERIA:

• Bipolar depression with current major depressive episode (MDE). Participants may be psychiatric medication-free, or if on psychiatric medication, not responding adequately given current MDE with suicidal ideation.
• Moderate to severe suicidal ideation
• 18-65 years old
• Patients will only be enrolled if they agree to voluntary admission to an inpatient research unit at the New York State Psychiatric Institute (NYSPI) for infusion phase of treatment.
• Pre-menopausal female participants of child-bearing potential must be willing to use an acceptable form of birth control during study participation such as condoms, diaphragm, oral contraceptive pills
• Able to provide informed consent
• Subjects 61-65 years old must score 25 or higher on the Mini-Mental State Examination (MMSE) at screening

EXCLUSION CRITERIA:

• Unstable medical condition or neurological illness, including baseline hypertension (BP>140/90) or significant history of cardiovascular illness
• Significant ECG abnormality
• Pregnancy and/or lactation
• Current psychotic symptoms
• Contraindication to any study treatment
• Current or past ketamine abuse or dependence ever (lifetime); any other drug or alcohol dependence within past 6 months; suicidality only due to binge substance use or withdrawal
• Inadequate understanding of English
• Prior ineffective trial of or adverse reaction to ketamine or midazolam
• Opiate use greater than total daily dose of 20mg Oxycodone or equivalent during the 3 days pre-infusion

6 months