RCT of Methotrexate Added to Treatment As Usual in Schizophrenia

NCT02074319 | Completed Phase 1

• 1 other identifier: RECOVERY-001
• Study Type: interventional
• Target: 92
• Locations: 1 country
• Sites: 4

Brief Summary

The aim of the this study is to evaluate the effectiveness of methotrexate added to treatment as usual on positive and negative symptoms, cognitive and social functioning and quality of life of patients suffering from schizophrenia.

Conditions

Schizophrenia; Schizoaffective Disorder; Schizophreniform Disorder

Keywords

Schizophrenia; Anti-Inflammatory; Methotrexate; Psychosis Not Otherwise Specified

Outcome Measures

Primary Outcomes (1)

• Positive and Negative Syndrome Scale PANSS

  PANSS is an assessment measures to assess severity of symptoms of schizophrenia

  3 months

Secondary Outcomes (1)

• CogState

  3 months

Other Outcomes (1)

• Social Functioning Scale

  3 months

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Matching placebo for methotrexate

Drug: Methotrexate

Methotrexate

EXPERIMENTAL

Methotrexate 10 mg once a week orally

Drug: Methotrexate

Interventions

Methotrexate DRUG

Treatment as usual or standard treatment for psychosis will be common in all arms

Methotrexate; Placebo

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Signed informed consent, indicating that the subject understood the purpose of and procedures required for the study, before the initiation of any study specific procedures
• Aged 18 to 35 years
• Diagnostic and Statistical Manual-IV (DSM-IV) diagnosed first episode psychosis, schizophrenia, schizoaffective disorder, psychosis not otherwise specified or schizophreniform disorder.
• First episode (within first 5 years of diagnosis)
• Competent and willing to give informed consent
• Medication remained stable 4 weeks prior to baseline.
• Able to take oral medication and likely to complete the required evaluations.
• Female participants of child bearing capability must be willing to use adequate contraceptives for the duration of the study, and, willing to have a pregnancy test pre treatment and at ten weekly intervals while on study medication.
• Adequate contraception is defined as use of contraceptive double barrier system (i.e. condom and spermicide) or contraceptive implant, oral contraceptive or injected depot contraceptive plus other form of contraceptive i.e. condom. Females will be considered incapable of child bearing if they are one year post-menopausal or irreversibly surgically sterilised.

You may not qualify if:

• Failure to perform screening or baseline examinations
• Relevant ICD 10 organic brain disease or neurological diagnoses
• Patients with liver disease
• Patients who will meet the criteria for a DSM-IV TR diagnosis of alcohol or substance abuse (other than for nicotine) within the last month or the criteria for DSM-IV TR alcohol or substance dependence (other than for nicotine) within the last 6 months
• Any change of psychotropic medications within the previous 4 weeks
• Recreational drugs or alcohol abuse
• Pregnant or lactating women and those of reproductive age without adequate contraception
• Relevant medical illness will be determined in the first instance by asking the patients mental health care team if the patient has any medical condition/problems. After consent has been obtained the research nurse/ research doctor will then have access to the patients' notes and will assess patient eligibility to take part in the clinical trial by scrutinising the patients' past medical history, most recent blood results, electrocardiograms, as well as any physical tests that have been performed on the patient.

Sponsors & Collaborators

• Pakistan Institute of Living and Learning: lead
• Abbasi Shaheed Hospital: collaborator
• Dow University of Health Sciences: collaborator
• Karwan e Hayat, Karachi, Pakistan: collaborator
• Institute of Behavioural Sciences, Karachi, Pakistan: collaborator

Study Sites (4)

Abasi Shaheed Hospital

Karachi, Sindh, 72000, Pakistan

Location

Civil hospital Karachi

Karachi, Sindh, 72000, Pakistan

Location

Institute of Behavioural Sciences

Karachi, Sindh, 72000, Pakistan

Location

Karwn e Hayat

Karachi, Sindh, 72000, Pakistan

Location

Related Publications (23)

• Chaudhry IB, Hallak J, Husain N, Minhas F, Stirling J, Richardson P, Dursun S, Dunn G, Deakin B. Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment. J Psychopharmacol. 2012 Sep;26(9):1185-93. doi: 10.1177/0269881112444941. Epub 2012 Apr 23.

