Investigating the Effect of Diroximel Fumarate on Glutathione in Schizophrenia

NCT06957808 | Recruiting

• 1 other identifier: 331465
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 3

Brief Summary

Schizophrenia is a condition that causes symptoms like delusions, hallucinations, reduced motivation and muddled thinking. It is a common, severe and disabling psychiatric illness affecting about 1/100 (1%) of people. It is ranked the third most disabling illness worldwide. Six in seven patients do not recover from the illness in 6-12 months and continue to experience psychotic symptoms. Therefore, there is a strong unmet need for new evidence-based treatments to target the neurobiology underlying schizophrenia. There is increasing evidence to indicate that glutathione (GSH), the main brain antioxidant, is abnormal in schizophrenia and may provide a new treatment target. In this study, the investigators plan to determine whether Diroximel Fumarate (DRF) (currently a treatment for a brain disorder called multiple sclerosis) can increase GSH in the brain of patients with schizophrenia using a brain scan (MRI) and explore whether changes in GSH are related to other brain measures (measured with MRI and EEG- which measures electrical activity in the brain), blood markers of GSH, and symptoms. During this study 30 people with schizophrenia will be recruited. Participants will take the drug DRF for two weeks, a computer will then decide randomly whether each person will continue to take DRF or a placebo/dummy pill for another two weeks. During this part of the study neither the patients nor the researchers will know which type of drug the patient is taking. Brain GSH and the other measures described will be assessed before and after taking the DRF and placebo/dummy pill. At the end of the study (2027), the investigators will see if taking DRF alters the brain chemical (GSH) in people with schizophrenia and whether this is linked to other measures and symptoms. It will also give researchers information about the best way to design future studies for patients with schizophrenia using this drug.

Conditions

Schizophrenia Disorders

Keywords

psychosis; schizophrenia; inflammation; diroximel fumarate; neuroimaging; antioxidant; glutathione

Outcome Measures

Primary Outcomes (1)

• MRS glutathione (GSH) levels in ACC

  Glutathione levels in the Anterior Cingulate Cortex (ACC) measured by magnetic resonance spectroscopy (1HMRS)

  Within one year of conclusion of the Research

Secondary Outcomes (1)

• MMN Amplitude

  Within one year of conclusion of the Research

Study Arms (3)

Open label

EXPERIMENTAL

Participants take the research drug for 14 days in an open label phase.

Drug: Diroximel fumarate (DRF)

Double-blind - DRF

ACTIVE COMPARATOR

After open label phase, participants can be randomised to either the research drug (diroximel fumarate, DRF) or placebo for a further 2 weeks.

Drug: Diroximel fumarate (DRF)

Double blind - Placebo

PLACEBO COMPARATOR

After open label phase, participants can be randomised to either the research drug (diroximel fumarate, DRF) or placebo for a further 2 weeks.

Drug: Placebo

Interventions

Diroximel fumarate (DRF) DRUG

Diroximel fumarate is an immunomodulating drug licensed for use in multiple sclerosis. It has been found to cross the blood brain barrier and increase brain glutathione levels.

Also known as: Vumerity

Double-blind - DRF; Open label

Placebo DRUG

A placebo pill given to participants.

Double blind - Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• years, diagnosis of schizophrenia (Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5)
• Stable antipsychotic dose (no change for 1 month)
• Currently stable with no evidence of relapse within the last 2 months prior to study enrolment
• Minimum of 60 on the Positive and Negative Syndrome Scale (PANSS)
• Capacity to provide informed consent

You may not qualify if:

