Effects of Ketamine and Risperidone on Cognition (Schiz_2)

Effects of NMDA Receptor Antagonism on Cognitive Processes in Healthy Volunteers and Its Reversal by a Dopamine Antagonist: Comparison to Patients With Schizophrenia

The primary objective of this study is:

• To determine the effects of ketamine, which blocks the ion-channel gated by the NMDA receptor, on performance of cognitive tasks and the extent to which these effects can be reversed by the dopamine receptor antagonist, risperidone.

The secondary objectives of this study are:

• To establish whether patients with schizophrenia are able to reliably complete the biomarker test battery and to assess whether their responses are similar to healthy volunteers treated with ketamine.
• To establish a multi-site recruitment and assessment capacity based on shared Standard Operating Procedures across three study centres.

Study Overview

• Status: Completed
• Conditions: Schizophrenia; Healthy Volunteers
• Intervention / Treatment: Drug: ketamine; Drug: risperidone; Drug: placebo risperidone; Drug: saline

Detailed Description

This study is a continuation from a previous study (P1V-SCH-CT01-07). The overall aim of the 2 studies is to identify and validate potential biomarker tasks that may be used to provide early indications into the use of new treatments for schizophrenia. The studies are considering two potential models for schizophrenia in healthy volunteers, the first model looks at high versus average schizotypy, schizotypy being a personality trait. The second model, explored in this study, is a ketamine infusion.

Healthy volunteers will be identified through advertising and will initially be asked to complete an online questionnaire.Suitability for the next stage of the study will be based on the responses to the online questionnaire. Telephone interviews will then be conducted to assess suitability for screening.Screening visits will then be carried out in which a full medical and lab screening is undertaken. participants will also complete a number of psychiatric questionnaires and interviews. If participants remain suitable they will be invited to an assessment day in which they will be randomised to one of four study medication arms. Participants will then complete the biomarker tasks followed by questionnaires, rating scales and interviews. Patients with schizophrenia will form the 5th study arm and will not receive medication. They will complete the biomarkers in the same way as healthy volunteers.87 participants are planned, 72 healthy volunteers, 15 patients with schizophrenia.

This study does not test any investigational medicinal product (IMP) so any ethical issues that are associated with introducing a participant to a study drug are not applicable in this study.

Ketamine is already a widely used anaesthetic agent but when given at sub-anaesthetic doses is a useful tool for modelling schizophrenia psychosis.

The current study aims to assess the sensitivity of a battery of biomarker tasks (biomarkers are measures of processes that go wrong in illnesses and that contribute to symptoms) to the cognitive deficits induced by ketamine.

It may in future be possible to evaluate the effects of novel treatment for schizophrenia in healthy volunteers using this model, which would then potentially provide a rapid indication of the potential efficacy of candidate compounds at an early phase of drug development .

The study will provide information about the sensitivity of the biomarker tasks in detecting the effects of the pharmacological treatments for schizophrenia in healthy volunteers.

• Study Type: Interventional
• Enrollment (Actual): 87
• Phase: Phase 4

Contacts and Locations

Study Locations

• United Kingdom
  • Cardiff, United Kingdom, CF10 3AT
    • School of Psychology, University of Cardiff
  • Manchester, United Kingdom, M13 9PT
    • University of Manchester (Dept of Neuropyschiatry)
  • Greater London
    • London, Greater London, United Kingdom, SE5 8AF
      • Institute of Psychiatry, King's College London

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

5.2.1 General inclusion criteria (healthy and schizophrenia groups)

• Male or female aged 18 to 45 years
• Fluent English speakers, preferably with English as first language.
• Normotensive with sitting (5 minutes) blood pressure of 100 to 140 mmHg systolic, and 60 to 90 mmHg diastolic.
• Negative alcohol breath test.
• Negative urine drug screen.
• Participant must have consumed only their normal intake of coffee or tea on the morning of the assessment day and not consumed any other beverages containing caffeine for 2 hours prior to the assessment visit.
• Willing to follow the protocol prohibitions and restrictions .
• Participant must have signed the informed consent form.
• Those participants willing to participate in the pharmacogenomic components of the study must have signed the appropriate informed consent form.

