Can a stint in the ‘fever machine’ treat depression?

MADISON, Wis. — The obsession was born over Chinese food with a Tibetan monk.

Dr. Charles Raison was working as an emergency room psychiatrist in Los Angeles, where he’d fallen in with a monk-turned-psychologist. Every Monday, they would have dinner at Panda Inn and talk Tibet.

One night, Raison’s companion told him about a meditation practice called “tummo,” a kind of fast track to enlightenment. Using only breathing and visualization techniques, he said, monks raised their body temperatures to feverish levels — so high that their body heat could steam dry sheets dipped in an icy Himalayan lake.

Raison was entranced. At that moment, he decided he would study how body temperature connected to feelings of bliss. That conversation would lead to decades of research — and a controversial idea for treating depression by putting patients inside a machine that induces fever. In May, his team published results of their first small clinical trial, which found that the machine eased some patients’ symptoms, at least by certain metrics.

Outside scientists aren’t convinced. But Raison believes the fever machine could help patients with intractable depression. He credits the monks for that first moment of inspiration.

“This was the craziest thing I ever did,” Raison said. “I had no funding. I had no research career. I just wanted to do this.”

The convert

Raison hadn’t always wanted to be a scientist. He’d wanted to write novels. But when he enrolled in grad school to try creative writing, he wasn’t just bad at it — he hated it.

Then, on Christmas Eve of 1984, as he was driving through the flatlands of coastal Texas, he had an epiphany. He left Corpus Christi not knowing what he wanted to do, and by the time he got to Houston he was set on becoming a psychiatrist. “It was like a religious conversion,” he remembered. “It was like Paul on the road to Damascus.”

Raison graduated from medical school at Washington University in St. Louis. After his stint as an emergency room psychiatrist, he joined the faculty at Emory University in Atlanta, hoping to research the monks.

An early mentor, Dr. Andrew Miller, the director of adult outpatient psychiatry at Emory University, steered him in a more practical direction: “I encouraged him to think about how the immune system might influence mood in the context of depression, given that he was a psychiatrist, and maybe it would make more sense to study psychiatric disease instead of meditating monks.”

Raison began to study the link between the immune system and mental illness. He received grants from the National Institutes of Health, publishing some 30 studies over the course of a decade.

But he never stopped thinking about what happens to the brain when your body gets hot.

It wasn’t until he met two young physical therapists from Europe that he found a way to study it.

The machine

They had found the machine in 2003, covered in ancient hospital linens.

As head of physical therapy at the Aeskulap Clinic in Brunnen, Switzerland, Kay-u. Hanusch been asked to expand the department, and was rooting around in the basement for furniture.

There, hidden among a century’s worth of bedpans and other medical castoffs, was a machine that Hanusch recognized immediately.

It was an earlier version of a device used in the oncology department. The oncologists had patients lie on a bed underneath its hulking metal frame, closed a cloth tent around them, and turned on infrared lamps. The tent would begin to get warm. Then hot. Then it became a scorcher. The idea was that increasing body temperature to a fever might just help beat back tumors.

But the oncologists had also described another result: Depressed cancer patients emerged from the machine with a renewed interest in life.

Hanusch brought the machine into his department and recruited a psychiatrist to help him. They used themselves as guinea pigs until they were convinced it was safe. By 2009, they were ready for patients. They treated 16 — and their responses seemed downright remarkable. “Like walking on clouds,” one reported. Before the treatment, she had been too depressed to spend time with her children.

The team needed a researcher who could help analyze the data and “bring it to the high scientific level that was necessary,” said Hanusch’s collaborator, Clemens Walter Janssen.

In 2011, they met Raison at a conference. He helped them publish a paper on their results — and then set out to take the research further.

The trial

Heat has been used as an antidote to depression for millennia; the first century physician Galen treated Roman emperors’ melancholia with warm baths.

These days, though, the idea of inducing fever with a hyperthermia machine is decidedly fringe. Sure, there are psychiatrists who research the antidepressant effects of hot yoga, but for most in the field, hyperthermia sounds more like something offered at a spa — or a 19th century insane asylum — than a cutting-edge medical treatment.

That made the work hard to do. Instead of his usual NIH funding, Raison — who was then a psychiatry professor at the University at Arizona — pieced together grants for the next hyperthermia experiment with money from private donors and foundations.

