Prevention of N-methyl-D-aspartate (NMDA) Antagonist-induced Psychosis in Kids
| Status: | Completed |
|---|---|
| Conditions: | Psychiatric, Psychiatric |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 7 - 17 |
| Updated: | 4/21/2016 |
| Start Date: | February 2003 |
| End Date: | October 2007 |
Prevention of NMDA Antagonist-induced Psychosis and Memory Impairment in Children
Ketamine, an FDA approved anesthetic agent, is becoming the sedative/analgesic of choice for
emergency sedation in children because it causes deep sedation with minimal respiratory
depression in comparison to other available agents. However, emergence reactions are an
important adverse effect of ketamine, characterized by transient changes in cognitive
function, dissociation and mild schizophrenia-like symptoms. These cognitive and behavioral
effects are dose-dependently induced by ketamine and other antagonists of the
N-methyl-D-aspartate (NMDA) glutamate receptor. NMDA receptor hypofunction can disinhibit
excitatory (cholinergic/glutamatergic) projections in key areas of the brain, and this has
been proposed to explain key features of schizophrenia. Several treatments that block
excessive excitatory transmitter release have also been shown to prevent cognitive and
behavioral effects of ketamine-induced NMDA receptor hypofunction in humans. Alpha-2
adrenergic agonists, which can presynaptically inhibit acetylcholine release, can prevent
mild ketamine-induced behavioral and cognitive symptoms in healthy human adults. However,
this prevention strategy has not been evaluated in children. Children currently receive
clinically-indicated treatment with the NMDA antagonist, ketamine, and this age group is an
important target for pharmacological strategies aimed at the prevention of schizophrenia.
This application proposes a double-blind, placebo-controlled, randomized trial to test the
safety and effectiveness of dexmedetomidine, an FDA approved alpha-2 adrenergic agonist, in
preventing ketamine-induced mental symptoms in children. Planned primary analyses will
evaluate effects of the hypothesized prevention treatment on clinical and cognitive
variables using analysis of variance (ANOVA). The proposed experiments are relevant to
future prevention trials for individuals at risk for schizophrenia, and to preventing
adverse effects of NMDA antagonist anesthetic agents (ketamine, nitrous oxide).
emergency sedation in children because it causes deep sedation with minimal respiratory
depression in comparison to other available agents. However, emergence reactions are an
important adverse effect of ketamine, characterized by transient changes in cognitive
function, dissociation and mild schizophrenia-like symptoms. These cognitive and behavioral
effects are dose-dependently induced by ketamine and other antagonists of the
N-methyl-D-aspartate (NMDA) glutamate receptor. NMDA receptor hypofunction can disinhibit
excitatory (cholinergic/glutamatergic) projections in key areas of the brain, and this has
been proposed to explain key features of schizophrenia. Several treatments that block
excessive excitatory transmitter release have also been shown to prevent cognitive and
behavioral effects of ketamine-induced NMDA receptor hypofunction in humans. Alpha-2
adrenergic agonists, which can presynaptically inhibit acetylcholine release, can prevent
mild ketamine-induced behavioral and cognitive symptoms in healthy human adults. However,
this prevention strategy has not been evaluated in children. Children currently receive
clinically-indicated treatment with the NMDA antagonist, ketamine, and this age group is an
important target for pharmacological strategies aimed at the prevention of schizophrenia.
This application proposes a double-blind, placebo-controlled, randomized trial to test the
safety and effectiveness of dexmedetomidine, an FDA approved alpha-2 adrenergic agonist, in
preventing ketamine-induced mental symptoms in children. Planned primary analyses will
evaluate effects of the hypothesized prevention treatment on clinical and cognitive
variables using analysis of variance (ANOVA). The proposed experiments are relevant to
future prevention trials for individuals at risk for schizophrenia, and to preventing
adverse effects of NMDA antagonist anesthetic agents (ketamine, nitrous oxide).
