Protomag

A Matter of Taste

2012-03-13T19:36:37-05:00

How people perceive and respond to the taste of food is largely a matter of evolution. We’re born loving sugar because it signals the presence of carbohydrates that fuel the body. We want salt because it maintains our cells’ electrolyte balance. Savory alerts us to amino acids, the building blocks of proteins. Bitter warns against ingesting toxic, noxious chemicals in plants, and sour saves us from spoiled, fermented food. Yet not all tasters get the same message. John Hayes drinks unsweetened black coffee but shuns grapefruit. His wife loves grapefruit but abhors black coffee. Their daughter likes both and sometimes prefers grapefruit to cheesecake.

Hayes is director of the Sensory Evaluation Center at Pennsylvania State University, and based on his research, he thinks he can relate those varying preferences to underlying biological differences in how tongues detect bitter compounds. Such innate variations, mostly determined by a person’s genetics, affect how responsive taste buds are to particular food molecules, as well as how many taste buds there are, and so how strong a signal they send to the brain. Varying perceptions of the five basic tastes—bitter, sweet, salty, sour and savory (or umami, a Japanese word for “delicious”)—affect food likes and dislikes, which influence our food choices.

Inborn attractions and aversions served humans well when the most important thing was getting enough food and not being poisoned by it. Yet our needs have evolved, and it would be ideal now if taste encouraged healthy food choices—rather than pushing people away from broccoli, for instance, which some find repulsively bitter, or drawing us to fattening sweets and carbohydrates. Indeed, bitter compounds also contain beneficial vitamins, antioxidants and flavonoids.

Scientists have only recently begun to understand how the tongue, much less the brain, responds to taste and how genetic variations affect its response. Now, as they trace connections among taste, flavor and food choices, they’re finding that people’s innate predispositions don’t always predict which foods they will actually like or dislike, and that environmental factors, including a mother’s choices passed along in amniotic fluid, also play a role. As researchers parse the interplay of all of these factors and their impact on health, some are looking ahead to a time when it may be possible to entice people toward foods they are hardwired to avoid and away from others they enjoy to an unhealthy extreme.

A large part of the gustatory system, which governs what and how we taste, is visible on any human tongue. There are small, mushroom-shaped structures called papillae that contain globular clusters of taste buds. Each taste bud in turn has 50 to 150 taste cells, each of which is studded with proteins known as chemoreceptors that detect only one of the five tastes. Chemoreceptors bind to a specific type of food chemical, variously known as a tastant, taste stimulus or ligand. For example, natural sucrose and similarly shaped molecules in artificial sweeteners are tastants that connect to sweet receptors, and when they make their wonted links, they trigger a reaction that sends a signal of sweetness to the brain. That message travels along a cranial nerve from the tongue to the medulla, in the brain stem, which connects to other brain regions involved in appetite, emotion and cognition.

Scientists knew much less about the physiology of taste 80 years ago, when DuPont chemist Arthur L. Fox made an accidental discovery. Fox was transferring a newly synthesized compound, phenylthiocarbamide, or PTC, to a container, and some of the powder wafted into the air. A colleague tasted something horribly bitter, but Fox detected nothing. Curious, he gave samples to other people, most of whom also thought it ghastly. But about a quarter of them, like Fox, found it tasteless. Fox and geneticist A.F. Blakeslee then took PTC to a scientific meeting and observed a 2.3-to-1 ratio of tasters to nontasters—close enough to the 3-to-1 inheritance pattern of dominant to recessive characteristics, as with Gregor Mendel’s peas, to indicate that nontasting was a recessive trait.

Yet why would humans have evolved in such a way that most were repelled by a nonnatural substance? The answer, which didn’t emerge until the 1950s, was that disliking PTC—and a related synthetic chemical, PROP—was a kind of accident. The innate aversion of those who could taste those compounds was to bitter chemicals, called glucosinolates, in cruciferous vegetables such as kale and brussels sprouts (PTC happens to mimic natural glucosinolates). One glucosinolate, goitrogen, is toxic to the thyroid in large quantities, so it made sense, in evolutionary terms, for people to have a sensitivity to it. However, in smaller amounts, other glucosinolates may help ward off cancer.

Levi Brown

By the 1960s, a few scientists had confirmed what the earlier research seemed to predict—that whether someone could taste PTC/PROP predicted how many foods they disliked. But that observation was largely ignored until the 1990s, when Linda Bartoshuk, then at Yale University and now at the University of Florida, discovered additional layers of complexity.

Bartoshuk found that some people qualified not only as tasters but as “supertasters,” at the opposite end of the spectrum from nontasters. Rather than determining whether people could detect low concentrations of PROP—the acid test dividing tasters from nontasters—Bartoshuk looked at how intensely people perceived higher concentrations. Using sound and light as a frame of reference, she discovered a wide range of intensities. “Most of us live in a world of pastel tastes, but about 25% of us have neon tastes,” she says. To those supertasters, bitter is more bitter, salt is saltier and sugar is sweeter—and food likes and dislikes tend to be more extreme.

Bartoshuk’s work led others to explore how genes influence taste. In subsequent studies, scientists found that each type of tastant—bitter, sweet, salty, sour or umami—triggered a different kind of chemoreceptor, and the observation of differences in how tastes are perceived suggested that those receptors might vary from person to person, because of variations in the genes controlling the receptors.

In the late 1990s, researchers began to identify those receptor genes, first in mice and then in humans. They knew that different strains of mice had distinct preferences for sweet and bitter, judged by how voraciously they would lap up sugar water of a particular concentration and whether they would shun water laced with bitter compounds. By then, human and mouse genome sequencing projects were well under way, and in 2000, Charles Zuker, a neuroscientist at Columbia University, working with National Institutes of Health scientists, identified a family of bitter receptors and showed that the mouse genes for those receptors came in taster and nontaster variants that resulted in different sensitivities to bitter chemicals.

