February 2013

Antipsychotics and their adverse metabolic effects

Fig. 1 from February 2013 Skrede et al commentary in the Journal of Lipid Research mentioning the Canfrán-Duque et al article in the same issue. The figure shows cellular lipid homeostasis and regulation of SREBP-controlled cholesterol and fatty acid biosynthetic gene expression in the absence or presence of antipsychotic drugs.

While it’s been known for years that the use of atypical antipsychotic medications is associated with various cardiovascular side effects, researchers still don’t have a clear picture of how these drugs might lead to such risk factors as weight gain, diabetes and high cholesterol.

Antipsychotics have been around since the 1950s and have been essential in the treatment of schizophrenia and other psychiatric disorders. More recently, they also have been prescribed for use in dementia. In 2011, antipsychotic drugs were prescribed to about 3.1 million Americans at a cost of $18.2 billion, according to the market research firm IMS Health.

In their findings presented in “Atypical antipsychotics alter cholesterol and fatty acid metabolism in vitro” in the February issue of the Journal of Lipid Research, Alberto Canfrán-Duque and colleagues at Hospital Ramón y Cajal in Madrid compared the effects of clozapine, risperidone and ziprasidone, three atypical (also known as second-generation) antipsychotics, with those of haloperidol, a first-generation antipsychotic, on intracellular lipid metabolism in three human cell lines. The team’s in vitro results indicated that all four drugs reduced de novo cholesterol biosynthesis, which seems to fly in the face of all the negative metabolic issues experienced by patients.

Canfrán-Duque et al. suggest reduced cholesterol synthesis may lead to a homeostatic feedback mechanism and thus transcriptional activation of fat synthesis. Further, their theory confirms previously published results from others implicating antipsychotics in the trapping of low-density lipoprotein-derived cholesterol in endosomes and lysosomes. While de novo cholesterol biosynthesis in the cell lines decreased in the presence of antipsychotics, biosynthesis of complex lipids like triglycerides and phospholipids increased, explaining the metabolic problems in patients taking antipsychotics.

All four antipsychotics targeted the same enzymes while inhibiting cholesterol biosynthesis, but different drugs had different activity levels against these enzymes, and the mechanisms by which the antipsychotics affect these enzymes still remain to be elucidated.

In a commentary in the same JLR issue, Silje Skrede, Vidar Martin Steen and Johan FernØ of the University of Bergen and Haukeland University Hospital summarize how antipsychotics may increase lipid biosynthesis and cause metabolic problems (see figure). Skrede et al. stress that the new theory put forth by Canfrán-Duque et al. may be relevant to mouse models and human studies and may lead to important research on how intracellular cholesterol biosynthesis and homeostatic activation of fat synthesis cause abnormal lipid levels and obesity.

Mary L. ChangMary L. Chang (mchang@asbmb.org) is managing editor of the Journal of Lipid Research and coordinating journal manager of Molecular & Cellular Proteomics.

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