RCT of Methotrexate Added to Treatment As Usual in Schizophrenia

Schizophrenia Clinical Trial

— RECOVERY  

Official title:

A Randomised Double Blind Placebo Controlled 12 Week Trial of Methotrexate Added to Treatment As Usual in Early Schizophrenia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02074319
• Other study ID #: RECOVERY-001
• Status: Completed
• Phase: Phase 1
• First received: February 26, 2014
• Last updated: September 19, 2015
• Start date: December 2013
• Est. completion date: August 2015

Study information

• Verified date: September 2015
• Source: Pakistan Institute of Learning and Living
• Contact: n/a
• Is FDA regulated: No
• Health authority: Dow University of Health Sciences: Pakistan
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 92
• Est. completion date: August 2015
• Est. primary completion date: July 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 35 Years

Eligibility

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.

Exclusion Criteria:

• Violation of any inclusion criteria

• 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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Disease
• Psychotic Disorders
• Schizoaffective Disorder
• Schizophrenia
• Schizophreniform Disorder

Intervention

Drug:
• Methotrexate
Treatment as usual or standard treatment for psychosis will be common in all arms

Locations

Country	Name	City	State
Pakistan	Abasi Shaheed Hospital	Karachi	Sindh
Pakistan	Civil hospital Karachi	Karachi	Sindh
Pakistan	Institute of Behavioural Sciences	Karachi	Sindh
Pakistan	Karwn e Hayat	Karachi	Sindh

Sponsors (5)

Lead Sponsor	Collaborator
Pakistan Institute of Learning and Living	Abbasi Shaheed Hospital, Dow University of Health Sciences, Institute of Behavioural Sciences, Karachi, Pakistan, Karwan e Hayat, Karachi, Pakistan

Country where clinical trial is conducted

Pakistan, 

References & Publications (22)

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Busse S, Busse M, Schiltz K, Bielau H, Gos T, Brisch R, Mawrin C, Schmitt A, Jordan W, Müller 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. — View Citation

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. — View Citation

Cronstein BN. Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis. Pharmacol Rev. 2005 Jun;57(2):163-72. Review. — View Citation

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. — View Citation

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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. — View Citation

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. Review. — View Citation

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. — View Citation

Monji A, Kato T, Kanba S. Cytokines and schizophrenia: Microglia hypothesis of schizophrenia. Psychiatry Clin Neurosci. 2009 Jun;63(3):257-65. Review. — View Citation

Morgan SL, Baggott JE, Vaughn WH, Austin JS, Veitch TA, Lee JY, Koopman WJ, Krumdieck CL, Alarcón 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. — View Citation

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. Review. — View Citation

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. Epub 2007 Nov 19. — View Citation

Procter A. Enhancement of recovery from psychiatric illness by methylfolate. Br J Psychiatry. 1991 Aug;159:271-2. — View Citation

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. Epub 2002 Oct 1. — View Citation

Schulte-Herbrüggen 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. Epub 2004 Dec 22. — View Citation

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. — View Citation

Whittle SL, Hughes RA. Folate supplementation and methotrexate treatment in rheumatoid arthritis: a review. Rheumatology (Oxford). 2004 Mar;43(3):267-71. Epub 2004 Jan 6. Review. — View Citation

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. — View Citation

* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Social Functioning Scale	Self-rating questionnaire assessing social functioning in 7 domains.	3 months	No
Primary	Positive and Negative Syndrome Scale PANSS	PANSS is an assessment measures to assess severity of symptoms of schizophrenia	3 months	No
Secondary	CogState	Measuring all seven domains recommended by MATRICS (NIMH initiative). These domains include speed processing, attention/vigilance, Working memory (nonverbal & verbal), verbal learning, visual learning, reasoning and problem solving and social cognitions.	3 months	No

External Links

•   Website of Pakistan Institute of Learning and Living