It's called the monoamine hypothesis, and while it's improved the lives of millions who experience depression, for countless others it's been no help at all.

That's because the hypothesis, which dates back to the 1950s, is the precursor for nearly all antidepressants – based on the observation that a deficiency of monoamine neurotransmitters (including serotonin) triggers depression, spurring the development of treatments such as selective serotonin reuptake inhibitors (SSRIs).

There's just one problem: the drugs don't work. At least, not for everybody.

"Thirty percent of people on these drugs do not experience an effect," explain neuroscientists Yumiko Saito and Yuki Kobayashi from Hiroshima University in Japan.

"We need another explanation for what could cause depression."

In a new study with mice, Saito and Kobayashi may have found just that.

In previous research analysing cells in vitro, Saito discovered that a protein expressed in the brain called RGS8 helps control the hormone receptor MCHR1, which is involved with sleep, appetite, and emotional responses.

The research showed that RGS8 inactivates MCHR1 – hypothetically mitigating depression symptoms – but as for how this might affect depression in living animals, nobody knew.

To try and get closer to an answer, in this new study the team ran experiments with two sets of mice: one group consisting of normal animals, and the other of mice genetically engineered to express higher levels of RGS8.

The mice were subjected to a forced swimming test, in which animals are placed into a tank of warm water they can't get out of, and constantly monitored as they swim around for a while before going immobile or "giving up", which is considered a characteristic similar to depression.

In the tests, the RGS8-boosted mice recorded shorter immobility times – suggesting they were swimming more, and therefore less depressed. When these mice were given an antidepressant drug (desipramine) that acts on monoamines, their immobility time was even further reduced.

When normal mice were given a drug called SNAP94847 that stops MCHR1 from working, it reduced their immobility time in the swimming tank – but when the RGS8-boosted mice took the same thing, it seemed to have no effect on their levels of negative mood.

"These mice showed a new type of depression," Saito explains.

"Monoamines appeared to not be involved in this depressive behaviour. Instead, MCHR1 was."

When the researchers examined the euthanised animals' brains under microscope, they found that the RGS8-boosted mice demonstrated longer neuronal cilia (in which MCHR1 is localised) than regular mice did, in a region of the hippocampus called CA1.

It's not exactly understood how this variation in cilia length is related to depression, but the researchers certainly don't think it's an accident.

"These findings suggest that the increased RGS8 protein level in the CA1 region is a possible causative factor for elongation of ciliary MCHR1," the team writes in its paper.

"Thus, it can be speculated that a significant change in cilia length may be associated with the behavioural consequences observed in RGS8 [mice]."

It's early days, and there's a lot more work to be done before we'll know if these results can be safely replicated in humans, but the researchers suspect this protein could be a promising candidate for a new generation of antidepressant drugs – one which might be able to help the millions of people for whom monoamine-based drugs currently don't work.

"Our findings demonstrate a modulatory role of RGS8 in the neurobiology of depressive-like behaviour," the researchers explain.

"The present findings may support the possible modulation of RGS8 function for the treatment of mood disorders including depression."

The findings are reported in Neuroscience.