A brief history of the development of antidepressant drugs: from monoamines to glutamate

Abstract

Major depressive disorder (MDD) is a chronic, recurring, and debilitating mental illness that is the most common mood disorder in the United States. It has been almost 50 years since the monoamine hypothesis of depression was articulated, and just over 50 years since the first pharmacological treatment for MDD was discovered. Several monoamine-based pharmacological drug classes have been developed and approved for the treatment of MDD; however, remission rates are low (often less than 60%) and there is a delayed onset before remission of depressive symptoms is achieved. As a result of a "proof-of-concept" study in 2000 with the noncompetitive NMDA antagonist ketamine, a number of studies have examined the glutamatergic systems as viable targets for the treatment of MDD. This review will provide a brief history on the development of clinically available antidepressant drugs, and then review the possible role of glutamatergic systems in the pathophysiology of MDD. Specifically, the glutamatergic review will focus on the N-methyl-D-aspartate (NMDA) receptor and the efficacy of drugs that target the NMDA receptor for the treatment of MDD. The noncompetitive NMDA receptor antagonist ketamine, which has consistently produced rapid and sustained antidepressant effects in MDD patients in a number of clinical studies, has shown the most promise as a novel glutamatergic-based treatment for MDD. However, compounds that target other glutamatergic mechanisms, such as GLYX-13 (a glycine-site partial agonist at NMDA receptors) appear promising in early clinical trials. Thus, the clinical findings to date are encouraging and support the continued search for and the development of novel compounds that target glutamatergic mechanisms.

Figure 1

Tripartite glutamatergic synapse and potential drug targets. Left panel: The presynaptic neuron releases glutamate in response to action potentials. Glutamate can bind to ionotropic (i.e. NMDA, AMPA, kainate) and metabotropic (i.e mGluR) receptors located on the presynaptic and postsynaptic neuron as well as on astrocytes. Synaptic glutamate reuptake is performed primarily by the EAAT2 located on astrocytes. Within the astrocyte, glutamate is converted to glutamine (glutamate/glutamine cycle) via glutamine synthetase and then resupplied to the presynaptic neuron where it is used for synthesis of glutamate. Right panel: Potential NMDA and EAAT2 drug targets: (A) Noncompetitive NMDA receptor antagonist (e.g. ketamine and memantine) and low-trapping NMDA receptor channel blockers (lanicemine [AZD6765]); (B) NR2B subunit selective NMDA receptor antagonists (e.g. traxoprodil [CP-101,606] and MK-0657); (C) Partial agonist at the glycine binding site of NMDA receptors (e.g. D-cycloserine, GLYX-13, and NRX- 1074); (D) EAAT2 enhancers (e.g. riluzole). Abbreviations: NMDA, N-methyl-_D-aspartate; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; mGluR, metabotropic glutamate receptors; EAAT2, excitatory amino acid transporter 2.