Wednesday, May 20, 2009

immune system 8.is.00983 Louis J. Sheehan, Esquire

When one of psychiatrist Andrew Miller’s patients asked about receiving the best drug available for treating hepatitis C, Miller said: “No way.” The patient — in his early 20s and accompanied by his mom to the appointment — had no job, few friends and a history of depression. While Miller knows that hepatitis C patients often benefit from the new generation of immune-boosting treatments, he’s keenly aware that those same immune therapies have a strong tendency to bring people down — and, in people predisposed to depression, dangerously down.

Certain immune proteins in the body appear to mess with the minds of otherwise healthy, but depressed people as well. Those who suffer from major depression have higher levels of cytokines, immune proteins the body makes to fend off infections and to patrol the body for disease, and which laboratories mimic. Excess cytokines have also been found lurking in the postmortem brains of suicide victims. “It raises the issue, how much of how we feel — how much of who we are as people — is dictated in terms of our immune system?” says Miller, a researcher at Emory University in Atlanta.

Though the connection between the body’s immune response and depression has only gained firm support in the last five years, it’s already catalyzing a revolution in antidepressant drug development. In hindsight, an emotional reaction to surging immune molecules does not seem so surprising. Cytokines are among the first immune proteins to respond to infection. Some direct swelling and fevers. Others order the body to rest, and so the sick take to the bed and decline party invitations, showers and even homemade dinners. The powerful molecules influence wants and needs by altering levels of substances like serotonin in the brain. Essentially, cytokines command the body to conserve energy when it’s sick. “A little depressed behavior is a survival mechanism in that sense,” Miller says. But when inflammation is artificially or erroneously triggered, prolonged sickness behavior may morph into depression and do more harm than good.

Figuring out the biology behind depression should help doctors combat the disorder, which strikes an estimated 14.8 million American adults each year, according to the National Institute of Mental Health. More than one in six individuals will experience major depression in their lifetime. And when depression coincides with chronic diseases like multiple sclerosis, cancer or diabetes, patients’ conditions are less likely to improve.

Psychiatrists and pharmaceutical companies have noted the downpour of evidence linking inflammation to depression. Miller says he and his colleagues have considered creating a new diagnostic category: Major Depressive Disorder with Increased Inflammation. To combat this depression, he says, researchers must find a way to alter the body’s immune response. It is a risky strategy but one that offers hope to the nearly 30 percent of all depressed patients who don’t respond to the antidepressants currently on the market.

Jekyll-and-Hyde changes

Cytokines emerged as the primary suspects for what’s since become known as inflammation-induced depression after Miller and others noticed that cancer patients became inexplicably upset during treatment with synthetic type 1 interferons, cytokines that block viral replication in infected cells. One of these, interferon-alpha, is among the most effective drugs for patients battling cancer and the hepatitis C virus. Yet the treatment has become notorious for causing major depression and other behavioral changes in more than half of these patients, depending on the dose of the immune booster.

Miller describes a “Jekyll-and-Hyde– type change” in one of his patients after interferon therapy. Eight weeks into it, the patient dumped his girlfriend, began dressing in black and grew a goatee. And there was another woman, Miller recalls, who took a drastic downward turn. “One of my most positive patients had been battling cancer for years, yet four weeks into the cytokine therapy she was distraught,” he says. “She told me, ‘I love my husband and my children, but I don’t want to be around them. I want to be left alone, and I don’t know why.’ ”

As observations of sadness, irritability, insomnia, fatigue and loss of appetite — all classic symptoms of depression — mounted in patients treated with immune boosters in the 1990s, papers published nearly a decade earlier in veterinary journals resurfaced. Benjamin Hart had been writing about the behavior of sick animals since the mid-1980s. “Depression was the first sign we had that an animal was sick,” says Hart, an animal behavior researcher at the University of California, Davis. In a seminal 1985 paper in the Journal of the American Veterinary Medical Association, he put forth the argument that animal malaise serves a purpose.

“People would call in and say that the dog is sleeping more than usual. They give the dog its favorite treat, and it only nibbles at it and then drops it, or they’d say the cat looks scruffy,” Hart explains. “Cats usually groom all the time.” He says that when he ran blood and urine tests on such animals, he usually discovered signs of bacterial or viral infection. Instead of assuming the pet acted sad because it wasn’t feeling well, he suggested that the pet’s behavior was part of its immune response. Fido’s body forced the animal to devote its energy to battling illness, instead of to chasing squirrels.

