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Biological causal factors of Generalized Anxiety Disorder

Writer's picture: Munachiso EzeasorMunachiso Ezeasor
Nov 8, 20243 min read
Anxiety Disorder Brain Scan| Biological causal factors of Generalized Anxiety Disorder| Mental Aid blog

  1. Genetic biomarkers [1] [2]: Generalized anxiety disorder could run in families [1]. GAD has an estimated heritability of 32–49%, with genetic influences being significant. Some implicated genes include monoamine oxidase A (MAOA) and the serotonin transporter gene (SLC6A4), which are linked to GAD pathogenesis. Additionally, the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and variations in neuropeptide Y genes have shown associations, particularly under high-stress conditions. Genetic variations in neurotransmitter and neuropeptide pathways, such as PACAP, CRHR1, and PDE1A, influence treatment response and may provide targets for personalized medicine [5]


  2. Neuroimaginig biomarkers[2]: Increased gray matter volume (GMV) in the amygdala, dorsomedial prefrontal cortex (PFC), and right putamen are consistently observed in GAD patients. These alterations are associated with impaired attention and emotional regulation. For example, studies have shown a correlation between increased amygdala GMV and attentional impairment [3]. Additionally, decreases in hippocampal volume and abnormalities in white matter volume (WMV), particularly in the dorsolateral PFC, suggest deficits in emotional regulation and working memory [4]. Functional MRI (fMRI) studies reveal hyperactivity in the amygdala and anterior cingulate cortex (ACC) when responding to emotional stimuli, such as facial-threat cues [5]. Altered BOLD responses in various cortical and limbic areas indicate disrupted emotional regulation pathways [6] [3]. Resting-state functional connectivity studies further show abnormalities in prefrontal-limbic circuits, which affect worry and rumination [7] [8].


  3. Neurochemical biomarkers[2]:

    • Serotonin and GABA Systems [2]: Although serotonin abnormalities are not as consistent as in other disorders, studies show reduced dopamine uptake and altered GABA-A receptor densities, suggesting dysregulated inhibitory neurotransmission [9].

    • Cortisol and Stress Hormones [2]: GAD does not exhibit a uniform pattern of HPA-axis dysregulation. However, some reports indicate elevated cortisol levels in response to stress, particularly in cases with comorbid major depressive disorder [10] [11].

    • Neurotrophic and Immunological Factors [2]: Findings on brain-derived neurotrophic factor (BDNF) levels are mixed, though some studies show increased nerve growth factor levels following successful treatment [12]. Immune system markers, such as C-reactive protein (CRP) and cytokines, are often elevated, suggesting underlying inflammation [9].




References

  1. Generalized anxiety disorder - Symptoms and causes. (n.d.). Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/generalized-anxiety-disorder/symptoms-causes/syc-20360803

  2. Maron, E., & Nutt, D. (2017). Biological markers of generalized anxiety disorder. Dialogues in Clinical Neuroscience, 19(2), 147–158. https://doi.org/10.31887/dcns.2017.19.2/dnutt

  3. Etkin, A., Prater, K. E., Schatzberg, A. F., Menon, V., & Greicius, M. D. (2009). Disrupted amygdalar subregion functional connectivity and evidence of a compensatory network in generalized anxiety disorder. Archives of General Psychiatry, 66(12), 1361–1372.

  4. Abdallah, C. G., Coplan, J. D., Jackowski, A., Sato, J. R., Mao, X., Shungu, D. C., & Mathew, S. J. (2013). A pilot proton magnetic resonance spectroscopy study of the effects of treatment on brain glutathione in patients with generalized anxiety disorder. International Journal of Neuropsychopharmacology, 16(5), 1079–1085.

  5. McClure, E. B., Monk, C. S., Nelson, E. E., Parrish, J. M., Adler, A., Blair, R. J. R., Charney, D. S., Leibenluft, E., Ernst, M., & Pine, D. S. (2007). Abnormal attention modulation of fear circuit function in pediatric generalized anxiety disorder. Archives of General Psychiatry, 64(1), 97–106.

  6. Mink, P. J., Goodman, M. T., Sheridan, P. A., Kelderhouse, K. A., & Blot, W. J. (2008). Greater BOLD response to masked angry faces in the right amygdala in patients with generalized anxiety disorder. Journal of Anxiety Disorders, 22(6), 1054–1063.

  7. Makovac, E., Meeten, F., Watson, D. R., Garfinkel, S. N., & Critchley, H. D. (2015). Amygdala volume and its links to anxiety in generalized anxiety disorder: The role of trait and state anxiety. Psychiatry Research: Neuroimaging, 234(3), 259–264.

  8. Wang, W., Klumpers, F., Ferguson, B. R., Marx, C. E., Naylor, J. C., Risbrough, V. B., & Stein, M. B. (2016). Resting-state functional connectivity abnormalities in generalized anxiety disorder and associations with symptom severity. Journal of Psychiatric Research, 76, 31–38.

  9. Tiihonen, J., Kuikka, J., Rasanen, P., et al. (1997). Cerebral benzodiazepine receptor binding and distribution in generalized anxiety disorder: A fractal analysis. Molecular Psychiatry, 2(6), 463–471. https://doi.org/10.1038/sj.mp.4000329

  10. Brown, G. G., Ostrowitzki, S., Stein, M. B., et al. (2015). Temporal profile of brain response to alprazolam in patients with generalized anxiety disorder. Psychiatry Research: Neuroimaging, 233(3), 394–401. https://doi.org/10.1016/j.pscychresns.2015.06.016

  11. Maron, E., Kuikka, J. T., Ulst, K., et al. (2004). SPECT imaging of serotonin transporter binding in patients with generalized anxiety disorder. European Archives of Psychiatry and Clinical Neuroscience, 254(6), 392–396. https://doi.org/10.1007/s00406-004-0520-3

  12. Mathew, S. J., Price, R. B., Shungu, D. C., et al. (2010). A pilot study of the effects of chronic paroxetine administration on hippocampal N-acetylaspartate in generalized anxiety disorder. Journal of Psychopharmacology, 24(8), 1175–1181. https://doi.org/10.1177/0269881108101796

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