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FOR IMMEDIATE RELEASE
Thursday, Sept. 2, 2010

In Mice, Compound Cleared Malaria parasites Quickly

 

 

A chemical that rid mice of malaria-causing parasites after a single oral dose may eventually become a new malaria drug if further tests in animals and people uphold the promise of early findings. The compound, NITD609, was developed by an international team of researchers including Elizabeth A. Winzeler, Ph.D., a grantee of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

“Although significant progress has been made in controlling malaria, the disease still kills nearly 1 million people every year, mostly infants and young children,” says NIAID Director Anthony S. Fauci, M.D. “It has been more than a decade since the last new class of antimalarials—artemisinins—began to be widely used throughout the world. The rise of drug-resistant malaria parasites further underscores the need for novel malaria therapies.”

Dr. Fauci adds, “The compound developed and tested by Dr. Winzeler and her colleagues appears to target a parasite protein not attacked by any existing malaria drug, and has several other desirable features. This research is also a notable example of successful collaboration between government-supported scientists and private sector researchers.”

The study, in the Sept. 3 issue of Science, was led by Thierry T. Diagana, Ph.D., of the Novartis Institute for Tropical Diseases (NITD), and Dr. Winzeler. Dr. Winzeler is affiliated with The Scripps Research Institute and the Genomic Institute of the Novartis Research Foundation, La Jolla, Calif.  

Work on what eventually became NITD609 began in Dr. Winzeler’s lab in 2007. Scientists screened 12,000 chemicals using an ultra-high throughput robotic screening technique customized to detect compounds active against Plasmodium falciparum, the most deadly malaria parasite. The screen identified a chemical with good parasite-killing abilities and the potential to be modified into a drug. Medicinal chemists at the NITD then synthesized and evaluated about 200 versions of the original compound to arrive at NITD609, which could be formulated as a tablet and manufactured in large quantities. NITD609 is one of a new class of chemicals, the spiroindolones, which have been described in recently published research by Dr. Winzeler and colleagues as having potent effects against two kinds of malaria parasites.

“From the beginning, NITD609 stood out because it looked different, in terms of its structure and chemistry, from all other currently used antimalarials,” says Dr. Winzeler. “The ideal new malaria drug would not just be a modification of existing drugs, but would have entirely novel features and mechanism of action. NITD609 does.”

In the current study, the scientists detail attributes of NITD609 that suggest it could be a good malaria drug. For example

  • In test-tube experiments, NITD609 killed two species of parasites in their blood-stage form and also was effective against drug-resistant strains. In humans, malaria parasites spend part of their life cycle in the blood and part in the liver.
  • The compound worked faster than some older malaria drugs, although not as quickly as the best current malaria drug, artemisinin.
  • Other laboratory tests showed that NITD609 is not toxic to a variety of human cells.

When given orally to rodents, the compound stayed in circulation long enough to reach levels predicted to be effective against malaria parasites. According to Dr. Winzeler, if NITD609 behaves similarly in people, it might be possible to develop the compound into a drug that could be taken just once. Such a dosage regimen, she says, would be substantially better than the current standard treatment in much of the world in which uncomplicated malaria infections are treated for three to seven days with drugs that are taken between one and four times daily.

“We were excited by the potential NITD609 showed in the first series of test-tube experiments,” says Dr. Winzeler. “We became even more enthusiastic when our co-investigators at the Swiss Tropical Institute in Basel tested NITD609 in a mouse model of malaria.”

Typically, she says, rodents infected with the mouse malaria parasite, Plasmodium berghei, die within a week. But a single large dose of NITD609 cured all five infected mice that received it, while half of six mice receiving a single smaller dose were cured of infection. Three doses of the smaller amount of NITD609 upped the cure rate to 90 percent.

The researchers also compared NITD609 with other malaria drugs in P. berghei-infected mice. “No other currently used malaria drug was as potent,” says Dr. Winzeler. NITD609’s effectiveness in relatively few doses is a key point in its favor, she adds. A novel malaria drug that works in as few doses as possible leaves less opportunity for parasites to develop drug resistance.

Additional tests in animals are under way and NITD609 could enter early-stage safety testing in humans later this year, says Dr. Winzeler. But, she adds, many drug candidates fail in clinical trials and thus it will be important for the community to continue to work on developing other potential antimalarial compounds.