Bitter receptors (and also those for sweet and umami) belong to a class called G protein–coupled receptors (GPCRs), with seven loops that span cell membranes, and have an extracellular extension like a Venus flytrap. This flytrap can bind to a chemical of a particular shape floating by on the tongue in lock-and-key fashion. When a bitter compound fits the lock, that connection causes the taste cell to send a signal to the brain.

Levi Brown

In the early 2000s, researchers used the results of the recently sequenced human genome to identify the human bitter taste gene TAS2R38, which governs the PROP/glucosinolate receptor. Subsequent studies showed that minute inherited differences in the gene change the shape of the receptor’s binding pocket—the lock in the lock-and-key connection in the flytrap. About one in four people (supertasters) receives two genes (one from each parent) that produce a receptor that binds strongly to PROP; another 25% (nontasters) receive genes that yield a receptor that binds weakly, if at all; the rest (mid-tasters) receive one of each.

Several labs have now shown that these small genetic modifications change the response to taste compounds, and scientists have engineered mice to tweak their sweet and bitter genes and alter their food preferences. “Taste is greatly affected by the activity of our receptors,” says Zuker. “And because receptors vary from person to person, so does the way we experience taste.” That means that people live in separate taste universes, and each person’s individual constellation can have much to say about overall health.

Yet these genetic differences alone don’t explain the wide variation in bitter perception, which may range from absolute distaste to active appreciation. “We can’t separate high tasters from mid-tasters with a genetic test,” says Hayes. And only certain bitter keys—PROP and the glucosinolates from kale and related vegetables—fit the binding lock of the protein produced by the TAS2R38 gene. It turns out humans have, in addition to PROP, some two dozen other bitter receptors. At least some of the genes for those receptors also have multiple versions, further explaining the wide variations in how people perceive different flavors.

Some of the most telling information about how a grab bag of genetic differences relates to taste comes from a study published in the March 2011 issue of Chemical Senses. Hayes, Bartoshuk and their colleagues examined DNA collected from participants and analyzed the genes associated with several bitter receptors to create a genetic profile of each participant. Then the researchers asked the participants to taste samples of three bitter drinks—unsweetened grapefruit juice, instant espresso and blended Scotch whisky—and rate the intensity of each sample. Some participants rated coffee as tasting twice as bitter as others found it, but not all of those same participants found grapefruit or Scotch to be exceptionally bitter. These broad variations arose because there are so many genes for bitter receptors, making it possible for each person to inherit an idiosyncratic combination. Hayes and his team found that an unknown bitter compound in grapefruit juice, possibly naringin, triggers the bitter receptor TAS2R19. Alcohol triggers both TAS2R16 and TAS2R38, and coffee may activate TAS2R3, TAS2R4 or TAS2R5.

This latest research is helping to explain how particular genes appear to relate to specific tastes, and the combination of gene variants that someone inherits seems likely to influence which foods that person will crave or avoid. But another factor, visible on the tongue, also affects the relative intensity of how tastes are experienced. When Bartoshuk discovered supertasters, she noticed that they had more papillae than non- and normal tasters. Having extra papillae also affects the perception of a food’s flavor—a quality that takes into account the pain of hot chili, the cool of mint, the texture of whole grains and the “mouth feel” of fat. And it turns out that papillae contain nerve fibers with receptors for touch—and those who have larger numbers of papillae, with additional nerve receptors, tend to experience foods more intensely.

That’s another reason, Bartoshuk says, that supertasters are likely to find bitter vegetables, sweet desserts and fatty, creamy foods unpleasantly vivid. They tend to gravitate toward mild food, eating fewer ribs, fries and desserts, but also less broccoli. That diet could give supertasters lower risks for obesity, diabetes and cardiovascular disease but might leave them lacking the protection against cancer that some vegetables may provide.

While it’s easy enough to test these hypotheses in genetically altered mice, it’s been difficult to establish definitive connections between high- and low-tasting receptors and human behavioral choices. The evidence that such links exist is strongest between bitter and vegetables, largely thanks to work by Valerie Duffy, a registered dietitian at the University of Connecticut. In a November 2010 study, Duffy, Bartoshuk and Hayes directly linked differences in vegetable intake to the TAS2R38 gene. Adults with one or two copies of the taster gene—a group that, in previous research, experienced more bitterness in vegetables in taste tests—reported eating about 25% less vegetables than those with two copies of the nontaster gene.

Levi Brown

Research on other types of food has found smaller effects, and none proves that taste genes determine food choices. Among the disparate findings are that adult supertasters like sweet foods somewhat less than others do, but supertaster children like them more. Among college males, supertasters are thinner. Supertasters have better lipid profiles, suggesting lower cardiovascular risk. Older male supertasters who report consuming fewer vegetables have more colon polyps (a risk factor for colon cancer).

Genes and the receptors they control are only part of the equation because they interact with environmental, behavioral and cultural influences. For example, illness and smoking can dull taste receptors, Grandma’s home cooking can make you love brussels sprouts, and fast foods can get you so accustomed to a lot of salt that regular food tastes bland. So food preferences are not predetermined, and in fact they’re quite malleable. Both early and late in life, there are windows of opportunity to modulate proclivities to avoid or embrace particular foods, says Gary Beauchamp, a taste researcher at the Monell Chemical Senses Center in Philadelphia.

“There’s a huge amount of data from animal studies showing a transfer of flavor via amniotic fluid from the mother to the fetus, and in rats, pigs and mice, babies will more readily eat foods their mothers ate,” Beauchamp observes. “We have found that human babies have similar tendencies.” The same is true of the foods a nursing mother eats, because flavor compounds dissolve in breast milk. “The foods a woman eats during pregnancy and nursing can have long-term implications for children’s preferences later in life,” he says.

