NIH-funded study finds youngsters treated with lithium had fewer manic episodes
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Meredith Carlson Daly: For years, doctors have prescribed the drug lithium to treat adults with bipolar disorder, a brain disorder marked by extreme mood swings from emotional highs to depressive lows. Studies have shown that in adults, the drug keeps these mood swings in check. Although doctors have treated children periodically with lithium, its effectiveness has not been studied in a controlled way.
Now a new study confirms that lithium is appropriate for children diagnosed with the form of the disorder known as bipolar type 1. This study was published in Pediatrics and was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the NICHD.
When approved drugs for children aren't available, doctors rely on their best judgment adapting adult dosages for their younger patients. This study was initiated under the terms of the Best Pharmaceuticals for Children Act, which directs NICHD to work with the FDA to test the effectiveness of drugs not yet tested for children.
Researchers enrolled 81 children ages 7 to 17 who were divided into two groups. Fifty-three received lithium for a period of 8 weeks, and 28 received a placebo. Neither the researchers nor the patients knew the makeup of the groups. At the end of the study, those receiving lithium experienced improved symptoms than their counterparts in the placebo group.
Researchers assessed improvements based on a standardized questionnaire to detect manic episodes, the elevated mood states that are a hallmark of this disorder. Also, children taking lithium didn't experience significant metabolic side effects—and particularly weight gain—as compared to other medications for bipolar disorder.
An estimated 1 percent of teens are affected by bipolar disorder, one of the leading causes of disability in adolescents. Bipolar disorder usually begins during adolescence or young adulthood.
Here to speak with us about this study is Dr. Anne Zajicek, Chief of Obstetrics and Pediatric Pharmacology and Therapeutics Branch at NICHD, and Dr. Perdita Taylor-Zapata, a pediatrician. Both Dr. Zapata and Dr. Zajicek oversaw the study. From the National Institutes of Health, I'm Meredith Carson Daly, and this is Research Developments, a podcast from the National Institutes of Health and the NICHD.
Doctors, thanks for being here today.
Dr. Anne Zajicek: Thank you.
Dr. Perdita Taylor-Zapata: Thank you.
Ms. Carlson Daly: I wonder if you could start by just telling us why it was important to study this drug in children and why such a short period of time, just 8 weeks.
Dr. Zajicek: Why don't I start out with the Best Pharmaceuticals for Children Act, just to give a background on our program, and then Perdita, who is much more of an expert in this area than I, will address the issue about the trial.
The FDA has made several attempts to improve pediatric labeling, starting with the 1997 FDA Modernization Act 2002, created the Best Pharmaceuticals for Children Act. And so NICHD, in particular my branch, has been implementing the Best Pharmaceuticals for Children Act at NIH, and our job is to receive input from various stakeholders, including pediatricians, experts in various areas, parents. Also, to propose disease areas and specific drugs in need of study, the NIH funds those studies and then submits the data to FDA for labeling purposes, and what became obvious is that there was a lack of information about lithium, which was a drug that had been around since 1949, lacked any labeling for anybody under the age of 18, and so this was the start of this project.
And I will now let Dr. Perdita Taylor-Zapata speak.
Dr. Taylor-Zapata: Thank you, Dr. Zajicek. You specifically asked a question about the 8 weeks, and I wanted to sort of piggyback on what Dr. Zajicek mentioned. When we decide to do a study, the study comes from a priority of studies that have been implemented through different stakeholders. Psychiatrists and pediatricians alike felt that this particular drug, which has been around since 1949, as she mentioned earlier, had not been studied and did not have information that was important for physicians to know how to dose this drug and if the drug was actually safe in a particular patient population.
So once we decided that this was an important drug to study, a written request actually came from the FDA, which gave us an outline of how the study should be designed, so there were actually two studies. The first study was a PK, a pharmacokinetic study, which studies the drug levels in the body and if the level is effective or if the level is good enough to be—
Dr. Zajicek: Yeah, effective and not toxic.
Dr. Taylor-Zapata: Effective, okay. That's the word: effective and not toxic. And so we did that study first, and then the second study is the effectiveness study, which actually outlines whether the drug actually works; once it gets in the body, does it have the effect that you want it to have? And so in order to do that, we picked an 8-week time window, which actually can—is a time where you can tell the difference between the actual drug and the placebo, which is the inertia drug, and so that time period was necessary to see a difference between those two drugs.
Ms. Carlson Daly: And how did researchers gage the effectiveness of significant adverse effects of the drug and measure whether the lithium did its job?
Dr. Taylor-Zapata: So we—of course, as I mentioned, we did a PK study, so we determined drug levels by drawing blood from patients and testing them in the lab and making sure the level was good enough to be showing effects, and also the drug levels actually determined not just the effectiveness, but if you're having toxicity, meaning you're having bad side effects or adverse side effects to the drug. And so we monitored that every week for 8 weeks in the patient population to make sure that they were not having adverse side effects and that the dose was at a reasonable level.
Ms. Carlson Daly: And what did they find? What were the results?
Dr. Taylor-Zapata: So the results were, after 8 weeks, we could see a difference between those patients who received lithium and those patients who did not. The patients who received lithium actually had a decrease in their manic symptoms, and this was shown in a scale called the YMRS, the Young Mania Rating Scale. And the difference between the two patient populations, the treatment population and the placebo population, was significant enough to show that lithium was effective in that patient population who received the drug.
Ms. Carlson Daly: Can you just explain for us what that scale is? How do they measure that?
