Moving from the old monoaminergic theory toward the emerging hypothesis in the rational design of rapid-onset novel antidepressants

Antidepressants can be classified into 13 different classes based on their pharmacological mechanisms of action. As of this present moment, 11 out of these 13 classes of antidepressants accomplish their pharmacoactivities by blocking one or more of the reuptake transporter pumps and/or receptors for the three monoaminergic neurotransmitters, namely serotonin, norepinephrine, and dopamine. The 12th class inhibits the enzyme monoamine oxidase, while the 13th class works by blocking the N-methyl-D-aspartate (NMDA)-glutamatergic ionoceptor. Previous experimental results suggest that depression is associated with hyperfunction of NMDA-glutamatergic receptors (NMDARs) in the subcortical regions (i.e., hippocampus, locus coeruleus, and amygdala); whereas at the same time, there is hypofunction of NMDARs in the cortical regions (i.e., prefrontal, perirhinal, and temporal cortices). Moreover, this finding has led to a conclusion that postulates the new “Glutamatergic hypothesis of depression” which is now moving our understanding of the pathophysiology of major depression disorder (MDD), a step further from the several decades' old “Monoaminergic theory of depression.” Collectively, clinical data suggest the involvement of the glutamatergic neurotransmission system in the pathophysiology of MDD or bipolar depression or schizoaffective depression, which includes disruptions in glutamatergic substrate concentrations and NMDAR alterations. Although the role of glutamatergic systems is yet to be fully elucidated, a “proof of concept” clinical study reported that the noncompetitive NMDAR antagonist ketamine produced rapid-onset and prolonged antidepressant effects in patients suffering from MDD or bipolar depression or schizoaffective depression. Still, this has generated tremendous interest in developing new drugs that will target the glutamatergic neurotransmission mechanisms for the treatment of MDD or bipolar depression or schizoaffective depression. These potential drug targets are the NMDAR as antagonist or inverse agonist or partial agonist, metabotropic glutamatergic receptors as positive or negative modulator, excitatory amino acid transporter-2 (EAAT-2) as a reuptake enhancer, and as a terminal presynaptic glutamate release inhibitor.