Adrenaline Packs a Powerful
Punch in the
Use of Antidepressants, According to an
Animal-Model Study at Penn
Adrenaline-Deficient Mice Lack Responses
to Antidepressant Drugs
(Philadelphia, PA)—Researchers from the University
of Pennsylvania School of Medicine found that
norepinephrine (adrenaline) plays an important role
in animals in determining behavioral effects in some
of the most commonly prescribed antidepressants, regardless
of which biochemical pathway the drug uses to alleviate
symptoms of depression. This finding -- published in
the May 2004 Proceedings of the National Academy
of Sciences -- should help scientists design more
effective drugs for patients.
Using genetically-altered mice unable to produce norepinephrine,
they tested behavioral changes brought on by two different
antidepressant classes. With the exception of one drug,
they found that those lacking norepinephrine did not
respond to the drugs. “Millions of Americans suffer
from major depressive disorders and this study helps
us understand how antidepressant drugs are processed
to produce clinical therapeutic effects. It helps us
understand how to redesign better drugs and which treatments
will work better for which patients,” says the
study’s lead author, Irwin Lucki, PhD,
Professor of Psychiatry and Pharmacology and Director
of the Behavioral Psychopharmacology Laboratory at Penn.
There are currently two major classes of antidepressants
used to treat depression: norepinephrine reuptake inhibitors
(which work by increasing the synaptic activty of adrenaline
in the brain); and selective serotonin reuptake inhibitors
(which elicit their effects by increasing the activity
of serotnin in the brain). Previously, it was believed
that SSRIs – whose over-the-counter names include
Prozac, Zoloft, Paxil, and Celexia – produced
effects on the serotonergic system only; but the Penn
researchers’ findings showed that the effects
of most SSRIs can also depend on responses from the
noradrenergic system. “This study is the first
to use this unique animal model to test whether the
drugs are still effective in animals that lack norepinephrine,
a key neurotransmitter in the brain,” Lucki adds.
The researchers tested eight commonly prescribed antidepressant
drugs, including four SSRIs. The SSRI medications tested
were fluoxetine (Prozac), sertraline (Zoloft), paroxetine
(Paxil) and citalopram (Celexia). In animal models,
those able to produce norepinephrine experienced behavioral
changes when given the antidepressants. But all of the
antidepressants, except citalopram, failed to work in
the models lacking norepinephrine. These results
provide striking evidence that norepinephrine plays
a critical role for the creation of desired behavioral
effects of most classes of antidepressant compounds
including the SSRIs.
Penn researchers also contributing to this study include:
John F. Cryan, Olivia F. O’Leary, Sung-Ha Jin,
Julie C. Friedland, Ming Ouyang, Bradford R. Hirsch,
Michelle E. Page, Ashutosh Dalvi, and Steven A. Thomas.
The study was funded by grants from the United States
Public Health Service, The National Institute of Mental
Health, The National Institute of Neurological Disorders
and Stroke, and a Young Investigator Award from the
National Alliance for Research on Schizophrenia and
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