The Effects of Fluoxetine and/or DHEA

Study Overview
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Brief Summary
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(1) To determine how the Selective Serotonin Reuptake Inhibitor (SSRI), fluoxetine (Prozac), an antidepressant often used to treat depression, stimulates the participant's body's ability to defend against low blood sugar (hypoglycemia). (2) To learn how a hormone, dehydroepiandrosterone (DHEA), stimulates the participant's body's ability to defend itself from low blood sugar (hypoglycemia). DHEA is a hormone produced naturally in the human body. However, it can be manufactured and is sold as an over-the-counter dietary supplement. The dose the investigators are giving in this study is higher than the usual recommended dosage taken as a supplement for certain medical conditions. (3) To study combined effects of fluoxetine and DHEA during low blood glucose. In the present study, the investigators will measure the participant's body's responses to hypoglycemia when given fluoxetine or DHEA or fluoxetine and DHEA or a placebo (a pill with no fluoxetine or DHEA). Approximately 64 individuals with type 1 diabetes will take part in this study.

Official Title
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The Effects of the Selective Serotonin Reuptake Inhibitor, Fluoxetine and/or DHEA, on Neuroendocrine, Autonomic Nervous System and Metabolic Counterregulatory Responses During Repeated Hypoglycemia in T1DM Individuals

Conditions
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Drug: Placebo Oral Tablet
* Drug: Placebo Oral Tablet
* Drug: Fluoxetine
* Drug: DHEA
* Drug: Fluoxetine and DHEA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 64 (32 males, 32 females) T1DM patients aged 18-50 yr. HbA1c < 11.0% No clinically diagnosed diabetic tissue complications (i.e. history of retinopathy, neuropathy, stasis ulcers, etc) Body mass index < 40kg · m-2 Exclusion Criteria: Pregnancy Subjects unable to give voluntary informed consent Subjects on anticoagulant drugs, anemic or with known bleeding diatheses Subjects taking any of the following medications will be excluded: Non-selective Beta Blockers, Sedative-Hypnotics, Anticonvulsants, Antiparkinsonian drugs, Antipsychotics, Antidepressants, Mood stabilizers, CNS Stimulants, Opioids, Hallucinogens Subjects with a recent medical illness or past history of severe depression, mania or psychotic disease Subjects that score greater than 50 on the depression scale Subjects unwillingness or inability to comply with approved contraception measures Abnormal results following screening tests and physical examination that are clinically significant Subjects with a history of severe uncontrolled hypertension (i.e., blood pressure greater than 160/100), heart disease, cerebrovascular incidents Clinically significant cardiac abnormalities (e.g. heart failure, arrhythmias, ischemic tachycardia, S-T segment deviations, etc.) from history or from cardiac stress testing in subjects ≥ 40 years old. Pneumonia Hepatic Failure/Jaundice Creatinine greater than 1.6 mg/dl Acute Cerebrovascular/ Neurological deficit Fever greater than 38 °C Screening Laboratory Tests Exclusion Criteria Hematocrit lower than 32 WBC lower than 3 thou/ul or greater than 14 thou/ul Liver Function Tests: SGOT and SGPT greater than twice upper limit of normal range (i.e. greater than 80 U/L). TBil greater than 2 mg/dl Alkaline Phosphatase greater than 150U/L Positive HIV, Hep B, Hep C Hepatic transaminase > 2x normal

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomized into 2 groups. Group 1 will consist of a random order of Protocol 1 and Protocol 5. Group 2 will consist of a randomized order of Protocols 2, 3, 4
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo 1<br>Visit 1: Study Day 1: Hyperinsulinemia/ euglycemia clamp in the AM and PM. Study Day 2: Hyperinsulinemia/ hypoglycemia clamp in the AM only. 8-weeks of treatment with placebo Visit 2: same as visit 1 | Drug: Placebo Oral Tablet<br>* There will be two 2-day inpatient visits with 8-weeks of treatment with placebo between those visits.<br>|
| Placebo Comparator: Placebo 2<br>Visit 1: Study Day 1: Hyperinsulinemia/ hypoglycemia clamp in the AM and PM. Study Day 2: Hyperinsulinemia/ hypoglycemia clamp in the AM only. 8-weeks of treatment with placebo Visit 2: same as visit 1 | Drug: Placebo Oral Tablet<br>* There will be two 2-day inpatient visits with 8-weeks of treatment with placebo between those visits.<br>|
| Active Comparator: Fluoxetine<br>Visit 1: Study Day 1: Hyperinsulinemia/ hypoglycemia clamp in the AM and PM. Study Day 2: Hyperinsulinemia/ hypoglycemia clamp in the AM only. 8-weeks of treatment with fluoxetine Visit 2: same as visit 1 | Drug: Fluoxetine<br>* There will be two 2-day inpatient visits with 8-weeks of treatment with fluoxetine between those visits.<br>|
| Active Comparator: DHEA<br>Visit 1: Study Day 1: Hyperinsulinemia/ hypoglycemia clamp in the AM and PM. Study Day 2: Hyperinsulinemia/ hypoglycemia clamp in the AM only. 8-weeks of treatment with DHEA Visit 2: same as visit 1 | Drug: DHEA<br>* There will be two 2-day inpatient visits with 8-weeks of treatment with DHEA between those visits.<br>* Other names: dehydroepiandrosterone;|
| Active Comparator: Fluoxetine and DHEA<br>Visit 1: Study Day 1: Hyperinsulinemia/ hypoglycemia clamp in the AM and PM. Study Day 2: Hyperinsulinemia/ hypoglycemia clamp in the AM only. 8-weeks of treatment with fluoxetine and DHEA Visit 2: same as visit 1 | Drug: Fluoxetine and DHEA<br>* There will be two 2-day inpatient visits with 8-weeks of treatment with fluoxetine and DHEA between those visits.<br>* Other names: Prozac, dehydroepiandrosterone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the level of catecholamines in plasma |  | An average of 3 years |