Identifying new pharmacologic treatments for trauma and PTSD

Post-traumatic stress disorder (PTSD) is a potentially chronic and debilitating condition associated with significant trauma such as injury and death, as well as disruptions in family, workplace, and social contexts. Extensive research has documented the negative consequences of trauma and PTSD, including other forms of psychopathology, such as depression, cardiovascular disease, a decline in quality of life because of poor health, and increased rates of suicide.

Eight percent of the US general population will develop PTSD at some point in their life, making it the fifth-most prevalent mental disorder in the country. PTSD is a particularly salient problem among military veterans—over 10% of Department of Veterans Affairs (VA) patients have a PTSD diagnosis. Thus, it is not surprising that PTSD is considered a significant health issue to society and the people directly affected by it. Advancements in the treatment of trauma and PTSD have taken on significant priority for clinicians and researchers.

As a response to this urgent need for new treatments, we are examining VA medical records that could spur further research into new pharmaceutical treatments for PTSD.

The need for better trauma and PTSD treatments

Despite the high prevalence and costly impact of PTSD, the few psychopharmacologic treatments for PTSD that are available do not work well enough. The VA PTSD Psychopharmacology Work Group recently published a statement in Biological Psychiatry that describes three aspects of the PTSD “pharmacotherapy crisis”:

Antidepressants

Antidepressants, the most commonly prescribed pharmacologic agent for PTSD, are associated with remission in fewer than half of the patients who take them. Currently, Sertraline and Paroxetine are approved for the treatment of PTSD by the Food and Drug Administration (FDA), but there are no other approved pharmacologic treatments for PTSD. Trauma treatment guidelines from the VA and DoD include two additional antidepressant medications, Fluoxetine and Venlafaxine, that have similarly limited effectiveness.

Off-label risks

The limited effectiveness of the approved medications for PTSD results in many patients receiving multiple medications prescribed off-label. These off-label medications have not been studied either as monotherapy or in conjunction with other medications serving trauma and PTSD, resulting in many patients receiving treatment, for which there is little information about the potential risks and benefits.

Lack of trauma and PTSD research

The FDA has approved no new drugs for the treatment of PTSD in almost two decades. The research and development of new medications for PTSD is limited, and current development may take many years to complete, resulting in a challenge to the field of how to proceed with identifying effective medications for PTSD treatment right now.

The VA PTSD Psychopharmacology Work Group concluded that there is “a serious knowledge gap related to the efficacy of commonly prescribed medications and novel compounds for the treatment of PTSD.” The burden of ineffectively treated PTSD on clinical, social, and financial systems is enormous. Yet, current knowledge leaves the field with few alternative pharmacologic treatment options in the near future.

Limitations of other therapies

Effective non-pharmacologic treatments for PTSD also have significant limitations. Multiple evidence-based psychotherapy (EBP) protocols have proven effective for treating PTSD in randomized controlled trials (RCTs). The VA has also engaged in considerable efforts to promote the use of EBPs for trauma and PTSD. A substantial number of VA patients receive prolonged exposure (PE) or cognitive processing therapy (CPT) for PTSD, yet the burden of PTSD symptoms and associated psychosocial impairments remain prominent in veterans treated at the VA.

Further, despite demonstrated efficacy of these treatments in randomized control trials, non-response is common. Thus, there is still a critical need for additional effective treatments for PTSD, including pharmacologic treatment options.

Promising opportunities for treating trauma and PTSD

Studies that use pre-existing VA EMR registry data provide a unique opportunity to address the PTSD pharmacotherapy crisis. PTSD is a common diagnosis among VA patients, and, further, VA patients with PTSD have a high degree of medical comorbidity and receive a wide variety of medications to address these illnesses. For example, PTSD is associated with inflammation, which is thought to contribute to excess mortality through higher risk for general medical illnesses, such as cardiovascular and rheumatologic diseases. It’s possible that anti-inflammatory agents used to treat these diseases may also reduce PTSD symptoms.

The VA patient population is the ideal population in which to begin to explore these complex interactions. Further, the VA maintains national registry data sources throughout the patient’s care, including:

• Patient demographics
• Procedural and diagnostic codes
• and pharmacy data (i.e., VA Corporate Data Warehouse or CDW). 

Notably, the CDW contains data sources not typically available in large administrative datasets, including clinical note text and structured data from standardized mental health symptom assessments, allowing for the ability to examine changes in disorder severity over time.

The rich available VA data, combined with a population characterized by a marked prevalence of PTSD and many other comorbid conditions, provides a unique opportunity to explore critical unanswered questions about the pharmacologic treatment of PTSD.

Currently, we have National Institute of Mental Health funding to conduct an initial, exploratory examination of medications prescribed to VA patients for other indications that may have an incidental impact on the improvement of associated trauma and PTSD symptoms using a novel pharmacoepidemiologic statistical tool called TreeScan to identify promising agents, followed by the use of rigorous causal methods to evaluate the most promising agents (grant # R01MH121397). This is just the start of an extensive line of research aimed at improving the pharmacologic treatment options of persons with PTSD.

In future work, specific medications and medication classes identified as potentially effective and safe in our current exploratory study can be more rigorously examined using prospective methods. This provides other researchers with valuable data that can be utilized in randomized controlled trials, or to prompt new drug discovery in targeted areas that appear clinically promising.

Dr. Jaimie Gradus is an Associate Professor of Epidemiology at Boston University School of Public Health and an Associate Professor of Psychiatry at Boston University School of Medicine. Her research interests are in the epidemiology of trauma and trauma-related disorders, with a particular focus on suicide outcomes.