The missing link between clinical endpoints and drug targets in depression.

Identification of the neurochemical processes associated with mood disorders has led to the selection of novel targets for the treatment of depression. Drug screening is consequently performed under the expectation of achieving clinical differentiation. Global disease severity measures such as the Hamilton Depression Rating Scale (HAM-D) are used as endpoints in the assessment of response to new agents. Here we discuss the implications of the limited sensitivity of global scales and of their individual items in discriminating response. Increasing evidence reveals that individual HAM-D items are insensitive to the mechanism of action of existing antidepressant drugs. Furthermore, little distinction can be made between active treatment or placebo. We anticipate that differentiation of novel compounds based on summary clinical scales is therefore unlikely. A mechanism-based approach accounting for the multidimensional nature of symptoms and signs is required. Composite endpoints that reflect the underlying mechanisms of action need to be developed without further ado.