A Placebo-controlled Trial of Folate with B12 in Patients with Schizophrenia with Residual Symptoms in Ethiopia Using a Sequential Parallel Comparison Design

Abstract

Background: Approximately 30% of patients with schizophrenia suffer from treatment-resistant psychotic symptoms, which can produce substantial distress, result in hospitalization and disrupt school or work functioning. Studies have found low blood folate concentrations in psychiatric populations and recent reports have consistently linked schizophrenia to low folate levels. We aim to examine the efficacy of a four-month trial of folate with B12 supplementation for reducing symptoms of schizophrenia. Methods: This study is a randomized, sequential parallel comparison design (SPCD) for double-blind phase fixed dose, 4-month trial of folate plus B12 as add-on therapy to reduce symptoms of schizophrenia. Participants will be adults (ages 18 to 65 years) diagnosed with schizophrenia, any subtype, who are psychiatrically and medically stable, but have residual positive or negative symptoms of moderate or greater intensity, despite antipsychotic treatment. The study is divided into 2 double-blind phases of 56 days each. Two hundred total participants will be randomized to adjunctive treatment with either folate with vitamin B12 (n=50) or placebo (n=150), with a 2:3:3 ratio for random assignment to the treatment sequences drug/drug (DD; n=50), placebo/placebo (PP; n=75), and placebo/drug (PD; n=75), while all continue to receive their current antipsychotic agent for the duration of the study. Diagnosis will be established using the Structured Clinical Interview for DSM-IV for clinical trials (SCID-CT). The primary outcome measure will be change in symptom severity measured by the change from baseline in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measures will include change in severity of psychotic symptoms as measured by the PANSS psychosis subscale score; and change in severity of negative symptoms as measured by the modified Scale for Assessment of Negative Symptoms (SANS) total score. Key assessments for primary and secondary outcomes will be conducted at baseline, week 8, and week 16. Trial Registration: Clinicaltrials.gov identifier: NCT01724476.