The design of new antidepressants: can formal models help? A first attempt using a model of the hippocampal control over the HPA-axis based on a review from the literature.

Research in the field of depression and antidepressants is hampered by the lack of relevant endpoints. The two most promising targets in this area are hypothalamus-pituitary-adrenal axis dysfunction and defects in hippocampal function. However, there is no available model aimed at providing a relevant description of the relationship of these two endpoints and of their relevance for major depression. Formal models have been used to model biological functions, but few applications have been developed in the field of biological psychiatry and psychopharmacology. Here, we use formal models to integrate the hippocampal and the hypothalamus-pituitary-adrenal dysfunctions in relationship to major depression and antidepressant action. Even if our proposal is an oversimplification, this model generates predictions for the discovery of new pharmacological targets that might be helpful in designing treatments for the future.