“For lack of a better word, it’s not sexy in the same way.”
Fact-check: true. Depression is not sexy enough for the spotlight. A major reason we neglect depression—even more than we neglect other psychiatric illnesses—is because the most devastating disease in the world, in terms of total disease burden, lacks that certain je ne sais quoi.
Governments, at least so far, have not stepped in to match the cash lost by the private sector’s exit. America’s National Institute of Mental Health is losing its research capacity;16 Canada’s federal and provincial governments have made big promises about boosting funding for brain research but we’re only beginning to see that cash materialize. Mental health research gets one-third the public funding cancer research gets, despite having, according to the World Health Organization, a higher burden of disease.17 And even within organizations dedicated to brain research, depression is not a sought-after subject: only one of the thirty-two Canada Brain Research Fund projects awarded in 2014 went to a depression-related initiative—one focusing on the use of transcranial magnetic stimulation as a way to treat treatment-resistant depression.18
So cash flow is a major issue. For all the stigma-busting, mental health boosterism coming from political circles of late, it’s empty rhetoric if it doesn’t come with funding attached.
Anyone waiting for better depression drugs—and (have I mentioned?) there are millions—has a lengthy wait. The prospect of a breakthrough a decade down the road is galvanizing if you’re a researcher or health-care practitioner dedicating your life to this stuff. But if you measure profit and growth in quarters rather than quarter-centuries, or if you wake up each morning wishing you hadn’t, it’s not terribly encouraging.
“We could be lucky,” Steven Hyman says to me in a voice that suggests you shouldn’t bank on luck. “But actually really novel, important treatments may be well more than a decade away. Which is heartbreaking. It’s not hopeless, but it’s hard.”
Like, ten-years-without-fancy-new-meds hard.
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Old Illness, New Tricks—The Electrode in Your Brain
So the status quo sucks. We’re dropping the ball when it comes to coming up with better ways to treat a pernicious condition. But there are some avenues of inquiry that could provide new tricks for tackling an old illness.
Helen Mayberg was drawn to psychiatry but not the psychology part, so she went into neurology, focusing on looking beyond the neurochemical models that have been our mainstay for decades, to map the brain circuits involved in depression, incorporating brain connections with imaging technologies that allow us to read the brain. She was drawn to depression, she tells me, because she felt neurology largely ignored it.
Mayberg talks, quietly but firmly, like someone at the forefront of her field because she is. In her work at Emory University and, since I spoke with her, in her new gig as founding director of the Center for Advanced Circuit Therapeutics at the Mount Sinai Health System in New York, she tries to pinpoint what brain activity abnormalities are present in depressed people and aren’t there in people who aren’t depressed, how those abnormalities change in people who get better with treatment, and what differentiates people who don’t get better on those treatments from those who do. As technology evolves, researchers have gone from simply observing brain function to intervening in it—seeing what happens when you stimulate one part versus another in different circumstances in people with different pathologies.
Eventually, Helen Mayberg hopes, you’ll be able to do a brain scan before starting someone on treatment and use it to decide what treatment will work best on that person.
“There are people who need therapy and should never go near a drug: it will not work. And, equally, there are people who need a drug and it doesn’t matter how badly they want to do it without drugs, it’s not going to work,” she says. The present trial-and-error modality “is very demoralizing….You have to give people what their brain needs, period.”1
She thinks brain imaging and brain stimulation hold the key to better depression diagnosis, treatment and treatment selection. But “everyone has a bias. If you’re a geneticist, you think genetics is the answer. If you’re a chemist, you think chemistry is the answer. I’m a neurologist: I think the brain is going to be effective. But I set up my experiments to prove myself wrong.”
Wonky circuitry’s role in depression notwithstanding, the science of neuroimaging is not nearly as reliable as news coverage of sci-fi brain scans suggests. In a 2009 study researchers showed an Atlantic salmon a series of photographs of humans in various social situations. The salmon was asked to determine what emotion the person in the photo was experiencing. The salmon was dead. Their scan returned neural activation results anyway. The falsest of false positives. The researchers concluded that the likelihood of random noise giving you misleading results in a scan involving some 130,000 separate bits of information necessitates multiple comparison controls.2 You’ve got to curb your neuroimaging enthusiasm, calculate the likelihood of noise and check to make sure the pretty colours you’re looking at aren’t just dead fish brainwaves.
Over the years, Helen Mayberg’s work studying what’s going on in the brains of profoundly depressed people led to new ideas about how to treat people who don’t respond to anything out there. Enter deep brain stimulation (DBS), where you implant electrodes in someone’s brain and a mini-pacemaker below their collarbone. It isn’t FDA-approved for depression but is already used for Parkinson’s and extreme cases of treatment-resistant epilepsy. Instead of burning spheres in your brain, as in a cingulotomy, Mayberg pioneered a method of implanting electrodes in your brain, attaching them to a battery-powered pulse generator, switching it on, and leaving it there, in the hopes that the ongoing electrical stimulus will right whatever’s listing in your brain activity. It had great results and then it didn’t and researchers are trying to figure out why.
