Cognitive Biases Under Ketamine (KETABI)

Cognitive Biases in Decision Making in a Pharmacological Model of Psychosis : a Study in Healthy Humans Recieving Low Dose Anesthetic, Ketamine Versus Placebo

Characterise cognitive biases resulting from low dose ketamine infusion, used as a pharmacological model of psychosis.

Our assumption is that low dose ketamine results in reasoning biases by impairing the way uncertainty is monitored and taken into account for decision making.

Study Overview

• Status: Unknown
• Conditions: Healthy Subjects
• Intervention / Treatment: Drug: Ketamine; Drug: Placebo

Detailed Description

Ketamine is a non-competitive glutamate NMDA antagonist. The infusion of subanesthetic doses of ketamine results in sub-clinical schizophrenia-like positive symptoms in healthy controls. The safety of ketamine use is attested by its daily use in child anesthesia and by a number of studies showing there is no medical, neural or cognitive complication after a single infusion.

Low dose ketamine is therefore a valid and safe human model to study psychosis. The objective of the study is to characterise cognitive biases resulting from low dose ketamine infusion, used as a pharmacological model of psychosis.

We designed four distinct paradigms designed to better characterize these biases.

P1 is a neuroeconomic task where subjects have to make binary choices to maximize gains, in a situation where either direct feedback information or additional counterfactual information is provided.

P2 is a neuroeconomic task where a direct manipulation of uncertainty is performed, and its impact on decision is measured.

P3 is a perceptual decision making task, where subjects have to classify a gabor orientation into the diagonal or cardinal category based on a rapidly presented series of individual gabors. The contribution of each piece of evidence to the final decision is measured and correlated to fluctuations in eeg data.

P4 is a perceptual decision making task, where subjects have to determine the global orientation of a series of sequentially presented gabor stimulus. There are interim responses and final responses, the influence of the former on the latter (confirmation bias) is studied.

Our assumption is that low dose ketamine results in reasoning biases by impairing the way uncertainty is monitored and taken into account for decision making.

The study design is as follows : randomized, double blind, controlled, against placebo, cross-over.

Healthy subjects will therefore be randomized to receive on the first visit either a ketamine infusion or a placebo infusion. The alternative condition will be applied on the second visit.

Ketamine will be prepared using KETAMINE PANPHARMA 250 mg/5mL, and infusion will be. This procedure should produce ketamine plasmatic levels of 140ng/ml. Two blood samples will be taken 30 and 90 minutes after infusion start to record actual ketamine plasmatic levels.

Placebo infusion will follow the same pattern of infusion, prepared using CHLORURE DE SODIUM 0,9% MACOPHARMA.

We will record both behavioral, electrophysiologic and psychometric data. Detailed assumptions are as folllows :

Behavioral data :

P1 and 2 : Significant impairment with ketamine in the ability to take into account uncertainty to guide decisions.

P3 : Significant decrease with ketamine in the ability to classify correctly the mean spatial orientation of stimuli according to the cardinal or diagonal direction.

P4 : Significant increase with ketamine in the confirmation bias following the interim choice.

Electroencephalographic data :

Correlation between the impairment in the ability to take into account uncertainty and the alteration of the Error Related Negativity and late inhibitory eeg signals, and decreased long distance synchrony as indicated by spectral analysis (P1 and 2).

The covariation of brain activity with the weight each stimuli sample will have in the final decision, will be increased as a result of ketamine infusion (P3).

Psychometric data :

Increase in the Brief Psychiatric Rating Scale (BPRS) as a result of ketamine infusion. The BPRS scale records the psychotic symtoms and is translated and validated in a french population sample.

• Study Type: Interventional
• Enrollment (Anticipated): 48
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Marie GODARD; Phone Number: 00 33 1 45 65 77 28; Email: m.godard@ch-sainte-anne.fr
• Study Contact Backup: Name: Raphaël GODARD, MD, PhD; Phone Number: 00 33 1 45 65 81 54; Email: r.gaillard@ch-sainte-anne.fr

Study Locations

• France
  • Paris, France, 75014
    • Recruiting
    • Centre hospitalier Sainte Anne
    • Contact: Marie GODARD; Phone Number: 00 33 1 45 65 77 28; Email: m.godard@ch-sainte-anne.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 39 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Right-handed (as assessed by the Edinburgh scale)
• Aged 18 to 39
• Having given an informed consent
• Health insurance

Exclusion Criteria:

