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As many as one-fifth of people experience depression at some point in their lives. Thankfully, for most, antidepressants and psychotherapy can reduce symptoms dramatically.

But they don't work for everyone. So doctors and scientists have been looking for ways to help people with treatment-resistant depression. And they seem to have found some really good alternatives.

The weird thing is: they don't know why these alternatives work — which underscores just how little we know about our brains. For example, a randomized controlled trial in 2013 found that ketamine significantly improved symptoms in people with treatment-resistant depression. Ketamine is perhaps best known as a party drug since taking it can induce euphoria, a sense of peace and serenity, and an altered perception of reality.

Doctors are excited, though, because even when doses are similar to recreational ones, its anti-depressive effects can last 1 to 2 weeks. That's long after the drug itself is gone from the person's body. And in addition to being long-lasting, it also starts working fast.

You usually have to take traditional antidepressants for weeks before their effects kick in. Ketamine can improve symptoms in as little as 4 hours. Why ketamine works so well is a mystery, though.

Medically, it's used to sedate patients before procedures — an effect which stems from blocking specific receptors in neurons involved in consciousness. But that doesn't explain how the drug continues to alleviate depression for weeks after it's gone. That's partly why scientists now think that ketamine triggers a chain of reactions that ultimately results in synaptogenesis — the process by which brain cells make more connections with one another.

People with fewer of these connections tend to be more depressed, so it could be that building new ones can relieve depression symptoms. But even though ketamine seems promising, you can't get a prescription for it just yet. We don't know if it's safe or effective if used repeatedly.

And doctors are concerned about the dissociative side effects — that detached from reality feeling that makes it such an appealing recreational drug. Several clinical trials are being conducted, though, so we'll know more soon. Another weird thing that mysteriously helps relieve depression is sleep deprivation.

In a large meta-analysis, about 60% of people with depression had their symptoms at least somewhat alleviated by being kept awake overnight. Like ketamine, the anti-depressive effects of sleep deprivation were felt within hours. But... most of the people returned to feeling crummy after they started sleeping again, so it's not really a long term solution.

Still, doctors are intrigued. If they can figure out how it works, they might be able to design a drug to mimic its effects without having to keep people up. The trouble is, sleep deprivation affects a lot in your brain, so it's hard to pinpoint what is making you feel better.

It could have something to do with the neurotransmitter adenosine, as staying awake all night increases the levels of it in the brain. Although the specifics aren't fleshed out, neuroscientists know that adenosine is important for regulating mood. But there are also studies which suggest sleep deprivation increases brain-derived neurotrophic factor — a protein that helps neurons survive and form new connections.

And in rats, it's even been shown to stimulate neurogenesis — the growth of new neurons — in the hippocampus, a region of the brain which is important for cognition and emotion. So that could be how it works. Or... it could be something else.

With all this uncertainty, it'll probably be awhile before any real treatments come out of this research. And while you could theoretically stay up a night or two to feel better, chronic sleep deprivation usually makes depression worse. Another experimental treatment that's a bit more sustainable, is vagus nerve stimulation or VNS.

The vagus nerve transmits information between the brainstem and organs like the lungs, heart ,stomach, and liver. And it's possible to get implanted with a device that electrically stimulates this nerve — kind of like a pacemaker. That's because in the 1980s, doctors demonstrated that stimulating this nerve can help with epilepsy.

But during trials, they noticed that using the device often improved patients moods, too even when it didn't stop their seizures. This led to larger clinical trials in people with treatment-resistant depression. And a 5 year study of nearly 800 patients found that about 68% of the ones that received.

VNS had their depression symptoms decrease by 50% or more. That's particularly impressive given that these patients had failed to respond to at least 4 other treatments for depression prior to the study. No one is quite sure why it works, though.

It may be that stimulating the vagus nerve activates areas of the brain like the prefrontal cortex and limbic system, which are important for regulating thoughts and emotions. Studies have also found that, like sleep deprivation, it can affect the levels of neurotransmitters often implicated in mood disorders. Or, it may be all about those connections again — VNS therapy can also increase neuronal growth.

But even though VNS stimulation seems to be effective for treatment-resistant depression, it's not easy to get an implant. While the nerve stimulation part is fairly safe, the initial surgery to put the device in is pretty invasive. And if things don't go well, you could lose the ability to speak.

So these implants are generally considered a last resort. And hopefully, less dangerous ways of stimulating the vagus nerve are on the horizon. Doctors are currently investigating devices that work from outside the body, and in Europe, they can be prescribed alongside another approved treatment for depression.

But for now, in the United States, they're only approved for treating migraines. And even if they're deemed safe and effective worldwide, neuroscientists won't consider their work done. They won't stop studying them until they understand why they help.

Like with sleep deprivation and ketamine, knowing how VNS works could lead to safer, more effective treatments. But in a more general sense, it can help scientists better understand the underlying causes of depression. We don't know how these treatments work because there's just still so much we don't know about our brains and why we experience depression.

And research into things like ketamine and sleep deprivation, as weird as they might seem, can help us fill in those gaps. Thanks for watching this episode of SciShow Psych! And thanks especially to our patrons on Patreon, who voted to make this brain-focused SciShow channel a reality.

Without their continued support, we wouldn't be able to make educational psychology episodes like this one. So if you like what you just saw and want to help us make videos like this, you can head over to Patreon.com/SciShow to learn more about joining our community of patrons. [ ♪OUTRO ].