Suicidal Ideation
Conditions
Keywords
suicidal ideation, major depression, treatment resistant, ketamine, glutamate
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.
Interventions
DRUGKetamine
single dose IV ketamine, .5mg/kg infused over 40 minutes
DRUGMidazolam
single dose IV midazolam, .45mg/kg infused over 40 minutes
Sponsors
James Murrough
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Beck Scale for Suicidal Ideation (BSSI) | baseline and 24 hours post infusion | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Montgomery-Asberg Depression Rating Scale (MADRS) | up to 7 days post infusion | 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. |
| Suicidality Item of the MADRS (MADRS-SI) | 24 hours post infusion | 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. |
| The Young Mania Rating Scale (YMRS) | baseline, 40 minutes post infusion, 240 minutes post infusion | 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. |
| The Brief Psychiatric Rating Scale (BPRS) | baseline, 40 minutes post infusion, and 240 minutes post infusion | The BPRS measures psychomimetic effects with higher scores indicating more severe symptoms (scale range 7 - 49). |
| The Clinician-Administered Dissociative States Scale (CADSS) | baseline, 40 minutes post infusion and 240 minutes post infusion | The CADSS measures dissociation with higher scores indicating more severe symptoms (scale range 0 - 92). |
| Patient Rated Inventory of Side Effects (PRISE) | duration of study | 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. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited through the inpatient psychiatric service or through an academic outpatient psychiatric clinic. All study treatments were performed at Mount Sinai Hospital between April 2012 and June 2014.
Participants by arm
| Arm | Count |
|---|---|
| Ketamine single dose IV ketamine, .5mg/kg | 12 |
| Midazolam single dose IV midazolam, .45mg/kg | 12 |
| Total | 24 |
Baseline characteristics
| Characteristic | Total | Midazolam | Ketamine |
|---|---|---|---|
| Age, Continuous | 42.4 years STANDARD_DEVIATION 13.3 | 39.1 years STANDARD_DEVIATION 10.6 | 45.8 years STANDARD_DEVIATION 15.2 |
| BSI score, baseline | 17.7 units on a scale STANDARD_DEVIATION 9.7 | 17.9 units on a scale STANDARD_DEVIATION 11.9 | 17.5 units on a scale STANDARD_DEVIATION 7.2 |
| Co-occurring disorders BPD | 1 participants | 0 participants | 1 participants |
| Co-occurring disorders GAD | 6 participants | 1 participants | 5 participants |
| Co-occurring disorders MDD | 4 participants | 2 participants | 2 participants |
| Co-occurring disorders OCD | 6 participants | 3 participants | 3 participants |
| Co-occurring disorders Panic disorder | 4 participants | 1 participants | 3 participants |
| Co-occurring disorders PTSD | 3 participants | 1 participants | 2 participants |
| Co-occurring disorders SAD | 6 participants | 4 participants | 2 participants |
| Gender Female | 16 Participants | 8 Participants | 8 Participants |
| Gender Male | 8 Participants | 4 Participants | 4 Participants |
| History of suicide attempt no | 9 participants | 3 participants | 6 participants |
| History of suicide attempt yes | 15 participants | 9 participants | 6 participants |
| MADRS score, baseline | 34.8 units on a scale STANDARD_DEVIATION 5.1 | 34.3 units on a scale STANDARD_DEVIATION 4.1 | 35.2 units on a scale STANDARD_DEVIATION 6.1 |
| Primary Diagnosis Bipolar disorder | 7 participants | 3 participants | 4 participants |
| Primary Diagnosis BPD | 1 participants | 0 participants | 1 participants |
| Primary Diagnosis MDD | 13 participants | 7 participants | 6 participants |
| Primary Diagnosis PTSD | 3 participants | 2 participants | 1 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 12 | 12 / 12 |
| serious Total, serious adverse events | 5 / 12 | 0 / 12 |
Outcome results
Primary
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.
Time frame: baseline and 24 hours post infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Change in Beck Scale for Suicidal Ideation (BSSI) | 10.8 units on a scale | Standard Deviation 8.5 |
| Midazolam | Change in Beck Scale for Suicidal Ideation (BSSI) | 14.0 units on a scale | Standard Deviation 10.2 |
p-value: 0.32t-test, 2 sided
Primary
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.
Time frame: baseline and 48 hours post infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Change in Beck Scale for Suicidal Ideation (BSSI) | 8.8 units on a scale | Standard Deviation 8.3 |
| Midazolam | Change in Beck Scale for Suicidal Ideation (BSSI) | 15.3 units on a scale | Standard Deviation 10.9 |
p-value: 0.047t-test, 2 sided
Secondary
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.
