IntroductionNew oral tyrosine kinase inhibitors (TKIs) are approved for metastatic colorectal cancer (mCRC). The aim of this study was to assess the neuropsychiatric adverse drug reactions (ADRs) of these drugs reported in the FDA Adverse Event Reporting System (FAERS) database.MethodsAll reports with regorafenib (REG) and encorafenib (ENC) as the primary suspect, and reported in the FAERS between 2012 and 2022, were collected. A descriptive and disproportionality analyses were conducted.ResultsOut of 4,984 cases, 1,357 (30.2%) reported at least one neuropsychiatric ADR. New potential signals for REG included neuropathy peripheral (n = 265; reporting odds ratio, ROR = 19.48, 95% confidence interval, CI 95% = 17.52-22.47; information component, IC = 2.89, IC₀₂₅-IC₀₇₅ = 2.77-3.02), hyperesthesia (n = 18; ROR = 12.56, CI 95% = 7.90-19.96; IC = 2.25, IC₀₂₅-IC₀₇₅ = 1.79-2.72), taste disorder (n = 41; ROR = 9.91, CI 95% = 7.29-13.49; IC = 2.18, IC₀₂₅-IC₀₇₅ = 1.88-2.49), poor quality sleep (n = 18; ROR = 6.56, CI 95% = 4.13-10.42; IC = 1.74, IC₀₂₅-IC₀₇₅ = 1.27-2.20), altered state of consciousness (n = 15; ROR = 5.50, CI 95% = 3.31-9.14; IC = 1.57, IC₀₂₅-IC₀₇₅ = 1.06-2.07), depressed mood (n = 13; ROR = 1.85, CI 95% = 1.07-3.19; IC = 0.58, IC₀₂₅-IC₀₇₅ = 0.04-1.13) and insomnia (n = 63; ROR = 1.48, CI 95% = 1.15-1.89; IC = 0.38, IC₀₂₅-IC₀₇₅ = 0.13-0.63). For ENC comprised depressed mood (n = 4; ROR = 5.75, CI 95% = 2.15-15.39; IC = 1.74, IC₀₂₅-IC₀₇₅ = 0.76-2.73) and cognitive disorders (n = 3; ROR = 4.71, CI 95% = 1.51-14.66; IC = 1.54, IC₀₂₅-IC₀₇₅ = 0.41-2.68).DiscussionThis study identified new unknown potential neuropsychiatric ADRs. Further investigations are required to better define the neurotoxicity of TKIs in mCRC patients.