Adults can also modify their preferences for salts, as Beauchamp demonstrated during the 1990s. Over a period of six to eight weeks, he gradually reduced the level of sodium in soup given to a panel of human subjects. In time, the salt concentration the testers had thought was ideal came to be perceived as too salty. “In theory we could use that approach to shift the whole population down to levels closer to that recommended by U.S. dietary guidelines,” he says.

Relearned perceptions of other tastes might one day help people overcome genetic proclivities—or drugs or food additives could be developed that make healthy but unpopular food choices more palatable. The goal, says Columbia University’s Zuker, is “to help people enjoy the things that make our sensory experiences rich in a healthy, productive way. If we could modulate the activity of taste receptors, we could perhaps help with serious problems in our dietary world.”

Dürer: Pinpointing Pain

2012-03-13T20:01:53-05:00

THERE IT HURTS, scribbled the German artist Albrecht Dürer five centuries ago on a postcard-size self-portrait he sent to a physician about his mysterious illness. Dürer’s symptoms included fever, nausea and pain, the site of which he marked with a yellow oval. Though it’s not known whether the drawing was of help, or even what the doctor’s diagnosis was (later theories ranged from malaria to tuberculosis to poisoning), Dürer’s practical masterpiece is the first known instance of a pain map. Simple outlines of the body on which patients pinpoint where it hurts, pain maps can help clarify, for instance, whether pelvic pain originates from internal organs or a musculoskeletal source. Most pain maps, like Dürer’s, involve pen and paper; however, researchers are developing 3-D computer versions to track pain more accurately, aiming to create software for chronic pain patients to chart the location and quality of their pain throughout the day.

Somber Questions

2012-03-19T14:43:49-05:00

More than one in 10 Americans takes one or more antidepressant medications, and for that large chunk of the population, recent events surely have been unsettling. Three books published in 2010 were uniformly damning of the No. 1 type of medication taken by people ages 18 to 44, though each author takes aim at antidepressants from a different angle. Clinical psychologist Irving Kirsch lays out evidence that antidepressants simply don’t work in The Emperor’s New Drugs: Exploding the Antidepressant Myth—he argues that they’re no more effective than the dummy pills used in clinical trials. Journalist Robert Whitaker, in Anatomy of an Epidemic: Magic Bullets, Psychiatric Drugs, and the Astonishing Rise of Mental Illness in America, makes a more harrowing claim—that chronic use of antidepressants and other psychotropic drugs has created legions of mentally disabled people who are far worse off as a result of treatment. And psychiatrist Daniel Carlat, in Unhinged: The Trouble With Psychiatry—A Doctor’s Revelations About a Profession in Crisis, charges that psychiatrists have engaged in “a binge of drug prescribing” because they can earn half again as much by adjusting medications as they would be paid for talk therapy. “The income differential is a powerful incentive to drop therapy from our repertoire of skills, and psychiatrists have generally followed the money,” Carlat writes.

One hallmark of depression is extreme self-doubt, and the furor the books have caused seems to have led many patients to question their treatment. In the wake of their publication, a number of people under the care of depression researcher Madhukar H. Trivedi abruptly stopped taking antidepressants. Some of those patients then relapsed, again suffering major depression, says Trivedi, professor of psychiatry and director of the Mood Disorders Research Program and Clinic at the University of Texas Southwestern Medical Center at Dallas. But others who quit the drugs have done just fine, Trivedi says.

That’s how it is with antidepressants. Physicians who prescribe them have no doubt that the drugs are essential for the treatment of many patients, particularly those who are most seriously ill. Yet uncertainty about how antidepressants work and whom they can help has increasingly fueled the notion that they may be useless or even dangerous. To improve the understanding of who is most likely to respond to the drugs in this rather broad class, Trivedi has launched a study that he hopes will identify a treatment response “signature.” Four hundred volunteers, randomly assigned to take an antidepressant or a placebo, will receive a battery of tests—functional and conventional magnetic resonance imaging, electrophysiology, and behavioral and cognitive assessments—at the start of the study and again after eight weeks. “We hope this trial will begin to give us biological and clinical signatures of people who are likely to do well versus those who won’t respond to antidepressants, as well as help us determine whether there are unique biological characteristics of those who report improvement with placebo alone,” says Trivedi, who expects results in mid-2014.

Such work could help explain why no current therapy, including psychotherapy without drugs, is consistently effective. “It’s important to ask whether and how well antidepressants work, just as we debate the effectiveness of mammography, prostate cancer screening and surgery for back pain,” says Andrew A. Nierenberg, co-director of the Bipolar Clinic and Research Program and associate director of the Depression Clinical and Research Program at Massachusetts General Hospital. But it’s crucial, says Nierenberg, for those on both sides of the antidepressant question to remain scientifically objective, for the sake of individuals suffering from depression. “People’s lives are at stake when they become needlessly frightened of antidepressants and stop taking them,” he says.

The first antidepressant was actually a tuberculosis drug, iproniazid, created in 1951 by Hoffmann-La Roche. But physicians noticed that many TB patients who were also depressed improved when they took iproniazid: It increased levels of serotonin and norepinephrine, chemicals called neurotransmitters that relay messages among the brain’s 100 billion neurons. Research in animals at about the same time found that a drug that reduced serotonin, norepinephrine and another neurotransmitter, dopamine, made the animals lethargic and apathetic. Noting how psychotropic drugs changed levels of neurotransmitters, other researchers began to hypothesize that abnormal amounts of neurotransmitters caused schizophrenia and other mental disorders. Even then, the evidence was inconclusive, with some studies finding a direct correlation between depression and low levels of serotonin, norepinephrine and dopamine, while others saw no connection. Nevertheless, the idea that chemical imbalances caused depression had taken hold, and creating drugs to restore neurotransmitter health seemed the most promising treatment.

