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Targeting a Specific Brain Area May Lead to an Entirely New Treatment for Depression

An innovative treatment that doesn’t focus on serotonin, dopamine, and norepinephrine.

| 2 min read

An innovative treatment that doesn’t focus on serotonin, dopamine, and norepinephrine.

Most of the current antidepressant drugs work by increasing levels of certain neurotransmitters — serotonin, dopamine, and norepinephrine — which all have an affect on mood and emotions.

However, as many as two-thirds of depressed patients don’t respond to the first antidepressant that they try, according to WebMD, and up to a third of patients don’t respond to several following attempts.

"There is a real need for new therapies to help patients desperate for alternatives to the available therapeutic options,” senior author Dr. Dane Chetkovich, a professor of neurology and physiology at Northwestern University, said in a press release.

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The fact that antidepressants don’t work for many patients suggests that there are additional mechanisms of the disorder that need to be focused on, and researchers at Northwestern University have discovered a novel target in the brain: the HCN channels (intermembrane proteins) in the hippocampus.

The hippocampus is a brain region involved in learning, memory, and emotional regulation, and the team of scientists had implicated the hippocampus as a target for depression in previous work.

Now, writing in the journal Molecular Psychiatry, the researchers have shown that a gene therapy that targets the hippocampus holds promise for a new depression treatment.

In the study, the scientists injected mice with a nontoxic virus engineered to express a gene that shuts down HCN channel function in hippocampal neurons.

"When the HCN channels stopped working, the mice behaved as if they'd been given antidepressant medications," Chetkovich said in the release.

Conversely, when the function of the HCN channels was increased, the antidepressant effect disappeared.

How is depression measured in mice, you may be asking? There are some standard tests used by the pharmaceutical industry to screen compounds for their effectiveness as antidepressants, called the forced swim test and the tail suspension test.

“Mice with genetic mutations that cause depression in humans, or that have been subjected to stressful situations to create models of depression, show more immobility when suspended from their tails or placed in water without a platform,” Chetkovich explained in an email to The Science Explorer.

“This is thought to be similar in some ways to increased behavioral despair in human patients with depression.”

Of course, this doesn’t perfectly translate over to the kind of complex depression that humans feel, so further research is required before we can conclude that this gene therapy is a new option.

Nonetheless, "This work not only identifies a totally new treatment target for depression, it provides a detailed molecular description of the structures that need to be manipulated for it to act as an antidepressant and develops viral tools to do so," Chetkovich says.

Going forward, the researchers are working on adapting the viral gene therapy for human patients.

Excitingly, the National Institute of Mental Health has already given them a grant to find small molecules that could be developed into oral medications to switch off the brain’s HCN channels.

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