Time frame: up to 7 days post infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketamine | Montgomery-Asberg Depression Rating Scale (MADRS) | 24 hours | 19.0 units on a scale | Standard Deviation 15.5 |
| Ketamine | Montgomery-Asberg Depression Rating Scale (MADRS) | 48 hours | 19.3 units on a scale | Standard Deviation 13.5 |
| Ketamine | Montgomery-Asberg Depression Rating Scale (MADRS) | 72 hours | 20.9 units on a scale | Standard Deviation 14.5 |
| Ketamine | Montgomery-Asberg Depression Rating Scale (MADRS) | 7 days | 21.7 units on a scale | Standard Deviation 13.1 |
| Midazolam | Montgomery-Asberg Depression Rating Scale (MADRS) | 7 days | 22.2 units on a scale | Standard Deviation 13.1 |
| Midazolam | Montgomery-Asberg Depression Rating Scale (MADRS) | 24 hours | 26.2 units on a scale | Standard Deviation 10.8 |
| Midazolam | Montgomery-Asberg Depression Rating Scale (MADRS) | 72 hours | 24.1 units on a scale | Standard Deviation 12.2 |
| Midazolam | Montgomery-Asberg Depression Rating Scale (MADRS) | 48 hours | 28 units on a scale | Standard Deviation 12.3 |
p-value: 0.17ANCOVA
Secondary
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.
Time frame: duration of study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ketamine | Patient Rated Inventory of Side Effects (PRISE) | 29 events |
| Midazolam | Patient Rated Inventory of Side Effects (PRISE) | 23 events |
Secondary
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.
Time frame: 24 hours post infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Suicidality Item of the MADRS (MADRS-SI) | 1.8 units on a scale | Standard Deviation 1.9 |
| Midazolam | Suicidality Item of the MADRS (MADRS-SI) | 3.3 units on a scale | Standard Deviation 1.6 |
Secondary
The Brief Psychiatric Rating Scale (BPRS)
The BPRS measures psychomimetic effects with higher scores indicating more severe symptoms (scale range 7 - 49).
Time frame: baseline, 40 minutes post infusion, and 240 minutes post infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketamine | The Brief Psychiatric Rating Scale (BPRS) | baseline | 7.7 units on a scale | Standard Deviation 1.12 |
| Ketamine | The Brief Psychiatric Rating Scale (BPRS) | 40 minutes post infusion | 9.9 units on a scale | Standard Deviation 3.3 |
| Ketamine | The Brief Psychiatric Rating Scale (BPRS) | 240 minutes post infusion | 8.1 units on a scale | Standard Deviation 1.6 |
| Midazolam | The Brief Psychiatric Rating Scale (BPRS) | baseline | 7.7 units on a scale | Standard Deviation 1.3 |
| Midazolam | The Brief Psychiatric Rating Scale (BPRS) | 40 minutes post infusion | 7.9 units on a scale | Standard Deviation 1.8 |
| Midazolam | The Brief Psychiatric Rating Scale (BPRS) | 240 minutes post infusion | 7.0 units on a scale | Standard Deviation 0.1 |
Secondary
The Clinician-Administered Dissociative States Scale (CADSS)
The CADSS measures dissociation with higher scores indicating more severe symptoms (scale range 0 - 92).
Time frame: baseline, 40 minutes post infusion and 240 minutes post infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketamine | The Clinician-Administered Dissociative States Scale (CADSS) | baseline | 1.1 units on a scale | Standard Deviation 2.6 |
| Ketamine | The Clinician-Administered Dissociative States Scale (CADSS) | 40 minutes post infusion | 17.1 units on a scale | Standard Deviation 19.9 |
| Ketamine | The Clinician-Administered Dissociative States Scale (CADSS) | 240 minutes post infusion | 1.2 units on a scale | Standard Deviation 1.9 |
| Midazolam | The Clinician-Administered Dissociative States Scale (CADSS) | baseline | 4.0 units on a scale | Standard Deviation 7 |
| Midazolam | The Clinician-Administered Dissociative States Scale (CADSS) | 40 minutes post infusion | 3.3 units on a scale | Standard Deviation 3.1 |
| Midazolam | The Clinician-Administered Dissociative States Scale (CADSS) | 240 minutes post infusion | 1.3 units on a scale | Standard Deviation 2.6 |
Secondary
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.
Time frame: baseline, 40 minutes post infusion, 240 minutes post infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketamine | The Young Mania Rating Scale (YMRS) | baseline | 0.0 units on a scale | Standard Deviation 0 |
| Ketamine | The Young Mania Rating Scale (YMRS) | 40 minutes post infusion | 0.0 units on a scale | Standard Deviation 0 |
| Ketamine | The Young Mania Rating Scale (YMRS) | 240 minutes post infusion | 0.2 units on a scale | Standard Deviation 0.6 |
| Midazolam | The Young Mania Rating Scale (YMRS) | baseline | 0.1 units on a scale | Standard Deviation 0.3 |
| Midazolam | The Young Mania Rating Scale (YMRS) | 40 minutes post infusion | 0.3 units on a scale | Standard Deviation 0.6 |
| Midazolam | The Young Mania Rating Scale (YMRS) | 240 minutes post infusion | 0.2 units on a scale | Standard Deviation 0.6 |