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.
Hallucinogens from different classes, such as scopolamine and psilocybin, show rapid antidepressant effects that are enhanced by blocking group II metabotropic glutamate (mGlu2/3) receptors. In mice, scopolamine reversed depressive-like behaviors induced by chronic mild stress, and a selective M1 muscarinic antagonist produced dose-dependent antidepressant effects potentiated by an mGlu2 receptor negative allosteric modulator. Scopolamine increased extracellular dopamine, serotonin, and glutamate in the frontal cortex, while the mGlu2 modulator had opposite effects on glutamate. A low dose of the mGlu2/3 antagonist LY341495 boosted the antidepressant effect of low-dose psilocybin in the tail suspension test, with rapid onset and long duration, while also reducing hallucinogenic-like head twitch responses. Combined targeting of these systems may allow lower doses and fewer side effects while maintaining antidepressant efficacy.