Modafinil and Cognitive Function in POTS

Postural Tachycardia Syndrome (POTS) is one of the most frequent forms of chronic orthostatic
intolerance and affects an estimated 500,000 people in the United States alone. This disorder
is a common source of disability in young adults, with a strong predilection for
premenopausal women. POTS is characterized by an excessive increase in heart rate (>30 bpm)
on assuming the upright position that is associated with orthostatic symptoms that are
relieved by lying down. These symptoms include palpitations, chest pain, lightheadedness or
dizziness, blurred vision, nausea and fatigue. In addition, POTS patients commonly report
mental clouding or "brain fog" even while lying down or seated, which can pose significant
limitations to daily life.

Although mental clouding is an almost universal complaint among POTS patients, this
phenomenon is poorly understood. As a result, the optimal treatment strategies to manage
cognitive dysfunction in this condition remain unknown. The purpose of this study is to
better define the mental clouding associated with POTS and to determine whether the
psychostimulant modafinil is a viable therapeutic option to improve cognitive function in
these patients. The investigators hypothesize that acute modafinil administration will
improve seated measures of cognitive function in POTS patients. The specific aims are:

1. To assess whether acute modafinil improves seated measures of cognitive function,
particularly measures of attention and executive function, in POTS patients compared to
placebo.

2. To assess whether propranolol, either alone as an active control or in combination with
modafinil to mitigate potential heart rate increases, can improve cognitive function in
POTS.

Patients will be studied on 4 separate days with oral administration of: placebo, modafinil
(200 mg), propranolol (20 mg) and the combination of modafinil (200 mg) and propranolol (20
mg). The order of administration will be randomized in a double-blind manner. Patients will
be seated during the study and cognitive testing will begin approximately 2.5 hours after
medication administration. Cognitive testing will consist of the CogState computerized brief
battery. Patients will also be asked to stand for 10 minutes (or as long as tolerated) at 1,
3 and 4 hours post medication, with some of the cognitive tests repeated while standing at
the 4 hour time point.

Inclusion Criteria:

- Males and females of all races between the ages of 18 to 60 years

- Diagnosed with POTS by the Vanderbilt Autonomic Dysfunction Center based on the
following consensus criteria:(a) an increase in heart rate ≥ 30 beats per minute
within 10 minutes of changing from the supine to standing position; (b) absence of
orthostatic hypotension (defined as a decrease in systolic blood pressure ≥ 20 mmHg or
diastolic blood pressure ≥ 10 mmHg upon standing); and (c) chronic symptoms (≥ 6
months) consistent with POTS that are worse with standing and are relieved by lying
down

- Able and willing to provide informed consent

Exclusion Criteria:

- Overt causes for POTS such as acute dehydration and bed rest deconditioning

- Patients taking serotonin-norepinephrine reuptake inhibitors (SNRIs) or norepinephrine
transporter (NET) inhibitors

- Known allergies or contraindications to study medications

- Pregnancy or breast-feeding

- Inability to give or withdraw informed consent

- Other factors which in the investigator's opinion would prevent the subject from
completing the study protocol such as poor compliance during previous studies

- Asthma (due to the contraindication of propranolol for asthma patients)