Could this be the reason that antidepressants don’t work on 30% of users?

Antidepressants are a lifesaver – quite literally – for millions of people. But for a startling 30%, they don’t actually work at all. This gulf can be ascribed to the prevailing knowledge of depression, knowledge based on the observation that it tends to flare up when your monoamine neurotransmitters (i.e. serotonin) are dwindling. This discovery lent itself to the production of selective serotonin reuptake inhibitors (SSRIs).

Could this be the reason that antidepressants don’t work on 30% of users?

But the fact that SSRIs fail to work for so many people indicates that there is something else causing depression, something that’s been overlooked now for quite a while. Step in Yumiko Saito and Yuki Kobayashi, neuroscientists at Hiroshima University, Japan, whose research has contributed significantly to answering this question.

“Thirty percent of people on these drugs (SSRIs) do not experience an effect,” their research asserts. “We need another explanation for what could cause depression.”

Saito’s previous research had led to the discovery that the protein RGS8, emitted in the brain, helps control MCHR1 – a hormone receptor involved in appetite, sleep, and emotional responses. In vitro, RGS8 was shown to inactivate MCHR1, a process which – in theory – mitigates the symptoms of depression.

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In order to take the research one step closer to fruition (read: human usage), the team experimented on two sets of mice: one set with “regular” brain chemistry, and the other chemically engineered to exhibit higher levels of RGS8.

In a feat reminiscent of year seven sports lessons, the mice were subjected to a forced swimming test. Those who phoned in their swimming efforts were counted as exhibiting the most depressive characteristics, their immobility equated with “giving up”.

The results were illuminating; RGS8-fuelled mice showed shorter immobility times, indicating more swimming time, and therefore lower levels of depression. Upon treatment with the antidepressant desipramine, which works on monoamines, the mice’s immobility times were curbed further.

Meanwhile, “regular” mice were given the drug SNAP94846, which stops MCHR1 from working. This reduced their immobility time considerably, whereas the same drug administered to the RGS8-imbued mice had no effect on their depression. As such, the experiment appears to unearth a “new type of depression”, Saito explains, one in which monoamines aren’t involved in depressive behaviour, but rather MCHR1 is.


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Upon further investigation, the RGS8-boosted mice exhibited longer neuronal cilia (the place where MCHR1 is localised) than their un-tampered-with counterparts. The team doesn’t know quite what’s causing this link yet, but they don’t think it’s an accident: “[I]t can be speculated that a significant change in cilia length may be associated with the behaviour consequences observed in RGS8 [mice],” explains the report.

If RGS8 does indeed play a “modulatory role […] in the neurobiology of depressive-like behaviour”, then future modulations of its levels and functions could provide viable and life-changing treatment for depression and other mood disorders. There you have it: if you’ve exhausted the healthy diet, regular exercise and meditation school of thought, and your mood is still unendingly low, it might just be your respective levels of RGS8 and MCHR1 playing up. There’s a long way to go before the treatment is tested on humans – treatments that work on mice often fail the step up to humanity – but it certainly sheds some preliminary light on an illness that baffles psychiatrists and sufferers alike.

Everyone will encounter stress and depression at some point in their lives and it is essential to spot warning signs early. If you ever have problems with stress or depression, whether it is struggling at work or you simply need some guidance, there are a number of support groups available including:

NHS Choices: considered the ‘online front door’ of the NHS, it can provide a range of health information

Samaritans: Call 116 123 – A free phone service is available 24 hours a day 365 days a year. They can help you with anything you are going through and will provide practical advice and support.

Health and Safety Executive: Government-backed website offering advice for a range of health issues, for both employees and employers.

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