• July 28, 2014

A Revolution in Mental Health

Inside a Revolution in Mental Health 2

Narayan Mahon

Bruce Cuthbert, lead architect of a restructuring of mental-health research.

By the time Bruce Cuthbert, director of adult translational research at the National Institute of Mental Health, paced to the podium at the annual convention of the Association for Psychological Science this May, the audience could be forgiven for thinking he wanted to rewrite the book on mental illness.

They had seen the stories: The National Institute of Mental Health was at war with the new edition of psychiatry's central text, the Diagnostic and Statistical Manual of Mental Disorders, an ever-growing catalog used in doctors' offices, insurance bureaus, and research labs. The institute's director, Thomas Insel, had written a gone-viral blog post saying so, declaring that the institute would slowly abandon the DSM in structuring its clinical research grants, in favor of its own, newly built system. Tweets fired. "A bombshell!" Blogs chattered. Book authors and the antipsychiatry movement gained a news peg. Psychiatry, it seemed, was in crisis.

Insel's blog post was actually not news—the institute had been stating its intentions for three years. But Cuthbert, the lead architect of NIMH's radical restructuring, had come down from his Bethesda office to set a few things straight. Don't worry, he told the scientists. The institute did not want to overturn everything they knew about mental illness. It just wanted change everything they knew about studying it.

A former military researcher with a keen technical mind, Cuthbert did not blunt his critique of the status quo.

The DSM diagnoses, which describe collections of symptoms, are the functional equivalent of saying someone has "headache disease," Cuthbert said. They are ignorant of biology, and often of behavior. Symptoms within a disorder vary wildly, and patients suffering from separate categories—say schizophrenia and bipolar disorder—share many of the same problems.

In many ways, he added, the field remains in the grip of Western cultural traditions going back to Plato. It struggles with Descartes's distinction between the mind and body, and lingers on naturalistic divisions between thought and emotion. It grants the human brain a certain exceptionalism, limiting comparisons with other animals. And that has all led to a host of problems.

Clinical researchers are failing; their work is hamstrung by the DSM's definitions. Geneticists have turned up few genes strongly tied to specific disorders; neuroscientists, likewise, have found few brain circuits unique to the manual's categories. There are few new effective treatments. Drug companies, lacking new targets, have pulled out of mental health; schizophrenia drugs are nearly unchanged from those used decades ago; and several researchers recently estimated that the average psychiatric drug helps only half the patients taking it.

Look at heart disease or leukemia—the mortality and prevalence in each disease has dropped precipitously over the past three decades. Now look at mental disorders. Prevalence, severity, impairment, and mortality have hardly changed over the last 20 years. Some treatments are effective, but rarely for everyone. There is little ability to predict who will get a disorder, or when. Scientists have not found a biomarker for any of the major DSM disorders, outside a neurological disease like Huntington's. There are no preventative treatments. None.

Insel and Cuthbert, along with many in the field, have long argued for a shift in how research is done. The debate over psychiatric nosology, as the classification of diseases is fussily known, is as regular as a comet's orbit. By the 1990s, however, it had come to a head, with clinical research sputtering to the point that a former director of NIMH said he felt guilty about investing public money into it. There was little science to lead a new way forward then. But that's no longer the case, Cuthbert told his audience.

"We know now better what to do," he said. "We've had a decade of the brain. We've had a decade of behavior and we're ready to move toward translational models and thinking about our disorders in a different way. We're ready to shift away from folk psychology."

NIMH is promoting a revolution, a genuine paradigm shift, but it is a revolution built in parts, and slowly assembled by many hands. It is perhaps most useful to see its effort, called the "Research Domain Criteria" project, or RDoC, as the victory of psychophysiology, a discipline that has labored to find the links between biology and mental illness but has often remained on the outskirts of clinical psychology.

It also happens to be the field where Cuthbert built his career. Many RDoC components go back to psychophysiology's earliest days, Cuthbert told the audience. "This is not new. Some of the first cohesive statements of this were issued by Peter Lang, my mentor, over 45 years ago."

Peter Lang? Few outside of psychology have ever heard of him, even though he is arguably one of the discipline's most influential researchers. And Lang is not just a forebear of NIMH's enterprise. He is a beneficiary. Though his career began in the 1950s, Lang remains active, and his lab, at the University of Florida, was one of the first to receive a grant from NIMH under its new guidelines.

"It's possible to put people in these boxes, these categories. But there's no clear water between them."

Looking at Lang and his position in psychiatry, then, is one way to understand where our concept of mental illness has been and where it could be. And so, this past March, I booked a flight to Gainesville.

