Hole in one: researchers demonstrate ketamine’s potential as an antidepressant
Researchers identify the mechanism behind ketamine’s psychological effects and show its potential as an antidepressant that could work within hours.
With a mock reputation as a horse tranquilizer and its approval for use as an anesthetic agent in humans by the FDA in 1970†; it might be hard to imagine ketamine doing much of anything with any speed or efficacy. This slothful reputation, however, may be undeserved when it comes to psychological benefits.
Ketamine works within hours compared to standard antidepressants, the effects of which can take several weeks to manifest. However, ketamine can only be prescribed for a limited time before the side effects outweigh its benefits. These side effects include blurred or double vision, nausea, vomiting, insomnia, drowsiness and addiction. This underscores the necessity to understand the mechanisms involved in ketamine’s rapid psychological effects.
This study conducted by researchers at Northwestern University Feinberg School of Medicine (IL, USA) is the first to identify how ketamine works and believe it could be adapted to have fewer side effects.
Using mice, the study illustrates that the rapid antidepressant effects are caused by increasing the activity of a restricted group of new neurons. Neurons are in continuous, yet slow, production and it is understood that increasing the number of neurons creates behavioral changes, which is how other antidepressants work. However, this is a process that can be weeks in the making. Ketamine, on the other hand, produces behavioral changes by increasing the activity of existing, recently produced neurons. Ketamine-activated cells display this effect in extremely short time frames.
Ketamine increases the activity of adult-born immature granule neurons (ABINs), which influences hippocampus-dependent behavior. The hippocampus, located in the temporal lobe, plays a significant part in learning and memory.
The activation of ABINs in the mouse study produced an extremely fast positive reaction in their behavior. The scientists, therefore, worked on the hypothesis that the increased activity of ABINS could mediate the behavioral impact produced by ketamine. To test this, researchers selectively inhibited the activity of ABINS in the hippocampus.
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The researchers created mice where the activity of ABINs could be selectively inhibited, without affecting other cells in the brain. At this point, the mice either received ketamine or saline and after 24 hours underwent behavioral testing.
Mice with active ABINs and provided with ketamine displayed a marked increase in social interaction ratio, social novelty (a sociability test), and were immobile for less time. Ketamine treatment had no impact on total ABIN count, only a significant increase in activation number. ABIN blocker administration prevented the ketamine-linked behavioral alteration but had no effect on saline-treated mice when compared with the control group. The results demonstrated that obstructing the hippocampal ABINs has a similar inhibitory effect on the behavioral impact of ketamine.
“The reason is these newborn neurons form synapses (connections) that activate the other cells in the hippocampus,” explains John Kessler, the lead author of the study. “This small population of cells acts like a match, starting a fire that ignites a bunch of activity in a lot of other cells that produce the behavioral effects.”
The question then is, how do you adapt ketamine so it can be used as an antidepressant without the side effects. The loss of hippocampal ABIN activity blocked the associated behavioral changes, suggesting that ABIN activation is a necessary component. However, ABIN activation induced the same effects in both quality and scale as ketamine, indicating that ABIN activity itself can induce ketamine-related changes. This provides a foundation for further studies focussing on ABIN and ABIN-related pathways.
The research paper describes how circumventing the limitations of ketamine use has driven interest into investigating other drugs and targets, hoping to find an equivalent rapid response. With few other drugs demonstrating a comparable efficacy, ketamine – without the side effects – could be a promising antidepressant.
Kessler summarized: “The goal is to develop an antidepressant that doesn’t take three to four weeks to work because people don’t do well during that period of time. If you are badly depressed and start taking your drug and nothing is happening, that is depressing in itself. To have something that works right away would make a huge difference.”
