Antipsychotics are used to treat severe mental and neurological pathologies such as schizophrenia and bipolar disorder. This class of drugs was first brought to market in the 1950s, and while effective, significant side effects were associated with these first generation anti-psychotic drugs. In the 1980s a second generation of antipsychotic drugs was introduced in an effort to minimise the side effects of the current treatments.While the second generation broadly improved upon the first, the new drugs have their own set of issues, and shared some side effects with the first generation antipsychotics including QT interval prolongation, increased likelihood of seizures (seizurogenic response), and potential hepatotoxicity.
Using a combination of in vitro platforms, we tested drugs from both generations in three whole-cell assays using both microelectrode array (MEA) technology and high content screening (HCS), to understand potential cardiotoxicity, neurotoxicity and hepatotoxicity. MEA was used to assess electrophysiological responses in both neurons and cardiomyocytes, and HCS was used to assess hepatotoxicity risk.
The neuronal MEA assay confirmed the neuroactive liabilities of the anti-psychotics including increased seizurogenic potential, while the cardiomyocyte MEA assay recorded data consistent with hERG channel inhibition. Furthermore, HCS methods accurately identified potential mechanisms of liver toxicity. Across all platforms, the assays showed strong concordance with known in vivo liabilities and side effects, and indicates the viability of this suite of assays as a drug discovery screening tool for early detection of potential liabilities relating to cardiotoxicity, neurotoxicity and hepatotoxicity.
This research was presented at 2016 SOT.