Peter Lang has a simple rule. He studies only what he can see.

We're sitting in his office, which wasn't easy to find. His lab hides far from the blue-and-orange-painted trees of central campus, past the softball and lacrosse stadiums, the swampy lake and the sewage treatment center. It's a matchbox of a building, single-story and cinderblock—nothing like the glossy new brain institute where many of his peers work. But that's just how Lang likes it.

Dressed in a dark-green flannel shirt and jeans, his white beard trimmed tight, Lang is spry, his voice gravelly. Through the lab's ramshackle hallways, he's posted black-and-white photos of dead philosophers and psychologists, including a young William James, on a trip to the Amazon, anonymous behind dark circular glasses.

If there's one sentence to sum up how Lang works, it's one he said to me: "Emotion is as emotion does." From the start of his career, he's studied only what he could measure about mental illness. And that has meant, to a large extent, avoiding any theories of the mind that derive from introspection. It's tough to beat Immanuel Kant in that respect, he says. Why try?

His devotion to the measurable brain began early, in the 1960s, when he became one of the first researchers to receive an NIMH grant to test a behavior therapy, what was then a new treatment for phobias called systematic desensitization, which involved gradually exposing the patient to the feared object. Unlike psychoanalysis, which left him cold, this could be tested.

"You could actually study it and get an answer to whether it's effective or not," he says. He found himself driving around Pittsburgh with fake snakes in his trunk—"Noah the Boa" and "Zsa Zsa"—scaring phobics. He and his colleagues soon found that hypnosis, which was used by the treatment's creator, was superfluous; it was all about the exposure. To this day, a similar treatment is used for phobics, including many who have sought treatment under Lang's care.

That work led Lang to more fundamental questions. Psychologists would talk about fear and other feelings, but these seemed like nebulous terms. At the time, there were fierce arguments—but little data—about whether there were four, eight, or sixteen basic emotions.

"That really got me thinking," he said. "What is fear? And then, what is any emotion? Trying to look at it from a natural-science perspective. And that means what you want are quantities that you can measure."

Lang judged that emotion could be measured in three ways: There was behavior, what we do in a situation. And there was language, which dominated at the time. ("How frightened are you, from 1 to 9?") But language is a distant event, filtered through consciousness's confusion. And so Lang added a third dimension: the body's response. Heartbeats, sweat, even the brain's electrical firing—these would be data that he could then compare to language and behavior, building a construct of fear. (Such constructs lie at the heart of NIMH's new system.) Along the way, he taught himself all the technical tricks needed for what only later came to be known as psychophysiology.

Lang and others eventually found two primal emotions: valence—how "good" or "bad" something is—and arousal, from calm to wired. At the same time, he also built standardized systems to elicit these two emotions, directing subjects to imagine themselves in a situation, or to look at photos of food, or erotica, or violence; this latter system, the International Affective Picture System, is widely used throughout psychology and neuroscience.

As his career progressed, Lang watched the evolution of psychiatry's diagnostic categories from a distance. He readily admits, as does Cuthbert, that the third edition of the DSM, released in 1980, helped save psychiatry, giving clinicians somewhat reliable diagnostic standards for disorders like agoraphobia, specific phobia, panic disorder, and others, and freeing them from their psychoanalytic shackles. But his work did not respect the arbitrary boundaries in the manual; he has always welcomed all kinds of anxiety patients at his labs, grouping them in the same projects. He watched with dismay as researchers Balkanized.

"That was very constraining, because the clinical material is not like that," he said. "The people who have only 'X' are rare." So he decided early on to try each one of these diagnostic labels on his patients, to see how much overlap there was among the disorders.

But what tool could he use? For a long time, Lang lacked a reliable way of separating "good" arousal from "bad" arousal: The photo of a gun in a subject's face would elicit as much sweat as some tasteful pornography. You couldn't tell them apart.

He needed a way to reach into the brain—a probe. And that's when he heard about some startled rats in New Haven.

There are few traits more common among sentient creatures than the startle, the six-millisecond SNAP! that runs through your nervous system at a sharp noise or unexpected physical presence. Anyone who has surprised another person in the bathroom can attest to startle's enduring spot in the human brain. And it is the reaction's universality that provided Lang with a decoder ring for fear.

