Rapid-Acting Antidepressants

Conventional antidepressants for major depression, which work by increasing monoamine neurotransmitters, can take weeks to produce a full response, a major limitation. This review describes compounds that provide immediate symptom relief, including ketamine, scopolamine, and newer agents like mGlu2/3 receptor antagonists, negative allosteric modulators of α5-containing GABAA receptors, and psychedelics. These rapid-acting drugs show large effect sizes and efficacy in treatment-resistant patients, though some have challenges with duration of effect and side effects. The proposed mechanism involves amplifying excitatory neurotransmission via AMPA receptors, triggered by increased glutamate efflux. Two compounds, GLYX-13 (Rapastinel) and esketamine, are in late-stage clinical development.

Study at a glance

Abstract

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.