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Initiating Ketamine in Acutely Suicidal Patients in the Emergency Department

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ClinicalTrials.gov Identifier: NCT04260607
Recruitment Status : Enrolling by invitation
First Posted : February 7, 2020
Last Update Posted : March 2, 2021
Sponsor:
Information provided by (Responsible Party):
Naval Medical Center Camp Lejeune

Tracking Information
First Submitted Date  ICMJE February 5, 2020
First Posted Date  ICMJE February 7, 2020
Last Update Posted Date March 2, 2021
Actual Study Start Date  ICMJE January 14, 2020
Estimated Primary Completion Date January 14, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 5, 2020)
  • Suicidal Severity-clinical efficacy [ Time Frame: 4 hour+/1 after infusion completion, performed for placebo and drug arms ]
    completion of BSSI to evaluate suicidal severity.
  • Suicidal Severity-clinical efficacy [ Time Frame: 24-36 hours after infusion completion, performed for placebo and drug arms ]
    completion of BSSI to evaluate suicidal severity.
  • Suicidal Severity-duration of efficacy [ Time Frame: 1week+/-1 day after infusion completion, performed for placebo and drug arms ]
    completion of BSSI to evaluate suicidal severity.
  • Depression symptoms-clinical efficacy [ Time Frame: 4 hours +/-1 after infusion completion, performed for placebo and drug arms ]
    completion of MADRS-S to evaluate depression symptoms.
  • Depression symptoms-clinical efficacy [ Time Frame: 24-46 hours after infusion completion, performed for placebo and drug arms ]
    completion of MADRS-S to evaluate depression symptoms.
  • Depression symptoms-duration of efficacy [ Time Frame: 1 week +/-1 day after infusion completion, performed for placebo and drug arms ]
    completion of MADRS-S to evaluate depression symptoms.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 5, 2020)
Length of Stay [ Time Frame: performed on medical record review at 1 week ]
inspection of admission and transfer or discharge date
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Initiating Ketamine in Acutely Suicidal Patients in the Emergency Department
Official Title  ICMJE Initiating Ketamine in Acutely Suicidal Patients in the Emergency Department
Brief Summary Current treatment for acutely suicidal patients are limited to hospitalization, psychotherapy, electro-convulsant therapy, or a combination of the aforementioned. However, this has added to the national boarding problem. Long term pharmacologic treatment for suicidal behaviors and mood stabilization has been studied in specific populations. In these populations, the decreases in suicidal ideation results from stabilization of the underlying psychiatric illness. Ketamine is most commonly used as an anesthetic with analgesic properties. It has been used off-label for pain management, procedural sedation, status epilepticus, and treatment resistant depression. It has been safely administered intravenously and well tolerated for chronic Post Traumatic Stress Disorder. It increases norepinephrine, dopamine, and serotonin through adrenergic neuron stimulation and prevention of catecholamine uptake. There is a strong corollary between stress and the development of depression and suicidal behaviors. It is proposed that the use of low dose intravenous ketamine may have benefit on the suicidal ideation of patients presenting to the Emergency Department.
Detailed Description

There is a strong corollary between stress and the development of depression and suicidal behaviors. The neurobiological mediators of stress are primarily controlled by the noradrenergic and corticotropin-releasing factor (CRF) median eminence systems. Furthermore, stress directly and indirectly, through the Hypothalamic Pituitary Axis, activates the Locus Coeruleus (LC), which is the primary producer of NE in the central nervous system (CNS). Directly, glutaminergic neurons send excitatory signals to the LC via interaction with N-Methyl-D-Aspartate (NMDA) receptors NMDA antagonists, such as ketamine, can dampen the glutaminergic system, which has been implicated during states of depression and low moods.

The neurobiological commonality between multiple psychiatric disorders and depression, suicide, and attempted suicide is a decrease in serotonergic activity. It has been shown that patients who died of suicide, have decreased serotonin transporter in the ventromedial prefrontal cortex and anterior cingulate, which are areas that control decision making or willful action. The prefrontal cortex is important for inhibitory behavioral control. A potential treatment modality of ketamine, is that it produces activation of this region.35 The anterior cingulate cortex has been shown to be associated with impulsive aggression compared to control. Clinical studies have shown that low CSF 5-HIAA, metabolite in serotonin system, has been implicated and positively correlated to aggression scores and impulsivity. This is interesting because, suicides in the military are thought to have an impulsivity component, triggered by one or more major life stressors.