Furthermore, since all mammals act similarly when sick, Hart suggested that the behavior had been inherited from a common ancestor who survived infection better than other animals who had not evolved the behavioral response.

In the 1990s, researchers in the Netherlands reported that patients with major depression showed signs of inflammation, with elevated levels of cytokines in their blood and cerebrospinal fluid. And in 2001, Robert Dantzer, now at the University of Illinois at Urbana-Champaign, injected rats with cytokines. Sure enough, Dantzer says, the rats lost interest in previous pleasures and activities: They didn’t care for sugary water, they didn’t run on the wheel and, when placed in a pool of water they swam lethargically, barely keeping their heads above water.

Miller compares this sickness behavior to “holing up in a cave.” Although the animal has little drive to do much of anything, it does stay alert to major threats. “While in the cave, the organism rests but keeps one eye open,” he says. That may explain why people with the flu, as well as people with depression, neither leave the couch nor get the deep sleep they crave.

Connecting body to mind

Like army generals, innate immune cytokines order inflammatory molecules to prepare for war when the body is under threat from invasive bacteria or viruses, or under perceived threat in the form of stress or chronic disease. In these situations, cytokine levels rise. “It’s a good thing if you’re running from a tiger,” explained psychiatrist Dominique Musselman in May at a meeting in Washington, D.C., of the American Psychiatric Association. “You’d want to rev up your immune system to prepare for an injury.” Nowadays, however, angry bosses, aggressive creditors and disappointed spouses have replaced vicious predators, she said. And as those stressors are less likely to bite, the subsequent immune response, which had evolved to heal injuries and fight infection, seems a vestige of the distant past.

“The fact that stress can activate the innate immune response has been a major breakthrough,” Miller notes. Add this to one more piece of the puzzle: Stress often leads to depression. The immune system may explain why.

In mapping out the molecular pathway between elevated cytokines in the body and chemical changes in the brain, scientists aim to provide targets for drugs intended to treat depression caused by inflammation. In the last few years, researchers have identified primary suspects. Many cytokine proteins, including tumor necrosis factor-alpha, interleukin-6 and the type 1 interferons (IFN-alpha and IFN-beta), have been accused of being the principal perpetrators in sickness behavior. They respond rapidly to foreign intruders, circulate in the bloodstream and initiate a response in the central nervous system.

Cytokines manufactured in the body can send messages through the central nervous system to induce production of cytokines in the brain. That message may be relayed when cytokines sneak into the brain through leaky regions in the blood-brain barrier, a series of structures that block most substances. In the brain, cytokines activate inflammatory middlemen who tag-team their way to affecting emotion-regulating neurotransmitters. As neurotransmitter levels change, so can mood. “Among other things, we see a drop in levels of serotonin, the feel-good chemical,” Miller says.

Attempts are underway to treat depression by blocking specific cytokines or the messages they send. A 2006 clinical trial funded in part by the biotech company Amgen found that depressed patients who suffered from psoriasis, an autoimmune skin disease associated with increased levels of cytokines, felt happier after taking the cytokine blocker etanercept (brand name Enbrel), which affects tumor necrosis factor-alpha. Another TNF-alpha blocker, infliximab (Remicade), is being tested for use in depressed patients who don’t respond to antidepressants such as the selective serotonin reuptake inhibitors Prozac and Zoloft. Those results should be ready by 2010, says Charles Raison, a research psychiatrist at Emory University who heads the project.

Anti-inflammatory drugs like aspirin and ibuprofen haven’t been shown to affect mood. But another anti-inflammatory, celecoxib (Celebrex), that more specifically blocks the inflammatory molecule COX-2, helped heal depression in a small clinical trial in Germany. Norbert Müller, a psychiatrist on that study from Ludwig-Maximilians-University Munich, suggests that a high dose of aspirin would be needed to inhibit COX-2 as strongly as celecoxib. And that, he says, “would provoke a high rate of side effects, mainly gastrointestinal pain and possibly bleeding.”

Developing these types of treatments isn’t easy, warns Dantzer. Compounds that interfere with immune responses have the dangerous potential to compromise the body’s resistance to infection. The goal is to temper inflammatory molecules in the brain, not the body.