To learn how parasites might develop resistance to this potential drug, the researchers also exposed parasites to sublethal levels of NITD609 continuously for several months until drug-resistant strains emerged. Then they analyzed those strains and determined that resistance results from a single change in one of the parasite’s genes. The gene contains the code to make a protein called PfATP4, which allows substances to cross cell membranes. No other anti-malaria drugs act on the PfATP4 protein, notes Dr. Winzeler. Having information in hand about the genetic basis for NITD609 resistance at this early stage of the compound’s development is advantageous, she adds, because it will allow scientists to rapidly detect drug-resistant strains in clinical settings if the compound is eventually approved as a drug for human use. 

More information about malaria and NIAID’s research programs on the disease is available on the NIAID malaria Web portal.

###

References:

M Rottmann et al. Spiroindolones, a new and potent chemotype for the treatment of malaria. Science DOI: 10.1126/science.1193225 (2010).

BKS Yeung et al. Spirotetrahydro β-carbolines (Spiroindolones): A new class of potent and orally efficacious compounds for the treatment of malaria. J. of Medicinal Chemistry  DOI: 10.1021/jm100410f (2010).


NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at www.niaid.nih.gov.

The National Institutes of Health (NIH)—The Nation’s Medical Research Agency—includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Last Updated September 02, 2010

A concept called kin selection has been widely used in explaining the evolution of highly social species such as colony-forming bees. A sharp critique of that idea has now stirred up a buzz among evolutionary biologists.

Photo Credit: Waugsberg/Wikimedia Commons

 

 

Prominent scientists dispute kinship’s role in self-sacrifice among highly social creatures

ScienceNews.org, September 2, 2010, by Susan Milius  —  A concept called kin selection has been widely used in explaining the evolution of highly social species such as colony-forming bees. A sharp critique of that idea has now stirred up a buzz among evolutionary biologists.Waugsberg/Wikimedia Commons

A furor has broken out among biologists over ant specialist E.O. Wilson’s latest attack on a concept used to explain the origins of self-sacrifice in the dog-eat-dog world of evolution.

The debate centers around an idea called kin selection, which biologists use to understand altruistic behaviors such as honeybee workers raising the queen’s young but never having their own. These selfless workers would seem to lose out in the evolutionary struggle to pass along genes to the next generation. But according to the idea of kin selection, workers without young more than compensate by sharing in the reproductive success of relatives, with whom they share genes.

In the Aug. 26 Nature, Wilson and two Harvard colleagues argue that the concept of kin selection is “limited” and “unnecessary.” And they propose steps for the evolution of ants, honeybees and other highly social species with such altruistic behaviors by just the broad “survival of the fittest” forces of natural selection without specifically invoking the power of kinship.

In recent years, Wilson has argued that the close family ties in ant colonies and other highly social groups may be consequences, rather than causes, of the evolution of such extreme social forms. In the new paper he combines his perspective with two coauthors’ mathematical critique of the methods used to calculate kinship effects, arguing that the techniques are as unnecessarily complicated as Ptolemaic astronomy.

“Babylonian astronomers look up in the heavens and they see the planets moving in ‘epicycles,’” says paper coauthor and mathematical biologist Martin Nowak. “But if you put the sun in the center, there are no epicycles.”

Some kin selection adherents are firing back that, even with new math, the challenge itself is old-fashioned. “This is such a tired old debate,” says Ben Oldroyd of the University of Sydney, who studies social insects.

The new analysis attacks the core of kin selection by examining how biologists calculate what’s called inclusive fitness. Evolutionary biologists measure fitness not by push-ups but by progeny, and inclusive fitness counts not just an individual’s direct offspring but some share of relatives’ youngsters. The closer the relative and the more the altruist helps to raise the young, the greater the share that counts.

Looking over decades of papers calculating inclusive fitness, coauthor and Harvard mathematician Corina Tarnita says that she was surprised to find no rigorous mathematical analysis had been done to assess the conditions under which an inclusive fitness calculation can be used. “I find that very dangerous,” she says.

Nowak and Tarnita did such an analysis for a hypothetical population in which organisms use either of two strategies (which could be genes or behaviors, like cooperation). Mathematically, the researchers argue, inclusive fitness works only under very limited conditions, such as when two strategies occur at nearly the same numbers in the population, and when interactions among individuals occur straightforwardly in pairs.

