Our Research

There is a tremendous need to investigate new and novel medications to treat PTSD. PTSD is a leading cause of distress and disability among trauma-exposed individuals and there are limited pharmacologic interventions. While two medications are currently FDA approved for PTSD, both antidepressants, the efficacy of these medications is quite limited. Both medications are selective serotonin reuptake inhibitors (SSRIs), meaning they work to reduce symptoms by altering serotonin levels in the brain. Though some people do very well with these medications, many gain little to no improvement in their symptoms. Further, these medications take weeks to months to reach their full benefit and often, even when some symptoms improve, others do not.

Ketamine, an FDA approved anesthetic medication, was found to have rapid and robust antidepressant effects when given at low doses. There is a great deal of interest in ketamine and some similar drugs as a potential treatment for depression and PTSD because they work in different ways in the brain than the traditional antidepressants, and even seem to work for many who haven’t had success with many other treatments.

This study is among the first to carefully evaluate the effects of ketamine in PTSD and the first to our knowledge to evaluate ketamine in a sample of Veterans. This study is a randomized clinical trial designed to investigate the safety, efficacy, and tolerability of repeated doses of ketamine in Veterans with PTSD. The study has three parallel treatment arms, meaning participants may be randomized to one of three treatments – placebo, low dose ketamine, or standard dose of ketamine to be administered approximately twice per week for a 4 week period. There is the option of a single open-label dose of ketamine for those who do not respond during the treatment period. The study also includes a 4-week follow-up period. The study will allow us not only to evaluate if ketamine is effective in treating PTSD, but also will allow us to investigate dose-effects, meaning we can see if there are differences in the lower and higher doses of ketamine.

Stress-related psychopathology, including depression and PTSD, are debilitating and chronic illnesses affecting millions of people across the world. To compound the problem of high prevalence rates, there are limited effective pharmacologic treatment options for these disorders. Traditional antidepressants, though effective for some people, produce little to no clinical improvement for many and takes weeks to months to reach their full benefit. There is a great deal of interest in exploring how depression and PTSD seem to affect the brain as this may help to identify new treatment targets. Evidence from animal studies suggests there may be glial and glutamatergic impairment in stress-related psychopathology. However, until recently, investigations of glial function and prefrontal glutamate/glutamine cycling were not possible. Glutamate is one of the most common and widespread neurochemicals in our brains and has been correlated to many aspects of day-to-day function, including emotion and cognition, both integrally connected to PTSD and depression. Glial cells are involved in helping to regulate glutamate activity in the brain. It is suspected that people struggling with PTSD and depression may have altered glial and glutamatergic functioning. This study uses advanced, state-of-the-art neuroimaging methods to evaluate glial and glutamate functioning. The results of this study can further our understanding of the effect of stress-related psychopathology in the brain and the potential role of the glutamatergic system.

This study involves two neuroimaging scan visits. The first will gather data regarding the basic structure and function of the brain. The second visit uses a novel imaging method called carbon 13 magnetic resonance spectroscopy. Briefly, we used acetate (a naturally occurring and safe substance the brain uses for energy like glucose) with the carbon 13 molecules labeled. This allows us to monitor how the acetate is metabolized in the brain and to investigate glial and glutamatergic function.

This study aims to explore, using non-invasive procedures like brain imaging and psychological interviews, the relationship between biological factors (such as the structure, chemistry, and physiology of the brain), and mood or behavioral factors (such as depression, PTSD, anxiety, suicidality, cognitive impairment, or other chronic-stress related symptoms) in an adult population. The goal of this approach is to identify biological indicators (“biomarkers”) that may help clinicians to more easily distinguish between these mood disorders, better predict the likelihood that a particular course of drug or behavioral therapy would be effective for a particular individual, and that will help researchers better understand the way that these trauma-and-stress related symptoms play out over time and across different populations. It is hoped that over time, and through additional research in the future, the understanding gained through this study may help improve treatment outcomes and overall quality of life for individuals suffering from these symptoms. This protocol is what the majority of our MRI scans are conducted under and those participants enrolled in any of our other studies will be asked to consent into this study as well. During this study, participants will complete self-report questionnaires, cognitive assessment tasks, and clinical interviews in addition to the scanning visits. The ability and willingness to participate in neuroimaging sessions is a requirement for participation in this study.

This is the neuroimaging protocol for our research program and participants engaged in any of our other studies may be invited to complete some or all of these procedures.

PTSD – dubbed a “signature injury” of the recent wars in Iraq and Afghanistan – has received unprecedented research and clinical focus because of its staggering prevalence rates among returning service members and Veterans. To compound the problem of prevalence, only two FDA-approved psychopharmacologic agents are available for PTSD (both SSRIs) and these require weeks or months to provide clinical benefit, offer limited efficacy, and do not target the cardinal cognitive symptoms of PTSD (e.g., impaired attention/concentration, memory, executive function). This last point is especially troubling as cognitive impairment in PTSD contributes significantly to overall morbidity and poor functional outcomes. Glutamate is responsible for many aspects of normal cognition and recent evidence suggests glutamatergic abnormalities in PTSD. Further, PTSD is associated with functional connectivity disturbances in multiple brain regions. Ketamine’s antagonism of the glutamatergic N-methyl-D-aspartate receptor appears to be the first step in a cascade of events that includes rapid increases in presynaptic glutamate release and improved signaling, enhanced regional activity in excitatory networks, and ultimately marked changes in synaptic plasticity and functional connectivity approximately 24-hours following a single sub-anesthetic dose (the peak time of ketamine’s antidepressant response). Considering the role of functional connectivity in cognitive function, there is strong support for using resting-state functional connectivity MRI (rs-fcMRI) to examine ketamine-induced neural system alterations that may have important implications for connectivity and cognition in PTSD, providing answers for ‘fast-tracked’ effects, both for overall symptom reduction and cognitive enhancement.

