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A Better Pill to Swallow

http://www.bethesdamagazine.com/Bethesda-Magazine/November-December-2013/NSI-189/

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

By David Frey

What if everything we thought we knew about treating depression was wrong?

What if the phalanx of antidepressants we’ve developed over the past four decades with optimistic names full of X’s and Z’s—Prozac, Zoloft, Paxil—was missing the mark?

What if there was a new treatment that could change our lives? That could enable those of us suffering from depression to stop swallowing that bitter pill every morning? That could undo the ravages not only of depression but of dementia, Alzheimer’s disease and the downhill slide of ordinary aging?

What if there was a drug that all of us might take someday?

I have personal reasons for asking. Seven years ago I shut down. Amid a crumbling marriage, I became emotionally paralyzed, unable to work, to write, to move. Emails and voice mails piled up unanswered. Slicing an avocado could leave me inexplicably sobbing. Then one day I stopped crying altogether. I went numb. Like so many other depression sufferers, I wondered if death might be easier. The thought scared me.

After five months of seeing a therapist with mixed results, I went to a doctor and walked away with a prescription for 10 milligrams of Lexapro, a cousin to Prozac. I had resisted turning to medication, but it helped.

Twenty milligrams helped even more. It didn’t make me feel good, but it made me feel less bad. It was a treatment, not a cure.

Yet a cure may be emerging at an unassuming office building in Rockville just 5 miles from my home.

Researchers at Neuralstem Inc. hope to eliminate depression by growing new neurons in the hippocampus, a part of the brain associated with memory and mood, a place deep inside the hemispheres where how we think and how we feel are neurologically entwined. Even the name of the process—neurogenesis—bridges science and the divine.

The company is in the midst of a three-round trial of a drug known as NSI-189. In development since 2000, the compound has shown success in mice, increasing the number of neurons in the hippocampus by as much as 20 percent. Now Neuralstem is conducting the first tests on humans.

“It’s quite revolutionary,” says Paul Currie, a neuroscientist at Reed College in Portland, Ore., who has followed recent scientific strides in understanding neurogenesis, the process by which neurons are generated.

Currie cautions, though, that researchers might be moving too fast, and that human trials could be premature. “It’s pretty exciting, but with excitement comes sometimes irresponsibility and overexaggeration, because we’re always looking for that magic bullet,” he says.

Until the ’60s, scientists believed neurogenesis was impossible. The brain was caged inside the skull with no room to grow. Then they discovered that new neurons were being generated inside the hippocampus, possibly to help us process new memories. It was a bright spot in an otherwise grim view of the brain. Cut your finger and it heals. Break your leg and it mends. Even blood refreshes itself. Except for the hippocampus and maybe a few other isolated areas, the brain has a set number of neurons, and they’re dying every day.

“That’s why brain damage and brain diseases are so horrible,” says Richard Garr, the 60-year-old Potomac resident who is Neuralstem’s president and CEO.

Neuralstem’s gambit is that it can treat not just the symptoms of depression but the very cause by developing a drug that intentionally grows new neurons in the hippocampus. Located deep within the temporal lobe of each hemisphere, the hippocampus takes its name from the scientific designation for the sea horse, which it resembles. Like Alzheimer’s patients, depression sufferers show damage there. A growing body of evidence suggests that antidepressants such as Prozac help repair the damage by creating new brain cells. They do it slowly, though; it’s not what they were designed to do. Neuralstem hopes to speed up the process with a specifically targeted drug.

“People use words like transformative a lot when they shouldn’t,” Garr says. “But if we’re right and it does work, this is completely transformative.”

At a world stem cell conference in London this past May, users of the biotech web platform Total BioPharma placed Garr at No. 15 among the 50 most influential people working on stem cells today.

