As the doctor gave her a physical exam, Mary* was unable to maintain eye contact. Although her depression had left her with a limited range of emotions, she still struggled to keep from crying.
“Restricted and tearful affect,” wrote the examining physician.
The results of her physical examination and routine laboratory tests were normal. And she had no psychotic symptoms or thoughts of hurting herself — this time.
Over two years before, Mary, a retired cafeteria worker, started having asthma-like symptoms treated with corticosteroids. She developed corticosteroid-induced psychosis with visual hallucinations and mania. When she was taken off of the corticosteroids, her psychotic and manic symptoms went away but were replaced with severe treatment-resistant depression.
Mary found it difficult to read a newspaper or follow television programs. She said she had “lost all interest in things” and felt “depressed 24 hours a day.” She was incapable of making even simple decisions and eventually was unable to get out of bed. She grew more and more anxious and felt “in constant fear” that she would never get well. She had thoughts of death and suicide.
For the next two years, Mary was treated with a wide range of antidepressant and anxiolytic medications, psychotherapy, and electroconvulsive therapy (ECT), all without long-term success. Mary was hospitalized several times yet remained depressed. She moved into an assisted living facility because she had become too disabled to live at home or with family.
Now Mary was back at the hospital. She was tired and desperate for relief, stating, “My days are hell.”
Her physician wanted to try ECT again, but this time with a longer course of treatment. Over the next month, Mary’s mood and activity levels slowly improved. In the following two months, with outpatient medication and maintenance ECT, Mary’s depression continued to improve, and she was finally able to live independently at home again.
A New Approach to Treatment-Resistant Depression
Up to a third of adults with major depression suffer from symptoms that do not respond to treatment or resolve briefly but come back. Some, like Mary, eventually find a treatment that works for them. However, approximately 10% to 15% of patients with major depression never respond to treatment and have an increased lifetime risk of suicide.
Fortunately, scientists at UC San Francisco’s Dolby Family Center for Mood Disorders can offer some hope for such patients. In the January 18th issue of Nature Medicine, Dr. Katherine Scangos and colleagues report a case study in which targeted neuromodulation was successfully used to provide relief from severe treatment-resistant depression symptoms within minutes.
As noted by Scangos:
Prior attempts to develop neuromodulation for depression have always applied stimulation in the same site in all patients, and on a regular schedule that fails to specifically target the pathological brain state. We know depression affects different people in very different ways, but the idea of mapping out individualized sites for neuromodulation that match a patient’s particular symptoms had not been well explored.
The team placed 10 intracranial electrodes into the brain of a patient with severe treatment-resistant depression. The electrodes were placed in several brain regions known to be likely to affect mood. They then mapped the effects of mild stimulation across those regions over the course of 10 days.
The investigators found that stimulation of several of the mood-related brain sites alleviated the patient’s symptoms. Specifically, the patient experienced higher energy levels, reduced anxiety, and a restored sense of pleasure in activities they once enjoyed.
Interestingly, some of the benefits were dependent on the patient’s mental state at the time.
The results are part of a five-year clinical trial to evaluate personalized neuromodulation effectiveness in 12 patients with severe treatment-resistant depression. The investigators will identify brain signatures in each participant that reflect their individual symptoms. Neuromodulation devices will then be programmed to detect deleterious changes in those signatures and respond in real-time with targeted corrective stimulation.
According to Dr. Andrew Krystal, co-senior author of the study:
Our trial is going to be groundbreaking in that every person in the study is potentially going to get a different, personalized treatment, and we will be delivering treatment only when personalized brain signatures of a depressed brain state indicate treatment is needed.
“The World Went From Shades of Dark Gray to Just — Grinning”
The patient is a 36-year-old woman who has had several bouts of severe treatment-resistant depression since childhood. In the past seven years, her symptoms made it impossible for her to maintain a job or drive.
Stimulation of several different brain sites for 90 seconds was found to reliably evoke an array of positive emotional states, as quantified with clinical scales designed to assess mood and depression severity. For example, stimulation of a region called the orbitofrontal cortex (OFC) produced a feeling of calm pleasure the patient likened to “reading a good book.”
When longer stimulation times (three- to 10-minutes) were tested, the investigators were surprised to find that stimulation affected the patient’s symptoms in different ways depending on her mental state at the time. For example, stimulation of the OFC was described as calming when she had been feeling anxious. Still, when the patient was feeling decreased energy, the stimulation caused her to feel overly sleepy and worsened her mood. In contrast, stimulation of other sites reversed her low energy feelings with feelings of increased arousal and energy levels.
The patient shared:
[W]hen they found the right spot, it was like the Pillsbury Doughboy when he gets poked in the tummy and has that involuntary giggle. I hadn’t really laughed at anything for maybe five years, but I suddenly felt a genuine sense of glee and happiness, and the world went from shades of dark gray to just — grinning.
For this patient, stimulation of a brain area called the ventral capsule/ventral striatum was the best at alleviating her primary symptoms of low energy and loss of pleasure in activities she once enjoyed. She recalled:
As they kept playing with that area, I gradually looked down at the needlework I had been doing as a way to keep my mind off negative thoughts and realized I enjoyed doing it, which was a feeling I haven’t felt for years.
The patient continued:
It struck me so clearly in that moment that my depression wasn’t something I was doing wrong or just needed to try harder to snap out of — it really was a problem in my brain that this stimulation was able to fix. Every time they’d stimulate, I felt like, ‘I’m my old self, I could go back to work, I could do the things I want to do with my life.’
The investigators discovered that the stimulation's effects could be tailored to the patient’s mood and could produce positive effects that lasted for hours. Throughout the 10-day study, her symptoms also got significantly better and led to a temporary remission that lasted 6 weeks.
New Device for Long-Term Relief
After the return of the patient’s symptoms, investigators moved on to the next phase of their study by implanting a device known as the NeuroPace RNS System — a device that is currently used to control seizures in epilepsy patients. For their severe treatment-resistant depression study participants, the device will be used to detect brain signature patterns that indicate a shift toward a highly depressed state. The device will then provide mild stimulation to counteract this mood shift.
According to Scangos, the idea is that by keeping neural circuit activity functioning along the correct track, “the pathways that support pathological negative thought processes in depression can be unlearned.”
It has been over 5 months since the NeuroPace device was implanted in this first patient, and she continues to report that her symptoms have almost completely disappeared:
I can’t tell exactly when the device turns on, but I generally feel more of a sense of clarity, an ability to look at my emotions rationally and apply the tools that I’ve worked on through psychotherapy, and that is so far from where I was before.
The patient noted that these results were particularly significant given various life stressors she has experienced during that period.
She shared, “2020 was terrible for everyone, and I’ve had some particularly stressful life events, but for the first time in a long time, I feel like I can bob back up again.”