Even in those special circumstances, Nowak says, mathematical approaches like those used in game theory can predict the same outcomes without using inclusive fitness.

Nowak clarifies that the team isn’t arguing that kinship is irrelevant in biology. “Relatedness does matter,” he says. What he and Tarnita are challenging is the accounting method of inclusive fitness, which he contends is overly complicated.

Michael Doebeli of the University of British Columbia in Vancouver says the analysis is “a very welcome attempt at clarifying several key issues in the theory of social evolution, yet it will surely take time before its conclusions will be embraced by more traditional evolutionary biologists.”

But others, like evolutionary biologist Andrew Bourke of the University of East Anglia in Norwich, England, disagree with the new argument. Bourke laments that the researchers take “a very narrow view of inclusive fitness theory, focusing on details of algebraic expression of the theory at the expense of its essential insights.”

Whether kin selection has indeed been useful is one of the more contentious arguments of the new paper. The authors dismiss most earlier work as finding mere correlation between kinship and social behavior without strict analysis of costs and benefits. “We can find no case that presents compelling evidence for the explanatory adequacy of kin selection and inclusive fitness theory,” they write.

As an alternative, Wilson, Nowak and Tarnita describe how extreme societies based on nonreproductive workers could evolve without invoking kin selection. Organisms might cluster at first for any reason, such as a good feeding site, and then accumulate traits that eventually prove important to a social structure, such as building defensible nests. Eventually crucial colony-building behaviors could evolve, such as adult children sticking around the home nest instead of striking out on their own.

The key argument in this scenario, says William Hughes at the University of Leeds in England, is that cooperation between individuals that share a gene vital for extreme social living would be enough to spur the evolution of altruism.

Hughes objects that previous studies have considered this scenario but found such genes vulnerable to cheating or to conflicts with other parts of the genetic instruction book.

“Previously I always had a nagging concern that maybe Wilson had thought of something that everyone else had missed,” Hughes says. “Having read this paper, I’m now quite confident that’s not the case.”

In all the furor, however, Tarnita says she’s looking forward to the comments she might hear several weeks after the publication. By then, she says, people should have had time to do the math.

Synthetic material revs up blood clotting at low cost

FORBES.com, September 2, 2010, by Rachel Ehrenberg, BOSTON — A new gel may provide a cheap means of stanching blood flow on the battlefield or in any other situation where there isn’t time for stitches. Estimates suggest that the gel would cost less than $10 per application, a fraction of the cost of other gels in use today, researchers reported August 23 at the American Chemical Society’s fall meeting.

The new blood-clotting material is a hydrogel, a Jell-O–like mixture of water and a fibrous polymer, in this case acrylamide decorated with positively charged nitrogen-containing groups. Experiments with blood plasma reveal that the gel kicks into gear a blood-clotting protein known as factor VII, a key player in the cascade of events that leads to coagulation, said biomedical engineer Brendan Casey of the University of Maryland in College Park.

“You can just slap it on a wound,” Casey said. In experiments in which Casey and colleagues made incisions in sheep lung and liver tissue, the hydrogel stopped the lung from bleeding in about two minutes, the liver in four to five minutes. The research team suspects that the polymer’s positive charge and stiffness induce the clotting.

Many other hydrogels used in medicine today are based on biological materials such as chitin, a structural component found in the cell walls of certain fungi, the beaks of squid and the shells of lobsters and crabs. While these materials have their plus sides, such as breaking down in a friendly manner inside the human body, they are more easily contaminated by viruses and other microorganisms than synthetic gels are and can trigger an allergic response in some people. And those biobased hydrogels cost $400 to $500 a pop, said Casey.

The team’s approach using a synthetic polymer seems like a promising strategy, said Sasa Andjelic of Ethicon, a Johnson & Johnson company in Somerville, N.J. While the gel isn’t absorbable by the body, he said, it looks like it would work well as a topical treatment.

Scientists are studying the glue-like substance in spider webs

USNews.com, August/September 2010

By Marlene Cimons, National Science Foundation

Anyone who brushes against a spider web knows how sticky it is. Scientists have long known that spiders make a glue-like substance that causes this stickiness, but until recently, they did not understand its mechanical behavior.

Researchers at the University of Akron believe they have figured out the nature of the microscopic glue-like substance that orb-weaving spiders produce along the round rings of silk they spin as part of their webs.  These droplets—three times tinier than the diameter of a single hair—capture flies and other insects that spiders eat.