Many of today’s antidepressants indeed increase the levels of neurotransmitters that neurons release into synapses—the spaces between neurons—causing neurons to fire and carry electrical impulses. After a neurotransmitter attaches to receptors on the receiving neurons, transporter pumps suck up and recycle the used chemicals to terminate the signal. Selective serotonin reuptake inhibitors, or SSRIs, are antidepressants that interrupt the transporter pumps so that serotonin remains in the synapses longer than it normally would. That’s supposed to compensate for low levels of the neurotransmitter in people with depression, and the best-known antidepressants—Prozac, Paxil, Zoloft, Celexa and Lexapro—are all SSRIs. Another class of antidepressants—serotonin and norepinephrine reuptake inhibitors, or SNRIs (Effexor and Cymbalta)—work by allowing both serotonin and norepinephrine to flood synapses. And yet another class enhances the release of norepinephrine and dopamine.

The only problem with these popular drugs is that the theory of chemical imbalances they’re based on has largely been discredited. Nierenberg says the neurotransmitter theory of depression is about 20 years out of date, and in his book, Robert Whitaker notes that in 1984 investigators at the National Institute of Mental Health concluded serotonin wasn’t likely to be associated with depression—four years before Prozac came to market, promoted as a new way to restore serotonin levels. Whitaker also quotes researchers writing in 1995, 2000, 2003 and 2005, all of whom say the neurotransmitter theory needs to be put to rest because it’s not true. As far back as 1956, a clinical trial of the drug reserpine, which decreases levels of norepinephrine, serotonin and dopamine, showed that the drug not only didn’t cause depression but actually alleviated it. And according to Kirsch, there have been at least 90 studies in which artificial depletion of neurotransmitter levels did not trigger depression in people with no history of the disease.

Video: Click to watch MGH chief of psychiatry Jerrold F. Rosenbaum on the ups and downs of antidepressants.

Such findings have fueled the controversy about antidepressants. If the drugs are designed to correct something that in fact has no negative effects, then it seems reasonable to ask why they should be prescribed at all. Nierenberg’s answer is that depression isn’t tied to a single neurotransmitter system or to one brain region, but rather is likely to involve multiple neural circuits and neurotransmitters, as some studies suggest. And antidepressants appear to do more than alter neurotransmitters. They also protect neurons and help reverse the negative changes that occur in the brain as a result of depression’s stresses, according to a study by an international group of researchers published in Molecular Psychiatry in 2011. And they may help impaired brains process information more efficiently so individuals can learn new ways of coping with stress. “We are at the very beginning of understanding the complexity of the brain,” says Nierenberg.

Kirsch isn’t persuaded by arguments about how antidepressants might work, and in The Emperor’s New Drugs, he writes that they are “drugs with very little specific therapeutic benefit, but with serious side effects....The belief that antidepressants can cure depression chemically is simply wrong.” To support his position, Kirsch analyzed the results of the randomized controlled clinical trials that pharmaceutical companies must do to obtain Food and Drug Administration approval to market any drug. Typically a drugmaker has to submit results from at least two trials showing that participants who received the active drug showed greater improvement than subjects who took a placebo. But because many antidepressant trials fail to demonstrate a positive effect, pharmaceutical companies often do lots of studies, and though they don’t publish the results of failed trials, they have to reveal them to the FDA. Using the Freedom of Information Act, Kirsch obtained records on every placebo-controlled clinical trial for six widely prescribed antidepressants: Prozac, Paxil, Zoloft, Effexor, Serzone and Celexa. According to his analysis of the published and unpublished studies, both groups of patients—those who took placebos and those who got antidepressants—showed improvement, and the difference between the two groups was not clinically significant except for the most severely depressed patients.

In Kirsch’s analysis, the effect attributable to antidepressants translated into less than a two-point improvement on the Hamilton Rating Scale for Depression, a questionnaire that evaluates the severity of depression on a scale of 0 to 52. In comparison, getting a good night’s sleep is worth six points, according to Kirsch. Moreover, he argues that the marginal advantage of antidepressants over placebo can be explained by side effects from the active drugs—when trial participants feel something while on a pill, they assume they’re receiving an active drug and therefore expect to feel better. “The more side effects that depressed patients experience on the active drug, the more they improve,” writes Kirsch.

The placebo effect or placebo response—that tendency of some patients to benefit just because they think they should—indeed has real power in treating depression, says Michael E. Thase, professor of psychiatry at the University of Pennsylvania’s Perelman School of Medicine. “The placebo response represents people’s inherent ability to get better when they’re cared for and engaged in an enterprise devoted to getting better,” Thase says. That’s exactly what happens in a drug trial, in which participants get attention and concern from investigators, are interviewed about their symptoms and find a receptive audience for talking about their depression.

Tina Tyrell

But that’s not to say antidepressants have no therapeutic effect. “If it were true that antidepressants are no better than placebo, you would expect, in the hundreds of clinical trials comparing drugs and placebo, for placebo to win half the time and the drugs to win half the time,” says Jerrold F. Rosenbaum, chief of psychiatry at MGH and president and executive director of MGH’s Mood and Anxiety Disorders Institute. “The reality is that though sometimes the drug wins and sometimes there’s a tie, placebo essentially never wins. Drugs do work, but the way the drugs are studied is so fraught with methodological problems and distortions that it’s extremely hard to detect a signal of effectiveness.”

It’s those issues—how drug trials are conducted and how their results are interpreted—that are at the heart of the controversy over the effectiveness of antidepressants. Kirsch looked at the average benefit of drugs vs. placebos, and he found the drugs’ impact to be marginal at best. But when Thase examined data from five trials of Lexapro, he noticed that among a particular subset of patients—those with the most severe symptoms—what he terms a “meaningful minority of patients” (almost one in four) showed a “massive amount” of improvement on the drug. A small mean difference between drug and placebo among all subjects may obscure a large benefit for individual participants.

In an effort to find out why so many trials fail, recently John H. Krystal, chair of the department of psychiatry at the Yale School of Medicine, and his team analyzed the data from all the trials Eli Lilly conducted to test Cymbalta, involving more than 2,500 people with major depression. They found that of the participants who received the active drug, about 75% responded favorably and 25% showed little or no improvement. “This tells us the clinical benefits of antidepressant medications are real,” he says. But because individual studies are conducted with much smaller groups of participants, the mix of people who respond to the drug and those who don’t can greatly skew the results. (Some people just don’t respond to antidepressants, and scientists don’t know why.)

