Therapeutic dosage of antipsychotic drug aripiprazole induces persistent mitochondrial hyperpolarisation, moderate oxidative stress in liver cells, and haemolysis

Aripiprazole has fewer metabolic side effects than other antipsychotics ; however, there are some severe ones in the liver, leading to drug-induced liver injury. Repeated treatment with aripiprazole affects cell division. Since this process requires a lot of energy, we decided to investigate the impact of aripiprazole on the rat liver cells and mitochondria as the main source of cellular energy production by measuring mitochondrial membrane potential, respiration, ATP production, oxidative stress, antioxidative response and human blood haemolysis. Here we report that mitochondrial hyperpolarisation by aripiprazole treatment is accompanied by higher ROS production and increased antioxidative response. Lower mitochondrial and increased glycolytic ATP synthesis demand more glucose through glycolysis for equal ATP production and may change the partition between the glycolysis and pentose phosphate pathway in the liver. Uniform low amounts of haemolysis in the aripiprazole presence of the erythrocytes of 25 individuals indicate lower amounts of NADPH+H+, which is in accord with decreased activity of glucose 6-phosphate dehydrogenase and the lower dehydrogenase activity upon aripiprazole treatment. Lower activity of glucose 6-phosphate dehydrogenase supports the shift to glycolysis, thus rescuing the decreased mitochondrial ATP synthesis. A putative reduction in NADPH+H+ does not seem to affect the oxidised to reduced glutathione ratio, as this remains equal to that in the untreated cells. The effect of aripiprazole on glutathione reduction is likely through direct binding, thus reducing its total amount. As a consequence, low haemolysis of human erythrocytes was observed. Aripiprazole causes moderate perturbations of metabolism, possibly with one defect rescuing the other. The result of increased antioxidant enzyme activity upon aripiprazole treatment is increased resilience to oxidative stress, which makes it an effective drug in schizophrenia in which oxidative stress is constantly present because of disease and ...