Abstract
Mental disorders form a broad category of disease that may manifest as emotional or behavioural changes. These disorders are common globally and account for a significant amount of morbidity. The most frequently occurring major category of mental disorder is the anxiety disorders, which manifest as acute (panic attacks) and/or chronic (persistent worry) anxiety.
Mental disorders can be viewed as structural or chemical changes in the brain that result from a combination of genetic and environmental risk factors. Fear and stress pathways are thought to contribute to the development of anxiety disorders, as are specific neurotransmitters and neuromodulators such as serotonin, GABA (γ-amino butyric acid), cholecystokinin and adenosine. Despite this knowledge, there is still much to learn about the pathogenesis of anxiety and pharmacotherapeutic action of the drugs used to treat it.
One means of investigating both of these areas is to study candidate genes. For example, cholecystokinin is a peptide that can induce panic attacks in both normal volunteers and panic disorder patients; the genes for cholecystokinin (CCK) and its two receptors (CCKAR and CCKBR) are, thus, good candidates for anxiety pathogenesis and treatment.
The aims of the present study were to determine whether common variation in any of the cholecystokinin system genes is associated with panic and whether expression levels of any candidate genes were altered in neuroblastoma cell lines following 28-days exposure of antidepressant drugs that have anxiety reducing (anxiolytic) effects.
The three genes from the cholecystokinin system were genotyped in a New Zealand family-based cohort (563 subjects) and analysed for association with panic and related phenotypes. HapMap data was used to select multiple variants within each gene ensuring good coverage of common variation. Significant associations were found with multiple CCKBR variants and panic, some of which met the adjusted significance threshold. Further analyses suggested that CCKAR variation might be associated with a co-morbid panic and bipolar disorder phenotype, though further research would be needed to confirm this.
Antidepressant drugs are among the most commonly prescribed treatments for the long-term control of anxiety, however, there has been little research into their anxiolytic effects and even less on the anxiety-increasing effects seen in some patients early in treatment. Thus, gene expression changes of a list of 20 candidate genes were investigated in three different neuroblastoma cell lines during a 28-day time course. The two most consistent changes were down-regulations of two-fold or more in the genes ADORA2A (encoding an adenosine receptor) and CCKAR. Both of these changes began early in the time course, and functional evidence from other studies suggests that the reduced expression may have anxiety-increasing effects. Subsequent protein quantification studies supported a reduction in levels of the adenosine A2a receptor. Thus, changes in one or both of these genes may be involved in the early anxiogenic effects of antidepressants.
A better understanding of both the pathogenesis and treatment of anxiety disorders is important as it may lead to improved diagnosis and treatment of high-risk individuals. This, in turn, should reduce the burden these common diseases cause to both affected individuals and to the broader society.