Novel Antidepressant Approaches for Refractory Depression

Abstract

Although monoaminergic antidepressants are effective for some depressed patients, at least a third remain treatment refractory even after multiple treatment trials. Investigation into novel antidepressant approaches targeted to specific mechanisms implicated in the pathophysiology of treatment-resistant depression (TRD) has significant potential to improve treatment response rates. This review highlights emerging novel antidepressant approaches for TRD, bridging neuromodulation and novel pharmacotherapeutics. We discuss how these new approaches target depression neurobiology via modulation of neurotrophic factors, cellular metabolic machinery, neurotransmitter systems, and inflammatory activity. Since a significant number of depressed patients do not respond to classic monoaminergic-based antidepressants, research focus has shifted to novel approaches that have been providing promising results in TRD. Recent studies detail plenty of new technologies in the field of electrical stimulation, antidepressant medications, and novel mechanisms that are hypothesized to provide antidepressant effects through modulating neurobiological pathways implicated in the neurocircuitry of depression. Some factors known to impair therapeutic efficacy of current front-line treatments include circadian disruption, inflammation, and metabolic disturbances. Dysregulation of these systems can be readily identified using peripheral markers, implying that biologically directed treatment stratification is possible. However, more work is needed to understand how to best align such biomarkers with emerging novel treatments. Nevertheless, this represents an exciting time in the development of novel treatment approaches for psychiatry. Understanding the neurobiology of novel therapies that have demonstrated potential antidepressant efficacy is a key factor for research in TRD. Improved alignment of these emerging novel treatments with the pathophysiological targets on which they act will move us a step closer to precision medicine approaches for psychiatry, which in turn, is likely to close the current “response failure” gap and overall levels of TRD.