Lithium for Bipolar Maintenance 'Safe, Tolerable' in Kids

Heather Boerner

February 14, 2019

Lithium is safe and tolerable as maintenance therapy for up to 28 weeks for children and teens with bipolar disorder (BD), new research suggests.

A randomized, double-blind study showed that participants who received lithium had a significantly lower relative risk for study discontinuation than those who received placebo — the primary outcome measure.

The researchers note that determining the best way to relieve BD symptoms in this patient population has always been challenging, especially because some of the tried-and-true treatments for adults haven't been studied in young people. However, that's beginning to change.

From the new study's results, clinicians have "a pretty decent signal" that after the danger of an acute episode has passed, lithium can effectively reduce the risk that children will experience relapse, lead author Robert Findling, MD, Johns Hopkins University School of Medicine, Baltimore, Maryland, told Medscape Medical News.

"Now, when physicians and families discuss this, [lithium] can be part of the conversation. They might at least think about treating with lithium," he added.

The findings were published in the February issue of the Journal of the American Academy of Child and Adolescent Psychiatry.

However, some concerns have been raised about the study, including the fact that it only included 31 young participants. In addition, one of its authors was required to return a $3 million research grant with regard to a different study.

The current study's funder, the National Institute of Child Health and Human Development (NICHD), told Medscape Medical News in a statement, "NICHD staff has no concerns about the integrity of the data" from the current study.

However, the journal's editor, Douglas Novins, MD, told Medscape Medical News that the journal's leadership is double-checking the data to confirm their strength.

"Starting From Scratch"

Although lithium has been around since the 1940s as a potential treatment for severe mood disorders, it only began to be tested in children relatively recently after passage of the 2002 Best Pharmaceuticals for Children Act.

That's where the Collaborative Lithium Trials (CoLTs) come in. The need for data meant that his team was "really starting almost from scratch," Findling said.

In the course of several years, CoLT defined the pharmacokinetics of and established evidence-based dosing strategies for the use of lithium in young people — all before studying how lithium actually worked to quell the acute bouts of mood disorder that come with BD.

The investigators also needed to create protocols to ensure that these studies were both accurate and ethical. In particular, they needed a protocol that worked as well for 7-year-olds as it did for 17-year-olds; and they needed to target the right group of participants.

This included children with BD serious enough to require a treatment such as lithium but not so severe that the patients who received placebo would need to be hospitalized for management of mood fluctuations.

The researchers also needed to figure out when to discontinue participation in the study when children were truly having a bipolar episode and when not to discontinue participation early on for children who were only having a "bad day," Findling noted.

"These are difficult studies to do," he said. "We didn't think it would be ethical to let them do poorly for any substantial period of time."

By the time of their study on maintenance therapy, the researchers had "pretty much characterized" how lithium functions in children, Findling said.

Avoiding Relapse

The investigators enrolled 31 children and teens from multiple sites as part of two of the foundational studies, CoLT1 and CoLT2. Six to eight weeks after starting lithium following an acute episode, the participants were randomly assigned to either continue receiving lithium treatment or to discontinue use of study drugs. Those patients whose treatment was discontinued served as a control arm.

For the next 28 weeks, participants visited the clinic regularly. During these visits, an unblinded physician ensured that for those patients in the lithium arm, trough lithium levels were between 0.8 and 1.2 mEq/L.

The Young Mania Rating Scale was used to assess mood; other measures were used to assess depression and symptom severity levels. Parents filled out the Parent General Behavior Inventory–10 Item Mania Scale.

Results showed that after 28 weeks, fewer than half of participants (42%) were still actively participating in the study. The vast majority of these patients who continued in the study (65%) were in the lithium-maintenance arm.

Of the 18 who discontinued, 13 did so because of mood symptoms that qualified as a relapse. The other five did so for non-mood-related reasons.

Side effects were more common in those receiving lithium. These side effects included stomachaches, headaches, bed wetting, insomnia, and vomiting.

Most of the patients' side effects were as expected from previous research, Findling said. "But one side effect we didn't see was weight gain," he noted.

"Really, what we saw was that lithium was effective treatment, even as maintenance therapy," he added.

Smart Study Design

Commenting on the study for Medscape Medical News, John T. Walkup, MD, professor of psychiatry and behavioral sciences at Northwestern University, Chicago, Illinois, called the design smart.

What the investigators really tested was whether participants stayed in the study or stopped for any reason, Walkup noted. The researchers could thereby judge effectiveness on the basis of whether more participants in the placebo group experienced relapse than in the lithium group, he said.

If that happened, "you could begin to say that lithium is not only effective, but that lithium offers ongoing effectiveness against relapse," added Walkup, who was not involved in the research.

Walkup was a coinvestigator the Treatment Moderators and Predictors of Outcomes in the Treatment of Early Age Mania (TEAM) study, which tested antipsychotics, anticonvulsants, and lithium against each other in young people with BD.

Results showed that risperidone (Risperidal, Janssen) was more effective than lithium, although lithium was just as effective when the participants did not have comorbid attention-deficit/hyperactivity disorder.

"We had this really huge gap in the literature," said Walkup, regarding placebo-controlled studies of lithium. "Now we have the data. Cross that off the list."

Still, there were problems with the current study, he noted.

"This is a big study from an importance point of view. But they ended up with only 31 patients," so the results cannot be definitive, Walkup said.

Walkup said he had few concerns about the data. What the study shows is "how hard it is to do this research," he said.

Although the findings aren't based on results involving hundreds of participants, the study does give clarity and helps providers who work with young people with BD, he added.

"This was an incredibly big step, but it's still incremental from a knowledge perspective," Walkup said.

The study was funded by the National Institute of Child Health and Human Development. Findling reports receiving fees for consulting services and speaking engagements or research support from Aivi, Akili, Alcobra, Amerex, the American Academy of Child and Adolescent Psychiatry, the American Psychiatric Press, Bracket, Epharma Solutions, Forest, Genetech, Ironshore, KemPharm, Lundbeck, Neurim, Nuvelution, Otsuka, Pfizer, Roche, Supernus Pharmaceuticals, Syneurx, Teva, Tris, TouchPoint, and Validus. Walkup has received consulting fees from Shire.

J Am Acad Child Adolesc Psych. 2019;58:287-296. Abstract

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