Rodent models of treatment-resistant depression

Abstract

Major depression is a prevalent and debilitating disorder and a substantial proportion of patients fail to reach remission following standard antidepressant pharmacological treatment. Limited efficacy with currently available antidepressant drugs highlights the need to develop more effective medications for treatment resistant patients and emphasizes the importance of developing better preclinical models that focus on treatment resistant populations. This review discusses methods to adapt and refine rodent behavioral models that are predictive of antidepressant efficacy to identify populations that show reduced responsiveness or are resistant to traditional antidepressants. Methods include separating antidepressant responders from non-responders, administering treatments that render animals resistant to traditional pharmacological treatments, and identifying genetic models that show antidepressant resistance. This review also examines pharmacological and non-pharmacological treatments regimes that have been effective in refractory patients and how some of these approaches have been used to validate animal models of treatment-resistant depression. The goals in developing rodent models of treatment-resistant depression are to understand the neurobiological mechanisms involved in antidepressant resistance and to develop valid models to test novel therapies that would be effective in patients that do not respond to traditional monoaminergic antidepressants.

Failure to detect the action of antidepressants in the forced swim test in Swiss mice

“…Laboratory animals resistant to the effects of monoaminergic antidepressants might be an opportunity for the discovery of new targets for these drugs (34,35). Although considered a promising candidate mechanism (36), the inhibition of histone deacetylases was ineffective in traditional animal models for antidepressant detection (37–41).…”

Animal models of major depression: drawbacks and challenges

“…Among many examples, mutation of genes implicated in depression induce depression-like phenotypes and resistance to ADs: serotonin transporter 5HTT knockout mice exhibit depression-like behaviours in FST which can or cannot be reversed by fluoxetine (Holmes et al 2003), serotonin receptor 5HT1a KO mice do not respond to SSRIs (Santarelli et al 2003), p11 knockout mice show reduced sensitivity to fluoxetine in NSF (Egeland et al 2010) and finally mutation of adrenergic receptor alpha2A (Schramm et al 2001) and dopamine beta-hydroxylase knockout mice (Cryan et al 2001, 2004) are less sensitive to conventional drugs in FST. Moreover, many selected lines show heightened vulnerability to stress, although at an insufficient level to meet the criteria for a TRD model, such as the HAB rats (insensitive to three ADs) and Flinders Sensitive rats, which are resistant to escitalopram in FST after depression-like states induced by maternal separation (for a review see Caldarone et al 2015). However, each of these models, particularly those with targeted mutations, might only be a relevant model for a specific cause of TRD: for example, the resistance shown by the 5HTT mutant might be an adequate model for resistance related to a polymorphism of the 5HTT, but not for other forms of TRD.…”

Dendritic Spines in Depression: What We Learned from Animal Models

“…Depression-like behaviors induced by these models can often be reversed by chronic antidepressant treatments [ 27 , 86 ]. It is, however, worth noting that there are some rats or mice that do not respond to traditional antidepressants, which is similar to treatment-resistant depression in human subjects [ 151 ]. Here, we briefly summarize our current understanding about these three animal models.…”