Gene-by-Stress Interactions in Intervention Studies Significance

In Aim 3, 100 subjects who participated in previous studies will be recruited to test the
ability of a 5HTR2C agonist (lorcaserin) to increase and antagonist (ziprasidone) to reduce
cortisol response to mental and metabolic stress in men carrying the rs6318 C allele and
women in the rs6318 CC genotype of 5HTR2C. Lorcaserin is serotonin receptor agonist indicated
for use as a weight loss drug. Ziprasidone is an antipsychotic indicated for treatment of
bipolar disorder. Subjects will be treated with a single dose of each drug, 1 to 2 weeks
apart, followed by a mental stress test and an oral glucose tolerance test with multiple
blood draws. Each subject will also receive a placebo drug during one of the study visits.

Inclusion Criteria:

- Men and women who have been enrolled in the STRRIDE, ENHANCED, and/or REMIT studies
age 18 years or greater.

- Ability and willingness to provide informed consent.

- Individuals with specific genotypes as determined from our previous work on their
samples through Aim 1 of this project.

Exclusion Criteria:

- Women who are known to be pregnant, intend to become pregnant, or breast-feeding will
be excluded. Women who are of child bearing potential (under age 55) will be informed
that they will need to have their urine tested for pregnancy and that they should not
participate in the research if they are not willing to have the Investigators provide
them with information on positive pregnancy test results. Subjects will be informed
that the pregnancy testing is not being performed for clinical purposes and that the
testing is not a substitute for their regular medical care if they need to know
whether or not they may be pregnant.

- History of Type II diabetes mellitus.

- History of prolonged QT interval.

- Participation in an investigational drug trial within the last 30 days.

- Already taking either ziprasidone or lorcaserin or any potential confounding
medications, for example, other weight loss medications or psychotropic medications.

- Unwillingness to fast for at least 6 hours prior to the research study visit.