Generalised Anxiety Disorder Health Article

Origin And Neurobiology

Anxiety is a normal human emotion that has analogues throughout the animal kingdom; to some degree, anxiety is probably of biological value. The higher prevalence of generalised anxiety disorder in women (almost double that of men) suggests an advantage of greater anxiety in the protection of offspring. However, patients with generalised anxiety disorder could have a specific cognitive bias that leads to increased attention to threat-related information and to misinterpretation of ambiguous stimuli as threatening: this bias has been shown to diminish with both cognitive behavioural therapy ³¹ and after selective serotonin reuptake inhibitor (SSRI) treatment. ³²

In 1977 it was discovered that the benzodiazepines interacted with a specific binding site in the CNS, which suggested that a natural substance (endogenous ligand) associated with benzodiazepines must be present in the brain. This binding site was found to be an integral part of the γ-aminobutyric acid A (GABA A) receptor complex, which was isolated and sequenced in 1987. ³³ GABA A is known to have 19 subunit variants, each encoded by a different gene; GABA A receptors are divided into eight different classes by sequence differences of the subunits.

The α1 subunit seems to be responsible for the sedative, amnestic, and anticonvulsant properties of benzodiazepines, whereas the α2 subunit appears to be involved in anxiolytic effects. The role of the α3 subunit is unknown. The α5 subunit has high density in the hippocampus and is involved in memory. GABA A receptor subtype agonists could therefore exert anxiolytic effects with a reduced risk of unwanted side-effects such as sedation. ³⁴ Tiihonen and colleagues ³⁵ showed decreased binding of a radiotracer ligand for GABA A receptors in the left temporal pole—an area involved in experiencing and controlling fear and anxiety. The GABA A receptor complex is affected by a cluster of genes on chromosome 5, ³⁶ but there is no evidence of any chromosomal abnormality specifically associated with generalised anxiety disorder.

There could be abnormalities of serotonergic and noradrenergic neurotransmission in patients with generalised anxiety disorder: ^36,37 for example, giving meta-chlorophenylpiperazine (a non-specific 5HT 1 and 5HT 2 agonist) to patients with this illness has been found to increase anxiety. ³⁸ Additionally, the reduced growth hormone response to clonidine (an α2 adrenoceptor agonist) seen in patients with generalised anxiety disorder suggests decreased α2 adrenergic receptor sensitivity, although this response was also seen in patients with major depression. ³⁹

Genetic studies suggest that generalised anxiety disorder and major depression could have a common genetic basis and that the environment affects their manifestation. ⁴⁰ Advanced genetic studies suggest that heterozygous GABA A γ2 subunit knockout mice are less sensitive to benzodiazepines, and display anxiety and hypervigilance, and show decreases in GABA A ligand binding throughout the brain, compared with normal mice. ⁴¹