Abstract
Weight gain and consequent metabolic alterations are common side-effects of many antipsychotic drugs. Interestingly, several studies have suggested that improvement in symptoms and adverse metabolic effects are correlated. We used next generation sequencing data from NT-2 (human neuronal) cells treated with aripiprazole, amisulpride, risperidone, quetiapine, clozapine, or vehicle control, and compared with the Pillinger P-score (ranked from 0 to 1, indicating greater increase in weight gain and related metabolic parameters) to identify the genes most associated with the drugs’ propensity to cause weight gain. The top 500 genes ranked for their correlation with the drugs’ propensity to cause weight gain were subjected to pathway analysis using DAVID (NIH). We further investigated transcription factors (TFs) that are more likely to regulate the genes involved in these processes using the prediction tool of key TFs from TRRUST. The results suggest an enrichment for genes involved in lipid biosynthesis and metabolism, which are of interest for mechanisms underpinning weight-gain. The list of genes involved in the lipid pathways that correlated with weight gain was enriched for genes transcriptionally regulated by SREBF1 and SREBF2. Furthermore, quetiapine significantly increased the expression of SREBF1 and SREBF2 in NT-2 cells. Our results suggest that the effects of these antipsychotic drugs on lipid metabolism may be mediated, at least in part, via regulation of SREBF1/SREBF2 expression, with evidence of a direct effect of quetiapine on the expression of SREBF1/2. The effects of antipsychotic drugs on lipid metabolism may influence white matter structure (therapeutic effect) and the risk of weight gain, lipid disturbances, and, consequently, metabolic syndrome (adverse effects). Understanding the different molecular effects of these drugs could inform a personalized medicine approach in treating patients with schizophrenia.
Highlights
Antipsychotic-Induced Weight Gain (AIWG) is a debilitating and common adverse effect of antipsychotic treatment, and negatively impacts on life expectancy, quality of life, treatment adherence, and the likelihood of developing the metabolic syndrome and type-2 diabetes [1]
We demonstrated that five commonly prescribed antipsychotic drugs change the expression of genes involved in the lipid biosynthesis and metabolic pathways, and that these genes might be regulated by SREBF1 and SREBF2
SREB proteins are transcription factors that play a key role in cholesterol biosynthesis influencing both uptake and fatty acid biosynthesis as well as upregulating the synthesis of sterol biosynthesis enzymes [27]
Summary
Antipsychotic-Induced Weight Gain (AIWG) is a debilitating and common adverse effect of antipsychotic treatment, and negatively impacts on life expectancy, quality of life, treatment adherence, and the likelihood of developing the metabolic syndrome and type-2 diabetes [1]. Several studies have investigated receptor binding profiles to explain the metabolic abnormalities related to weight-gain. The participation of the serotonin 5-HT2 receptors in control of feeding behavior is well established [4], and more recently genetic polymorphisms in the serotonin receptor 2C were associated with an increase in AIWG [5]. With respect to receptor binding profiles olanzapine and clozapine, which block histamine H1, serotonin 5-HT2A/C and dopamine D2/3 receptors, cause the greatest weight gain [6]; while compounds with little or no histamine and serotonin affinity—lurasidone and aripiprazole for example—have a lower risk of weight gain [7]. The effects of neurohormones such as leptin, adiponectin, glucagon like protein 1 (GLP-1), and insulin suggests the involvement of the gut–brain axis might underly both the therapeutic and weight-gain sides [8,9]
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