OBJECTIVES: Adjunctive treatments with atypical antipsychotics have demonstrated efficacy in major depressive disorder (MDD) patients that respond insufficiently to conventional antidepressants. As most trial designs have limited duration, simulation allows for extrapolation, to inform on optimal treatment sequences over a longer period. We estimated the life-time health outcomes for augmentation therapies with atypical antipsychotics in MDD patients who fail to respond to conventional antidepressants. METHODS: A discrete event simulation model was built simulating MDD patients between major depressive episodes (MDEs) and remission periods over lifetime based on published data. During MDEs, patients were treated with adjunctive aripiprazole, quetiapine or olanzapine. Patients who did not respond at 6 weeks were switched to subsequent treatment lines. Comparative effectiveness between treatments was imputed using an indirect comparison combining 6-week published studies. Health related quality of life (QoL) data were obtained from published studies. Uncertainty of results was assessed by probabilistic sensitivity analyses (PSA). RESULTS: Over life-time, compared to adjunctive quetiapine and olanzapine, patients starting on adjunctive aripiprazole spent less time in MDEs compared to quetiapine (0.11 years) and olanzapine (0.17 years) and had an improvement of 0.06 and 0.04 quality adjusted life years respectively.  PSA estimated an 88% and 80% probability that aripiprazole improved QoL compared to quetiapine and olanzapine respectively. CONCLUSIONS: This novel DES model is well suited to account for the highly heterogeneous patient population, the deteriorating disease course and the use of different sequential treatment alternatives that is specific to MDD. The results indicate that adjunctive treatment with aripiprazole provides health benefits compared to quetiapine and olanzapine in patients with MDD that fail to respond to conventional antidepressants. With country specific cost-data, this model is also suited to assess the cost-effectiveness of different adjunctive strategies in MDD in different countries.