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Anxiety disorders are prime candidates for biological investigation. If one accepts the notion, for example, that fear in animals is a reasonable facsimile of anxiety responses in humans, then we already have an impressive preclinical neurobiology from which to draw scientific ideas. Neuroscientists such as Joseph LeDoux and Michael Davis have shown convincingly that conditioned fear in rodents and other species is absolutely dependent on intact function of the central nucleus of the amygdala and its afferent brain stem projections, while the ability to appreciate the contextual aspect of fear requires neurons in the hippocampus. This opens the way for us to use modern brain imaging techniques to describe a coherent neuroanatomy of anxiety in humans. Studies of enduring disruption in normal hypothalamic-pituitary-adrenal axis function in animals exposed to separation distress during infancy by scientists such as Paul Plotsky and Jeremy Coplan offer fascinating overlaps with observations made in studies of the development of anxiety disorder in humans from childhood to adulthood. Hence, one feels assured that brain imaging, molecular biology, and advanced genomics will give us substantial advances in understanding the anxiety disorders.
Despite this justified excitement in the potential for basic and applied neuroscience, four articles in this month's Journal once again show us that phenomenology, epidemiology, and rigorous clinical observation remain indispensable tools if we are to make progress in understanding pathological anxiety. Each one of these papers raises points that scientists and clinicians alike wonder about and wish someone would address. In each case, the data provided have the potential both to be clinically useful and to guide neurobiological investigation.
Posttraumatic stress disorder (PTSD) is the only anxiety disorder with a known cause. In previous incarnations of DSM, it was assumed that if exposed to a properly horrifying traumatic event, anyone would be expected to develop PTSD. This notion has proven untenable as studies repeatedly show that only a subgroup of individuals exposed to the same qualifying event develop PTSD. Classen et al., for example, found that only 12 (33%) of 36 people involved in a terrifying mass murder in a California office building developed the acute form of PTSD, now called acute stress disorder in DSM-IV. The presence of acute stress disorder, and particularly the symptom of dissociation, predicted the development of PTSD symptoms at 7- to 10-month follow-up. We now need to discover what factors—perhaps genetic—interact with traumatic events to produce syndromal PTSD.
Social phobia has been studied less than other anxiety disorders, a significant problem given the fact that the disorder affects more than one in eight people and carries with it a substantial burden of functional impairment and substance abuse. There has been a tendency to trivialize social phobia; many ask if the common fear of speaking in public ought to be included as a psychiatric illness. In this issue, Murray Stein teams up with Ronald Kessler and Patricia Berglund to tap the rich National Comorbidity Survey to ask whether pure speaking phobia is really as serious as more extensive social phobia. Perhaps not surprisingly, they found that "social phobia characterized by pure speaking fears was less persistent, less impairing, and less highly comorbid.than was social phobia characterized by other social fears." This puts the social phobia situation in needed perspective and also shows us how the National Comorbidity Survey can be used. The National Comorbidity Survey yields very high rates of psychiatric illness in the population: approximately 50% of all people meet lifetime criteria for at least one DSM-III-R diagnosis. On the other hand, not all of these people are seriously ill, impaired, or even in need of clinical attention. Although the rates of serious psychiatric illness in the population turn out to be staggeringly high, the National Comorbidity Survey helps us sort out which clinical scenarios are most likely to require the most urgent attention.
Panic disorder, first described in detail as a unique entity by Donald Klein, has been the subject of an enormous amount of research and is now one of the most eminently treatable of all psychiatric illnesses. Nevertheless, many clinical observations persist in bedeviling the field. One of them is why panic disorder should be more common in women than in men. A second is whether panic disorder involves abnormal genes. Neither of the two papers on panic disorder in this issue can answer those questions, but both provide information that may keep us on track. Using the Harvard/Brown Anxiety Disorders Research Program, a national treasure directed by Martin Keller, Yonkers et al. examined 412 men and women with panic disorder over a period ranging up to 5 years. They found that although the rates of remission were equivalent in men and women, symptomatic recurrence was nearly twice as likely at some point in the follow-up period in women than in men. Their speculation that this may be because of fluctuations in the putative endogenous anxiolytic progesterone is intriguing and, if true, could help to explain the difference in prevalence as well. Battaglia et al., an outstanding research group from Milan, obtained direct family history information from 38 families, looking for evidence of anticipation—the tendency for subsequent generations to develop an illness at an earlier age. This phenomenon has been found in a number of other medical conditions and is believed to be linked to a specific type of genetic abnormality, trinucleotide repeat mutations. Using several methods of analysis and attempting to control for the myriad known confounding variables in this kind of investigation, they indeed found earlier age at onset in the younger than in the older generation for both the first panic attack and for panic disorder. We already know that panic disorder is one of the most highly "familial" of all psychiatric illnesses; does this prove that it is a "genetic" illness? Hardly, because one can still conceive of many pitfalls in the search for anticipation in any psychiatric illness, including the simple fact that people may not accurately remember when they had their first panic attack, and also of nongenetic reasons why the son or daughter of a panic disorder patient may have a first panic attack at an earlier age than his or her parent. Still, the work is careful, and the results are presented cautiously. The likely result will be renewed interest in trying to locate chromosomal markers and abnormal genes for panic disorder.
Anxiety disorders are both very common and very treatable. Our next task will be to bring the insights already accumulated from the preclinical laboratory to bear on the search for the pathophysiology of anxiety. In the meantime, each of these four studies is a reminder that the scientific approaches that have gotten us so far in modern psychiatry, including careful diagnosis and epidemiology, remain powerful tools.
Address reprint requests to Dr. Gorman, Department of Psychiatry, Columbia University, 722 West 168th St., New York, NY 10032.
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