Blues Brothers

Doctors have approached depression like aliens examining an ailing car. They’ve checked the tires, even pushed it into starting—everything but lifted the hood. Now two neuroscientists are doing just that.

By Marjorie Centofanti

Their first symposium on transverse myelitis—an often-paralytic autoimmune disease—had just ended, and the psychiatrist and neurologist were ready to lean back for a gentle postmortem. The two days had gone well. Patients had pumped their hands in gratitude and the succession of speakers showed TM was being taken seriously. The TM center Kerr had founded at Hopkins felt real in a way it hadn’t before. Ripe with possibility.

Then, a woman eyed them across the meeting room and Kaplin registered telltale signs as she approached: “I need help,” she told the two men quietly. Talking with the other TM patients had pushed her into despair. In her case, the disease had caused only mild sensory upsets like numbness (in severe forms, it can result in incontinence, lower body paralysis and constant urges to urinate). But it had devastated her emotionally. People in much worse physical shape, the woman said, didn’t feel half as low as she did. In the months since she’d been stricken with TM, she’d sold all her belongings and stockpiled lethal drugs. “I’m overwhelmed,” she said. “I’m going home to kill myself.”

Kaplin and Kerr were startled, but not surprised. In the five years they’ve been with TM patients, they’d seen a number of them slip into depression. But TM is a depressing disease. The angry sore that materializes in the spinal cord typically does so suddenly. Patients can go to bed humming and wake up paralyzed. “Who wouldn’t be upset by incontinence and inability to walk, from a disease barely anyone has heard about?” Kaplin asks.

Nevertheless, over the last few years, he and Kerr haven’t accepted this explanation. Instead they began making quiet scientific inquiries into the tie between depression and TM. Now they find themselves at a lovely precipice for scientists, looking on as their increasingly telling studies come together. What they’re on the way to finding, it appears, besides just how TM injures the spinal cord, is a psychiatric holy grail: a realistic, useful model of human depression.

Pharma companies already rely on a range of animal models of depression to winnow out chemicals that will act as antidepressants. Small libraries of books discuss using animal models to reflect mental illness, and journals wrangle about which animals more accurately reflect depressed people—helpless ones or those who are socially isolated, for example. Specialized philosophers even ponder whether you can ever compare human and animal thought. But nobody’s found a way to tell if a mouse is feeling guilty—or is capable of it—or if a rat with shaky self-esteem worries he’s not cutting the same figure as a few months ago. Also, the sheer variability of depression makes modeling hard.

“Depression is defined as having five of nine classic symptoms,” says Kaplin, as he rattles off—in six seconds flat—sleep, interest, guilt, energy, low mood, concentration, appetite, psychomotor retardation, suicidal ideation.

“That’s hundreds of possible combinations. A tremendous heterogeneity! A patient could be in a depression study with someone else but only share one symptom! So”—he counts on his fingers—“we need a model based on something physical, something you can measure that changes the brain—something with a standard biology and predictable resulting behavior.” And it would also be nice to use depressed people whose illness matches what’s going on in the animal, point for point.

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Not long after the TM clinic opened, Doug Kerr was struck by how many depressed patients he was seeing—“well beyond what you’d expect.” He also realized that the degree of depression seemed strangely out of sync with the severity of the patients’ illness. One morning, he stopped by to talk about this with Adam Kaplin. Kerr trusted Kaplin’s opinion and he wanted to ask his help in exploring what he’d observed. The two had met several years before as interns at Hopkins and become friends. Both have Ph.D.’s as well as M.D.’s—Kerr’s is in molecular biology, Kaplin’s in neuroscience. Their wives and children think nothing of poking in each other’s refrigerators. And Kerr routinely passes patients on to Kaplin.

“So Adam saw my patients,” Kerr says. “And then he made this extraordinary statement: that TM was also a disease of the brain, not just the spinal cord. I mean, come on! It’s well known TM is a focal inflammation of the spinal cord. MRIs of patients’ brains show nothing, no lesions. If there were, we’d call it multiple sclerosis. But Adam said no, patients are so depressed that something must be going on. To which Kerr remembers replying: “That’s the biggest bunch of hogwash I’ve ever heard.” Kaplin spent the next year or so convincing him he was wrong.

Adam Kaplin’s mentor was Hopkins psychiatrist Peter Rabins. Rabins pioneered the idea of depression as part and parcel of multiple sclerosis—another autoimmune disease of the nervous system. He showed that full-fledged blues can exist even without a family history of depression. And Rabins also found that MS patients have twice the depression risk of the healthy: Some 60 percent have suffered from it—usually, he noted, in the midst of an MS attack. Suicide is the third leading cause of death in the disease.

