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FEWER SEROTONIN RECEPTORS FOUND IN PATIENTS WITH PANIC DISORDER

People who suffer from panic disorder have a decreased number of serotonin receptors in the brain, according to researchers at the National Institute of Mental Health (NIMH).

NIMH PET studies revealed that serotonin type-1A receptor (5-HT1AR) binding is reduced by an average of about one-third in three areas – the anterior cingulated gyrus, posterior cingulate, and the raphe — straddling the center of the brain. The study results provide for the first time evidence in living humans of the involvement of the 1A receptor in the pathophysiology of panic disorder (PD). The findings, reported in the January 21st issue of the Journal of Neuroscience, also suggest the possibility that reduced 5-HT1AR expression is associated with a genetic risk factor for PD (2004;24:589–591).

Neuronal type-1A receptors regulate the action of serotonin, which is involved in determining mood and anxiety. About 2.4 million people in the US suffer from panic disorder, a syndrome characterized by recurrent episodes of intense fear, thoughts of death, overwhelming dread, heart pounding, chest discomfort, shortness of breath, dizziness, and sweating.

“This is the first finding that shows a really profound difference between patients with panic disorder and healthy controls in an imaging study,” said Alexander Neumeister, MD, the study's lead author and a visiting scientist in the Mood and Anxiety Disorders Research Program at the National Institute of Mental Health (NIMH). Dr. Neumeister and Wayne Drevets, MD, Chief of the Section on Neuroimaging of Mood and Anxiety Disorders at NIMH, used PET to assess 5-HT1A receptors in 16 unmedicated, symptomatic patients with PD. Seven of the patients also suffered from major depression. Fifteen healthy controls were also scanned.

WHAT IMAGING FOUND

Binding by highly selective radioligands, or tracers, made it possible to reveal the receptor locations. “The technological advance made the study possible,” said Dr. Neumeister. “The radioactive tracer allows you to define the structures in the brain and visualize the receptor system in question.”

In patients with panic disorder, including those with comorbid depression, the number of receptors was reduced by an average of nearly a third in the anterior cingulate gyrus, the posterior cingulate, and the raphe nucleus in the midbrain.

Figure

PET shows distribution of serotonin 5-HT1A receptors (front of brain is at top), which were reduced by about a third in the raphe in panic disorder patients.

A 1999 PET study by Dr. Drevets and colleagues (Biol Psychiatry 1999; 46:1375–1387) also found reduced 5-HT1AR binding in subjects with primary major depressive disorder, but the reductions were less pronounced in the anterior cingulate and the posterior cingulate, the areas that regulate mood and anxiety through postsynaptic serotonin receptors.

Dr. Neumeister said: “We found that the difference can't be accounted for by the comorbidity with depression, because there was no difference between patients with panic alone and those with depression as well. So this reduction is specific to panic disorder.”

He pointed out that the 1999 study showed a 41 percent reduction of 5-HT1AR binding in the raphe, a deficiency similar to the 34 percent receptor reduction in the current study. The raphe is the area of the brain that regulates serotonin synthesis and release. “There the receptors are presynaptic,” he said. “So you can assume serotonin transmission is affected not only in the raphe but in the whole brain.”

He noted that the new study found no difference in blood cortisol levels, indicators of stress, of patients and healthy controls on the day of the study.

He said that the receptor deficiency could be caused by genetic variations, but “you have to keep in mind the patients studied here have all been symptomatic.”

FUTURE RESEARCH

The next step, he added, is to study people whose symptoms are in remission to see if the same receptor differences are still there. “If it's really a genetic finding, we should find the same patterns,” he said.

Another possible direction would be to study healthy relatives of people with panic disorder compared to healthy controls without a family history of the disease. “If non-affected relatives have a receptor reduction but no symptoms, you might say that the deficiency is a vulnerability factor,” Dr. Neumeister said.

Dr. Neumeister's findings build on previous research on mice genetically engineered to lack the 1A receptor during early development. A 2002 Columbia University study reported in the journal Nature showed that the transgenic mice exhibited anxiety traits, such as a reluctance to eat in an unfamiliar environment (416:306–400). They also found that administration of a selective serotonin reuptake inhibitor (SSRI) drug stimulated formation of new neurons via the 1A receptor, producing anti-anxiety effects.