In fact, how trial volunteers are chosen is a major reason drugs often show little benefit over placebos. To demonstrate that a medication works, drugmakers tend to select trial participants who have only mild symptoms of depression and no other psychiatric or medical problems. Real-world patients, in contrast, may have severe depression that may be accompanied by such problems as drug or alcohol abuse, panic disorder, or anxiety or personality disorders. According to a 2005 study, 79% of depressed patients treated in clinical practices had multiple issues that would exclude them from drug trials.

Because volunteers accepted for trials tend to be less sick than many depressed patients are, there’s a better chance that all of those in a study will get a little better. And some candidates, eager to be chosen (either for the attention or to try a drug that might make them feel better), may exaggerate their symptoms and not have depression at all, Nierenberg observes. The private research companies paid to fill slots in a study may also overstate the severity of volunteers’ conditions. “Then, trial participants want to please the investigators, so those on placebo report that they are getting better even when they aren’t,” says Nierenberg. Another problem is that as many as a third of trial subjects don’t even take the drug, according to research undertaken at Sweden’s Uppsala University Hospital and published in 2003 in International Clinical Psychopharmacology.

So what would better-designed research reveal about the effectiveness of antidepressants? Unlike trials sponsored by pharmaceutical companies, which advertise for volunteers, the $35 million STAR*D (Sequenced Treatment Alternatives to Relieve Depression) trial—the largest and longest study to evaluate treatment for major depression—recruited patients newly diagnosed with depression through psychiatric and primary care practices. In addition to having moderate to severe depression, which was often chronic (in other words, constant) or recurrent, many subjects also had other significant problems, such as alcohol and drug abuse or other psychiatric disorders that make treating depression especially challenging. Moreover, STAR*D set a higher bar for results than the standards used in most drug company trials. “This was the first large-scale trial that used complete remission of symptoms—not just feeling better—to define a successful outcome,” says Trivedi, a leader of the study.

Four thousand patients participated, and 10 drugs used to treat depression were tested in four phases, with results published in 2008. After the first round of therapy—12 to 14 weeks on Celexa, an SSRI—about a third of subjects achieved full remission of their depression and an additional 10% to 15% reported some improvement.

Volunteers who were still depressed then entered Phase II, in which they had the option either to switch to a different antidepressant or to add a second treatment to Celexa. They also could choose to begin psychotherapy, with or without drugs. In the group that switched to a new antidepressant, 25% became symptom-free, and among those who added a second drug, about a third achieved remission. Switching to or adding cognitive therapy ultimately achieved results similar to the drug-only treatments, though the drugs worked faster.

Those who still hadn’t improved moved to Phase III. They either switched to an antidepressant targeting a different neurotransmitter or added such a drug to a previous medication. Participants in the add-on group were also randomly prescribed lithium, a mood stabilizer, or a thyroid drug known to enhance the effectiveness of antidepressants. Depending on which treatment they received, 12% to 20% became symptom-free. And in the final phase of the study, subjects who were still depressed were taken off antidepressants and prescribed other drugs thought to work in people resistant to other treatments. Only 7% to 10% of the Phase IV group achieved remission of their depression.

In all, about half of the people in the STAR*D trial were symptom-free after two treatments, and almost 70% achieved remission after four treatments. But with each subsequent treatment, fewer additional people got well and increasing numbers dropped out of the study because of drug side effects. “Once you haven’t been successful treating depression with two treatments, additional treatments don’t produce as much benefit as we used to think,” says Trivedi, who terms the percentage of people in STAR*D who achieved remission of their depression on antidepressants decent, but not optimal. According to Peter Kramer, clinical professor of psychiatry at Brown University and author of Listening to Prozac, “medications for mental illness are as effective as medications doctors use for other indications. Doctors treating hypertension, for example, often need to switch or supplement medications. The use of antidepressants is comparable.”

The results of STAR*D suggest that antidepressants do help many patients. But that still leaves the contentions in the other two books—psychiatrist Carlat’s assertion that there is rampant overuse of the drugs at the expense of such alternatives as psychotherapy, and journalist Whitaker’s argument that a surge in antidepressant use has led to a rise in debilitating mental illness.

Tina Tyrell

A report last year from the Centers for Disease Control and Prevention indeed showed that antidepressant use in the United States had soared 400% between 1988 and 2008, and Whitaker contends that the numbers of disabled mentally ill people have skyrocketed during the same period. Tallying how many people receive a monthly Supplemental Security Income or Social Security Disability Insurance payment because mental illness makes it impossible for them to support themselves, he finds that, in 2007, one in 76 Americans received SSI or SSDI payments, more than double the number in 1987. And as antidepressants gained popularity during the 1990s, the number of people disabled by depression and bipolar disease, including children, began to climb, Whitaker asserts. By 2002, one in 40 children was taking an antidepressant compared with one in 250 children in 1988. And in 2007, more than 561,000 children received a federal payment for a serious mental illness, 35% more than two decades earlier.

But according to Nierenberg, epidemiological and other data simply don’t support Whitaker’s contentions. Citing statistics from the U.S. Census Bureau, Nierenberg shows that the percentage of Americans whose depression or anxiety seriously interfered with their functioning stayed steady at around 2% in 1991, 1997 and 2002. Nor has the prevalence or severity of mental disorders increased in the United States, according to a 2005 epidemiological study by Harvard Medical School, published in the New England Journal of Medicine. It found that from 1990 through 1992, 29.4% of the U.S. population had anxiety, mood and substance disorders; from 2001 through 2003, a nearly identical 30.5% of the population had those mental conditions.