Kaplin and Kerr began monitoring TM patients the same way, comparing their moods with those of MS patients and controls. And because mental ability acts like a miner’s canary in reflecting even mild perturbations in the brain, patients also underwent cognitive testing.

“We clearly showed that how depressed people were had nothing much to do with how physically disabled they’d become. That tells us depression is inherent in the disease,” Kaplin explains. The work also confirmed TM’s subtle cognitive problems, like difficulties in shifting from one task to another—the same ones found in MS.

“So now we believe TM and MS have similar brain effects,” says Kaplin. “That would explain why, out of almost 500 patients in the TM clinic, there’ve been six suicides—an astronomical incidence. And we’re certain TM also alters brain tissue, even though patients lack MS-like lesions.” But how? What can trouble brain tissue without actually killing it?

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The worst thing about the flu isn't just the aching or the chills; it's the just-let-me-die-now feeling, the craving for nothing except to see the inside of your eyelids and lie unmolested in your bed. In 1988, Benjamin Hart, a California veterinary professor, recognized the same sickness behavior in animals—the lethargy, appetite loss and “not tonight, dear” antisocial behavior he presumed was evolution's way to channel energy into fighting infection.

This pairing of depression’s symptoms with a riled immune system has surfaced in enough human and animal studies that now some scientists believe immune agents can alter or, as they say, disregulate, parts of the brain related to mood. Specifically, they’re focusing on signaling molecules called cytokines, plentiful during infection.

Kaplin dubs this research “tantalizing tidbits from a variety of places.” New work, he says, suggests that cytokines may have a hand in Alzheimer’s, the disease that destroys the thinking brain. Particularly impressive are studies on cancer patients who took the immune-boosting cytokine called interferon alpha. Even though the interferon slowed cancer, patients became dramatically depressed, with many opting out of the study. The more interferon, the darker the mood.

In transverse myelitis, Kaplin and Kerr believe they've found the ideal disease as a model of depression. For one thing, says Kaplin, most patients have no history of depression. And the depression itself seems predictable. “In some depressions, people become irritable, but with TM, they’re more lethargic, melancholic. It's curiously similar from patient to patient.”

So, are cytokines at the heart of TM? Of depression?

With Kerr making room for Kaplin in his lab, the two assayed some 40 different cytokines in blood from patients entering the TM clinic—a period when their immune systems were typically shooting sparks. Getting accurate cytokine measurements isn’t easy, and a number of things, even diet, can be confounding. But the degree of elevated cytokines matched the severity of disease, they found. One patient—a rare death from TM—had levels of the cytokine interleukin-6 (IL-6) some 1,700 times greater than normal. “It was so high,” Kaplin notes, “that we had to use a separate graph for it in the journal article we've submitted.”

The process begins, the researchers think, with immune cells massing inside the inflamed spinal cord. The cells start signaling via cytokines. Like a call to arms, their signal rouses other immune cells to release IL-6, among other things, which spills into the spinal fluid bathing the brain and spinal cord. Effects then appear in both places.

Talking about the details of their work at this point makes both scientists understandably uneasy. The work is seminal and too close to journal submission to “spill the beans.” But they’re eager to get across the idea of two separate systems, one immune and one for mood, interacting and doing harm.

“The brain does amazing things,” says Kaplin. “Cognition, sensory and movement control, autonomic function, vision. Why is it so hard for people to think of fine-tuning mood as one more function of the brain, to realize that any sort of depression means a basic system is out of tune? That it’s one you can put right?”

Moreover, what has the two researchers electrified, they say, is the possibility of a two-way street. It’s an idea that a revved-up immune system’s ability to alter the brain’s mood pathways might be reversed or lessened by repairing the depression. “One study with MS suggests that patients with untreated depression have more serious disease,” says Kerr. “It’s an amazing notion: Treating the mood may damp down inflammation and help the illness.”

“That possibility makes us quick to monitor mental health in our TM patients,” says Kaplin. And here he shakes his head. His fist thumps gently on his desk.

“The irony is that few people pay attention to depression in autoimmune disease, even though it may be a leading cause of death. Open up the latest patient book on MS. It has chapters on bladder, bowel, sexual dysfunction—everything under the sun—but not one on depression. In 100 pages, there’re two sentences on that.

“Worse, for MS or TM patients, symptoms such as hopelessness or loss of interest are often interpreted as being weak or lazy. ‘Buck up!’ is what they hear. So to know it’s depression, just to have a name for it, not to feel like it’s a weakness, a failure to cope or adapt...that’s an immense relief.”

As for the woman bent on suicide, “we threw her in the back of my car,” says Kaplin. They hurried to campus and had her admitted to the Hospital. Now she’s no longer depressed. And, more than many TM patients, she has a clear idea why she was.