Understanding Ketamine’s Brain-Specific Actions Could Lead to Better Antidepressants

Researchers from Zhejiang University have uncovered the mechanistic basis behind ketamine’s rapid antidepressant effects. Published in Science, this study holds significant promise for developing more effective antidepressant treatments.

Traditional antidepressants take several weeks to work

Depressive disorder, commonly referred to as depression, affects around 280 million people around the world. This mental health condition is characterized by a persistently low mood and a diminished interest in or enjoyment of activities. In severe cases, depression can result in suicide, claiming the lives of over 700,000 people annually.

Current treatments for depression include psychotherapy and antidepressant medications such as selective serotonin reuptake inhibitors. Traditional antidepressants can offer relief for some patients, however, these medications often take several weeks to become effective.

Ketamine is a psychedelic drug known for its pain-relieving, dissociative and euphoric effects. Although it has long been used as an anesthetic in hospitals and veterinary clinics, ketamine has recently gained attention for its rapid and sustained antidepressant effects. In 2019, a prescription version of ketamine, called esketamine (Spravato), was approved by the US Food and Drug Administration (FDA) for treatment-resistant depression. This drug acts as a non-competitive antagonist of the N-methyl-D-aspartate receptor (NMDAR), a mechanism thought to contribute to its antidepressant properties, though the exact process of how this happens remains unclear.

Ketamine has a brain region-specific action

Since NMDAR is ubiquitously expressed throughout the brain, it is unclear whether ketamine acts on many brain regions at once or if it targets one, or a few, primary sites that result in a signaling cascade. Previous studies using animal models of depression have suggested that the lateral habenula (LHb), also termed the brain's "anti-reward center”, plays a role in both the development of depression and ketamine's mechanism of action, due to observed hyperactivity of NMDARs.

To investigate ketamine's mode of action, mouse models were exposed to chronic restraint stress to induce a depression-like state, then were injected with either saline or ketamine. The NMDAR-mediated synaptic currents were measured in the LHb and hippocampal neurons. One hour post-injection, brain slices were prepared and analyzed using in vitro slice electrophysiology. In vivo tetrode recording was also performed to assess the basal firing rate and bursting rate in neurons from both brain regions.

The in vitro experiments revealed a single systemic injection of ketamine specifically blocked NMDAR currents in the LHb neurons but not in the hippocampal neurons. The in vivo recordings also supported this finding, showing the basal firing rate and bursting rate were much higher in the neurons from the LHb compared to those in the hippocampus. LHb neural activity was also suppressed significantly within minutes after the ketamine injection.

The researchers hypothesized this action occurs due to ketamine being a use-dependent blocker – meaning it only inhibits NMDARs when they are in an open activated state – since LHb neurons have an increased activity in the depressive-like state compared to hippocampal neurons. Upon altering the activity levels of neurons in both the hippocampus and LHb, the researchers were able to swap the individual region’s sensitivity to ketamine.

Conditional knockouts of NMDARs in the LHb also prevented ketamine’s antidepressant effects by blocking the systemic ketamine-induced increase of serotonin and brain-derived neurotrophic factor in the hippocampus.

Designing efficient antidepressants

Ketamine likely impacts multiple brain regions to produce its antidepressant effects. However, understanding the timing of these regions' involvement is crucial for comprehending how the drug delivers its full range of benefits.

“We suggest that neurons in different brain regions may be recruited at different stages, and that an LHb-NMDAR–dependent event likely occurs more upstream, in the cascade of ketamine signaling in vivo,” the authors wrote in the paper.

“Overall, these primary/direct and secondary/indirect changes in different brain areas may work in concert to execute the full spectrum of ketamine’s long-term effects,” they wrote.

“This distinction of the primary versus secondary brain target(s) of ketamine should help with the design of more precise and efficient antidepressant treatments,” the authors concluded.

Reference: Chen M, Ma S, Liu H, et al. Brain region–specific action of ketamine as a rapid antidepressant. Science. 2024. doi: 10.1126/science.ado7010

This article is a rework of a press release issued by the American Association for the Advancement of Science.  Material has been edited for length and content.