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While we have a number of treatments available for clinical depression, many of them have significant side effects, and many people struggle to find a drug that they respond to. The situation is compounded by our limited understanding of the biology underlying depression. We don’t know how to make targeted drugs, so most of the available treatments are blunt instruments that can take weeks to months to take effect.
In that light, it came as a shock to find that a drug we took recreationally and before anesthesia could relieve the symptoms of depression in less than 24 hours. Unfortunately, the drug in question, ketamine, also has a collection of nasty side effects, and we had no idea how it worked.
But significant progress has been made in unraveling the confusion over ketamine, with researchers identifying a ketamine derivative that addresses depression with far fewer side effects. And this week, a team of researchers from China’s Zhejiang University announced they’ve discovered where in the brain ketamine works when it blocks depression, a finding that gives us important insights into the biology of the condition.
Ketamine and Depression
The new studies are based on the work of a number of other labs, which have identified a specific structure deep in the brain linked to depression. It is called the lateral habenula and is associated with a variety of activities, the most relevant of which seems to be the processing of unpleasant results and punishment. Electrodes implanted there have been used in at least one instance to alleviate depression.
To test whether this could be the site of ketamine’s activity, a team of researchers injected the drug directly into the lateral habenula of rats with depression-like symptoms; it blocked them. So was a separate chemical that inhibits the same proteins that ketamine acts on. By monitoring activity in the area, the researchers were able to show that there are bursts of activity in rats with symptoms of depression that are absent in healthy rats. The drugs that blocked depression suppressed these flares.
To confirm that this was truly causal, the researchers performed the reverse experiment, engineering cells in the lateral habenula to emit bursts of activity in response to light. This showed that the outbursts themselves were sufficient to cause depressive symptoms in these animals.
A second paper, produced by many of the same researchers, describes what happens at the cellular level in the habenula. In this work, the team induced depression in rats, either chemically or by inducing what’s called “learned helplessness.” (The latter involves training the rats to recognize that they have no control over negative consequences in their environment.) The team then took tissue samples from the lateral habenula and examined each individual protein produced there, looking for differences between depressed and healthy animals.
ion current
The most interesting result that came out of this was a protein that controls the flow of ions between a cell and its environment. That’s not much of a surprise, since nerve impulses are driven by the exchange of ions across a nerve cell’s membrane. But the protein identified here is not made by nerve cells. Instead, it is made by a type of cell called an astrocyte.
It was once thought that astrocytes were just supporting cells that helped provide a good environment for nerve cells. But we’ve developed a significant body of evidence to suggest that they may also be involved in nerve signaling.
In the case of depression, there seems to be no direct signaling involved. Instead, it is involved in the process of resetting the nerve cell after an impulse, collecting all the ions that flowed out of the cell during the impulse. By changing the amount of potassium available to the nerve cell, the protein identified by this team changes the ease with which a nerve cell can fire again. By increasing the dose of this gene, the researchers were able to induce depression-like symptoms in mice; turning off the gene reduced their ability to induce depressive behavior.
None of this is to say that this team has found a “cause of depression” or anything like that. Depression is a complicated condition and it is unlikely that there will be a single underlying cause. However, what they have found is something that is likely central to generating the symptoms we associate with the condition. Excessive activity of a brain region thought to be involved in processing negative rewards makes sense as a trigger for the symptoms of depression, while the protein identified here makes sense as a trigger for this excessive activity.
Equally critical, the work shows that drugs can disrupt this process. We’re still at the point where these drugs have significant side effects, but we know a little bit about what their targets are doing and where to act. Hopefully that will lead to something more specific in the not too distant future.
Nature2017. DOI: 10.1038/nature25509, 10.1038/nature25752 (About DOIs).
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