Effect of N-acetylcysteine on Brain Glutamate (NAC)

A Randomised Controlled Double Blind Crossover Study of the Effect of a Single Dose of N-acetylcysteine Versus Placebo on Brain Glutamate in Patients With Psychotic Disorders

A double-blind, placebo controlled, crossover study to determine whether a single dose of N-acetylcysteine (a nutritional supplement) can reduce brain glutamate levels in patients with a psychotic disorder. Secondary outcomes are to determine the pattern of alteration in brain perfusion and activity following a single dose of N-acetylcysteine.

Study Overview

• Status: Completed
• Conditions: Psychosis
• Intervention / Treatment: Dietary supplement: N-Acetylcysteine; Other: Placebo

Detailed Description

This is a physiological, proof-of-concept study designed to investigate whether a single administration of N-acetylcysteine can reduce brain glutamate levels in people with psychotic disorders.

Previous research suggests that poor response to antipsychotics may be linked to increased levels of glutamate in the brain (Egerton et al., 2012; Demjaha, Egerton et al., 2013). Reducing brain glutamate levels may therefore be therapeutic. This study tests whether it is possible to reduce brain glutamate levels in psychotic disorders.

This is a small pilot study to determine whether a single administration of NAC can reduce brain glutamate levels in psychosis. At the same time, we will also examine the effects of NAC on brain resting perfusion and activity, to gain more information about how NAC may be acting.

This study will recruit participants with a previous diagnosis of a psychotic disorder. There will be three study visits, 1-2 weeks apart. The first visit will involve a physical health check, blood sample and an interview to assess current symptoms and confirm medical history. On the second and third visits participants will have an MRI scan, lasting one hour, after taking capsules containing either 2400mg NAC or placebo.

• Study Type: Observational
• Enrollment (Actual): 20

Contacts and Locations

Study Locations

• United Kingdom
  • London
    • Denmark Hill, London, United Kingdom, SE5 8AF
      • Institute of Psychiatry, Psychology and Neuroscience

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients will be identified:

1. Via South London and Maudsley (SLaM) clinical teams.
2. If they have previously indicated to local research teams that they would like to be contacted about future research.

2. Through the SLaM NIHR Bioresource, including patients in CRIS, the research informatics database, who have given consent to be contacted about research projects.

Description

Inclusion Criteria:

• Over 18 years of age
• Diagnosis of a psychotic disorder
• Have mental capacity to consent

Exclusion Criteria:

• Diagnosed drug or alcohol dependency, with the exception of nicotine
• Pregnancy, as determined through a urine pregnancy test
• Presence of any physical health abnormality which may impact on safety to participate in the research, as determined by a study clinician on the basis of the physical health check and the available medical information.
• Presence of electronic or metallic implants contraindicated to MRI scanning at 3 Tesla, or presence of any other contraindication to MRI
• History of asthma
• History of epilepsy or any other seizure
• Under 18 years of age
• Lacking mental capacity to consent
• Current or previous use of NAC
• Currently prescribed clozapine

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
NAC or Placebo; Participants will receive 2400mg capsules of N-Acetylcysteine or placebo	Dietary supplement: N-Acetylcysteine; Participants will receive 2400mg of N-Acetylcysteine orally via 6 x 400mg capsules.; Other: Placebo; Participants will receive 2400mg of placebo orally via 6 x 400mg capsules.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in brain glutamate	The within-subjects difference in brain glutamate concentration following a single oral administration of placebo compared to 2400mg N-acetylcysteine	One hour post capsule

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain perfusion	The within-subjects change in regional brain perfusion, as assessed using pulsed continuous arterial spin labelling (pCASL) MRI, following a single oral administration of placebo compared to 2400mg N-acetylcysteine.	One hour post capsule
Regional activity and connectivity	The within-subjects change in regional brain activity or connectivity, as assessed using resting state functional magnetic resonance imaging (rsfMRI), following a single oral administration of placebo compared to 2400mg N-acetylcysteine.	One hour post capsule

Collaborators and Investigators

• Sponsor: King's College London
• Investigators: Principal Investigator: James H McCabe, King's College London

Publications and helpful links

General Publications

• Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I, Anderson-Hunt M, Judd F, Katz F, Katz P, Ording-Jespersen S, Little J, Conus P, Cuenod M, Do KQ, Bush AI. N-acetyl cysteine as a glutathione precursor for schizophrenia--a double-blind, randomized, placebo-controlled trial. Biol Psychiatry. 2008 Sep 1;64(5):361-8. doi: 10.1016/j.biopsych.2008.03.004. Epub 2008 Apr 23.
• Egerton A, Brugger S, Raffin M, Barker GJ, Lythgoe DJ, McGuire PK, Stone JM. Anterior cingulate glutamate levels related to clinical status following treatment in first-episode schizophrenia. Neuropsychopharmacology. 2012 Oct;37(11):2515-21. doi: 10.1038/npp.2012.113. Epub 2012 Jul 4.
• Demjaha A, Egerton A, Murray RM, Kapur S, Howes OD, Stone JM, McGuire PK. Antipsychotic treatment resistance in schizophrenia associated with elevated glutamate levels but normal dopamine function. Biol Psychiatry. 2014 Mar 1;75(5):e11-3. doi: 10.1016/j.biopsych.2013.06.011. Epub 2013 Jul 25. No abstract available.

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Actual): February 28, 2017
• Study Completion (Actual): February 28, 2017

Study Registration Dates

• First Submitted: June 24, 2015
• First Submitted That Met QC Criteria: June 25, 2015
• First Posted (Estimate): June 26, 2015

Study Record Updates

• Last Update Posted (Actual): March 8, 2018
• Last Update Submitted That Met QC Criteria: March 7, 2018
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Psychotic Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: BRCNAC