The drops are composed of highly entangled polymers, which are physically or chemically cross-linked and transmit forces very efficiently. Under a microscope, the researchers pulled on individual glue drops while measuring their force-extension behavior–not easy to do using a tiny probe.

Video: Silk’s Many Strengths

They found the material to be both viscous and elastic, properties very valuable in catching fast-flying incoming insects, and in keeping them trapped long enough for the spider to subdue—and devour—them.

Its simplest description, however, is that it’s not like liquid or honey, or even silly putty.

“It feels like chewing gum,’’ said Ali Dhinojwala, a professor and chair of the university’s department of polymer science. “It just keeps stretching and stretching.”

It is also water resistant, a useful feature since spiders work in humid conditions, including rain. In fact, the material loses its stickiness without moisture, “unlike scotch tape, which isn’t sticky anymore once you put water on it,’’ Dhinojwala said. “This glue needs water to be sticky.’’

The information could have widespread applications in the development of new bio-adhesives, particularly in bandages and other products that must retain their stickiness when in contact with water.

“Sometimes you want your bandages to work under water,’’ Dhinojwala said. “Also, there are quite a number of times we want to attach things under water. Water is always a problem with adhesives. But this can hold under water.’’

The researchers, who also included Todd Blackledge, professor of biology, and doctoral candidate Vasav Sahni, studied only orb-weaving spiders, which are commonly found in trees and grasses. As their name suggests, they spin an orb-like web, that is, a web in the shape of a circle, with spokes and rings.

The spiders use different glands in their stomachs to secrete proteins that make up the web.

The thread of the spokes, which provides the web’s strength, comes from a gland known as the “major ampullate.’’ Each spider has two of these. “That thread is well-known for its strength,’’ Dhinojwala said. “It supports a lot of weight. By weight, that silk is stronger than steel.’’

The circles, where the glue is deposited, come from the “minor ampullate’’ gland. Each spider has two of these as well.

“The material is called spiral silk and its purpose is to catch insects, so they are sticky, ’’ Dhinojwala said.  “If you look at spiral silk under a microscope, you will see these little drops: the glue.’’  These come from yet another gland, known as the aggregate gland. Each spider has four of these. “This is where the glue comes from,’’ he added.

The researchers used spiders from Blackledge’s lab. Essentially, the spiders spun their webs in a box in the lab “and we collected the samples,’’ Dhinojwala said. “We put the spider web in a glass plate, and used a tiny probe to poke it and measure how much force was required to pull it off.  We tested the strength and the elasticity, not just its sticking power, but how elastic and stretchy it was, which is critical for stickiness, and the major crux of understanding the adhesion.’’

The objective was to determine “how it behaves, and why it’s so sticky,’’ he added.  “It was viscous and elastic; if it was just a liquid, the force number would have been much lower.’’

Dhinojwala and his colleagues have long been interested in how nature produces its own adhesives. He has studied how the gecko lizard can stick to surfaces without any glue-like substance, and currently is creating synthetic material inspired by knowledge gleaned from his gecko research. “We designed tapes without glue based on what we learned from the geckos,’’ he said.

He hopes to do the same using the new spider web data. “What the spider does is evolution at its finest,’’ he said. “They have survived by using nature effectively. The more we learn of how nature uses these materials, the better position we will be in to take advantage of this and design things based on what we learn.’’

The researchers’ findings were published in the journal Nature Communications. The work was funded by a $224,000 National Science Foundation grant

http://www.usnews.com/science/articles/2010/08/23/spinning-spider-webs-into-human-uses.html

 

Photo: Chris Bickford for The New York Times

Kyle Warren at 6 years old. At 18 months, Kyle started taking a daily antipsychotic drug on the orders of a pediatrician trying to quell the boy’s severe temper tantrums.

Kyle Warren at age 3. His weight increased as a side effect of the antipsychotic medicines he was taking.

The New York Times, September 2, 2010, by Duff Wilson, OPELOUSAS, La. — At 18 months, Kyle Warren started taking a daily antipsychotic drug on the orders of a pediatrician trying to quell the boy’s severe temper tantrums.

