How Genes Could Predict Who Will Get PTSD

National Journal
Aug. 13, 2014, 9:41 a.m.

Can you screen for posttrau­mat­ic stress dis­order in the same way you screen for breast can­cer? A new pa­per from re­search­ers at the Mount Sinai School of Medi­cine sug­gests that gene ex­pres­sion could re­veal which in­di­vidu­als are most likely to de­vel­op PTSD, a de­vel­op­ment that could ac­cel­er­ate the search for a ther­apy to ef­fect­ively pre­treat the dis­order through a pill.

The re­search­ers from the Icahn School of Medi­cine at Mount Sinai took a group of male and fe­male rats and trau­mat­ized them by ex­pos­ing them to the smell of cat ur­ine. Sev­en days later, the re­search­ers sep­ar­ated those rats that were dis­play­ing PTSD-like symp­toms from those that coped with the stress­ful event. An ana­lys­is of the gene ex­pres­sion in the an­im­als showed sup­pressed glu­c­o­cor­tic­oid re­cept­or sig­nal­ing in their brain and blood of the PTSD-stricken ro­dents.

The way your glu­c­o­cor­tic­oid re­cept­ors sig­nal in the face of trau­mat­ic stim­uli af­fects the way the hip­po­cam­pus and the amy­g­dala pro­cess the memory of events. The hip­po­cam­pus serves, in a way, as the brain’s Google. When a per­son is con­fron­ted with new ex­per­i­ences in the form of visu­al, aud­it­ory, and oth­er stim­uli, it’s the hip­po­cam­pus that searches through the brain’s memory to find rel­ev­ant files to in­form the per­son’s re­sponse. Loud noise = ex­plo­sion = run. The amy­g­dala con­trols the brain’s fear level, ef­fect­ing how we ex­per­i­ence stim­uli and how charged are our memor­ies after the fact. To carry the Google meta­phor a bit fur­ther, the amy­g­dala af­fects page rank. Glu­c­o­cor­tic­oid re­cept­or sig­nal­ing can change the way all of these parts of the brain work to­geth­er. The re­search re­vealed some of the path­ways and net­works of gene ex­pres­sion that al­low the re­cept­ors to go off track.

“We meas­ured 22,500 genes and when you meas­ure all those genes you can do com­pu­ta­tion­al ana­lys­is that gives you the tran­scrip­tion factors and the path­ways. So what you can do is you can un­der­stand, through com­pu­ta­tion, what the net­works are,” Dr. Rachel Ye­huda, dir­ect­or of the Trau­mat­ic Stress Stud­ies Di­vi­sion at Icahn School of Medi­cine at Mount Sinai and the study’s lead au­thor, told De­fense One.

Here’s what Ye­huda’s re­search means: We’re one step closer to treat­ing PTSD long be­fore it ru­ins the lives of those it af­fects and, in the case of sol­diers, costs the gov­ern­ment a lot of money. To fur­ther test their the­ory, the re­search­ers gave some of the rats a hor­mone called cor­ticos­t­er­one, (CORT “” equi­val­ent hor­mone of cortisol for ro­dents) about an hour after ex­pos­ing them to the cat ur­ine. They then re­tested them sev­en days later and found “in both sexes, CORT pre­vent­ive treat­ment was as­so­ci­ated with lower anxi­ety be­ha­vi­or in [pred­at­or-scent-stress-ex­posed] rats,” ac­cord­ing to their pa­per, “Ex­pres­sion Pro­fil­ing As­so­ci­ates Blood and Brain Glu­c­o­cor­tic­oid Re­cept­or Sig­nal­ing With Trauma-Re­lated In­di­vidu­al Dif­fer­ences in Both Sexes,” which was pub­lished in the Pro­ceed­ings of the Na­tion­al Academy of Sci­ences on Aug. 11.

The re­la­tion­ship between low cortisol, stress, and sus­cept­ib­il­ity to PTSD has been es­tab­lished for dec­ades, but ther­apies that use cortisol to pre­vent or pre­treat stress are still in the ex­per­i­ment­al phase, and some of the most am­bi­tious work is tak­ing place out­side of the United States.