This study is an add-on trial to other studies in our research program. This means this study does not directly recruit – all participants in this study will be engaged in another study in our program (e.g., one of our ketamine trials).

Suicide is the 10th leading cause of death in the United States and U.S. military Veterans comprise almost one-quarter of these deaths. An estimated 22 Veterans die by suicide each day. Individuals with PTSD have significantly increased risk for suicidal ideation and behavior as compared to members of the general population. Currently, only two medications are FDA approved for PTSD and these require weeks to months to take effect and leave many individuals with persistent symptoms, including suicidal ideation (SI). A large body of research demonstrates that ketamine, an investigational antidepressant, may be effective at reducing symptoms of PTSD, and specifically SI in a rapid manner. Research suggests that ketamine’s effect begin within two hours after dosing and peak approximately 24-hours after treatment. Considering the incredible burden and risk for those with severe PTSD symptoms and SI, fast-tracked anti-suicidal effects are urgently needed. This study uses functional magnetic resonance imaging (fMRI), clinical, and cognitive assessment to examine neurobiological mechanisms underlying SI in Veterans with PTSD.

This study is an add-on trial to other studies in our research program. This means this study does not directly recruit – all participants in this study will be engaged in another study in our program (e.g., one of our ketamine trials).

Ketamine is a novel antidepressant medication with mounting evidence suggesting it produces fast-acting symptom reductions in depression, even among individuals who have struggled to obtain clinical benefit from other traditional antidepressant medications. Some controversy exists in the field regarding exactly how ketamine works in the brain to produce these antidepressant effects. Better understanding the mechanisms underlying ketamine’s antidepressant effects is very important as this can inform novel drug development for depression as well as other psychiatric disorders.

The immunosuppressant drug sirolimus (also called rapamycin) is known to have an impact on depressive symptoms based on some preclinical or animal studies. Sirolimus works in the brain along part of the same pathway it is suspected ketamine may work. The purpose of this study is to investigate what effect a single dose of sirolimus has on the antidepressant effects of ketamine. It is possible this will have a no demonstrated effect on ketamine response or perhaps will have a synergistic effect or a blocking effect. The results will provide additional evidence as to whether this is in fact, the pathway ketamine is working on, as well as giving some insight into what happens when part of this pathway is blocked.

This is a double-blind, randomized, cross-over clinical trial. All study participants will receive two doses of ketamine separated by a two-week period, they will be randomized to one of two groups – ketamine+sirolimus (with placebo at infusion 2) or ketamine+placebo (with sirolimus at infusion 2). Each infusion visit requires a 24-hour follow-up in which our research team members will carefully assess for any changes in symptoms, side-effects, or adverse events. The visit occurs 24-hours after the ketamine dose as this appears to be the peak-time of ketamine’s antidepressant effects. Further, data from neuroimaging studies suggest 24-hours is also the peak of brain changes (e.g., alterations in functional connectivity and neuroplasticity) secondary to ketamine administration.

PTSD is a debilitating and chronic psychiatric disorder with limited treatment options. Currently, there are only two FDA-approved medications to treat PTSD and both are monoaminergic antidepressants (SSRIs specifically). There are high rates of non-response or partial response to these medications. Thus, there is urgent need to explore other medications that may be effective in reducing symptoms of PTSD.

Riluzole is an FDA-approved medication for Amyotrophic Lateral Sclerosis (ALS), which is also known as Lou Gehrig’s Disease. Preclinical animal studies have shown riluzole to modulate glutamate release and clearance, and to have potent neuroprotective properties, promoting neuro-resilience. Other preclinical data also show the drug to have anxiolytic-like (anti-anxiety) and antidepressant-like effects in rodent models of stress. In addition, several open-label clinical studies further suggest riluzole has anxiolytic and antidepressant properties, even in patients who do not respond to standard monoaminergic antidepressant and anxiolytic medications. However, to date, riluzole has not been studied in patients suffering from PTSD. The proposed study will provide pilot data on the efficacy of riluzole in PTSD. An optional component of this study will investigate the mechanisms underlying its effect on the brain by using advanced magnetic resonance imaging and spectroscopy methods.

This is a 12-week open-label trial. All study participants will receive the active drug. Participants will be asked to take the medication daily over a 12-week period and will attend a once-weekly brief visit to monitor for symptom changes, side-effects, and adverse events.

Ketamine is an FDA-approved anesthetic agent that has been found to produce rapid and potent antidepressant effects in individuals with severe depression. Mounting evidence suggests ketamine administration produces a surge in glutamate neurotransmission in the brain, that is likely associated with the antidepressant effects (as well as some of the side-effects of the medication). Until recently, we have been unable to examine glutamate neurotransmission in human participants because we lacked appropriate and safe methods to do so. This study uses new, state-of-the-art neuroimaging methods to measure the effect of ketamine on glutamate/glutamine neurotransmission in the brain. It is suspected that ketamine will cause a significant increase in the rate of neurotransmission and that these changes will correlate to antidepressant effects. The results of this study can help to inform how ketamine works in the brain and how glutamate neurotransmission may be related to changes in depressive symptoms, which can inform novel drug development.

This study involves four neuroimaging scan visits. Two of these visits will use MRI methods to evaluate the structure and function of the brain. Two visits will use a novel imaging method called carbon 13 magnetic resonance spectroscopy. Briefly, we use glucose or acetate (a naturally occurring and safe substance the brain uses for energy like glucose) with the carbon 13 molecules labeled. This allows us to monitor how the glucose/acetate is metabolized in the brain and to investigate how this is influenced by ketamine. We complete structural/functional scans before and after ketamine administration.