(AACAP stands for the American Academy of Child and Adolescent Psychiatry, while P&T stands for Pharmacy and Therapeutics).
AACAP is always a fascinating opportunity for me to learn about psychiatry in children, as well as pediatric use of medicines, so what follows are several extra AACAP 2019 stories.
Statistics: No Difference in Fracture Rate Among Girl and Boy Initiators of Benzodiazepines and SSRIs
A poster comparing the risk for fracture in young anxiety disorder patients treated with benzodiazepines compared with SSRIs did not find a statistically significant difference stratified by sex, according to Greta Bushnell, PhD, postdoctoral fellow in the department of epidemiology at Columbia University Mailman School of Public Health, in New York City.
“We did see an elevated fracture
rate in boys compared to girls, which is consistent with the literature,” added
Bushnell, lead author on poster 5.11, “Benzodiazepine treatment and fracture
risk: Gender differences in children with anxiety disorders.”
Generally speaking, studies
sometimes show greater fracture risk in girls than boys, but in this study, among
benzodiazepine initiators, boys had 45 limb fracture rates per thousand patient
years, compared to 26 among girls. Among SSRI initiators; the rates were 33
among boys and 20 among girls.
The study was an analysis of the
MarketScan Commercial Claims Database from 2007 to 2016, yielding information
on 46085 boys and 74,630 girls according to the poster.
“Benzodiazepines are recommended
for short-term treatment and, in our data, we see that the majority of children
only have one benzodiazepine prescription fill before treatment
discontinuation,” said Bushnell.
“The few randomized controlled trials
of benzodiazepines conducted in children with anxiety disorders have not shown
efficacy, whereas SSRIs have shown efficacy for anxiety disorders in children.
The lack of efficacy coupled with safety concerns, such as dependency, lead
most recommendations to call for SSRIs over BZD for children with anxiety
disorders,” she added.
However, the poster indicated that
the adjusted upper-and-lower limb fracture rate for boys was 13.5%, compared
with 6.5% among girls. The rate for boys of any fracture was 14%, compared with
5.2% among girls.
“The effect estimates suggest an
increased risk of fractures in boys and girls initiating benzodiazepine
treatment compared to SSRI treatment, with a slightly higher rate difference in
boys. It will be important to see if similar results are observed in future
work,” said Bushnell.
Poster Reviews 35 publications Studying SSRIs for Anxiety, a Chronic Pediatric Condition
A poster at AACAP reviewed 35
publications, and discussed eight treatment regimens for anxiety disorders in children.
“Anti- Anxiety related response of
antidepressant is apparent in the first 2 weeks with more significant
difference evident by 6 weeks of treatment. Appropriate recommended duration of
treatment of pediatric anxiety disorder is about 6-9 months,” concluded Poster
5.17, “Pediatric Anxiety Disorders (PAD) and pharmacologic intervention: Which
medication to pick?” (Memon et al).
Untreated anxiety disorders are
associated with serious comorbidities such as mood instability, substance use,
and suicidal ideation and attempts.
“For mild-to-moderate anxiety,
maybe you can start with only therapy,” said Sadiq Naveed, MD, assistant
professor of psychiatry at the University of Kansas Medical Center, in Overland
Park, Kansas, an author on the poster.
However, anxiety is a chronic
condition with a lifetime prevalence of around 25 to 32%.
The study was published in a review
article this month in the Journal of the American Academy of Child and
Adolescent Psychiatry (JAACAP).
The study was not a meta-analysis,
but more of a descriptive study, emphasized Naveed.
The poster described the prevalence
of several disorders of the anxiety class, including: social anxiety disorder (9.1%);
specific phobias (19.3%), such as thunderstorms, injection, or the sight of
blood; and panic disorder (2.3%), for example.
The poster also discussed a study
of the ADHA psycho-stimulant methylphenidate used in patients with anxiety
disorders and ADHD.
“The study did not combine the
effects of different studies, and say whether a medication is better than
another one,” said Naveed.
However, one of the studies
described in Naveed’s poster found that 80% of patients did report a response
to cognitive behavioral therapy and sertraline, compared to 59% of the patients
treated with only cognitive therapy and 54.9% with only sertraline, for
example.
“The best are the SSRIs,” Naveed
concluded.
“In our review article, we didn’t
come across any studies looking at anti-psychotic medication for anxiety
disorders,” he noted.
However, the poster doesn’t
describe all of the studies; the 35 studies are discussed in two companion
articles [one of them a draft], he added.
Alpha2 Agonists Said to be of Little Benefit in Institutionalized Patients with Intellectual Impairment
Use of clonidine was associated with a greater rate of seclusion when used to treat children and adolescents in a psychiatric inpatient setting, according to a retrospective study of patient charts presented at AACAP 2019.
