Strattera Risks May Widen

FDA", default",s warning about Eli Lilly's drug Strattera causing suicidal thinking in children used for ADHD caught many parents and doctors by surprise.

This week's new FDA warning about the ADHD drug's side effects may not be the last one added to its label.
By David Stipp
Friday, September 30, 2005

Thursday's Food and Drug Administration warning about suicidal thinking in a small fraction of kids taking Eli Lilly's attention deficit hyperactivity disorder drug caught parents and doctors by surprise. But in fact, concerns about the side effects of the drug, Strattera, originally emerged a full year before this week's FDA warning.

Launched in 2003, Strattera has been widely regarded as a safer alternative to the amphetamine-like medicines, such as Novartis's Ritalin and Shire Pharmaceuticals Group's Adderall, that have long been used to treat ADHD. That's largely because Strattera is the first non-stimulant prescription for ADHD, and hence doesn't pose the risk of substance abuse that the older drugs do.

Concern about Strattera's potential to induce extreme mood swings, which can lead to suicidal thinking, were noted in the Sept. 3, 2004, issue of the journalPediatrics. "Our clinical experience [with Strattera] has been that mood destabilization is a much more prevalent risk than was observed" in the medicine's clinical trials, two physicians wrote in a letter to the periodical.The doctors, Theodore Henderson of Denver and Keith Hartman of Osceola, Wis., noted that a third of 153 children treated with Strattera at two clinics in their areas manifested extreme irritability, aggression or mania—a state of wild excitement typified by racing thoughts, insomnia and inappropriate acts—soon after going on the drug. Three had to be hospitalized, including one 11-year-old boy who stripped off his clothes, covered his body with markings using a felt-tipped pen, flew into a screaming rage and threatened family members with a sword belonging to his father. Three others were incarcerated in juvenile detention centers for violent behaviors.

During the clinical trials that led to Strattera's FDA approval, between 2% and 5% of patients experienced mood swings, 8 experienced irritability and 1% discontinued the trials due to aggression or irritability, according to the drug's label insert. But after the drug's introduction, "we and a lot of other doctors were seeing a rash of cases" of mood destabilization among kids taking Strattera, says Dr. Henderson. "It was anecdotal, but we felt that it was a significant trend that needed to be studied."

Anecdotal reports on a drug's side effects must be taken with a grain of salt-they lack the rigor of clinical trials, including comparative data from patients taking placebos. And it's important to note, as Drs. Henderson and Hartman did, that 80% of the kids who experienced mood destabilization on Strattera had histories of mood symptoms. Thus their emotional problems while taking the drug may have stemmed from underlying disorders and not from the medicine. However, in six of the 51 cases (or 11%), extreme mood states on the drug did occur in kids with no personal or family history of mood disorders.

A.J. Allen, Lilly's medical director of global neuroscience, says that the company had observed an "increased frequency" of hostility and aggression in patients on Strattera compared with those on placebos in its studies, but that the increase wasn't statistically significant. In April, Lilly added language to its label about that risk. He contends that the mood-swing cases noted by Drs. Henderson and Hartman probably reflect an unusually high rate of pre-existing mood disorders among the patients they were treating. He also added that reports about adverse drug reactions tend to appear in the medical literature more frequently for new drugs like Strattera than for ones whose side effects are already well known to doctors. That may give a false impression that newer drugs are more risky than the older ones.

For its part, the FDA has been aware of Strattera's association with mood destabilization, says Thomas Laughren, director of the agency's psychiatric products division. There have been similar concerns about other ADHD drugs-earlier this year the agency said it planned to add cautionary language about psychiatric side effects, including aggression and suicidal thoughts, to the labels of several of the medicines, including Johnson & Johnson's Concerta, a time released form of Ritalin.

Dr. Laughren says the agency also plans to ask Lilly to include a stronger caution on Strattera's label about its risk of inducing mania and similar mood destabilization, along with the new "black box" warning out this week. The new warning will focus on the drug's risks for kids with undiagnosed bipolar illness, according to Dr. Laughren. In fact, "very often bipolar illness is not recognized until you [give] patients a drug like Strattera," he says.

That's not surprising: Strattera is chemically similar to tricyclic antidepressants, an older class of drugs that have long been known to occasionally induce mania in people with bipolar illness. It is also not surprising that few such cases occurred in Lilly's clinical trials with Strattera, since the company excluded patients with histories of mood disorders from the trials. The more frequent appearance of extreme mood swings that seems to be occurring among Strattera takers in the real world may largely reflect the prevalence of undiagnosed mood disorders in the general population. Between 1% and 3% of the U.S. population suffers from bipolar disorder, according to surveys. Bipolar and other affective disorders are particularly difficult to diagnose in children and adolescents, whose natural moodiness and surging hormones cause emotional instability that's hard to distinguish from real illness.

The message that patients using psychiatric drugs should be carefully monitored for possible mood destabilization, including suicidal thoughts is becoming a familiar one. Last year, the FDA warned that a class of antidepressants called SSRIs, such as Pfizerr's Zoloft and GlaxoSmithKline's Paxil, have been shown in clinical trials to double the risk of suicidal thinking and behavior in children and adolescents compared with those given a placebo; about 4% of patients on the drugs experienced such symptoms, compared with 2% on dummy pills.

Indeed, the heightened concern about Strattera is part of a bigger, ongoing examination in medicine about the risks of widely prescribing psychotropic drugs to youngsters with relatively mild symptoms of depression, ADHD or other mental disorders. Says Dr. Henderson: "The bar has been raised for prescribing psychotropic medicines to kids."