• Clonidine appears to be associated with
significantly higher rates of adverse events rated at least"
moderate" when used along with methylphenidate or alone for the
treatment of ADHD in children. The data were reported by W. Burl Daviss, M.D.
(University of Pittsburgh Medical Center) on behalf of the Clonidine in ADHD
Treatment Study Group.
In a 16-week trial, 122 children (aged 7-12) with ADHD were randomly
assigned to take clonidine alone (n=31), methylphenidate alone (n=29), both
medications together (n=32), or placebo (n=30). Doses were flexible, up to a
maximum of 0.6mg/d for clonidine and 60 mg/d for methylphenidate. Doses were
titrated by clinicians to optimize tolerability and clinical response.
Rates of adverse events (AEs) and changes in electrocardiograms, blood
pressure, and pulse were compared. Both groups taking clonidine had higher
rates of AEs rated by a study investigator as "moderate" or"
severe," compared with the two groups of patients not receiving
clonidine (79 percent compared with 49 percent). However, groups taking
clonidine also had lower drop-out rates compared with those taking
methylphenidate alone or placebo.
The most common AEs were nervousness, somnolence, apathy, depression, and
dyspepsia. However, rates of somnolence and fatigue were significantly higher
in those taking clonidine. In both groups taking clonidine, heart rate was on
average four beats per minute slower, compared with all patients not receiving
clonidine. No other significant cardiovascular differences were seen in any of
the four groups, and there was no evidence of an interactive effect between
methylphenidate and clonidine in patients who received both.
New Research B8; AACAP, Toronto, 2005
• Atomoxetine may be associated with a potentially
higher risk of aggression or hostility-related adverse events compared with
placebo, according to a meta-analysis reported by John Polzer, D.V.M. (Lilly
Research Laboratories). The analysis included data from acute, double-blind,
clinical trials that were either placebo or comparator controlled. A total of
1,308 children and adolescents were randomly assigned to atomoxetine and
compared with 806 patients randomly assigned to placebo. An additional 566
patients randomly assigned to atomoxetine were compared with 472 patients who
randomly received methylphenidate as an active comparator.
In the 11 placebo-controlled trials, there were 21 aggression/hostility
events in patients taking atomoxetine (1.6 percent occurrence rate) compared
with nine events in those on placebo (1.1 percent), a difference that was not
statistically significant. In six trials comparing atomoxetine with
methylphenidate, there were seven events in atomoxetine patients (1.2 percent)
compared with four events in those receiving methylphenidate (0.8 percent);
again no statistical significance.
The overall relative risk of an aggression/hostility-related adverse event
occurring to a patient taking atomoxetine, relative to placebo, was 1.33. The
relative risk for atomoxetine versus methylphenidate was 0.96. Although the
risk of a patient developing aggressive or hostile behavior appears
numerically greater with atomoxetine compared with placebo, the meta-analysis
found the differences were not statistically significant.
New Research B17; AACAP, Toronto, 2005
• A new film-coated formulation of modafinil, being
referred to as modafinil-ADHD, is effective and safe for
treating ADHD in children and adolescents aged 6-17, according to clinical
trials data presented by Joseph Biederman, M.D. (Massachusetts General
Hospital/Harvard Medical School) and Christopher Kratochvil, M.D. (University
of Nebraska Medical Center). The tablet has release and absorption
characteristics that are significantly different from the formulation already
approved for sleep disorders and sleep apnea. In addition, modafinil-ADHD
contains a higher dose than modafinil. (The U.S. FDA issued an"
approvable letter" for modafinil-ADHD—one step before final
marketing approval of a product—on October 21, one day after these data
were presented in Toronto.)
The data were pooled from three randomized, double-blind,
placebo-controlled studies, two of which allowed flexible dosing of modafinil,
while the third used a fixed-dose protocol. A total of 638 patients received
either modafinil (n=423) or placebo (n=215). Modafinil-ADHD was associated
with significantly greater improvements in ADHD symptoms, compared with
placebo. Patients were assessed using the ADHD-Rating Scale-IV school and home
versions, including total scores and subscores for inattention and
hyperactivity-impulsivity. Scores on the Clinical Global
Impression-Improvement scale also improved significantly greater in those on
modafinil-ADHD, compared with changes in scores in those taking placebo. Both
parent ratings and teacher ratings showed the same patterns, indicating
improvements in symptoms both at home and at school.
