Transcriptome analysis of human induced excitatory neurons supports a strong effect of clozapine on cholesterol biosynthesis

Antipsychotics are known to modulate dopamine and other neurotransmitters which is often thought to be the mechanism underlying their therapeutic effects. Nevertheless, other less studied consequences of antipsychotics on neuronal function may contribute to their efficacy. Revealing the complete pic...

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Bibliographic Details
Published in:Schizophrenia research 2021-02, Vol.228, p.324-326
Main Authors: Das, Debamitra, Peng, Xi, Lam, Anh-Thu N., Bader, Joel S., Avramopoulos, Dimitrios
Format: Article
Language:English
Subjects:
Antipsychotic Agents - pharmacology
Antipsychotic Agents - therapeutic use
Antipsychotics
Cholesterol
Cholesterol metabolism
Clozapine
Clozapine - pharmacology
Clozapine - therapeutic use
Gene expression
Gene Expression Profiling
Humans
Neurons
Olanzapine - therapeutic use
Schizophrenia
Schizophrenia - drug therapy
Transcriptome
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Summary:Antipsychotics are known to modulate dopamine and other neurotransmitters which is often thought to be the mechanism underlying their therapeutic effects. Nevertheless, other less studied consequences of antipsychotics on neuronal function may contribute to their efficacy. Revealing the complete picture behind their action is of paramount importance for precision medicine and accurate drug selection. Progress in cell engineering allows the generation of induced pluripotent stem cells (iPSCs) and their differentiation to a variety of neuronal types, providing new tools to study antipsychotics. Here we use excitatory cortical neurons derived from iPSCs to explore their response to therapeutic levels of Clozapine as measured by their transcriptomic output, a proxy for neuronal homeostasis. To our surprise, but in agreement with the results of many investigators studying glial-like cells, Clozapine had a very strong effect on cholesterol metabolism. More than a quarter (12) of all annotated cholesterol genes (46) in the genome were significantly changed at FDR 
ISSN:0920-9964
1573-2509
DOI:10.1016/j.schres.2020.12.041