Inflammation and Threat Sensitivity in PTSD

Posttraumatic stress disorder (PTSD) is a disabling chronic psychiatric disorder that affects
more than 8% of the population. New treatments for PTSD symptoms are desperately needed
because current pharmacologic and behavioral treatments for PTSD are inadequate or they have
low uptake. Accumulating evidence supports elevated inflammation as a new potential treatment
target for PTSD. Inflammation is increased in PTSD, and can promote threat sensitivity, a
core mechanism underlying several PTSD symptoms. Two major gaps in knowledge prevent progress
towards effective anti- inflammatory treatments for PTSD symptoms. First, researchers know
little about the relationship between chronic inflammation and exaggerated threat
sensitivity. Second, no studies have directly examined the effects of acute inflammation on
neural and behavioral measures of threat sensitivity in PTSD. The objective of this study is
to uncover the effects of chronic and acute inflammation on neural mechanisms and behavioral
measures of threat sensitivity in individuals with and without PTSD symptoms. The central
hypothesis is that both chronic and acute inflammation will be associated with exaggerated
threat sensitivity overall, with particularly strong relationships in PTSD. The scientific
rationale is that establishing a link between elevated inflammation and threat sensitivity in
both observational and experimental studies in individuals with and without PTSD symptoms
will drive progress towards a targeted approach to identifying effective anti- inflammatory
treatments for PTSD symptoms. In particular, this work has the potential to identify a target
for clinical trials of anti-inflammatory interventions in PTSD. Guided by preliminary data,
hypotheses will be tested by pursuing two specific aims: 1) Examine the association of
chronic inflammation with threat sensitivity; and 2) Determine the effects of an acute
inflammatory challenge on threat sensitivity. To achieve these aims, 40 participants with
moderate to severe PTSD symptoms and 40 age- and body mass index-matched trauma-exposed
participants with no history of PTSD will be recruited. The investigators will assess chronic
resting levels of inflammation (Aim 1) and will randomize participants to placebo or
inflammatory challenge using polysaccharide typhoid vaccine (i.e., endotoxin) (Aim 2) and
will use validated functional MRI paradigms and behavioral tasks to assess threat
sensitivity.

Inclusion Criteria:

All Subjects:

- Veterans aged 30-60.

PTSD Subjects:

- Positive for current chronic moderate to severe PTSD symptoms of at least three months
duration as indexed by the Clinically Administered PTSD Scale for DSM 5 (CAPS-5).

Control Subjects:

- Negative for lifetime PTSD.

- Negative for lifetime diagnosis of Mood Disorders, Generalized Anxiety Disorder,
Obsessive-Compulsive Disorder and Panic Disorder.

Exclusion Criteria:

All Subjects:

- Lifetime history of any psychiatric disorder with psychotic features, bipolar
disorder, panic disorder, obsessive-compulsive disorder, alcohol or substance
dependence, or a history of alcohol or substance abuse within the past 2 years.

- Currently exposed to recurrent trauma or have been exposed to a traumatic event within
the past 3 months.

- Diagnosis of neurologic disorder, systemic illness affecting central nervous system
function, and/or anemia.

- Prominent suicidal or homicidal ideation.

- Current and planned ongoing use of medications that impact inflammation or immune
function, or use of such medications in the past 6 months.

- Subjects currently receiving serotonin reuptake inhibitors (SSRIs), benzodiazepine or
benzodiazepine receptor agonists, anticonvulsants, atypical antipsychotic medication,
any antidepressant medication including trazodone.

- Termination of SSRIs, benzodiazepine or benzodiazepine receptor agonists,
anticonvulsants, atypical antipsychotic medication, any antidepressant medication
including trazodone in the last month or plans to start these medications during the
course of the study.

- Contraindications to Magnetic Resonance Imaging (MRI), which include claustrophobia
severe enough to prevent MRI examination and presence of ferrometallic objects in the
body that would interfere with MR examination and/or cause a safety risk (e.g., pace
makers, implanted stimulators, pumps).

- Contraindications to typhoid vaccine, which include acute febrile illness within the
past two weeks, disorders characterized by a deficiency in ability to mount a humoral
or cell-mediated immune response, use of anti-malarial medications in past six months,
antibiotics in past three months, a history of hypersensitivity to typhoid vaccine or
any other vaccine, previous immunization with whole-cell typhoid or live, oral typhoid
vaccine, vaccination with the polysaccharide version of the typhoid vaccine within the
past 3 year, coagulation disorders and thrombocytopenia.

- Conditions or use of substances that may be associated with inflammation independent
of trauma and PTSD, including chronic physical disease.

- History of neurologic disorders, traumatic brain injury (TBI), brain tumor, brain
hemorrhage, or head injury with loss of consciousness.

- Women who are currently, or are planning to become, pregnant during the study.

The investigators will not exclude PTSD patients who are receiving psychotherapy, but will
apply the following criteria: patients must have been in treatment for 6 months, meet
symptomatic criteria for inclusion, and do not have plans to discontinue treatment during
the course of the study.