New Drugs for Children in the Pipeline
7/19/02 article from Brown University about how there are 11
new psychiatric drugs planned for kids (9 of them are old drugs with a new
spin).
~~~~~~~~~~~
Drugs in the Pipeline
New Drugs and New Indications for Children and Adolescents
Brown University Child and Adolescent Psychopharmacology Update
4(7):1, 2-3, 2002.
© 2002 Manisses Communications Group, Inc.
Posted 07/19/2002
A survey by the Pharmaceutical Research and Manufacturers of America (PhRMA),
released May 29th, reported 194 medicines in clinical trials for children, 11 of
which are for psychiatric disorders. Nine of the 11 are old drugs seeking
approval for new indications, including attention-deficit/hyperactivity disorder
(ADHD), depression, post-traumatic stress disorder, schizophrenia and acute
bipolar disorder.
ABT 089 (2-methyl-3-(2-(S) pyrrolidinylmethoxy) pyridine) from Abbott
Laboratories is one of the two new drugs under study. It is a potent, selective
neuronal cholinergic channel modulator that has shown cognition-enhancing
activity in several animal paradigms.[1] Neuronal nicotinic acetylcholine
receptors are a complex superfamily of pentmeric ligand gated ion channels that
are activated by acetylcholine. On the basis of its biological activity, ABT 089
is being investigated for its potential ability to act at the neuronal nicotinic
receptors to exert beneficial effects in ADHD.[2]
Timothy E. Wilens, M.D., and colleagues at Massachusetts General Hospital in
Boston are conducting the Phase I clinical trials, but are not at liberty to
disclose information about them at this time.
It is commonly known that nicotine possesses beneficial pharmacological actions.
Michael A. Schwartz, M.D., clinical professor of psychiatry at Case Western
Reserve University, says the cholinergic system, seen as a problem in the old
days, is now appreciated as another neuromodulating system like the
norepinephrine, dopamine and serotonin systems with broad effects on attention,
alertness and specific effects on memory.
"This has particularly happened since the development of the dementia drugs, the
cholinesterase inhibitors," says Schwartz. "And of course people who smoke
cigarettes get alert and aroused and focused from the nicotinic effect. There's
a high comorbidity between nicotine addiction and ADHD."
The manufacturers of Aricept (donepezil), Eisai Inc., are seeking an indication
for treatment of ADHD in children and adolescents ages 7 to 16. Donepezil is a
selective acetylcholinesterase inhibitor developed for the treatment of
Alzheimer's disease. Schwartz says it is already being used for ADHD in children
off-label by some clinicians.
"People have found that drugs like Aricept can sometimes help patients with
ADHD, maybe more with memory than attention, but memory is a problem in ADHD,
[as it relates to] organization, executive functioning," says Schwartz. "We now
know that the anticholinergic drugs diminish your memory and cause a little
confusion, and the drugs that promote the cholinergic system, the cholinesterase
inhibitors, have the potential for increasing attention, memory and
concentration and focus," Schwartz says.
Wilens and colleagues[3] identified five case studies in the literature of
adjunctive donepezil treatment of ADHD in children ages 8 to 17, all of whom
demonstrated improvement.
Atomoxetine, Eli Lilly's contribution to ADHD treatment, is the other new agent
this year, although by now you've heard about it so much it can hardly seem new
any longer (see the January issue of The Brown University Psychopharmacology
Update). Atomoxetine is a non-stimulant, selective norepinephrine reuptake
inhibitor (SNRI). The new drug application has been filed with the FDA and is
under review. It could be on the market shortly. It has been shown to be very
effective in four placebo-controlled studies, three in children and one in
adults, said Schwartz. Weight loss is a side effect in 10 to 15 percent of
patients.
"This medicine originally was a depression and anxiety medication, but the
manufacturer realized norepinephrine is norepinephrine, whether it's coming from
release and reuptake more rapidly with stimulants or more slowly with
antidepressants," says Schwartz.
Effexor XR (venlafaxine extended release), from Wyeth Laboratories, is in Phase
III trials for treatment of depression in children ages 8 to 16.
"I used that even before they had started the testing, and that tells something
because I am extremely conservative," says Elizabeth B. Weller, M.D., professor
of child and adolescent psychiatry and pediatrics at the University of
Pennsylvania and Children's Hospital of Philadelphia.
