Vidar Martin Steen´s group

Molecular mechanisms of antipsychotic-induced metabolic adverse effects

Background

Antipsychotic agents are essential in the treatment of schizophrenia and important supplements in the treatment of other serious psychiatric disorders. While effectively alleviating psychotic symptoms, these agents have serious adverse effects complicating their use. Older, so-called first-generation, agents induce distressing motor symptoms. Modern (second-generation) drugs are known to severely increase the risk of metabolic side effects such as increased food intake, obesity, dyslipidemia, and type 2 diabetes (1). Weight gain is generally believed to be caused by increased food intake; however, recent studies have indicated that some metabolic adverse effects, such as dyslipidemia, may occur independent of weight gain (2).

Metabolic adverse effects reduce compliance and likely contribute to increased cardiovascular disease mortality among schizophrenic patients (3). Targeted augmenting strategies or, ideally, antipsychotic agents without metabolic adverse effects would greatly improve psychiatric care. As the molecular mechanisms behind metabolic adverse effects may not be straightforwardly explained by their receptor binding profiles, our work revolves around the elucidation of these mechanisms. Our work has shown that antipsychotic agents directly activate the SREBP transcription factors, pivotal regulators of lipid biosynthesis.

Animal models for antipsychoic-induced weight gain

Many attempts have been made in order to model antipsychotic-induced metabolic dysfunction, predominantly in rodents. Former work has centred on the most readily observable metabolic side effect, namely weight gain, which has been reported in female rats treated with antipsychotic agents (4, 5). In male rats, treatment with antipsychotics does not induce weight gain, but adipose tissue mass has been shown to increase during subchronic treatment (6, 7). Our main utilization of MR is to quantify adipose tissue mass before and after treatment with antipsychotics, in order to determine whether increased adipose tissue mass is solely responsible for weight gain in female rats. Working with Tina Pavlin and Sveinung Fjær, we have developed a protocol and method of analysis for visualisation and quantification of abdominal adipose tissue. An example of acquired images is shown in Figure 1.

Figure 1. Screen shot of T1-weighted multi-spin multi-echo (MSME) image showing transverse section through the abdomen of a female rat treated with an antipsychotic drug for 6 weeks. The kidneys are easily identified, and are surrounded by adipose tissue (white). Images are respiratory triggered to avoid respiratory artifacts.

Present projects

Moving from experiments in cell culture to animal experiments, we have performed both acute and chronic experiments in rats. An important issue, as mentioned above, is whether dysmetabolic features other than weight gain may develop in the absence of increased body weight. Manipulating animal models by altering parameters such as food intake, thus controlling weight gain, may shed light on such issues. Other fields of interest are gender-specific drug effects in rodents and mechanisms underlying increased food intake. Imaging techniques will be valuable in characterizing the metabolic phenotype of our animal model.

Participants/collaborators

1. Vidar Martin Steen, professor, Dr. Einar Martens Research Group for Biological Psychiatry
2. Johan Fernø, post doc, Dr. Einar Martens Research Group for Biological Psychiatry
3. Silje Skrede, PhD student, Dr. Einar Martens Research Group for Biological Psychiatry
4. Sveinung Fjær, M.Sc., computational mathematics, MS group, Department of Neurolgy
5. Marianne Nævdal, research technician, Dr. Einar Martens Research Group for Biological Psychiatry

References

1. D. B. Allison, A. D. Loebel, I. Lombardo, S. J. Romano and C. O. Siu: Understanding the relationship between baseline BMI and subsequent weight change in antipsychotic trials: effect modification or regression to the mean? Psychiatry Res, 170(2-3), 172-6 (2009)
2. A. B. Birkenaes, K. I. Birkeland, J. A. Engh, A. Faerden, H. Jonsdottir, P. A. Ringen, S. Friis, S. Opjordsmoen and O. A. Andreassen: Dyslipidemia independent of body mass in antipsychotic-treated patients under real-life conditions. J Clin Psychopharmacol, 28(2), 132-7 (2008)
3. J. W. Newcomer and C. H. Hennekens: Severe mental illness and risk of cardiovascular disease. JAMA, 298(15), 1794-6 (2007)
4. M. J. Fell, K. M. Marshall, J. Williams and J. C. Neill: Effects of the atypical antipsychotic olanzapine on reproductive function and weight gain in female rats. J Psychopharmacol, 18(2), 149-55 (2004)
5. M. Kalinichev, C. Rourke, A. J. Daniels, M. K. Grizzle, C. S. Britt, D. M. Ignar and D. N. Jones: Characterisation of olanzapine-induced weight gain and effect of aripiprazole vs olanzapine on body weight and prolactin secretion in female rats. Psychopharmacology (Berl), 182(2), 220-31 (2005)
6. V. L. Albaugh, J. G. Judson, P. She, C. H. Lang, K. P. Maresca, J. L. Joyal and C. J. Lynch: Olanzapine promotes fat accumulation in male rats by decreasing physical activity, repartitioning energy and increasing adipose tissue lipogenesis while impairing lipolysis. Mol Psychiatry (2010)
7. J. Minet-Ringuet, P. C. Even, P. Valet, C. Carpene, V. Visentin, D. Prevot, D. Daviaud, A. Quignard-Boulange, D. Tome and R. de Beaurepaire: Alterations of lipid metabolism and gene expression in rat adipocytes during chronic olanzapine treatment. Mol Psychiatry, 12(6), 562-71 (2007)