Add-on Methotrexate for the Treatment of Schizophrenia

OBJECTIVES The objective of the study is to evaluate the efficacy of Methotrexate compared to placebo, as add-on to anti-psychotics in the treatment of patients with schizophrenia or schizoaffective disorder. ENDPOINTS Primary outcome measure: PANSS positive score at the end of the trial. Secondary outcome measures: PANSS total, negative and general psychopathology scales, Clinical Global Impression Scale-Severity (CGI-S) and Global Impression Scale-Improvement (CGI-I), Social Functioning Scale Assessment (PSP) and rates of drop outs before the end of the trial. DESIGN Randomized, add-on to anti-psychotics, double blind, placebo-controlled trial. ASSESSMENTS * Positive and Negative Syndrome Scale (PANSS). PANSS is a 30-item rating scale widely used in assessment of medication effects in schizophrenia. * Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I). CGI-S and CGI-I will be used to assess severity of the illness and global improvement. * The Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale: will be used to assess commonly occurring side effects caused by anti-psychotics. * The methotrexate toxicity checklist includes rash, oral ulceration, nausea and vomiting, diarrhea, new or increasing dyspnea, new or increasing dry cough, severe sore throat, and abnormal bruising. * The Personal and Social Performance (PSP) scale will be used to assess social functioning. PROCEDURE At the screening visit informed consent will be obtained, inclusion and exclusion criteria will be examined, and demographic information will be collected. The PANSS, CGI-S and SCID assessment will be administered, a physical examination will be done, psychiatric and medical history obtained, and blood samples for chemistry and CBC, and urine samples for urinalysis will be taken. Patients will liver function levels higher than normal will be excluded. Females of child-bearing potential will be tested for pregnancy. Patients will be screened for HIV, Hepatitis B and C. At the baseline visit, The PANSS, CGI-S, UKU, and PSP will be administered. Patients will be randomized to start study medication: Methotrexate 10 mg/week or equivalent dose of placebo will be administered to patients. Medication dose will start at 10mg for the first two weeks and will then be increased to 15 mg. Patients will also be instructed to take 5 mg/day of folic acid for 6 days/week in order to avoid vitamin deficiencies due to the methotrexate use. In order to monitor potential side-effects, blood tests for CBC and SMA will be taken at screening, week 2, week 4, week 8, week 12, and week 16 (EOS). Subjects will be assessed at clinic visits according to timelines described above. Additionally, during the weeks in which patients will not come for clinic visits, they will have phone visits in order to monitor medication adherence and adverse events. Throughout all the visits between baseline and end of study, patients will be checked for methotrexate toxicity using the methotrexate toxicity checklist which inquires for includes rash, oral ulceration, nausea and vomiting, diarrhea, new or increasing dyspnea, new or increasing dry cough, severe sore throat, and abnormal bruising. A final, End-of-Study, clinical evaluation will occur on Week 16, or at the time of early discontinuation from the study, and will include a physical examination; vital signs; rating of the PANSS, CGI-S, CGI-I, UKU, PSP, review of adverse events, methotrexate toxicity checklist and concomitant medications. Blood samples will be taken for SMA, CBC, and urine samples for urinalysis. Females of child-bearing potential will be tested for pregnancy, and a blood sample for medication levels will be taken.