Nicotinic Modulation of Schizophrenia-Like Information Processing Deficits in Healthy Subjects - Full Text View

Sponsored by:	Yale University
Information provided by:	Yale University
ClinicalTrials.gov Identifier:	NCT00690170

Purpose

Converging lines of evidence suggest that deficits in the NMDA glutamate receptors may contribute to the behavioral symptoms and cognitive deficits associated with schizophrenia. Schizophrenia patients have several informational processing abnormalities including deficits in P50 gating (ability to filter out irrelevant auditory stimuli and focus on salient stimuli), MMN (pre-attentive brainwave response to stimuli that deviate in physical nature from preceding stimuli), and P300 (the apportionment of attention to novel stimuli). NMDA antagonists impair information processing. Ketamine elicits impairments in MMN and P300 in healthy humans and Phencyclidine, which is much more potent than ketamine, was shown to disrupt P50 gating in rats. Studies at our center demonstrate that at doses similar to the dose proposed in this study, ketamine disrupts P50 gating in humans. Nicotine has been reported to improve performance on tasks of attention, learning and working memory in humans and animals. Other reports suggest that nicotine impairs or does not affect spatial working memory in healthy humans. Finally, the effects on P300 are equivocal in healthy humans.

Schizophrenic patients may be self-medicating informational processing deficits: Smoking or nicotine improved deficits in P50 gating transiently, prepulse inhibition, smooth pursuit eye movement, and Continuous Performance Task in schizophrenic patients. This may explain the inordinately high rates and amounts of nicotine use in schizophrenia. However, the mechanism/s underlying nicotine effects on information processing abnormalities are poorly understood.

The aim of this study is to determine whether nicotine improves the deficits in attention and information processing induced by a drug that blocks NMDA receptors in humans.

Hypotheses:

The primary hypothesis is that nicotine will improve abnormalities in amplitude and/or latency of P300 and mismatch negativity induced by NMDA antagonism.
The secondary, exploratory hypothesis is that NMDA antagonist-elicited schizophrenia-like psychotic symptoms, attention and working memory will be attenuated by nicotine.

Condition	Intervention	Phase
Healthy Subjects	Drug: Ketamine Drug: Nicotine Drug: Placebo Drug: Ketamine and Nicotine	Phase I

MedlinePlus related topics: Memory Psychotic Disorders Schizophrenia

Drug Information available for: Sodium chloride Nicotine polacrilex Nicotine tartrate Ketamine Ketamine hydrochloride Chlorides

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Basic Science, Randomized, Double Blind (Subject, Caregiver, Investigator), Crossover Assignment, Efficacy Study
Official Title:	Nicotinic Modulation of (NMDA) Receptor Antagonist Schizophrenia-Like Information Processing Deficits in Humans

Further study details as provided by Yale University:

Primary Outcome Measures:

ERP recording procedures: Brain wave activity during tasks involving in processing auditory and visual stimuli with different degrees of attentional and memory demands will be recorded. [ Time Frame: +65 ] [ Designated as safety issue: Yes ]
IntegNeuro is a computerized battery that consists of an automated stimulus presentation to measure cognitive function. [ Time Frame: +25 ] [ Designated as safety issue: Yes ]
Positive and Negative Syndrome Scale will be used to measure psychotic symptoms. [ Time Frame: -90, +10, +105, +180 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

CADSS: scale that measures perceptual alterations. [ Time Frame: -90, +10, +105, +180 ] [ Designated as safety issue: Yes ]
Visual Analog Scale: a 5-item feeling state scale associated with ketamine. [ Time Frame: -90,+10, +105, +180 ] [ Designated as safety issue: Yes ]
Ketamine, nicotine and cotinine blood levels will be measured to rule out any pharmacokinetic interactions [ Time Frame: -60,+5(ketamine only), +20(nicotine and cotinine only), +65, +100,+180 ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	30
Study Start Date:	December 2002
Estimated Study Completion Date:	January 2009
Estimated Primary Completion Date:	October 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Ketamine and Nicotine: Active Comparator 0.23 mg/kg of ketamine bolus IV (in the arm) over one minute followed by maintenance infusion at 0.58mg/kg/hour x 30 minutes, followed by 0.29 mg/kg/hour x 64 minutes. 13.5 µg/kg of nicotine IV (in the arm) given over 10 min (1.35 µg/min/kg), followed by a constant infusion of 31.02 µg/kg given over 85 min (0.365 µg/min/kg)	Drug: Ketamine and Nicotine 0.23 mg/kg of ketamine bolus IV (in the arm) over one minute followed by maintenance infusion at 0.58mg/kg/hour x 30 minutes, followed by 0.29 mg/kg/hour x 64 minutes. 13.5 µg/kg of nicotineIV (in the arm) given over 10 min (1.35 µg/min/kg), followed by a constant infusion of 31.02 µg/kg given over 85 min (0.365 µg/min/kg)
Placebo Comparator: Placebo Comparator -Placebo administration: Normal saline (sodium chloride 0.9%)over 95 minutes	Drug: Placebo Normal saline (sodium chloride 0.9%)administered via IV (in the arm) over 95 minutes
Ketamine and Placebo: Active Comparator Ketamine administration: 0.23 mg/kg bolus over one minute followed by maintenance infusion at 0.58mg/kg/hour x 30 minutes, followed by 0.29 mg/kg/hour x 64 minutes Placebo administration: Normal saline (sodium chloride 0.9%)over 94 minutes	Drug: Ketamine Ketamine: 0.23 mg/kg bolus over one minute followed by maintenance infusion at 0.58mg/kg/hour x 30 minutes, followed by 0.29 mg/kg/hour x 64 minutes
Nicotine and Placebo: Active Comparator Nicotine: 13.5 µg/kg given over 10 min (1.35 µg/min/kg)IV (in the arm), followed by a constant infusion of 31.02 µg/kg given over 85 min (0.365 µg/min/kg) Placebo: Normal saline (sodium chloride 0.9%)IV (in the arm)	Drug: Nicotine Nicotine: 13.5 µg/kg given over 10 min (1.35 µg/min/kg),IV (in the arm) followed by a constant infusion of 31.02 µg/kg given over 85 min (0.365 µg/min/kg) Placebo: Normal saline (sodium chloride 0.9%)IV (in the arm)

