PTSD and the Brain: What's New in Basic Research
A National Center for PTSD Fact Sheet
Ronald Duman, Ph.D., is Director of the Laboratory of Molecular Pathogenesis
and Treatment Mechanisms within the Clinical Neurosciences Division of the National
Center for PTSD in West Haven, CT. He and his staff are engaged in basic research
on the effects of stress on brain structure and brain chemistry, research that
may point the way to more effective treatments for PTSD in the future. In August
2002, Janet Bailey interviewed Dr. Duman about his lab's research.
What kind of research is taking place in your lab right now?
We are studying the mechanisms that underlie the effectiveness of the
antidepressant drugs used to treat depression and PTSD, which often co-occur.
We know that these drugs are effective, but we don't fully understand what they
do to the brain over the long term. The primary mechanism, which happens very
quickly, is maintaining the levels of the substances norepinephrine and
serotonin, which are molecules that transmit information from one neuron to
another in the brain. But we also know that there are other effects that happen
later, and it is these long-term effects that are of interest to us.
In our lab, we typically will administer different classes of drugs to rats
or mice for different periods of time, and then we examine their brain tissue
to study the effects. We're basically
trying to identify all the different signaling pathways that can be affected by
the antidepressant drugs.
Do the antidepressant drugs work on both depression and PTSD?
The two diseases are actually quite different. However, there is a high
level of co-morbidity-that is, where people who are depressed also have PTSD
and vice versa-so there may be something underlying both diseases. In both
diseases, for instance, we see a shrinking in the size of the hippocampus,
which is an area of the brain involved in memory. But, that could simply mean
that both groups of patients are under a great deal of stress. At this stage,
we don't know enough to determine what the underlying neurobiological imbalance
is for each illness. That is one of the goals of our work.
We're at a stage with our medication repertoire [where] clinicians often use
what's available. So, the antidepressant medications are used not just for
depression but also for anxiety disorders as well as PTSD. They aren't perfect,
but they seem to help many patients.
How did you get started on this line of inquiry?
In the mid-1990s, there was work at both the basic research level and the
clinical level showing that stress and trauma have damaging physical effects on
the brain. Clinical studies had demonstrated the reductions in the size of the
hippocampus in patients with PTSD or depression. At the same time, basic
research on the hippocampus in animals was revealing that stress causes a
reduction in the levels of neurotrophic factors, which are chemical substances
in the brain that are necessary for the survival and health of cells. Other
studies showed that the processes of neurons were reduced by stress. So there
was a convergence of basic and clinical research.
Here in West Haven, we were studying the antidepressant drugs. Clinicians
were beginning to use these drugs to treat patients with PTSD, even though it
wasn't clear how effective they really were.
What have been some of the key findings about the antidepressant drugs?
What we have found over the past several years has been very interesting. We
have demonstrated that these drugs have a number of effects. They can block the
adverse actions that are caused by stress, such as reductions in neurotrophic
factors and atrophy of neurons in the hippocampus. More recently, we found that
antidepressants can actually increase the number of new neurons in the adult
brain.
This last item was a remarkable finding. It was always thought that once you
reach your adult age the number of neurons in the brain is fixed-that is, if
you lose any neurons for any reason, say through aging or brain damage, you
don't replace them. The idea of adult neurogenesis, or growing new neurons, was
not accepted. However, it's now clear that new neurons are born in adulthood,
and the results from our laboratory demonstrate that antidepressant drugs
increase this normal process.
We've also had some success in understanding the longer-term effects of
antidepressant drugs on brain chemistry. One of the most important long-term
effects is an increase in one of the major neurotrophic factors in the brain
called "Brain Derived Neurotrophic Factor," or BDNF. We've been studying ways
to regulate the production of BDNF, which has led us to identify a molecule
called "Cyclic AMP," which increases levels of BDNF. We've found that if we
block the breakdown of Cyclic AMP, we see an increase in BDNF.
We interpret all this to mean that the antidepressant drugs can act in a
very beneficial manner to block the destruction of neurons, increase neural
regeneration, and increase the production of neurotrophic factors, all of which
would provide a healthy condition for the survival and functioning of neurons in
the brain.
What else is going on besides research on drugs?
We've recently gotten involved in some genetic research, trying to identify
the genes involved in PTSD.
Everyone has a fixed complement of genes at birth, which is what's called the
DNA sequence. Our bodies are made up of proteins, which are the product of the
genetic makeup that we have. Proteins have to be constantly renewed through a
process called the "expression" of the genes.
