RCT of Methotrexate Added to Treatment As Usual in Schizophrenia

NCT ID: NCT02074319

Last Updated: 2015-09-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 92 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-12-31
• Study Completion Date: 2015-08-31

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.

Detailed Description

The purpose of the study is to test the prediction that addition of methotrexate to treatment as usual (TAU) for patients with schizophrenia will result in following outcomes:

• Primary:

• improvement in negative symptoms
• improvement in positive symptoms
• Secondary:

• improvement in social functioning
• improvement in cognitive functions
• acceptability and tolerability of methotrexate added to TAU A total 72 participants (36 participants in intervention group and 36 in control group) meeting inclusion criteria of the study will be recruited and randomized in study in two arms. Research assistants and participating psychiatrists will assess participants for eligibility criteria. After providing detailed information regarding study by using patient information sheet, written informed consent will be taken from participants. Trained research assistant will asses participants at baseline, 2, 4, 6 and 12 weeks.

Conditions

Schizophrenia; Schizoaffective Disorder; Schizophreniform Disorder

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Placebo

Matching placebo for methotrexate

Group Type: PLACEBO_COMPARATOR

Methotrexate

Intervention Type: DRUG

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

Methotrexate

Methotrexate 10 mg once a week orally

Group Type: EXPERIMENTAL

Methotrexate

Intervention Type: DRUG

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

Interventions

Methotrexate

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

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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.

1. 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.

• 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Abbasi Shaheed Hospital

OTHER

Sponsor Role: collaborator

Dow University of Health Sciences

OTHER

Sponsor Role: collaborator

Karwan e Hayat, Karachi, Pakistan

UNKNOWN

Sponsor Role: collaborator

Institute of Behavioural Sciences, Karachi, Pakistan

UNKNOWN

Sponsor Role: collaborator

Pakistan Institute of Living and Learning

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Prof Imran B Chaudhry, MD

Role: PRINCIPAL_INVESTIGATOR

University of Manchester

Locations

Abasi Shaheed Hospital

Karachi, Sindh, Pakistan

Civil hospital Karachi

Karachi, Sindh, Pakistan

Institute of Behavioural Sciences

Karachi, Sindh, Pakistan

Karwn e Hayat

Karachi, Sindh, Pakistan

Countries

Pakistan

References

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.

Reference Type: BACKGROUND

PMID: 22526685 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19091984 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19589054 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22917959 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15914465 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19837763 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16580814 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 1974941 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16368293 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15639649 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22624729 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21641581 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19579286 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 7978695 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22404766 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18005941 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 1773245 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12359872 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15710474 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18534557 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 14963199 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19884981 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25563714 (View on PubMed)

Related Links

http://pill.org.pk

Website of Pakistan Institute of Learning and Living

Other Identifiers

RECOVERY-001

Identifier Type: -

Identifier Source: org_study_id