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Karen Houseknecht, Ph.D., professor of Pharmacology in the ɫ����ƵCollege of Osteopathic Medicine and interim dean of the College of Pharmacy, has published novel findings about the effects of risperidone, a widely-used antipsychotic drug, on bone loss in the July 2017 issue of BONE.

Houseknecht’s laboratory focuses on understanding the links between mood and metabolism. Specifically, the lab is interested in understanding why patients with mood disorders have a higher incidence of metabolic disease and why medications used to treat mood disorders often cause metabolic disorders such as obesity, diabetes and bone loss. Atypical antipsychotic (AA) drugs, including risperidone, are FDA-approved to treat psychosis associated with schizophrenia and bipolar disorder, and some are approved to treat irritability associated with autism in children. Despite FDA warning labels relating to significant safety issues in the elderly, over 20% of nursing home residents are prescribed AA drugs. Additionally, many children, adolescents and adults are prescribed AA drugs for diagnoses with no FDA-approved indication for AA use.

AA drugs have been found to cause significant metabolic side effects including obesity, type 2 diabetes, hyperglycemia, sleep disruption and cardiac arrest. Emerging research from Houseknecht and her team has shown that bone is another “off-target” site for AA side effects.

Clinical studies show that patients treated with risperidone have reduced bone density and increased fracture risk. These findings are concerning in populations such as the elderly, where fracture risk is already elevated, and in adolescents who are experiencing peak bone growth. In this paper, Houseknecht and her multi-institutional, collaborative team investigated two fundamental questions: 1) are the negative effects of risperidone on bone due to drug-induced hypogonadism (diminished functional activity of the gonads) and 2) are there direct effects of risperidone on bone?

It is known that risperidone can cause hypogonadism in some patients and hypogonadism is known to cause significant bone loss, as seen with menopause. Houseknecht’s team showed that hypogonadism in mice causes significant bone loss, and that adding risperidone increased the bone loss even more. This indicated that hypogonadism is not the only cause of risperidone-induced bone loss.

Houseknecht then examined the novel hypothesis that antipsychotic drugs could have direct effects on bone. Her team showed for the first time that the function of bone cells that break down bone, osteoclasts, are inhibited by dopamine. The team also found that risperidone, a dopamine blocker, stimulates osteoclast function which is consistent with increased bone loss.  In addition, they reported the novel finding that dopamine and risperidone are found in significant quantities in bone marrow following an oral dose of risperidone in mice, indicating that the drug accumulates in bone.

“We are very excited about these findings as they shed new light on how bone biology is regulated by dopamine, a molecule that is known to be important in regulating mood, and a target for many psychiatric medications,” said Houseknecht. “Our overarching goal is to explore ways to create safer medications to treat mood disorders. Furthermore, we want to inform prescribing practices in order to optimize efficacy and safety for our most vulnerable patients.”

The research team comprises:

Katherine J. Motyl, Ph.D., of the Center for Molecular Medicine at Maine Medical Center Research Institute

Megan Beauchemin, Ph.D., NIH funded post-doctoral fellow in ɫ����Ƶ’s College of Osteopathic Medicine (Houseknecht lab)

Deborah Barlow of ɫ����Ƶ’s College of Osteopathic Medicine (Houseknecht lab)

Phuong T. Le, of the Center for Clinical and Translational Research at the Maine Medical Center Research Institute

Kenichi Nagano, Ph.D., of the Department of Oral Medicine, Infection and Immunity at the Harvard School of Dental Medicine

Annika Treyball, Ph.D., of the Center for Molecular Medicine at Maine Medical Center Research Institute

Anisha Contractor, Morgane Fellow and medical student in ɫ����Ƶ’s College of Osteopathic Medicine

Roland Barron, D.D.S., Ph.D., of the Department of Oral Medicine, Infection and Immunity at the Harvard School of Dental Medicine

Clifford J. Rosen, M.D., of the Center for Clinical and Translational Research at the Maine Medical Center Research Institute

Karen L. Houseknecht, professor of Pharmacology at ɫ����Ƶ’s College of Osteopathic Medicine and interim dean of the College of Pharmacy

This research was funded by NIH grants to Karen Houseknecht (DK095143), Katie Motyl (AR061932 and AR067858) and Cliff Rosen (AG040217). Anisha Contractor was supported by a ɫ����Ƶ College of Osteopathic Morgane Fellowship. Deborah Barlow was supported in part by the ɫ����Ƶ Center for Excellence in Neuroscience.

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