Where do we go next in antidepressant drug discovery? A new generation of antidepressants: a pivotal role of AMPA receptor potentiation and mGlu2/3 receptor antagonism
Andrzej Pilc, Agata Machaczka, Paweł Kawalec, Jodi L. Smith, Jeffrey M. Witkin
Expert Opinion on Drug Discovery August 8, 2022 DOI: 10.1080/17460441.2022.2111415 via OpenAlex
Summary
AI-generated from the abstractA new generation of antidepressant drugs is emerging that works faster and helps patients who do not respond to current treatments. Unlike standard antidepressants that take weeks to work, these compounds—including ketamine, psilocybin, and scopolamine—can produce rapid effects, often after a single dose, and their benefits outlast the drug's presence in the brain. Their mechanism involves enhancing AMPA receptor function and antagonizing mGlu2/3 receptors, pointing to a strong glutamatergic component. Based on accumulating preclinical and clinical data, new drug approvals are expected soon.
Study at a glance
| Characteristics | Opinion piece Peer reviewed |
|---|---|
| Interventions | Ketamine Psilocybin Scopolamine |
| Topics | Depression |
| Keywords | Antidepressant Pharmacology Ampa receptor Glutamatergic |
| Citations | 20 |
| Key finding | A new class of antidepressants—including NMDA receptor antagonists, psychedelics, and muscarinic receptor antagonists—shows rapid, sustained efficacy in treatment-resistant depression, likely through glutamatergic mechanisms involving AMPA receptor facilitation and mGlu2/3 receptor antagonism. |
Abstract
INTRODUCTION: Major depressive disorder remains a prevalent world-wide health problem. Currently available antidepressant medications take weeks of dosing, do not produce antidepressant response in all patients, and have undesirable ancillary effects. AREAS COVERED: The present opinion piece focuses on the major inroads to the creation of new antidepressants. These include N-methyl-D-aspartate (NMDA) receptor antagonists and related compounds like ketamine, psychedelic drugs like psilocybin, and muscarinic receptor antagonists like scopolamine. The preclinical and clinical pharmacological profile of these new-age antidepressant drugs is discussed. EXPERT OPINION: Preclinical and clinical data have accumulated to predict a next generation of antidepressant medicines. In contrast to the current standard of care antidepressant drugs, these compounds differ in that they demonstrate rapid activity, often after a single dose, and effects that outlive their presence in brain. These compounds also can provide efficacy for treatment-resistant depressed patients. The mechanism of action of these compounds suggests a strong glutamatergic component that involves the facilitation of AMPA receptor function. Antagonism of mGlu2/3 receptors is also relevant to the antidepressant pharmacology of this new class of drugs. Based upon the ongoing efforts to develop these new-age antidepressants, new drug approvals are predicted in the near future.