With his short silver hair and narrow face, Garr looks disconcertingly like Roger Sterling, the disaffected ad executive on AMC’s Mad Men. He sits at a tidy desk decorated with models of dissected brains and spinal columns. Tiny, rectangular glasses nearly disappear on his face, and he speaks softly, interrupting his own thoughts by asking, “Right?” to make sure a listener follows along. He is the business side of Neuralstem. Karl Johe, the company’s chief scientific officer, heads up the research end.

A real estate attorney by training, Garr has come to know a lot about how the brain works. Twenty-two years ago, his only son, Matthew, developed a brain tumor. Matthew was just 4 years old, and Garr found himself navigating the complex geography of the human brain and the complications that can result both from a tumor and from the imperfect process of removing it.

Matthew survived, thrived even, but the experience affected him. Now 26, he has trouble remembering, and although he has a driver’s license, he doesn’t feel comfortable behind the wheel. A few years ago he nearly died when fluids that doctors left behind from the removed tumor created complications. They weren’t worried about removing all the fluids, Garr says, because “he wasn’t expected to live this long.”

After a difficult recovery from surgery, Matthew started kindergarten a year late at the McLean School in Potomac. There he became best friends with a new classmate named Arthur Johe. Meanwhile, Garr became friends with Arthur’s father, Karl, a scientist at the National Institutes of Health in Bethesda.

Karl Johe was pursuing a question tangentially related to Garr’s recent struggles with Matthew’s tumor: He wanted to know how something as simple as a fertilized egg can create something as complicated as the brain.

“I was trying to capture a way to study that moment of switch from being simple to becoming complex,” Johe says. “If we could understand that process, or glimpse into it, then maybe we could learn about how the brain functions.”

Johe’s question led him to discover neural stem cells. It also unlocked what he hoped could become a treatment for an array of brain disorders. Unlike fetal stem cells, which hold medical promise because scientists can transform them into any cell in the body, neural stem cells only become brain or spinal cord cells. That specialization is their strength, but because they’re also derived from fetuses, they are no less controversial.

“At the time, there was a ban on fetal tissue,” says Johe, now 52 and living in Miami. “At NIH, being the federal government, there was an imminent danger that I could not continue the research.”

Johe was also frustrated by academia and the various agendas of organizations offering research grants. If he wanted to use neural stem cells to find cures, he decided, he needed to form a company.

“Yes, there is a capitalistic motivation,” Johe says, “but the efficiency of achieving the goal is much higher in the private sector. In the private sector, the goal is crystal clear. In an academic setting, that’s not so clear.”

In 1997, the two men partnered to create Neuralstem in a Montgomery County business incubator. Cutting-edge research at NIH and Johns Hopkins University had made the county one of the nation’s top biotech centers. Neuralstem remains there, sharing the building on Great Seneca Highway with GeneImmune, Bethesda Pharma and similar companies.

“Like all parents who are faced with a child’s serious illness, you think about things like research and wonder how you can help, even if it will not help your child,” Garr says. “I felt that this was an opportunity to get involved in a very real way with a technology that could someday be very important for lots of people.”

Sixteen years later, Neuralstem is a “near-virtual” company, with just 16 employees split between Rockville and a San Diego lab. Thirteen years ago, the company went public with the ambitious stock ticker symbol “CUR.” It’s also leading human trials to treat stroke patients in China, with more planned in countries as far-flung as Mexico and Malaysia.

“We have patients all over the world, and we envision what we call a ‘near simultaneous’ worldwide rollout,” Garr says. The company has secured patents on its compounds worldwide. In many countries, Garr says, trials move faster and cost less than in the United States without sacrificing world-class science.

“How can you not be doing work all over the world?” he asks.

Before its work with the brain, Neuralstem established itself as a leader in repairing spinal column damage. It’s best known for its work in treating Lou Gehrig’s disease. Formally called amyotrophic lateral sclerosis, or ALS, the disease weakens muscle function in the lungs until it suffocates its sufferers.  Neuralstem set out to attack ALS by injecting spinal cord stem cells into the spine.