The proposed study will be conducted using existing dedicated clinical and research space in
St. Louis Children's Hospital's Emergency Department, Pediatric Clinical Research Center
(PCRC), and Orthopedic Clinic. This project has 3 major aims and 1 exploratory aim addressed
by a prospective randomized blinded placebo controlled drug trial to test whether a
pharmacological strategy can prevent NMDA receptor hypofunction-induced behavioral and
cognitive dysfunction in pre- and post-pubertal children. Based on previous preclinical and
clinical research on the effects and blockade of the effects of ketamine and similar
compounds, the study investigators have carefully selected a dose of the alpha-2 adrenergic
agonist dexmedetomidine that will permit this study to be conducted with low risk to
enrolled subjects who are undergoing clinically-indicated ketamine sedation for forearm
fracture reduction.
General Experimental Design: This project will test the safety and effectiveness of
dexmedetomidine for preventing ketamine-induced behavioral and cognitive symptoms in healthy
human children undergoing clinically indicated ketamine sedation for forearm fracture
reduction.
Aims 1 and 2 will be addressed by randomized, blinded administration of dexmedetomidine or
saline placebo to ketamine-sedated subjects to test the efficacy of dexmedetomidine in
preventing ketamine-induced behavioral and cognitive changes during recovery from sedation.
Aim 3 will be addressed by comparing between the subjects randomized to receive
dexmedetomidine or saline placebo measurements of distress and frequency of adverse
cardiopulmonary effects during sedation, fracture-reduction, and recovery.
St. Louis Children's Hospital's Emergency Department, Pediatric Clinical Research Center
(PCRC), and Orthopedic Clinic. This project has 3 major aims and 1 exploratory aim addressed
by a prospective randomized blinded placebo controlled drug trial to test whether a
pharmacological strategy can prevent NMDA receptor hypofunction-induced behavioral and
cognitive dysfunction in pre- and post-pubertal children. Based on previous preclinical and
clinical research on the effects and blockade of the effects of ketamine and similar
compounds, the study investigators have carefully selected a dose of the alpha-2 adrenergic
agonist dexmedetomidine that will permit this study to be conducted with low risk to
enrolled subjects who are undergoing clinically-indicated ketamine sedation for forearm
fracture reduction.
General Experimental Design: This project will test the safety and effectiveness of
dexmedetomidine for preventing ketamine-induced behavioral and cognitive symptoms in healthy
human children undergoing clinically indicated ketamine sedation for forearm fracture
reduction.
Aims 1 and 2 will be addressed by randomized, blinded administration of dexmedetomidine or
saline placebo to ketamine-sedated subjects to test the efficacy of dexmedetomidine in
preventing ketamine-induced behavioral and cognitive changes during recovery from sedation.
Aim 3 will be addressed by comparing between the subjects randomized to receive
dexmedetomidine or saline placebo measurements of distress and frequency of adverse
cardiopulmonary effects during sedation, fracture-reduction, and recovery.
Inclusion Criteria:
Patients presenting to St. Louis Children's Hospital's Emergency Department who require
reduction of an acute forearm fracture will be recruited for enrollment if they satisfy
the following:
1. Age 7-17 years, inclusive;
2. Are psychiatrically healthy (i.e. have never been under the care of a psychiatrist or
taken psychiatrically active medications);
3. Meet American Society of Anesthesiologist (ASA) Class I and II criteria (I=healthy,
II=chronic disease under good control);
4. Have had no prior fracture reduction or ketamine administration;
5. Present for care when research assistants are present (Monday-Friday, 09:00-23:00);
and
6. Have a home telephone or ready means of establishing telephone contact.
All subjects and their parent/guardian will give Washington University Human Studies
Committee approved written informed assent and consent prior to participation.
Exclusion Criteria:
1. Solid food intake 2 hours or less before procedure;
2. Compromised cardiorespiratory function; central nervous system, hepatic, or renal
abnormality;
3. History of psychosis in patient or first degree relative;
4. Currently taking medications that stimulate or depress mental function, e.g.
methylphenidate for attention deficit hyperactivity disorder or drugs of abuse;
5. History of allergy or adverse reaction to alpha-2 adrenoreceptor agonist drugs, e.g.
clonidine.
These exclusion criteria relate to contraindications for use of the agents employed in the
study. Criteria 1, 2, 3 and 4 are current routine practice for ketamine sedations.
We found this trial at
1
site
Click here to add this to my saved trials