EXPERTS COMMENT

Christopher M. Filley, MD, Professor of Neurology and Psychiatry at the University of Colorado Health Sciences Center in Denver, said “the NIMH findings help substantiate one piece of the puzzle by directly implicating a role for serotonin and also support the growing use of SSRI drugs as first line medications for patients with panic disorder.”

He added that a complete explanation of panic disorder will probably require an understanding of the role of other regions of the brain, such as the amygdala, hippocampus, thalamus, hypothalamus, periaqueductal gray, and locus ceruleus. “Attempts should be made to integrate all the components of the fear network — perhaps most importantly the amygdala — into a comprehensive theory of the neurobiology of panic disorder,” he said.

He suggested that the NIH findings should be replicated with more subjects because panic disorder is a criteria-based diagnosis with no neurobiological marker. Further studies should also address whether the 5-HT1AR reduction results from stress-induced glucocorticoid effects or is genetically determined, he added.

Figure

Statistically-analyzed PET scan data superimposed on structural MRI scan (front of brain is at right) shows areas in the anterior and posterior cingulate where panic disorder patients had nearly one third fewer serotonin 5-HT1A receptors compared to healthy control subjects. The lighter the color, the greater the difference between patients and controls.

Richard M. Restak, MD, Clinical Professor of Neurology at George Washington Hospital University School of Medicine and Health Sciences in Washington, DC, said the NIMH study was “generally one of these types of research findings that break down different illnesses to neurotransmitter bindings sites, so you're going to have a profile or a signature for the illnesses.”

He said the reduced 5-HT1AR binding could be a signature for panic disorder, but “the big problem is the crossover and the overlap with depression. You can't distinguish a person with panic disorder with depression from a person who just has pure panic disorder.”

Dr. Restak added that the overlap is “not a weakness of the study.” He said the illnesses are all on the anxiety spectrum, so “we can't expect that the receptor binding profile is going to necessarily correlate with our clinical descriptions, which are fairly primitive.”

The ability to create individual illness profiles in terms of receptor bindings and neurotransmitter alterations could lead to significant advances in treatment, he said. With comprehensive brain scans, drug therapies could be individualized to be “neurotransmitter specific,” addressing the particular patterns of individual patients.

“You could tell right away whether drugs are working,” Dr. Restak said. “There's the old way – asking patients how they're doing. But it would be also good to see if the drug is a match in terms of receptor binding.”

ARTICLE IN BRIEF

✓ A study spearheaded by Dr. Alexander Neumeister, of the National Institute of Mental Health, reported the first evidence in living humans of the involvement of the 1A receptor in the pathophysiology of panic disorder.

EXTENSION OF TEMPORARY CRITERIA FOR CERTIFICATION IN THE SUBSPECIALTY OF NEURODEVELOPMENTAL DISABILITIES

In September 2003, the American Board of Medical Specialties extended the time period for the temporary criteria for certification in the subspecialty of neurodevelopmental disabilities (NDD) through the 2007 examination.

In addition to meeting licensure requirements, applicants must be certified in neurology with special qualification in child neurology and must meet one of the three sets of temporary requirements:

  • Satisfactory completion of 24 months of formal training in NDD acceptable program for subspecialization in NDD.
  • Satisfactory completion of 12 months of formal training in NDD and 50 percent of practice time devoted to NDD for the previous two years.
  • Fifty percent of practice time devoted to NDD for the previous five years.

After the 2007 examination, candidates applying for examination must complete ACGME-accredited residency training in NDD.

The application deadline for the April 6, 2005, NDD examination is September 1, 2004. Applications will be available in Spring 2004 and can be downloaded from the ABPN website (www.abpn.com) or requested from the ABPN office. Questions should be directed to the ABPN's Credentials Department.

REFERENCES

• Neumeister A, Baine E, Nugent AC, et.al. Reduced serotonin type 1A receptor binding in panic disorder. J Neurosci 2004;24:589–591.
• Gross C, Zhuang X, Stark K, et.al. Serotonin type 1A receptor acts during development to establish normal anxiety-like behavior in the adult. Nature 2002;416:306–400.