A survey by the Pharmaceutical Research and Manufacturers of America (PhRMA),
released May 29
th, 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]
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.
