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

NCT ID: NCT00205712

Last Updated: 2016-01-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2003-02-28
• Study Completion Date: 2007-10-31

Brief Summary

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).

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.

Conditions

Psychoses, Substance-Induced

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Ketamine plue saline

Ketamine without dexmedetomidine

Group Type: PLACEBO_COMPARATOR

Ketamine

Intervention Type: DRUG

Ketamine without dexmedetomidine

Ketamine plus dexmedetomidine

Ketamine infusion plus dexmedetomidine

Group Type: EXPERIMENTAL

Dexmedetomidine

Intervention Type: DRUG

Ketamine plus dexmedetomidine

Interventions

Ketamine

Ketamine without dexmedetomidine

Intervention Type: DRUG

Dexmedetomidine

Ketamine plus dexmedetomidine

Intervention Type: DRUG

Other Intervention Names

Ketanest; Ketaset; Ketalar; Precedex

Eligibility 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.

• Minimum Eligible Age: 7 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Alliance for Research on Schizophrenia and Depression

OTHER

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

John W. Newcomer, M.D.

Role: PRINCIPAL_INVESTIGATOR

Washington University School of Medicine and Florida Atlantic University

Locations

Washington University School of Medicine, Psychiatry Dept.

St Louis, Missouri, United States

Countries

United States

Other Identifiers

01-0886

Identifier Type: OTHER

Identifier Source: secondary_id

NARSAD - Kids

Identifier Type: -

Identifier Source: org_study_id