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."▪