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Generalized anxiety disorder (GAD) is one of the most common anxiety disorders in adults, affecting approximately 5% of the general population. It is often a chronic disorder and is associated with substantial impairment in quality of life. Additionally, GAD is frequently comorbid with depression and other anxiety disorders. Remarkably, when compared with other anxiety disorders, there is a striking lack of research into the biology of GAD.
Studies on the genetics, structural, and functional neuroanatomy, as well as neurochemistry of this syndrome are available, which are helping to paint a more coherent picture of the neurobiology of GAD. The overall lack of understanding of the underlying pathophysiology of GAD has been a major impediment in the development of novel treatment strategies.
This review is divided into two main sections: neurobiology and genetics of GAD. In the neurobiology section, structural and functional neuroanatomy, as well as neurochemistry (neurotransmitters) and neuroendocrine findings in GAD are described. In the genetics section, we summarize family, twin, and molecular genetic studies.
Neurobiology
Structural Neuroanatomy
Only a handful of imaging studies have specifically focused on brain structural abnormalities in children, adolescents, and adults suffering from GAD.1--5 Findings in pediatric samples have been very heterogeneous. In one study,2 GAD patients exhibited larger amygdala volumes than healthy controls; Milham et al.4 described the opposite finding. The latter group studied children with different anxiety disorders, including social phobia, GAD, and separation anxiety. Relative to healthy comparison subjects, the patients had reduced amygdala volumes. This reduction was most pronounced in the GAD patients. A third investigation1 observed increased gray and white matter volume in the superior temporal gyrus (STG), as well as a correlation of lateral STG white matter asymmetry with anxiety symptoms.
The two morphometric studies in GAD adults revealed similar results, namely increased amygdala volume.3,5 Moreover, Schienle et al.5 observed increased volume of the dorsomedial prefrontal cortex (DMPFC) in GAD patients. This volume increase was positively correlated with patients' scores on the Penn State Worry Questionnaire,6 a measure of GAD symptom severity.
In addition to the amygdalar abnormalities in GAD (increased volume and disrupted connectivity with cortical and subcortical regions), hippocampal alterations have been detected by magnetic resonance spectroscopy (MRS) measurements of local concentrations of the...