How Ketamine Could Cure Depression

The major excitatory neurotransmitter in the central and peripheral nervous system, glutamic acid, has been known for more than 50 years to produce its actions through various ionotropic channels (NMDA and AMPA) and G-coupled metabotropic receptors (mGluR 1 to 5). The glutamate-sensitive ion channels comprise multiple protein subunits and are subject to many regulatory and modulatory controls. Such intrinsic mechanisms are most apparent in the N-methyl D-aspartate (NMDA) receptor-operated ion channel which, in turn, offers countless opportunities for drugs to selectively exploit the ubiquity of glutamate’s excitatory role.

Discovery of NMDA antagonists

Considerable discovery efforts in the early 90s targeted various components of the NMDA receptor complex with the aim of developing new treatments for neurodegeneration – Alzheimer’s, Parkinson’s, Huntington’s diseases, stroke, traumatic brain injury – as well as epilepsy and pain, with some interest directed to psychiatric indications like anxiety.

When the undesirable CNS side effects of many of these new drug candidates became apparent much of this research was curtailed, although several compounds with weak, or non-selective effects on the NMDA receptor were subsequently approved  e.g. memantine, adamantine, methadone, and dextromethorphan.

Return of the NMDA antagonist – the Ketamine breakthrough

Targeting NMDA receptors came back into vogue at the turn of the 21st century with the remarkable and somewhat serendipitous finding that a 60-year old anesthetic drug, ketamine, produces a profound and quick-acting antidepressant effect in patients who had already failed to respond to several other traditional anti-depressant drugs.

Such a result with ketamine in so-called Therapy Resistant Depression (TRD) was anticipated from the work of Phil Skolnick and colleagues in the 1990s in which they demonstrated an important role for glutamatergic dysregulation in depression. Still its demonstration in patients, beginning with the early trials by Rob Berman and colleagues, was to signal the advent of a completely novel approach to treating depression.

How does Ketamine work in depression?

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