Elaboration of the New Theory of Depression and Conclusions

Abstract

To find better treatments for major depression we have to (1) advance knowledge about the psychopathologic structure of the depressive disorders and (2) resolve how the array of different established drugs bring about therapeutic effects. Failure to move forward on these issues has stalled drug development resulting in the failure to introduce new classes of ADs since the SSRIs. The findings and novel concepts reported include: (1) the “opposed neurobehavioral states” hypothesis, a theory about the nature of depression that better explains the psychological experience, its multifaceted quality, and its basis at the neurobehavioral level. Questioning whether the current concept of “depression” adequately represents the disorder’s complexity and turmoil-like quality, (2) presents a new model for clinical research and trials more appropriate to the revised concept of depression, (3) summarizes results from two multidisciplinary projects structured in accord with the new model, showing earlier basic assumptions about specificity and timing of drug clinical actions to be false, (4) by applying the alternative model new, more refined data on the nature, onset and sequence of drug-induced behavioral actions is generated. It indicated that the various AD classes induce different behavioral changes and that efficacy can be achieved through several different behavioral pathways, facilitating novel approaches to drug development. At the practical level, the clinician will now be able to more judiciously select the appropriate treatment, and predict, from the patient’s behavioral reactivity in the first 2 weeks, the clinical response at outcome.