Ketamine in the treatment of depression: clinical utility, safety, and mechanism of action
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Ketamine has shown promise as a novel treatment for depression and as a means to investigate the biology of depression. The drug effectively and rapidly treats depressed patients with the effects lasting approximately 1 week. However, concerns about ketamine’s efficacy do exist because of the inadequacy of blinding procedures used in existing trials. A dose of 0.5 mg/kg has been found to be most effective. Prolonged ketamine infusions have not extended the antidepressant effect beyond the timeframe of a regular infusion. Repeat infusions may be successful in extending ketamine’s effect, but definite conclusions cannot yet be made in this regard. Combination treatment with escitalopram and cognitive behavioral therapy (CBT) hold promise, as does the development of an intranasal formulation. Ketamine has shown additional efficacy as an acute anti-suicide treatment. Side effects from a single administration usually fade within a few hours and commonly include dissociation, elevations of blood pressure, nausea, and anxiety. Less data is available on the side effects caused by repeated ketamine infusions. Concerns exist regarding genitourinary, hepatic, and cognitive side effects after repeated infusions, as well as a risk of addiction. Research on ketamine’s mechanism of action has focused on the glutamate system in the brain. Ketamine may act by inhibiting release of γ–aminobutyric acid (GABA) from interneurons, activating intrasynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), increasing mammalian target of rapamycin complex 1 (mTORC1) and extracellular signal-regulated kinase (ERK) signaling, enhancing brain-derived neurotrophic factor (BDNF) production, inhibiting glycogen synthase kinase 3 (GSK3), blocking extrasynaptic N-Methyl-D-aspartate receptors (NMDARs), and promoting synaptogenesis and neuroplasticity. The two existing ketamine stereoisomers, (R)- versus (S)-ketamine, have different actions and potentially different efficacies and side effect profiles. Ketamine also produces regional changes in brain activity and connectivity. These include decreased burst firing in the lateral habenula (LHb), increased activity in the prefrontal cortex (PFC) and subgenual anterior cingulate cortex (ACC), and alterations in the amygdala’s response to angry and happy faces. Ketamine has the potential to be developed into a novel and useful clinical tool in the treatment of depression and to advance the understanding of the biology of depression.
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