Pharmacology of novel, fast-acting, non-monoaminergic antidepressants

Neuropsychopharmacol Hung. 2025 Mar;27(1):37-50.

ABSTRACT

For decades, the molecular target of drug therapy in the treatment of major depression has been the monoamine system, primarily the serotonin transporter (SERT) and the norepinephrine transporter (NAT). Newer antidepressants have a better side effect profile than first-generation drugs due to their selectivity, but the monoaminergic target and the associated difficulties and challenges remain, primarily the problem that some of their neurochemical effects appear immediately, but it takes weeks for the antidepressant effect to develop. As a result of intensive research over the past decade, four approved antidepressants are now available whose molecular target is not a member of the monoamine system; they are not serotonergic or noradrenergic, but have a glutamatergic or GABAergic mechanism of action. Their advantages include the short time required for the onset of the effect; they exert their antidepressant effect within hours or days instead of weeks; their side effect profile is better, and they also offer a new treatment option for therapy-resistant patients. Two glutamatergic drugs, esketamine and dextromethorphan-bupropion (AXS-05), have already been approved for the treatment of treatment-resistant depression. The GABAergic drugs brexanolone and zuranolone are approved for the treatment of postpartum depression. These novel treatment options pave the way for novel avenues for further research and new targets in the treatment of depression. Keywords: depression, antidepressant, glutamate, fast-acting antidepressant, non- monoaminergic antidepressant.

PMID:40173429