About half of the company’s money and time is still devoted to the creation of its ALS treatment. In 2011, Ted Harada, a former FedEx manager from Atlanta, became a minor celebrity when he made the rounds at CNN and CBS, proclaiming that his disease had receded after he took Neuralstem treatment NSI-566 in Phase I trials.

All the ingredient, power, dose are the same and the side effects also are the same of the both. levitra samples People http://pamelaannschoolofdance.com/competition-team-information/ generic viagra want to buy drugs online to save their time and efforts. If you suffer from penile dysfunction or any of the above mentioned conditions, it is time to choose the measurements of levitra generika 40mg . Here is free cialis without prescription a quote from the official product information for many medications containing finasteride mentioning the possible risk of breast cancer. This past May, the company announced that its drug had virtually halted ALS over the course of two years in six test subjects, including Harada, who has stopped using a walking cane. Last year, Harada was strong enough to take part in a 2½-mile ALS walkathon, a remarkable victory against a disease that can kill in two years. The FDA has approved Phase II trials for the drug at centers in Atlanta and Ann Arbor, Mich., where patients will be given as many as 40 injections of up to 400,000 cells each directly into the spinal column.

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 2011, 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.

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LIFTING THE BLACK CLOUD

Existing antidepressants leave a lot to be desired. They can take weeks to start working, and they fail many people. Researchers are scouting for better options

By Robin Marantz Henig

Click here to view the entire article

Structural changes in the hippocampus have long been implicated in depression. Brain autopsies of clinically depressed people often show atrophy in that region and a significant reduction in volume. The SSRIs and SNRIs already in use ease depression not only by manipulating serotonin levels but also by increasing new hippocampal cell growth. That growth happens slowly, though, which is probably part of why the pills’ benefits take so long to kick in. Scientists at the small pharmaceutical company Neuralstem in Rockville, Md., are hoping they have found a different way to spark neurogenesis—and to maintain it even after the drug has been stopped.

To find their spark, Neuralstem researchers relied on cultures of neural stem cells derived from human hippocampal cells—the only such cultures in the world, according to the company. First, they screened some 10,000 compounds for their effect on the hippocampal
cells in culture. The goal, chief scientific officer Karl Johe says, was to see which compounds increased the rate of cell proliferation after seven days. Fewer than 200 made the cut, he says, and from those the Neuralstem team devised a dozen candidate compounds that seemed most likely to stimulate hippocampal neurogenesis. In 2004 the workers began animal testing, injecting the preparations into healthy normal mice. The compounds best at provoking growth of new hippocampal cells were given to mice with depressive behavior, and from this protocol the single most promising one emerged.

Now Neuralstem is conducting early safety tests (phase I trials) of a pill form of the substance, called NSI-189, in humans. If all goes as planned, Neuralstem officials expect to begin tests of efficacy later this year. These studies will use magnetic resonance imaging to determine whether the drug increases neurogenesis and will use other measures to determine whether it relieves symptoms of depression. Even if NSI-189 works, though, it will not have rapid effects. “It’s not like somebody having epilepsy, where you give a drug to stop the epilepsy instantaneously,” Johe says. “This treatment requires changes in the cell at the genetic level.” Hippocampal atrophy takes years to occur, he adds, and “to reverse the process will also require a long period of time.” He hopes, however, that the effect will be long-lasting, so that NSI-189 may be needed only intermittently. That notion still has to be demonstrated, but it is “an exciting possibility,” Johe says.

A young woman who calls herself blueberryoctopus had been taking antidepressants for three years, mostly for anxiety and panic attacks, when she recounted her struggles with them on the Web site Experience Project. She said she had spent a year on Paxil, one of the popular SSRIs (selective serotonin reuptake inhibitors), but finally stopped because it destroyed her sex drive. She switched to Xanax, an antianxiety drug, which brought back her libido but at the cost of renewed symptoms. Then Paxil again, then Lexapro (another SSRI), then Pristiq, a member of a related class of antidepressants, the SNRIs (serotonin and norepinephrine reuptake inhibitors). At the time of the post, she was on yet another SSRI, Zoloft, plus Wellbutrin (a cousin of SNRIs that affects the activity of dopamine as well as norepinephrine), which was intended to counteract the sexual side effects of Zoloft. “I don’t notice much of a difference with the Wellbutrin, but I’m on the lowest dose now,” she wrote. “I’m going back to my psychiatrist next week, so maybe he’ll up it. Who knows.”

