OBJECTIVES:  Improvement in outcomes of schizophrenia is challenging to assess in a clinical trial setting. The objective of this study is to draw on the results of the ACTIONS study to highlight the challenges faced while conducting the economic evaluation. METHODS:  The ACTIONS study (n=62), a multicenter, double-blind, randomized, placebo-controlled trial, sought to establish the clinical and cost-effectiveness of augmenting antipsychotic medication with the antidepressant citalopram for the management of negative symptoms in schizophrenia. Patients with schizophrenia on continuing, stable antipsychotic medication with persistent negative symptoms were followed for 12 months. A within-trial economic evaluation was conducted. RESULTS:  The importance of measuring outcomes that are sensitive to changes, and assess productivity loss and carer burden are imminent. While the clinical analysis found trend towards improved outcomes in terms of avolition/amotivation, there was no evidence of improvement either in the EQ-5D-3L or ICECAP-A measures. This questions if these measures are able to capture additional changes in the negative symptoms alongside the improvement in positive symptoms. After adjusting for baseline differences, there was no statistically significant difference between arms in any cost category, except non-mental health inpatient costs but was this due to the infrequent occurrence of non-mental health hospital use. Costing brought up issues of potential selection imbalance at randomization and representativeness in terms of employment, substance abuse, and residency in psychiatric institutions. CONCLUSIONS:  Small sample size, randomization imbalance respective of health economic factors, lack of adherence to medications and doctor visits, and loss-to-follow-up due to changing residency status of the patients pose additional challenges of assessing the outcomes and costs of schizophrenia patients for economic evaluation. Future clinical studies in schizophrenia should consider including employment, substance abuse, and current residential status in the study inclusion/exclusion criteria in order to reduce variability in the costs.