Pharmacoepigenetics of Bipolar Disorder Treatment
| Status: | Completed |
|---|---|
| Conditions: | Psychiatric, Bipolar Disorder |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 18 - 65 |
| Updated: | 2/16/2018 |
| Start Date: | November 2015 |
| End Date: | September 2017 |
Pharmacoepigenetics of Second Generation Antipsychotic-Induced Insulin Resistance in Bipolar Disorder
Insulin is a hormone produced by the body to regulate blood sugar. Insulin resistance is a
state when the body is not using insulin correctly, and more insulin is needed to maintain
normal blood sugar. Insulin resistance is common in bipolar patients and even more common in
bipolar patients treated with antipsychotics. Insulin resistance from antipsychotics can lead
to type 2 diabetes, metabolic syndrome and cardiovascular disease and is known to lead to
worse psychiatric outcomes (less mood stability) and lower life expectancies in bipolar
disorder. Abnormal regulation of the folate cycle is known to play a role in
antipsychotic-induced insulin resistance and the main endpoint to the folate cycle is the
production of methyl donors for DNA methylation. DNA methylation is critical as it regulates
how genes are expressed. Thus, changes in DNA methylation may play a role in the disease
process of antipsychotic-induced insulin resistance. The purpose of this study is to examine
the differences in the DNA methylation of candidate tissues known to have a role in the
development of insulin resistance. The three groups of bipolar patients to be studied are 1)
antipsychotic treated patients with impaired glucose tolerance, 2) antipsychotic treated
patients with normal glucose tolerance and 3) lithium treated patients with normal glucose
tolerance. Group 1 will be compared to groups 2 and 3 in order to assess how DNA methylation
in the skeletal muscle and fat tissue changes due to medication effects (group 2 vs. 3) and
medication side effects (group 1 vs. 2). Secondary analyses include the analysis of how fats
are processed in skeletal muscle and fat tissue in relation to antipsychotic-induced insulin
resistance and the correlation of DNA methylation across different tissues. The investigators
hypothesize that antipsychotic-induced insulin resistance is to due changes in the way DNA is
expressed (through epigenetic changes) which causes further changes in the way fats are
processed in the body eventually leading to insulin resistance. This work is based on
preliminary findings however further work is needed to identify the true mechanisms behind
antipsychotic-induced insulin resistance and in particular, the main tissue in which this
mechanism occurs.
state when the body is not using insulin correctly, and more insulin is needed to maintain
normal blood sugar. Insulin resistance is common in bipolar patients and even more common in
bipolar patients treated with antipsychotics. Insulin resistance from antipsychotics can lead
to type 2 diabetes, metabolic syndrome and cardiovascular disease and is known to lead to
worse psychiatric outcomes (less mood stability) and lower life expectancies in bipolar
disorder. Abnormal regulation of the folate cycle is known to play a role in
antipsychotic-induced insulin resistance and the main endpoint to the folate cycle is the
production of methyl donors for DNA methylation. DNA methylation is critical as it regulates
how genes are expressed. Thus, changes in DNA methylation may play a role in the disease
process of antipsychotic-induced insulin resistance. The purpose of this study is to examine
the differences in the DNA methylation of candidate tissues known to have a role in the
development of insulin resistance. The three groups of bipolar patients to be studied are 1)
antipsychotic treated patients with impaired glucose tolerance, 2) antipsychotic treated
patients with normal glucose tolerance and 3) lithium treated patients with normal glucose
tolerance. Group 1 will be compared to groups 2 and 3 in order to assess how DNA methylation
in the skeletal muscle and fat tissue changes due to medication effects (group 2 vs. 3) and
medication side effects (group 1 vs. 2). Secondary analyses include the analysis of how fats
are processed in skeletal muscle and fat tissue in relation to antipsychotic-induced insulin
resistance and the correlation of DNA methylation across different tissues. The investigators
hypothesize that antipsychotic-induced insulin resistance is to due changes in the way DNA is
expressed (through epigenetic changes) which causes further changes in the way fats are
processed in the body eventually leading to insulin resistance. This work is based on
preliminary findings however further work is needed to identify the true mechanisms behind
antipsychotic-induced insulin resistance and in particular, the main tissue in which this
mechanism occurs.
This study will be composed of 2 visits. The first visit will be used as a screening visit
for inclusion of the three groups of patients for the second visit where the outcomes will be
collected (e.g., tissue samples for DNA methylation and lipidomic analysis).
for inclusion of the three groups of patients for the second visit where the outcomes will be
collected (e.g., tissue samples for DNA methylation and lipidomic analysis).
Inclusion Criteria:
1. Aged 18-65 with a Bipolar Spectrum Diagnosis (Bipolar I, II or NOS)
2. Currently treated with lithium or an antipsychotic as determined by a physician for at
least 3 months at a stable dosage.
3. Non- obese with BMI < 30
4. Able to communicate meaningfully with the investigator and legally competent to
provide informed written consent.
5. Females must be non-lactating, have a pregnancy test and be on acceptable birth
control
105 subjects will be studied in total from three groups:
1. One group will consist of 35 bipolar patients currently stable on an antipsychotics
with impaired glucose tolerance (2-hour postprandial plasma glucose of 140-199mg/dL).
2. The second group will consist of 35 age, gender, and body composition matched bipolar
patients currently stable on an antipsychotic with normal glucose tolerance (2-hour
postprandial plasma glucose <140mg/dL.
3. The third group will consist of 35 age, gender and body composition matched bipolar
subjects stable on lithium with normal glucose tolerance.
Exclusion Criteria:
1. Currently diagnosed with diabetes (type I or II) or receiving treatment for diabetes.
Any history of metabolic complications (weight gain, high cholesterol, high blood
pressure) before taking an antipsychotic.
2. Active diagnosis of alcohol or substance abuse.
3. Primary relative diagnosed with type II diabetes.
4. Treated with any of the following medications: a) Systemic glucocorticoids (more than
2 weeks), antineoplastic agents, transplant medications, anti-retroviral medications
within 6 months prior to screening.
- Start or change of hormonal replacement therapy within 3 months prior to
screening.
5. History or presence of any of the following conditions
- Clinically significant heart disease (New York Heart Classification greater than
grade II; more than non-specific ST-T wave changes on the EKG)
- Peripheral vascular disease (history of claudication)
- Clinically significant pulmonary disease.
- Current uncontrolled hypertension (systolic BP>160 mmHg, diastolic BP>100 mmHg)
- History or presence of malignancy other than basal cell or squamous cell skin
cancer
- Clinically significant hematologic disease
6. Any of the following abnormal laboratory values:
- Hematocrit < 35 vol%
- Serum creatinine > 1.6 mg/dl
- aspartate aminotransferase (AST), alanine aminotransferase (ALT) or Alkaline
phosphatase > 2.5 times the upper limit of normal
- Prothrombin time (PT), Partial thromboplastin time (PTT) outside the normal
reference range
- thyroid-stimulating hormone (TSH) outside the normal reference range
- Triglycerides > 400 mg/dl
- Platelet count < 50,000
7. Blood donation within 2 months prior to screening
8. Engage in exercise with moderate to hard intensity for greater than 1 hour per day for
5 or more days per week.
We found this trial at
1
site
Detroit, Michigan 48202
Principal Investigator: Kyle J Burghardt, PharmD
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