Advances in pharmacology (San Diego, Calif.)
January 1, 2019
Jeffrey M. Witkin, Anna E Martin, Lalit K Golani et al.
71 citations
A new class of antidepressants, emerging since 2006, offers rapid onset, large effect size, and efficacy after single or few doses, even in treatment-refractory patients and against symptoms like anhedonia. Controlled clinical studies have demonstrated rapid-acting effects for ketamine, other NMDA receptor antagonists, and scopolamine, with less clinical data for psychedelic drugs such as psilocybin, LSD, and ayahuasca. The mechanisms are not fully understood, but potentiation of AMPA receptor function appears to be a general trigger. Durability is limited for ketamine and scopolamine, while psychedelics may produce effects lasting months. Side effects and lack of enduring effects are primary impediments. Esketamine is FDA-approved; compounds in clinical development include (R)-ketamine, Rapastinel, and TAK-653. Preclinical evidence suggests potential for mGlu2/3 receptor antagonists, AMPA receptor potentiators, and GABAA(α5) negative allosteric modulators.
International Journal of Molecular Sciences
June 20, 2024
Hana Shafique, Julie C Demers, Julia Biesiada et al.
29 citations
NMDA receptor antagonists show promise for neurological and psychiatric conditions such as neurodegenerative diseases, epilepsy, traumatic brain injury, substance use disorder, and major depressive disorder. (S)-ketamine was the first rapid-acting antidepressant approved for medical use. Its stereoisomer, (R)-ketamine (arketamine), is under development for treatment-resistant depression and has shown efficacy in multiple animal models. Two clinical studies reported efficacy in treatment-resistant depression and bipolar depression, though a sponsor study failed to meet primary endpoints; post hoc analysis indicated efficacy. (R)-ketamine is less sedating, produces fewer psychotomimetic or dissociative effects, and has lower abuse potential than (S)-ketamine. Its antidepressant mechanisms may involve NMDA receptor antagonism and non-NMDA receptor pathways. Further clinical research may lead to improved treatments for underserved neurological and psychiatric disorders.
Expert Opinion on Drug Discovery
August 8, 2022
Andrzej Pilc, Agata Machaczka, Paweł Kawalec et al.
20 citations
A 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.
Expert Review of Clinical Pharmacology
April 1, 2023
Jeffrey M. Witkin, Lalit K Golani, Jodi L Smith
18 citations
Standard antidepressants have limitations, driving the search for new drugs. Rapid-acting antidepressants, such as those based on ketamine, show promise for treatment-resistant depression. This review documents newly approved and emerging medicines for major depressive disorder, evaluating their efficacy, tolerability, and safety. Many new drugs rely on glutamatergic mechanisms, including mGlu2/3 receptor antagonists, AMPA receptor potentiators, and novel NMDA receptor modulators. Companies are also developing novel psychedelic drugs, though the necessity of psychedelic activity remains unclear. Gaps persist in matching patients to specific treatments and in developing medicines to prevent MDD or its progression.