Inverse - 🧠 Let’s talk about depression

Sarah Sloat

Sunday Scaries

Hello! My name is Sarah Sloat and welcome to Sunday Scaries #179. Thanks for reading this chill newsletter for not-chill people.

This week’s chill icon

This week’s chill icon is Terry — a “cat napper” who volunteers at his local shelter. And yes, his volunteer work includes taking naps with cats. I’m giving this a 10/10.

Have you encountered a chill icon (or icons) IRL or during your internet browsing? If so, I want to hear from you. Send an email over to sundayscaries@inverse.com and you might see them in next week’s newsletter.

Let’s talk about depression

Unless you are a scientist, you may never have considered RNA — ribonucleic acid found in all living cells — in any great detail until the advent of the mRNA (micro RNA) vaccine against Covid-19.

Fundamentally, RNA enables genes to make proteins. But there are variations on the theme, including a kind of RNA called long non-coding RNA, or lncRNA, which interacts with other RNA, protein, and DNA to play a role in how distant genes express themselves. If that all sounds a bit vague, then know this: Scientists agree that long noncoding RNAs are pretty confusing.

What we do know, however, is that mammalian genomes encode tens of thousands of lncRNAs, and about 40 percent are specific to the brain. And lncRNAs appear more abundant in complex organisms, especially primates. But as to what they do there, the science is a little murky.

“We have absolutely no idea what many of them are doing,” says Orna Issler, an instructor at the Icahn School of Medicine at Mount Sinai.

Because so many lncRNAs are specific to the brain, Issler and her team think they could unlock a new understanding of how the mind works — and especially how all of this relates to depression. Long non-coding RNAs, they suggest, could be a target for new treatments.

One lncRNA dubbed FEDORA is particularly intriguing for Issler. In a recent study, FEDORA was singled out as a potential sex-specific regulator of depression — a discovery that could help explain why women are twice as likely to develop the condition compared to men. This knowledge may, in turn, lead to improved diagnosis and treatment.

“Our vision is that one day we’ll have improved, individually tailored therapeutics for depression — and potentially different ones for men and women,” Issler says.

Sex differences and mental health

Mental health conditions are caused by a combination of genetic, environmental, and biological factors. This is why molecular mechanisms can’t provide all the answers when it comes to the question of why women are more likely to be diagnosed with depression than men.

But they can offer some clues. Depressed women tend to have slightly different symptoms compared to men, and these may be more severe. They are also more likely to have anxiety and depression.

There are also sex differences in responses to antidepressants. Premenopausal women tend to show a better response to serotonergic antidepressants like Lexapro and Zoloft, while men typically respond better to tricyclics like Norpramin and Tofranil. Meanwhile, antidepressants can also cause more side effects in women, especially when taken with different drugs.

Despite these differences, there are no official guidelines for treating women and men differently. This, Issler says, should change if we want to improve outcomes.

“The sex of the patient should be one of the factors we think about when we’re providing treatment,” she explains.

A new understanding of depression

Issler and her team’s study reveals several insights. For example, an examination of postmortem human brain samples shows FEDORA is mostly found in cells related to the nervous system called oligodendrocytes and, to a lesser extent, neurons.

They also examined FEDORA in samples of people between the ages of 18 and 65 already participating in a study where they receive ketamine as a treatment for depression. Blood samples show that there were higher circulating levels of FEDORA in women diagnosed with major depressive disorder compared to men and women without depression. Further, falling levels of FEDORA correlate with the degree to which ketamine alleviates the participant’s symptoms.

The study team also genetically engineered mice to express the long non-coding RNA in the prefrontal cortex. Overall, they found an association between FEDORA and the development of anxiety and depression — but only in the female mice.

These sex differences are likely due to genetic differences between the sexes rather than hormones, the team observes.

Now, Issler wants to study the mechanisms driving this connection and probe the potential of other long noncoding RNAs.

“We opened this Pandora’s box and we want to find out more,” Issler says.

Now look at this oddly satisfying thing

This gorgeous structure is called Glasshouse, and it’s located in Woolbending Gardens in the UK.

Have you seen something strangely satisfying online or IRL? Send your best examples to sundayscaries@inverse.com for consideration for next week.

What I’m reading this week

Distract yourself from the scaries with these reads:

The wreckage of ancient hurricanes could predict future storms. It’s time to pay attention.

Can this bird self-medicate with plants to kill parasites? Here’s some weird science at its finest.

Science and superheroes invented the multiverse by mistake. They’re still fighting over it today.

And if it’s midnight and you’re still feeling the scaries…

Tremble at the presence of Lobstah Mickey.

That’s it for this week — thanks for stopping by!

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Inverse - 🧠 Let’s talk about depression

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