Noradrenergic and Stress-Related Etiologies of Chronic Fatigue Syndrome

Symptoms of Chronic Fatigue Syndrome (CFS) are critically important to study as patients
report that these symptoms are often profoundly debilitating and an impediment to effective
daily functioning as well as effective vocational and social functioning, while also
contributing to a significantly increased risk of psychiatric illness and diminished quality
of life. Previous Phenome-Wide Association (PheWAS) studies revealed a link between a
norepinephrine transporter (NET) genetic variant and CFS. Based on the potential function of
the variant and published literature, elevated norepinephrine (NE) levels may underlie at
least some cluster of fatigue symptoms. Some patients may experience chronic fatigue that is
due to an excess of circulating NE, and fatigue symptoms are reported by our patient
population to be commonly exacerbated by stress. This study will test the hypothesis that in
a subset of people with severely debilitating fatigue of long duration (>6 months) that is
worsened by stress identified through the Vanderbilt electronic health record phenotyping
study, have chronic over-release of the hormone NE into the bloodstream/periphery over time
that results in an overload of NE. This overload of NE causes a compensatory but deleterious
effect on the brain and nervous system, including sympathetic effects and dysregulated
physiologic response to stress. Thus, while numerous currently approved therapies that target
NET inhibit the transporter, a drug with the opposite mechanism of action, a NET activator
that would decrease circulating NE, may have efficacy in treating underlying pathophysiology
of chronic fatigue.

Baseline NE levels and stress-induced NE levels in patients who fulfill criteria for CFS and
who self-identify with stress induced worsening fatigue, will be compared to data from normal
individuals pre and post-stress. After all inclusion criteria has been confirmed, an IV will
be placed for blood collection, a continuous electrocardiographic trace and blood pressure
cuff will be placed on the subject's arm and finger. Subjects will undergo a posture study,
autonomic reflex testing, and Stroop stress testing each followed by blood specimen
collection. An optional blood draw for DNA analysis will occur after patients have been
provided lunch. Questionnaires will be completed after study procedures and patients have
been provided lunch. Study blood collection will total up to 28 milliliters (mL): 5 mL for
cytokines, 20 mL for catecholamines, and optional 3 mL for DNA.

Chronic Fatigue Participants:

Inclusion Criteria:

- Confirmed chronic fatigue with severity >50 on a scale of 1 to 100 that is not
improving over time

- Meet The Centers for Disease Control and Prevention (CDC) diagnostic criteria of CFS
(self-reported persistent or relapsing fatigue lasting 6 or more consecutive months)

Exclusion Criteria:

- Male and female subjects <18 or >60 years

- Obesity, defined as a BMI of 30 or more

- Presence of other medical or psychiatric conditions known to cause fatigue
(alcohol/drug abuse, anorexia nervosa, bipolar disorder, bulimia nervosa, dementia,
major depression, psychotic/delusional disorders, schizophrenia)

- Presence of sleep disorder/disruption known to cause fatigue (sleep apnea, narcolepsy)

- Cardiovascular, pulmonary, hepatic, or hematological disease by history or prior
testing defined as significant by investigator (including but not limited to chronic
hepatitis, chronic kidney disease, cirrhosis, emphysema, heart failure, HIV, lupus,
multiple sclerosis, myasthenia gravis, rheumatoid arthritis)

- History of hypertension defined as supine resting BP>145/95 mmHg off medications or
needing antihypertensive medication

- Patients taking medications that can affect autonomic function or plasma
catecholamines (vasoactive drugs), stimulants, and/or are sedatives

- Other factors which in the opinion of the investigator could potentially impact the
study outcomes (e.g., underlying disease, medications, history)* or prevent the
participant from completing the protocol (poor compliance or unpredictable schedule)

- Inability to stand unassisted for 10 minutes

- Patients who are bedridden or chair-ridden

- Patients who are colorblind

- Inability or refusal to give informed consent for any reason including a diagnosis of
dementia or cognitive impairment

- Patients who are pregnant or breastfeeding

Healthy Control Participants:

- Participant with no significant reported conditions or medications.

Exclusion Criteria:

- Male and female subjects <18 or >60 years

- Obesity, defined as a BMI of 30 or more

- Presence of any serious or chronic disease, or prescription medication as deemed by
investigator including hypertension as defined by supine resting BP >145/95 mmHg off
medications or needing antihypertensive medication

- Other factors which in the investigator's opinion would prevent the participant from
completing the protocol, including poor compliance during previous studies or an
unpredictable schedule

- Inability to stand unassisted for 10 minutes

- Patients who are bedridden or chair-ridden

- Patients who are colorblind

- Inability or refusal to give informed consent for any reason including a diagnosis of
dementia or cognitive impairment

- Patients who are pregnant or breastfeeding

- Stress Overload Score above 66