MEtformin and Lorcaserin for WeighT Loss in Schizophrenia

Overview of Procedures: All procedures will be conducted at either the UNC Hospitals
outpatient clinic in Chapel Hill, NC, at the outpatient North Carolina Psychiatric Research
Center (NCPRC), a specialized program of the University of North Carolina Center for
Excellence in Community Mental Health in Raleigh, NC or at the Lieber Schizophrenia Research
Clinic at the New York State Psychiatric Institute (NYSPI) in New York, NY.

Screening: During the initial clinic visit and after giving informed consent, prospective
subjects' psychiatric and medical histories will be reviewed, physical exams conducted,
demographics and vital signs taken, and blood and urine collected. Fasting labs will be
ordered to measure metabolic parameters (lipid profile, glucose, hemoglobin A1C, insulin and
lipids) as well as a complete blood count (CBC), electrolytes, liver/renal function tests,
TSH, urinalysis (UA), serum pregnancy test, and urine drug screen (UDS). The Structured
Clinical Interview for DSM-IV will be administered to confirm diagnoses and the Clinical
Global Impressions-Severity (CGI-S) will be used to evaluate global psychopathology.

The baseline visit will be scheduled within 28 days of the screening visit. A battery of
assessments will be administered including the Clinical Global Impressions-Severity (CGI-S),
the Alcohol Use Scale (AUS), Drug Use Scale (DUS), Brief Psychiatric Rating Scale (BPRS),
Columbia Suicide Severity Rating Scale (C-SSRS), three assessments to measure eating behavior
(EDE-Q, TFEQ, and FCI). In addition to the paper pencil assessments, a 24 hour food recall
assessment will be administered as a telephone questionnaire by trained personnel from the
UNC Nutrition and Obesity Research Center. Accelerometry will also be used to estimate
subjects' sedentary and active behavior. Dual-Energy X-ray Absorptiometry (DXA) will also be
conducted at the baseline visit (UNC location only). Lastly, the first behavioral
intervention lesson will occur at the baseline visit, providing direct lesson instruction and
a diary for subjects' to take home for recording their homework and progress.

At the completion of the baseline visit, subjects who continue to meet study inclusion
criteria will be randomized to one of the three treatment groups (lorcaserin & metformin,
lorcaserin, and placebo). Lorcaserin will be administered in dosages of 10mg with a maximum
dose of 20mg. Metformin will be administered in dosages of 500mg with a maximum dose of
2,000mg. In addition, matching placebos will be administered for each drug. Doses will be
adjusted based on subject tolerability.

All participants will be offered a behavioral intervention of weekly diet and exercise
counseling aimed at modifying cardiovascular risk factors including weight, activity level,
blood glucose, blood pressure and lipids. This intervention will be provided by a trained
clinician in individualized sessions at all study visits after the Baseline Visit and
supplemented with weekly interim phone calls to reinforce lessons between visits. The
intervention was adapted from a weight-reduction program developed for patients with severe
mental illnesses (Brar et al., 2005) and was used in the METS (Jarskog et al., 2013) and CAMP
(Stroup et al., 2012) trials and is therefore well known to our research group and readily
implemented as part of the current proposal.

After study enrollment, subjects will be scheduled for a Week 1 and Week 2 study visit. The
purpose of these visits will be to assess medication management (i.e., symptoms, adverse
events/side effects, adherence, adjust dose as indicated), collect vital signs, and provide
the behavioral therapy intervention. The CGI-S will be completed again at both Week 1 and
Week 2, however, the BRPS and C-SSRS will be completed at Week 2 only.

The next 5 study visits will be scheduled as bi-weekly in-person visits. These visits will be
similar to Week 1 and Week, 2 with the addition of the Substance Use Scale and Alcohol Use
Questionnaire. After the first two behavioral intervention sessions, interim telephone calls
will be made between in-person study visits to each participant to reinforce elements of the
program and to answer questions.

After the Week 12 study visit, all in-person study visits will transition to monthly visits
for the rest of the year. The interim telephone calls will be made bi-weekly between the
in-person study visits to each participant to continue to reinforce elements of the program
and to answer questions.

At Week 52, all study measures and fasting labs will be collected again.

Vital signs, adverse events, and side effects will be obtained at all in-person study visits.
Monitoring labs and appetite regulating hormones will be done at Week 12, Week 24, Week 36,
and Week 52.

Inclusion Criteria:

- Outpatients with a diagnosis of schizophrenia or schizoaffective disorder as defined
by DSM-IV-TR criteria (see Appendix 3 and Appendix 4) and confirmed by the Structured
Clinical Interview for DSM-IV (SCID).

- Duration of psychotic illness must be greater than one year, as defined by having
initiated antipsychotic treatment at least 1 year prior to study enrollment.

- Must be 18-65 years of age.

- Must demonstrate adequate decisional capacity to make a choice about participating in
this research study and must provide written informed consent to participate.

- BMI greater than or equal to 27 kg/m2

- Currently treated with one or a combination of two FDA-approved antipsychotic
medications (typical or atypical antipsychotics) AND on that drug regimen for at least
two months prior to study entry (with stable dosages for at least 1 month).

- Concomitant medications are allowed if agents and doses are unchanged for at least 1
month prior to study entry and if these medications are not among those excluded in
the Exclusion Criteria.

- Women who can become pregnant must be using an adequate method of contraception to
avoid pregnancy throughout the study and for up to 4 weeks after the study in such a
manner that the risk of pregnancy is minimized. Acceptable methods include oral,
injectable or implanted contraceptives, intrauterine devices or barrier methods such
as condoms, diaphragm and spermicides. Women who can become pregnant must have a
negative serum pregnancy test at the Screening Visit.

Exclusion Criteria:

- Inpatient status

- Clinical Global Impression Severity (CGI-S) score greater than or equal to 6

- Current treatment with more than 2 antipsychotics

- HbA1c greater than or equal to 6.5%

- Diagnosis of diabetes mellitus or current treatment with insulin or oral hypoglycemics

- Current or prior treatment with metformin within the past 3 months

- Current or prior treatment with lorcaserin within the past 3 months

- Current or prior treatment with a 5-HT2B agonist (e.g. cabergoline) within the past 45
days due to potential risk for heart valve defects

- Current treatment with two or more antidepressants

- Current treatment with a single antidepressant prescribed in excess of the maximum
approved dose

- Current treatment with monoamine oxidase inhibitor (MAOI) class of antidepressants
(isocarboxazid, phenelzine, selegiline, tranylcypromine)

- Concurrent treatment with any of the following pro-serotonergic drugs: meperidine,
buspirone, dextromethorphan, triptans, tramadol, ritonavir, tryptophan, ginseng, St.
John's wort

- Diagnosis of congestive heart failure

- Uncorrected thyroid disorder

- Renal impairment as evidenced by estimated glomerular filtration rate (eGFR) 50
mL/min/1.73 m2

- Hepatic disease (ALT, AST, or GGT > 2 times upper limit of normal (ULN), total
bilirubin > 1.2 times ULN)

- Metabolic acidosis (serum CO2 <20 mEq/L)

- Known hypersensitivity to metformin or lorcaserin

- Women who are pregnant or breastfeeding

- Recent (in the past 30 days) or scheduled radiological studies involving iodinated
contrast material

- Alcohol abuse/dependence as determined by SCID within the past month

- Other serious and unstable medical condition in the judgment of the investigator

- DSM-IV diagnosis of mental retardation or dementia

- Any medication (prescription or non-prescription) used for weight loss must have been
discontinued 3 months prior to study entry.