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Abstract
Two illnesses, one drug, two results - and pictures to prove it. That's what researchers have after comparing brain scans from patients treated for obsessive-compulsive disorder or for major depression.
| The same drugs treat both depression and OCD. |
These two mood disorders, major depression and obsessive-compulsive disorder (OCD), are very different psychiatric conditions in terms of patient behavior, as well as in their biochemical markers and physiology. Yet both conditions respond to treatment with the same class of drugs, the selective serotonin reuptake inhibitors, says Sanjaya Saxena of the University of California at Los Angeles.
This apparent paradox left Saxena and his colleagues Arthur Brody and Lewis Baxter wondering how one drug could help patients suffering from such distinct illnesses: Is the drug working in the same way in the two groups of patients, or is it actually working on the different brain systems and circuits that mediate the symptoms of the two disorders?
| Researchers investigated the paradox using brain scans. |
To answer the question, the researchers performed positron emission tomography (PET) and magnetic resonance imaging (MRI) scans of patients with either major depression or OCD prior to treatment, and then again after several weeks of treatment with paroxetine, a serotonin reuptake inhibitor commonly known as Paxil.
When they compared the initial patient brain scans with those of healthy control subjects they found - as others have previously - that there are areas of the brain that have unusual activity levels in the patients. Some regions are hyperactive compared with the controls; some regions show reduced metabolism. Significantly, the two disorders affect different regions of the brain.
| Drug effects differed in the two groups. |
Approximately two-thirds of the patients in each group responded to treatment. "But," says Saxena, "the changes we saw in the brains of these patients were different," despite the fact that they were treated with the same medication at the same dose for the same duration.
"We saw specific regions involved in OCD, and we saw completely different regions involved in patients with depression."
OCD, says Saxena, is a well-defined and relatively homogeneous condition, and the results uncovered by the researchers are crisp.
| SSRIs reduced orbitofrontal activity. |
Patients with OCD have excessive activity in the orbitofrontal cortex, which is the region of the frontal lobe just above the eye sockets and in the circuits connecting it to certain subcortical areas, including the caudate nucleus and the thalamus. "When people respond to treatment, whether it is medication or interpersonal therapy," says Saxena, "the activity in those areas of the brain is reduced to normal. So that is pretty strong evidence that those areas and the circuits that link them together are the primary ones responsible for the symptoms of OCD."
It makes sense, continues Saxena, that these are the regions involved in OCD because scientists know from studying animals and humans that this region is involved in perceiving biologically significant stimuli, things that have to do with danger, cleanliness, and territory. In patients with OCD, this circuit seems to be hyperstimulated, so they experience an overwhelming sense of worry.
| With depression, the picture was less clear. |
By comparison, the results of the brain scans from the depressed patient population are not so clear-cut. There is a lot more variability in both the baseline scans performed prior to treatment and in the scans performed after treatment. But looking past these inconsistencies, the researchers detected significant changes in metabolism in some regions of the brain. For example, there was a reduction in activity in the ventral-lateral prefrontal cortex of patients who responded to treatment.
The lack of uniformity in the results from the depressed patient group doesn't surprise Baxter, who collaborated with Saxena from the University of Alabama at Birmingham. "The reason probably is that this condition is a syndrome. It is undoubtedly a collection of illnesses," rather than one clear-cut illness as is OCD.
| Imagers attempt to sort out the heterogeneity of depression. |
In fact, Baxter says that one of the major areas of work in the field of mood disorders and brain imaging is an effort to develop imaging techniques that can distinguish groups of patients. "A lot of work is being done now to look at predictors of response," says Baxter. "It is not here yet, but the early stages of the work do look quite promising."
Wayne Drevets, chief of the Section on Neuroimaging in Mood and Anxiety Disorders at the National Institute of Mental Health, thinks that advances in two areas will be necessary before imaging can be used as a diagnostic tool in major depression. One is the need for improved resolution in the techniques themselves, and the other is the need for more restrictive criteria for patients enrolled in the studies.
| There is no "normal range" in brain imaging. |
"The imaging technology to date just hasn't given us a big enough effect size," says Drevets. And since the effect size is what gives you a notion of how big the abnormality is relative to the variability between scans, researchers can't yet decipher diagnostic criteria. The variability is just too high to say what is outside the normal range. By way of analogy, Drevets suggests looking at the blood sugar levels of a diabetic; if a doctor saw a patient with a level of 400, she'd know the patient was way outside of normal. But thus far the normal range in brain imaging studies just hasn't been resolved adequately to define normal.
Also, trimming down the heterogeneity of the patient population in major depression, which Baxter alluded to, is of paramount importance when developing diagnostic criteria, says Drevets. Otherwise, imaging results will be all over the map; they are for many current studies in major depression. To get around this problem, Drevets' group is very cautious about choosing the patients that they enroll in their studies, reasoning that if they more tightly restrict the definition of major depression, then they will end up with a more homogeneous - and therefore more informative - set of results. They require, for example, that patients have a family history of depression and that their depression be a primary disorder, not a secondary result of something else such as alcoholism. That's not to imply that other individuals aren't suffering from significant depression, but rather that researchers will only be able to uncover the basis of the disease by looking at one homogeneous group at a time.
| Drevets hopes imaging can guide genetic studies. |
Drevets also thinks that a key to developing more effective diagnostic criteria and treatments is to move forward with the genetics - and he hopes imaging can guide that effort. Previous studies looking into the genetic basis of depression have failed to identify a gene, although certain chromosomal regions do appear to be involved. "But we haven't had a good objective way to subtype the syndromes," Drevets says. "We are hoping that imaging can be that method and can help guide these genetic studies in a more meaningful way."
But, in the meantime, how is it that one drug can affect different sets of circuits in two different patient populations, while leaving the normal regions of the brain untouched? That, says Saxena, still isn't clear. But preliminary data from several research groups suggest that not much happens to psychiatrically healthy people when they take Paxil or other selective serotonin reuptake inhibitors at the doses used for treatment. "The medication will change your brain function, but only if you had some brain dysfunction that is influenced by serotonin," says Saxena. Miraculously, many neurochemicals appear to return the activity of a brain region to a normal level, whether that means boosting the activity level or bringing it down, thus restoring homeostasis.
Rabiya S. Tuma is a freelance science writer based in Oregon and New York.
Susan Wolsborn is Web designer of HMS Beagle.
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National Institute of Mental Health - offers extensive resources for researchers and the public. Includes information on Depression, Genetics and Mental Disorders, Depression Research, Obsessive-Compulsive Disorders, and more.
The Neurobiology of Depression - an overview of recent genetic and biochemical research. From the June 1998 issue of Scientific American.
Drug Treatment for Mood Disorders: Depression and Bipolar Disorder - discusses the different types of antidepressants and their pharmacodynamics. From Psychopharmacology at Viterbo University.
Depression and the Brain - a transcript from Gray Matters, a radio show. Consists of a discussion by psychiatrists, researchers, and a few well-known people who suffer from depression.
Obsessive-Compulsive Foundation - offers extensive information and resources.
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