Effects of Ketamine on Mentalizing and Metacognition in Healthy Volunteers (METAKETAII)

A Randomized Control Trial Employing fMRI to Investigate the Effects of Ketamine on Mentalizing and Metacognition in Healthy Volunteers

Antipsychotic medication shows generally good effect sizes when looking at reduction of positive psychotic symptoms of schizophrenia, such as paranoia or delusion. However, social functioning often remains deficient in patients, meaning dopamine-receptor antagonists are not sufficient in treatment of people with schizophrenia.

A naturalistic video-based paradigm, named MASC has been used in the past to model over- and undermentalizing in patients with autism spectrum disorder and schizophrenia, since deficits in mentalizing can be explained by either overinterpreting a social situation (e.g. paranoid thoughts about intentions of others towards self) or by lacking the skill to read intentions of others.

To find out whether experimental manipulation via a non-competetive N-methyl-D-aspartate antagonist can induce difficulties with social cognition similar to those observed in people with schizophrenia, the investigators will conduct a RCT applying either ketamine or a placebo intravenously while participants are completing the above mentioned mentalizing task in the fMRI-scanner.

Study Overview

• Status: Completed
• Conditions: Ketamine-Induced Psychotic Disorder; Social Cognition; Theory of Mind
• Intervention / Treatment: Drug: Nacl 0.9%; Drug: Ketamine

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Bonn, Germany, 53127
    • Department of Psychiatry and Psychotherapy, University Hospital Bonn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Potential participants are excluded based on the following criteria:

• history of psychiatric/neurological disorder (self and first-degree relatives)
• learning disabilities, or loss of consciousness for more than 5 minutes
• history of alcohol or drug abuse within the last 12 months
• history of ketamine abuse
• history of complications during anesthesia (self and first-degree relatives)
• serious physical illness
• claustrophobia
• color-blindness
• metalliferous implant
• visual impairments other than corrective lenses
• injury or disease of the inner ear with loss of hearing
• consumption of any prescription or over-the-counter medication 3 days previous to the examination
• pregnancy
• currently breastfeeding a baby
• hypotension (blood pressure < 100/60)
• hypertension (blood pressure > 140/90)
• underweight (BMI <17)
• overweight (BMI ≥30)

Recruited participants are required to meet the following criteria:

• height between 150 and 195 cm
• bodyweight between 50 and 99kg
• male or female
• right-handed
• physically, neurologically and psychiatrically healthy
• non-smoker
• normal or corrected-to-normal eye-sight
• good command of German language

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Participants receive a saline-solution intravenously	Drug: Nacl 0.9%; Saline solution will also be applied with the Graseby 3500 intravenous infusion pump controlled by the STANPUMP software (Steven Shafer, M.D., Anesthesiology Service, PAVAMC 3801 Miranda Ave., Palo Alto, USA).
Experimental: Ketamine; Participants receive ketamine (Plasma-level 100 ng/ml with an initial bolus administered as a 2 mg/ml solution)	Drug: Ketamine; Ketamine is applied with a Graseby 3500 intravenous infusion pump controlled by the STANPUMP software (Steven Shafer, M.D., Anesthesiology Service, PAVAMC 3801 Miranda Ave., Palo Alto, USA). Target plasma levels are 100 ng/ml with an initial bolus administered as a 2 mg/ml solution.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Mentalizing/Theory of Mind	Over- and undermentalizing as characterized by the Movie for the assessment of social cognition (MASC). Higher scores on the "Mentalizing"-scale indicate better performance. Scores are divded between 4 scales (Mentalizing, No Mentalizing, Overmentalizing, Undermentalizing), each ranging from 0 to 27. Higher scores in one of the scales pertaining to "no Mentalizing, Overmentalizing or Undermentalizing mean a deficiency in mentalizing skills.	During ketamine/placebo application in MRI
Neural response to ketamine/placebo during social cognition	fMRI imaging will be performed to measure blood oxygen level-dependent (BOLD) signal in response to mentalizing cues in the MASC-task under ketamine/placebo. BOLD-signal will be measured with T2-weighted images in a 3T MRI. Data will be analyzed using SPM 12 in MATLAB. Deviations in BOLD-activity under ketamine compared to placebo (higher or lower activity of certain voxels/clusters compared all other voxels in the brain) will mean a change in neural response due to the effect of the substance	During ketamine/placebo application in MRI

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Psychotic symptom load in PANSS-Questionnaire	Positive and negative symptoms measured with questionnaire used in schizophrenia-research (Positive and Negative Symptom Scale). The PANSS uses a scale ranging from 1 to 7 in three different subscales (positive, 7 items; negative, 7 items; disorganized, 16 items). Higher numbers mean more psychotic symptoms.	10 minutes after cessation of MRI and ketamine/placebo application
Metacognitive-Questionnaire (MCQ)	Metacognitive typology as assessed with the MCQ. The MCQ is a questionnaire containing 30 items, based on a 4-point Likert scale (dont agree - strongly agree) from 1 to 4. It measures metacognitive ability in 5 subscales, each containing 6 items (Uncontrollability and Danger, Cognitive Self-Consciousness, Need to control thoughts, Positive Beliefs, Cognitive Confidence). This is a short form of the widely used Metacognitions Questionnaire that measures individual differences in a selection of metacognitive judgments and monitoring tendencies considered important in the metacognitive model of psychological disorders	20 minutes after cessation of MRI and ketamine/placebo application

Collaborators and Investigators

• Sponsor: University Hospital, Bonn

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2019
• Primary Completion (Actual): September 27, 2020
• Study Completion (Actual): September 27, 2020

Study Registration Dates

• First Submitted: March 14, 2022
• First Submitted That Met QC Criteria: April 1, 2022
• First Posted (Actual): April 11, 2022

Study Record Updates

• Last Update Posted (Actual): April 18, 2022
• Last Update Submitted That Met QC Criteria: April 11, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: social cognition; psychosis; fMRI; ketamine; metacognition; mentalizing
• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Psychotic Disorders; Mental Disorders; Shared Paranoid Disorder; 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: #19-03-29 (METAKETA)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No