In the pooled safety/tolerability analysis, the most common AEs seen in
patients receiving modafinil-ADHD at a statistically significantly greater
rate than placebo were insomnia (27 percent), headache (20 percent), decreased
appetite (16 percent), abdominal pain (10 percent), and fever and nervousness
(5 percent each). A total of eight serious AEs occurred in four patients
taking the drug, versus no serious AEs in those taking placebo. No clinically
significant differences were seen in cardiovascular changes (HR, BP) or in
weight changes between the groups. Abrupt discontinuation of modafinil-ADHD
did not appear to result in emergence of acute withdrawal symptoms or rebound
New Research B12, B18; AACAP, Toronto, 2005
• Lithium appears to be safe and effective in
treatment of adolescent bipolar depression, according to a small study
presented by Nick Patel, PharmD., Ph.D. (University of Cincinnati). A series
of 27 adolescents (aged 12-18) hospitalized with a depressive episode and
diagnosed with DSM-IV bipolar I disorder, were included in the
six-week, open-label exploratory trial. Seven patients did not complete all
six weeks of lithium treatment, primarily due to lack of effectiveness.
However, in the remaining patients, a highly statistically significant
reduction in scores on the Children's Depression Rating Scale-Revised was seen
as early as week 1, and the improvement was maintained through week 6.
At week 6, 48 percent of the patients were responders to lithium (at least
a 50 percent reduction in CDRS-R score), and 30 percent achieved remission (an
endpoint CDRS-R score of 28 or less and a Clinical Global Impression-Bipolar
score of 1 or 2.)
The most common adverse events seen were those already known to be
associated with lithium, such as headache (74 percent), nausea/vomiting (67
percent), polyuria (33 percent), stomach ache (30 percent), polydipsia (26
percent), and abdominal cramps (19 percent).
New Research C37; AACAP, Toronto, 2005
• Quetiapine and divalproex show
similar efficacy in treatment of aggression in patients with bipolar disorder
and comorbid disruptive behavior disorders, reported Drew Barzman, M.D.
(University of Cincinnati Children's Hospital Medical Center). Thirty-three
adolescents (aged 12-18) were randomly assigned to either quetiapine or
divalproex for 28 days. Patients with bipolar I disorder and a comorbid
disruptive behavior disorder were included only if they scored 14 or higher on
the Positive and Negative Syndrome-Excited Component (PANSS-EC). Both patients
taking quetiapine and those taking divalproex showed statistically significant
reductions in PANSS-EC ratings, with no statistically significant differences
between the two groups in change in PANSS-EC or rate of improvement in
Sedation and fatigue were the most common AEs in both groups, with both
occurring statistically significantly more often with quetiapine.
Gastrointestinal upset and headache also occurred in both groups, with no
statistically significant difference between groups.
New Research C35; AACAP, Toronto, 2005
• Antidepressants are not linked to increased
suicidality in youth, according to an analysis of nearly 2,500"
real-world" trials of antidepressant medications in 1,742
patients. The report, by Daniel Deutschman, M.D. (Case Western Reserve
University) found that overall, apparent increases in suicidality after
beginning medication were more likely due to obvious intervening stressors or
interruption of treatment. On average, about half of the patients improved
symptomatically with medication treatment, but no significant differences were
found among different drugs. Suicidal thoughts did increase in a small number
of patients (2.6 percent), compared with a decrease in suicidal thoughts in 11
percent of patients and decreased suicidal threats/gestures in 12.4 percent of
patients. An electronic medical record review of every patient with an
increase in any risk signal for suicidal thoughts or behaviors revealed that,
in each case, medication was not believed to be the proximal cause. Obvious
intervening stressors were identified in 38 percent of cases, interruption of
treatment was evident in 27 percent of cases, and documentation error
accounted for 26 percent of cases recorded as an increase in suicidal thoughts
New Research C64; AACAP, Toronto, 2005
• Both olanzapine and risperidone
appear to be effective in maintenance treatment of youth with psychosis,
reported Linmarie Sikich, M.D. (University of North Carolina at Chapel Hill).
A small study randomly assigned 50 youngsters (aged 8-19) to eight weeks of
double-blind therapy with either olanzapine, risperidone, or haloperidol.
While diagnoses varied, all patients had at least one positive psychotic
symptom of moderate or greater severity on the Brief Psychiatric Rating Scale
for Children. At the end of week 8, 29 of the 50 patients were considered
responders and continued for an additional 12 weeks of double-blind
Although all patients experienced significant reductions in psychotic
symptoms in the acute trial, few patients gained any additional benefit during
the extension of the trial through 20 weeks. AEs varied little between the
three groups. However, 3 of 8 patients taking haloperidol reported blurry
vision, compared with no such reports in patients taking the other drugs. Dry
mouth was most common in those taking risperidone (5 of 8 patients) versus
haloperidol (4 of 8 patients) and olanzapine (2 of 13 patients). Sedation was
most commonly seen in those taking haloperidol (all 8 patients), followed by
risperidone (7 of 8) and olanzapine (6 of 13). Weight gain was observed in all
three groups and was most significant during the first eight weeks. Changes in
blood glucose levels were significantly more likely to occur in those taking
olanzapine, while changes in triglyceride levels were more common with both
olanzapine and risperidone, compared with haloperidol.
New Research C50; AACAP, Toronto, 2005