5.2.2 Inclusion criteria applicable to healthy volunteers only

• SPQ score of 21 to 36.
• BMI of 18 to 30 kg/m².
• Non-smoker or light smoker (less than 5 cigarettes per day).
• Has not smoked in the 2 hours prior to the assessment visit.
• Females should be surgically sterile or abstinent or practising an effective method of birth control; they should have a negative urine pregnancy test.
• Healthy at screening and assessment visits as determined by the study physician, based on a medical evaluation including medical history, physical examination, laboratory tests, vital signs, 12-lead ECG and pre-study psychological tests.

5.2.3 Inclusion criteria applicable to participants with schizophrenia only

• Documented history of a diagnosis of schizophrenia as confirmed by GP or psychiatrist or by previous research diagnostic interview.
• Confirmation of diagnosis of schizophrenia, based on the MINI structured clinical interview, carried out by the study physician.
• In good physical health at screening and assessment visits as determined by the study physician, based on a medical evaluation including medical history, physical examination, laboratory tests and vital signs1.

Exclusion Criteria:

5.3.1 General exclusion criteria (healthy and schizophrenia groups)

• History of alcohol or substance dependence.
• Consumption of large amounts of caffeinated drinks.
• Have received over-the-counter medicine within 48 hours prior to assessment visit (apart from paracetamol) unless it will not interfere with the study procedures or compromise safety.
• History of, or current condition of, migraine headaches.
• Significant hearing impairment which in the opinion of the Investigator may interfere with the performance of the psychological test battery.
• Significant visual impairment or history of ocular treatment or ongoing condition which may interfere with the performance of the psychological test battery.
• Participated in a trial with any drug within 84 days of assessment visit.
• Unable or unwilling to comply with study procedures.

5.3.2 Exclusion criteria applicable to healthy volunteers only

• Known or suspected hypersensitivity or intolerance to risperidone or any of their excipients.
• Known or suspected hypersensitivity or intolerance to ketamine or any previous adverse reaction to anaesthesia.
• If female: are pregnant or are trying to get pregnant or are currently breast feeding.
• Relevant history, or presence upon clinical examination, of cardiac, ophthalmologic, gastro-intestinal, hepatic, or renal disease or other condition known to increase risk of side effects.
• History or presence of neurological or psychiatric conditions.
• Have received prescribed medication within 14 days prior to assessment visit (apart from the contraceptive pill) unless it will not interfere with the study procedures or compromise safety.

