Etiology and Pathophysiology
Family studies suggest a familial (and probably a genetic) ba-sis for certain anxiety disorders such as panic disorder. Genetic transmission of a disorder suggests that certain gene-encoded changes in proteins and the resulting biological abnormalities may play a role in the pathophysiology of specific disorders. Skre and collaborators (1993) examined 20 monozygotic and 29 dizy-gotic twins with DSM-III-R-defined GAD. They found GAD to be diagnosed in 22% of first-degree relatives of 33 probands with anxiety disorders. In the largest twin study to date which included 1033 female twin pairs, Kendler and associates (1992) found that genetic factors play a significant, but not overwhelming role in the etiology of GAD, with the heritability of GAD estimated at around 30% in comparison to 70% heritability in major depres-sion. In addition, the authors found that the vulnerability to GAD and major depression is influenced by the same genetic factors. In short, the available data suggest at most a modest genetic con-tribution to the etiology of GAD.
Relatively few studies have addressed issues regarding the bio-logical aspects of GAD. Existing studies have focused on the evaluation of catecholamine and autonomic responses, neu-roendocrine measures, sleep, neuroanatomical/neuroimaging studies, infusion studies and evaluation of other neurotrans-mitter systems. There is not strong evidence for abnormalities in catecholamine or thyroid function in GAD patients. Some studies have shown a higher prevalence of an “escape” (non-suppression) response in following dexamethasone adminis-tration (that was not attributable to the presence of depression) in GAD patients when compared with normal comparison subject. These data indicate that there may be dysregula-tion of the HPA axis in these patients, as observed following dexamethasone.
Although restless and decreased sleep are common com-plaints in GAD patients, there have been only a few polysom-nographic studies in this patient population. There is some ev-idence suggesting that patients with GAD have a longer rapid eye movement (REM) latency, shorter REM duration, increased sleep onset latency and less total sleep time compared with con-trol subjects (Papadimitriou et al., 1988). These findings may dif-ferentiate patients with GAD from patients with depression, who show shorter REM latencies.
Alterations in different neurotransmitter systems have been implicated in the pathophysiology of various anxiety dis-orders. It is generally accepted that anxiety disorders are not as-sociated with abnormalities in only one neurotransmitter system; rather dynamic interactions among several different neurotrans-mitter systems are believed likely to underlie different anxiety states. Presently, there are data suggesting that the catecholamine serotonin and GABA-benzodiazepine systems may be involved in the pathophysiology of anxiety disorders.
Benzodiazepines have been the treatment of choice for many patients with GAD. They act at specific recognition sites in the brain, the benzodiazepine receptors, which are located in a subu-nit of a receptor for gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain. Several lines of evidence suggest that the GABA-benzodiazepine re-ceptor complex may be involved in the mediation of anxiety responses. Studies with animals suggest a relationship be-tween benzodiazepine receptors, and fear and anxiety. Mod-els using gamma-2 knockout mice have shown a reduction in GABAA receptor clustering in the hippocampus and cerebral cortex along with behavioral inhibition to aversive stimuli and increased responsiveness in trace fear conditioning (Lesch, 2001).
Alterations in serotonergic (5-HT) neurotransmission have been implicated in the mediation of fear and anxiety responses in ani-mal models and in humans. Specifically, researchers hypothesize that anxiety may represent dysregulated serotonergic activity in critical brain areas. Given the available data, whether overactivity or underactivity of the 5-HT system is the mechanism for GAD development remains unclear.
Cholecystokinin (CCK), a highly abundant neurotransmitter in the brain, has also been implicated in anxiety in humans. CCK may be possibly involved in the pathophysiology of panic dis-order and may also play a role in the biology of GAD. Cortico-tropin-releasing factor (CRF), a major physiological regulator of adreno corticotropic hormone (ACTH), appears to be involved in stress and anxiety responses. Administration of CRF to various parts of animal brains has elicited anxiety and fear responses, e.g., suppression of exploratory behavior, shock-induced freez-ing. Interestingly, both these peptides are functionally antago-nized by benzodiazepines. Neuropeptide Y, glutamate and tachy-kinins may also play a role in anxiety.
Several potential neuroanatomic anxiogenic sites in the central nervous system (CNS) have been proposed based on brain imag-ing and neuroanatomic studies. The areas potentially involved in anxiety are the parts of the limbic system involving the hippoc-ampus, prefrontal cortex, occipital lobes, basal ganglia and brain stem structures, specifically the locus coeruleus, nucleus para-gigantocellularis and periaqueductal gray (Gray, 1988). These structures are rich in noradrenergic, GABAergic and serotoner-gic receptors which are believed to be involved in the pathophysi-ology of different anxiety states such as GAD.
Only a few imaging studies in GAD have appeared in the lit-erature. In one study, patients with GAD displayed decreases in cortical blood flow compared with control subjects. Significant negative correlations between state anxiety and cerebral blood flow in most brain regions were observed. Wu and colleagues (1991) evaluated 18 patients who met DSM-III criteria for GAD using positron emission tomography (PET) measurements of cerebral glucose at “baseline” (during a passive viewing task), following a cognitive vigilance task designed to stimulate anxi-ety, and following treatment with benzodiazepines. They found a higher relative metabolic rate for GAD patients in parts of the oc-cipital, temporal, frontal lobes and cerebellum relative to normal control subjects during a passive viewing task. The authors also found a decrease in absolute basal ganglia metabolic activity in GAD patients. During the vigilance task, GAD patients showed a significant increase in relative basal ganglia metabolism. The authors did not find a global decrease in cortical metabolism, as had been predicted by blood flow studies. Finally, benzodi-azepine treatment resulted in a significant decrease in glucose metabolism in cortical surface (especially in the occipital cortex), the limbic system and basal ganglia compared with patients re-ceiving placebo.
MRI and SPET studies have found that those with GAD have decreased benzodiazepine receptor binding in the left tem-poral pole as compared with matched healthy controls. In a study using functional MRI in GAD patients, Lorberbaum and col-leagues (2001) found greater activity in the right cingulate, right medial prefrontal and orbitofrontal cortex, right temporal poles and right dorsomedial thalamus, during periods of anticipatory anxiety, compared with rest periods, than matched control sub-jects. Further, only matched control subjects displayed increased activity in the medial prefrontal cortex.