  PMID: 22526685 BACKGROUND

• Behrens MM, Ali SS, Dugan LL. Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia. J Neurosci. 2008 Dec 17;28(51):13957-66. doi: 10.1523/JNEUROSCI.4457-08.2008.

  PMID: 19091984 BACKGROUND

• Bernstein HG, Steiner J, Bogerts B. Glial cells in schizophrenia: pathophysiological significance and possible consequences for therapy. Expert Rev Neurother. 2009 Jul;9(7):1059-71. doi: 10.1586/ern.09.59.

  PMID: 19589054 BACKGROUND

• Busse S, Busse M, Schiltz K, Bielau H, Gos T, Brisch R, Mawrin C, Schmitt A, Jordan W, Muller UJ, Bernstein HG, Bogerts B, Steiner J. Different distribution patterns of lymphocytes and microglia in the hippocampus of patients with residual versus paranoid schizophrenia: further evidence for disease course-related immune alterations? Brain Behav Immun. 2012 Nov;26(8):1273-9. doi: 10.1016/j.bbi.2012.08.005. Epub 2012 Aug 14.

  PMID: 22917959 BACKGROUND

• Cronstein BN. Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis. Pharmacol Rev. 2005 Jun;57(2):163-72. doi: 10.1124/pr.57.2.3.

  PMID: 15914465 BACKGROUND

• Doorduin J, de Vries EF, Willemsen AT, de Groot JC, Dierckx RA, Klein HC. Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nucl Med. 2009 Nov;50(11):1801-7. doi: 10.2967/jnumed.109.066647. Epub 2009 Oct 16.

  PMID: 19837763 BACKGROUND

• Drzyzga L, Obuchowicz E, Marcinowska A, Herman ZS. Cytokines in schizophrenia and the effects of antipsychotic drugs. Brain Behav Immun. 2006 Nov;20(6):532-45. doi: 10.1016/j.bbi.2006.02.002. Epub 2006 Apr 3.

  PMID: 16580814 BACKGROUND

• Godfrey PS, Toone BK, Carney MW, Flynn TG, Bottiglieri T, Laundy M, Chanarin I, Reynolds EH. Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990 Aug 18;336(8712):392-5. doi: 10.1016/0140-6736(90)91942-4.

  PMID: 1974941 BACKGROUND

• Gong K, Zhang Z, Sun X, Zhang X, Li A, Yan J, Luo Q, Gao Y, Feng Y. The nonspecific anti-inflammatory therapy with methotrexate for patients with chronic heart failure. Am Heart J. 2006 Jan;151(1):62-8. doi: 10.1016/j.ahj.2005.02.040.

  PMID: 16368293 BACKGROUND

• Johnston A, Gudjonsson JE, Sigmundsdottir H, Ludviksson BR, Valdimarsson H. The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules. Clin Immunol. 2005 Feb;114(2):154-63. doi: 10.1016/j.clim.2004.09.001.

  PMID: 15639649 BACKGROUND

• Mansur RB, Zugman A, Asevedo EM, da Cunha GR, Bressan RA, Brietzke E. Cytokines in schizophrenia: possible role of anti-inflammatory medications in clinical and preclinical stages. Psychiatry Clin Neurosci. 2012 Jun;66(4):247-60. doi: 10.1111/j.1440-1819.2012.02354.x.

  PMID: 22624729 BACKGROUND

• Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011 Oct 1;70(7):663-71. doi: 10.1016/j.biopsych.2011.04.013. Epub 2011 Jun 8.

  PMID: 21641581 BACKGROUND

• Monji A, Kato T, Kanba S. Cytokines and schizophrenia: Microglia hypothesis of schizophrenia. Psychiatry Clin Neurosci. 2009 Jun;63(3):257-65. doi: 10.1111/j.1440-1819.2009.01945.x.