At least part of the jump in antidepressant use appears to have resulted from efforts to alleviate rampant undertreatment of depression. During the 1990s, responding to evidence that only 20% of Americans with depression were getting any kind of help, the National Institute of Mental Health launched an initiative to educate people on the dangers of untreated depression. And while more people with severe depression are getting antidepressants today, the disorder is still undertreated, Thase says. However, he agrees with critics of antidepressants that they shouldn’t be the default treatment. “The consequence of that 400% increase is that alternative therapies, such as counseling, psychotherapy and exercise programs, haven’t been widely used,” Thase says. “The ease of prescribing antidepressants and the influence of marketing, including on physicians, have caused us to undervalue nonmedication alternatives.”

Indeed, Krystal thinks that people who stay on antidepressants that haven’t been effective should consider alternative treatments. If the treatment is in fact blocking their recovery, getting off medication and trying psychotherapy might be the answer. Or perhaps they’d do better on a different type of psychotropic drug, such as a mood stabilizer or a second-generation antipsychotic medication. “Some doctors and patients consider no change an acceptable outcome for depression treatment, and our data suggest such patients may be missing an opportunity to get better,” says Krystal.

“Our challenge is to learn enough about the biology of depression and its genetic propensities to be able to predict and match treatments to those patients so we get it right,” says Rosenbaum at MGH. “We are now quite primitive” in that knowledge, which is a fact everyone can agree on.

Homeless Health Care

2012-03-20T18:22:20-05:00

Homelessness is as varied as the individuals who make up this disenfranchised and vulnerable population. Their stories are difficult to hear—raw, heartbreaking, often fraught with loss and tragedy. And there are so many stories. The number of people in the United States who experience homelessness in a given year is thought to be around 3.5 million, though identifying and counting the homeless is imprecise at best. Delivering care to this growing population represents one of medicine’s most difficult challenges.

Homeless people are nearly six times more likely to become ill than are people who have a place to live. Homelessness is often accompanied by poor nutrition, hygiene and dental care. Medical conditions common among the homeless include heart disease, cancer, liver disease, kidney disease, skin infections, HIV, pneumonia and tuberculosis. The homeless are also at high risk for frostbite and hypothermia; more than 30% suffer some sort of mental illness; substance abuse tends to be high; and many have injuries related to the violence of urban streets.

Fortunately, there are dedicated people such as Jim O’Connell, who has shaped the care of the homeless into a specialty of sorts. A physician at Massachusetts General Hospital and president of the Boston Health Care for the Homeless Program, O’Connell designed and implemented the nation’s first system of computerized medical records for homeless patients. He is editor of one of the most widely used texts about homeless health care, and for more than 25 years, O’Connell’s exam rooms have been on the street, under bridges, in doorways, in subway stations and in large cardboard boxes. His tools go far beyond pills and ointments, extending to socks, blankets, sandwiches, hot coffee, compassion and respect.

In this issue of Proto, we offer a glimpse of how O’Connell and other dedicated caregivers have pioneered innovative ways to help the homeless. An accompanying video introduces those who take to the streets and shelters to deliver care to those who so desperately need help but are often reluctant to seek it.

Humanitarians in Boston and in cities across the nation who deliver health care to the homeless have chosen to pursue a field of medicine in which the frustrations are often overwhelming and the rewards may be few and far between. We salute them.

Peter L. Slavin, M.D.
President
Massachusetts General Hospital

David F. Torchiana, M.D.
CEO and Chairman
Massachusetts General Physicians
Organization

Second Opinion

2012-03-20T18:49:16-05:00

A Dangerous Ripple Effect

Proto’s comprehensive review of the nation’s drug shortages (“Museum Pieces,” Summer 2011) emphasizes the impact of this crisis on the care of cancer patients. Many of the drugs in short supply are used not only in cancer treatment but in clinical research as well.

At New Jersey’s National Cancer Institute–designated Comprehensive Cancer Center, our clinical investigators often design protocols testing new agents in combination with existing drugs. If those existing drugs are not available, the trial may need to be halted. This action delays the opportunity to bring new lifesaving treatments to cancer patients.

A bipartisan bill recently introduced in the House of Representatives (the Drug Shortage Prevention Act) calls for an expedited review of drugs that are identified as vulnerable to shortage because of challenges with active-ingredient sources and a limited number of manufacturers. It also mandates better communication between key stakeholders regarding pending shortages. Such actions are needed to help reduce this dangerous ripple effect in which today’s drug shortage is hindering care for today’s patients and the future of cancer treatment.

Robert S. DiPaola // Director, The Cancer Institute of New Jersey, New Brunswick, N.J.

Afterbirth, Not an Afterthought

Proto’s article “Organ of Change” (Summer 2011) was interesting in highlighting the potential links between placental dysfunction and abnormal neurodevelopment. However, the evidence that the abnormal placenta has a key role in all pregnancy diseases—preeclampsia, fetal growth restriction and prematurity—needs to be emphasized. It is also becoming clear that placental dysfunction is probably a key factor in about half the cases of stillbirth in the Western world. As 1 in 200 pregnancies in the United States and the United Kingdom still ends in this heartbreaking way—a rate that has not changed in more than a decade—the need for more research on the placenta becomes apparent.

Colin Sibley // Director, “Tommy’s” Maternal and Fetal Health Research Centre, University of Manchester

Treating Trauma

Proto’s focus on traumatic brain injury (“The Injured Brain,” Summer 2011) offered a hopeful glimpse into the future for people who experience it. But big challenges lie ahead. As our veterans return to work and school following service in Iraq or Afghanistan, primary care clinicians and first responders must be able to recognize signs of traumatic brain injury in patients. It is estimated that one-third of the men and women who served in these conflicts will experience TBI or post-traumatic stress disorder. Differentiating between PTSD and TBI is not easy. Indeed, many of the symptoms are identical and include insomnia, headaches, memory problems, trouble concentrating, irritability and anxiety. Given the stigma veterans feel about seeking care for these conditions, it is important that clinicians be vigilant and aggressive in encouraging their veteran patients to seek care.