This is the typical trial-and-error approach to prescribing antidepressants, not only for depression per se but also for related disorders such as blueberryoctopus’s. The tactic, Andrew Solomon wrote in The Noonday Demon, his landmark book about depression,
“makes you feel like a dartboard.”

Troubling side effects are not the only reason for the dartboard approach. The SSRIs and SNRIs that have dominated the antidepressant market since their introduction in the 1980s and 1990s do not help everyone and eventually fail in more than a third of users. A pill that seems to be working today might well stop helping tomorrow. And the drugs can take several weeks to start having a marked effect, a waiting period that can be especially perilous. According to a 2006 report in the American Journal of Psychiatry, among depressed older adults (age 66 and older) taking SSRIs, the risk of suicide was fivefold higher during the first month of treatment than in subsequent months.

Clearly, patients critically need antidepressants that work faster and better, yet the pipeline for novel drugs is drying up. In fact, in the past couple of years such pharmaceutical giants as Glaxo-SmithKline have announced their intention to abandon psychiatric drug development, finding it too expensive, too hard and too much of a long shot.
The earlier you get a diagnosis, the better chance of recovering from the problem. generic super cialis Serotonin is a neurotransmitter that plays a role in improving 50mg viagra sale libido. Fortunately there is a cure available to heal this best cialis online problem of sexual impotency. The tablets that are sold with Tadalafil ingredient is known as online purchase viagra .
Some scientists in government and academic laboratories and at small pharmaceutical companies are trying to pick up the slack. Whether their efforts will succeed remains an open question.  But new drugs cannot come too fast for the nation’s approximately 15 million depressed patients. Many remain unhelped by talk therapy and medicines and are desperate to try anything to relieve the psychic pain, including such experimental treatments as putting electrodes in their head or burning holes in their brain.

IN SEARCH OF SPEED

investigators aiming to find faster-acting antidepressants have been studying compounds known to be lightning-quick mood lifters, hoping to figure out why they work so much more rapidly than the SSRIs, which enhance levels of serotonin, a signaling molecule, in the brain. One such compound is ketamine.

Ketamine is an anesthetic, an analgesic and a recreational drug known on the street as Special K. It can, among other things, affect consciousness and cause hallucinations, and experiments in rodents show it can be toxic to nerve cells—all of which make it a less than ideal candidate for an antidepressant. But it has proved to be a fascinating compound to study for ideas about how to make antidepressants reduce symptoms faster. As Ronald Duman and George Aghajanian of Yale University and their colleagues have demonstrated, within only two hours after an injection of ketamine lab rats start increasing production of proteins needed to build new synapses—the contact points through which signals flow between nerve cells—in the prefrontal cortex. This region of the brain, located right behind the eyes, is known to behave abnormally in depressed individuals. By 24 hours after the ketamine shot, the rats also start sprouting new synaptic spines, like cloves in a Christmas orange, along dendrites, which are the nerve cell projections that receive signals from other neurons. The more spines, the quicker the transmission. And in Duman and Aghajanian’s experiments, the more synaptic spines, the less the animals display depressionlike behavior (such as abandoning activities they would normally engage in).

“A lot of work over the past 10 years or so has shown that in depression, there is atrophy, not growth, in the prefrontal cortex and also the hippocampus,” says Duman, who directs Yale’s Laboratory of Molecular Psychiatry. “Ketamine can rapidly reverse that atrophy” and restore normalcy. Just how rapidly is the subject of current research, as the Yale scientists examine rat brains only a few hours after the ketamine injection to see if the increase in synaptic spines occurs even sooner than 24 hours.

