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. 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.
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 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.
Brown University Child and Adolescent Psychopharmacology Update 4(7):1, 2-3, 2002. © 2002 Manisses Communications Group, Inc.