Fig. 6. Clinically-relevant differences among antipsychotics in vitro.

Olanzapine overloads endolysosomes with cholesterol, affecting lysosomal function and autophagosome degradation. Moreover, it induces SREBPs cleavage, SREBPs target gene transcription and it induces lipid droplets accumulation, without affecting AMPK. Risperidone induces the transcription of lipid synthesis enzymes and lipid droplets accumulation, without perturbing endolysosomes. Metformin reverts the effects of risperidone and olanzapine on lipid droplets in an AMPK-dependent way, by inhibiting the transcription and function of lipid synthesis enzymes and by promoting autophagy. Metformin reverts partially the effects of olanzapine on cholesterol and lysosomes by promoting cholesterol clearance through bile acid formation, and by promoting autophagy in an AMPK-dependent way; it does not revert the SREBP2 activation due to olanzapine, putatively caused by molecular mimicry on cholesterol biosynthesis, that was not investigated in this work. Ziprasidone, as metformin, activates AMPK improving the autophagic flux and reducing lipid droplets accumulation. LDL Low Density Lipoproteins, fC free cholesterol, CE cholesterol ester, BA bile acids, OLA olanzapine, RIS risperidone, Met Metformin, ZIP ziprasidone.