He drew on the work of Michael Davis, then a psychiatrist at Yale University. In the early 1980s, Davis showed that fear-conditioned rats—those who expected a Pavlov-type electric shock—startled much more acutely than rats who had not been conditioned to expect the shock. The difference in those reaction sizes served, in effect, as a measure of their fear. And since there are few qualms about cutting into living rat brains, Davis soon delineated, following pioneering work by Eric Kandel into sea-slug neurons, a fear-response neural pathway in the rats, mediated by the amygdala. It was clear all mammals, including humans, shared a similar pathway.

As Davis's work came out, the DSM-III had only recently appeared, codifying distinct anxiety disorders. Every month, there would be a new article on the psychophysiology of specific phobia or PTSD; it's all about the amygdala, each proclaimed. These were all different disorders, yet somehow their physiology was the same. How could that be? It's a question Cuthbert had been asking for some time.

Cuthbert studied under Lang as a graduate student at the University of Wisconsin at Madison, where he was soon drafted into the Vietnam War. He stayed in the U.S. Army for a decade, serving as an investigator at the Walter Reed Army Institute of Research, studying stress and circadian rhythms. Lang then lured Cuthbert down to Gainesville, where he had just set up shop. They were joined by Margaret Bradley, a UF research professor. (Lang and Bradley are married.) Together they established a lab environment that has changed little over the past 30 years, adopting new technologies, like MRI scans, as they arose.

The amygdala fear circuit of the rats was fascinating, but Lang seized on the startle response. They finally had a physical measurement of fear, a probe that plunged through the baggage of consciousness to a fundamental emotion. And that meant, finally, they could study how this emotion was malfunctioning in their anxiety patients—which they have done, for more than a decade, on almost 500 people.

Lang offered to show me how.

We walked into the front of his clinic, which looks like any other small doctor's office: framed pictures of yellow flowers on the wall, a courteous young assistant behind a desk. In the morning, Lang explained, the patients go through a thorough clinical exam with the lab's psychologist, "because we didn't want the DSM'ers coming back," Lang laughed, "you know, saying that we hadn't been thorough." More seriously, the clinician makes sure the patient gets the best possible current care. This is an important point: Many anxiety disorders have behavioral treatments that are effective, especially for specific fears, like heights.

Lang asked Robert Henderson, one of his graduate students, to model the experiment. Henderson sat down in the experiment room, a spare affair with a chair facing a boxy computer monitor, while an assistant applied sensors to his body: heart rate on the arm; skin conductance on the hands; and another on a muscle beneath the eyes for startle. There's no more reliable measure for startle than blinking, Lang said.

The assistant fitted an EEG net over Henderson's brown curly hair, its 128 electrodes finishing his morph into a character from a schlock 1980s psychological thriller. We watched him through glass from the control room. He was asked to read from a short story, imagining himself in the situation it described, and rating his feelings on Lang's two emotional dimensions.

"As I perform the C-section, I can't breathe," one story goes. "What if I can't get the baby's head out and it dies? My heart beats faster and I feel hot. I can't leave this room. I'm dizzy."

As Henderson read, white noise, 95 decibels strong, urgent as a fortissimo piano, burst into his headphones. He startled, his head bucking. He read another story. They buzzed him again. On a normal day, this would continue for nearly an hour.

There have been many normal days, but only recently has the work led to a provocative result: The patients suffering from specific fears or one-time traumatic events showed a heightened startle, similar to Davis's early experiments. The patients who suffered from strong, prolonged distress, however, had blunted reactions, their startle barely a blip—a pattern that held true across the different anxiety diagnoses. Somehow, this dimension, the fear circuit, had gone dysfunctional or burned out. But it's hard to say exactly how without getting these patients under an MRI machine.

"Now the big thing to do is see if these same patterns show up in the brain itself," Lang said. And that's exactly what he'll be doing for RDoC.

Cuthbert stayed in Lang's lab for 17 years, leaving in 1998 for NIMH, where he served as chief of adult psychopathology and prevention research for seven years. He found his new world to be constricted by the DSM's categories, the research siloed in terms of "depression" or "bipolar disorder." This was not like the work they were doing in Gainesville.

"We weren't getting at these fundamental mechanisms," he says.

His frustration was shared all the way to the top. At the time, Steven Hyman, now director of the Stanley Center for Psychiatric Research at the Broad Institute, led NIMH. Looking at the results of his institute's grants, Hyman became worried that he was wasting public money on clinical research undercut by the DSM's disorders. "As a result of the DSM," he says, "investigators failed to see all of the mixed symptoms." Nature is a meatloaf, he knew, yet these "fictive diagnostic silos" were holding the science back.