• History of significant co-morbid medical or neurological disorder including but not limited to HIV, malignancies, Systemic Lupus Erythematosus, sarcoidosis, autoimmune vasculitis, bone marrow transplantation
• Current use of medication that is known to interact with DRF, live vaccines given within the period of DRF treatment, nephrotoxic medication (including but not limited to aminoglycosides, diuretics, non-steroidal anti-inflammatory drugs, Lithium)
• Contraindications to DRF (pregnancy, women of childbearing potential not currently using effective contraception (combined pill (oestrogen \& progesterone), progesterone -only with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner, sexual abstinence), breast feeding, severe hepatic impairment, moderate renal impairment, severe active gastrointestinal disease, lymphocyte count - below the Lower Limit of Normal (LLN) for the local laboratory (e.g 1.30 x109/L LLN for Viapath King's College London), suspected or confirmed progressive multifocal leukoencephalopathy (PML), presence of risk factors for PML (previous and/or current immunosuppressant or immunomodulatory treatment (including natalizumab, other fumaric esters including Dimethyl Fumarate (DMF) (topical or systemic)), serious infection, current or recent herpes virus infection)
• Substance dependence/abuse other than to cigarettes
• Current high suicide risk
• Participation in a clinical study of unlicensed medicines within the previous 30 days
• Presence/history of other acute or chronic illness that would make participating unsafe or unsuitable, any contraindication to MRI scanning (e.g. claustrophobia, metallic implants, pacemaker, vascular clips, metal in eyes, pregnancy)
• Allergies to any of DRFs ingredients
• Taking part in a research study involving an unlicensed medicine within the last 30 days

Sponsors & Collaborators

• King's College London: lead
• Rosetrees Trust: collaborator
• South London and Maudsley NHS Foundation Trust: collaborator

Study Sites (3)

South London and Maudsley NHS Foundation Trust

London, Greater London, SE58AZ, United Kingdom

RECRUITING

Department of Computer Science, Faculty of Engineering Science, University College London

London, Greater London, WC1E 6BT, United Kingdom

RECRUITING

School of Psychology, University of birmingham

Birmingham, B15 2TT, United Kingdom

RECRUITING

Related Publications (13)

• Gawryluk JW, Wang JF, Andreazza AC, Shao L, Young LT. Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. Int J Neuropsychopharmacol. 2011 Feb;14(1):123-30. doi: 10.1017/S1461145710000805. Epub 2010 Jul 16.

  PMID: 20633320 BACKGROUND

• Ustun TB, Rehm J, Chatterji S, Saxena S, Trotter R, Room R, Bickenbach J. Multiple-informant ranking of the disabling effects of different health conditions in 14 countries. WHO/NIH Joint Project CAR Study Group. Lancet. 1999 Jul 10;354(9173):111-5. doi: 10.1016/s0140-6736(98)07507-2.

  PMID: 10408486 BACKGROUND

• Raffa M, Mechri A, Othman LB, Fendri C, Gaha L, Kerkeni A. Decreased glutathione levels and antioxidant enzyme activities in untreated and treated schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry. 2009 Oct 1;33(7):1178-83. doi: 10.1016/j.pnpbp.2009.06.018. Epub 2009 Jul 2.

  PMID: 19576938 BACKGROUND

• Owjfard M, Karimi F, Mallahzadeh A, Nabavizadeh SA, Namavar MR, Saadi MI, Hooshmandi E, Salehi MS, Zafarmand SS, Bayat M, Karimlou S, Borhani-Haghighi A. Mechanism of action and therapeutic potential of dimethyl fumarate in ischemic stroke. J Neurosci Res. 2023 Sep;101(9):1433-1446. doi: 10.1002/jnr.25202. Epub 2023 May 14.

  PMID: 37183360 BACKGROUND

• Linker RA, Lee DH, Ryan S, van Dam AM, Conrad R, Bista P, Zeng W, Hronowsky X, Buko A, Chollate S, Ellrichmann G, Bruck W, Dawson K, Goelz S, Wiese S, Scannevin RH, Lukashev M, Gold R. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain. 2011 Mar;134(Pt 3):678-92. doi: 10.1093/brain/awq386.

  PMID: 21354971 BACKGROUND

• Jauhar S, Veronese M, Nour MM, Rogdaki M, Hathway P, Turkheimer FE, Stone J, Egerton A, McGuire P, Kapur S, Howes OD. Determinants of treatment response in first-episode psychosis: an 18F-DOPA PET study. Mol Psychiatry. 2019 Oct;24(10):1502-1512. doi: 10.1038/s41380-018-0042-4. Epub 2018 Apr 20.

