Need for a new paradigm for the clinical trials of antidepressants

The current clinical trials model for antidepressants (AD) was developed in the 1960s. It views major depression as a unitary disorder, and "antidepressants" as having illness-specific therapeutic actions. The established efficacy measures are the Hamilton symptom rating scale and the CGI, which provide summary measures of improvement. In contrast, the DSM IV defines depression as heterogeneous, with such broad classes as unipolar and bipolar showing different response to treatments. Research further indicates depression to be comprised of major affective and behavioral components which vary in intensity across patients, and the tricyclic ADs to have multiple actions that affect various components sequentially. "New" ADs, products of rapid advancements in the neurosciences, are more precise in their actions on brain monoamine systems, targeted to affect behaviors with greater specificity. A new trials model sensitive to the varied behavioral effects needs to be developed to adapt to these quicker acting, targeted antidepressants. A componential model is recommended that employs an array of behavioral methods, and subtype classification and statistical approaches to estimate onset and sequence of multiple drug actions. The NIMH can intervene to accelerate improvements by initiating funding programs to implement more effective clinical methods and models.