Leveraging Neuroplasticity to Enhance Adaptive Learning: The Potential for Synergistic Somatic-Behavioral Treatment Combinations to Improve Clinical Outcomes in Depression

Until recently, therapeutic development in psychiatry was targeted solely toward symptom reduction. While this is a worthwhile goal, it has yielded little progress in improved therapeutics in the last several decades in the field of mood disorders. Recent advancements in our understanding of pathophysiology suggests that an impairment of neuro-plasticity may be a critical part of the development of neuropsychiatric disorders. Interventions that enhance or modulate neuroplasticity often reduce depressive symptoms when applied as stand-alone treatments. Unfortunately, when treatments are discontinued, the disease state often returns as patients relapse. However, treatments that enhance or modulate plasticity not only reduce symptom burden, but also may provide an opportune window wherein cognitive or behavioral interventions could be introduced to harness a state of enhanced neuroplasticity and lead to improved longer-term clinical outcomes. Here, we review the potential of synergistically combining plasticity-enhancing and behavioral therapies to develop novel translational treatment approaches for depression. After reviewing relevant neuroplasticity deficits in depression, we survey biological treatments that appear to reverse such deficits in humans, including N-methyl-D-aspartate receptor modulators (ketamine, D-cycloserine), electroconvulsive therapy, and transcranial brain stimulation. We then review evidence that either directly or indirectly supports the hypothesis that a robust enhancement of neuroplasticity through these methods might promote the uptake of cognitive and behavioral interventions to enhance longer-term treatment outcomes through a synergistic effect. We identify key missing pieces of evidence and discuss future directions to enhance this emerging line of research.