Genetic Variation That Affects Fear and Anxiety May Advance Personalized Psychiatry

This finding, published March 3 in Nature Communications, could pave the way to establishing a psychiatric genetic biomarker, and shows the promise of precision medicine to advance patient care in the field.

Dr. Francis Lee

“You want to be able to design treatments for people where you have some precision in what you’re doing,” said co-senior author Dr. Francis Lee, a professor of psychiatry at Weill Cornell and a psychiatrist focusing on post-traumatic stress disorder (PTSD) at NewYork-Presbyterian/Weill Cornell Medical Center. If this discovery leads to the development of a genetic biomarker, “With one simple genetic test, you will be able to tailor the therapy you have for your patients.”

The research that resulted in this finding was led by Dr. Lee and Dr. BJ Casey, director of the Sackler Institute of Developmental Psychobiology at Weill Cornell, as well as co-first authors Dr. Iva Dincheva, Andrew Drysdale, Dr. Catherine Hartley and Dr. David Johnson at Weill Cornell, along with colleagues at the University of Calgary and the Scripps Research Institute. They started with prior knowledge of a common variation in a gene that is involved in processing the brain’s naturally-occurring marijuana-like substance – a cannabinoid – called anandamide. Named for the Sanskrit word for bliss, anandamide is known to have a calming effect when it binds itself to the brain’s cannabinoid receptors. When you have this genetic mutation, you have higher levels of anandamide. An op-ed article on this “Feel-Good Gene” and their research ran March 6 New York Times.

The genetic alteration that affects the fatty acid amide hydrolase (FAAH) gene and boosts anandamide is only found in humans, and although it has been known about and studied for a decade, earlier research determined only correlations between its existence and lower levels of anxiety and drug dependence. This study, which took a two-pronged approach and involved biochemical, neuroanatomical and behavioral research on mice and humans, is the first to establish a causational relationship between having the mutation and having improved fear extinction – the ability of let go of fear through exposure-based therapy – in both subjects. Researchers hope that this finding might someday lead to better, more-targeted treatment options for patients dealing with anxiety disorders and post-traumatic stress disorder (PTSD).

Cross-species approach to studying genetic polymorphisms
Image credit: Charles Glatt

“Fear extinction learning is an optimal behavior to test the FAAH polymorphism,” said Dr. Casey. “The brain circuits and behavioral expression of fear extinction are similar from mouse to human, and impaired fear extinction is the core problem in anxiety disorders and particularly PTSD, so anything we learn has clinical relevance.”

Now that researchers have a solid hypothesis about this mutation being a potential biomarker that indicates an individual’s ability to better deal with anxiety and respond to fear extinction therapy, the next step, Dr. Iva Dincheva, a postdoctoral fellow at Weill Cornell, said, is to set up clinical tests and look at patients who suffer from anxiety disorders or PTSD in a more focused way. These patients will likely respond to treatment differently depending on whether or not they have the FAAH mutation, and thus higher (or lower) levels of anandamide.

Knowing if a patient has this genetic variation, which can be determined through a simple spit test, becomes important when you talk about introducing drug treatment, Dr. Lee said. “If a patient has PTSD, before coming up with a treatment plan, you could conduct a simple genetic test and determine who might respond better or worse to these drugs.”

If a patient has the genetic mutation (20 percent of Americans of European descent do), he probably wouldn’t prescribe one of these drugs, Dr. Lee continued, because it wouldn’t be necessary. Instead, he might recommend a treatment approach that’s heavy on behavioral therapy, which would likely work very well. “With this approach, you’re doing a much more sophisticated type of algorithm in terms of how you treat your patients.”

While additional follow-up studies in a clinical population are necessary to determine if this mutation is actually a biomarker, “This is how you begin that process,” Dr. Lee said. And it’s an exciting start.

The research was supported by a generous gift by the Dr. Mortimer D. Sackler family, as well as by grant from the National Institutes of Health (MH079513, MH060478, NS052819, GM07739, EY007138, DA017259), the Pritzker Neuropsychiatric Disorders Research Consortium, the NewYork-Presbyterian Hospital Youth Anxiety Center, Brain and Behavior Research Foundation and DeWitt-Wallace Fund of the New York Community Trust.