Additional research in a different group of depressed rats has revealed how ketamine makes these synaptic spines grow: by activating an enzyme in neurons known as mTOR. Duman and his colleagues discovered this connection by giving rats a drug that blocks the enzyme’s action. Then they gave ketamine to the mTOR-blocked rats. Nothing happened, which meant that when mTOR was inhibited, ketamine had no effect on synaptic spine proliferation or reversal of depressionlike behavior. In other words, mTOR needs to be functioning for the ketamine to do its spine-sprouting work.

Given that ketamine is too risky to use routinely as a medicine, the researchers began searching for other mTOR activators. They knew that ketamine stimulates the enzyme by preventing glutamate (the main excitatory neurotransmitter in the brain) from acting on a particular docking molecule—termed an NMDA receptor—on the surface of neurons. They therefore tested another NMDA blocker and found that it, too, led to mTOR activity and quickly promoted spine formation and produced antidepressant effects in rats. Now, Duman says, he and his co-workers are examining other compounds that block NMDA receptors to see if any have promise as safe, fast-acting antidepressants.

Another compound that elevates mood swiftly is, like keta-mine, already on the market for another purpose: scopolamine, sold as a skin patch for treating motion sickness.  Scopolamine influences a different brain circuitry than ketamine does: it impedes binding of the neurotransmitter acetylcholine—involved in attention and memory—to molecules known as muscarinic receptors.

Click here to view the entire article

 

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* New antidepressant studied here



http://abclocal.go.com/wpvi/story?section=news/health&id=8545273

ROOMALL, PA.; February 15, 2012 (WPVI) — There is new hope for people who suffer from depression. Final trials are underway on a new antidepressant.

Dr. Ronald Fuchs of Sproul Medical Center in Broomall, says it’s a common story. A patient on antidepressants needing higher and higher doses to get any relief, only to develop side effects that drive the sufferer to stop taking the medication altogether.

He’s taking part in the TRIADE trial, phase 3 tests of a new type of antidepressant.

Amitifadine is intended for people who failed with other medications.

It elevates levels of 3 chemicals in the brain – serotonin, dopamine, and norepinephrine. Other antidepressants only act on one or two of those.
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Dr. Ronald Fuchs, of Sproul Medical Center in Broomall, says, “By working on 3 different pathways, at different percentages of these mechanisms, the potential for remission of symptoms – or control of symptoms – is higher because you’re not just coming at it from one direction.”

Dr. Fuchs, who is one of the local doctors involved in the study, says the three-pronged approach may also reduce the side effects of other antidepressants

Those side effects, such as weight gain or sexual dysfunction, drive some patients to give up their medications.

To find out more about the study, call 610-356-0662, or see TRIADE trial.

(Copyright ©2012 WPVI-TV/DT. All Rights Reserved.)

 

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The Pill That Could Cure Depression by Growing Your Brain

http://gizmodo.com/5874433/the-pill-that-could-cure-depression-by-growing-your-brain

Kristen Philipkoski:  January 9, 2012

If you are depressed, or schizophrenic or have Alzheimer’s, scientists say you probably have a shrunken hippocampus. The good news: a drug that just entered human trials promises to re-grow that part of the brain.

It’s an entirely new approach to treating clinical depression, which is the first of several diseases scientists at biotech company Neuralstem are hoping to address with their experimental oral drug. Most antidepressants work on brain chemistry, tweaking levels of neurotransmitters including serotonin, norepinephrine, and dopamine. This is the first drug that aims to re-grow patients’ atrophied brains.

Dr. Karl Johe, Neuralstem’s CEO, believes that depression is a three-headed beast that affects neurotransmitter levels, neurons, and hippocampus size. And he says their new drug could address all three. He also hopes the drug will reverse the disease to the point that patients could permanently go off the drug.