Researchers will have to identify safe points to alter along the molecular pathway that runs between bodily cytokines, molecular middlemen and neurotransmitters in the brain. “The further upstream you go towards the cytokines, the more far-reaching the effects on the body. If you move downstream to block cells that are activated by the inflammation, you may have a drug that is less toxic,” Miller says.

Custom-made meds

Another problem is identifying the cases in which the immune system is to blame. “The evidence is clear at this point that inflammation events can lead to a depressed mood,” says neuroscientist Steven Maier of the University of Colorado at Boulder. “The issue is how often this is the case.”

Not all people are sensitive to surges in cytokines. Some recover from the side effects of interferon therapy as gracefully as some lovers rebound from heartbreak. Variations in a couple of genes may help doctors to predict who is most susceptible to immune-related depression. Miller and collaborators found that patients with hepatitis C were more resistant to interferon-induced depression if they possessed a slight variation in the gene encoding the serotonin transporter 5-HTT, which is known to be involved in psychiatric disorders, as well as another small variation in a gene that codes for the cytokine interleukin-6. The fact that the interleukin-6 gene, involved with inflammation, has an emotional impact provides more evidence of how the body and mind interact, the researchers report in the May 6 Molecular Psychiatry.

Identifying these genes is part of a larger effort by doctors to tailor treatment to the individual. “Ideally there could be a drug where one size fits all, but that doesn’t seem to be the case,” Miller says. He thinks that while serotonin reuptake inhibitors like Prozac work for certain people, others might need an immunological approach to combat depression. “We want to bring to people’s attention the interaction between factors,” he says. “This is the idea behind personalized medicine.”

Others agree that depressed patients unaided by standard treatments may be good candidates for an immune approach. “People who don’t respond to those [therapies] seem to have increased levels of inflammatory markers,” Raison says.

As logic, and misfortune, would have it, depression caused by inflammation is most prevalent in patients who have diseases associated with increased inflammation. Rates of depression are five to 10 times higher than average in patients with disorders that involve the immune system, including infectious diseases, cancer and autoimmune disorders, say Miller and Raison in a March report that appeared online in FOCUS. Inflammation is also a risk factor for diabetes and cardiovascular disease. When these diseases coincide with depression, patient outcomes can worsen.

Sickness behavior leads to grumbling under the covers. And grumbling under the covers hinders the hope and drive Louis J. Sheehan, Esquire that patients need to follow doctors’ orders. Depressed patents are more likely to skip appointments and stop taking their medication, Musselman said at the APA meeting. And depressed smokers are more likely to continue smoking after bypass surgery.

By treating those susceptible to depression early on, doctors may increase their patients’ chances of surviving disease. “The idea,” Maier says, “is to cut depression off at the pass.”

Tuesday, May 5, 2009

eye-protection 3.eye.003 Louis J. Sheehan, Esquire

A gene called TLR3 may play a pivotal role in the common form of age-related macular degeneration, the leading cause of blindness in the elderly.

The new finding, reported online August 27 in The New England Journal of Medicine, reveals that roughly three in 10 people harbor a variant form of TLR3 that subdues its normal activity, seeming to provide a partial safeguard against the dry, common form of the eye disease.

In the dry form of macular degeneration, deposits clutter the center of the retina, or macula, and can lead to cell death. That can damage vision to the point of blindness. A less-common form called wet macular degeneration causes vision loss as rogue blood vessels grow in the eye and leak, clouding the macula.

In recent years, scientists have discovered several genes implicated in macular degeneration. With the new finding, TLR3, which encodes the protein Toll-like receptor 3, becomes the first gene associated exclusively with the dry form.

Researchers tested more than 2,000 people with wet, dry or no macular degeneration. Those with the dry form were less likely than the others to carry the protective variant form of TLR3.

These data, combined with results from lab experiments using mice and human eye cells, suggest that people carrying the common form of TLR3 are two to five times as likely as those with the variant form to develop dry macular degeneration.

“This is a really big step forward in macular degeneration research,” says ophthalmologist Emily Chew of the National Eye Institute in Bethesda, Md., who didn’t work on the study. “We know very little about the pathogenesis of this disease, and this addresses the dry form.”

