Early Medication Discontinuation and Long-term Clinical Outcome in FEP

Design: This is a follow up or extension to the double-blind randomized placebo-controlled 12-month study (Chen et al., BMJ 2010;341:C4024-4). At any point during the 12-month study, patients who had relapsed or discontinued would stop the study medication (quetiapine or placebo) and that would be the end point of the randomized phase of the study. After completion of the randomized phase, patients will receive clinical guideline-based, open-label treatment. Trained research assistants will approach patients at their upcoming out-patient consultations to introduce the follow-up study and to obtain their written informed consent. Data analysis plan \& handling of missing outcome data: Statistical analyses will be carried out according to the intention-to-treat principle. The primary outcome measure of the long-term clinical outcomes (suicide, clozapine treatment, persistent positive symptoms) between the groups randomized to early treatment discontinuation (placebo) or maintenance treatment (quetiapine) will be compared using risk ratios \[RR\] and 95% confidence intervals \[CI\]. For all patients, long-term outcome assessments will include longitudinal chart review over the follow-up period indicating suicide or clozapine treatment. Positive symptom will be assessed at the 10-year face-to-face interview, or in the situations where this data is not available, will be based on the last positive symptom assessment from the randomized study. We will assess the possible effect of this approach by conducting sensitivity analyses, namely re-classifying patients with missing end-point interviews as either all good outcome, or all poor outcome. A mediation analysis will also carried out to examine whether the effects of the intervention on long-term outcome are linked to relapse during the randomized phase. The secondary outcome measures of social and occupational functioning will be analysed using RR or independent t-tests. Standardized mortality ratios (SMRs) based on age-sex population mortality rate and age-sex suicide rate will also be calculated.