5.3.3 Exclusion criteria applicable to participants with schizophrenia only

• Changes to antipsychotic medications within 30 days of assessment visit.
• Admission to hospital, involvement with the home treatment team for psychiatric reasons or documented relapse of psychiatric symptoms within last 3 months.
• History or presence of psychiatric or neurological conditions other than schizophrenia, major depression and generalised anxiety disorder.
• Current extra-pyramidal symptoms and/or adverse effects from antipsychotic medications that, in the opinion of the study physician, will interfere with completion of the study tasks.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ketamine and risperidone; Oral risperidone pretreatment and intravenous ketamine infusion	Drug: ketamine; ketamine infusion to achieve plasma concentrations of 100 ng/mL. Duration approximately 3 hours; Other Names: ketalar; Drug: risperidone; risperidone (2 mg) capsule. One dosing of 2 mg.; Other Names: risperdal
Active Comparator: ketamine and placebo; Oral placebo risperidone pretreatment and intravenous ketamine infusion	Drug: ketamine; ketamine infusion to achieve plasma concentrations of 100 ng/mL. Duration approximately 3 hours; Other Names: ketalar; Drug: placebo risperidone; placebo capsule to match risperidone 2 mg capsule; Other Names: placebo risperdal
Active Comparator: saline and risperidone; Oral risperidone pretreatment and intravenous saline infusion	Drug: risperidone; risperidone (2 mg) capsule. One dosing of 2 mg.; Other Names: risperdal; Drug: saline; saline infusion. Duration approximately 3 hours
Placebo Comparator: saline and placebo; Oral placebo risperidone pretreatment and intravenous saline infusion	Drug: placebo risperidone; placebo capsule to match risperidone 2 mg capsule; Other Names: placebo risperdal; Drug: saline; saline infusion. Duration approximately 3 hours
No Intervention: Patients with Schizophrenia; Patients with schizophrenia will not receive study drug and will not undergo randomisation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biconditional learning task	Accuracy (% correct) for simple and biconditional learning trials, averaged over 8 blocks	6 months
Eye movement task	Antisaccade error rate.; Antisaccade correction rate.; Antisaccade latency.; Antisaccade amplitude gain.; Antisaccade peak velocity.; Prosaccade error rate.; Prosaccade correction rate.; Prosaccade latency.; Prosaccade amplitude gain.; Prosaccade peak velocity.; Smooth pursuit gain at three different target speeds.; Smooth pursuit saccadic frequency at three different target speeds.	6 months
Salience Attribution task	Implicit aberrant salience (ms).; i. Overall reaction time b.ii. Implicit adaptive salience (ms). c. Explicit adaptive salience (mm). d. Explicit aberrant salience (mm). e. Commission errors. f. Omission errors.	6 months
Signal detection task	d׳ value; Hits, when participants respond positively and a voice is present.; False alarm rate.; β value.	6 months
N-Back	Correct responses across three levels of difficulty.; Percentage of overall responses that was correct.; Errors of omission.; Errors of commission.	6 months
Spatial working memory	Between search error rate - errors due to a participant returning to a treasure chest which had previously contained some treasure on an earlier trial within the same block.; Within search error rate - errors due to a participant returning to the same treasure chest more than once within a trial.; Average time to complete each difficulty level	6 months
Verbal Fluency	Number of words generated.; Number of repetition errors: When the same word is repeated more than once within the letter or category.; Number of set loss errors: These are: i.) Words that start with a letter which do not fit the trial; ii.) Words which are names of people or places or numbers; iii.) Grammatical variants of an already stated word; and iv.) Non-words.	6 months
Event-related potentials (Manchester EEG pilot study only)	Amplitude and latencies of the positive peak in the 80-160 ms range (P1) and the negative peak in the 160 - 250 ms range (N1) for the Kanitsa and non-Kanitsa conditions.; Evoked gamma (30-100 Hz) and beta (14-30 Hz) oscillations in the 30 - 350 ms range to the Kanitsa condition.; Evoked alpha (8-12 Hz) and theta (4-8 Hz) oscillations in the 30-500 ms range to both conditions.; Coherence within and between frontal and occipital electrodes in the 100 - 400 ms range	6 months
Questionnaires and assessment scale scores	CADSS.; BPRS.; Effects of Drug Rating Scale.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacogenomic analysis	An exploratory genetic analysis aiming to correlate any genetic polymorphisms associated with schizotypy, schizophrenia or brain development with study outcomes.	12 months

Collaborators and Investigators

• Sponsor: University of Manchester
• Collaborators: King's College London; Cardiff University; P1vital Limited
• Investigators: Principal Investigator: Professor Bill Deakin, University of Manchester

Publications and helpful links

Helpful Links

• website

Study record dates

Study Major Dates

• Study Start: June 1, 2010
• Primary Completion (Actual): November 1, 2010
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: June 8, 2010
• First Submitted That Met QC Criteria: June 8, 2010
• First Posted (Estimate): June 9, 2010

Study Record Updates

• Last Update Posted (Estimate): November 9, 2016
• Last Update Submitted That Met QC Criteria: November 7, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Keywords: schizophrenia; healthy volunteers; cognitive processes; NMDA receptor antagonism; dopamine antagonist
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; 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; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Dopamine Agents; Serotonin Antagonists; Dopamine Antagonists; Ketamine; Risperidone
• Other Study ID Numbers: P1V-SCH-CT02-09

Plan for Individual participant data (IPD)

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