"I actually decreased the amount of translational research NIMH was doing," Hyman says. Instead, he put that money into basic neuroscience and genetics, investments that would build RDoC's foundations. He even considered establishing a new research diagnostic system but concluded there was not enough science to go on. He also worried about dividing scientists and clinicians, a fear he holds to this day.

The agency did get close to an RDoC-type initiative during Cuthbert's stay, just before Hyman left, in 2001, called the "modular phenotyping of mental disorders." It was a huge disappointment. The agency didn't send out a single grant under its auspices; the applicants and peer reviewers didn't understand it. Cuthbert became frustrated enough to leave in 2005, founding a lab at the University of Minnesota-Twin Cities: "I said, OK, if you want something done, you have to do it yourself."

While Cuthbert made his move, his fellow researchers were tearing the last chunks out of the DSM's foundations. Work by Lang, Davis, and many others on the brain's fear circuit had reverberated into a broader "brain circuit" hypothesis of mental illness, where disorders are caused by malfunctions in long chains of neurons, often beginning in the brain's early development. Discrete sections can't be tied to depression, just as dopamine, the neurotransmitter, can't be called a "love hormone." Many different dysfunctions in these whole-brain circuits could result in, say, hallucination. Should all those paths be diagnosed as schizophrenia?

At the same time, advanced DNA sequencing was beginning to show that many of the DSM disorders were linked to the same gene variants, called alleles. "You can pretty easily see that risk alleles don't respect diagnostic criteria at all," says Michael Owen, a geneticist and dean of research at the Cardiff University School of Medicine, in Wales. His lab first found that schizophrenia and bipolar disorder shared deep genetic similarities. Then they found links to autism, ADHD, and even intellectual disabilities.

"This got us thinking, looking at the clinical data, that yeah, it's possible to put people in these boxes, these categories," Owen says. "But there's no clear water between them. It made me realize these were categories we were imposing on people."

The final break from the DSM categories for Owen and other geneticists was the demise of the family studies, classic work that had shown that disorders like schizophrenia are strongly heritable, giving the diagnosis credibility. But once these family studies grew larger, researchers saw, for example, that schizophrenics had just as many bipolar relatives.

"When that broke, it did cause a bit of a paradigm shift," Owen says. "People thought: 'Crikey!'"

This was the ferment in the field, to the point that a passel of leading researchers, in pointing the way forward, could title their essay "The Future of Psychiatric Research: Genomes and Neural Circuits." And this thinking had never left NIMH, which Thomas Insel has led for 11 years, since Hyman's departure. The agency began building a new strategic plan in the last decade, and many geneticists and neuroscientists told Insel, in effect, "You have to do something about the DSM." That became, in 2008, one of its primary strategic aims: "Develop, for research purposes, new ways of classifying mental disorders based on dimensions of observable behavior and neurobiological measures."

Cuthbert had nothing to do with writing that aim; he was off starting his lab, and didn't rejoin the agency until 2009. But he did visit the institute for a conference, where he gave Insel the full Gainesville spiel. "I remember him telling me," Lang says, "'Tom is really interested in this stuff.' He was amazed. I was, too." A couple days later, Insel gave Cuthbert a call. Would he come back to NIMH to lead the revolution?

Cuthbert and his team began the Research Domain Criteria project four years ago, and from the start it's been grounded in incremental, built consensus, arrived at primarily through workshops.

The agency has identified five primary "domains" of mental function, which are subdivided into lower-level systems, like the fear response, that have some known tie to behavior and a brain circuit. These domains can be simply stated: one for keeping the brain up and running; one for social processes; one for storing and using information; one for moving toward positive rewards, like food and shelter; and one for avoiding harm, which is where the fear circuit resides.

This is rather abstract, so let's take major depression, as defined by the DSM, as an example. As an RDoC-style researcher might describe it, multiple mechanisms are at play in a severely depressed person, and they vary from patient to patient. There may be dysfunction in the neuroendocrine system; in reward-seeking activities; in emotion regulation; in neurotransmitter systems; in cognition; in epigenetic controls. Many of these mechanisms are still poorly understood at a basic level, let alone in how they may connect to a circuit of dysfunction and illness. Cuthbert wants to give scientists permission to start exploring those connections.

If you start thinking about mental illness in the RDoC way, the dimensionality of it begins to click. We are all in its dimensions, our brain circuits shaped or misshaped by our genes and lives. Take anxiety. I'm a fearful driver, but perhaps not to the point that a clinician would diagnose me with specific phobia. But I'm certainly on that spectrum. I feel it each time I take to the road.

