Background: The aim of this study was to compare the antidepressant efficacy of standard dose, dose optimization of antidepressant drug and buspirone augmentation strategies. Methods: 120 outpatients with a DSM-IV diagnosis of unipolar depression were randomised to 12-weeks of open label treatment with fluoxetine 20 (flx(20)) or 40 mg (flx(40)) daily or fluoxetine 20 mg plus buspirone 20 mg daily (flx(20)-plus-buspirone). The severity of depression was assessed by Hamilton Depression Rating Scale (HDRS). Response was defined as a 50% or greater reduction of the baseline HDRS total score. A response, which began at any time of the Study and was maintained until the last visit, was defined as a Sustained response. Results: The proportion of responders was not significantly different among the treatment groups at the endpoint. Survival analysis showed, however, a significant faster response in the patients treated with flx(20) or flx(40) alone than flx(20)-plus-buspirone. The mean times to onset of a sustained response were 33, 24 and 40 days, respectively. Limitations: The lack of treatment-resistant group is a methodological limitation of this study. Conclusions: Adding buspirone to fluoxetine in the treatment of major depressive disorder may delay the time to onset of antidepressant efficacy. In order to accelerate and maximise the clinical response in depressive patients, clinician should prefer to optimize the fluoxetine dose instead of in combination with buspirone. (C) 2003 Published by Elsevier B.V.