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

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).

Conditions

• Psychoses, Substance-Induced

Interventions

DRUG

Ketamine

Ketamine without dexmedetomidine

DRUG

Dexmedetomidine

Ketamine plus dexmedetomidine

Sponsors & Collaborators

• National Alliance for Research on Schizophrenia and Depression

  collaborator OTHER

• Washington University School of Medicine

  lead OTHER

Principal Investigators

• John W. Newcomer, M.D. · Washington University School of Medicine and Florida Atlantic University

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Model

PARALLEL

Eligibility

Min Age

7 Years

Max Age

17 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2003-02-28

Primary Completion

2007-10-31

Completion

2007-10-31

Countries

• United States

Study Locations