Psychotic disorder induced by a combination of sorafenib and BAY86-9766

The Ras-Raf-mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK cascade is important in the intra-cellular transduction of neurotransmitters, such as dopamine and glutamate. Sorafenib (Nexavar), a multi-kinase inhibitor targeting Raf kinase, vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor, has shown promising results in the treatment of malignancies. BAY86-9766, a novel selective MEK 1/2 inhibitor, is being evaluated in clinical trials as an anticancer drug. We describe herein a hepatocellular carcinoma patient presenting with recurrent psychotic symptoms in the course of the BASIL trial (assessing BAY86-9766 plus sorafenib for the treatment of liver cancer). In this case, VEGFR inhibition caused by sorafenib alone may have contributed to the development of psychosis. A change in ERK activity might also have been involved. However, whether single or combination use of the two drugs is responsible for inducing the psychotic symptoms remains unclear. In summary, the role of the ERK pathway in psychosis is still vague. Further investigation of the ERK activity in patients with psychotic disorders may disclose its role in the pathophysiology of psychosis.