Ketamine as a Rapidly-Acting Antidepressant in Depressed Emergency Department Patients

To explore the use of ketamine as a potential rapidly-acting antidepressant (RAA) for
Emergency Department (ED) patients with major depressive disorder (MDD).

Investigators will conduct a randomized controlled study to evaluate the rapidity and
persistence of antidepressant effects of a single sub-anesthetic dose of intravenous (IV)
ketamine (0.25mg/kg) or an equivalent volume of diphenhydramine (25mg) delivered IV over 1-2
minutes, by comparing measures of mood pre- and post-infusion in Emergency Department (ED)
patients with MDD. Subjects will be randomly assigned (1:1) to receive a bolus of ketamine or
diphenhydramine. To supplement self-reported measures of depressive symptoms (e.g., mood,
suicidal ideation, etc.), investigators will obtain objective measures of heart rate and
heart rate variability, measure serum levels of the pro- and anti-inflammatory cytokines
(interleukin IL-1, IL-2, IL-6, IL-8, IL-10, IL-12, and tissue necrosis factor, TNF-α), which
have been shown to play an important role in stress, depression and suicidal behavior. In
addition, investigators will obtain serum levels of brain derived neurotrophic factor (BDNF)
because reduced serum BDNF has been described during acute depressive episodes in patients
with MDD, with reports of rescue effects following treatment with various antidepressants and
with ketamine (Aydemir 2005, Gervasoni 2005, Karege 2002, Karege 2005, Duncan 2013, Shimizu
2003). Investigators will also measure serum magnesium levels, as these have been shown to
correlate in a predictive manner with response to conventional antidepressants (Camardese
2012), and there are data to suggest that ketamine's efficacy in treatment-resistant
depression could be related to a relative magnesium deficiency in such patients (Murck 2013).

This study will allow investigators to determine to what extent low-dose ketamine, an
N-Methyl-D-Aspartate (NMDA) antagonist, achieves a rapid reduction in symptoms for severely
depressed ED patients with or without suicidal ideation. For decades, much higher doses of IV
ketamine (1-2mg/kg) have been used routinely in the ED as a dissociative anesthetic (Green
2011). In 2011, an open-label study was the first published of the use of low dose ketamine
(0.2mg/kg), administered by rapid intravenous infusion, in the ED setting for acutely
depressed patients which demonstrated its feasibility, safety, preliminary efficacy and
acceptability to both ED patients and staff (Larkin 2011). One long-term goal of this
research is to expand treatment options available to depressed ED patients that mitigate the
need for inpatient admission and serve as a safety bridge to future out-patient treatment for
major depression. As an adjunct to standard treatment, low-dose NMDA receptor antagonists
have the potential to positively impact: ED waiting times; repeat visits to the ED;
short-term risk of suicide attempts; length of stay on inpatient units and the need for
hospital admissions for many acutely depressed patients.

Inclusion Criteria:

- Medically stable as determined by the medical physician

- Meets criteria for Major Depressive Disorder (MDD) based on a structured clinical
Interview (MINI International Neuropsychiatric Interview).

- Reports symptoms of severe depression at the time of presentation, defined as a score
of 24 or greater on the MADRS.

- Patients for whom a psychiatric evaluation and disposition decision has been made by
emergency psychiatry staff to admit to an inpatient psychiatric unit at Bellevue
Hospital Center or NYU Tisch Hospital.

- Each subject must have a level of understanding sufficient to sign an informed consent
stating that the treatment being offered is not FDA approved for the treatment of
depression and is being provided as an off-label option.

Exclusion Criteria:

- Pregnancy

- Inability to read or understand English

- Current clinical signs of intoxication or delirium at time of study intervention

- Overdose, within previous 24 hours, of any agent which would impair ketamine
metabolism

- Lifetime misuse/abuse of ketamine, phencyclidine (PCP),or related substances

- Lifetime history of psychotic spectrum illness

- First-degree relative with history of psychotic illness

- Lifetime diagnosis of borderline personality disorder, or as confirmed by assessment
using items #90-104 of the SCID-II (for DSM-IV).

- Subjects with clinically significant abnormal findings as determined by medical
history, physical examination, vital signs (blood pressure, heart rate, and
respiration rate), O2 saturation measure, 12-lead ECG, clinical laboratory tests (CBC,
chemistry panel, thyroid function tests), urine drug screen, and urine pregnancy test
(for females of childbearing potential only).

- Clinically unstable medical, surgical or neurological conditions at ED presentation

- History of stroke or intracranial hypertension

- History of glaucoma

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

- Current NMDA antagonist medications (eg. Amantadine, Rimantadine, Lamotrigine,
Memantine, Dextromethorphan)

- Known hypersensitivity to ketamine or amantadine

- Anti-psychotic medications (Typicals or Atypicals), with the exception of low-dose
quetiapine (total daily dose of 100mg or less).

- Actively trying to commit suicide, even in a hospital setting

- Current homicide risk

- Unable or unwilling to give informed consent according to HIC guidelines

- Unable or unwilling to provide 2 contact phone numbers or be followed up per study
protocol.

- Previous enrollment in this study.

- Concurrent enrollment in a research protocol investigating experimental pharmacologic
treatments for depression at this or any other institution.