A new study from the University of Maryland School
of Medicine suggests that depression results from a
disturbance in the ability of brain cells to
communicate with each other. The study indicates a
major shift in our understanding of how depression
is caused and how it should be treated. Instead of
focusing on the levels of hormone-like chemicals in
the brain, such as serotonin, the scientists found
that the transmission of excitatory signals between
cells becomes abnormal in depression.
The research, by senior author Scott M. Thompson,
Ph.D., Professor and Interim Chair of the Department
of Physiology at the University of Maryland School
of Medicine, was published online in the March 17
issue of Nature Neuroscience.
According to the Centers for Disease Control and
Prevention, between 2005 and 2008, approximately one
in 10 Americans were treated for depression, with
women more than twice as likely as men to become
depressed. The most common antidepressant
medications, such as Prozac, Zoloft and Celexa, work
by preventing brain cells from absorbing serotonin,
resulting in an increase in its concentration in the
brain. Unfortunately, these medications are
effective in only about half of patients. Because
elevation of serotonin makes some depressed patients
feel better, it has been thought for over 50 years
that the cause of depression must therefore be an
insufficient level of serotonin. The new University
of Maryland study challenges that long-standing
explanation.
Depression affects more than a quarter of all U.S.
adults at some point in their lives, and the World
Health Organization predicts that by 2020 it will be
the second leading cause of disability worldwide.
Depression is also the leading risk factor for
suicide, which causes twice as many deaths as
murder, and is the third leading cause of death for
15-24 year olds.
The first major finding of the study was the
discovery that serotonin has a previously unknown
ability to strengthen the communication between
brain cells. "Like speaking louder to your companion
at a noisy cocktail party, serotonin amplifies
excitatory interactions in brain regions important
for emotional and cognitive function and apparently
helps to make sure that crucial conversations
between neurons get heard," says Dr. Thompson. "Then
we asked, does this action of serotonin play any
role in the therapeutic action of drugs like Prozac?"
To understand what might be wrong in the brains of
patients with depression and how elevating serotonin
might relieve their symptoms, the study team
examined the brains of rats and mice that had been
repeatedly exposed to various mildly stressful
conditions, comparable to the types of psychological
stressors that can trigger depression in people.
The researchers could tell that their animals became
depressed because they lost their preference for
things that are normally pleasurable. For example,
normal animals given a choice of drinking plain
water or sugar water strongly prefer the sugary
solution. Study animals exposed to repeated stress,
however, lost their preference for the sugar water,
indicating that they no longer found it rewarding.
This depression-like behavior strongly mimics one
hallmark of human depression, called anhedonia, in
which patients no longer feel rewarded by the
pleasures of a nice meal or a good movie, the love
of their friends and family, and countless other
daily interactions.
A comparison of the activity of the animals' brain
cells in normal and stressed rats revealed that
stress had no effect on the levels of serotonin in
the 'depressed' brains. Instead, it was the
excitatory connections that responded to serotonin
in strikingly different manner. These changes could
be reversed by treating the stressed animals with
antidepressants until their normal behavior was
restored.
"In the depressed brain, serotonin appears to be
trying hard to amplify that cocktail party
conversation, but the message still doesn't get
through," says Dr. Thompson. Using specially
engineered mice created by collaborators at Johns
Hopkins University School of Medicine, the study
also revealed that the ability of serotonin to
strengthen excitatory connections was required for
drugs like antidepressants to work.
Sustained enhancement of communication between brain
cells is considered one of the major processes
underlying memory and learning. The team's
observations that excitatory brain cell function is
altered in models of depression could explain why
people with depression often have difficulty
concentrating, remembering details, or making
decisions.
Additionally, the findings suggest that the search
for new and better antidepressant compounds should
be shifted from drugs that elevate serotonin to
drugs that strengthen excitatory connections.
For more information
University of Maryland Medical Center
(MDN)
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