AMPA Receptor Potentiators as Potential Rapid-Acting Antidepressants

Major depressive disorder (MDD) is the leading cause of disability worldwide and contributes importantly to the global burden of morbidity according to reports from the World Health Organization. Several types of antidepressant medications are used to treat moderate and severe depressive disorders although weeks or even months are required to produce clinical improvement. However, an estimated one third of the patients have inappropriate responses or no response at all to treatment. Hence, finding new, more efficient and rapid-acting antidepressant therapies is urgently needed. The discovery that ketamine produced rapid and sustained antidepressant effects has been the major breakthrough in the field of pharmacotherapy for MDD. Interestingly, studies with rodents have shown that the antidepressant-like effects of ketamine are dependent on the activation of AMPA receptors (AMPARs) because its behavioral action is blocked by AMPAR antagonists. Moreover, the removal of specific AMPAR subunits from birth results in behavioral and neurochemical characteristics relevant to depression. Taken together, these findings suggest that the stimulation of AMPARs may be a useful approach to treat MDD. Preclinical studies have reported that positive allosteric modulators (PAMs) – also known as ampakines or AMPAR potentiators – manifest antidepressant-like effects. These molecules bind allosterically to AMPARs and prolong the duration of AMPAR-mediated responses, theoretically without an overstimulation of excitatory transmission. In this chapter, we will review the most important preclinical data to date on the antidepressant-like effects of AMPA potentiators discussing their potential use as therapeutic tool in the clinic.