Kids With Bipolar + ADHD Respond to Added Stimulant

Treating children and adolescents who have both bipolar disorder and attention-deficit/hyperactivity disorder (ADHD) with a mood stabilizer first, then adding a stimulant, proved safe and effective, according to a small, randomized, controlled trial that also added insight into the nature and diagnosis of these illnesses when they are comorbid.

“Pediatric patients with bipolar disorder and concurrent ADHD can be safely and effectively treated with mixed amphetamine salts after their manic symptoms are stabilized with divalproex sodium,” said Russell E. Scheffer, M.D., and colleagues in an article in the January American Journal of Psychiatry. “Mixed amphetamine salts was more effective than placebo when added to ongoing divalproex sodium to treat concurrent ADHD symptoms.”

Divalproex alone stabilized mood but did not help with ADHD symptoms, they said, but adding amphetamine salts (Adderall) reduced ADHD symptoms without inducing mania.

“Stimulant treatment in the context of bipolar disorder raises the possibility of the worsening of mania or the induction of cycling,” said Scheffer. This is the first prospective, randomized, controlled trial of stimulant treatment of ADHD concurrent with pediatric bipolar disorder, he said.

“This is an innovative trial and will be highly useful clinically,” said Timothy Wilens, M.D., director of substance abuse services in the Pediatric and Adult Psychopharmacology Clinics at Massachusetts General Hospital and associate professor of psychiatry at Harvard Medical School. “There have been a number of retrospective studies, but no prospective trials. This is an important contribution.”

ADHD “co-occurs with pediatric bipolar disorder in 29 percent to 98 percent of patients,” said Scheffer, director of child and adolescent psychiatry training at the University of Texas Southwestern Medical Center in Dallas.

The combination of disorders is a not a mild phenotype, said Wilens.“ This is a severe affliction, and either one is enough to disable a child.”

Some retrospective studies and chart reviews suggested that ADHD symptoms could be improved once mania was controlled by mood stabilizers, while others indicated that stimulants might be useful for ADHD patients with bipolar disorder. In addition to potential avenues for treatment, the trial clarifies some controversies in diagnosis. Until recently, some researchers maintained that these children suffered from an intensive form of ADHD. The separate effects of the two study drugs offer evidence of not one but two illnesses, said Wilens. “It takes a therapeutic paper like this to highlight that there are actually two co-occurring, treatable disorders.”

The researchers tested the combined therapy in 40 young people aged 6 to 17. Average age for girls was 10.0 years and for boys, 9.3 years. They began with eight weeks of open treatment with divalproex (median dose, 750 mg a day). Eighty percent of the subjects achieved at least a 50 percent reduction in manic symptoms, but only a nonsignificant decrease in Clinical Global Impression (CGI) subscale rankings for ADHD.

Thirty evaluable patients continued into a four-week, randomized, double-blind, placebo-controlled crossover trial of mixed amphetamine salts versus placebo. Treatment with divalproex continued throughout this second phase.

Taking stimulants or placebo first or second in the crossover phase apparently made no difference in the outcome, said the authors. Improvement in CGI scores was significantly greater while taking amphetamine salts (5 mg b.i.d.). The few side effects reported were transient and of low to moderate severity, they said.

A final, 12-week, open-label, follow-up phase of the trial held divalproex dosage steady in each patient, and data showed that amphetamine salts had no effect on metabolism or serum levels of valproic acid. About 45 percent of patients required an increase in amphetamine salts dosage. Average study dose at the study's end was 14.5 mg per day. One patient presented manic symptoms during this phase, but they resolved four weeks after amphetamine salts were stopped.

This combined treatment requires a larger, more generalizable trial to test its efficacy and to determine appropriate dosage levels of both drugs, said Scheffer.

“This is a nicely designed, nonesoteric study,” said Elizabeth Weller, M.D., professor of psychiatry and pediatrics at the University of Pennsylvania and Children's Hospital of Philadelphia. “Most pediatric bipolar patients with ADHD comorbidity are treated with mood stabilizers, but that doesn't touch the ADHD. This study shows it's okay to add a stimulant.”

The study was especially valuable because so few trials have addressed these patients, said Weller. Her only reservation concerned the open-label nature of the first part of the trial, although she added that it was probably designed for patient-safety reasons. Approved use of divalproex for these patients will require at least two double-blind randomized trials, she said.

“Most physicians listen to the [Food and Drug Administration], but they are dealing with children who can't function in school or anywhere else and are desperate,” said Weller. “A lot of doctors may give this combination a try. They will have to watch their patients carefully, but it may have benefits for clinicians dealing with very sick children.”▪