news_12_08

Reuters, 12/8/03

ATTENTION DEFICIT DRUGS MAY HAVE LONG-TERM EFFECTS

WASHINGTON -- Drugs given to children to treat attention deficit hyperactivity disorder could have long-term effects on their growing brains, studies on rats suggest.

Several studies published Monday show that rats given a popular ADHD drug were less likely to want to use cocaine later in life, but also often acted clinically depressed and behaved differently from rats give dummy injections.

While rats are different from humans, the studies suggest that doctors should watch children for long-term effects, too.

In the United States between 3 percent and 5 percent of children are diagnosed with attention deficit disorder, marked by reduced ability to concentrate, difficulty in organizing and impulsive behavior.

Patients are commonly prescribed stimulants but the practice is sometimes controversial.

William Carlezon of McLean Hospital and Harvard Medical School in Boston and colleagues raised two groups of rats. One was given Ritalin, known generically as methylphenidate, during the rat equivalent of pre-adolescence, while the other was given a salt water injection.

When they matured, the rats were tested for "learned helplessness" -- how quickly they gave up on behavioral tasks under stress.

"Rats exposed to Ritalin as juveniles showed large increases in learned-helplessness behavior during adulthood, suggesting a tendency toward depression," Carlezon said in a statement.

But rats, which generally like cocaine, were less likely to eat it if they had been give Ritalin.

Carlezon said he did not believe the effects were specific to Ritalin, made by Swiss drug giant Novartis. It could instead be a general effect of stimulant drugs, many of which act by increasing the activity of a key message-carrying chemical called dopamine.

Higher dopamine levels could affect the way brain cells cement their connections during development, Carlezon wrote in the Dec. 15 issue of the journal Biological Psychiatry.

Elsewhere, a team at the University of Texas Southwestern Medical Center at Dallas found that adult rats were less responsive to rewarding stimuli and reacted more to stress if they had been given methylphenidate as youngsters.

Also, a third study done by a team at Finch University of Health Sciences and the Chicago Medical School found changes in how dopamine neurons responded to methylphenidate.

"These three studies remind us how limited our knowledge is of the neurochemical and functional characteristics of the human brain during childhood and adolescence and on the effects of psychotropic drugs on brain development," Dr. Thomas Insel, Director of the National Institute of Mental Health, wrote in a commentary.

HealthDayNews, 12/18/03

PROLONGED USE OF RITALIN MAY CHANGE BRAIN

THREE ANIMAL STUDIES FOUND DIFFERENCES IN THOSE EXPOSED TO STIMULANT DURING CHILDHOOD

Misuse of Ritalin may have possible long-term effects on the brain and behavior, claim three animal studies in the December issue of Biological Psychiatry.

Ritalin is the recommended treatment for attention-deficit hyperactivity disorder (ADHD). Numerous previous studies have shown it's safe and effective when used as prescribed.

But these three studies found Ritalin caused changes in the brains of adolescent and pre-adolescent animals that persisted into adulthood. If the findings are applicable to humans, they could offer important information about young people who use Ritalin and similar stimulants as recreational drugs.

The first study found low doses of Ritalin caused changes in rat brain cells that made them more sensitive to the rewarding effects of cocaine. The second study found exposing pre-adolescent rats to Ritalin actually decreased sensitivity to cocaine reward when the rats reached adulthood, but increased other behaviors that could indicate depression.

The third study found adult rats chronically exposed to Ritalin before adolescence were less responsive to natural rewards, such as sugar and sex, and more sensitive to stressful situations. The adult rats also demonstrated increased anxiety behaviors and enhanced blood levels of stress hormones.

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WebMD Medical News, 12/8/03

PRETEEN RITALIN MAY INCREASE DEPRESSION

EARLY USE OF ADHD DRUG ALTERS BRAIN, RAT STUDIES SHOW

By Daniel DeNoon

Ritalin use in preteen children may lead to depression later in life, studies of rats suggest.

It's an open question whether what passes for depression in lab rats has anything to do with depression in humans. But early use of Ritalin and other stimulant drugs seems to permanently alter animals' brains. That raises concerns that the same thing might be happening in children who take these drugs for attention deficit hyperactivity disorder (ADHD).

The findings come from a research team led by William A. Carlezon Jr., PhD, director of the behavioral genetics laboratory at McLean Hospital and associate professor at Harvard Medical School. The study appears in the Dec. 15 issue of Biological Psychiatry.

"Rats exposed to Ritalin as juveniles showed large increases in learned-helplessness behavior during adulthood, suggesting a tendency toward depression," Carlezon says in a news release. "These rats also showed abnormally high levels of activity in familiar environments. [This] might reflect basic alterations in the way rats pay attention to their surroundings."

Ritalin, Cocaine, and the Brain

Ritalin and cocaine have different effects on humans. But their effects on the brain are very similar. When given to preteen rats, both drugs cause long-term changes in behavior.

