Drug Tolerance: A Known Unknown in Translational Neuroscience

In neuropsychiatric drug development, the rate of successful translation of preclinical to clinical efficacy has been disappointingly low. Tolerance, defined as a loss of efficacy with repeated drug exposure, is rarely addressed as a potential source of clinical failures. In this review, we argue that preclinical methods of tolerance development may have predictive validity and, therefore, inclusion of studies using repeated drug exposure early during the drug discovery and development process should serve to mitigate a proportion of clinical failures. Our analysis indicates that many published preclinical efficacy studies in the neuropsychiatry arena are conducted with acute drug administration only. Furthermore, specifically in the field of schizophrenia, there are several examples where tolerance development may be suspected as a factor contributing to translational failures. These and other examples highlight the need for built-for-purpose tolerance studies to be conducted, regardless of the target interaction mode of the drugs (i.e., agonist or antagonist, allosteric or orthosteric). We suggest that, for compounds that have failed in clinical studies, preclinical efficacy data sets need to be revisited to estimate the potential impact of tolerance development, one of the most significant known unknowns in the preclinical-to-clinical translation.