The occurrence of psychotic manifestation following the initiation of everolimus in a patient with tuberous sclerosis: a possible involvement of dysregulated mTOR cascade

Abstract

Tuberous sclerosis (TSc) is an autosomal dominant multisystemic disorder. Mutant TSC1 and TSC2 are the responsible genes for the disorder that leading to a hyperactivation of the mammalian target of rapamycin (mTOR), a signaling cascade involved in cell growth, proliferation, protein synthesis, and metabolism. Everolimus and sirolimus, the mTOR inhibitors, are recently offered to restore pathologically up-regulated mTOR pathway in TSc. However, the neuropsychiatric side effects of these drugs are yet to be studied. Here we reported a 22-year-old male patient, with diagnoses of tuberous sclerosis, epilepsy, learning disability, and organic personality disorder without any psychotic manifestations, who was admitted to our outpatient clinic because of disorganized behavior, hallucinations, and delusions with a recent history of hostility and aggression. The aforementioned psychotic manifestations initiated soon after he had undergone on a placebo-controlled double-blind study of everolimus 6 mg/daily for TSc for last four months. Clinical examination, laboratory screening, and magnetic resonance imaging (MRI) of the brain have not revealed any other organic causes of psychosis. His symptoms resolved over the next ten or so days with moderate doses of antipsychotics. The current case is presented in order to discuss possible underlying neuronal signaling mechanisms those may lead psychosis following a short-term mTOR inhibition treatment. Although it would be difficult to allege the direct involvement of short-term everolimus exposure in the development of psychotic symptoms, impaired protein synthesis related to the mTOR inhibition leads to impaired neuronal network and plasticity, and may predispose to the development of psychotic symptoms, consequently.

Target Discovery Using Deep Learning-Based Molecular Docking and Predicted Protein Structures With AlphaFold for Novel Antipsychotics

“…Everolimus, also an immunosuppressant, is a drug that acts on the mechanistic target of rapamycin and that affects the growth of neural stem cells [ 66 ]. A case study has been reported in which everolimus also induced psychosis [ 67 ], but in a previous study, the use of everolimus in children and adolescents with tuberous sclerosis resulted in a decrease in prepulse inhibition, an indicator of psychosis and sensorimotor gating [ 68 - 70 ]. In this study, high binding affinities between cyclosporine and everolimus, and the receptors found in this study, were discovered.…”