His general hypothesis: Heating up the whole body would send an electrical impulse up the spinal cord into specific brain regions like the dorsal raphe nucleus, which releases serotonin, a neurochemical also stimulated by traditional antidepressants. Raison believes the heat treatment can target the serotonin release more specifically in the brain than pills like Prozac.

He would like to test that mechanism in more detail in the future. But first, he wanted to double check those results from Switzerland in a more controlled study.

To do that, he’d have to compare the heat treatment to a placebo in a clinical trial.

But what could work as a placebo for the hyperthermia machine?

That took a bit of creativity. Raison’s team painted regular light bulbs orange to create the sunset-like glow of the infrareds but not their feverish heat. They turned on heating coils so that the patient would feel warm without getting a real fever treatment.

Recruiting by TV and radio ads, social media posts, and emails drew around 30 participants who met their criteria. One by one, the volunteers climbed into the machine and lay there for about two hours, with a rectal thermometer tracking their core body temperature.

The results

Raison was excited as he started looking at the patients’ results on a diagnostic questionnaire used to assess depression.

Nine of the patients who got the fever treatment responded, meaning that their scores on that depression assessment dropped significantly. Among those who got the fake treatment, only one person responded.

When Raison tried to measure depression in other ways — for instance, by asking patients about their quality of life — the results didn’t match the benefits he saw on the questionnaire. That inconsistency, among others, has made outside researchers skeptical.

But from what Raison could tell, the treatment seemed to work for some patients, and work more quickly than traditional antidepressants, which can take weeks. Some participants liked it so much, they asked to climb into the fever machine a second or third time, even paying $800 to cover the costs, Raison said.

One patient in particular made him “a true believer:” a woman in her 40s from Colorado who had dealt with depression for some 13 years. She had tried Zoloft and other drugs, but they didn’t work.

The fever treatment made her euphoric for days. That faded, but her depression didn’t come back immediately. “It was just me and my life again, rather than me trying to struggle through my life,” she said.

The depression began to return after six weeks. She would have liked to get the treatment again, but by then, the University of Wisconsin-Madison had offered Raison a more attractive professorship. He cancelled his five other registered clinical trials on hyperthermia and headed north.

The aftermath

Many scientists greeted Raison’s study, published in JAMA Psychiatry in May, with deep skepticism.

Some said the placebo effect could still be at play, despite Raison’s elaborate efforts to fake out his patients. Only 71 percent of the group who got the fake heat treatment believed it was real, while 93 percent of those who got the real thing believed it.

Others were suspicious about how well the treatment seemed to be working. In particular, they found the effect size that Raison reported — a figure that allows scientists to compare results across different kinds of studies — to be unbelievably high.

“If this is the real effect size, this would be more effective than any other treatment in the whole of psychiatry, and I think that’s rather unlikely,” said University College London neuroscientist Jonathan Roiser.

Raison agreed that the effect size was inflated but blamed that on peer reviewers’ suggestion that he use a particular statistical model when analyzing his data.

Most psychiatrists can agree that there is a problem with current methods for treating depression. “People are eager — they’re desperate — to find something that helps,” said Eiko Fried, a psychology research fellow at the University of Amsterdam.

But to Fried, the goal of depression research is to provide relief for those desperate patients — and he wonders how such tiny studies could help.

“It’s a highly implausible result. That said, if it’s replicated in a larger sample, it would be a very exciting result,” said Dr. Jonathan Alpert, the head of depression research at Massachusetts General Hospital.

Raison isn’t giving up on heat as a possible treatment for some patients.

He has other studies in mind and has been negotiating the internal review board at UW-Madison to get them approved. He’s also busy approaching other private donors. In the meantime, his hyperthermia machine sits unplugged in a hallway of labs at the university’s School of Pharmacy.

Sometimes, Raison sounds exasperated. But as he stood by the fever machine recently, he talked of sweat lodges, meditating monks, and the euphoria felt after hot yoga.

And he talked of his own experience in the fever machine. As the infrared lights heated up the tent, he remembers his mind popping with new directions for research. His ideas were coming, quite literally, at a feverish pace.

“It’s very mysterious,” he said, “this inflammation having not just antidepressant effects, but almost cosmic effects. But that’s unknown territory.”