  PMID: 29679071 BACKGROUND

• Jaaskelainen E, Juola P, Hirvonen N, McGrath JJ, Saha S, Isohanni M, Veijola J, Miettunen J. A systematic review and meta-analysis of recovery in schizophrenia. Schizophr Bull. 2013 Nov;39(6):1296-306. doi: 10.1093/schbul/sbs130. Epub 2012 Nov 20.

  PMID: 23172003 BACKGROUND

• Halstead S, Siskind D, Amft M, Wagner E, Yakimov V, Shih-Jung Liu Z, Walder K, Warren N. Alteration patterns of peripheral concentrations of cytokines and associated inflammatory proteins in acute and chronic stages of schizophrenia: a systematic review and network meta-analysis. Lancet Psychiatry. 2023 Apr;10(4):260-271. doi: 10.1016/S2215-0366(23)00025-1. Epub 2023 Feb 27.

  PMID: 36863384 BACKGROUND

• Gysin R, Kraftsik R, Sandell J, Bovet P, Chappuis C, Conus P, Deppen P, Preisig M, Ruiz V, Steullet P, Tosic M, Werge T, Cuenod M, Do KQ. Impaired glutathione synthesis in schizophrenia: convergent genetic and functional evidence. Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16621-6. doi: 10.1073/pnas.0706778104. Epub 2007 Oct 5.

  PMID: 17921251 BACKGROUND

• Gold R, Arnold DL, Bar-Or A, Fox RJ, Kappos L, Mokliatchouk O, Jiang X, Lyons J, Kapadia S, Miller C. Long-term safety and efficacy of dimethyl fumarate for up to 13 years in patients with relapsing-remitting multiple sclerosis: Final ENDORSE study results. Mult Scler. 2022 Apr;28(5):801-816. doi: 10.1177/13524585211037909. Epub 2021 Sep 1.

  PMID: 34465252 BACKGROUND

• Do KQ, Trabesinger AH, Kirsten-Kruger M, Lauer CJ, Dydak U, Hell D, Holsboer F, Boesiger P, Cuenod M. Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. Eur J Neurosci. 2000 Oct;12(10):3721-8. doi: 10.1046/j.1460-9568.2000.00229.x.

  PMID: 11029642 BACKGROUND

• Do KQ, Cabungcal JH, Frank A, Steullet P, Cuenod M. Redox dysregulation, neurodevelopment, and schizophrenia. Curr Opin Neurobiol. 2009 Apr;19(2):220-30. doi: 10.1016/j.conb.2009.05.001. Epub 2009 May 27.

  PMID: 19481443 BACKGROUND

• Burgdorf JS, Christian EP, Sorensen L, Stanton PK, Leaderbrand K, Madsen TM, Khan MA, Kroes RA, Moskal JR. A translational EEG-based approach to assess modulation of long-lasting NMDAR-dependent synaptic plasticity. Psychopharmacology (Berl). 2019 Dec;236(12):3687-3693. doi: 10.1007/s00213-019-05341-w. Epub 2019 Aug 7.

  PMID: 31392357 BACKGROUND

Related Links

• Study reference

MeSH Terms

Conditions

Schizophrenia; Psychotic Disorders; Inflammation

Interventions

diroximel fumarate

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Katherine Beck, Clinical Lecturer

  Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Violeta Perez-Rodriguez, Clinical Research Associate

CONTACT

(+44)07871777185; violeta.perez_rodriguez@kcl.ac.uk

Zeryab Meyer, Clinical Research Associate

CONTACT

zeryab.meyer@kcl.ac.uk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Lecturer and Consultant Psychiatrist

Model Details: Open label for 2 weeks then randomised to placebo or active drug for further 2 weeks

Study Record Dates

• First Submitted: May 2, 2025
• First Posted: May 5, 2025
• Study Start: January 10, 2025
• Primary Completion (Estimated): January 20, 2027
• Study Completion (Estimated): January 20, 2027
• Last Updated: February 13, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

GB (3)