Effects of Ketamine and Risperidone on Cognition (Schiz_2)

University of Manchester

Status and phase: Completed; Phase 4

Conditions: Healthy Volunteers; Schizophrenia

Treatments: Drug: risperidone; Drug: placebo risperidone; Drug: ketamine; Drug: saline

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT01140620

P1V-SCH-CT02-09

Details and patient eligibility

About

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.

Full 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.

Enrollment: 87 patients

Sex: All

Ages: 18 to 45 years old

Volunteers: Accepts Healthy Volunteers

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.

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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87 participants in 5 patient groups, including a placebo group

ketamine and risperidone

Experimental group

Description:

Oral risperidone pretreatment and intravenous ketamine infusion

Treatment:

Drug: ketamine

Drug: risperidone

ketamine and placebo

Active Comparator group

Description:

Oral placebo risperidone pretreatment and intravenous ketamine infusion

Treatment:

Drug: ketamine

Drug: placebo risperidone

saline and risperidone

Active Comparator group

Description:

Oral risperidone pretreatment and intravenous saline infusion

Treatment:

Drug: saline

Drug: risperidone

saline and placebo

Placebo Comparator group

Description:

Oral placebo risperidone pretreatment and intravenous saline infusion

Treatment:

Drug: saline

Drug: placebo risperidone

Patients with Schizophrenia

No Intervention group

Description:

Patients with schizophrenia will not receive study drug and will not undergo randomisation.