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There is a recognized gap between knowledge derived from 'efficacy' data - based on usually brief randomized controlled trials and findings in natural practice 'effectiveness' studies. In considering the limitations of current antidepressants in clinical practice, we have selected three clinically important issues to examine in a natural practice data base that has been in existence for several years. These relate to: (1) Diagnostic heterogeneity and potential advances using functional brain imaging; (2) Variability of outcome measures during treatment and (3) Time to response and prediction of outcome. Copyright 2001 John Wiley & Sons, Ltd.