Thus began a troubled toddler’s journey from one doctor to another, from one diagnosis to another, involving even more drugs. Autism, bipolar disorder, hyperactivity, insomnia, oppositional defiant disorder. The boy’s daily pill regimen multiplied: the antipsychotic Risperdal, the antidepressant Prozac, two sleeping medicines and one for attention-deficit disorder. All by the time he was 3.

He was sedated, drooling and overweight from the side effects of the antipsychotic medicine. Although his mother, Brandy Warren, had been at her “wit’s end” when she resorted to the drug treatment, she began to worry about Kyle’s altered personality. “All I had was a medicated little boy,” Ms. Warren said. “I didn’t have my son. It’s like, you’d look into his eyes and you would just see just blankness.”

Today, 6-year-old Kyle is in his fourth week of first grade, scoring high marks on his first tests. He is rambunctious and much thinner. Weaned off the drugs through a program affiliated with Tulane University that is aimed at helping low-income families whose children have mental health problems, Kyle now laughs easily and teases his family.

Ms. Warren and Kyle’s new doctors point to his remarkable progress — and a more common diagnosis for children of attention-deficit hyperactivity disorder — as proof that he should have never been prescribed such powerful drugs in the first place.

Kyle now takes one drug, Vyvanse, for his attention deficit. His mother shared his medical records to help document a public glimpse into a trend that some psychiatric experts say they are finding increasingly worrisome: ready prescription-writing by doctors of more potent drugs to treat extremely young children, even infants, whose conditions rarely require such measures.

More than 500,000 children and adolescents in America are now taking antipsychotic drugs, according to a September 2009 report by the Food and Drug Administration. Their use is growing not only among older teenagers, when schizophrenia is believed to emerge, but also among tens of thousands of preschoolers.

A Columbia University study recently found a doubling of the rate of prescribing antipsychotic drugs for privately insured 2- to 5-year-olds from 2000 to 2007. Only 40 percent of them had received a proper mental health assessment, violating practice standards from the American Academy of Child and Adolescent Psychiatry.

“There are too many children getting on too many of these drugs too soon,” Dr. Mark Olfson, professor of clinical psychiatry and lead researcher in the government-financed study, said.

Such radical treatments are indeed needed, some doctors and experts say, to help young children with severe problems stay safe and in school or day care. In 2006, the F.D.A. did approve treating children as young as 5 with Risperdal if they had autistic disorder and aggressive behavior, self-injury tendencies, tantrums or severe mood swings. Two other drugs, Seroquel from AstraZeneca and Abilify from Bristol-Myers Squibb, are permitted for youths 10 or older with bipolar disorder.

But many doctors say prescribing them for younger and younger children may pose grave risks to development of both their fast-growing brains and their bodies. Doctors can legally prescribe them for off-label use, including in preschoolers, even though research has not shown them to be safe or effective for children. Boys are far more likely to be medicated than girls.

Dr. Ben Vitiello, chief of child and adolescent treatment and preventive research at the National Institute of Mental Health, says conditions in young children are extremely difficult to diagnose properly because of their emotional variability. “This is a recent phenomenon, in large part driven by the misperception that these agents are safe and well tolerated,” he said.

Even the most reluctant prescribers encounter a marketing juggernaut that has made antipsychotics the nation’s top-selling class of drugs by revenue, $14.6 billion last year, with prominent promotions aimed at treating children. In the waiting room of Kyle’s original child psychiatrist, children played with Legos stamped with the word Risperdal, made by Johnson & Johnson. It has since lost its patent on the drug and stopped handing out the toys.

Greg Panico, a company spokesman, said the Legos were not intended for children to play with — only as a promotional item.

Cheaper to Medicate

Dr. Lawrence L. Greenhill, president of the American Academy of Child and Adolescent Psychiatry, concerned about the lack of research, has recommended a national registry to track preschoolers on antipsychotic drugs for the next 10 years. “Psychotherapy is the key to the treatment of preschool children with severe mental disorders, and antipsychotics are adjunctive therapy — not the other way around,” he said.

But it is cheaper to medicate children than to pay for family counseling, a fact highlighted by a Rutgers University study last year that found children from low-income families, like Kyle, were four times as likely as the privately insured to receive antipsychotic medicines.

Texas Medicaid data obtained by The New York Times showed a record $96 million was spent last year on antipsychotic drugs for teenagers and children — including three unidentified infants who were given the drugs before their first birthdays.

