Depression: 'Orphan' brain receptor may be to blame

New research uncovers a brain receptor that could explain why some people experience major depressive disorder after a stressful event, while others do not.

Recently, an increasing amount of studies have been focusing on the neurological causes of depression, which is a psychiatric condition affecting more than 16 million adults in the United States.

Only a few months ago, one such study pointed out that depression originates in brain areas associated with memory and reward.

And, just a few days ago, another study laid out an electrical brain map of depression that could predict who develops the condition.

Now, researchers from The Scripps Research Institute (TSRI) in Jupiter, FL, may have uncovered a new drug target for the treatment of depression.

Scienitsts led by Kirill Martemyanov, Ph.D. — co-chair of the TSRI Department of Neuroscience — focused on a brain receptor called GPR158 after they noticed that levels of the GPR158 protein were very high in people with depression.

So, Martemyanov and colleagues examined the behavior of this brain receptor in mice that had been subjected to chronic stress. Their findings were published in the journal eLife.

Studying 'orphan brain receptors' in mice

The researchers examined both rodents that had the receptor and those that did not. Exposing the mice that did have GPR158 to chronic stress increased the levels of the protein in the rodents' prefrontal cortices.

Martemyanov and colleagues also noticed that excessive levels of GPR158 led to behavioral signs of depression in mice such as anhedonia — or the sudden inability to enjoy activities that used to be pleasurable — and anxiety-like physiological reactions.

By comparison, the researchers report that genetically removing GPR158 "led to a prominent antidepressant-like phenotype and stress resiliency," in the mice.

Martemyanov explains that GPR158 brain receptors are called "orphan receptors" because it is not yet known what chemical the protein binds to.

These are "proteins that look like they will bind and respond to a hormone or a brain chemical, based on the similarity of their sequences to other proteins." However, their binding partner(s) remain mysterious.

Why are some people resilient to depression?

Things such as going through a divorce, the death of a loved one, or losing one's job can all be traumatic experiences.

While the risk of depression increases after such experiences, some people go on to develop the condition while others do not.

As the authors of the new study explain, their findings might offer some clues as to why this happens. They hypothesize that perhaps in humans, too, a lack of GPR158 makes people genetically resistant to depression.

As co-first study author Laurie Sutton, Ph.D. — a research associate at TSRI — explains, the findings seem to support observational evidence of individuals who have been subjected to chronic stress. "There's always a small population that is resilient — they don't show the depressive phenotype," she says.

Findings may change treatment

There is a dire need for alternatives to traditional treatments for depression, the scientists explain. They say that the effects of current antidepressants may sometimes take a month to kick in, and that the drugs don't work for everyone who has depression.

Also, even when they are effective, antidepressants can have a range of side effects, such as the blunting of emotions or a decreased sex drive.

Co-first study author Cesare Orlandi, Ph.D. — a senior research associate at TSRI — says, "We need to know what is happening in the brain so that we can develop more efficient therapies."

Now that the researchers have uncovered the role of GPR158, "The next step in this process is to come up with a drug that can target this receptor," says Martemyanov.

In fact, this team is not the only one attempting to come up with alternative treatments for major depressive disorder; we recently covered studies exploring the benefits of psilocybin — the psychoactive compound in magic mushrooms — or those of grape extracts for treating the condition.