For the past two years, the Red Sox Foundation and Massachusetts General Hospital Home Base Program have been providing clinical care to Iraq and Afghanistan veterans and families affected by PTSD and TBI. Each day we learn from and are inspired by their resilience.

Ross Zafonte // Clinical and Research Leader for Traumatic Brain Injury, Red Sox Foundation and Massachusetts General Hospital Home Base Program, Boston

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Predicting Suicide

2012-03-20T19:28:37-05:00

Why do some people take their own lives—as many as 36,000 each year in the United States alone—and why do warning signs go unheeded? Though suicide is the 10th leading cause of death in the United States (after kidney disease and influenza/pneumonia), answers have been elusive, in part because collecting adequate numbers of subjects who’ve attempted suicide has been difficult. Matthew Nock, a Harvard psychology professor and faculty member at the Massachusetts General Hospital Academy who was recently awarded a MacArthur Fellowship for $500,000, is involved in the first large-scale international study of suicidal behavior and an investigation of suicides in the U.S. Army. He will use his MacArthur money to refine methods he has developed to assess suicide risk. Already, his computer tests, which use word associations, have been good predictors of who will attempt suicide—more accurate than what clinicians or patients themselves predict.

Q: How have physicians tried to determine if someone is suicidal?

A: In really primitive ways. We basically ask people: Are you going to kill yourself? If they say yes, we lock them up until they can convince us they are no longer at risk. But studies show that the week after those who’ve attempted suicide leave the hospital, there’s a huge spike in their suicide rates. In other words, we can’t rely on what patients tell us.

Q: Is suicide a bigger problem now, given societal pressures such as the recession?

A: No. The U.S. suicide rate is about the same now as it was 100 years ago. The good news is that more people are getting treated for suicidal thoughts and behaviors now compared with just 10 years ago.

Q: Yet there have been persistent reports of a spike among baby boomers.

A: Suicide rates fluctuate slightly from year to year, and these ups and downs are more pronounced when you look at small subgroups. The most marked change in the past 15 years has been a decrease in the suicide rate among men 65 years old and older, which is the group currently at highest risk for suicide death.

Q: Isn’t depression the biggest risk factor?

A: Depression is important in predicting the onset of suicidal thoughts, but it doesn’t predict which people with such thoughts go on to make an attempt. Disorders characterized by anxiety, agitation and poor impulse control, and particularly a combination of these, are better predictors.

Q: So how can we get better at predicting suicide?

A: One thing we need to do is develop more objective methods. We’ve adapted the Implicit Association Test, which was created, using word pairs, to evaluate subjects’ unconscious biases. In our test, patients are asked to classify words related to life (like breathing) and death (dead), and me (mine) and not me (them). Quicker responses to death/me pairings than to life/me combinations suggest a stronger association between death and self. In one of our studies involving 157 patients in the MGH psychiatric emergency department, we found that those who associated themselves with suicide-related words were six times likelier to attempt suicide again within six months than the others.

Q: You also use a variation of the Stroop test, which requires subjects to name the color of a printed word (red or blue) and measures their reaction time. Why is this useful?

A: We hypothesized that people who are thinking about suicide show greater attention to suicide-related words. We asked 124 patients being treated in the MGH emergency department to identify the randomly assigned ink colors of suicide-related words like funeral, negative words like alone or rejected, and neutral words like museum or paper. We found that people who have recently made a suicide attempt are significantly slower to name the color of a suicide-related word—presumably because it captures their attention and interferes with their ability to respond. Other studies show a similar effect among combat veterans with post-traumatic stress disorder when responding to combat-related words.

Q: What’s the next step for your research?

A: We’re working to modify these tests so that they not only diagnose but also treat suicidal thinking. We’re using one of the tests in the MGH inpatient psychiatry unit to see if we can train participants who have attempted suicide to disengage more easily from thinking about suicide-related words. By training subjects to just let the words come and go, we hope to decrease the likelihood that they’ll harm themselves.

Click here to watch Nock describe what's next for his research.

Health Literacy: Comprehension Test

2012-03-20T19:38:21-05:00

12
Estimated percentage of American adults who can adequately apply reading and analytical skills to understand and use health information effectively—skills ranging from following prescription instructions to using a table to calculate an employee’s share of health insurance costs

2011
Year in which a systematic review of studies concluded that low health literacy was consistently associated with more hospitalizations, greater use of emergency care, poor ability to take medications properly, and, among elderly people, poor overall health status and high mortality rates

30
Approximate percentage of patients at a Los Angeles hospital who were unable to identify the date of their follow-up appointment from a standard appointment slip

39.4
In one study, percent mortality rate after six years among patients aged 65 and older who demonstrated inadequate health literacy; those with adequate skills experienced a mortality rate of 18.9%

2:1
Increased odds that a type 2 diabetic patient with low health literacy will experience retinopathy, even after adjustment for sociodemographics, diabetes education, treatment regimen and duration of diabetes

1,000
Users, including hospitals, HMOs and state Medicaid offices, of the Health Literacy Advisor, a software program that suggests plain-language alternatives for difficult medical terms and phrases in Website copy, consent forms, patient education materials and medication inserts—such as heart attack for myocardial infarction, swelling for edema, and fever for pyrexia

The Newborn Score

2012-03-20T19:55:53-05:00

Sixty years ago, Virginia Apgar confessed her disappointment to the annual Congress of Anesthetists meeting. “Seldom,” she said, “have there been such imaginative ideas, such enthusiasms and dislikes, and such unscientific observations and study about one clinical picture” as of the newborn in crisis. Doctors and nurses who delivered babies lacked a common language to decide whether a newborn would require more than routine medical care.