In addition, foster care children seem to be medicated more often, prompting a Senate panel in June to ask the Government Accountability Office to investigate such practices.

In the last few years, doctors’ concerns have led some states, like Florida and California, to put in place restrictions on doctors who want to prescribe antipsychotics for young children, requiring a second opinion or prior approval, especially for those on Medicaid. Some states now report prescriptions are declining as a result.

A study released in July by 16 state Medicaid medical directors, which once had the working title “Too Many, Too Much, Too Young,” recommended that more states require second opinions, outside consultation or other methods to assure proper prescriptions. The F.D.A. has also strengthened warnings about using some of these drugs in treating children.

No Medical Reason

Kyle was rescued from his medicated state through a therapy program called Early Childhood Supports and Services, established in Louisiana through a confluence of like-minded child psychiatrists at Tulane, Louisiana State University and the state. It surrounds troubled children and their parents with social and mental health support services.

Dr. Mary Margaret Gleason, a professor of pediatrics and child psychiatry at Tulane who treated Kyle from ages 3 to 5 as he was weaned off the heavy medications, said there was no valid medical reason to give antipsychotic drugs to the boy, or virtually any other 2-year-old. “It’s disturbing,” she said.

Dr. Gleason says Kyle’s current status proves he probably never had bipolar disorder, autism or psychosis. His doctors now say Kyle’s tantrums arose from family turmoil and language delays, not any of the diagnoses used to justify antipsychotics.

“I will never, ever let my children be put on these drugs again,” said Ms. Warren, 28, choking back tears. “I didn’t realize what I was doing.”

Dr. Edgardo R. Concepcion, the first child psychiatrist to treat Kyle, said he believed the drugs could help bipolar disorder in little children. “It’s not easy to do this and prescribe this heavy medication,” he said in an interview. “But when they come to me, I have no choice. I have to help this family, this mother. I have no choice.”

Ms. Warren conceded that she resorted to medicating Kyle because she was unprepared for parenthood at age 22, living in difficult circumstances, sometimes distracted. “It was complicated,” she said. “Very tense.”

Behavior Problems

Kyle was a healthy baby physically, but he was afraid of some things. He spent hours lining up toys. When upset, he screamed, threw objects, even hit his head on the wall or floor — not uncommon for toddlers, but frightening.

“I’d bring him to the doctor and the doctor would say, ‘You just need to discipline him,’ ” Ms. Warren said. “How can you discipline a 6-month-old?”

When Kyle’s behavior worsened after his brother was born, Ms. Warren turned to a pediatrician, Dr. Martin J. deGravelle.

“Within five minutes of sitting with him, he looked at me and said, ‘He has autism, there’s no doubt about it,’ ” Ms. Warren said.

Dr. deGravelle’s clinic notes say Kyle was hyperactive, prone to tantrums, spoke only three words and “does not interact well with strangers.”

He prescribed Risperdal. At the time, Risperdal was approved by the F.D.A. only for adults with schizophrenia or acute manic episodes. The following year it was approved for certain children, 5 and older, with autism and extremely aggressive behavior. It has never been approved by the F.D.A. for use in children younger than 5, although doctors may legally prescribe it as an off-label use.

“Kyle at the time was very aggressive and easily agitated, so you try to find medication that can make him more easily controlled, because you can’t reason with an 18-month-old,” Dr. deGravelle said in a telephone interview. But Kyle was not autistic — according to several later evaluations, including one that Dr. deGravelle arranged with a neurologist. Kyle did not have the autistic child’s core deficit of social interaction, Dr. Gleason said. Instead, he craved more positive attention from his mother.

“He had trouble communicating,” Dr. Gleason said. “He didn’t have people to listen to him.”

After the neurologist review, the diagnosis changed to “oppositional defiant disorder” and the Risperdal continued.

“Yes, I did ask for it,” Ms. Warren said. “But I was at my wit’s end, and I didn’t know what else to do.”

Dr. deGravelle referred her to Dr. Concepcion, who in turn diagnosed Kyle’s condition as bipolar disorder.

“Some children, when they come to me, the parents are really so frustrated,” Dr. Concepcion said in a phone interview. “Especially the mothers are so scared or desperate in getting help. Their children are really acting psychotic.”

Dr. Concepcion also spoke with Dr. Charles H. Zeanah, a Tulane medical professor, who disagreed with both the diagnosis and the treatment. “I have never seen a preschool child with bipolar disorder in 30 years as a child psychiatrist specializing in early childhood mental health,” Dr. Zeanah said.