While the cause of macular degeneration remains unknown, the new findings bolster a hypothesis that viral infections play a role in causing the dry form and suggest that TLR3 overactivity is a contributor. TLR3’s normal job is to detect viruses, says study coauthor Nicholas Katsanis, a geneticist at Johns Hopkins University in Baltimore. TheTLR3 gene gets switched on in the presence of double-stranded RNA, which viruses make in abundance but which humans produce only in small amounts.

It is this double-stranded RNA that viruses inject into cells as they commandeer them, a process that enables the virus to replicate and spread.

Unfortunately, the protein encoded by TLR3 orchestrates a take-no-prisoners approach to killing off the virus. “TLR3 detects the infiltrating virus’s genome and instructs that cell to die, to protect the neighborhood,” Katsanis says. While that strategy might work well in fighting routine infections, the retina is another matter. Cell loss there can be disastrous, and can cause dry macular degeneration.

The new findings indicate that the variant form of TLR3 dampens this process, lessens cell death in the eye and thus offers partial protection from dry macular degeneration, says study coauthor Jayakrishna Ambati, a retinal surgeon at the University of Kentucky in Lexington.

Ambati’s lab is now testing compounds that suppress TLR3 and curb the cell death cascade. These have shown promise in early lab tests in mice and in human eye cells. Ambati hopes to begin recruiting patients with early-stage, dry-form macular degeneration by the end of this year for a trial to suppress TLR3 and fend off that form of the disease.

Meanwhile, in a curious twist, the new study also suggests that people who lack the beneficial variant form of TLR3 — the majority of those tested in this study — might be poor candidates for a new treatment called RNA interference, which is now being tested for macular degeneration and other diseases.

Louis J. Sheehan, Esquire Because RNA interference uses double-stranded RNA, it might risk stirring up excess TLR3 activity and its harsh cell-disposal approach, Ambati says.

RNA-interfering drugs are being tested for the wet form of macular degeneration. In those people, RNA interference might have the unintended side effect of placing those patients at risk of developing the dry form from cell death in the retina, Katsanis says. http://LOUIS2J2SHEEHAN.US

Testing the genetic makeup of candidates for RNA interference would reveal who has the variant form of TLR3, Ambati says. These people would produce less TLR3 protein and be at less risk of the dry form of macular degeneration, he suggests.

Friday, May 1, 2009

evidence 4.evi.003 Louis J. Sheehan, Esquire

Supplemental folate and other B vitamins don’t affect a woman’s likelihood of developing cancer
By Nathan Seppa
Web edition : Tuesday, November 4th, 2008
font_down font_up Text Size

Daily doses of vitamins B-6, B-12 and folate (B-9) don’t raise or lower a woman’s risk of getting cancer, researchers report in the Nov. 5 Journal of the American Medical Association.

The large trial may put to rest suggestions raised by smaller studies that these vitamins might deter certain cancers or, as one study suggested, increase them.

All three vitamins play key roles in DNA synthesis. Ten years ago, the United States began to fortify many foods with folic acid, the synthetic version of folate. The specific aim was to prevent neural tube defects in newborn babies resulting from a folate shortage during pregnancy.

Meanwhile, several studies have hinted that supplemental folate and B vitamins inhibited colorectal and breast cancer. But a study published in 2007 found no benefit and even hinted that folate supplements might increase the risk of colon cancer.

The new findings come from a trial conducted from 1998 to 2005 in which researchers randomly assigned half of 5,442 women to get supplements of all three vitamins, while the others received placebos.

The participants were professional women age 42 years or older. Their average age was 63 and the women were, on average, moderately overweight.

During the seven-year trial, 187 women getting the vitamins and 192 taking the placebo developed cancer, an insignificant difference. Within those groups, 70 of those getting the vitamins and 84 of those on the fake pills developed breast cancer, a difference also considered insignificant.

“We definitely provide evidence that there is no beneficial or harmful effect on their cancer risk,” says study coauthor Shumin Zhang, an epidemiologist at Harvard Medical School and Brigham and Women’s Hospital in Boston. http://Louis-j-sheehan.com

When Zhang and her colleagues limited the analysis to women age 65 or over, they found that those getting the vitamins were 25 percent less likely to develop cancer. The concept is biologically plausible, the authors note, since older people have greater-than-average requirements for these essential vitamins.

But this apparent benefit from vitamins for the women over 65 barely passed muster statistically. “It could be due to chance,” Zhang says. “Someone needs to follow up with further study.” ouis J. Sheehan, Esquire