An already-approved muscle relaxant may offer relief for U.S. military veterans and first responders suffering from combat-related post-traumatic stress disorder (PTSD). The Phase 2 trials of the drug, TNX-102 SL, which contains the same chemical property as Flexeril, identified a dose and administration method that statistically improved participants’ PTSD symptoms among several mental health indices.
The findings were announced this month at the American Society of Clinical Psychopharmacology Annual Meeting (ASCP), and could eventually lead doctors to unroll the first PTSD drug in more than a decade, said Dr. Harry Croft, Chief of CNS Studies at Clinical Trials of Texas. Croft, who has also headed the investigation of 60 similar clinical trials over the last 25 years, said current PTSD treatments either don’t address every individual’s range of PTSD symptoms, pose unwanted side effects, or have poor adherence rates. Thus, scientists have continued searching for new PTSD treatments.
“The suffering caused by this condition is significant, not just for the veteran but for their family members,” Croft, medical director of the San Antonio Psychiatric Research Center, one of 24 U.S. research sites for the drug, told FoxNews.com. “We’re hopeful that we’re on the right track with this medication.”
New PTSD treatments: What’s the holdup?
U.S. combat servicemen and women serving in the Iraq and Afghanistan wars are the first in American history to be discharged multiple times, and soldiers today are more likely to suffer from PTSD than they are to get injured or die in combat. It was only after American soldiers returned from the Vietnam War that scientists coined the term PTSD, formerly referred to as shell shock— an effect the military simply associated with a lack of masculinity or patriotism.
In World War I, soldiers who presented trauma-related were executed by firing squad for perceived cowardice, said Stephen Stahl, a psychiatry professor at the University of California, San Diego.
Today, although PTSD’s pathology continues to mystify scientists, studies link the disorder with an increased risk of depression, anxiety and suicide. According to the National Institutes of Health (NIH), PTSD affects about 7.7 million American adults, including about 20 percent of Iraqi war veterans and about 11 percent of Afghanistan war veterans.
The Department of Veterans Affairs (VA) and the Department of Defense (DoD) have poured hundreds of millions of dollars into PTSD research, and are conducting brain imaging and biomarker studies, Ndidi Mojay, a VA spokeswoman, told FoxNews.com in an email. Researchers with the agencies have also established a database to monitor, identify risks for, and prevent suicide among the population, she added.
However, no new PTSD drug has been approved by the Food and Drug Administration (FDA) since Paxil in 2001, and before that, Zoloft in 1999.
Those drugs cause sexual dysfunction in up to 60 percent of patients, Croft said, and other drugs— like selective serotonin reuptake inhibitors (SSRIs)— address just individual PTSD symptoms, like depression. Meanwhile, cognitive behavioral therapy, a common treatment for PTSD, has only a 50 percent adherence rate, possibly because its mechanism is counterintuitive. “One of the symptoms of PTSD is avoidance, which means a conscious effort to not want to talk about it or be around anything that exposes you to it, whereas cognitive behavioral therapy forces you to do that,” Croft said.
Demonstrating a drug’s efficacy in a military setting has proven difficult for scientists because veterans’ experiences at war aren’t limited to single instances of trauma, Croft said.
Stahl, also the director of psychopharmacology of California Department of State Hospitals who has consulted with the U.S. Army on PTSD, said persistent attitudes about PTSD in the military as well as poor study design may also be to blame.
“The sweet spot of treatment may very well be as close to experiencing the trauma,” Stahl said.
The drug Croft’s team studied, TNX-102 SL, was administered to participants six to seven years after their PTSD-producing traumatic incident.
U.S. Navy Capt. Dr. Mike Colston, director of the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury at the DoD, said, besides research, the DoD and the VA have made strides toward better addressing PTSD through campaigns such as the American Psychological Association Presidential Task Force on Military Deployment Services for Youth, Families and Service Members, which was formed in 2007.
But he added that, in addition to the FDA’s lengthy but necessary approval process, a challenge that continues to trouble scientists who want to study PTSD while solders are in combat is, like Croft said, the heterogeneous symptom set of PTSD’s victims.
Hope for relief in a muscle relaxant?
TNX-102 SL, which is the chemical cyclobenzaprine, blocks certain neurotransmitters in the brain and receptors that scientists believe causes arousal responses and recurrent thinking, two signs of PTSD. The drug blocks the histamine receptor, too, which causes the side effects dry mouth and day sedation.