More Pills

“It’s a controversial diagnosis, I agree with that,” said Dr. Concepcion. “But if you will commit yourself in giving these children these medicines, you have to have a diagnosis that supports your treatment plan. You can’t just give a nondiagnosis and give them the atypical antipsychotic.”

He also prescribed four more pills.

Kyle’s third birthday photo shows a pink-cheeked boy who had ballooned to 49 pounds. Obesity and diabetes are childhood risks of antipsychotics. Kyle smiles at the camera. He is sedated.

“His shell was there, but he wasn’t there,” Ms. Warren said. “And I didn’t like that.”

Dr. Concepcion referred Kyle to the early childhood support program, which has helped about 3,000 preschoolers from low-income families at risk for mental health problems since 2002.

His speech improved. He threw fewer tantrums. “They started working with us as a family,” said Ms. Warren, who also received parenting advice. “That helps.”

Kyle’s treatment was directed by Dr. Gleason, a Columbia medical graduate who had led a team that wrote 2007 practice guidelines for psychopharmacological treatment of very young children.

“Families sometimes feel the need for a quick fix,” Dr. Gleason said. “That’s often the prescription pad. But I’m concerned that when a child sees someone who prescribes but doesn’t do therapy, they’re closing the door that can make longer-lasting change.”

Off most drugs, Kyle started losing weight and his behavior improved. Ms. Warren’s life also improved. She met a man and they moved into their own house five miles out of Opelousas, a town of 25,000. They were married last Saturday.

At their home recently, Kyle and his brother, Jade, ran and played while their baby sister watched from a playpen. Their clothes were neatly folded in a shared bedroom. They often responded “Yes, ma’am” or “Yes, sir.”

“They’re respectful, but they’re hyper kids,” Ms. Warren said. “Once he came off the medication, he’s Kyle. He’s an intelligent person. He’s loud. He’s funny. He’s smart. He’s bouncy. I mean, there’s never a dull moment. He has a few little behavior issues. But he’s like any other normal 6-year-old.”

Kyle paused to show a reading report card from the end of his kindergarten year, with an A grade.

“Awesome job, Kyle!” his kindergarten teacher wrote.

Suicide isn’t even in the index of the 900-page bible of psychiatric disorders, Diagnostic and Statistical Manual of Mental Disorders IV

FORBES.com, September 2, 2010, by Robert Langreth  —  Few psychotherapists want to take on patients who kick in walls, play Russian roulette with a loaded gun, slice up their arms with a knife, or end up in the intensive care unit twice in one month from suicide attempts. University of Washington psychologist Marsha Linehan specializes in them.

The mental health industry has ignored suicidal patients so much that suicide isn’t even in the index of the 900-page bible of psychiatric disorders, Diagnostic and Statistical Manual of Mental Disorders IV.  Doctors pessimistically have figured there isn’t much that can be done beyond standard drugs and psychotherapy.

Linehan deserves much of the credit for demonstrating that suicidal patients can be successfully treated. Now 67, she almost became a nun but realized she was too nonconformist. She got into the therapy business in the 1970s after deciding there was too little evidence backing psychiatry. “She started decades ago and has paved the way for others to treat high-risk patients,” says psychologist David Rudd, dean of the University of Utah’s college of social and behavioral science.

After getting a doctorate in psychology from Loyola University in 1971, Linehan wanted to devote her career to helping the most miserable people in the world. She got hands-on experience as an intern at a suicide crisis center in Buffalo, learned behavior therapy at SUNY Stony Brook and eventually landed at the University of Washington. “I called up all the hospitals and said, ‘Give me your worst.’ They were only too happy to send them,” she recalls. Her patients had suffered horrifying past traumas and were prone to crises at all hours. She had to convince the university human subjects board that it was possible to treat suicidal patients outside of the hospital. Her argument: “There’s no evidence hospitalization has kept anyone alive five minutes.”

Reading the literature, she realized that many patients suffered something called borderline personality disorder, in which people lack any ability to control everyday emotions. Their feelings spiral out of control at the slightest push, like a car parked on a steep hill without an emergency brake. It has a 10% lifetime suicide rate. “My fundamental theory is that highly suicidal people don’t have the skills to regulate their behavior and emotions. … You have to teach those skills,” Linehan says.

