Ketamine - precursor of a new generation antidepressant drugs

Abstract

Depressive disorders are one of the most common mental disorders in the world. Treatment of depression is an important medical problem but current pharmacological strategies based on balancing monoaminergic transmissions in the brain are associated with a delayed onset of antidepressant response. Moreover, the proportion of patients suffering from treatment-resistant depression who do not achieve remission after antidepressant treatment is increasing. Results of recent studies indicate that changes in neural plasticity may be responsible for the development of depression, and restoration of neuroplasticity may result in a rapid antidepressant effect. Ketamine is the first drug with rapid-onset antidepressant action. This intravenous general anesthesia drug is a non-competitive antagonist of glutaminianergic NMDA receptors. Blocking of NMDA receptors located on inhibitory GABA-ergic interneurons leads to release of glutamate, stimulation of postsynaptic AMPA receptors, and subsequent activation of brain-derived neurotrophic factor (BDNF) synthesis. By stimulating TrkB receptors, BDNF triggers a cascade of intracellular biochemical processes, as a result of which synapses are rebuilt as well as the number and functioning of synaptic connections are improved. Some studies show that ketamine may also restore normal neuronal plasticity by improving the excitation - inhibition balance in the neuronal microcircuits. The drug inhibits the activity of overstimulated eEF2K kinase by blocking postsynaptic NMDA receptors in the hippocampus, which results in unblocking synaptic protein synthesis and restoration of neuronal plasticity. The use of ketamine as an antidepressant and anti-suicidal drug is limited due to its adverse effects, primarily psychotomimetic ones. For this reason, research has been conducted on the use of ketamine enantiomers: (S+)-ketamine (esketamine) and (R-)-ketamine (arketamine), which potentially can have more favorable safety profiles, in the treatment of depression. Currently, esketamine (a nasal spray) is approved in adult patients with treatment-resistant depression or endogenous depression with suicidal thoughts or behavior. In therapy, it is used in combination with an oral antidepressant drug (SSRI or SNRI). The discovery of the antidepressant efficacy of ketamine has changed our understanding of the pathophysiology of depressive disorders and initiated a new approach in depression research. However, it should be remembered that ketamine exerts serious toxic effects in high doses and is also used as a hallucinogenic compound.

Keywords

• neuroplasticity
• depression
• ketamine
• toxicity
• bdnf
• glutamate
• nmda receptor