DBS surgery begins in a fashion similar to cingulotomies: with an MRI. Local lidocaine to numb your scalp. Metal scaffolding frame affixed to your head, then to the bed once you’re wheeled into the operating room, so your head, neck, skull are immobile. Another scan. A precision drill bores holes through your skull, but instead of the anterior cingulate cortex (that place where your horns, if you had them, would be), Mayberg’s team threads a pair of tiny electrodes a bit lower down, into what’s known as Brodmann area 25, which tends to be too hyperactive in depression.
The tiny electrodes are then connected via spiderweb-thin wires to a battery-operated implant—a pulse generator—that’s inserted under your collarbone during a separate surgery.
Mayberg and her colleagues were surprised how quickly it worked on people for whom it was effective. One of her first patients, having had that node implanted and turned on the very first time in 2004, told Mayberg it felt like an Off switch for her depression. That patient was Deanna Cole-Benjamin, who spoke with me in a Kingston, Ontario, coffee shop one November morning a dozen years after she lay in an operating room, smelling and hearing the surgeons drilling holes through her skull.
“When they’re drilling, it’s noisy,” a cross between a dentist’s drill and something you’d use for home renovations. “You feel the vibrations and you smell it. Kind of like a burning smell, I guess.”3
And then she overheard her brain.
At first she thought one of the many machines she’d been hooked up to was malfunctioning. But it was her brain activity expressed aurally.
“You hear the electricity in your brain, you hear the synapses. It just sounds like radio static, or a TV station that’s not in tune. Like, ‘chhhhh’ the whole time….
“So that was sort of cool.”
Deanna was in a Toronto operating room, becoming the sixth person in the world to receive DBS for depression.
She’d spent most of the previous four years living in a Kingston, Ontario, psychiatric hospital in the grips of a depression that sucked her under out of the blue one summer. She came to that oper
ating table borne by desperation: nothing else had worked. After years of trial and error and error and error, her doctor called up a colleague in Toronto who was trying out an invasive new depression treatment. Would his patient be a good candidate?
It sounded crazy, but if anything, the total foreignness of the procedure, the lack of any cultural association, positive or negative, actually made its imagining less scary. “We really felt like we were coming to the end of a road….We just thought, if there’s an option, we have to take it.” So there she was, in the operating room, scalp anaesthetized, screws of a stereotactic metal scaffold pinning her head in place. She remembers a room full of people, the procedure so new it was spectacle. Surgeons sliced and peeled back a flap of skin, drilled burr holes through her skull and wove hair-thin flexible filaments, tips studded with tiny electrodes, into her brain tissue. They turned on the electrical stimulus, snaked the electrodes into a different location, turned on the stimulus again—to see how she’d respond with electrical jolts at different places. Kept asking her questions—Is it sunny outside?—to ensure her cognitive faculties remained intact while they tinkered inside her head. With the electrode in one particular position, Deanna remembers seeing Helen Mayberg’s eyes—“Elizabeth Taylor eyes”—as though for the first time. And, all of a sudden, an optical assault of psychedelic colours—like going from Kansas to Oz. So vibrant she felt nauseous, needed sunglasses.
“It was really, truly, like a light switch went on. I processed colour that I hadn’t processed at all in those four years.”
The sensation disappeared when the electrode was moved or the current was switched off but it was a sign to her doctors that they’d found a sweet spot.
Then general anaesthetic for another surgery, this one putting a pulse generator beneath her clavicle and threading the twin wires wormed into her brain down inside the right side of her neck and connecting them to her new battery pack. In the Kingston coffee shop she lets me feel the ridged uneven bumps of skin on her right upper chest and on either side of the top of her head. Surgical souvenirs.
They didn’t flip her switch right away: Deanna returned to the Toronto hotel where she was staying to recover, then went back to hospital to have the current turned on. Then back and forth for months to figure out what level of electricity worked best. First big shifts, to find a setting that made enough of a difference that Deanna was well enough to return home to Kingston; then “a little bit of fiddling” she’d drive into town for. “They literally just hold a remote control over the battery….There’s an On and an Off button and there’s an Up and a Down button, and it’s like a phone screen so you can see the voltage.”
And, somehow, the numbness lifted.
For the first time in four years, she could hug her kids and feel it.
She returned to work, astonishing herself. “That was never even a goal.” In some ways, the transition was weirder for her colleagues than it was for herself. “Not, ‘She’s a loose cannon; we can’t trust her,’ but, ‘Let’s not give her too much because we don’t want to stress her out.’ That took a period of time for people to feel confident that I was okay.”
Deanna’s had electrodes buzzing in her brain ever since. Lows like her grandmother’s death a couple of years later were bad, but not nearly as catastrophic as she’d feared. She goes back under the knife every couple of years to get the pulse generator removed from her chest cavity and the battery replaced.
“It’s a bit of a pain. But it works….I don’t want to go there ever again in my life.”
