A New Path for Bipolar's Doggedly Impervious

A New Path for Bipolar’s Doggedly Impervious
   

Two summers ago, John Helliwell rounded up his pill bottles, the remains of a dozen or so medications supposed to dispel the depression that had cycled relentlessly in and out of his life for years. He’d been 12 the first time he tried suicide. Now at 43, he was unable to work, again putting his wife and teenage son through what he describes as “holy hell.”

Diagnosed with bipolar disorder five years ago, the Baltimore man had been given virtually every antidepressant drug, often in combination.  Some would help briefly, then wane. Others launched him—despite the lithium he took to stabilize his mood—into mania. He often didn’t know from day to day what self he’d see on waking up. Helliwell concluded there was only one thing his pills could do for him. He opened his assorted bottles and swallowed the contents. 

"I could tell it wasn't the placebo," says Helliwell of riluzole, normally an ALS drug.

Fortunately, Helliwell was brought back from his overdose. And soon after, he happened upon an ad for Jennifer Payne’s clinical trial, one the Hopkins psychiatrist had opened to people who, like him, were doggedly impervious to known antidepressants. With a shrug, he called Payne up.

  
Riluzole, the drug under study, at first seems an odd candidate for a depression therapy. Approved as a way to slow the motor nerve disease ALS, riluzole’s action isn’t crystal clear, though research shows that it inhibits release of glutamate—the brain’s most widespread neurotransmitter. But antidepressants typically target serotonin-based nerve circuits. Why turn to a different system?

 “The classic medications—the SSRIs, for example—can induce manic symptoms in bipolar patients,” Payne explains. “And as Mr. Helliwell knows, they can also bring rapid cycling. Our thinking was that a drug that didn’t work through usual pathways might be worth investigating.”

   
Payne’s focus on riluzole began during postdoctoral studies at the NIH. The rationale for trying it came from news that many antidepressants indirectly affect glutamate neurons. Also, agents that block glutamate receptors seemed to lessen signs of depression in animal models and in some people. Payne helped run a small study of riluzole for treatment-resistant patients with major depression, with encouraging results. And in NIH’s trial of bipolar patients, after she’d left for Hopkins, the drug was also significantly positive.
   

 “But we desperately needed a larger, double-blind, placebo-controlled trial,” she says—the gold standard of clinical research. Now, with a grant from the Stanley Medical Research Institute, Payne’s running such a study for some 60 bipolar patients. Half in it receive riluzole; the others, a placebo. All are kept on their lithium, depakote or other mood stabilizers. “That gives the study double value,” she says. “It’s rare to see a trial of mood stabilizers alone these days. But there’s evidence that on their own, they help depressive symptoms in some patients while they dampen mood swings.”
   

As for Helliwell, one of Payne’s first enrollees, he wasn’t surprised, at the end of his eight weeks, to learn he’d received riluzole, not the placebo. “It’s the longest any drug has worked for me,” he says. “After years of curling up in a ball on the sofa, I now get up every day and move forward. For me, that’s a major feat.”