  PMID: 19579286 BACKGROUND

• Morgan SL, Baggott JE, Vaughn WH, Austin JS, Veitch TA, Lee JY, Koopman WJ, Krumdieck CL, Alarcon GS. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann Intern Med. 1994 Dec 1;121(11):833-41. doi: 10.7326/0003-4819-121-11-199412010-00002.

  PMID: 7978695 BACKGROUND

• Myint AM. Kynurenines: from the perspective of major psychiatric disorders. FEBS J. 2012 Apr;279(8):1375-85. doi: 10.1111/j.1742-4658.2012.08551.x. Epub 2012 Mar 27.

  PMID: 22404766 BACKGROUND

• Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry. 2008 Apr 15;63(8):801-8. doi: 10.1016/j.biopsych.2007.09.024. Epub 2007 Nov 19.

  PMID: 18005941 BACKGROUND

• Procter A. Enhancement of recovery from psychiatric illness by methylfolate. Br J Psychiatry. 1991 Aug;159:271-2. doi: 10.1192/bjp.159.2.271.

  PMID: 1773245 BACKGROUND

• Rajagopalan PT, Zhang Z, McCourt L, Dwyer M, Benkovic SJ, Hammes GG. Interaction of dihydrofolate reductase with methotrexate: ensemble and single-molecule kinetics. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13481-6. doi: 10.1073/pnas.172501499. Epub 2002 Oct 1.

  PMID: 12359872 BACKGROUND

• Schulte-Herbruggen O, Nassenstein C, Lommatzsch M, Quarcoo D, Renz H, Braun A. Tumor necrosis factor-alpha and interleukin-6 regulate secretion of brain-derived neurotrophic factor in human monocytes. J Neuroimmunol. 2005 Mar;160(1-2):204-9. doi: 10.1016/j.jneuroim.2004.10.026. Epub 2004 Dec 22.

  PMID: 15710474 BACKGROUND

• van Berckel BN, Bossong MG, Boellaard R, Kloet R, Schuitemaker A, Caspers E, Luurtsema G, Windhorst AD, Cahn W, Lammertsma AA, Kahn RS. Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. Biol Psychiatry. 2008 Nov 1;64(9):820-2. doi: 10.1016/j.biopsych.2008.04.025. Epub 2008 Jun 4.

  PMID: 18534557 BACKGROUND

• Whittle SL, Hughes RA. Folate supplementation and methotrexate treatment in rheumatoid arthritis: a review. Rheumatology (Oxford). 2004 Mar;43(3):267-71. doi: 10.1093/rheumatology/keh088. Epub 2004 Jan 6.

  PMID: 14963199 BACKGROUND

• Zhang Z, Zhao P, Li A, Lv X, Gao Y, Sun H, Ding Y, Liu J. Effects of methotrexate on plasma cytokines and cardiac remodeling and function in postmyocarditis rats. Mediators Inflamm. 2009;2009:389720. doi: 10.1155/2009/389720. Epub 2009 Oct 26.

  PMID: 19884981 BACKGROUND

• Chaudhry IB, Husain N, ur Rahman R, Husain MO, Hamirani MM, Kazmi A, Baig S, Haddad PM, Buch MH, Qureshi I, Mehmood N, Kiran T, Fu B, Afsar S, Deakin B. A randomised double-blind placebo-controlled 12- week feasibility trial of methotrexate added to treatment as usual in early schizophrenia: study protocol for a randomised controlled trial. Trials. 2015 Jan 7;16:9. doi: 10.1186/1745-6215-16-9.

  PMID: 25563714 DERIVED

Related Links

• Website of Pakistan Institute of Learning and Living

MeSH Terms

Conditions

Schizophrenia; Psychotic Disorders

Interventions

Methotrexate

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Prof Imran B Chaudhry, MD

  University of Manchester

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 26, 2014
• First Posted: February 28, 2014
• Study Start: December 1, 2013
• Primary Completion: July 1, 2015
• Study Completion: August 1, 2015
• Last Updated: September 22, 2015

Record last verified: 2015-09

Locations

PA (4)