Assessing Trauma-related Links Between Affective and Metabolic Systems

Background and Study Objective: Post-traumatic stress disorder (PTSD) affects as many as 15% of Veterans following deployment and is associated with high rates of medical comorbidities linked to insulin resistance (IR), which is present in over half of people with PTSD. PTSD severity is prospectively associated with increased risk of both worsening IR severity and new-onset type 2 diabetes mellitus, leading to premature mortality. Biological effects of trauma exposure are linked to downstream disruption of both brain and metabolic processes, with mounting evidence that trauma-related mechanisms leading to IR may be biologically distinct from that of IR in the general population. One potential mechanism linking trauma exposure to IR lies in studies of noradrenaline (NA) blockade, with 1 adrenoreceptor antagonists demonstrating benefit for insulin sensitivity in patients with IR and hypertension. While a substantial body of evidence supports a role for increased NA signaling in PTSD, the potential link between NA and IR in the context of PTSD deserves further investigation. This connection suggests that increased IR following trauma also has the potential to play a causal role in the generation of psychiatric symptoms, particularly depressive symptoms, with multiple studies suggesting a potential causal relationship of IR on depressive symptoms. Defining mechanistic links between mental health and metabolic disorders have important clinical implications that may improve our approach to treating both mental and physical health disorders in Veterans with a history of trauma.

Study Design and Methods: Interrelationships among NA signaling (estimated by standing systolic blood pressure), insulin sensitivity (estimated by Oral Glucose Insulin Sensitivity index), and mental health symptoms will be examined in a population of Veterans with current PTSD. The effect of prazosin-mediated 1 adrenoreceptor antagonism on insulin sensitivity will be assessed in an open label single-arm interventional clinical trial design, with exploratory analysis of a potential mediating effect of improved insulin sensitivity on improvement in depression. These measures will be used to test the hypotheses pertaining to Veterans with PTSD: (1) increased NA signaling and hyperarousal symptoms are associated with lowered insulin sensitivity, (2) lowered insulin sensitivity is associated with elevated depression symptoms, (3) insulin sensitivity will improve with prazosin-mediated 1 antagonism, and (4) improvement in insulin sensitivity will be associated with improvement in depressive symptoms in response to prazosin.

This work is expected to contribute to Veteran's health in three major ways: (1) The investigators are investigating biological mechanisms in Veterans with insulin resistance and PTSD. If this is successful, it will contribute to our understanding of why Veterans with PTSD are at increased risk for comorbid medical conditions related to insulin resistance such as diabetes. (2) The investigators are testing whether noradrenergic blockade with the medication prazosin, currently used to treat PTSD, affects insulin sensitivity in Veterans with PTSD. If successful, this would identify a specific biological pathway that could be targeted for development of novel pharmacotherapeutic approaches to insulin resistance and downstream diabetes in Veterans with PTSD. (3) Our results may also provide information about the effect of insulin sensitivity on depressive symptoms in PTSD. This information has potential to contribute to the development of new strategies for treating, or even preventing, depression in PTSD, as well as overall PTSD treatment strategies.

• prazosin (Drug), also known as Minipress: All participants will receive prazosin for 12 weeks according to a titration schedule informed by our prior studies, up to a minimum of 1mg in the morning and 3mg at night, up to a total daily dose of 16mg as tolerated. Higher doses may be considered as clinically appropriate.

Primary outcomes

• Noradrenergic signaling and insulin sensitivity [5 years]: Correlation between baseline noradrenergic signaling (standing systolic blood pressure) and insulin sensitivity (OGIS)
• Insulin sensitivity change after prazosin [5 years]: Change in insulin sensitivity (OGIS) in response to prazosin

Sex: All, ages: 21 Years to 75 Years

Inclusion Criteria:

1. Veteran of the US military
2. Diagnosis of post-traumatic stress disorder (PTSD) defined by Diagnostic and Statistical Manual of Mental Disorders (DSM-5) symptom count on Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)

Exclusion Criteria:

1. Any form of diabetes as defined by the American Diabetes Association. Exceptions may be made for participants with previously undiagnosed, early, asymptomatic Type 2 Diabetes Mellitus (T2DM) who meet American Diabetes Association criteria for diabetes during study screening who wish to be included
2. Diagnosis of DSM-5-defined bipolar I, schizophrenia spectrum or other psychotic disorders (by MINI)
3. Diagnosis of dementia or related progressive neurocognitive disorder, based on clinical records
4. Diagnosis of moderate or severe substance use disorder (except for caffeine and nicotine) during the preceding 3 months
5. Current use or use within the past 2 weeks of a medication with significant 1-AR or 2-AR activity (prazosin, doxazosin, alfuzosin, clonidine, guanfacine), or opiates
6. Current use or use within the past 3 months of antipsychotics, glucocorticoid medications, or glucose-lowering medications, including but not limited to metformin and GLP-1 agonists
7. Contraindication to prazosin
8. History of moderate or severe Traumatic Brain Injury (TBI) as defined by the Ohio State University TBI Identification Method
9. Increased risk of suicide that necessitates inpatient treatment, intensive outpatient care, or treatment excluded by the protocol
10. Pregnancy or lactation, or anticipated pregnancy at any point during study participation
11. Ongoing or initiation of new treatment with evidence-based trauma-focused therapy for post-traumatic stress disorder (PTSD) within 2 weeks of baseline. Supportive psychotherapy may be continued during the study.
12. Current enrollment in another interventional trial for post-traumatic stress disorder (PTSD)

• Katharine J Liang, MD PhD, Principal investigator, VA Puget Sound Health Care System Seattle Division, Seattle, WA