A Pill-Free Antidepressant

As Rachel Force bobs around her classroom at Elon University in North Carolina, she sports a blue headband and fanny pack, two accessories that are actually part of a device that delivers a low-level electric current to specific locations on her forehead. Force is an assistant professor of behavioral neuroscience, and she’s also the subject of her own neuroscience experiment with transcranial direct current stimulation, or tDCS. From her few sessions with the device, Force has seen “profound” changes.

“I just felt generally less anxious,” she says.

Force felt more spontaneous and extroverted in social situations that, prior to tDCS, she might have shied away from. She also takes an antidepressant that helps reduce the symptoms of her anxiety, but the tDCS “actually changed my behavior patterns.”

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Rachel Force occasionally teaches while wearing a tDCS device.

The device releases a small amount of current, so small that most people don’t even feel it. The electrodes stimulate certain sections of the brain, but not enough to actually cause a neuron to fire. Rather “they change the cell properties” says Abhishek Datta, chief scientific officer for tDCS device-maker Soterix.

The current will cause a cell membrane to polarize—either bump up or decrease the negative charge within—in a way that will affect the neuron’s potential to fire a signal. Just changing that potential is enough to make an impact, Datta says. Some studies have shown that tDCS can alleviate symptoms of depression, enhance cognition, aid in stroke rehabilitation, and reduce chronic pain. The technique has already been approved in Europe and Canada for treating pain and depression.

In the United States, tDCS hasn’t been approved by the FDA for clinical use, though similar devices can be purchased as long as the company selling them makes no medical claims. And while researchers have found brain stimulation can treat depression, pain, speech, and motor problems, they don’t yet know exactly how it works or how to make the best use of it.

But if they settle those questions, the payoff—for patients and companies—could be substantial.

Possible Advantages Over Pills

If tDCS is approved, it could treat people who don’t respond to medication or simply can’t take it. Take Force, for example. While nursing her children, she needed to switch antidepressants to one that doesn’t cross over into breast milk. She found one that worked for her, but some women may not have that option, especially when facing depression during pregnancy, which affects approximately 12% of pregnant women. These same women may not want to stay on or take antidepressants because experts don’t know how this type of medication may affect a developing brain. But at the same time, they can’t necessarily go untreated since depression can harm both the woman and the fetus.

If those patients could instead switch to tDCS, they’d be able to use a depression treatment that is localized to their own brain and wouldn’t impact a developing a fetus. Or at least, that’s the theory.

“People are more and more recognizing the potential advantages of something that is not a pill,” says Simone Vigod, a psychiatric researcher at the University of Toronto.

Vigod is running a small pilot randomized controlled trial of tDCS on depressed pregnant women who don’t want to take antidepressants. For three weeks, participants will either get 15 sessions of tDCS (each lasting a half hour) or a sham procedure that serves as a control.

The 18 participants in the trial come into an obstetric clinic five days a week to monitor the fetus while in their tDCS session. Not only do the nurses gather data for the study, the fact that they’re monitoring the fetus during the procedure has been reassuring for the women.

“We really want to show how focal tDCS is,” says Vigod, who hopes to publish the data from the study next year. “If we showed that it was effective and also that it’s safe, this is something that women could use at home,” she adds.

It’s not just depressed pregnant women who could benefit from tDCS. As many as half of all depressed patients fail to respond to the current roster of antidepressants.

“The issue of non-response to antidepressants is a big, big problem,” says Daniel Blumberger, the co-director for Temerty Centre for Therapeutic Brain Intervention at the University of Toronto.

Take-Home Kit for Depression

Blumberger studies the gamut of brain stimulation, which include tDCS, electroconvulsive therapy (ECT), and repetitive transcranial magnetic stimulation (rTMS). All these techniques have different advantages and disadvantages. Both ECT and rTMS have been approved for depression treatments in the United States, unlike tDCS.

The downside of ECT, says Blumberger, is it’s fairly invasive: patients need muscle relaxant and a sedative since the procedure induces seizure. Plus, people are still scared of it because of its old reputation as “shock therapy.”

The other, rTMS, uses a magnetic field to induce an electrical field and is less invasive but cumbersome and expensive, requiring a trained technician.

Blumberger has studied use of rTMS and tDCS on older adults, who may avoid taking antidepressants because of the sheer number of other medications they need.

TMS, while more cumbersome than tDCS, can also be used to treat depression with surprising results.

“When it does work, people are very grateful, because these are people who have not responded or who have not been able to take other treatments,” Blumberger says.

Though rTMS has a good track record, it’s hard to say if tDCS will offer the same results.

“It’s working a slightly different mechanism of action than rTMS,” says Blumberger of tDCS. Still, he adds, “it can be an effective treatment for depression.”

While some studies have found significant improvements when using tDCS over a placebo, one of Blumberger’s studies found no significant difference in results.