To un­der­stand the fu­ture of PTSD dia­gnostics, you have to go to an emer­gency room in Is­rael.

Pic­ture an Is­raeli sol­dier walk­ing in­to a hos­pit­al after a rock­et at­tack. He’s dis­play­ing minor cuts but he’s more agit­ated than some of the oth­er vic­tims who have come in with far worse in­jur­ies. An at­tend­ing doc­tor gives the pa­tient a pill, not a sed­at­ive to change his mood but an ex­per­i­ment­al cortisol ther­apy, in the hopes of chan­ging the way the sol­dier’s brain is pro­cessing the event. If the treat­ment is suc­cess­ful, the memory of the bomb­ing has be­come less sa­li­ent and will lose its emo­tion­al charge. A per­son who would have de­veloped PTSD is spared the af­flic­tion. It’s re­search that Ye­huda has been col­lab­or­at­ing with on for about three years now un­der Joseph Zo­har, head of the psy­chi­atry de­part­ment at Is­rael’s Sheba Med­ic­al Cen­ter. The re­search is fun­ded by the Na­tion­al In­sti­tute of Men­tal Health.

Ye­huda’s work takes that re­search to an im­port­ant new level, help­ing, po­ten­tially, to en­sure that that ther­apy only goes to those in­di­vidu­als who would be­ne­fit from it so doc­tors aren’t juicing people’s cortisol levels willy-nilly. “The prob­lem in the idea of giv­ing a pro­phy­lact­ic treat­ment is that you don’t want to fix what isn’t broken. You wouldn’t want to try and pre­vent PTSD in someone you didn’t think was go­ing to get it.”

She says that a hand­held dia­gnost­ic tests cap­able of telling a mil­it­ary med­ic or an emer­gency-room nurse if the pa­tient that they’re deal­ing with is a good can­did­ate for a cortisol pill is tech­no­lo­gic­ally pos­sible today, but un­achiev­able without more data.

The De­fense De­part­ment has put ap­prox­im­ately $600,000 in­to Ye­huda’s re­search so far, through the award of an ini­tial concept grant of $150,000 and a sup­ple­ment­al grant of $450,000, and has in­ves­ted mil­lions more in clin­ic­al stud­ies.

Any dis­cus­sion of ge­net­ic dia­gnostics should touch on the policy im­plic­a­tions of know­ing which in­di­vidu­als are more or less sus­cept­ible to ill­nesses on the basis of mo­lecules. Is it pos­sible to sub­ject po­ten­tial mil­it­ary re­cruits to a ge­net­ic screen in or­der to de­term­ine which sol­diers have the greatest chance of de­vel­op­ing PTSD? Is it really so dif­fer­ent from the way that cer­tain ge­net­ic mark­ers such as the BRCA1 and the BRCA2 gene can in­dic­ate an el­ev­ated like­li­hood for de­vel­op­ing breast can­cer?

A ge­net­ic PTSD pre­screen­ing is pos­sible, but Ye­huda says it’s not the best use of the data (and cer­tainly not the goal of her re­search.) “Mo­lecu­lar in­form­a­tion alone should not de­term­ine someone’s fate,” she said. “The in­form­a­tion from gene ex­pres­sion is more use­ful as dia­gnos­is rather than a pre­dic­tion of you who you might be “¦ be­cause there are so many factors.”

In the same way that are there many ways to cope with an el­ev­ated risk for de­vel­op­ing breast can­cer (and also to avoid it without a mam­mo­graphy), so too can in­di­vidu­als take steps to pre­vent the de­vel­op­ment of PTSD even if they want to serve in high-stress en­vir­on­ments. “Gene ex­pres­sion bio­logy is not des­tiny. You can make be­ha­vi­or­al changes and oth­er changes “¦ even psy­cho­ther­apy can change these glu­c­o­cor­tic­oid mark­ers,” Ye­huda said. “We’re not us­ing those net­works to pre­dict the fu­ture. We’re us­ing the data to de­scribe the present mo­ment.”

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