Another region associated with suicide is the infralimbic cortex. A recent study, based on neuroimaging techniques, demonstrated that glucose metabolism in this region was associated with SI at baseline, and decreases in SI was observed after ketamine infusion. This is the same region target by deep brain stimulation, for depression treatment. Additionally, the infralimbic cortex has been implicated in behavioral flexibility. Implicating that ketamine's anti-suicidal properties may stem from its ability to promoting cognitive flexibility. Most likely due to its ability to increase brain-derived neurotrophic factor (BDNF), which is a major contributor to neuronal plasticity. BDNF also plays key roles in synaptic and long-term potentiation, which may counteract the decreased levels in Mood Disorder (MDD) patients. Furthermore, ketamine infusion has been shown to change sleep slow wave activity. This biomarker is functionally related to increased synaptic strengthening and cortical synchronization. These factors, combined, may be implicated in not only ketamine's antidepressant effects and counteraction of decreased synaptic plasticity seen mood disorders, but also its ability to have week long lasting effects.

This information leads us to hypothesize that treatment of acutely suicidal patients with ketamine would: 1) decrease suicidal ideationto a clinically significant degree, and 2) the effect of ketamine will be seen for as long as one-week post administration.

To the best of our knowledge, this study does not duplicate any ongoing work. Instead, it would strengthen power to past studies and current work. There are four clinical trials investigating ketamine's effect on SI. One has an unknown status. There are two that are investigating ketamine in relationship to psychiatric standard of care, whereas this study is investigating its effects against a saline placebo. Finally, the last clinical trial is investigating the Neurobiology of Suicide. Their phase 2 component, which utilizes a similar protocol, uses ketamine as a tool to identify potential biomarkers for suicide. Furthermore, this study differs from Janssen Research & Development's clinical trial in administration route and study design. Their study focuses on using ketamine through intranasal administration. Their primary outcomes are the long-term safety and efficacy, and the design of their study is an open label multicenter trial.

This research does not duplicate any prior work. To date, there is only one study, from Iran, that evaluates the effectiveness of ketamine in high risk patients, or those that present as acutely suicidal to the ED. This was a single blinded trial that utilized 0.2mg/kg infused over one minute. The study indicated significant decrease in their measurement outcomes. However, they concluded that ketamine is not a good choice for treatment because it did not meet their cut off values. Their results might have been influenced by the rapid infusion over one minute, which differs from our study as well as the vast majority of the literature. We believe the slower 40-minute infusion is necessary for optimal results, as the larger dosage has produced more clinically meaningful results in prior studies, and the slower infusion produced less negative side effects. They chose the minimal dose shown to diminish SI41 200 ng/ml (0.2 mg/kg), which provokes lateral nystagmus.35 This protocol utilizes a higher dose, 0.5 mg/kg, which is the ED50 for narcosis. Our study is medically relevant because dosage effects on SI have not been studied. Comparison of our studies may address questions regarding the optimal dose and infusion rate.

The BSSI will measure the severity of SI. It is based on the interviewer rated version of the original Scale for Suicidal Ideation (SSI), which is one of the few document suicide assessment tools with predictive validity for suicide completion. The internal reliability, test and retest validity, as well as invariance over time has been demonstrated for the BSS. Furthermore, the first five items of the BSSI are a common clinical screening for the presence of suicidal thoughts. For these reasons, the BSSI was chosen as our primary outcomes measure. Two studies have indicated that the cut off between high and low risk is a BSS ≥ 2. A recent investigation has determined BSSI ≥ 6 is predictive of future suicide attempts. These two values will serve in our analysis.

