Antipsychotic Drugs and Diabetes Research
Treatment for schizophrenia and bipolar disorder often includes prescriptions for atypical antipsychotic medications. It has been observed that many patients receiving these drugs experience rapid and substantial weight gain. Some patients treated with antipsychotics develop Type 2 diabetes, and those already diabetic find their blood sugars harder to control. Renowned Cedars-Sinai diabetes and obesity researchers Marilyn Ader, PhD, and Richard Bergman, PhD, are investigating these side effects.
Cedars-Sinai Diabetes and Obesity Research Institute (DORI) scientists examined two of the most commonly prescribed antipsychotic drugs on the market. Animal models were given olanzapine, risperidone or a placebo, and body weight and fat and the secretion and effectiveness of insulin was measured before and after six weeks of treatment. The researchers discovered that animals receiving olanzapine developed more metabolic problems. While weight gain did not differ appreciably between groups, magnetic resonance imaging revealed an inordinate increase of fat tissue in animals receiving olanzapine. Furthermore, they observed that as animals treated with olanzapine became insulin resistant, the pancreas did not release more insulin to compensate for the resistance, as it would normally. This abnormality of insulin secretion may be the critical factor that increases diabetes risk in subjects taking this medication.
Ader, associate director of DORI, initially began studying antipsychotic drugs through a researcher-initiated application in 2000. After publishing her early findings in top scientific journals and presenting her results at diabetes and psychiatry conferences throughout the U.S. and abroad, Ader was awarded a grant from the National Institutes of Health to continue her explorations into this important public health problem.
Investigation is now focused on determining how antipsychotics prevent the pancreas from responding to insulin resistance. Because these drugs work on many receptors on cells throughout the body, scientists are simultaneously looking at signaling to the pancreas as well as pancreas and liver function.
Current DORI research on antipsychotic drugs includes the following:
- Determine how antipsychotic drugs impair the ability of the pancreas to compensate for insulin resistance.
- Examine pancreas and beta-cell signaling in animal models.
- Identify which steps in the insulin secretory process are altered during drug treatment.
- Determine whether drugs are impairing the pancreas or interfering with circulating signals that provoke the pancreas to release more insulin when insulin resistance develops.
- Assess the extent to which antipsychotics may impair the ability of the liver to clear insulin from the circulation in the metabolic compensation for insulin resistance.
- Investigate the mechanism by which drugs increase body fat.
- Examine pancreas and beta-cell signaling in animal models.
The adverse side effects of antipsychotic drugs on metabolism are a major public health concern. The broad impact of these drugs is due largely to a dramatic increase in off-label prescribing practices, which has resulted in their use for a wide range of conditions, including for children with autism, aggressive behavior, or ADHD, and for seniors, to treat dementia, depression or anxiety. Some of these patient populations have increased diabetes risk even in the absence of antipsychotic drug use. Children develop insulin resistance during the normal hormonal changes of puberty. African-American and Hispanic subjects have increased diabetes risk and may be more susceptible to the adverse metabolic side effects of antipsychotics. As research elucidates how antipsychotic drugs cause the side effects of weight gain and increased risk of Type 2 diabetes, psychiatrists can better assess the balance between treatment efficacy and negative side effects as they decide the optimal therapy for each patient.
Clarity on the mechanisms affecting fat increase and diabetes may help drug makers create next-generation antipsychotic therapies that will not result in metabolic dysfunction. Ultimately, this research may provide insight on how to curtail obesity and diabetes in the general population.
- Ader M, Kim SP, Catalano KJ, Ionut V, Hucking K, Richey JM, Kabir M, Bergman RN. Metabolic dysregulation with atypical antipsychotics occurs in the absence of underlying disease: a placebo-controlled study of olanzapine and risperidone in dogs. Diabetes. 2005;54(3);862-871. http://diabetes.diabetesjournals.org/content/54/3/862.full.
- Ader M, Garvey WT, Phillips LS, Nemeroff CB, Gharabawi G, Mahmoud R, Greenspan A, Berry SA, Musselman DL, Morein J, et al. Ethnic heterogeneity in glucoregulatory function during treatment with atypical antipsychotics in patients with schizophrenia. J Psychiatr Res. 2008;42(13):1076-1085. http://www.journalofpsychiatricresearch.com/article/S0022-3956(08)00006-X/fulltext.
- Bergman RN, Ader M. Atypical antipsychotics and glucose homeostasis. J Clin Psychiatry. 2005;66(4):504-514. http://europepmc.org/abstract/med/15816794.
- Gohlke JM, Dhurandhar EJ, Correll CU, Morrato EH, Newcomer JW, Remington G, Nasrallah HA, Crystal S, Nicol G; Adipogenic and Metabolic Effects of APDs Conference Speakers [including Ader M], et al. Recent advances in understanding and mitigating adipogenic and metabolic effects of antipsychotic drugs. Front Psychiatry. 2012;3:62. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385013/.
- Ader M, Stefanovski D, Kim SP, Richey JM, Ionut V, Catalano KJ, Hucking K, Ellmerer M, Van Citters G, Hsu IR, et al. Hepatic insulin clearance is the primary determinant of insulin sensitivity in the normal dog. Obesity (Silver Spring). 2014;22(5):1238-1245. http://onlinelibrary.wiley.com/doi/10.1002/oby.20625/abstract.
- Ader M, Stefanovski D, Richey JM, Kim SP, Kolka CM, Ionut V, Kabir M, Bergman RN. Failure of homeostatic model assessment of insulin resistance to detect marked diet-induced insulin resistance in dogs. Diabetes. 2014;63(6):1914-1919. http://diabetes.diabetesjournals.org/content/63/6/1914.abstract.
- Bergman RN, Kim SP Catalano KJ, Hsu IR, Chiu, JD, Kabir M, Hucking K, Ader M. Why visceral fat is bad: mechanisms of the metabolic syndrome. Obesity (Silver Spring). 2006 Feb;14 Suppl 1:16S-19S. http://onlinelibrary.wiley.com/doi/10.1038/oby.2006.277/full.
- Bergman RN, Kim SP, Hsu IR, Catalano KJ, Chiu JD, Kabir M, Richey JM, Ader M. Abdominal obesity: role in the pathophysiology of metabolic disease and cardiovascular risk. Am J Med. 2007 Feb;120(2 Suppl 1):S3-S8; discussion S29-S32. http://www.amjmed.com/article/S0002-9343(06)01361-1/fulltext.
- Hamilton-Wessler M, Ader M, Dea MK, Moore D, Loftager M, Markussen J, Bergman RN. Mode of transcapillary transport of insulin and insulin analog NN304 in dog hindlimb: evidence for passive diffusion. Diabetes. 2002;51(3):574-582. http://diabetes.diabetesjournals.org/content/51/3/574.
- Ader M, Joyce M. Richey JM, Hucking K, Ionut V, Catalano KJ, Kim SP, Kabir M, Bergman RN. Oral glucose tolerance test fails to reveal substantial metabolic abnormalities induced by antipsychotic agents. Meeting: 66th Scientific Sessions (2006). Abstract Number: 1507-P. Category: Integrated Physiology - Regulation of Glucose Kinetics. http://professional.diabetes.org/abstract/oral-glucose-tolerance-test-fails-reveal-substantial-metabolic-abnormalities-induced.
- Ader M, Catalano KJ, Ionut V, Kim SP, Hucking K, Richey JM, Kabir M, Bergman RN. Increased caloric intake explains weight gain with some, but not all, antipsychotic therapy. Meeting: 65th Scientific Sessions (2005). Abstract Number: 1848-P. Category: Obesity - Human.
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