Nancy A. Melville

June 05, 2017

MIAMI – The lack of progress in development of drugs to effectively treat posttraumatic stress disorder (PTSD) has become a "crisis" and has led to a significant shift in the US Department of Veterans Affair's (VA's) clinical practice treatment guideline for the disorder, experts say.

"I can report that the updated guideline is going to read that we 'recommend' – which is the highest level of recommendation ― that evidence-based, trauma-focused psychotherapy be offered over other treatments for PTSD," Lori L. Davis, MD, of the VA's PTSD Psychopharmacology Working Group, told delegates attending the American Society of Clinical Psychopharmacology (ASCP) 2017 Annual Meeting.

"Pharmacotherapies were more prominently discussed in previous guidelines, so this is quite a shift," she said. The updated clinical practice guidelines are scheduled for release this summer.

Only two medications – sertraline (Zoloft, Pfizer) and paroxetine (multiple brands) – are currently approved by the US Food and Drug Administration (FDA) for the treatment of PTSD. Although these drugs and a few others have modest effect sizes, they are not as effective as trauma-focused psychotherapies, as reported in a recent systemic review, which, Dr Davis said, factored largely into the pivotal clinical guidelines shift.

Although the results reflect the potentially robust efficacy of psychotherapy, they also underscore the need for better medications, a sentiment that Dr Davis and her colleagues on the working group noted in a consensus statement.

"There is an urgent need to address a critical lack of advancement in the psychopharmacologic treatment of posttraumatic stress disorder," the authors write.

Sad State of Affairs

Since 2006, only four industry-sponsored studies of drugs for the treatment of PTSD have been conducted in the United States, said Dr Davis. "This represents more than decade of research, and I find it to be just kind of sad."

Of these four studies, three failed to show that the study drugs were of benefit. Research on the drug orvepitant (GlaxoSmithKline) was terminated early with no conclusions. Findings on the drug 7-Keto DHEA (Humanetics Corp) were not published, and research on the drug brexpiprazole (Otsuka Pharmaceuticals) for the treatment of PTSD was terminated because of challenges in patient selection.

The fourth study, which examined TNX-102 SL (Tonix Pharmaceuticals), a sublingual tablet formulation of cyclobenzaprine (CBP), failed to meet its primary endpoint but showed some promise in a military PTSD population.

The study did not meet its primary endpoint of statistically significant improvement with the lower dose of 2.8 mg on scores on the Clinician Administered PTSD Scale for DSM-5 (CAPS-5) among 90 patients from baseline to week 12 compared to placebo. However, 49 patients who received the higher 5.6-mg dose showed significant improvements at week 12, with an effect size of .36 (Cohen's d).

The 5.6-mg dose was associated with improvement in sleep and hyperarousal by week 2 and subsequent improvement in CAPS-5 scores for PTSD at week 12.

"The relationship between early sleep improvement and week 12 PTSD recovery supports the mechanistic hypothesis that improved sleep quality is a mediator of TNX-102 SL treatment response," said Gregory Sullivan, MD, of Tonix Pharmaceuticals.

The drug received breakthrough therapy designation for PTSD by the FDA.

Encouraging Developments

Dr Davis said these developments are encouraging.

"The [TNX-102 SL cyclobenzaprine] trial didn't pass its primary endpoint compared to placebo, but there was a strong trend in the higher 5.6-mg dose, especially in patients with more severe PTSD, and that did ignite a spark to reenergize the field," she noted.

Dr Davis highlighted a list of the top therapeutic targets for PTSD that were identified by a group of 27 experts. The top five are NMDA receptor antagonists, cannabinoid receptor modulators, glucocorticoid receptor agonists, non-SSRI antidepressants, and opioid receptor agonists.

Obstacles slowing research efforts into effective PTSD medications are multifactorial and range from the complexity of the condition to the cost of clinical trials. However, interest in the research is looking up, Dr Davis told Medscape Medical News.

"PTSD is complex and heterogeneous condition. Patients are reluctant to take part in a research study. Drug discovery takes time and funding. However, there are many drugs with novel mechanisms of action that are under consideration," she said.

"The VA, Department of Defense, and industry have been showing more interest in psychopharmacology research for PTSD than ever before," she added.

The benefits of trauma-focused psychotherapy range from providing human contact to better ability to target specific comorbidities. Yet, psychotherapy has some notable drawbacks compared to medication, including problems regarding access, scheduling, adherence, costs, insurance coverage, differences in training of providers, and symptoms of anxiety that can be provoked through practices such as exposure therapy, Dr Davis said.

The benefits of medications include the fact that they are accessible in the primary care setting, they involve fewer and less frequent follow-up visits, they require less time in clinic, and they are relatively inexpensive.

Combining medications with psychotherapy for PTSD often does provide significant improvements by addressing comorbidities such as depression and anxiety, better therapies are needed, Dr Davis said.

"Current treatments are effective, but not curative," she said.

"Residual symptoms can cause interference with full functioning, especially at work and in relationships. Just like any other psychiatric or medical disorder, treatment will always need to be multipronged and include medication, psychosocial, family, complimentary, spiritual, physical, and vocational treatments, delivered in a way that emphasizes recovery and restores hope for the future."

National Strategy Needed

Commenting on the presentation, Richard C. Shelton, MD, the Charles B. Ireland Professor and vice chair for research at the University of Alabama, Birmingham, School of Medicine, agreed that organized efforts to find better pharmacotherapies for PTSD are needed.

"I am encouraged to hear of efforts to try to set a strategy for this moving forward, and I agree that the US needs a national strategy for PTSD. People are getting this every day, and a strategy is needed to do the research to differentiate the current treatments but also to develop new therapies," he said.

"While there are a lot of potential targets, there is very little work going on in these pharmacological domains, and one of the reasons is research to establish an effective treatment for PTSD would involve very high cost to companies," Dr Shelton added.

Dr Davis has received research funding from the VA, SAMSHA, Forest, Merck, and Otsuka and has been a consultant for Otsuka. Dr Shelton has received grants for clinical research from Abbott, Eli Lilly, GlaxoSmithKline, Janssen, Pfizer, and Wyeth-Ayerst. He is on the speaker's bureau for Abbott, Forest, GlaxoSmithKline, Janssen, Pfizer, Eli Lilly, and Wyeth-Ayerst. He has also served as an advisor or consultant for Janssen, Pfizer, and Wyeth-Ayerst.

American Society of Clinical Psychopharmacology (ASCP) 2017 Annual Meeting. Presented June 1, 2017.

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