The Montgomery- Åsberg Depression Rating Scale (MADRS) is a widely known 10 item clinician administered measure of depression severity. Since it's development in the late 1970s, it has become more popular than the gold standard, Hamilton rating scale for Depression (HAM-D). It is considered to be more sensitive to change, just as effective, and simpler to use clinically. However, the reliability depends on good interrater agreement. Difficulties in clinical trial to show signal detection for known effective drugs have implicated clinician administered measurement as a possible source of error. To avoid poor interrater reliability, rater bias, and variable interview quality, this trial will utilize the self-administered version of the MADRS-S. This has 9 items and a total score ranging from 0 to 27.50 The scoring of MADRS-S has shown to be similar to that of physician scoring.

The emotional pain of the suicidal patient requires empathetic care that may not always be possible with the time pressures, volume, and pragmatic nature of the ED environment. A pharmacologic intervention with rapid effects to decrease SI would play a vital role in improving the standard of care for this vulnerable population.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Intervention Model Description:
Experimental versus Placebo
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
Triple masked study (patient, healthcare provider, outcomes assessor) performed by pharmacy investigators not involved in study recruitment or assessment.
Primary Purpose: Treatment
Condition  ICMJE
  • Suicide
  • Suicide Threat
  • Depression Severe
Intervention  ICMJE
  • Drug: Ketamine Hydrochloride

    Experimental Procedure

    1. Baseline evaluation of suicidal severity (BSSI) & degree of depressive symptoms (MADRS-S) will be evaluated through self-administered questionnaires.
    2. The experimental and placebo arms will receive a single dose of IV ketamine, 0.5 mg/kg in 100 cc NS or 100 cc of NS infused over 40 minutes.
    3. Post ketamine re-evaluation of outcome measures at four and twenty-four hours will determine clinical effectiveness of ketamine intervention
    4. Inspection of admission and transfer time provides time measurement for LOS. This secondary measure is needed to determine efficiency of intervention.
    5. Post ketamine re-evaluation of outcome measure at one-week post infusion will elucidate ketamine's durability of effect.
    Other Name: Experimental Arm
  • Drug: Normal saline

    Experimental Procedure

    1. Baseline evaluation of suicidal severity (BSSI) & degree of depressive symptoms (MADRS-S) will be evaluated through self-administered questionnaires.
    2. The placebo arms will receive a single dose of 100 cc of NS infused over 40 minutes.
    3. Post Placebo infusion re-evaluation of outcome measures at four and twenty-four hours
    4. Inspection of admission and transfer time provides time measurement for LOS. This secondary measure is needed to determine efficiency of intervention.
    5. Post Normal Saline re-evaluation of outcome measure at one-week post infusion.
    Other Name: Placebo Comparator
Study Arms  ICMJE
  • Experimental: Experimental-Ketamine
    single dose IV Ketamine (Ketalar) 0.5mg/kg in 100ml Normal Saline infused over 40 minutes
    Intervention: Drug: Ketamine Hydrochloride
  • Placebo Comparator: Placebo-Saline
    100ml Normal Saline infused over 40 minutes
    Intervention: Drug: Normal saline
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Enrolling by invitation
Estimated Enrollment  ICMJE
 (submitted: February 5, 2020)
62
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 14, 2022
Estimated Primary Completion Date January 14, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Subject Inclusion and Selection Criteria

  1. Patient demographics will consist of Active, Reserve, or retired military personnel or their dependents.

    Subjects must meet the following inclusion criteria:

  2. Adult (18 to 89 years old)
  3. Present with active SI
  4. Deemed to being admitted to inpatient psychiatric unit

Subject Exclusion Criteria:

  1. Age < 18 years old or > 89 years old
  2. Currently presenting with psychosis as determined by mental health consultant
  3. Have a history of Cognitive disorder that would impair understanding of consent
  4. Have a personal/family history of Schizophrenia
  5. Currently pregnant or nursing
  6. Serious and unstable medical condition/problems
  7. Inability to medically clear
  8. Non-English Speakers
  9. Civilian Humanitarians
  10. Have previously enrolled in this study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 89 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04260607
Other Study ID Numbers  ICMJE NMCCL.2018.0011
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Naval Medical Center Camp Lejeune
Study Sponsor  ICMJE Naval Medical Center Camp Lejeune
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Naval Medical Center Camp Lejeune
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP