Rethinking depression and the actions of antidepressants: Uncovering the links between the neural and behavioral elements

Despite major strides in the understanding of mechanisms of antidepressant drug action, few, if any, widely applicable drug treatments with new mechanisms have been developed since the selective serotonin reuptake inhibitors in the late 1970's. One factor that may contribute to this lack of advance is reliance on a set of flawed assumptions that have guided most new drug development over the past quarter century. These assumptions have been particularly deleterious to the development of treatments with mechanisms distinctly different from currently approved treatments. One such assumption is that antidepressant actions on clinical aspects are delayed for several weeks. We review the results of studies on time to improvement and describe two collaborative, multidisciplinary studies during this period which employed a behavioral component model for assessment of change, as an alternative to the conventional "diagnostic-specific" research model. These studies incorporated a novel neurobehavioral framework for describing depressive episodes. The studies indicated that (1) depressive states are comprised of relatively independent and somewhat opposed behavioral and emotional components of anxiety-agitation and depression-retardation, coexisting with a third dimension, hostility, all of which might indicate some degree of mixed state phenomenology, (2) drugs selectively targeted at serotonergic and noradrenergic systems have differing profiles of impact on the behavioral dimensions of depressive states and (3) the sequence of behavioral improvements initiated by pharmacodynamically different drugs also differ. In the aggregate these consistent observations provide the basis for a new paradigm on the nature of major depression. The proposition links drug-induced neural and behavioral changes of antidepressants with prediction of clinical outcome based on early response. We submit that the proposed approach may bring about a new paradigm for improving behavioral technology and design of studies capable of identifying drugs with novel properties and rapid onset of improvement, while avoiding some problematic constructs in past biological research on depression.