Researchers at Hiroshima University (HU) in Japan have identified a new form of depression they believe explains why some many patients are unresponsive to current medications.

The findings of the study, published in May 2018 in the journal Neuroscience, shed light on how a certain protein — RGS8 — plays a role in the condition.

Depression, which can be lethal, affects more than 300 million people around the world and is 2.7 times more prevalent among adults with Attention-Deficit Hyperactivity Disorder (ADHD).

According to a 1995 study published in the American Journal of Psychiatry (Biederman, Wilens, Mick, et al, Am J of Psychiatry 152:11, p. 1654, November 1995) major depression and anxiety disorders have been found in more than 30 percent of clinical and epidemiological samples of children, teens and adults with Attention-Deficit Hyperactivity Disorder (ADHD).

There are many reasons for the high rates of depression in the ADHD population, but the fact remains that treating the condition is still a serious challenge for many psychopharmacologists, particularly when faced with the need to create “cocktails” — combinations of medications — and particularly when the depression doesn’t respond to the standard medications.

According to the monoamine hypothesis theory, people who struggle with depression lack two chemicals (neurotransmitters) in the brain: serotonin and norepinephrin (NE). Currently some 90 percent of all anti-depressant medications that are produced are produced based on this concept. However, some 30 percent of people in treatment, however, are non-responders to these medications.

“Obviously, we need a new drug!” said Yumiko Saito and Yuki Kobayashi, neuroscientists at HU’s Graduate School of Integrated Arts and Scientists. “We need another explanation for what could cause depression.”

In their study, Saito’s team studied depression in mice at the behavioral level, and at the immunohistological level.  First the mice were taken through a swim test, with researchers measuring the time each mouse was active and subtracting that from the total test time. The amount of immobility time was used to determine depressive behavior in the mice on the swim test.

At the immunohistological level, Saito and her team built upon previous work in which the team had discovered that the RGS8 protein controls a hormone receptor called MCHR1.

The researchers discovered that the MCHR1 hormone receptor, when active, helps regulate sleep, feeding and mood responses. And the RGS8 protein shuts off the MCHR1 hormone receptor in cultured cells.

Mice with more RGS8 in their nervous systems were recorded with shorter immobility times than those with a normal amount of RGS8.  Immobility times did not change in mice who received medication that blocked MCHR1, and when given antidepressant medication that acts on monoamines, the RGS8 mice recorded even shorter immobility times.

The team concluded that the mice were exhibiting a form of depression, one that was treatable with current medication regimens.

“These mice showed a new type of depression,” Saito said. “Monoamines appeared not to be involved in this depressive behavior. MCHR1 was.”

The researchers later examined the brains of the mice under the microscope and found the RGS8 mice had longer cilia (antennae-like organelles involved in cellular communication) sprouting from cells in a region of the hippocampus called the CA1, where RGS8 concentration was highest.

The RGS8 mice who received medication that blocked MCHR1 from working had longer cilia — and less depressed behavior.

Saito’s group concluded that RGS8 appears to be a promising candidate towards the development of new antidepressant medications and a focus for future research.

“The present study may support the possible modulation of RGS8 function in mood disorders,” they wrote in their findings.