Dr. Taylor-Zapata: So the YMRS is a questionnaire that is administered to the patient and to the parent, and the scores are then tabulated to see if the drug is having an effect. So, over the 8-week period, every week we would monitor. The study team would ask the patients and the parents questions about how their symptoms were changing, if they were improving, if they were not, if they were having side effects, and so based on the patient and the parents' responses, we tallied that up over a time period and looked at the difference between the start of the study and then the end of the study. And the difference between those two times show that the lithium patients did have a better response to the drug than the placebo patients.
Ms. Carlson Daly: And what do we do with that information now?
Dr. Taylor-Zapata: So now the data that we have from that study, we are submitting to the FDA, and actually probably in the next few weeks actually submitting that data to the FDA. They have to do their own evaluation of our data to make sure that they can replicate that data and that the data are valid and that the data are of good quality, and once they determine that, they will then go and negotiate with the pharmaceutical companies, who actually own the drug still, to decide whether to change the label or not. So we believe in the next several months that this will go forward.
Ms. Carlson Daly: So parents might see—you know, on lithium, safe for children—
Dr. Taylor-Zapata: Yes.
Ms Carlson Daly: —if the FDA accepts the data that you have presented.
Dr. Taylor-Zapata: Absolutely! And so the actual label currently does have information in adults. It has some information in children down to 12 years of age, but that information is taken from adults. It actually was not directly studied in patients and definitely not in patients younger than 12. So that data, patients who are younger than 12, we will have that data from our study on the dosing and the effectiveness and also safety in kids younger than 12 and older than 12, and we hope that information is what will be able to go into the label for practitioners and families to be able to see what they can use in this drug.
Ms. Carlson Daly: And, Dr. Taylor-Zapata, since you were so close to this study, give us a sense of—it's a vulnerable population?
Dr. Taylor-Zapata: Yes.
Ms. Carlson Daly: Was it a difficult study to undertake? Was it a difficult population to work with?
Dr. Perdita Taylor-Zapata: Yes and yes. So it was a difficult study to undertake for many reasons. As you mentioned, it is a very vulnerable population, and sometimes when you're conducting clinical trials in vulnerable populations, there's a lot of difficulty in recruiting them into a study, especially if you're using a placebo, where you're not guaranteed that a drug is going to be used, and also because of the demographics of the patient population. Keeping them maintained in a clinical trial is very difficult. So patient recruitment was a big issue for the study, and patients—
Ms. Carlson Daly: And just to interrupt you for a second—and the folks who were participating didn't know—
Dr. Taylor-Zapata: Correct.
Ms. Carlson Daly: —whether they were going to get the placebo—
Dr. Taylor-Zapata: Or the drug.
Ms. Carlson Daly: —or the actual drug.
Dr. Taylor-Zapata: Absolutely, that's correct.
Ms. Carlson Daly: So that's difficult.
Dr. Taylor-Zapata: That's very difficult, very difficult. And then once they agree to become—to be in the study, to actually retain them in the study was also difficult because if they started having symptoms or started having side effects, you know, the parents were likely to pull the plug and say, "I want my kid to go back on something that I know what they're getting," and so it's very difficult to study. But it was very important to do because we needed the information for the drug, and we're very thankful for the parents and the patients who did participate in the study and were able to give us the information that we needed to really get this drug approved.
Ms. Carlson Daly: And, Dr. Zajicek, can you tell us what the takeaway here is for parents?
Dr. Zajicek: I think the takeaway is that there is a place to do these kinds of difficult studies. This is one of the advantages of having, you know, the federal government involved in medical research that we're not here for, you know, this is not a financial issue for the federal government. We're not going to be making any money on this, but it's important medically and for health purposes. This is a real role of the NIH to perform these kind of trials so that you know, you know, no one had a conflict of interest here. There was no money at stake here. We just wanted to get at the truth about whether the drug worked or didn't work, and if the drug didn't work, so be it. The drug worked; that's fine too. We just really wanted to know whether the drug was effective and safe as well.
Ms. Carlson Daly: And now you have evidence that shows that in fact the drug is effective with children under 12, and you have data to show in what dosages it's effective.
Dr. Zajicek: Precisely.
Ms. Carlson Daly: Are you both comfortable enough knowing that 8 weeks gave you enough evidence to show the results are—
Dr. Zajicek: Well, the 8 weeks was helpful to show the efficacy, but there were other issues about safety, and there were—there was a longer period of time where we're looking at the safety as well.
Dr. Taylor-Zapata: The—12 weeks -
[Simultaneous speaking.]
Dr. Zajicek: Exactly. The other issue has been, because a lot of these patients wind up getting—frequently are dosed with antipsychotic medications, typically antipsychotics for the behavior problems, about whether there was an issue about weight gain because that's been an enormous problem with the atypical antipsychotics, and there was no evidence of weight gain in these patients. So from a safety point of view as well as an efficacy point of view, the drug seems to be safe and effective.
Ms. Carlson Daly: Is there anything I haven't asked or mentioned that you—either of you would like to point out?
Dr. Zajicek: The issue around these clinical trials comes back to the problem that if you don't do the clinical trials, these children are getting the drugs anyway. So you really want to know that they have been studied. We want to make sure these trials are done correctly, so you know what dose the child should be getting, whether the drug is effective, and whether the drug is safe in a controlled manner.
Ms. Carlson Daly: Well, thank you so much. I've been speaking with Dr. Anne Zajicek, Chief of the Obstetrics and Pediatric Pharmacology and Therapeutics Branch at NICHD, and Dr. Perdita Taylor-Zapata, a pediatrician also in the branch. We really appreciate you explaining this study, and thanks so much.
Dr. Taylor-Zapata: Thank you very much.
Dr. Zajicek: We appreciate your interest. Thank you so much.
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About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Institute's website at http://www.nichd.nih.gov/.
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