Right now, about half of all people who take medicine for an anxiety
disorder don't get much help from it. And doctors have no definitive
way to predict who will, and who won't, benefit from each anti anxiety
prescription they write.
But a University of Michigan Medical
School researcher and his team are working to bring more certainty to
how doctors and patients choose anxiety treatments, by probing the
connection between brain activity, genetics and medication.
In a paper last month in the Journal of Neuroscience,
K. Luan Phan, M.D., and his former University of Chicago colleagues
reported intriguing findings from a brain imaging study in occasional,
non-dependent, marijuana users.
In a placebo controlled design, they made the findings after giving the
volunteers delta 9 tetrahydrocannabinol (THC), the active ingredient in
marijuana, and exposing them to photographs of emotional faces, which
served as signals of social communication.
The study results, which
showed that THC reduces the response to threat in a brain region called
the amygdala, allowed the researchers to zero in on an area of the
brain that might serve as a good target for new anti-anxiety drugs.
Now, with a new clinical trial that is currently seeking participants,
Phan is searching for more clues as to how anxiety treatment could be
tailored to the individual patient, to give the best chance that a
treatment will work for him or her.
The new study will test a generic form of the drug Zoloft (sertraline), a selective serotonin reuptake inhibitor (SSRI) approved
by the U.S. Food and Drug Administration for social anxiety disorder
and other anxiety disorders. Both people with social anxiety disorder
and a comparison group of people without anxiety are needed for brain
scanning and genetic testing.
The idea is to see whether variations in the genes for certain brain
receptors and transporters are linked with variations in how a person's
brain reacts to pictures of emotional faces, and variations in how they
respond to the anti-anxiety drug. This information could lead to an
individualized or personalized approach to medical care.
"These two studies are trying to get to the same goal: to find better
treatments for anxiety disorders that affect millions of Americans and
seriously interfere with their functioning," says Phan, an assistant
professor of psychiatry at U-M and the VA Ann Arbor Healthcare System.
"The cannabis study highlights a new avenue that we need to explore
further as we try to develop novel medications, while the sertraline
study will try to find out if we can tell which patients might or might
not respond well, and by what mechanism, to an already existing
medication known to have some efficacy in treating anxiety disorders."
Phan led the cannabis study at the University of Chicago, collaborating
with Harriet deWit, Ph.D., the director of the Human Behavioral
Pharmacology Laboratory in the Department of Psychiatry there. Their
results are based on brain scans of 16 recreational marijuana users who
agreed to undergo functional magnetic resonance imaging, or fMRI.
The researchers chose fMRI because it allows them to see in real time
which areas of the brain are most active while a volunteer is
performing a certain task for example, viewing a picture of a human
face that is expressing anger or fear, or performing a decision-making
exercise.
That same approach will be used in the new sertraline study, with two
different scans before and after anxiety patients are prescribed the
medication. The healthy volunteers in the study will also have fMRI
scans, though they will not receive the drug. All study participants
must between 18 and 55 years old, and those with anxiety disorders must
not be taking any other medication that could be affecting the brain in
order to qualify to enter the study.
The cannabis study used THC, and a placebo caplet that looked exactly
like the THC caplet. The researchers found that when the marijuana
users received THC, their brain's response to "threatening" faces was
less than it was when they received a placebo.
The difference in response was seen in an area of the brain called the
amygdala, which is a hub for the brain's ability to process signs of
danger or warning, and to decide how to respond. But there were no
differences between THC and placebo in the areas of the brain that
process non-emotional visual signals or govern body movement suggesting
that THC had a specific effect on a specific brain region and on a
specific task of processing fear. Other researchers have shown this to
be a region that's rich in a receptor called CB1, part of the brain's
"cannabinoid" system.
The human brain produces compounds called endocannabinoids that act on
these receptors, and are involved in anxiety and fear-learning, or the
learning of which threats to be afraid of. But little has been known
about the effect of THC, an exogenous cannabinoid, on the brain's own
system.
For ethical reasons, the researchers did not give THC to non-marijuana
users, and the study was small. But the findings in the study
volunteers suggest that THC and other compounds that act on the CB1
receptors in the amygdala could be fruitful targets for new
anti-anxiety medicines. Phan notes that rimonabant, a smoking-cessation
and weight-loss drug not yet available in the United States for
clinical use, also acts on the CB1 receptor.
Understanding how drugs such as marijuana affect the brain may also
help reveal more about why people become addicted to illicit drugs or
abuse certain prescription drugs, Phan notes. Some individuals may be
using illicit drugs and misusing prescribed drugs to alleviate their
anxiety. He hopes to investigate this issue further by studying people
who have used prescription pain drugs recreationally (such as
oxycodone), using new funding from the National Institutes of Health.
The THC study links three key domains of human behavior: a specific
region of the brain, the function of that area, and a neurochemical
agent (THC) that appears to act on them. The new sertraline study will
take it one step further, by looking at genetics too. Specifically,
Phan and his colleagues will look for variations ("functional
polymorphisms") among several genes in individual subjects.
Key among them is the gene (5-HTTLPR) that encodes the serotonin transporter protein that transports the neurotransmitter serotonin in and out of brain cells. Serotonin has long been known to be involved in depression and anxiety, and indeed most modern antidepressant and anti-anxiety drugs (such as SSRIs) work on this transporter.
Reference:
Journal of Neuroscience, March 5, 2008, Vol. 28, No. 10, 2313-2319
University of Michigan Health System
2901 Hubbard St., Ste. 2400
Ann Arbor, MI 48109-2435
United States
http://www.med.umich.edu
View drug information on Zoloft