Interaction of hallucinogenic rapid-acting antidepressants with mGlu2/3 receptor ligands as a window for more effective therapies.

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.

Study at a glance

Abstract

The desire to find a gold-standard therapy for depression is still ongoing. Developing one universal and effective pharmacotherapy remains troublesome due to the high complexity and variety of symptoms. Over the last decades, the understanding of the mechanism of pathophysiology of depression and its key consequences for brain functioning have undergone significant changes, referring to the monoaminergic theory of the disease. After the breakthrough discovery of ketamine, research began to focus on the modulation of glutamatergic transmission as a new pharmacological target. Glutamate is a crucial player in mechanisms of a novel class of antidepressants, including hallucinogens such as ketamine. The role of glutamatergic transmission is also suggested in the antidepressant (AD) action of scopolamine and psilocybin. Despite fast, robust, and sustained AD action hallucinogens belonging to a group of rapid-acting antidepressants (RAA) exert significant undesired effects, which hamper their use in the clinic. Thus, the synergistic action of more than one substance in lower doses instead of monotherapy may alleviate the likelihood of adverse effects while improving therapeutic outcomes. In this review, we explore AD-like behavioral, synaptic, and molecular action of RAAs such as ketamine, scopolamine, and psilocybin, in combination with mGlu2/3 receptor antagonists.