Tricyclic Antidepressants (TCAs) on Gastric Emptying

The normal control subjects will be randomized to receive either amitriptyline or
desipramine as the tricyclic antidepressant agent, with 30 subjects per group. Subjects will
undergo two outpatient gastric emptying/volume tests and two satiety tests; one of each
after 7 days of treatment with oral consumption of the study agent and the other one of each
after 7 days of treatment with placebo. The order of the treatments (active drug or placebo)
will be randomized with 7 days washout between the studies. During the study, the subjects
will consume their regular diet. Subjects will also be randomized to receive either
amitriptyline 25 mg po qhs as the active drug or desipramine 25 mg po qhs as the active
drug. Side effects of the agents will be monitored during the study.

Each subject will undergo a brief history and physical exam prior to entering the study. The
subject will have height and weight measured. A questionnaire will be administered to the
subject inquiring about gastrointestinal symptoms and medical history. This is to screen for
a history of underlying pulmonary, cardiovascular, or gastrointestinal disease. Females will
be studied only during the follicular phase (days 1-10) of the menstrual cycle, to minimize
the effect of the menstrual cycle on motility (Wald, at al). In addition, females will be
given pregnancy screening with a urine beta-human chorionic gonadotropin pregnancy test
(Sure-Vue; Fisher Scientific, Inc) prior to the start of the study.

For the simultaneous gastric volume/emptying tests, subjects will be studied in the fasting
condition. The study subject history and physical examination form will be filled out which
captures information on symptoms for the last week. An intravenous line will be started. The
subject will take study medication with a small sip of water. After 10 minutes, 10 mCi 99mTc
pertechnetate will be infused intravenously over 30 seconds. Imaging of the stomach will be
performed with a gamma camera 20 minutes after injection with both anterior and posterior
imaging followed by SPECT imaging using the General Electric Dual Head MAXXUS (General
Electric Medical Systems) connected to a General Electric Starcam 4000i computer. A total of
360o rotation around the subject will be obtained using a circular orbit (32 stops at 15 sec
per stop) with the heads for the camera close to the subject. After this, the patient will
ingest an egg sandwich labeled with 300 µCi 111Indium-oxine cooked into the eggs to label
the solid material. The subject will consume 300 ml of unlabelled water. Imaging will then
commence immediately after meal ingestion (time 0) for 111In counts to assess solid-phase
gastric emptying using both anterior and posterior imaging. This will be followed
immediately by imaging for the 99mTc counts to assess gastric volumes. Imaging for 99mTc
will be performed with SPECT 3-D imaging. These will be repeated at 20, 40, 60, 80, 100,
120, 150, 180, 210, and 240 minutes after the meal ingestion. Our prior studies show that 4
hour gastric emptying best characterizes gastric emptying. Peak gastric accommodation occurs
at 0-40 minutes. At the time of each imaging, symptoms will be monitored. Symptoms of
abdominal fullness, nausea, abdominal discomfort, and bloating will be graded by the study
subject from 0 (none) to 5 (severe). In addition, an inquiry into possible side effects to
TCAs (sedation, confusion, disturbed concentration, dry mouth, constipation, nausea, and
urinary retention) will be made.

On the next day, the subject will return in a fasting condition for the satiety test. The
methods are similar to those of Tack et al and Chial et al. The subject will take their
study medication. After 30 minutes, the subject will drink the nutrient drink Ensure at a
rate of 100 ml every 5 minutes until the subject feels completely full. After each 100 ml,
symptoms will be monitored, scoring the symptoms of satiety (fullness), nausea, abdominal
discomfort, and bloating on a scale of (0-5). The volume of Ensure consumed by the subject
will be recorded.

Inclusion Criteria:

- Sixty normal subjects, males and females within the ages of 18 to 65 years, will be
studied. Normal control subjects will be recruited for voluntary participation
through poster advertisements. A normal subject is defined as a person with no
gastrointestinal (GI) symptoms; no prior history of peptic ulcer disease or irritable
bowel disease; no previous history of a GI motility disorder (including, but not
limited to, achalasia, gastroparesis); on no medications for GI disorders; no history
of prior surgery on the GI tract (esophagus, stomach, large or small intestine); and
a normal physical examination.

Exclusion Criteria:

- History of a motility disorder (including, but not limited to, achalasia,
gastroparesis)

- History of peptic ulcer disease

- Symptoms referable to gastric dysmotility (nausea, vomiting, early satiety,
heartburn, postprandial abdominal distension)

- Use of medications that may affect GI motor function (beta adrenergic receptor
blockers, calcium channel blockers, histamine type 2 receptor antagonists, proton
pump inhibitors, prokinetic agents, antidepressants, and the use of narcotic
analgesics)

- Regular use of nonsteroidal anti-inflammatory medications

- Use of monoamine oxidase inhibitors

- Pregnancy or breast feeding

- Prior gastrointestinal surgery (except appendectomy)

- Contraindications to amitriptyline or desipramine, which will be exclusion criteria
to the study, include hypersensitivity or allergy to any tricyclic drug, concomitant
therapy with a monoamine oxidase inhibitor, recent myocardial infarction, myelography
within previous 48 hours, or lactation. In addition, history of prostate problems,
history of urinary retention, known glaucoma, history of seizures, or thyroid or
liver dysfunction are exclusionary criteria to the use of TCAs and to entry into this
study.