The excitement over DBS’s initial success was contagious enough to infect commercial medical device-makers, who went forward with clinical trials. The two trials—one by Medtronic, a maker of high-tech surgical, cardiovascular, gastrointestinal and neurological tools; the other by St. Jude Medical, maker of the now-ubiquitous mechanical late-1970s heart valves, among other things—both flopped. The Medtronic study was “discontinued owing to perceived futility” after failing to show significant improvement compared to sham treatment after sixteen weeks; St. Jude’s was discontinued after an analysis predicted the probability of a successful outcome to be 17.2 percent, at most.4
St. Jude Medical declined my request for an interview. “Unfortunately we do not have FDA approval to offer DBS for depression. We conducted a trial years ago, but we do not have that indication and can’t talk about it outside of a research context,” a spokesperson wrote in an email, suggesting I speak with Helen Mayberg.5 Medtronic declined too. Talking to me without FDA approval “would constitute off-label promotion,” a spokesperson wrote in an email whose chain included a delicious forwarded note from another Medtronic comms person: “I normally don’t support books…[ellipsis in original] passing this request if it’s of interest. No clue who this person is.”6
The studies’ failures were a blow to Mayberg. Talking to her more than a year later, in early 2016, it still stung.
“My advice [to them] was, ‘You don’t know enough to proceed [with clinical trials yet].’ They thought they did….It’s wildly disappointing to see something I know works not do well in the trial….That’s just maddening. How can it not be? You can only set examples by publishing your results, demonstrating that what you did worked, and hope that people follow suit. I’m not queen, okay.”
What may have happened, she said, is that the researchers mistook a shift from the emotional flatlining of despondence to a fluctuating instability as a bad sign, when it may have been the mind shaking itself awake. Or the researchers picked the wrong patients in the first place. She suspects no one will want to pursue this kind of clinical trial again until they have a reliable biomarker with which to pick the right candidates. But none of this has dampened her faith in her method or her plans to pursue it. What she’s left asking herself is whether it’s ethical to provide a treatment that’s been shown to work in individual cases but not in clinical trials; whether it’s ethical to deny it to desperate people who’ve exhausted all other options.
She figures more than three hundred patients have gotten DBS for depression at three different brain sites. In most cases, over the long term, Mayberg says, it works—“It doesn’t mean they can’t have bad days or even depressions but they are no longer treatment resistant as they were prior.”7
There’s certainly demand for it, although most of the people banging down Helen Mayberg’s door asking her to plant electrodes in their brains don’t qualify for the procedure: they haven’t failed all existing approved treatments yet. “I’ve had thousands of calls to my lab, and we take one in three hundred people. Because two hundred and ninety-nine out of three hundred don’t meet that criteria. They haven’t had ECT at all, they haven’t had effective treatment, and they’re calling to get brain surgery.”
* * *
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THERE’S MORE THAN one way to plant an electrode in your brain, and Darin Dougherty, the psychiatrist and director of neurotherapeutics at Massachusetts General Hospital, is chasing a more precise way to jolt your neurons into health. Affable and patient, this is the guy who walked me through all the -otomies when describing the way surgeons burn sugar-cube-sized spheres in your brain to treat your depression.
The electrode setups that have been tried so far for depression—Helen Mayberg’s included—are “open loop” systems, where the electrodes are basically in “go” mode from day one. Dougherty is working on a “closed loop” system—a bit more complicated and more sophisticated, he suggests: you have a responsive electrode that’s monitoring your brain activity and, when it senses any abnormality associated with the pathology it’s there to treat, it switches on and buzzes until your brain activity is normal again, at which point it turns itself off.
So what suspicious neural activity could precipitate electrode-buzzing? Darin Dougherty’s trying to figure that out. You can’t measure any of this well without getting deep into brain tissue so he’s using people with severe epilepsy as “patients of opportunity, because we can’t
just take somebody off the street and put electrodes in their brain.”8 So while epileptic inpatients sit in hospital with a slew of electrodes nestled in their brains measuring seizure activity, Dougherty and his team run them through other behavioural tests to see how they respond to various situations that give researchers a sense of how their emotional processing is doing. Some of the epilepsy patients Dougherty is studying have mental illnesses like depression; others don’t. So he can compare the differences in neural activity for each task between the healthy and unhealthy groups.
Dougherty’s research team got a $30 million grant from the Department of Defense to study the use of closed-loop deep brain stimulation on veterans with depression, post-traumatic stress disorder, traumatic brain injury and substance use. Maybe the coolest thing they’ve made so far is a little box they implant inside your brain that measures everything—all the neural activity you’d otherwise use a wardrobe-sized contraption to track. This is the thing that would notice something wrong and tell various nodes of the electrodes snaking between the gyri of your brain to turn on or off.
Like the National Institute of Mental Health and others fed up with the maddeningly inconsistent ways the disease we call depression manifests itself, Darin Dougherty is focusing his research on addressing underlying symptoms rather than a one-size-fits-all label of depression. He points out that a diagnosis of depression has to satisfy five of the nine DSM criteria, yet two people could have vastly different manifestations of the same disease, even if certain symptoms correlate—can you wake up in the morning? Do you want to die? “To assume their circuitry is identical is somewhat foolhardy and, in retrospect, could explain why open-loop deep brain stimulation wasn’t effective….So we’re not even going there again. Been there, done that.”
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