Epigenetics: Is DNA methylation a way forward in the treatment of anxiety?

Anxiety disorders typically have an early age of onset,1 and persist in various forms over the lifespan of patients. It is therefore a public-health challenge to find effective treatments to manage and if possible prevent these conditions. These challenges were addressed by Prof Stefano Pini, Italy, Dr Marcel Romanos, Germany, Prof Nicolas Singewald, Austria and Dr Miriam Schiele, Germany. 

The challenges of separation anxiety disorder

One example of a disorder that presents challenges at several levels is separation anxiety disorder (SAD). The lifetime prevalence of SAD is around 5%; persistence into adulthood is relatively common and more than 40% of patients report onset in adulthood.2

Symptoms in adults (e.g. stalking, suicidal ideation) are not the same as those in children. In addition, several features of this condition overlap with those of others, making differential diagnosis difficult. Moreover, patients and their friends and families adapt to their fears and collude in discounting them as a source of dysfunction in the patient, making even the description of symptoms a challenge. Nevertheless, based on the substantial prevalence of this condition, and on the risk to adult patients, there is an urgent need to develop effective treatments for it.


Epigenetics a possible key to new treatments

In the last decade, no new drug has been approved for an anxiety disorder, and those drugs that are available were developed originally as antidepressants. There is therefore a need to develop new drugs and treatment mechanisms for the anxiety disorders. One promising strand of research is in the interactions between genetic expression and the environment, that is epigenetic mechanisms. Two such mechanisms are histone acetylation and DNA methylation.3

Epigenetic mechanisms point to new treatments for anxiety

Histone deacetylases (HDAC) condense chromatin, and thereby turn off gene transcription. HDAC gene expression is up-regulated in the brains and blood of patients with depression and comorbid anxiety.4 In HAB mice selectively bred for anxiety-related behaviour, these animals showed reduced acetylation in the cingulate cortex. The hyper-anxiety of these mice on the light/dark compartment test could be attenuated by treatment with HDAC inhibitors. In addition, treatment with an HDAC inhibitor enhanced fear-inhibitory memory long-lasting, suggesting that such inhibitors could be a promising adjunct to exposure-based therapies in patients with anxiety.


DNA methylation as a marker of effective treatment

DNA hypomethylation of the monoamine oxidase A gene has been demonstrated in several anxiety disorders.5These methylation patterns have been shown to respond to the individual’s environment: negative events in the previous year were associated with a relative reduction in methylation and an increased risk for anxiety, and positive events with an increase in methylation and relative resilience to anxiety.6

DNA methylation may represent a dynamic marker of effective treatment of anxiety disorders


Treatment of anxiety disorders with CBT has been shown to be associated with an increase in DNA methylation at the MAO-A gene in responders, compared with non-responders. Therefore DNA methylation may represent a dynamic correlate of treatment success in these disorders. It is also possible that some treatments may promote resilience in individuals before the onset of anxiety disorders, via epigenetic mechanisms, providing a possible preventive treatment for anxiety.



  1. Beesdo-Baum K, Knappe S. Child Adolesc Psychiatr Clin N Am 2012;21(3):457–78.
  2. Silove D et al. Am J Psychiatry 2015;172(7):647–56.
  3. Schiele MA Clin Psychol Rev 2020;77:101830.
  4. Rey R et al. Mol Neurobiol 2019; 56(7): 4697–4707.
  5. Schiele MA et al Int J Neuropsychopharmacol 2018; 21(9): 822–27.
  6. Domschke K et al. Int J Neuropsychopharm 2012;15:1217–28.