For the study, Croft’s team randomized about 230 patients to take either 2.8 milligrams or 5.6 milligrams, or a placebo once a day for 12 weeks, sublingually, before bedtime. Flexeril is typically taken at a 30 milligram dose and orally. Neither researchers nor the patients knew which dose they received, making it double-blinded.
Participants had to either serve in the military or be a first responder, and have a trauma-producing incident that led them to reach a CAPS score of at least 29, indicating moderate PTSD on a scale of 0 to 80. At the onset, doctors used the CAPS-5 (Clinical-Administered PTSD Scale for DSM-5, an index of mental health diagnoses) score to evaluate an individual’s mental health and functioning. Researchers completed evaluation training to ensure consistency across study sites, and found participants’ average CAPS score was about 40, indicating severe PTSD. They used other standard assessment tools, like the Clinical Global Impression–Improvement (CGI-I) scale, to evaluate participants’ depression and suicide risk at the beginning of the study.
More than 80 percent of patients had gone to college, and two-thirds were employed. The average number of their deployments was 2.3 times.
Periodically, researchers assessed patients’ CAPS scores. At the outset they found those patients who received the higher dose resulted in statistically significant PTSD symptom improvement. Those patients’ CGI-I scores, which evaluate how an individual’s health changes over time, showed similar results to that of effective antidepressants.
Not only did TNX-102 SL help patients sleep better, but it also reduced arousal and reactivity, anxiety, hypervigilance, and trouble concentrating— all symptoms of PTSD— Croft said.
“The good news is because it goes directly into the bloodstream at a much smaller dose than the oral medication used for muscle relaxation, it seems to be well tolerated, and it was well tolerated in this study,” Croft said.
When applied under the tongue instead of orally, the drug bypasses the liver and avoids getting metabolized. As a result TNX-102 SL has a shorter half-life and produces norepinephrine at lower levels. That neurotransmitter is thought to worsen PTSD, Croft said.
The future of TNX-102 SL
Study participant Mark Bratton was deployed five times overseas, two that were combat related, during his service in the U.S. Marine Corps from 2004 to 2013. His personal relationships suffered and he began coping with depression in 2007, when he returned home to Harlingen, Texas, from Iraq. But he pushed his discomfort aside because he didn’t want to be perceived negatively in the military or risk not being deployed again, he said.
He was diagnosed four months before he was discharged from the Marines, and since then he’s tried several approaches— from Zoloft to cognitive behavioral therapy, to Wellbutrin, a mood stabilizer— to ease his symptoms.
Therapy helped for a while, as did the Wellbutrin, but Zoloft made him feel “cloudy” and “zombie like,” he said.
TNX-102 SL, along with his service dog, a yellow Labrador retriever named Benny, has helped Bratton feel safer in crowds by reducing hypervigilance, and has helped him sleep better at night with fewer nightmares.
“My depression started to ease up, and all these feelings of worthlessness, and just not feeling good about myself, started to subside,” Bratton, 30, told FoxNews.com of his experience with the drug.
Bratton, who’s now studying history at Texas A&M University, said he was worried about stopping the drug after the study ended. But, to his surprise, the relief continued.
“I think it flipped a switch on in my head, and I knew how I could be, and knew I could feel great and knew I could feel normal,” he said.
Stahl said it “makes complete sense” that TNX-102 SL helps relieve PTSD symptoms based on its mechanisms. He is part of an effort in California that’s working to reclassify drugs from their market names to their chemical properties. The idea is to help scientists more easily repurpose drugs for different conditions, like cyclobenzaprine.
Despite its potential promise, Stahl said he was skeptical over whether there would be enough resources to get TNX-102 SL to market. According to a 2014 report by the Tufts Center for Study of Drug Development, the cost of developing a prescription drug and making it commercially available has surpassed $2.5 billion.
Colston called cyclobenzaprine an “innovative approach” that could make for a good adjunct to current treatments like cognitive behavioral therapy.
Phase 3 studies of TNX-102 SL, which would be conducted in a larger population of veterans with both combat- and non-combat-related PTSD, may begin as early as the first quarter of 2017.
“Because of this study, they’ll probably use the higher dose,” Croft said. “We’re very excited about finally, hopefully, having something that will make a real difference for these folks because, as you know, they’re suffering and their families are suffering.”