Can a Recent Lab Discovery Lead to a New Treatment for PTSD?

Summary: Yes, new treatment for PTSD may be the result of a new finding reported in a study published this summer in Korea.

Key Points:

• Potential new treatment for post-traumatic stress disorder (PTSD) targets brain processes connected to fear and memories of fear.
• Clinical research in humans identified brain activity common to people with PTSD.
• Research confirmed the neurological connection to PTSD in lab animals.
• Lab animal studies led to a new drug treatment for PTSD, currently in human trials.

New Treatment for PTSD, Discovered in a Novel Way

In most cases, medical research follows this pattern:

1. Medical scientists identify an aspect of a disease or disorder that warrants research.
2. For medications, research typically begins in the laboratory, using experiments confined to test tubes, petri dishes, and the like.
3. Research on medications often relies on post-mortem examination of human systems, to help target the biomedical, test-tube-based laboratory research.
4. Medications with positive results move to trials in lab animals.
5. If successful, scientists begin testing the medication in humans.

However, the researchers behind this new study in Korea engaged in what they call a process of reverse translation. Instead of the typical research flow we outline above, the research team reports the following:

“Through our comprehensive human clinical research, including both cross-sectional and longitudinal studies, we revealed a compelling link between dysregulated prefrontal gamma-aminobutyric acid (GABA) levels and PTSD symptoms. Notably, elevated prefrontal GABA levels in PTSD patients are associated with impaired cerebral blood flow (CBF) and symptom severity, normalizing with recovery, highlighting GABA dysregulation as a key mechanism in the disorder.”

Based on this observation, the research team conducted post-mortem analyses on people with PTSD and confirmed structural brain changes associated with the brain dysregulation identified in clinical studies. Next, the researchers simulated PTSD-like symptoms in laboratory animals using a rodent model, mirroring the structural changes they observed in human brains and the behavioral dysregulation associated with humans with PTSD.

Then, using pharmacological techniques – i.e. experimental medication – they reversed both the structural and behavioral dysregulation associated with PTSD. After these successful lab efforts, the research team received approval for testing the new medication in humans with PTSD.

Typically, observations at the cellular level will lead to animal studies that then lead to human studies. In this case, the process was reversed, and then came full circle: observations in humans led to lab studies that led animal studies that led back to clinical trials in humans.

Let’s take a look at the details of this research on a new treatment for PTSD.

Persistent Fear: A Problem for People With PTSD

The latest reports from the U.S. Department of Veterans Affairs (VA) shows the following prevalence of PTSD among adults in the U.S.:

• Past 12 months diagnosis: 13 million people
• Any PTSD diagnosis during lifetime: 20 million

Those millions of people with PTSD regularly experience four types of PTSD symptoms:

1. Intrusive memories
2. Avoidance behaviors
3. Changes in thought/mood
4. Changes in physical/emotional reactions

Since PTSD develops after a traumatic event that elicits emotions too overwhelming for an individual to process with typical coping skills, the intrusive memories persist. Each time they appear, they cause a fear response – i.e. trigger the fight or flight response – which can be disruptive to the point of being debilitating.

The remaining three symptoms – avoidance, changes in thinking, changes in the body and emotions – stem from the recurrence of fear and from reliving the fear associated with the initial traumatic event. The research team calls the neurobiological basis of this recurring fear with a complex sounding phrase:

“…dysregulation of fear extinction.”

In a human without PTSD, a process called fear extinction occurs. This means that over time, a stimulus that once triggered fear no longer triggers fear, and the fear becomes extinct, i.e. gradually dies off. Fear extinction is associated with the following brain areas:

• Prefrontal cortex (PFC), known primarily for its role in executive function, decision-making, and critical thinking, also associated
• Infralimbic region of the PFC (IL), facilitates fear extinction
• Prelimbic area of the PFC (PL), modulates fear extinction
• Amygdala, involved in memory, emotion, and the fight-or-flight response

Additionally, research shows that reduced activity of GABA receptors in those brain areas impair fear extinction. To reiterate, altered, impaired, or nonexistent fear extinction is a primary cause of PTSD symptoms.

With all that information in mind, let’s look at what the research team found:

Restoring Fear Extinction May Reduce PTSD Symptoms

Using their novel, multi-pronged approach – a combination of human clinical studies, post-mortem brain studies, and PTSD-associated symptoms in the rodent model – the research team made the following observations:

• Atypical GABA levels and activity disrupted cerebral blood flow (CBF) to key brain areas associated with PTSD symptoms.
• Presence of brain chemicals MAOB and ABAT caused GABA dysregulation.
• Pharmacological inhibition of MAOB and ABAT reversed GABA dysregulation.
• Pharmacological inhibition of MAOB and ABAT restored fear extinction.

In those bullet points, pharmacological inhibition means “stopped with medicine.” Therefore, using a new medication – the pharmacological inhibition mentioned – may be an effective new treatment for PTSD.

Here’s how Dr. C. Justin Lee, the lead scientist on the study, describes these findings:

“This work represents a successful example of reverse translational research, where clinical findings in human guided the discovery of underlying mechanisms in animal models. By identifying astrocytic GABA as a pathological driver in PTSD and targeting it via MAOB inhibition, the study opens a completely new therapeutic paradigm not only for PTSD but also for other neuropsychiatric disorders such as panic disorder, depression, and schizophrenia.”

The new medication, called KDS2010, passed initial safety trials in humans and is now in phase 2 of clinical trials. If found safe and effective, this could represent a sea-change in the way we treat trauma-related disorders. There are currently two medications approved for PTSD, and they’re only effective in 20-30 percent of patients. An effective new treatment for PTSD would be a welcome addition to the current first-line treatments available, and offer hope for people seeking relief from the persistent and disruptive symptoms of PTSD.