She spent years coming up with a combination of techniques to help. Her DBT is an offshoot of cognitive behavioral therapy, which focuses on correcting distorted thought patterns that can make people depressed.  Her treatment, while keeping CBT’s pragmatic, problem-solving approach, drops the emphasis on directly changing thoughts and focuses more on a variety of behavioral techniques that Linehan found helpful.

Among other things, she added Zen acceptance techniques she learned from living one summer in a Buddhist monastery in California and from a Zen master in Germany. DBT teaches patients to tolerate the stresses of the moment, accept that imperfect lives are worth living and gain the skills to cope with raging emotions.

The therapy often starts with crisis control. Over the years her group has had a doctor who played Russian roulette with a loaded gun, patients who kicked in walls and one who threatened to kill the President. Some patients come in using so many psychiatric meds they can barely stay awake. Linehan tapers them down to the essential ones. Sometimes she practices tough love. When one patient had her stomach pumped in the er after an attempted antidepressant overdose, Linehan told her parents not to come, and had her take a cab home and report for work the next day. “That was the best thing that ever happened to me,” says the woman, who recovered, got married and is raising a 2-year-old boy.

The woman entered treatment because she  had been cutting herself on the arm with a Swiss army knife. She was depressed over her job and her weight, but otherwise can’t explain why. (She does not want to be identified because her new friends don’t know about her past.) Linehan’s DBT taught her meditation techniques, slow breathing, and other methods to shut down bad emotions before they spiraled out of control.  “I think the person I am today because of Marsha,” she says. “After working with her I just snapped out of it.”

Linehan’s first small study (1991) showing that DBT reduced suicide attempts was criticized because the patients got intensive treatment by experts like her, which might have accounted for the improvement. But in 2006 Linehan assigned 111 suicidal patients to receive either DBT or intensive treatment using other techniques. Patients on DBT had half the rate of attempted suicides over the next two years and were hospitalized less often for suicidal thoughts, according to the results in the Archives of General Psychiatry.

DBT usually requires six months or a year of twice-weekly sessions, but shorter courses of therapy can also help. University of Pennsylvania researchers found that ten weeks of cognitive behavioral therapy reduced the rate of repeat suicide attempts by half in patients who reported to the emergency room after an attempt. One key was logistics: A huge effort had to be made in tracking the patients and making sure they came to the sessions, says University of Pennsylvania psychologist Gregory Brown.

For frontline docs, Brown and Columbia University’s Barbara Stanley are testing a safety plan that patients write out with a clinician and keep with them at all times. Essentially a list of distracting things to do and people to call when suicidal urges arise, “it is the equivalent of ’stop, drop, and roll,’” says Stanley. One patient, she says, “went to a bridge, reached into his pocket, realized the safety plan was there–and didn’t do it.”

(Come back tomorrow for Part IV in our series on Medicine’s Suicide Problem: Why Drug Companies Won’t Study Suicidal Patients.  Read the full story in the September 13 issue of Forbes on newsstands now. Former Forbes staff writer Rebecca Ruiz is co-author of this series.)

Dr. Warren Breidenbach of Kleinert Kutz Hand Care Center, left, asks Dr. Richard Edwards to move his fingers during a news conference at at Jewish Hospital, in Louisville Thursday, Sept. 2, 2010. The 55-year-old chiropractor from Edmond, Okla., had his hands severely burned in a fire in 2006. Edwards was the nation\’s third double hand transplant recipient. (AP Photo/The Courier Journal, Michael Hayman) No sales No mags No archives

FORBES.com, September 2, 2010, by Dylan Lovan, LOUISVILLE, Ky. — The recipient of a rare double hand transplant says he feels “fantastic” and can wiggle fingers on both his new hands.

Richard Edwards made his first appearance on Thursday, about a week after he underwent a nearly 18-hour transplant procedure at a hospital in Louisville. The 55-year-old chiropractor from Edmond, Okla., had his hands severely burned in a fire in 2006.

Edwards was the nation’s third double hand transplant recipient. The surgery was performed at Jewish Hospital, the site of the world’s first successful hand transplant in 1999.

Doctors say Edwards’ progress is ahead of other patients because they were able to route his existing nerves into the donor hands. Edwards lost seven fingers after his accident but retained most of his original hands, though they were badly burned.