Administration of alpha2 agonists clonidine and guanfacine was not related to length-of-stay among institutionalized children (including a subset with intellectual impairment), and otherwise was of uncertain benefit.
“For intellectually impaired
children and adolescents, treatment with Clonidine and Guanfacine during
psychiatric inpatient stay may be of little benefit,” concluded Poster 3.40, “Clonidine
Versus Guanfacine in Intellectual Disability:
Tangible Outcomes in the South Bronx Child and Adolescent Psychiatric Inpatient Setting.”
Patients with intellectual
disability tend to have elevated rates of psychiatric comorbidities and
increased aggression, the poster said.
“I’d heard that clonidine doesn’t
work in autism spectrum disorder patients, but that guanfacine does. In the
in-patient setting, alpha2 agonists may be of little benefit in kids with IQs
below 80,” said Robert Dugger, MD, a psychiatry resident at the Icahn School of
Medicine in New York City. “We were expecting to see a significant difference,
but didn’t,” summarized Dugger, lead author on the poster.
In the study, researchers reviewed
the charts of 156 patients aged 6 through 17 (with a mean age of 13.4). The
patients’ IQs were evaluated between December 3, 2012 and April 3, 2017 at the
BronxCare Health System in New York. Of the patients, 54.5% were Hispanic,
37.2% African American, and 0.6% Caucasian, according to the poster.
Most of the patients (102) received
no alpha2 agonist, 36 received clonidine, and 18 received guanfacine.
Patients treated with clonidine
were secluded more times on average (p<.001). “When we controlled for length
of stay, this dropped to insignificance,” explained Dugger.
The patient population was highly
comorbid, according to the poster: at discharge, 32.7% of the patients were
diagnosed with depression, dipolar disorder, or mood disorders; 19.9% with a
schizoaffective condition or psychosis; and 12.2% with ADHD, among other
comorbidities.
“Our findings are not necessarily
representative of the rest of the country; about 99.9% of our patients were
covered by Medicare / Medicaid,” cautioned Dugger, noting that the
institution’s formulary does not include long-acting guanfacine.
The only variable to significantly
predict length of stay was age, with older patients having reduced length of
stay (p=.007), the study concluded.
The Return of
Viloxazine?
Three posters at AACAP described
three ADHD phase III clinical trials of a new, extended-release version of an
old anti-depressant, Viloxazine, which was pulled from the European market
voluntarily in its original formulation, and never licensed in the US.
According to the posters, 1.70 and
1.72, a dose of 200 milligrams per day in children between six and 11 was
associated with statistically significant improvements as much as 400
milligrams. (Poster 1.70 was called “A Phase 3, Randomized, Double-Blind,
Placebo-Controlled Study (P301) Assessing the Efficacy and Safety of
SPN-812 (Extended-Release Viloxazine)
100 and 200 mg for the Treatment of Attention-Deficit/Hyperactivity Disorder
(ADHD) in Children”; Poster 1.72 was called “A Phase 3, Randomized,
Double-Blind, Placebo-Controlled Study (P303) Assessing the Efficacy and Safety
of SPN-812 (Extended-Release Viloxazine)
200 and 400 mg for the Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD)
in Children Azmi Nasser, PhD1.”
Poster 1.71 presented the results
of a phase III trial in adolescents, in which the new formulation showed
efficacy in the patients’ Clinical Global Impression-Improvement (CGI) score,
but not other measures. (“A Phase 3, Randomized, Double-Blind, Placebo-Controlled
Study (P302) Assessing the Efficacy and Safety of SPN-812 (Extended-Release Viloxazine) 200 and 400 mg
for the Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in
Adolescents”).
“You’ve got to look at how many
patients discontinued,” said an individual associated with Supernus
Pharmaceuticals, who presented the poster.
Across the three posters,
discontinuation due to adverse events varied among the patient populations and
dosage, from 1.2% to 5.6%.
There are currently insufficient
options for patients with ADHD, according to a spokesperson for the company.
“The stimulants, while highly effective, have a side effect profile that makes
it difficult or even impossible for some patients to use them,” noted Peter
Vozzo, managing director of Supernus’ outside investor relations firm.
However, a phase II trial of the
new formulation showed a high rate of discontinuations (27.9%, including
discontinuations not due to adverse events), according to a recent article in
the Journal of Attention Disorders ("A Phase II Double-Blind,
Placebo-Controlled, Efficacy and Safety Study of SPN-812 (Extended-Release
Viloxazine) in Children With ADHD,” Johnson, et al).
While the original formulation of
viloxazine was approved in Europe for depression, it was voluntarily withdrawn
for unknown reasons, according to corporate spokespersons. Apparently, it was
never submitted in the US.
More recently, however, the FDA has
approved two phase II trials and four phase III trials, and the company plans
to submit a new drug application to the FDA in 2019, Vozzo said.
