Potential New Drug Target for PTSD

Deborah Brauser

September 13, 2011

September 13, 2011 — Reduced serotonin type 1B receptor activity, especially in the brain's caudate area, is strongly associated with trauma exposure and may represent a biomarker for the development of posttraumatic stress disorder (PTSD), new research suggests.

In a study of 96 participants who underwent positron emission tomography scans, those with PTSD had significantly lower serotonin 1B levels than did those without the disorder. Interestingly, the levels were also lower in those who experienced severe trauma, including childhood abuse, domestic violence, and military violence, but did not have a PTSD diagnosis compared with their nontraumatized peers.

"Lower serotonin 1B levels were also strongly associated with age at first trauma. The earlier the trauma exposure, the greater the brain alterations and the greater the severity of PTSD symptoms, and the greater the risk of developing comorbidities," senior author Alexander Neumeister, MD, associate professor of psychiatry at Mount Sinai School of Medicine in New York City, told Medscape Medical News.

Dr. Alexander Neumeister

"These findings establish that trauma at a young age causes long-lasting neurobiological and psychological effects in survivors with PTSD. In other words, early-life trauma can interfere with normal brain development," he said.

The investigators add that this study is "the first evidence of a potential drug target" for this disorder.

"Currently the only medication treatment options for the nearly 8 million American adults with PTSD are antidepressants and anti-anxiety medications, which show little benefit in improving the mental health of these patients," added Dr. Neumeister in a release.

"Our research sets the stage for the development of therapies that target serotonin 1B receptors."

The study appears in the September issue of the Archives of General Psychiatry.

Traumatic Stress Mechanisms

The investigators write that "relatively little is known regarding the human neurobiological mechanisms that underlie adaptive or pathologic responses to traumatic stress."

Although the medications currently approved by the US Food and Drug Administration for the treatment of PTSD target the serotonin system, defining the system's specific role in treating this disorder "has been challenging in the face of a wide and complex diversity of receptor subtypes and their functions," the researchers explain.

As reported at the time by Medscape Medical News, Dr. Neumeister presented studies at the 2009 American College of Neuropsychopharmacology Annual Meeting showing that veterans with PTSD had lower expression of serotonin 1B receptor availability in an amygdala-cortical-striatal circuit than did age- and sex-matched healthy control patients.

In addition, lower 1B receptor availability in this area was more pronounced in the participants with PTSD and major depressive disorder than in those who had PTSD only, whereas those with comorbid alcohol dependence actually showed elevated ventral striatal binding potential.

"Unfortunately, people with PTSD often have additional psychiatric illnesses, such as major depression, or may develop substance use problems as an avenue for relieving their symptoms," said Dr. Neumeister.

In the current study, 49 participants with PTSD, 20 of whom had experienced trauma but did not have a diagnosis of PTSD (trauma/no PTSD), and 27 healthy control patients were enrolled at academic and Veterans Affairs centers.

All patients underwent injections with the newly developed serotonin type 1B receptor selective radiotracer [11C]P943, followed by resting-state positron emission tomography scans. The main outcome measure was regional binding potential of the [11C]P943.

The Clinician-Administered PTSD Scale was used to measure PTSD symptom severity, and the Traumatic Life Events Questionnaire was used to quantify trauma history. Other measurements included the Hamilton Rating Scale for Anxiety and the Montgomery-Asberg Depression Rating Scale.

Trauma Reduces Binding

Results showed that the participants with past exposure to severe trauma showed significant reductions in [11C]P943 binding potential in the caudate, amygdala, and anterior cingulate cortex (ACC)

Compared with the healthy control patients, those in the PTSD group showed a significant 18.8% reduction in binding potential in the caudate (P = .006), a 10.9% reduction in the amygdala (P = .047), and a 9.1% reduction in the ACC (P = .048).

Those in the trauma/no PTSD group had significant binding potential reductions compared with the healthy controls in the caudate (by 25.8%; P = .002) and amygdala (by 14.7%; P = .03).

There were no significant binding differences in these areas found between the PTSD and trauma/no PTSD groups, and no significant differences in the hippocampus or globus pallidus regions for any group.

In those with PTSD, age at first trauma was significantly correlated with low binding in the caudate (P < .001) and ACC (P = .003), meaning that "the earlier the first trauma exposure, the lower the [11C]P943 [binding potential]," explain the researchers.

In the trauma/no PTSD group, age at first trauma was significantly associated with low binding in the caudate (P < .001) and the amygdala (P = .04).

Finally, in secondary analysis, those with PTSD and major depressive disorder had greater PTSD symptom severity, a significantly earlier onset of trauma, and more lifetime traumatic experiences than those with PTSD only.

Because low [11C]P943 binding potential was found in both of the trauma groups, this "suggests that abnormal serotonin type 1B expression does not sufficiently explain the phenotype of PTSD," write the researchers.

"Thus, the data more strongly support the hypothesis that the extent of...alteration reflects features of trauma exposure...rather than the nature of the response to the trauma."

Dr. Neumeister noted that currently available medications or psychotherapy are often ineffective for traumatized patients.

"Their symptoms and comorbidities are associated with poor treatment outcome, increased suicidality, and an overall decreased quality of life. So unfortunately, the earlier you experience your first trauma, the higher your risk that you'll have a very bad course of PTSD with a number of complications."

He added that clinicians should ask about past traumas, especially because patients often will not bring up these experiences on their own.

"We had several patients report that when they presented to their physician for depression, nobody ever asked about their trauma history. Yet we know that treatment for depression without trauma is different than that for people who have been traumatized. So it's very important to actively screen," said Dr. Neumeister.

"A Whole New Perspective"

"I think this is very intriguing and gives a whole new perspective on the effects of traumatic experiences," David Spiegel, MD, professor and associate chair of the Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine, California, and director of Stanford's Center on Stress and Health, told Medscape Medical News.

Dr. David Spiegel

Dr. Spiegel, who was not involved with this study, said that prior research examining the effects of trauma have focused on the hypothalamic/pituitary/adrenal axis and cortisol system and its poor response to stress.

"This is more interesting because it's very involved with depression, as well as involved with regulating the [hypothalamic/pituitary/adrenal]/cortisol system," he noted.

He added that the results showing that reduced serotonin receptor activity occurs "in parts of the brain that regulate emotion, among other things, makes a whole lot of sense."

However, he said that what gave him "pause" was that this finding occurred in both the study participants with PTSD and those patients who were trauma-exposed, yet without PTSD.

"So this is not a significant finding about PTSD. It's about brain effects of early-life trauma. I think the most important contribution of this study is that it makes it clear that early traumatic experience has neurophysiological effects not just psychological effects. And obviously they interact with one another," Dr. Spiegel said.

He agreed with Dr. Neumeister that clinicians should always screen for past trauma.

"This is not a routine part of our psychiatric exam, but it should be. You'll know more about your patient's brain, as well as about how they live their lives, if you take a trauma history," he explained.

"These experiences can understandably affect how people manage their mood, and whether they're likely to get depressed. And it can affect the rest of their lives."

The study was supported by the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Veterans Affairs National Center for PTSD. The study authors and Dr. Spiegel have disclosed no relevant financial relationships.

Arch Gen Psychiatry. 2011;68:892-900. Abstract

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