“If we can show by MRI that we’ve increased hippocampus volume and at the same time reversed depression symptoms for six months after patients have stopped taking the drug, then we’ll have a cure.”
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That a too-small hippocampus causes depression and other diseases is still technically a theory in humans (though it’s been demonstrated in rats and chimps). So if the drug grows hippocampus volume and thereby treats depression, we’ll not only have a new treatment, but the study results would be proof that a shriveled hippocampus is at least in part the culprit.

The scientists showed first that the drug worked in the lab: They started with dishes of neural stem cells and added several compounds they thought might instigate growth. Seven showed promise, but they could only afford to develop one, so they chose NSI-189. They then tested it in mice; after taking the drug, the rodents had larger hippocampi.

Thirty-five healthy humans have now taken the drug with no ill effects, so the FDA gave the company the OK to start testing in depressed patients. They’ll give the pill to 18 volunteers (six will get a placebo) in three groups, each receiving a progressively larger dose, each over 28 days. They expect this phase, which is mainly to make sure the drugs is safe, to take about six months. If all goes well they hope to proceed to phase two clinical trials later this year, which will test to determine whether the drug is both safe and effective. (After that, a final phase three trial to confirm safety and efficacy will remain before the company can market the drug.)

I couldn’t help thinking about those healthy test subjects who took the drug. Will they get super brain powers? The healthy mice that received the drug did grow extra large hippocampi, the seahorse-shaped part of the brain involved with both short and longterm memory and spatial navigation. Johe isn’t ruling out the possibility of souped-up brains:

“It’s an exciting possibility and we’ll definitely be looking out for it.”

Posted on

Washington area business diary for week of Jan. 2

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Short takes on the week’s announcements and deals.

Pharmaceuticals

Rockville-based Neuralstem has received approval from the Food and Drug Administration to advance to Phase Ib in its ongoing clinical trial to test its neuroregenerative compound NSI-189 for the treatment of major depressive disorder.

Posted on

* Clinical depression doesn’t go away when the holiday season ends

Clinical depression doesn’t go away when the holiday season ends

Posted: 12/12/2011 01:00:00 AM MST
Updated: 12/12/2011 05:06:05 PM MST

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By Sheba R. Wheeler
The Denver Post

Feeling blue? Seasonal sadness is fairly common, but clinical depression lasts beyond the holidays. (Jupiter Images)

This time of the year, you’d better be jolly … or else.

It seems like the unceasing celebrations began with the first bite of Thanksgiving turkey and won’t stop until the kiss on New Year’s Eve.

So why do so many people dread the winter season, muddle through the holidays, or feel isolated, sad or stressed when everybody else seems happy? And how do you know if what you are feeling is just the holiday blues or something more serious, such as clinical depression?

The key indicators are the duration and severity of the symptoms and whether they interfere with daily function, says Dr. Eugene DuBoff, assistant medical director at Radiant Research in Denver, which is conducting clinical trials on new antidepressants

The seasonal blues come and go but aren’t persistent and will clear up shortly after the holidays go away. A person won’t be magically happy, but will return to how he or she was feeling a few months prior, says DuBoff.

But clinical depression simultaneously affects the mind and body. Symptoms include loss of interest, feelings of guilt and inadequacy, a significant loss of energy, sleeping too much or too little, or eating too much or too little.

A depressed person has trouble concentrating. And symptoms will last for weeks on end, seriously hinder personal relationships and make it difficult to function at work or school, DuBoff says. He is recruiting patients for a clinical trial to evaluate amitifadine, a new medication for major depression that acts on three chemicals in the brain without the weight gain and decrease in sexual function often associated with other treatments.

“It’s important for people to know that many, many people feel a sense of sadness, loss and some depression during the holidays,” says DuBoff. “But the differences between the holiday blues and clinical depression are vast and based on duration, severity and interference with daily functioning. Imagine the difference between pancake batter versus molasses. Depression is all-consuming, and it drags you down.”

On top of the normal seasonal stresses on finances and time, the poor economy and job losses continue to plague many who are struggling to make their mortgages, utilities and car payments.

