The Natural History of Generalized Anxiety Disorder: A Review

Catherine L. Woodman, MD


Medscape Psychiatry & Mental Health eJournal. 1997;2(3) 

In This Article

Familial Transmission

In psychiatry, where few biologic markers for disease exist, family and follow-up studies provide the scientific infrastructure for diagnosis and classification. Familial transmission is a strong validator of psychiatric syndromes. Schizophrenia and bipolar spectrum disorders provide good examples of this principle. Studies of families have shown that these illnesses breed true--that probands with one illness have increased numbers of relatives with that illness, but not with other psychiatric disorders.[12,13,14] Family studies can also determine whether subsyndromal cases of a disorder are transmitted familially. In this way, family studies can provide validation of the existence of disease entities and contribute to defining their diagnostic boundaries. The importance of diagnosis and classification has taken on new meaning in the era of molecular genetics, because in order to succeed, strategies that aim to find disease genes require biologically valid phenotypes.

Family studies of the individual anxiety disorders have found that there is an elevated risk of the index anxiety disorder in first-degree relatives, but that other anxiety disorders are not increased.[15,16,17,18,19,20,21,22] These studies, however, have been done using clinical populations and probands with only one disorder.

Two studies have examined the transmission of GAD in families. They both used clinic populations of probands without comorbid illness, and looked at the transmission of more than one type of anxiety disorder. Noyes and colleagues[19] compared first-degree relatives of 20 probands with GAD, 20 with panic disorder without agoraphobia, 20 with agoraphobia, and 20 controls. They found that each disorder was transmitted to relatives at a significantly higher rate and that other anxiety disorders were not, indicating that there is a distinction between the 3 disorders and that there may be a genetic component to the illness.

Mendelwitz and associates[23] compared the first-degree relatives of 25 probands with panic disorder without agoraphobia, 25 with GAD, 25 with major depressive disorder (MDD), and 25 normal controls. Unfortunately, the panic disorder probands were diagnosed using the Structured Clinical Interview for DSM-III (SCID) and DSM-III criteria, whereas the GAD and major depressive disorder probands were diagnosed using the Schedule for Affective Disorders and Schizophrenia (SADS-LA) and Research Diagnostic Criteria (RDC). The correlation between instruments is not well established, and the impact that it had on this study is not known. This study found that the relatives of panic disorder probands had panic disorder at rates significantly higher than the relatives of GAD, MDD, and control probands, and that they did not have higher rates of GAD, MDD, or agoraphobia. They did not find an elevated risk of GAD in the relatives of GAD probands or of MDD in the relatives of MDD probands, in contrast to previous family studies.[19,24] Table III summarizes the available data from family studies of anxiety disorders.

Twin studies of anxiety disorders have, for the most part, been general-population studies, and probands may have had more than 1 anxiety disorder diagnosis as well as major depression. While this is more representative of how these disorders occur in clinical populations as well as in the general population, these studies have not been easy to reconcile. Slater and Shields[25] reported on a twin study of anxiety neurosis which found that 7 of 17 monozygotic (MZ, "identical") twin pairs (41%) were concordant for anxiety neurosis, compared with 1 of 28 dizygotic (DZ, "fraternal") pairs (4%). The study by Torgersen[26] of anxiety in twins was gathered from a nationwide study in Norway of adult same-sex twins who had been treated for a psychiatric disorder in the 1970s. Torgersen found no difference in concordance between MZ and DZ twins for GAD, but the number of affected twins was small in this study.

In a larger study, Andrews and coworkers[27] evaluated anxiety disorders in 446 pairs of same-sex and opposite-sex twins from the Australian twin registry. The mean age and the sex distribution were not reported. The investigators found a concordance rate for GAD of 21.5% (13/63 twin pairs) in MZ twins, compared with a 13.5% (11/81) concordance rate in DZ twins. The differences were not statistically significant, but the numbers were small, and, in contrast to Torgersen's findings, the trend in this study was towards a greater concordance for GAD among MZ twins than DZ twins. Similarly, Kendler and associates[28,29] examined 1033 same-sex female twin pairs from the Virginia twin registry and found statistically significant evidence for a genetic effect in GAD. However, they did not use DSM-III or DSM-IV criteria exclusively--they used 9 different sets of diagnostic criteria, searching for the criteria that revealed the largest genetic effect. For example, they found that a 1-month duration criterion, which was used as the duration criterion in DSM-III, was more heritable than the 6-month duration criterion used in DSM-III-R and DSM-IV. This study did evaluate comorbid diagnoses and found that GAD was heritable regardless of comorbid anxiety disorders or depression.

The twin studies, like the family studies, do not agree on the heritability of GAD. The larger studies have found a greater genetic contribution, but there is clearly an environmental component as well. Studying adoptees who were separated from their biological families at birth and reared by adoptive families is an excellent method of evaluating genetic and environmental influences independent of one another. Unfortunately, there have not been any adoption studies of anxiety disorders. It is difficult to do adoption studies for chronic but less incapacitating illnesses, such as anxiety disorders, where patients are infrequently hospitalized and reliable data are harder to obtain. In the absence of a genetic marker for GAD, we are left with family and twin studies. A likely explanation of the differences in findings between these studies is that when genetic effects are modest, as they appear to be with GAD, larger samples and more severely ill samples are required to identify them.


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