Animal models that mirror bipolar disorder’s pathophysiologic complexities: focused review of common models

INTRODUCTION: It is difficult to model bipolar disorder in animals because the illness has opposed behavioral expressions and a multitude of associated pathophysiologic anomalies. AREAS COVERED: The authors undertook a focused narrative review. The authors searched PubMed for all animal models of mania or bipolar disorder but focused on three models that meet all three validity criteria - the circadian, amphetamine, and ouabain models of mania. EXPERT OPINION: The three groups of models that meet face, construct, and predictive validity criteria, are the circadian, amphetamine, and ouabain models of mania. Despite significant differences in the intervention that alters the animal, these models display known associated biologic anomalies including an excessive dopamine signal, oxidative stress, inflammation, and mitochondrial dysfunction. These similarities inform that it is not how models differ that is instructive, but the fact that different models converge and disrupt a small number of key systems. Nonetheless, the ouabain model is the only model that has demonstrated spontaneous transitioning from mania to depression, and antidepressant-induced mania. Since no animal model accurately reproduces human bipolar disorder, the goals of animal models are best accomplished, and the benefits most likely achieved, when several models are studied in tandem.