Before implanting a deep brain stimulation device, the patient's brain activity was mapped to determ...

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Scientists achieve a remarkable breakthrough for treatment-resistant depression

Deep brain stimulation for depression has yielded mixed results. These researchers think they've fixed the problem.

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Being diagnosed with treatment-resistant depression went like this: Somewhere on the internet, I read a story that explained treatment-resistant depression was a diagnosis for people who had routinely failed to respond to antidepressants.

At that time, I was on something like my fifth antidepressant. When I saw my doctor, I asked her if that meant I had treatment-resistant depression. She took a quick look at all the medications I’d been on and said “yep.”

The initial article I’d read let me know I wasn’t alone, but I didn’t yet know how common the condition is. About 30 percent of people with major depressive disorder (MDD) don’t respond to traditional antidepressants — that’s over half a million people in the United States alone. When the outcomes for people with MDD can include death, the world is in desperate need of effective treatments for the condition.

A proof-of-concept study published Monday in Nature Medicine may indicate a significant breakthrough for researchers trying to find treatments for the stubborn condition.

The study focuses on a promising treatment held back by inconsistent outcomes: deep brain stimulation (DBS). In the case of a 36-year-old woman, DBS was administered in a new way — and achieved remarkable results.

What are the options for someone with treatment-resistant depression?

Scientists are pursuing a number of therapeutics as potential treatments for treatment-resistant depression. Some have already been approved, and others are in the works.

For example, ketamine is already being used off-label in some states. Esketamine, a ketamine-derived drug, was approved in 2019 by the FDA for treatment-resistant depression when used in conjunction with an oral antidepressant. In 2020 it was approved for adults with MDD who have acute suicidal ideation or behavior.

In 2018, the FDA granted “breakthrough status” to psilocybin, one of the psychoactive substances in magic mushrooms to be used in clinical trials of psilocybin-assisted therapy.

Meanwhile, in June, results from a Phase 2 trial suggested a one-hour treatment combining oxygen and laughing gas improved symptoms among people with treatment-resistant depression.

Some researchers are taking a more direct approach — literally. Transcranial magnetic stimulation is a non-invasive technique, which uses electromagnetic fields to stimulate nerve cells in the brain. Studies suggest it can provide relief for people diagnosed with severe depression.

Others, like the researchers behind the Nature Medicine study, have been researching something called deep brain stimulation.

What is deep brain stimulation?

Deep Brain Stimulation (DBS) was initially developed to treat people with Parkinson’s Disease.

In DBS, small electrodes are placed in specific areas of the brain. In Parkinson’s Disease, those electrodes are often placed in the globus pallidus, an area of the brain associated with movement. According to the Mayo Clinic: “These electrodes produce electrical impulses that regulate abnormal impulses.”

This has been proven to help people with Parkinson’s control the involuntary movements characteristic of the disease.

Most often used to treat symptoms of Parkinson’s Disease, deep brain stimulation is increasingly considered for treatment-resistant depression. Getty

In people with MDD, the electrodes can also be placed in areas of the brain that regulate mood, the nucleus accumbens. Currently, the electrodes “deliver fixed and constant electrical stimulation to a single brain structure and thus is incapable of responding to variability in a patient’s symptoms,” according to the study team.

A major challenge with using DBS for depression is that even among people with major depressive disorder, symptoms aren’t consistent. Sometimes, a person may be experiencing relatively light or even no symptoms, and at other times they’re debilitatingly severe.

So far, DBS has treated all of those states with functionally the same treatment: the electrodes fire the same no matter how severe the symptoms are. That’s something researchers are attempting to address.

Case in point: This study team attributes previous inconsistent results from current DBS treatments to this inability to personalize the treatment to patients with varying symptoms.

These researchers also believe they may have fixed that issue.

What they did— The researchers focused on a 36–year-old patient who had been living with treatment-resistant depression since she was a child.

First, they mapped the woman’s brain-activity patterns that correlated with her depressive symptoms. This helped them identify where the activity causing depression was happening in the brain and what it looked like.

Then, the researchers placed a device that could fire only when it sensed those specific severe-depression conditions.

In this photograph, a patient in France is being treated for Parkinson's disease through deep brain stimulation. BSIP/Universal Images Group via Getty Images

Think of it like a smoke-triggered sprinkler system: you only want the sprinklers to go off when there’s smoke in the building. If it’s going off all the time, you might be safe from a fire, but everything else is getting soaked.

Those constant pulses are perfect for something like Parkinson’s, where you simply want to quell the activity in one area of the brain that’s responsible for an undesirable symptom. Depression, however, is much more complex, and personal. A device that could adapt to that complex personalization, seemingly, could be the best of both worlds.

What they found— Prior to her treatment, the patient’s depression was a 33 Montgomery and Asberg Depression Rating Scale (MARDS) and the severity of her symptoms was also a 33, this time on the Hamilton Depression Rating Scale (HAMD-6).

The first “during treatment” assessment after the device has been switched on occurred 12 days after the device was turned on. After those 12 days, the severity of her symptoms dropped from 33 to 14. Several months later, that number was 10, which is considered remission.

What it means for the future — Obviously, these results are from just one person. It’s too soon to determine if this treatment would be broadly effective for people with treatment-resistant depression.

But that’s by design. A proof-of-concept study is just what the name implies: proof that the idea, in this case, of personalized DBS, is possible and may be effective.

For people like me, proof-of-concept translates to a sliver of hope.

Not the delusion that this treatment will be immediately available or accessible, or even ultimately makes sense for me. But it means researchers are committing to finding new treatments for this too-common mental illness. Some of that research is very promising — and helping some individuals already.

Abstract: Deep brain stimulation is a promising treatment for neuropsychiatric conditions such as major depression. It could be optimized by identifying neural biomarkers that trigger therapy selectively when symptom severity is elevated. We developed an approach that first used multi-day intracranial electrophysiology and focal electrical stimulation to identify a personalized symptom-specific biomarker and a treatment location where stimulation improved symptoms. We then implanted a chronic deep brain sensing and stimulation device and implemented a biomarker-driven closed-loop therapy in an individual with depression. Closed-loop therapy resulted in a rapid and sustained improvement in depression. Future work is required to determine if the results and approach of this n-of-1 study generalize to a broader population.
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