"To me, Effexor is like cleaned-up tricyclics," Weller adds. "They have gotten
rid of most of the side effects; you don't need to get scared about cardiac
arrythmias and all that stuff. It's tolerated very nicely," Weller says. "I also
like it for anxiety disorder and when children have comorbid conditions. ADHD is
very common in the [child] population that we treat. I find it a lot more
helpful than the SSRIs because they really do not help with the attentional
problems of kids who have anxiety and ADHD, or depression and ADHD."
Schwartz says Effexor differs from the SSRIs in that, in addition to being a
serotonin reuptake inhibitor -- as the dose increases -- it is also a
norepinephrine reuptake inhibitor.
"Many studies show that it has at least 30 percent more capability to cause
remission [in adults], which is getting to wellness, than single
neurotransmitter drugs," says Schwartz. "What's limited its use in depression is
that it's a novel medicine. Doctors are more familiar with SSRIs. Effexor can
raise blood pressure but typically only in high doses. So, it will be good to
have clinical trials. And it even has some possible benefits in comorbid ADHD."
Risperdal (risperidone) from Johnson and Johnson Pharmaceutical is in Phase III
trials for treatment of schizophrenia for adolescents. Both Schwartz and Weller
express concerns about this agent.
Weller and Schwartz raised a number of issues concerning the use of risperidone
to treat schizophrenia. These included the potential for increased prolactin
levels at higher doses and secondary endocrinologic effects as well as weight
gain secondary to increased appetite, a problem that is not unique to
risperidone.
Topamax (topiramate) is indicated as adjunctive therapy for the treatment of
adults and children ages 2 to 16 with partial onset seizures, or primary
generalized tonic-clonic seizures, and in patients 2 years old and older with
seizures associated with Lennox-Gastaut syndrome. It has been studied as a mood
stabilizer to treat bipolar disorder in adults, and it is used off-label for
this purpose. The manufacturer, Johnson and Johnson Pharmaceutical, is now
seeking an indication for treatment of acute bipolar mania in pediatric
patients. The compound is in Phase III trials.
Weller says she likes topiramate, although she doesn't use it as her first drug
of choice because of a lack of data.
"What I like about it is that it is tolerated very nicely," she says. "When I
give it to patients who haven't done well on other medications, they tell me
it's tolerated much easier, and much better. They don't get a lot of side
effects on it."
Weller thinks there is a "myth" that topiramate dulls cognition in adults.
Schwartz disagrees that it is a myth, saying his patients feel as though "half
their brain has been disconnected" and have trouble with word-finding and
memory. The problem passes over a period of months, he says.
[Editor's Note: Cognitive blunting may reflect individual
patients' varying susceptibility to side effects, as is also noted with
decreased appetite and weight loss. Further observation and study of this
appears warranted. -- HL [[this editor's note was already in the forward we
received]]
Weller has used topiramate with children and adolescents with bipolar, but very
sparsely.
"I have [used it with] kids or adolescents who have not responded to lithium, if
Depakote and Tegretol hasn't worked, I have given topiramate. Also I have given
it to the children of two adult patients who had not responded to anything but
topiramate -- then it makes all the sense. Luckily, both of the kids did well on
it, and I haven't seen any cognitive changes. If anything their schoolwork has
gotten better," she says.
Other drugs in clinical trials for children and/or adolescents are Serzone (nefazodone)
for depression; Zoloft (sertraline) for depression and PTSD; Ritalin QD
(methylphenidate) for ADHD; Methypatch (methylphenidate) for ADHD; and, Remeron
(mirtazapine) for depression.
References
1. Bryan PD, Emry ML, El-Shourbagy TA: Determination of ABT-089 in human plasma
by high performance liquid chromatography using in situ precolumn derivatization
with 7-fluoro-4-nitrobenzo-2-oxa-1, 3-diazole. Journal of Pharmaceutical and
Biomedical Analysis 1999; 20(1-2):49-63.
2. Meyer MD, Sullivan HP, Williams M: The neuronal nicotinic acetylcholine
receptor family as a novel drug target. Albany Molecular Research: Technical
Reports 2000; 5(18):7. www.albmolecular.com/features/tekreps/vol05/no18
3. Wilens TE, Biederman J, Wong J, et al.: Adjunctive donepezil in attention
deficit hyperactivity disorder youth: case series. Journal of Child and
Adolescent Psychopharmacology 2000; 10(3):217-222.
