Investigating Resistance to Antidepressants in Animal Models

Major depressive disorder is one of the most prevalent psychiatric diseases, and up to 30–40% of patients remain symptomatic despite treatment. Novel therapies are sorely needed, and animal models may be used to elucidate fundamental neurobiological processes that contribute to human disease states. We conducted a systematic review of current preclinical approaches to investigating treatment resistance with the goal of describing a path forward for improving our understanding of treatment resistant depression. We conducted a broad literature search to identify studies relevant to the preclinical investigation of treatment resistant depression. We followed PRISMA (Preferred Reporting Items for Systemic Reviews and Meta-Analyses) guidelines and included all relevant studies. We identified 467 studies in our initial search. Of these studies, we included 69 in our systematic review after applying our inclusion/exclusion criteria. We identified 10 broad strategies for investigating treatment resistance in animal models. Stress hormone administration was the most commonly used model, and the most common behavioral test was the forced swim test. We systematically identified and reviewed current approaches for gaining insight into the neurobiology underlying treatment resistant depression using animal models. Each approach has its advantages and disadvantages, but all require careful consideration of their potential limitations regarding therapeutic translation. An enhanced understanding of treatment resistant depression is sorely needed given the burden of disease and lack of effective therapies.