Apgar’s solution was a numerical scale that could predict which babies were likely to thrive and which needed immediate resuscitation. The following year, she published her scoring system in Current Researches in Anesthesia and Analgesia, revolutionizing neonatal care the world over. Virtually every baby born in a hospital today undergoes the Apgar test. The simple checklist assesses five physiological categories: heart rate; breathing; reflexes, particularly to irritating stimuli like a bulb syringe in the mouth to clear the airways; muscle tone and movement; and color (babies are born bluish but should turn pink as their heart pumps blood through their body). The score later was acronymized to APGAR: Appearance, Pulse, Grimace, Activity, Respiration.

For each of the five categories, a score of 0, 1 or 2 is possible, allowing for a maximum score of 10. Babies who receive a total score of three or less are in serious trouble; most newborns scoring in this range have high levels of acid in their blood, a condition that can lead to brain damage or death. Mechanical ventilation or even life support might be required.

“In the past, attention was concentrated on the mother’s survival,” says Linda Polley, a past president of the Society for Obstetric Anesthesia and Perinatology. “Apgar’s system focused attention on the condition of the newborn.”

Born in 1909, Apgar entered the emerging field of anesthesiology in the 1930s at a time when it was still largely the domain of nurses and male physicians. In 1937 she accepted a position at Columbia University’s Presbyterian Hospital to lead the new division of anesthesia.

An idea as effective yet simple as the Apgar score was destined to gain traction beyond the labor and delivery unit. A recent study in the journal Anesthesiology, for example, found that a modified Apgar score predicted mortality for patients undergoing most types of operations. In other words, a patient undergoing surgery might well owe a double debt to Apgar’s insight. Apgar is reported to have declared: “Nobody, but nobody, is going to stop breathing on me.”

Protecting Children’s Hearts

2012-03-20T20:14:14-05:00

At the next visit to the pediatrician, parents of children ages 9 to 11 might be in for a surprise: a cholesterol test. Though heart attacks usually strike after age 60, powerful evidence now indicates that atherosclerosis—the accumulation of cholesterol, fats and other substances in the arteries that causes most heart attacks—often begins in childhood. Armed with that knowledge, an expert panel supported by the National Heart, Lung, and Blood Institute recommended in November that physicians perform baseline screening of cholesterol and other lipids in all children ages 9 to 11. Though some argue that this dramatic—and controversial—change to current recommendations will save lives in decades to come, others see it as pointless and even dangerous.

Routine screening in children will accomplish two goals, says Johns Hopkins University School of Medicine lipidologist Peter O. Kwiterovich, a member of the NHLBI panel. First, it will help identify the one in 500 children with familial hypercholesterolemia (FH), an inherited condition that causes an increased risk of heart attack before age 50. Universal screening will also identify the roughly one in four children in this age bracket who have elevated cholesterol associated with factors such as obesity, poor diet and lack of exercise.

In the past, most physicians checked a child’s cholesterol only if there was a family history of FH or early heart disease, or if the child was obese (about 40% of obese children have lipid problems). But research shows that using these parameters misses too many kids with unhealthy lipids, notes Kwiterovich, citing several studies that link high cholesterol in childhood to clinical evidence of cardiovascular disease in early adulthood.

Yet critics warn that some children diagnosed with high cholesterol will be given statins even though there has never been a clinical trial showing that taking statins in childhood prevents heart attacks decades later, or that cholesterol-lowering in kids is safe. “What is the advantage of treating high cholesterol in a 10-year-old versus a 20- or 30-year-old? Nobody knows,” says H. Gilbert Welch, a professor of medicine at Dartmouth Medical School and co-author of Overdiagnosed: Making People Sick in the Pursuit of Health. Moreover, Welch notes that cholesterol is a vital component of androgens and estrogens, the sex hormones. He worries that using drugs to block production of cholesterol in children who have not yet gone through puberty may put them at increased risk for health problems.

Kwiterovich estimates that only about 1% of children identified as having high cholesterol through universal screening will meet the NHLBI’s criteria for receiving a statin or other lipid-lowering drug. Yet some observers are convinced that a far greater number of children will eventually be given prescriptions. Inevitably, predicts Michael L. LeFevre, a professor of family medicine at the University of Missouri School of Medicine, some physicians will prescribe drug therapy for children unable to bring down their cholesterol with lifestyle changes. “The pressure is there to try to do something,” says LeFevre.

Kwiterovich finds it ironic that some of the same pediatricians who dutifully perform annual physical exams—which rarely uncover anything important—bridle at the suggestion of uncovering a potential heart concern in about 25% of patients. Kwiterovich is pleased that testing is in place. “That’s the most important thing,” he says, “rather than doing nothing.”

Health Care Costs: Parsimonious Care

2012-03-20T20:34:22-05:00

parsimonious care [pär-sə-mō-nē-əs ker] n: a practice encouraged by guidelines from the American College of Physicians, lauded by some as a high-profile acknowledgment of the need to control skyrocketing medical costs but criticized by others as an opportunity for physicians to withhold care.

In January, when the ACP published its new ethics manual for its 132,000 members (it is the second-largest physician group after the American Medical Association), interest was piqued by one passage: “Physicians have a responsibility to practice effective and efficient health care and to use health care resources responsibly. Parsimonious care that utilizes the most efficient means to effectively diagnose a condition and treat a patient respects the need to use resources wisely and to help ensure that resources are equitably available.”

In an accompanying editorial, physician and bioethicist Ezekiel Emanuel of the University of Pennsylvania deemed the guideline “truly remarkable”: “These positions on efficiency, parsimony and cost-effectiveness constitute an important shift, if not in ethics then in emphasis.”

Yet some physicians and bioethicists are uncomfortable with the shift, not least because of the ACP’s word choice. Though the first dictionary definition of parsimonious may be “careful with money or resources,” it’s followed by a decidedly negative connotation: “especially: frugal to the point of stinginess.” Critics express concern that some physicians, under pressure to control costs, will withhold a test or treatment despite clear benefit, and foresee that the debate will help fuel already heated discussions about health care spending.