Detailed Description:

This study examines the interactive effects of ketamine and nicotine. Ketamine is an Food and Drug Administration approved anesthetic. Sub anesthetic doses of ketamine temporarily interferes with the brain's ability to process information and may temporarily produce schizophrenia-like symptoms. Some of these symptoms include electrophysiological indices of altered information processing. Nicotine is hypothesized to reduce these schizophrenia-like information processing deficits. A screening day determines eligibility based on a thorough medical evaluation including nonsmokers and smokers aged 18-50 years old. Healthy subjects are recruited from the community and complete 1 training day which involves familiarizing with the cognitive test battery and 4 test days. Each test day is separated by at least 3 days, during which they will receive ketamine or placebo and nicotine or placebo in a double-blind counterbalanced design. There are 4 treatment conditions in a random order:

ketamine and nicotine
placebo (saline) and nicotine
ketamine and placebo (saline)
placebo (saline) and placebo (saline)

Ketamine and nicotine are infused over about 95 minutes. Throughout the day subjects will be asked questions about their thinking and mood, and asked to perform computer tasks. Memory, attention concentration and planning are tested. In addition, heart rate, blood pressure and temperature will be checked by a research nurse. Blood samples will be collected several times throughout the day. These evaluations will continue periodically throughout the test day. There will also be follow up questionnaires at one week, three months and six months.

Eligibility

Ages Eligible for Study:	18 Years to 50 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

18-50 years old
Deemed healthy by the Structured Clinical Interview for DSM, non-patient version (SCID-NP) and collateral information
Smokers will be defined as recent nicotine users (heavy, moderate or light), including cigarette/cigar/pipe smokers, who are not interested in quitting nicotine use.

Exclusion Criteria:

DSM-IV diagnosis of alcohol or substance dependence in the past year
DSM-IV Axis I diagnoses (other than nicotine dependence in smokers) and Axis II diagnoses
Unstable medical conditions that necessitate frequent changes in treatment: for example, recent myocardial infarction and uncontrollable hypertension. At the discretion of the investigator, subjects with unstable medical conditions that may necessitate changes in medical treatment and hence influence study outcomes will be excluded.
A hearing deficit in greater than one band in an ear detected using a Welch-Allyn audioscope (500, 1000, 2000 and 4000 Hz threshold will be evaluated)
Positive pregnancy test
Major current or recent (<6 weeks) stressors
History of counseling, except if counseling was for a life circumstance disorder (e.g., bereavement, divorce)
Lifetime history of treatment with any psychotropic medications for > 1 month duration: for example, antipsychotics, antidepressants, mood stabilizers and anxiolytics used to treat a psychiatric condition except medications used for sleep
Axis I diagnoses of psychotic disorders in first-degree relatives

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00690170

Contacts

Contact: Jacqueline P Elander, B.A.

203-932-5711 ext 4523

jacqueline.elander@yale.edu

Locations

United States, Connecticut
Veterans Administration Hospital	Recruiting
West Haven, Connecticut, United States, 06516
Contact: Jacqueline P Elander, B.A 203-932-5711 ext 4523 jacqueline.elander@yale.edu
Principal Investigator: Deepak C D'Souza, M.D.

Sponsors and Collaborators

Yale University

Investigators

Principal Investigator:

Deepak C D'Souza, M.D.

Yale University School of Medicine Department of Psychiatry

More Information

Responsible Party:	Yale University, Department of Psychiatry ( Deepak Cyril D'Souza, M.D. )
Study ID Numbers:	18014
Study First Received:	May 30, 2008
Last Updated:	May 30, 2008
ClinicalTrials.gov Identifier:	NCT00690170
Health Authority:	United States: Food and Drug Administration

Keywords provided by Yale University:

ketamine
nicotine
schizophrenia
cognitive deficits

P300 oddball paradigm
Mismatch Negativity
P50 gating

Study placed in the following topic categories:

Nicotine polacrilex
Schizophrenia
Excitatory Amino Acids
Nicotine
Mental Disorders

Ketamine
Psychotic Disorders
Healthy
Schizophrenia and Disorders with Psychotic Features

Additional relevant MeSH terms:

Anesthetics, Intravenous
Neurotransmitter Agents
Cholinergic Agonists
Molecular Mechanisms of Pharmacological Action
Nicotinic Agonists
Physiological Effects of Drugs
Anesthetics
Central Nervous System Depressants
Central Nervous System Stimulants
Excitatory Amino Acid Agents
Cholinergic Agents

Anesthetics, Dissociative
Pharmacologic Actions
Autonomic Agents
Sensory System Agents
Anesthetics, General
Therapeutic Uses
Ganglionic Stimulants
Peripheral Nervous System Agents
Analgesics
Central Nervous System Agents
Excitatory Amino Acid Antagonists

ClinicalTrials.gov processed this record on January 15, 2009