Animal models of major depression: drawbacks and challenges

Abstract

Major depression is a leading contributor to the global burden of disease. This situation is mainly related to the chronicity and/or recurrence of the disorder, and to poor response to antidepressant therapy. Progress in this area requires valid animal models. Current models are based either on manipulating the environment to which rodents are exposed (during the developmental period or adulthood) or biological underpinnings (i.e. gene deletion or overexpression of candidate genes, targeted lesions of brain areas, optogenetic control of specific neuronal populations, etc.). These manipulations can alter specific behavioural and biological outcomes that can be related to different symptomatic and pathophysiological dimensions of major depression. However, animal models of major depression display substantial shortcomings that contribute to the lack of innovative pharmacological approaches in recent decades and which hamper our capabilities to investigate treatment-resistant depression. Here, we discuss the validity of these models, review putative models of treatment-resistant depression, major depression subtypes and recurrent depression. Furthermore, we identify future challenges regarding new paradigms such as those proposing dimensional rather than categorical approaches to depression.

Keywords: Animal models; Antidepressant; Depression; Treatment-resistant depression; Validity.

Fig. 1

Behavioural endpoints measuring aspect of the anxio-depressive phenotype in rodents

Fig. 2

Animal models of depression. The models are mimicking different causes: early life adversity, biological causation, stress at adulthood

Fig. 3

The unpredictable chronic mild stress (UCMS) model of depression. a Different stressors can be sued, including changes in lighting, contention in a small tube, introduction of rats faeces, cage tilting, social stress, cage changes, sawdust changes, no sawdust, humid sawdust, water in the cage. b Different endpoints can be measured after UCMS, including coat state, reward maze test, nest building, splash test, novelty suppression of feeding test