University of Nebraska Medical Center researchers have received a three-year,
$497,000 grant funded by the National Institute of Mental Health (NIMH),
to develop laboratory animal models of testing antidepressants in children
and adolescents.
The National Institutes of Health, the premier public source of medical
and behavioral research support in the United States, funds scientific
studies at universities and research institutions across the country.
Like other drugs approved for use in humans, researchers first must
test antidepressants in humans. Before drugs can be tested in humans, researchers
may first use animal models to screen a multitude of drugs. For anti-depressant
drugs, researchers are likely to turn to adult rodent models.
But researchers say a rodent model designed to test the effectiveness
of antidepressants in children and adolescents is needed.
Tricyclic antidepressants used in adults, for example, have not been
shown to be effective in treatment of child and adolescent clinical depression
said David Bylund, Ph.D., UNMC professor of pharmacology and principal
investigator of the UNMC study titled, Animal Models of Childhood and Adolescent
Depression. We think that tricyclics tend to work on a different neurochemical
system in the brain than do serotonin uptake inhibitor drugs, he said.
Researchers hope their study can explain the lack of effectiveness of
the tricyclic antidepressants in children and adolescents and more importantly,
a rodent model of child and adolescent depression should help predict the
classes of antidepressants that will be effective in children and adolescents.
There are many differences between juvenile and adult animals.
If we can develop a juvenile animal model that can predict which drugs
might be useful in child and adolescents, we might find new classes of
drugs which are effective in children even if theyre not effective in
adults, Dr. Bylund said. And, there may be drugs that have been overlooked
because theyve only been studied in adult animal models with depression
as oppose to juvenile animal models.
He said an important difference between clinical depression in children
and adolescents, as compared to adults, is response to anti-depressant
drugs.
There are no established juvenile rodent animal models of clinical
depression, said Dr. Bylund. We have reasonable rodent animal models
for adults that predict more than 90 percent how well drugs work in adult
humans, but no one to this point has looked at models in the young animal
to see what drugs might be effective in children and adolescents.
In their study, researchers will assess the validity and usefulness
of two established rodent animal models of adult clinical depression as
models of childhood and adolescent clinical depression.
Research of antidepressants in children is a relatively recent phenomena.
Prior to the 1990s, it was generally considered unethical to do controlled
clinical trials in children, Dr. Bylund said. But in the 1990s, when the
U.S. Food and Drug Administration began allowing studies in young people,
controlled clinical trials with tricyclic antidepressants showed no benefits
in children compared to placebo. In the later 1990s, the FDA demanded studies
be done in children.
Although antidepressant drugs have numerous neurochemical actions,
the therapeutic mechanisms of action of antidepressant drugs in relieving
depression remain unknown, Dr. Bylund said. We need to better understand
the neurobiology underlying the differences between children and adolescents,
and adults in the response to pharmacological treatment of clinical depression.
Christopher Kratochvil, M.D., UNMC child and adolescent psychiatrist
who has been treating children and adolescents with depression for about
eight years, and is nationally known for his work in clinical research
on pediatric depression, said the study is unique in that it is taking
a look at depression in children from a very different perspective.
By developing a model for pediatric depression in animals, it could
be much easier to assess potential treatments prior to progressing to human
studies, Dr. Kratochivil said. We know when compared to adulthood depression,
that pediatric depression can present quite differently in the clinic.
Additionally, not all treatments that are effective in adults with
depression are effective in children with depression, he said. This line
of study may provide an effective in way to conduct a systematic line of
research on childhood depression, and learn much more about a very common
problem in the pediatric population.
It is estimated up to 2.5 percent of children and up to 8.3 percent
of adolescents in the U.S. suffer from depression. According to the National
Institute of Mental Health (NIMH), depressive disorders can have far reaching
effects on the functioning and adjustment of young people, including an
increased risk for illness and interpersonal and psychosocial difficulties
that persist long after the depressive episode is resolved.
In adolescents, there is also an increased risk for substance abuse
and suicidal behavior. In addition, research indicates that depression
onset is occurring earlier in life today than in past decades.
According to the NIMH, although the scientific literature on treatment
of children and adolescents with depression is far less extensive than
that concerning adults, a number of studiesmostly conducted in the last
four to five yearshave confirmed the short-term efficacy and safety of
treatments for depression in youth. Larger treatment trials are needed
to determine which treatments work best for which youngsters.
Also collaborating on the UNMC study is Frederick Petty, M.D., Ph.D.,
Creighton University Medical Centers Department of Psychiatry vice-chair
of research.