Animal models exhibiting sensitivity to chronic, but not acute, antidepressant treatment are greatly needed for studying the neural mechanisms of the antidepressant response. Although several models of acute antidepressant effects provide excellent tools for antidepressant discovery, they do not permit investigation into their therapeutic effects, which require several weeks of treatment to emerge. The inhibition of feeding produced by novelty, termed 'hyponeophagia', provides an anxiety-related measure that is sensitive to the effects of chronic, but not acute or subchronic, antidepressant treatment. This review evaluates the value of hyponeophagia-based tests as tools for investigating the neurobiology of the therapeutic response to antidepressant treatment. Criteria for the development and validation of animal models used to study neurobiological mechanisms of the antidepressant response are presented. Methodological considerations affecting the reliability, specificity, and ease of use of hyponeophagia-based models are also discussed. Lastly, we present a newly revised hyponeophagia paradigm, called the novelty-induced hypophagia (NIH) test, which attempts to maximize the predictive validity and practicality of the test. The NIH paradigm provides a promising new model for investigations into the neurobiology underlying the antidepressant response.