One of the changes seems good. Early exposure to Ritalin makes rats less responsive to the rewarding effects of cocaine. But that's not all good. It might mean that the drug short-circuits the brain's reward system. That would make it difficult to experience pleasure -- a "hallmark symptom of depression," Carlezon and colleagues note.

The other change seems all bad. Early exposure to Ritalin increases rats' depressive-like responses in a stress test.

"These experiments suggest that preadolescent exposure to [Ritalin] in rats causes numerous complex behavioral adaptations, each of which endures into adulthood," Carlezon and colleagues conclude. "This work highlights the importance of a more thorough understanding of the enduring neurobiological effects of juvenile exposure to psychotropic drugs."

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The following is a press release issued on December 10 by the National Institute of Drug Abuse, part of the federal National Institutes of Health:

NEW RESEARCH IN ANIMALS REVEALS POSSIBLE LONG-TERM EFFECTS OF STIMULANTS ON BRAIN AND BEHAVIOR

Three new studies conducted in animals, published in the December issue of the journal Biological Psychiatry, provide evidence that misuse of the stimulant methylphenidate (Ritalin) may have long-term effects on the brain and behavior. While methylphenidate and other stimulant medications are the recommended treatments for Attention Deficit Hyperactivity Disorder (ADHD), based on the more than 150 controlled studies demonstrating their safety and efficacy when used as prescribed, these three studies showed changes in the brains of young (adolescent or pre-adolescent) animals that persisted into adulthood. In both animals and humans, the brain continues to develop throughout adolescence. If the current studies are applicable to humans, they could have important implications for young people who use stimulants for recreational purposes.

In the first study, Dr. Cindy Brandon and her colleagues at the Finch University of Health Sciences and the Chicago Medical School examined how low doses of methylphenidate affect dopamine cells in the brains of adolescent rats. Dopamine is a brain chemical that has been implicated in natural rewards, such as food and sex, as well as in drug abuse and addiction. The study showed that the rats experienced brain cell changes that subsequently made them more sensitive to the rewarding effects of cocaine.

In the second study, Dr. William Carlezon, Jr., and his colleagues at Harvard Medical School and McLean Hospital in Belmont, Massachusetts, looked at how pre-adolescent exposure to methylphenidate affected certain behaviors in rats when they reached adulthood. They found that early exposure to twice-daily injections of methylphenidate actually reduced the sensitivity to cocaine reward, but increased other behaviors that could indicate depression. The timing of exposure to methylphenidate may be important — in this study the rats were exposed at an age corresponding to childhood, whereas in the study by Dr. Brandon et al., the rats were slightly older, more akin to adolescence.

In the third study, Dr. Carlos Bolaños and his colleagues at the University of Texas Southwestern Medical Center in Dallas assessed certain behaviors of adult rats given methylphenidate prior to adolescence. They found that compared to drug-naive rats, those chronically exposed to methylphenidate were less responsive to natural rewards, such as sugar and sex, and more sensitive to stressful situations. The methylphenidate-exposed animals also had increased anxiety-like behaviors, and enhanced blood levels of stress hormones.

In an editorial accompanying the Brandon, Carlezon, and Bolaños papers, Dr. Nora D. Volkow, director of the National Institute on Drug Abuse (NIDA), and Dr. Thomas Insel, director of the National Institute of Mental Health (NIMH), both components of the National Institutes of Health, articulate the important contributions of these studies as well some of the caveats that need to be considered before these results can be applied to humans. Importantly, the studies show changes in the function of brain dopamine cells and in behavior following chronic exposure to doses of methylphenidate similar to those used to treat ADHD in children.

ADHD affects an estimated 3 to 5 percent of school-age children around the world and is considered to be the most prevalent psychiatric disorder of childhood. Among the caveats noted by Drs. Volkow and Insel in their editorial, is the way in which the drug is administered to rats (by injection into the abdominal cavity) compared to the oral route (by tablet) used by humans. This could lead to differences in how much and how quickly the drug affects the brain. In addition, for these studies to be truly applicable to ADHD, they may need to be carried out in an animal model of the disorder, rather than in normal rats. Thus, the results may be more applicable to children and adolescents who do not have ADHD, but who take stimulants for non-medical purposes, or to those who are treated with stimulants as a result of misdiagnosis. This underscores the importance of proper diagnosis of this disorder.

Drs. Volkow and Insel further state that "Because the use of stimulant medications for the treatment of ADHD has increased significantly over the past 10 years, it is vitally important that we evaluate the long-term effects of these drugs in the human brain and on behavior. Such knowledge is essential for a better understanding of ADHD and its management, and will help inform those with ADHD and their relatives about the risks and benefits of stimulant medications."

The National Institute on Drug Abuse is a component of the National Institutes of Health, U.S. Department of Health and Human Services. NIDA supports more than 85 percent of the world’s research on the health aspects of drug abuse and addiction. The Institute carries out a large variety of programs to ensure the rapid dissemination of research information and its implementation in policy and practice. Fact sheets on the health effects of drugs of abuse and information on NIDA research and other activities can be found on the NIDA home page at www.drugabuse.gov