Heart Rate Variability in Response to Metformin Challenge

Diseases caused by brain energy supply defects can be innate (fibromyalgia secondary to familial mitochondrial disorders) or acquired (tardive dyskinesia or weight gain associated with prolonged antipsychotic use). Patients with these possible mitochondrial disorders will provide a baseline resting heart rate sample, ingest low-dose metformin (500 mg), and then provide an additional sample 2 hours later.

Doctors need to develop tests which inexpensively and reliably evaluates brain metabolism. Current diagnostic tests sample other tissues which often run on different fuels (fats), utilize unproven and often insensitive brain imaging scanners, or sequence thousands to millions of base-pairs of DNA. All of these tests are expensive. None of these tests accurately or completely capture the interactions between the 1000s of proteins involved in brain metabolism. The investigators suspect that mathematical analysis of the resting heart rate may provide some insight into brain metabolism. The brain controls heart rate in response to changes in blood pressure and blood gases like carbon dioxide and oxygen. Tight control of heart rate is necessary to make sure that the brain has the right mix of fuel and air. Because the brain can't respond instantly to changes in its fuel supply, this system acting as a biological carburetor has a natural oscillatory rhythm that can be monitored just like frequencies on the radio. The investigators propose to amplify these rhythms by modestly metabolically stressing the brain with metformin, a inhibitor of complex 1 in the mitochondria.

metformin, mitochondria, complex 1, fibromyalgia, neurogenic pain, diabetes, tardive dyskinesia, heart rate variability

Fibromyalgia (subgroups: opioid responsive, opioid resistant, opioid intolerant) Metformin 500 mg orally in the morning

Antipsychotic use (subgroups: no side effects, dyskinesia, weight gain) Metformin 500 mg orally in the morning

ratio of the standard deviation of sampled intervals between each heart beat for ten minutes at time 1 (prior to metformin ingestion) over standard deviation of the sampled intervals between each heart beat for ten minutes at time 2 (2 hours post metformin ingestion)

total power in the frequency domain is estimated for 10 minutes prior to metformin ingestion and then divided by the total power in the frequency domain estimated for 10 minutes 2 hours after metformin ingestion. Ratio is log-transformed.

Patient after testing generated an unprompted list of observed side effects from the medication. Many reported none. Results were scored as the binary presence or absence of side effect

Inclusion Criteria: EITHER chronic neurogenic pain meeting American College of Rheumatology criteria for fibromyalgia or previous/current exposure to antipsychotic medications Exclusion Criteria: recent infection, renal failure, pre-existing cardiac disease, chronic obstructive pulmonary disease inability to participate in informed consent, lack of transport to return home from study site, severe fasting intolerance or hypoglycemia, history of stroke-alike episode, uncontrolled migraine or cyclic vomiting, diabetes on insulin or sulfonylurea, non-English speaker, medications with strong effects on baseline heart rate variability