June 7, 2004 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 Depression.
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