Treatment-resistant depression: are animal models of depression fit for purpose?

Willner, Paul; Belzung, Catherine

doi:10.1007/s00213-015-4034-7

Cited by 115 publications

(92 citation statements)

References 246 publications

(249 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In fact, an increase in the AEA level (Hill et al 2008c; Ho et al 2012) and a decrease in the 2-AG level were observed in human female patients with major depression (Hill et al 2008c). It should be noted that the WKY rats are a useful model that captures specific functional domains relevant to clinical depression and would seem most consistent with a melancholic depression profile showing severe symptoms of anxiety and depression (Willner and Belzung 2015). The WKY rats seem to be a genetic model of childhood depression (Malkesman and Weller 2009), while the OBX rats are more representative for depression in adults.…”

Section: Discussionmentioning

confidence: 99%

Changes in the Brain Endocannabinoid System in Rat Models of Depression

et al. 2017

View full text Add to dashboard Cite

A growing body of evidence implicates the endocannabinoid (eCB) system in the pathophysiology of depression. The aim of this study was to investigate the influence of changes in the eCB system, such as levels of neuromodulators, eCB synthesizing and degrading enzymes, and cannabinoid (CB) receptors, in different brain structures in animal models of depression using behavioral and biochemical analyses. Both models used, i.e., bulbectomized (OBX) and Wistar Kyoto (WKY) rats, were characterized at the behavioral level by increased immobility time. In the OBX rats, anandamide (AEA) levels were decreased in the prefrontal cortex, hippocampus, and striatum and increased in the nucleus accumbens, while 2-arachidonoylglycerol (2-AG) levels were increased in the prefrontal cortex and decreased in the nucleus accumbens with parallel changes in the expression of eCB metabolizing enzymes in several structures. It was also observed that CB1 receptor expression decreased in the hippocampus, dorsal striatum, and nucleus accumbens, and CB2 receptor expression decreased in the prefrontal cortex and hippocampus. In WKY rats, the levels of eCBs were reduced in the prefrontal cortex (2-AG) and dorsal striatum (AEA) and increased in the prefrontal cortex (AEA) with different changes in the expression of eCB metabolizing enzymes, while the CB1 receptor density was increased in several brain regions. These findings suggest that dysregulation in the eCB system is implicated in the pathogenesis of depression, although neurochemical changes were linked to the particular brain structure and the factor inducing depression (surgical removal of the olfactory bulbs vs. genetic modulation).

show abstract

Section: Discussionmentioning

confidence: 99%

Changes in the Brain Endocannabinoid System in Rat Models of Depression

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Although the non-response of Wistar rats could result from a flooring effect, these studies illustrate the need for an appropriate selection of strain based on study design. The Wistar-Kyoto strain, for instance, meets several criteria for modeling treatment-resistant depression [42], and given the interest in ketamine’s efficacy in treatment-resistant patients [43], represents an interesting choice for deciphering ketamine’s potential in this population.…”

Section: Sex Differences In Antidepressant Response Under Stressmentioning

confidence: 99%

Integrative analysis of sex differences in the rapid antidepressant effects of ketamine in preclinical models for individualized clinical outcomes

Saland

Duclot

Kabbaj

2017

Current Opinion in Behavioral Sciences

View full text Add to dashboard Cite

In major depressive disorder, women exhibit higher lifetime prevalence and different antidepressant response rates than men, which illustrates the importance of examining individual differences in the pathophysiology of depression and therapeutic response. In recent years, the consideration of sex in related preclinical research has thus gained interest—particularly in light of novel evidence for rapid-acting antidepressants. Notably, the literature recently revealed a higher sensitivity of females to the antidepressant effects of the N-methyl-D-aspartate receptor antagonist ketamine, in both baseline and preclinical conditions. Combined with its fast-acting and relatively sustained properties, this evidence highlights ketamine as a particularly interesting therapeutic alternative for this sensitive population, and supports the value in considering sex as a critical factor for improved individualized therapeutic strategies.

show abstract

“…There are limitations to traditional animal models of major depression (Berton et al, 2012), with treatment-resistant depression proving to be particularly challenging (Willner and Belzung, 2015). While nonhuman primate models have been underutilized in studies of depression (Shively and Willard, 2012), the use of phMRI in conscious animals could be particularly important for investigating the mechanisms underlying the rapid antidepressant effects of ketamine.…”

Section: Future Directionsmentioning

confidence: 99%

Ketamine and pharmacological imaging: use of functional magnetic resonance imaging to evaluate mechanisms of action

Maltbie¹,

Kaundinya²,

Howell

2017

Behavioural Pharmacology

View full text Add to dashboard Cite

Ketamine has been used as a pharmacological model for schizophrenia, as sub-anesthetic infusions have been shown to produce temporary schizophrenia-like symptoms in healthy humans. More recently, ketamine has emerged as a potential treatment for multiple psychiatric disorders, including treatment-resistant depression and suicidal ideation. However, the mechanisms underlying both the psychotomimetic and therapeutic effects of ketamine remain poorly understood. This review provides an overview of what is known of the neural mechanisms underlying the effects of ketamine and details what functional magnetic resonance imaging studies have revealed at a systems level focused on brain circuitry. Multiple analytic approaches show that ketamine produces robust and consistent effects at the whole-brain level. These effects are highly conserved across human and nonhuman primates, validating the use of nonhuman primate models for further investigations with ketamine. Regional analysis of brain functional connectivity suggests that the therapeutic potential of ketamine may be derived from a strengthening of executive control circuitry, making it an intriguing candidate for the treatment of drug abuse. There are still important questions about the mechanism of action and therapeutic potential of ketamine that can be addressed using appropriate functional neuroimaging techniques.

show abstract

Treatment-resistant depression: are animal models of depression fit for purpose?

Abstract: Further development is needed to validate models of antidepressant resistance that are fit for purpose. The criteria used in this review may provide a helpful framework to guide research in this area.

Cited by 115 publications

References 246 publications

Changes in the Brain Endocannabinoid System in Rat Models of Depression

Changes in the Brain Endocannabinoid System in Rat Models of Depression

Integrative analysis of sex differences in the rapid antidepressant effects of ketamine in preclinical models for individualized clinical outcomes

Ketamine and pharmacological imaging: use of functional magnetic resonance imaging to evaluate mechanisms of action

Contact Info

Product

Resources

About