Background: Conventional antidepressants are thought to produce their impact on clinical symptoms
by increasing the central availability of biogenic amine neurotransmitters (the monoamine hypothesis of depression).
These drugs continue to be the primary medicines used in major depressive disorder. Although they have
biological effects after acute dosing, full antidepressant response generally takes weeks of daily administration.
Lack of rapid onset is a large limitation in antidepressant therapy (e.g., suicide, lack of medication compliance,
difficulty switching medications).
Methods: The present review of the literature discusses the preclinical and clinical findings on compounds that
can produce immediate symptom relief.
Results: These compounds include ketamine, scopolamine, and mechanistically-related drugs. Newer additions to
the list of potential rapid-acting agents include antagonists of metabotropic (mGlu) 2/3 receptors, negative allosteric
modulators of α5-containing GABAA receptors, and psychedelic compounds. An additional benefit of these
compounds is that they have demonstrated large effect sizes and, importantly, demonstrated efficacy in patient’s
refractory to other treatments. A drawback of some of these compounds, to date, is finding ways to expand the
duration of clinical efficacy. In addition, for some compounds, the side-effect profile requires management. A
primary mechanism by which rapid effects might be produced is through the amplification of excitatory neurotransmission
through activation of AMPA receptors. The extracellular efflux of glutamate induced by these drugs
has been documented and provides the hypothesized triggering mechanism for AMPA receptor amplification.
Conclusion: The preclinical and clinical literature strongly suggests that rapid-acting antidepressants are the
current focus of antidepressant drug discovery. Promising clinical findings exist for several compounds including
ketamine and other NMDA receptor antagonists, scopolamine, and psilocybin. Two compounds are in late stage
clinical development: GLYX-13 (Rapastinel) and eskekamine.