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.
Developing a universal pharmacotherapy for depression is challenging due to symptom complexity. Understanding of depression's pathophysiology has shifted from the monoaminergic theory after ketamine's discovery, focusing on glutamatergic transmission as a new target. Glutamate plays a key role in rapid-acting antidepressants (RAAs) like ketamine, scopolamine, and psilocybin. These hallucinogens provide fast, robust, and sustained antidepressant action but have significant undesired effects that limit clinical use. This review explores combining lower doses of RAAs with mGlu2/3 receptor antagonists to reduce adverse effects and improve outcomes, examining behavioral, synaptic, and molecular actions.