Prevention of N-methyl-D-aspartate (NMDA) Antagonist-induced Psychosis in Kids

This study has been completed.
Sponsor:
Collaborator:
National Alliance for Research on Schizophrenia and Depression
Information provided by (Responsible Party):
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT00205712
First received: September 13, 2005
Last updated: March 18, 2014
Last verified: March 2014
  Purpose

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).


Condition Intervention Phase
Psychoses, Substance-Induced
Drug: Ketamine
Drug: Dexmedetomidine
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
Official Title: Prevention of NMDA Antagonist-induced Psychosis and Memory Impairment in Children

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • Brief Psychiatric Ratings Scale (BPRS) Positive Symptom Subscale Score [ Time Frame: Before Ketamine, During Ketamine ] [ Designated as safety issue: No ]
    Participant received behavioral ratings before medication and during medication for the primary analysis comparison. This is an observer-scale with a value range from 0-6 (0=no symptoms 6=worst symptoms)


Secondary Outcome Measures:
  • Visual Analog Scale (VAS) Pain Intensity [ Time Frame: Before Ketamine, During Ketamine, Post Ketamine and 1 Week Follow up ] [ Designated as safety issue: No ]
    Pain intensity was measured on a scale of 1-10 (1=lowest pain intensity, 10=highest pain intensity) in participants before medication, during medication, post medication and 1 week follow up.

  • Visual Analog Scale (VAS) Anxiety Rating [ Time Frame: Before Ketamine, During Ketamine, Post Ketamine, 1 week follow up ] [ Designated as safety issue: No ]
    Anxiety was measured on a scale of 1-10 (1=lowest pain intensity, 10=highest pain intensity) in participants before medication, during medication, post medication and 1 week follow up.


Enrollment: 40
Study Start Date: February 2003
Study Completion Date: October 2007
Primary Completion Date: October 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Ketamine plue saline
Ketamine without dexmedetomidine
Drug: Ketamine
Ketamine without dexmedetomidine
Other Names:
  • Ketanest
  • Ketaset
  • Ketalar
Experimental: Ketamine plus dexmedetomidine
Ketamine infusion plus dexmedetomidine
Drug: Dexmedetomidine
Ketamine plus dexmedetomidine
Other Name: Precedex

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   7 Years to 17 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00205712

Locations
United States, Missouri
Washington University School of Medicine, Psychiatry Dept.
St. Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
National Alliance for Research on Schizophrenia and Depression
Investigators
Principal Investigator: John W. Newcomer, M.D. Washington University School of Medicine and Florida Atlantic University
  More Information

No publications provided

Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT00205712     History of Changes
Other Study ID Numbers: NARSAD - Kids, 01-0886
Study First Received: September 13, 2005
Results First Received: October 27, 2009
Last Updated: March 18, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Washington University School of Medicine:
NMDA antagonist-induced psychosis
Children
Memory Impairment
Decreased cognitive function
Increased memory impairment

Additional relevant MeSH terms:
Psychoses, Substance-Induced
Mental Disorders
Psychotic Disorders
Shared Paranoid Disorder
Poisoning
Substance-Related Disorders
Schizophrenia and Disorders with Psychotic Features
Schizophrenia
N-Methylaspartate
Ketamine
Dexmedetomidine
Excitatory Amino Acid Agonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Anesthetics, Dissociative
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
Central Nervous System Depressants
Central Nervous System Agents
Therapeutic Uses
Excitatory Amino Acid Antagonists
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Hypnotics and Sedatives
Analgesics, Non-Narcotic

ClinicalTrials.gov processed this record on July 26, 2014