SAN DIEGO—Whole body hyperthermia shows potential to treat depression, said Charles Raison, MD, during the Welcome Session of the 28th Annual U.S. Psychiatric and Mental Health Congress. Dr. Raison presented data on his recently completed study of whole body hyperthermia as a novel therapeutic for depression.
“Whole body hyperthermia grows out of a way of thinking of depression that’s somewhat at odds with the rank-and-file standard thinking,” said Dr. Raison.
He noted that the field believes that mental disorders are brain disorders and that many scientists take the idea literally, to the point that they believe the brain is the only cause and location of mental illnesses.
That way of thinking is incorrect, he said, given the extensive research showing that many factors outside the brain cause major depression. For example, family relationships drive depression. In one study, the children of parents who were treated with and responded to an antidepressant had a greater response than their parents, even though none of the chemical touched their bodies.
“Human relationships are biological entities that drive states of mind. We’re medicines for each other or poison for each other,” said Dr. Raison.
He added, “Just because the brain is the proximal cause of all mental states does not mean it is the most important, interesting, or therapeutically useful cause for all cases of major depression.”
Beyond the Brain
If we accept that factors outside the brain can cause depression, then that opens the door to the possibility that factors outside the brain can also treat depression. Dr. Raison first explored this approach in a study of infliximab for major depression that investigated whether blocking inflammation could block depression.
Sixty medically healthy patients with major depression were randomized to receive either a saline solution or an infusion of infliximab, a powerful biological molecule that only blocks inflammatory cytokines. The molecule is large, “the size of a school bus,” said Dr. Raison, and it doesn’t penetrate the blood-brain barrier.
After breaking the blind on the study, Dr. Raison and his colleagues found that only patients who had high levels of inflammation prior to the infusion experienced antidepressant effects. The study suggested that turning off depression in the body, in the form of inflammation, also worked to turn off depression in the brain.
“This was the beginning of the realization that the immune system, which is a sensory pathway, might provide access to deep brain stimuli,” he said.
Some Like it Hot
From there, Dr. Raison’s research interest turned to temperature, a sensory pathway that has shown a strong association with depression. People with depression have higher body temperatures and sweat less, suggesting that mood disorders are thermoregulatory disorders.
“There are a few things that people have done over and over throughout history to feel better and have spiritual experiences. Sweat lodges are near the top of the list. It’s amazing how many indigenous cultures around the world semi-independently invented sweat lodges,” said Dr. Raison.
This phenomenon points to a pathway that runs from the skin to specific areas of the brain that are turned on by warm temperatures and turned off abruptly by temperatures that hurt. “We think that pathway is an antidepressant modality,” said Dr. Raison.
Putting the Pathway to the Test
When people with depression enter a hyperthermia chamber their depression decreases and their body temperature drops as well. The body temperature reduction may seem counterintuitive, but it makes sense, explained Dr. Raison.
“Think about it—why does this pathway exist? The brain wants to stay the same temperature. When this pathway is activated, it makes you sweat, it makes you try to cool down,” he said.
For his study on whole body hyperthermia, Dr. Raison predicted that people would feel less depressed and have a lower body temperature after undergoing treatment.
Results confirmed his hypothesis. People who were treated with whole body hyperthermia experienced a large reduction in depression after treatment, as well as a reduction in core body temperature. Interestingly, the 3 people who did not experience an antidepressant effect were taking an SSRI, and the hotter the body temperature of the participants at the start of the study, the better their antidepressant response.
“Why were these people hot? We think it’s because the pathway wasn’t working correctly so they couldn’t lose heat, which elevated their body temperature. But giving the treatment lowers body temperature and makes the pathway more sensitive,” he said.
One of the challenges with this study, said Dr. Raison, was developing a convincing placebo. With some creativity, the researchers devised a sham therapy that convinced 75% of the patients that they were receiving the active treatment.
Those in the active treatment group experienced reduction in depression with effect sizes (1.4 at one week) compared to placebo that dwarf those of SSRIs and their placebos. “This is almost two and a half times larger an effect,” said Dr. Raison.
In addition, although Dr. Raison and his colleagues predicted that the effects would disappear after 6 weeks, many people were still significantly improved compared with placebo.
“Like ketamine, like scopolamine, and other rapid treatments for depression that are of intense interest in psychiatry, hyperthermia shows the same effect. It doesn’t take a week or two to work. People feel better very, very quickly, and the effects appear to persist for an extended period of time,” said Dr. Raison.