As the evidence reviewed in this article emphasizes, it is crucial to redefine the way we understand and define the clinically relevant concepts associated with the therapeutics of depression. The model currently used has focused on weekly evaluation of available pharmacological approaches; such evaluations yield mainly small differences between agents that are known to have limited potential to induce rapid antidepressant actions.
A faster and sustained antidepressant response represents a key challenge in the development of new effective therapeutics for depression and may prevent the deleterious neurobiological and psychosocial effects secondary to recurrent or unremitting depressive episodes. Rapid onset of antidepressant action occurring within hours or days instead of weeks or months can and should be our overall goal. This new paradigm in the therapeutics of depression is expected to include not only the development of novel and improved therapeutics, but also the development of tools that enable us to evaluate antidepressant efficacy within hours or days of first administration; many other areas of medicine such as cardiology, neurology, oncology, and endocrinology currently have the tools necessary to evaluate therapeutic onset quickly and reliably. Furthermore, as our understanding of the genetics of depression expands, this knowledge can be used to inform decisions about which patients are likely to respond to which therapeutic approach. A combination of these three facets—better therapies, better evaluative tools, and better understanding of a patient’s genetic profile—has the power to revolutionize current conceptions and treatments for depression.
Regarding the development of novel therapeutics, it should be pointed out that many substances are capable of inducing transitory euphoria and hyperactivity (also including psychomimetic effects) limited to the half-life of the compound being administered, but these effects cannot be characterized as a true improvement of core depressive symptoms. Thus, agents that result in rapid and sustained antidepressant effects (in core depressive symptoms and constructs) well beyond the half-life of the drug being administered may be considered a key hallmark of new pharmacological treatments potentially able to produce rapid antidepressant actions.
New interventions able to induce rapid antidepressant actions may rapidly restore disrupted neuronal circuitry, thus improving symptoms, functional well-being, and quality of life. Thus, the discovery of novel antidepressants that achieve antidepressant response and remission in a shorter period of time should be a priority in mood disorder research. Clinical and preclinical studies have been performed in this area, searching for genes, signaling pathways, and/or neurochemical circuits that might be involved in these therapeutic effects. Potential targets for future studies in this area may include common targets related to both glutamatergic modulation, neuro-biomolecular basis for sleep, wakefulness, SD, and electrical activity in limbic-cortical circuits (e.g. stimulation of subgenual cingulate white matter with DBS).
In terms of instruments that measure early improvement, present evaluative strategies fall short. For instance, if ratings are only obtained weekly, then early response and identification of key symptoms/clusters predictive of ultimate response—perhaps occurring within hours or days of administration—will be missed. In this context, future study designs evaluating rapid improvement may only require two weeks of duration, which would have the advantage of exposing fewer patients to an experimental compound. Such pilot studies would then inform the design of future ones. These studies will also need to have both a placebo and active comparator arm.
We propose that research on rapid antidepressant actions should occur on two fronts. The first front is to identify specific symptoms or clusters that respond quickly to current antidepressant treatments, and that predict sustained improvement either for all or a subset of patients. Defining such characteristics would help personalize treatment, so that early changes (or conversely, the absence of early changes) could help physicians determine whether patients should remain in a particular trial. Patients could thus avoid trials that are not likely to result in improvement.
The second major focus should be in designing antidepressants that work rapidly within hours or a few days. There is abundant evidence from other areas of medicine that this goal is possible. For example, high blood pressure or blood glucose, pain, or a migraine attack can all be averted within a few hours. In other words, our current expectations regarding antidepressant treatments are too low; instead of assuming that patients will respond within weeks or months, we should expect and be able to measure properly antidepressant treatments that might work within hours or days. Fortunately, much of the ongoing research into antidepressant strategies holds considerable promise. It is our hope that such research will raise the bar for developing the next generation of faster-acting and more effective antidepressants to better treat this devastating illness.