Ketamine For Suicidal Ideation

Study Overview
=================
Brief Summary
-----------------
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).

Detailed Description
-----------------
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.

Official Title
-----------------
Investigating Rapid Anti-Suicidal Ideation Effects of Intravenous (IV) Ketamine in Hospitalized Patients

Conditions
-----------------
Suicidal Ideation

Intervention / Treatment
-----------------
* Drug: Ketamine
* Drug: Midazolam


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketamine<br>single dose IV ketamine, .5mg/kg | Drug: Ketamine<br>* single dose IV ketamine, .5mg/kg infused over 40 minutes<br>* Other names: N-methyl-D-aspartate (NMDA) glutamate receptor antagonist;|
| Placebo Comparator: Midazolam<br>single dose IV midazolam, .45mg/kg | Drug: Midazolam<br>* single dose IV midazolam, .45mg/kg infused over 40 minutes<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Beck Scale for Suicidal Ideation (BSSI) | Change in BSI score at 24 hours following treatment as compared to baseline. Beck Scale is a 21-item self or clinician administered instrumentation used to measure the current intensity of patients' specific attitudes, behaviors and plans to commit suicide. Score range 0-42, with higher score indicating higher intensity. | baseline and 24 hours post infusion | 
| Change in Beck Scale for Suicidal Ideation (BSSI) | Change in BSI score at 48 hours following treatment as compared to baseline. Beck Scale is a 21-item self or clinician administered instrumentation used to measure the current intensity of patients' specific attitudes, behaviors and plans to commit suicide. Score range 0-42, with higher score indicating higher intensity. | baseline and 48 hours post infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Montgomery-Asberg Depression Rating Scale (MADRS) | The MADRS is a 10-item instrument used for the evaluation of depressive symptoms in adults and for the assessment of any changes to those symptoms. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. | up to 7 days post infusion | 
| Suicidality Item of the MADRS (MADRS-SI) | The MADRS-SI ranges from 0 to 6; a score of 2 corresponds to fleeting, passive SI; a score of 4 indicates that SI is frequent with at least moderate intensity but without specific plans or intention; a score of 6 corresponds to active intention and planning for suicide. | 24 hours post infusion | 
| The Young Mania Rating Scale (YMRS) | An 11-item questionnaire, used to assess manic symptoms based on the patient's subjective report of his or her clinical condition. There are four items that are graded on a 0 to 8 scale (irritability, speech, thought content, and disruptive/aggressive behavior), while the remaining seven items are graded on a 0 to 4 scale. The scores from each question are added together to form a total score ranging from 0 to 60, with higher scores indicating a greater severity of symptoms. | baseline, 40 minutes post infusion, 240 minutes post infusion | 
| The Brief Psychiatric Rating Scale (BPRS) | The BPRS measures psychomimetic effects with higher scores indicating more severe symptoms (scale range 7 - 49). | baseline, 40 minutes post infusion, and 240 minutes post infusion | 
| The Clinician-Administered Dissociative States Scale (CADSS) | The CADSS measures dissociation with higher scores indicating more severe symptoms (scale range 0 - 92). | baseline, 40 minutes post infusion and 240 minutes post infusion | 
| Patient Rated Inventory of Side Effects (PRISE) | The PRISE assesses the presence of treatment side effects in nine organ/function systems (gastrointestinal, nervous system, heart, eyes/ears, skin, genital/urinary, sleep, sexual functioning, and other). Data reported in in Adverse Events section. | duration of study | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
suicidal ideation, major depression, treatment resistant, ketamine, glutamate