Modulating Neuroplasticity: Lessons Learned from Antidepressants and Emerging Novel Therapeutics

Purpose of review: Antidepressants share a common mechanism of action downstream of pharmacological drug targets. Rapid-acting antidepressants, such as ketamine, have highlighted the immense clinical potential of directly targeting neurotrophic signalling pathways. In turn, these neurotrophic mechanisms effectively reverse the deleterious effects of stress and other factors implicated in the aetiology of mood disorders at the cellular level. Treatments that target synaptic plasticity can restore functional synaptic connections in stress-sensitive neural circuits to improve mood regulation and cognitive function. Here, we describe the neurotrophic mechanisms of antidepressants and describe current and novel treatment modalities that can restore neural circuit function by directly engaging neuroplasticity. Recent findings: The discovery of ketamine as a rapid modulator of synaptic plasticity with associated therapeutic actions for major depressive disorder and other psychiatric disorders has accelerated interest in the potential surrounding the direct targeting of neurotrophic pathways. Targets to the glutamatergic system currently seem to be the most promising area of novel drug discovery and development. Other systems such as the cholinergic and inflammatory systems are gaining traction as well. While cellular and animal studies have provided exquisite insights into the molecular mechanisms that influence plasticity, ongoing work demonstrating the therapeutic impact of targeting these mechanisms with neuromodulation, pharmacological, and/or behavioural interventions in human subjects is needed. Summary: Targeting the neurobiological mechanisms that regulate neuroplasticity will be of relevance to a range of neurological and neuropsychiatric disorders beyond depression. However, the factors responsible for disrupting synaptic integrity across the disorders will vary. Consequently, the treatments targeting plasticity need to be optimally aligned to the specific pathophysiological context of the illness, which can vary even within a specific diagnostic category. © 2021, The Author(s), under exclusive licence to Springer Nature Switzerland AG.