Ketamine boosts serotonin in PET study

The anesthetic ketamine, used in both humans and animals, may have a new use: treating chronic, drug resistant major depression, according to a study published Jan. 7 in Translational Psychiatry.

Ketamine is associated with recreational drug use and has been known to create psychotic symptoms, but more recently the pharmaceutical has been shown to be a potentially long-lasting treatment for depression. A research team including Hajime Yamanaka from the bio-function imaging team, at the RIKEN Center for Life Science Technologies, in Kobe, Japan, conducted a preclinical study to gauge the change in serotonin activity when subjects were administered the drug.

“Although recent studies provide insight into the molecular mechanisms of the effects of ketamine, the antidepressant mechanism has not been fully elucidated,” wrote Yamanaka et al.

This preliminary study focused on two serotonin biomarkers, C-11 AZ10419369 and C-11 DASB. Both are “highly selective” imaging of the 5-HT1B receptor and serotonin transporter. Results of quantitative analysis revealed that biomarker binding to 5-HT1B receptors was affected by activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. In further analysis, in order to clue into how this mechanism works, researchers administered 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBOX) prior to imaging. This agent has been known to block ketamine in previous studies. Results of this research showed that NBOX blocked 5-HT1B receptors, but not serotonin transporters, indicating back-end pharmacological effect. 

“This indicates the involvement of AMPA receptor activation in ketamine-induced alterations of 5-HT1B receptor binding,” the authors wrote. “Because NBQX is known to block the antidepressant effect of ketamine in rodents, alterations in the serotonergic neurotransmission, particularly upregulation of postsynaptic 5-HT1B receptors in the nucleus accumbens and ventral pallidum may be critically involved in the antidepressant action of ketamine.”

Both of these areas of the brain are implicated in motivation and instances of depression. Further study is required to validate the full benefit of ketamine for the treatment of major depression in humans. If validated, additional treatment options could be made available for those who struggle with the mood disorder.