"The DSM doesn't really say much about what's normal, it just says what's abnormal," Cuthbert says. If mental illness is on a gradient, "it's not that you're healthy until you're sick and have a disorder, in the sense that you're healthy until you have the flu, and then you have the flu." But "because our disorders were defined in an era when we didn't know what our basic functions were, how to measure them, they naturally sound clinical."

"But what's the opposite of being depressed? There isn't one. What's the dimension of that? So you're 'fine.' There's no measure of what's it mean to be fine and to be depressed."

The defining image of RDoC, then, is not two buckets, one full of the healthy, the other the ill. It is a grid. Down the side run the domains and their dimensions. Across the top go the means of probing them: through genes, molecules, cells, circuits, physiology, behavior, self-reports, and "paradigms." (Lang's fear-conditioning through imagery is a paradigm.) The grid puts the lie to any notion that RDoC is all biology and no psychology, Cuthbert said at the May meeting.

"Nothing could be further from the truth," he said. "If you think about it the way I think about it, actually the DSM is sloppy in both counts. There's no particular biological test in it, but the psychology is also very weak psychology. It's folk psychology without any quantification involved.

"What we really need to do is elevate both."

Every scientist I talked with for this article supported those elevation efforts—which, of course, is not the same as saying they had no criticisms of how it's gone.

There are fears that in seeking to steer the science, even in an attempt to save it, the agency could miss promising work couched in DSM terms. According to David Barlow, a Boston University anxiety researcher who supports NIMH's goals, the agency has been too aggressive. "They're turning down most applications that kind of focus on DSM categories," he said.

NIMH insists that's not the case; its introduction of RDoC is gradual, and it'll continue to finance each research style for the foreseeable future. Its leaders recognize that many scientists work at entire institutes devoted to one DSM disorder and can't easily change their frame. (Such centers are a great example of what psychologists call "reification": how the building of institutes or the filing of insurance claims has made the DSM's diagnoses "real.") And, of course, nothing has changed about the money NIMH puts into basic research—about half its grant budget.

The threat also remains that in searching for better answers, researchers could alienate doctors and clinicians, the people who deal in the traditional mental disorders every day. Imagine bringing a new treatment to the FDA, says Hyman, the institute's former director. For the next decade or two, it's likely that treatment would have to be framed in DSM terms. They must work hard to find a way for next-generation research to be translated back into the old diagnoses.

"As flawed as the DSM is, we have no substitute for the clinical realm for insurance reimbursement," Hyman says. "We won't have anything better for a very long time. While the criticisms are germane, we blow it up at our peril."

The relationship between the institute's dimensions and the DSM's disorders will be complex, but not confrontational, which is why so much discussion of Insel's blog post struck a false note. RDoC will never seek to supplant the DSM. It will never be "released," because it will never be done. It is a database, a framework, shifty by design. Only a decade or two from now, if Insel and Cuthbert are successful, will the DSM change, shaped by the research they financed.

During his May presentation, Cuthbert displayed two photos. The first was a Frank Lloyd Wright house, immaculate in construction, tailored, down to its tables, before it was ever built. That's the DSM model. Next, a picture of steelworkers eating lunch up on a skyscraper's unfinished beams. That's RDoC, he said. Cuthbert likes to think of himself as one of those guys, up on the girders.

And if RDoC is a steel frame, down beneath Cuthbert, still clanging away after all these years on the building's core, there would be Lang.

Naturally, Lang was one of the first to apply for an RDoC grant, and one of the first to win one. It's some $250,000 a year toward repeating their recent large anxiety experiment in the lab and under an MRI machine at UF's McKnight Brain Institute. The experiment will run until 2017. Lang, who's also a painter, often jokes that all the great masterpieces were done by people over 75. When this last run ends, he will be 87.

"I've been at it a long time," he says. "I figure this is my shot."

Back in his Gainesville office, we looked up at his photo of William James in the Amazon. Lang has been feuding with James, and much of the rest of psychology, for most of his career. Psychology began as the study of the mind, and it's hard to give the mind up, he said. Genomics, brain circuits, and animal models alone won't fill that void. A vast yawning gap of uncertainty fills it. That won't go away.

"It's very hard to get away from the idea that I wake up in the morning and I'm the master of my fate, the captain of my soul, and I do things because I want to do them," Lang said. "And of course, you know, the hope that we will ultimately understand consciousness, that it will be in some terms that we can discuss scientifically."

Until then, he said, let's give the brain a shot.

"Give us a century."

Paul Voosen is a senior reporter for The Chronicle.

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