November-December 2013 | Bethesda Health

A Better Pill to Swallow

A writer's search for an alternative to antidepressants leads him to an unassuming office in Rockville and a potential miracle drug dubbed NSI-189

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The company’s work with depression was serendipitous. Working with neural stem cells meant growing lots of tissue to test various drugs. That process, the company discovered, had other uses.

In the late ’90s, the Clinton administration sought to create a “super soldier” who could stay awake and alert for a week at a time. Neuralstem won a contract to work on the “warfighter of the future” project, Garr says.

The company wasn’t focused on creating a drug to keep soldiers awake, however; rather, it was interested in dealing with the consequences of long-term wakefulness. Without sleep, we become irritable, forgetful, irrational—all outward signs of the cell damage that can occur in the sleep-deprived hippocampus.

The Defense Advanced Research Projects Agency (DARPA) eventually canceled the project, Garr says, but Neuralstem moved forward, and NSI-189 was born. If the drug could help sleep-deprived soldiers, as its tests on mice had suggested, then maybe it could help others experiencing cell death in the hippocampus. Maybe it could treat depression, Alzheimer’s, even aging. As we get older, we all lose hippocampal cells. Could this drug make us super seniors?

“Yes,” Johe says. “There’s no question that degeneration of the hippocampus and other parts of the brain is part of the aging process. As we now take many different food supplements to counter or slow that aging process, I see this as a potential ‘vitamin for the brain’ to slow down or counter that aging process in our mental capacity.”

Currie, the Reed College neuroscientist, remains skeptical, however. “The human brain has taken how many millions of years to evolve? I don’t think it’s as simple as, ‘Well, we can improve it,’ ” he says.

Some 27 million Americans like me take antidepressants, according to researchers at Columbia University and the New York State Psychiatric Institute, which published their findings in the Archives of General Psychiatry in 2009. That’s one in 10 people lining up at the movies, driving the Beltway, sampling cheese at the farmers market. More women than men, more whites than African-Americans. And the number is growing.

Is it because depression is being diagnosed more often? Because antidepressants work better than before? Because pharmaceutical companies pressure doctors to prescribe them? Are we more stressed out? More isolated? Are we looking for a quick fix?

Nobody knows for sure, Currie says, but the answer is probably yes to all those questions.

Equally perplexing is why the United States, one of the world’s wealthiest countries, has one of the world’s highest rates of depression. In a 2011 World Health Organization study of 18 countries, only France, land of joie de vivre, had a worse case of the blues, with 21 percent of the population reportedly suffering from depression, compared with 19.2 percent in the United States. South Africa’s rate was half that of the U.S. In Montgomery County, according to a 2009 Centers for Disease Control survey, 16.8 percent of residents reportedly had been diagnosed with a depressive disorder.

Is depression a disease of the privileged? “We just don’t know,” Currie says.

My own depression is relatively mild. I managed to smile and even laugh, so friends and family members didn’t know there was a problem until I told them.

But there definitely was a problem.

A few months into the onset of my depression, I was walking with my dog into a snow-covered field at twilight. The sun had set, and the snow reflected the gray-blue light. Everything around me was a pallid veil. This is what depression looks like, I thought. It felt like I had crawled under a 50-pound blanket and I couldn’t lift it off.

For a while, talk therapy helped, but it didn’t push back the darkness. Mindfulness meditation made it easier to live with, but didn’t lessen it. Medication, however, lifted the veil. I could divorce, remarry, move, start over, get a second chance. Medication was life-changing for me.

Even leading researchers don’t entirely know why the drugs work, however. We do know that the brain fires impulses from neuron to neuron by way of a number of chemical messengers called neurotransmitters. One of these is a chemical called serotonin. One neuron fires a shot of serotonin across the synapse, the chasm between neurons. The next neuron takes up the message, and the sending neuron recycles the serotonin to do it all again. Prozac and similar drugs called selective serotonin reuptake inhibitors (SSRIs) block that reuptake process, keeping more serotonin at play between the neurons, and apparently boosting the mood-elevating signal.

But what does serotonin do? Unlike other brain chemicals—oxytocin, for instance, which we release during sex; or endorphins, which convert pain into pleasure, like a runner’s high—serotonin doesn’t seem to be a happy-making chemical. So why do drugs that keep more serotonin in our brains seem to make us happier?

Recent studies of neurogenesis suggest it may not be antidepressants’ effect on serotonin that makes the difference. Studies on mice have shown that depression symptoms coincide with hippocampal damage.

Antidepressants seem to heal that damage. A 2010 Columbia University study found that blocking the healing process prolonged depression, suggesting that without neurogenesis, antidepressants don’t work.

That’s where Neuralstem comes in with its potential wonder drug aimed specifically at rebuilding neurons in the hippocampus.

