A Novel Trial for Pediatric Bipolar Disorder

The FDA studies of medications for children and adolescents diagnosed with bipolar disorder have included the age range of 10 to 17 years. Results of the studies have been reported for the patients grouped together by age. The studies have not provided separate data for 10 to 12 year olds compared with 13 to 17 year olds. This has deprived professionals and consumers of the opportunity to learn more about differences between bipolar disorder in prepubertal children compared to postpubertal adolescents. In a recently published study of lamotrigine in bipolar children and adolescents, the data were reported separately for children these two groups (1). The results of this study confirm the value of reporting the 10-12 and 13-17 age groups separately.

Lamotrigine is unusual medication in the treatment of bipolar disorder. It is FDA approved for the treatment of seizures; it is not FDA approved to treat bipolar disorder by itself. In 2003, it was approved by the FDA to delay the onset of another manic episode in patients who were already treated for acute bipolar disorder; it has not been approved as a standalone medication for bipolar disorder. In adult bipolar patients, lamotrigine is given to treated bipolar patients who continue to take medications that have helped them with their bipolar disorder. Lamotrigine delays the onset of a subsequent bipolar episode in these patients.

Lamotrigine has been reported to work with children and adolescents in case reports and open studies for the treatment of bipolar disorder, ADHD, and depression. The present report is the first double blind study of lamotrigine for bipolar disorder in children and adolescents. The purpose of the study was to examine the ability of lamotrigine to extend the time of the next bipolar event (TOBE) in children and adolescents, as it had done in adults.

301 subjects between 10 years and 17 years with a diagnosis of bipolar 1 disorder enrolled in the study; they were already treated with a variety of agents used to treat the disorder. The purpose of the research was to study the effect of lamotrigine on extending the time until the next bipolar event in children and adolescents. Despite the treatment they were receiving, they remained moderately symptomatic with the disorder at the time they first enrolled in the study ((CGI-BP(S)= 4.4)).

The study began with an 18 week open phase in which all subjects were treated by study investigators and all subjects received lamotrigine in addition to the medications they were taking at the time the study began. Doses of lamotrigine and other medications could be modified to optimize the subjects’ response. Both the subjects and the investigators knew the medications prescribed during this open phase of the study. In order to then be randomized, subjects had to show improvement over the course of the 18 week optimization phase. 301 began the open phase and 125 patients withdrew from this phase of the study. Among the reasons for withdrawal from the study were: adverse events, 26 patients; limited response to treatment, 14 patients; and withdrawals of consent for reasons unclear, 36 patients.

The double blind randomized phase of the study began with 173 patients who had completed the open phase of the study. 87 patients were randomly assigned to the lamotrigine group to continue receiving the lamotrigine they had been receiving during the open study, and 86 patients were randomly assigned to the placebo group. The placebo group had their dose of lamotrigine reduced to zero. The investigators and the subjects were blind to the group assignment.

In the placebo group, 65 subjects withdrew from the blind study. Among the reasons the subjects from the placebo group withdrew were: adverse events, 26 subjects; limited response to treatment, 11 subjects; and withdrawal of consent, 14 subjects. Twenty-one subjects completed the placebo phase.

In the lamotrigine medication group, 67 subjects withdrew from the study. Among the reasons subjects withdrew from the lamotrigine group were: adverse events, 17 subjects; limited response to treatment, 11 subjects; and withdrawal of consent, 22 subjects. 20 subjects completed the lamotrigine portion of the double blind study.

For the placebo group the mean time to a bipolar event was 120 (12.2) days, and for the lamotrigine group the mean time to a bipolar event was 163 days (12.2) days. Many other data points seemed to favor lamotrigine over placebo. When the data were analyzed statistically, the TOBE treatment effect between the two groups was not significantly different (stratified log rank p=.072). Using a different statistical analysis that allowed for statistical control of several relevant variables found the differences between placebo and lamotrigine significantly favored lamotrigine (p=.047). The investigators had specified that they would make the former analysis decisive in the research plan before the study began. The study concluded that for both ages combined lamotrigine did not significantly reduce the time to the next bipolar event.

In a further analysis the investigators found the stratified log rank analysis significant in the 13 to 17 year old subjects (p=.015) but not in the 10 to 12 year old subgroup (p=0.887). The two age groups responded differently to lamotrigine. Lamotrigine significantly increased the time to the next bipolar event in adolescents but failed to do this in 10 to 12 year olds diagnosed with bipolar disorder.

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Those who argue for the existence of bipolar disorder in children rest their case, in part, on similarities childhood and postchildhood forms. The failure of children diagnosed with bipolar disorder to respond to lamotrigine as adolescents and adults diagnosed with bipolar disorder respond, provides support for a pharmacological distinction between the two disorders. The authors of the study note, “The weaker treatment effect in the 10- to 12-year-old subgroup is consistent with observations that BD differs between younger children and adolescents; in the latter group BD resembles adult BD" (p. 1028).

Lamotrigine is associated with a large number of side effects. 83% of the subjects in this study had at least two side effects. The number of side effects may have been increased by subjects in the study taking at least one or more additional medications for their bipolar disorder along with the lamotrigine.

The two side effects with the most life threatening potential associated with lamotrigine are suicidality and skin rash. In the open phase, 7% of subjects reported suicidality related adverse events. In the double-blind randomized phase, 6 subjects in the lamotrigine group reported a suicidality related adverse event, and only 1 subject in the placebo group reported a suicidality related adverse event. There was one suicide attempt in each group.

Another dreaded side effect of lamotrigine is the Stevens-Johnson syndrome. This is a hypersensitivity skin reaction with no specific treatment that can lead to death. (See photo above. The offending agent in the photo is unknown.) Stevens-Johnson syndrome is associated with other seizure disorder medications used to treat bipolar disorder, and about 100 other medications as well. It is rare- about one in one to two million cases. Often it begins with a rash. About 10% of patients treated with lamotrigine develop a rash, and one in a hundred children treated with lamotrigene develop a serious rash (2). There were no cases of Stevens-Johnson syndrome during the lamotrigene trial, but the investigators carefully reported and described the rashes that developed during the study. During the open label phase, 11 patients had 13 rash events. In the randomized phase, 2 lamotrigine treated patients reported three rash events, and 1 placebo treated patient reported a rash event. Overall, 3 rashes were regarded as severe, 3 as moderate, and the remaining 10 as mild.

Because lamotrigine does not work in children 12 and under and has potentially life threatening side effects, there seems to be little reason to prescribe this medication to children 12 and under diagnosed with bipolar disorder.

References

1. Findling, R. et al, Adjunctive Maintenance Lamotrigine for Pediatric Bipolar I Disorder: A Placebo-Controlled, Randomized Withdrawal Study. JAACAP:54; pp 1020-1031, December 2015.

2.Alan Schatzberg, M.D. & Charles DeBattista, DMH., M.D. Manual of Clinical Psychopharmacology p. 366. American Psychiatric Publishing, Washington D.C. 2015.

Copyright: Stuart L. Kaplan, M.D., 2016.

Stuart L. Kaplan, M.D., is the author of Your Child Does Not Have Bipolar Disorder: How Bad Science and Good Public Relations Created the Diagnosis. Available at Amazon.com.