The pharmaceutical industry is facing enormous challenges due to high drug attribution rates. For the past decades, novel methods have been developed for safety and efficacy testing, as well as for improving early development stages. In vitro screening methods for drug-receptor binding are considered to be good alternatives for decreasing costs in the identification of drug candidates. However, these methods require lengthy and troublesome labeling steps. Biosensors hold great promise due to the fact that label-free detection schemes can be designed in an easy and low-cost manner. In this paper, for the first time in the literature, we aimed to compare the potential of label-free optical and impedimetric electrochemical biosensors for the screening of antipsychotic drugs (APDs) based on their binding properties to dopamine receptors. Particularly, we have chosen a currently-used atypical antipsychotic drug (Buspirone) for investigating its dopamine D3 receptor (D3R) binding properties using an impedimetric biosensor and a nanoplasmonic biosensor. Both biosensors have been specifically functionalized and characterized for achieving a highly-sensitive and reliable analysis of drug-D3R binding. Our biosensor strategies allow for comparing different affinities against the D3R, which facilitates the identification of strong or weak dopamine antagonists via in vitro assays. This work demonstrates the unique potential of label-free biosensors for the implementation of cost-efficient and simpler analytical tools for the screening of antipsychotic drugs.