title: 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.
abstract: BACKGROUND
  Methotrexate is a commonly used anti-inflammatory and immunosuppressive drug. There is growing evidence that inflammatory processes are involved in the pathogenesis of schizophrenia. In our recent randomised double-blind placebo-controlled clinical trial in Pakistan and Brazil, the addition of minocycline (antibiotic and anti-inflammatory drug) for 1 year to treatment as usual reduced negative symptoms and improved some cognitive measures. A meta-analysis of cytokine changes in the peripheral blood has identified IL-2, IFN-gamma, TNF-alpha and soluble IL-2 receptor as trait markers of schizophrenia because their levels were elevated during acute exacerbations and reduced in remission. This suggests immune activation and an inflammatory syndrome in schizophrenia. Based on the evidence of the strong anti-inflammatory properties of methotrexate, we propose that low-dose methotrexate may be an effective therapy in early schizophrenia.
  
  
  METHODS
  This is a double-blind placebo-controlled study of methotrexate added to treatment as usual for patients suffering from schizophrenia, schizoaffective disorder, psychosis not otherwise specified or schizophreniform disorder. This will be with 72 patients, 36 in each arm over 3 months. There will be screening, randomisation and follow-up visits. Full clinical assessments will be carried out at baseline, 2, 4, 8 and 12 weeks. Social and cognitive assessments will be carried out at baseline and 12 weeks. Methotrexate will be given at a dose of 10 mgs orally once a week for a 3-month period.
  
  
  CONCLUSIONS
  Evidence suggests inflammatory processes are involved in the pathogenesis of schizophrenia and anti-inflammatory treatments have shown to have some beneficial effects. Methotrexate is a known immunosuppressant and anti-inflammatory drug. The aim of this study is to establish the degree of improvement in positive and negative symptoms, as well as cognitive functioning with the addition of methotrexate to treatment as usual.ClinicalTrials.gov identifier: NCT02074319 (24 February 2014).
authors.affiliation: University of Manchester & Lancashire Care Early Intervention Service, Manchester, UK. ibchaudhry@btinternet.com.
authors.forename: Imran B
authors.initials: IB
authors.lastname: Chaudhry
authors.forename: Nusrat
authors.initials: N
authors.lastname: Husain
authors.forename: Raza
authors.initials: R
authors.lastname: ur Rahman
authors.forename: Mohammed Omair
authors.initials: MO
authors.lastname: Husain
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Hamirani
authors.forename: Ajmal
authors.initials: A
authors.lastname: Kazmi
authors.forename: Shakeel
authors.initials: S
authors.lastname: Baig
authors.forename: Peter M
authors.initials: PM
authors.lastname: Haddad
authors.forename: Maya H
authors.initials: MH
authors.lastname: Buch
authors.forename: Inti
authors.initials: I
authors.lastname: Qureshi
authors.forename: Nasir
authors.initials: N
authors.lastname: Mehmood
authors.forename: Tayyeba
authors.initials: T
authors.lastname: Kiran
authors.forename: Bo
authors.initials: B
authors.lastname: Fu
authors.forename: Salahuddin
authors.initials: S
authors.lastname: Afsar
authors.forename: Bill
authors.initials: B
authors.lastname: Deakin
mesh_terms: D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D002985:Clinical Protocols; D004311:Double-Blind Method; D005240:Feasibility Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008727:Methotrexate / Q000627:therapeutic use*; D010154:Pakistan; D011569:Psychiatric Status Rating Scales; D012107:Research Design; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D014150:Antipsychotic Agents; D007166:Immunosuppressive Agents; D008727:Methotrexate