The question of tDCS’s effectiveness could be settled with large clinical trials involving hundreds of patients, but scientists and device manufacturers haven’t wanted to fund those trials until they know the precise optimal dose and environment for using tDCS.

Though they don’t know exactly how it works, one theory is that, in depressed people, an area of the brain at the left dorsolateral prefontal cortex—a region through to be involved in working memory, decision making, and social behavior—is less activated than in non-depressed individuals.

When placing a positive electrode or anodal electrode on that region of the scalp, that region of the brain becomes more excitable and could alleviate the depression, says Datta, the Soterix CSO.

“We’re targeting the right brain regions,” he says. “So right now it’s about maximizing the beneficial effects we’ve seen on smaller populations.”

Ideally, tDCS will be another tool kit available for treating depression or other disorders. “You may come across patients who do not respond to drugs, who do not respond to rTMS, and tDCS presents them with yet another option to try out,” Datta says.

Currently in the United States, if depressed patients fail to respond to one of four different drug treatments, the doctor may use rTMS to relieve the symptoms. But with rTMS, the patient has to go to a clinic. Soterix is also hoping to create a tDCS device that could potentially be used at home by patients.

A Warning

A number of companies—including Soterix—provide tDCS equipment to researchers studying the technology. Normally, such restricted use would continue until the FDA approved the devices for use outside the lab, but consumers haven’t been waiting around. So long as a company makes no medical claims, manufacturers can sell brain stimulation devices direct to consumers, marketing them with claims that they will enhance skills or athletic performance.

Some people have taken to creating their own devices to improve their memories or learn new skills more quickly. However, the evidence supporting tDCS for cognitive enhancement is mixed. Such uses of brain stimulation have been hyped to the extent that neuroscience researchers recently put out a warning letter in the Annals of Neurology against do-it-yourself experiments.

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One device available to consumers is mounted on the connecting band of a pair of headphones. Sold by Halo Neuroscience, it targets athletes.

One of the letter’s co-authors, University of Pennsylvania researcher Rachel Wurzman, emphasizes that scientists don’t know the potential harms that could come from tDCS. The most robust positive clinical trial results have been in depression and pain, she says, but even positive outcomes in tDCS trials are not enough to predict how an individual might respond to the treatment. Researchers have seen tremendous variability in cognitive measures and outcomes, Wurzman says.

When using tDCS for cognitive enhancement, for example, about one-third of participants respond how researchers predict, one-third may respond in the opposite way, and another third may respond in a mixed fashion or not at all, Wurzman says.

Depression studies with tDCS have a better record, but there are still many unknowns. Datta explains that a number of factors can dictate the effectiveness of brain stimulation devices. There’s the placement of the electrodes, called the montage, which determines what section of the brain will be stimulated. There’s the dose, which can include the amplitude of current used and the amount of time a tDCS session runs. Finally, there’s the issue of what the person is doing while they receive treatment. Is the patient relaxed or excited? Amused or angry? What about active or sleepy? All could affect the outcome of tDCS treatments. Certain medications can also change people’s responses. Even hormonal cycles can affect the outcomes, Wurzman adds.

Even if researchers see improvements for a particular function, it’s hard to tell if the same treatment is impairing a different one. In some cases, increased activity from one part of the brain will down-regulate transmission in another part of the brain, Wurzman says.

“The brain tends to adapt in various ways,” she says. It could cause beneficial results, she adds, “but we need the research to measure the effects at that level.”

Subtle changes in treatment can have an outsize impact, which is why researchers are so concerned with people playing with the technology. In some cases, merely changing the amplitude from 1 milliamp to 1.5 milliamps, researchers can see a response that’s opposite what they had wanted. Even head shape can affect the outcome by introducing variation in current flow.

“There is no guarantee that the current flow in your brain is like the current flow on someone else on a reddit board’s brain, much less like the current flow in the 14 people that may have been tried in the depression study,” Wurzman says.

Potentially Life Changing

Despite the unknowns, Wurzman and other researchers are excited about the potential for tDCS to improve people’s lives.

For pregnant women, depression during pregnancy is the biggest risk factor to developing postpartum depression. Both those disorders are linked to poor outcomes for a child, such as delayed motor development, Vigod says.

“If we can treat women while they’re pregnant, that may be preventing a whole host of intergenerational problems,” she says.

While Wurzman is encouraged by the clinical response to tDCS, particularly for ailments like depression and pain, she and her colleagues first need to understand just who will respond to this treatment best and what the circumstances of their treatment should be.

“We don’t know what the optimal activity would be for different purposes, whether that’s cognitive enhancement or depression.”

Force, the Elon University professor, suspects her classroom tDCS sessions have contributed to her new extroversion—after all, that part of her was on display as she taught. It could be possible that the tDCS treatment gave the part of the brain responsible for outgoing behavior a further boost, Force says.

However it works, even after just a few sessions, Force noticed a powerful effect.

“It really did change my life.”