Simple tests for antidepressant-like activity, such as 5-HTP-induced syndrome or reserpine-induced hypomotility, are often mechanism-based tests, pharmacologically specific for certain known classes of therapeutically successful antidepressant agents. Many of these behavioural assays have been superseded by neurochemical techniques such as in vivo microdialysis. In contrast to these mechanistic-based models, investigators have also endeavoured to reproduce in the laboratory, factors that are believed to precipitate depression in people. It is a strong assumption in this approach that depression is a response to stress. This strategy profiles the consequences of chronic stress particularly psychosocial stress or early life events, in order to reproduce in animals the behavioural signs and pathologies associated with depression. The advances in the social psychological, clinical pathological and new areas such as neuroimaging research offer the possibility of establishing more sophisticated models for depression in animals with a broader range of biomarkers from the immunological and endocrinological to neurochemical and behavioural. Combining these novel insights with more traditional tests of depression may not only increase our understanding of the neurobiology of depression but also afford more precise and predictive preclinical models of depression. The responsiveness of different strains or genetically modified animals to stress is likely to be a key area of study. Furthermore we must look to individual differences in subjects, even within the same strain, to more fully understand why some individuals show pathological responses to stress whereas others appear unaffected. Conversely in validating our models using currently available treatments we must include the concept of non-responders so as not to disregard models that may extend therapeutic possibilities in these patients.

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