We've done some interesting genetic research with transgenic mice-mice that
are engineered to have more or less of a particular gene product. In our
research with these animals, we can identify and manipulate a particular gene
and then study how it influences behavior in that animal. For instance, we have
introduced a gene that causes an animal to overproduce the substance BDNF, and
we hypothesize that they will be PTSD-resistant. We've also obtained mice from
other labs where that particular gene has been knocked out, and those animals
turn out to be more susceptible to PTSD.
We're also developing behavioral models of PTSD to help in this research.
For instance, we will place an animal in a stressful situation and then ask the
animal to perform a task. Typically, a stressed animal doesn't perform that task
very well. We then manipulate substances like Cyclic AMP or BDNF in these
animals and try to see if it influences their performance or whether it blocks
or promotes a PTSD-like response.
How do you translate the results you're seeing from animals to people?
It's sometimes hard to make the jump from our studies of experimental
animals to the clinic. We can make strong hypotheses, but there's a lot more
work to be done. What makes this research particularly interesting, though, is
that brain imaging studies in people show a shrinking in the hippocampus as a
result of PTSD, a situation that could be explained by the kinds of results
that we're seeing in experimental animals.
What we really need to do now is morphological analysis on human brains,
where you can actually see the size of neurons, the number of neurons, the
processes of neurons, and so forth. Unfortunately, we are limited in what we
can investigate because we can't take biopsies. In any other field of medicine,
you can take a biopsy-a sample of tissue-and figure out what's wrong with the
patient. You can't do that with psychiatric illnesses such as PTSD, though,
because you can't reach in and take samples of people's brain tissue.
So how do you get around this?
[Division Director] John Krystal has been spearheading the development of a
PTSD "brain bank," which doesn't exist right now anywhere in the world. In all
the other major psychiatric disorders, such as depression or schizophrenia,
researchers have established brain banks. They obtain postmortem brains from
patients who die, and they work with county coroners to collect brains from
suicide victims, accident victims, and so forth. Scientists can then use these
human brains in their research. It's a really key area, because right now it's
one of the few ways we have of studying the neurochemistry and neurobiology of
these illnesses.
How will the results of your research improve treatment of PTSD? Is it possible that new drugs will be
developed and introduced as a result of your research?
There is a great deal of interest in BDNF as a target in a variety of
neurological disorders, like multiple sclerosis, and many more studies like
ours are now taking place.
Unfortunately, there hasn't been much success yet in making drugs that act
like BDNF in the brain. Typically, a drug is developed by identifying a
substance in the body that has a particular effect, and then making a drug that
acts like that substance. But we haven't figured out a way to do that yet with
BDNF, mainly because the molecule is very large and therefore very difficult to
reproduce, though a lot of people have been trying for a long time.
There's also a lot of interest from pharmaceutical companies in Cyclic AMP
and various enzymes that could regulate the body's own production of BDNF, and
in the results of our genetic studies.
We've also had some interesting evidence that drugs aren't necessarily the
only answer. It's been demonstrated that exercise has a very positive effect on
neurotrophic factors-actually more significant effects than drugs in many
cases. We've found that if we give a mouse a running wheel, he'll get on it and
run for miles and within a few weeks we see a dramatic upturn in the production
of neurotrophic factors!
The more we understand normal brain chemistry, as well as the imbalances
that occur, the more we can work toward designing and developing new
medications and other effective treatments for PTSD.
Where does funding come from for your research?
We get funding from a variety of sources, including the National Institute
of Mental Health (NIMH), National Institute on Drug Abuse, and the VA. We also
are funded by some private organizations and a number of drug companies that
are interested in our work and in having us test their drugs. We're also
connected to Yale University and the Yale New Haven Hospital. Besides me, the
staff in my laboratory consists of eight postdoctoral researchers, three
students, and three technicians.
Is there anything else you want people to know about your work?
When talking about this, it can all sound very negative: shrinking
hippocampus, damaging effects of stress, and so forth. But the data we have,
and data from clinical studies, shows that these effects are reversible to a
much greater extent than we thought. We used to think that the brain was like a
computer, all hard-wired and fixed. We're now finding that it's really very
changeable and adaptable. The fact that you can grow new neurons, and that the
processes of neurons can be altered, indicates that it's not at all hopeless.
So, even though we see negative effects from PTSD and other disorders, we also
see that these effects are reversible through treatment with drugs, behavioral
therapy, and even exercise. There's enormous potential for the future to be
able to go into the brain and fix things. That is certainly the goal-just figuring
out how to do it is the question.
Related Fact Sheets
Common
reactions to trauma
An explanation of common reactions to trauma by Dr. Edna Foa
Medication
for PTSD
A discussion of who should receive pharmacological treatment for PTSD and what
pharmacological agents clinicians might prescribe
Treatment
Information on availble treatments for PTSD
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