Psychoses, Substance-Induced Clinical Trial
Official title:
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).
| Status | Completed |
| Enrollment | 40 |
| Est. completion date | October 2007 |
| Est. primary completion date | October 2007 |
| Accepts healthy volunteers | No |
| Gender | Both |
| Age group | 7 Years to 17 Years |
| Eligibility |
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. |
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment
| Country | Name | City | State |
|---|---|---|---|
| United States | Washington University School of Medicine, Psychiatry Dept. | St. Louis | Missouri |
| Lead Sponsor | Collaborator |
|---|---|
| Washington University School of Medicine | National Alliance for Research on Schizophrenia and Depression |
United States,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Brief Psychiatric Ratings Scale (BPRS) Positive Symptom Subscale Score | 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) | Before Ketamine, During Ketamine | No |
| Secondary | Visual Analog Scale (VAS) Pain Intensity | 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. | Before Ketamine, During Ketamine, Post Ketamine and 1 Week Follow up | No |
| Secondary | Visual Analog Scale (VAS) Anxiety Rating | 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. | Before Ketamine, During Ketamine, Post Ketamine, 1 week follow up | No |