The Brain’s Most Miserable Molecule

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How, you might ask, do antidepressants work?

The easy answer is: We don’t know.  This makes drug treatment for depression and anxiety a guessing game where a multitude of drugs are prescribed in a course of trial and error.  One person may respond to one drug and not another; it’s difficult to predict individual response.  It’s no wonder that people get frustrated and often give up taking meds altogether. Or get kicked off reality TV shows like “Celebrity Rehab”.

Recently scientists discovered a 3D structure of a brain protein receptor, CRF1, a molecule on the outside of cells on the pituitary gland, that releases CRF, hormones involved in regulating our stress response that over time contribute to anxiety and depression.

This is great news, because knowing the structure can help researchers make drugs that mimic CRF1 and block it’s capability of creating the hormone that causing the stress response.

CRF1 is made by the gene CRHR1. I looked up the gene to see if there are any significant known mutations.  In mice models, disruption of the gene (knocking it out, or mutating it) reduced anxiety-related behavior under both basal conditions and following alcohol withdrawal.  According to the Online Mendelian Inheritance in Man “The results demonstrated a key role of the Crhr1 receptor in mediating the stress response and anxiety-related behavior. CRH had been previously identified as a potent mediator of endocrine, autonomic, behavioral, and immune responses to stress and had been implicated in the stress-like and other adverse consequences of drug abuse, such as withdrawal from alcohol.”

Could this mean the end of television shows like “Celebrity Rehab” and “Intervention”? Probably not. Stress response is a necessary tool for survival, honed over time by evolution. We can’t knock out the gene in people, but drugs may be able to mimic the knockout response.

At this time, a gene test wouldn’t reveal much information, but there could be different forms of the gene that produce more or less amount of the protein.

Link to article on CFR1:

http://www.popsci.com/science/article/2013-07/scientists-identify-molecule-responsible-stress-and-anxiety

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Plane crash, Patty, and PTSD

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An Asiana plane from Korea crashed in San Francisco two days ago.  Two women were killed, and about 149 people were injured.  My gut reaction to the crash was concern for the survivors who would have to get back on a plane to go home.  I don’t know of any other way to get to Korea or China.  Some will have post-traumatic stress disorder, and it will be hard to board that flight home.

 

PTSD was defined in the 1980’s.  It was thought that the triggering event had to be beyond the range of normal human experience- very unusual events. Patty Hearst’s trial in 1976, pre-PTSD, used the phrases “Stockholm Syndrome” and “POW Survivor Syndrome”. She had been kidnapped and raped by the Symbionese Liberation Army, and participated in an armed robbery.  Her experience wasn’t unusual enough for the jury, and they convicted her. I was 11 years old at the time and was surprised by the conviction. Even a little kid could figure out that Patty wasn’t fully in control. (Jimmy Carter, a President who was often ridiculed for being a “Peanut Farmer”, had the intelligence to commute Patty’s sentence after she served 22 months in prison.)

 

Later it was figured out that traumatic stress is not that unusual- 50% of Americans experience some traumatic stress in their lifetimes (in other countries where civil unrest is common, the incidence is higher). I’m the 50%.  In my teens, I was the victim of a home invasion, was tied up and robbed at gunpoint. I can’t describe the feeling that someone you don’t know is going to kill you for a pointless reason (money). I declined the police request to look at mug shots because the robbers said they would come back and kill me and my roommates if we reported them.  Within a week I denied the robbery even happened to an inquisitive workmate.  The denial was out of my mouth before I was even aware of it.  I didn’t mention the robbery for ten years- I couldn’t.  Sometimes I would hear young guys brag about how they would take a gun away from someone, and I would go mute.  When I finally did tell a friend about it, I was still as a stone, no emotion at all.  It was the only way I could get it out, as if I was reporting on a story that happened to someone else.  Twenty years after the robbery, I had a friend show me how to use his gun.  When we went to get ammo I walked out of the gun store and sat on the curb, hyperventilating. I can’t imagine what it’s like to deal with combat stress.

 

There is evidence for genetic predisposition for PTSD. Twin studies have all shown monozygotic twins to have significantly higher concordance for PTSD than dizygotic twins, resulting in heritability estimates in the range of 30% to 40%. Women have higher rates of PTSD- At least 1 in 9 American women and 1 in 20 American men will meet criteria for the diagnosis in their lifetime. There’s no gene test, so we can’t know who will come back from Iraq with the disorder.

The good news is that PTSD is treatable, and a grief counselor was available for some of the plane crash survivors. Hopefully all the passengers will get some counseling in the near future to help with the long term effects of the crash.

 

Article on PTSD genetics: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108177/

 

Good info on PTSD: http://www.pbs.org/wgbh/pages/frontline/shows/heart/themes/ptsd.html

 

“I mean, they call it Stockholm Syndrome and post-traumatic stress disorder. And, you know, I had no free will. I had virtually no free will until I was separated from them for about two weeks.” Patty Hearst