• Pregnant or breastfeeding woman (a urine pregnancy test will be offered in doubt)
• Personal or first-degree family history of psychosis
• Personal history of mood disorder, anxiety disorder, obsessive-compulsive disorder, somatoform disorder, dependence on a psychoactive substance, behavior disorder incompatible with a 2 hours EEG recording.
• Psychotropic treatment, current or stopped for less than 1 month, including antidepressant, anxiolytic but excluding hypnotic treatments.
• Personal history of neurologic disorder in relation to the central nervous system : congenital malformation of the brain, brain tumor, multiple sclerosis, degenerative disease of the central nervous system, epilepsy, current or in remission for less than 3 years or still requiring a medical treatment, inflammatory disease of the central nervous system dating under a year or having resulted in sequelae.
• Known hypertension or blood pressure above 140/90 mmHg upon clinical examination, congenital heart disease, ischemic heart disease, cardiac insufficiency, supraventricular and ventricular heart rhythm disorder.
• Person with restricted liberty, as a result of judicial or administrative measures
• Persons under involuntary commitment as a result of a psychiatric disorder.
• Person subject to a measure of legal protection or unable to consent.
• Known intolerance ketamine.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ketamine then placebo; Infusion of low dose Ketamine then infusion of a saline solution	Drug: Ketamine; KETAMINE PANPHARMA 250 mg/5mL, solution for infusion : Initial rapid infusion of 0,23 mg/kg; Infusion from minute 2 to minute 30 : 0,00967 mg/kg/min; Infusion from minute 31 to minute 120 : 0,00483 mg/kg/min; Drug: Placebo; CHLORURE DE SODIUM 0,9 % MACOPHARMA : Initial rapid infusion of 0,23 mg/kg; Infusion from minute 2 to minute 30 : 0,00967 mg/kg/min; Infusion from minute 31 to minute 120 : 0,00483 mg/kg/min
Experimental: Placebo then ketamin; Infusion of a saline solution then infusion of low dose Ketamine	Drug: Ketamine; KETAMINE PANPHARMA 250 mg/5mL, solution for infusion : Initial rapid infusion of 0,23 mg/kg; Infusion from minute 2 to minute 30 : 0,00967 mg/kg/min; Infusion from minute 31 to minute 120 : 0,00483 mg/kg/min; Drug: Placebo; CHLORURE DE SODIUM 0,9 % MACOPHARMA : Initial rapid infusion of 0,23 mg/kg; Infusion from minute 2 to minute 30 : 0,00967 mg/kg/min; Infusion from minute 31 to minute 120 : 0,00483 mg/kg/min

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evidence for biaises in decision making in an uncertain environment.	Behavioural analyses of decision making during the neuroeconomic or perceptual decision makin tasks (Paradigms 1 to 4)	During infusion of Ketamine / Placebo (expected 2 hours)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Electroencephalographic data	Correlation between the impairment in the ability to take into account uncertainty and the alteration of the Error Related Negativity and late inhibitory eeg signals, and decreased long distance synchrony as indicated by spectral analysis (Paradigms 1 and 2). The covariation of brain activity with the weight each stimuli sample will have in the final decision, will be increased as a result of ketamine infusion (Paradigm 3)	During infusion of Ketamine / Placebo (expected 2 hours)
Brief Psychiatric Rating Scale (BPRS)		30 and 90 minutes after infusion onset
Heart rate		Every 15 minutes during infusion
Pulse oxymetry		Every 15 minutes during infusion
Blood pressure		Every 15 minutes during infusion
Clinician administred dissociatives states scales (CADSS)		30 and 90 minutes after infusion onset

Collaborators and Investigators

• Sponsor: Centre Hospitalier St Anne
• Collaborators: Fondation pour la Recherche Médicale; Fondation Fyssen; Comité pour la Recherche Hospitalière Médicale; Association Schizo Oui
• Investigators: Principal Investigator: Raphaël GAILLARD, Centre Hospitalier St Anne

Study record dates

Study Major Dates

• Study Start (Actual): September 8, 2014
• Primary Completion (Anticipated): October 1, 2019
• Study Completion (Anticipated): October 1, 2019

Study Registration Dates

• First Submitted: August 12, 2014
• First Submitted That Met QC Criteria: September 5, 2014
• First Posted (Estimate): September 9, 2014

Study Record Updates

• Last Update Posted (Actual): October 20, 2017
• Last Update Submitted That Met QC Criteria: October 18, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Schizophrenia; Ketamine; Uncertainty; Cognitive biases
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Ketamine
• Other Study ID Numbers: D512; 2013-002056-33 (EudraCT Number)