Ignite Creation Date:
2024-05-06 @ 2:16 PM
Last Modification Date:
2024-10-26 @ 1:27 PM
Study NCT ID:
NCT04260607
Status:
TERMINATED
Last Update Posted:
2023-10-16
First Post:
2020-02-05
Brief Title:
Initiating Ketamine in Acutely Suicidal Patients in the Emergency Department
Sponsor:
Naval Medical Center Camp Lejeune
Organization:
Naval Medical Center Camp Lejeune
Study Overview
Official Title:
Initiating Ketamine in Acutely Suicidal Patients in the Emergency Department
Status:
TERMINATED
Status Verified Date:
2023-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
As a busy MTF we were unable to retain a health care provider with the appropriate expertise to buy-in to this study once the initiating PI left military service
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 region35 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 ketamines 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 ketamines 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 ketamines 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 Developments 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 02mgkg 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 ngml 02 mgkg which provokes lateral nystagmus35 This protocol utilizes a higher dose 05 mgkg 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 its 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 2750 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
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 region35 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 ketamines 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 ketamines 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 ketamines 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 Developments 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 02mgkg 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 ngml 02 mgkg which provokes lateral nystagmus35 This protocol utilizes a higher dose 05 mgkg 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 its 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 2750 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None