Like Currie, Lois Winsky, a pharmacology research chief at the National Institute of Mental Health in Bethesda, is reserving judgment of the drug until test results are available and Neuralstem reveals how its stew of organic chemicals works. But she notes that creating new cells isn’t necessarily enough. Those cells have to survive and integrate themselves into circuits that affect mood. It’s not clear if neurogenic drugs can make that happen, she says.

And while dead neurons seem linked to depression, it’s not clear how or why. Losing neurons doesn’t seem to directly cause depression, and more neurons don’t necessarily translate into more happiness. And that’s just in mice, Winsky says. We still don’t know what happens with people.

Even so, other companies are moving in a similar direction, though Neuralstem is the closest to bringing a neurogenic drug to market. Dr. Andrew Pieper, a psychiatrist at the University of Iowa, is also working on a drug to spur neurogenesis. His compound has only been tested on mice, with promising results, but he’s searching for a partner to develop it further. He’s interested in seeing what happens at Neuralstem.

“I really hope their compound works,” he says. “It would fill an important, unmet need for patients. Although some doctors and scientists don’t believe that neurogenesis can be critically involved in depression, we simply won’t know the answer until the hypothesis is tested. I’m eager to see the outcome of their clinical trials.”

Pieper says his compound works by keeping existing cells from dying, allowing more newborn neurons to become integrated into the hippocampus. It also seems to protect cells in other parts of the brain and in the spinal column, possibly offering treatments for Parkinson’s disease and ALS, as well as depression.

“The fact is, the current treatment options for patients with depression simply aren’t good enough,” Pieper says. “Many people are resistant to the effects of the current classes of antidepressant medications available, so we need new treatment options for patients suffering from depression.”

Neurogenic drugs like his or Neuralstem’s may be used alongside antidepressants. Or they may replace them, offering hope to people for whom antidepressants don’t work.

In 2012, 41 patients took Neuralstem’s NSI-189 during a seven-day safety trial. They showed no side effects, Garr says. That paved the way for the Food and Drug Administration to permit further Phase I testing, with 24 otherwise healthy depression sufferers taking increasingly higher doses in three rounds of tests at a center in Glendale, Calif.

In the first round, launched last year, healthy patients were given 40 milligrams a day for four weeks to test the drug’s safety. In the second, patients who were suffering from depression took NSI-189 twice a day. In the final round, due to wrap up this fall, depressed patients take three 40-milligram doses a day.

Throughout each 28-day trial, participants must stay at the center, watching TV or using the exercise facilities to pass the time while researchers monitor their brain activity daily and check their blood, urine and saliva.

Researchers give them MRIs when they show up, when they leave, and then four weeks and eight weeks later. It’s a double-blind study. Patients don’t know if they’re taking the drug or a placebo. Researchers won’t know the findings until all three rounds are complete.

If the results look promising and the FDA approves Phase II for NSI-189, Neuralstem will begin stretching the dosing to 90 days and expanding the number of subjects. The company may also launch additional trials involving patients with Alzheimer’s, dementia, traumatic brain injury and degenerative brain diseases.

Neuralstem is also working with members of the National Football League Alumni Association to develop a trial for treating ex-athletes. There have been a number of high-profile suicides among former players in recent years, some of whom had been diagnosed with traumatic brain injury. Lee Nystrom, a former NFL Alumni Association chairman and ex-Green Bay Packer, says his group is ready to start “pushing the envelope to create therapies” to help ex-players suffering from brain injuries that linger long after they’ve hung up their jerseys.

If the results of Neuralstem’s second phase are strong, a third phase would involve hundreds, maybe thousands, of subjects.  But even in the best-case scenario, Garr says, it will be five years before someone like me buys NSI-189 at the pharmacy.

Until that time, there are the standard antidepressants.

Over the years, I’ve taken ever-changing drugs and dosages. Ten milligrams of Lexapro, then 20. Forty milligrams of Celexa, Lexapro’s weaker sibling, then down to 20. A year ago I weaned myself off Celexa, chopping the pill into smaller and smaller pieces, and spacing the dosages farther and farther apart until I stopped altogether. I felt good. For a while. Then that familiar feeling returned. Dullness. Darkness. My body so heavy I couldn’t lift it. Thoughts so slow I felt I could grab them out of the air. I made it through six months before I needed to erase the pain.

Now I’m on antidepressants again. Every couple of weeks I grab a handful of pills and subject them to a pill cutter, a little guillotine that slices the pink ovals into two half moons. I take half a day. It’s an act of hope and submission. I still need you, I’m saying, but I only need half of you. One day, maybe, I won’t need you at all.

David Frey has written for the San Francisco Chronicle and for Sunset magazine. He lives in Gaithersburg.