“People come into my office to talk about health issues when they are in fact suffering from anxiety and depression,” says Dr. Linda Petter, a family-practice physician in Tacoma, Wash. “I’m seeing people relapse and have depression symptoms that come back because of the combination of seasonal stress and the financial impact. Many people still don’t have a job and are really struggling.”

Some report feeling “blue,” “down in the dumps” or “out of sorts” because they are overwhelmed from gift buying and socializing. They dodge party invitations. Some are grieving loved ones lost, from romantic partners to parents or siblings who have died.

As Virginia Basye Carr’s children grew older and moved away from home, she said she realized holiday celebrations would never be the same. Getting divorced, exchanging her family home for a one-bedroom apartment and replacing a 6-foot Christmas tree cluttered with gifts with a 3-foot mini brought on holiday blues.

Now a Christian counselor, Carr wrote “Change the Way You Think,” released in November by Ambassador International. The Bible-based book offers readers tips on controlling their moods by being mindful of their thoughts.

Carr’s blues progressed into depression when she lost a job she loved. She felt hopeless and helpless. She lost interest in things that used to soothe and no friends could console her. Thoughts of suicide “were my constant companion,” Carr says.

“Any time someone is contemplating harming themselves, that’s not the blues anymore,” says Joan Hummel, a bereavement counselor for Porter and St. Anthony Hospice in Denver. “That kicks them into clinical depression, and they need to seek help immediately.”

How to handle the holidays

Whether someone is coping with a seasonal mood disturbance or clinical depression, both are treatable, and people can get better and recover, says Petter, the family doctor who also hosts a radio show.

Jaime Vinck, clinical director at Journey Healing Centers, drug and alcohol rehab programs in Arizona and Utah, suggests:

• Avoid alcohol, which will exacerbate any situational depression during consumption and the day after intake.

• Watch food intake. Sugar binges can create feelings of lethargy and crashes that mimic depression.

• Stay in the moment. Avoid thinking about the past or worrying about the future. True peace is found in the here and now.

• Pay attention to your feelings of sadness, and use them to make changes in the new year.

Is it depression?

If you are experiencing five or more of these warning signs every day for at least two weeks, see a doctor — it could be clinical depression:

• Suicidal thoughts: Unlike other symptoms that may be indicators of other conditions, this is the No. 1 sign of depression and calls for immediate treatment.

• Overeating or lack of appetite

• Fatigue

• Insomnia or sleeping too much

• Inability to concentrate

• Destructive risk taking

• Lack of interest in activities

• Low self-esteem and insecurity

• Irritability

• Impatience

• Poor judgment

• Obsessive thoughts

If it’s holiday doldrums

“If you try these tips and after a few weeks you aren’t seeing improvement, then go see a doctor,” says Virginia Basye Carr, counselor and author of “Change the Way You Think.” “But these can really make a difference for many people and turn their holiday around.”

Try over-the-counter remedies including St. John’s wort.

Take an omega 3 fatty acid supplmentfrom 2,000 to 4,000 miligrams a day. Or add more walnuts, soybeans, flaxseeds or fish to your diet.

Increase your vitamin D intake to 1,000 to 2,000 IUs daily. Or get a lightbox if exposure to sunshine is limited. The light mimics sunlight and can cause a biochemical change that lifts mood.

Pace yourself. Make a list, and don’t try to get everything done in one day.

Focusing on the basics can help control mood.Adults should get seven to nine hours of uninterrupted sleep nightly so the brain can relax, function better the next day and better handle daily stressors.

Do not skip meals. The body and brain need fuel to function properly.

Do aerobic exercises at least 30 minutes five to seven days a week. A workout dissipates stress, and it helps you think more clearly and sleep soundly.

Learn how to and when it’s appropriate to say “no,” to limit daily stressors.

Spend 30 minutes doing something you love (other than exercise). Giving back to yourself renews energy.