Are We Getting Closer to Valid Translational Models for Major Depression?

Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania, Philadelphia, PA 19104, USA.
Science (Impact Factor: 33.61). 10/2012; 338(6103):75-9. DOI: 10.1126/science.1222940
Source: PubMed


Advances in characterizing the neuropathology and functional dysconnectivity of depression and promising trials with emerging circuit-targeted and fast-onset therapeutics are providing unprecedented opportunities to gain deeper insight into the neurobiology of this devastating and pervasive disorder. Because of practical and ethical limitations to dissecting these mechanisms in humans, continued progress will critically depend on our ability to emulate aspects of depressive symptomatology and treatment response in nonhuman organisms. Although various experimental models are currently available, they often draw skepticism from both clinicians and basic research scientists. We review recent progress and highlight some of the best leads to diversify and improve discovery end points for preclinical depression research.

Download full-text


Available from: Olivier Berton,
  • Source
    • "Animal models of neurological and psychiatric diseases are utilised for understanding the pathophysiology and investigating the brain–behaviour relationship that cannot be studied in humans 3. Important considerations of animal models in translational research When using models, whatever the species, researchers are facing a catch-22 situation (i.e. unsolvable as it involves mutually conflicting or dependent conditions (Berton et al., 2012; Nestler & Hyman, 2010). Controversies regarding animal models might come from the distinct definitions of validities used by researchers (Belzung & Lemoine, 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although everyone would agree that successful translation of therapeutic candidates for central nervous disorders should involve non-human primate (nhp) models of cognitive disorders, we are left with the paucity of publications reporting either the target validation or the actual preclinical testing in heuristic nhp models. In this review, we discuss the importance of nhps in translational research, highlighting the advances in technological/ methodological approaches for 'bridging the gap' between preclinical and clinical experiments. In this process, we acknowledge that nhps remain a vital tool for the investigation of complex cognitive functions, given their resemblance to humans in aspects of behaviour, anatomy and physiology. The recent improvements made for a suitable nhp model in cognitive research, including new surrogates of disease and application of innovative methodological approaches, are continuous strides for reaching efficient translation for human benefit. This will ultimately aid the development of innovative treatments against the current and future threat of neurological and psychiatric disorders to the global population. Copyright © 2015. Published by Elsevier Inc.
    Neurobiology of Learning and Memory 06/2015; 124. DOI:10.1016/j.nlm.2015.06.012 · 3.65 Impact Factor
  • Source
    • "Animal models are pivotal in the effort to understand the neurobiology of major depressive disorder and to develop new treatments (Berton et al., 2012). In this regard, Wistar Kyoto (WKY) rat strain has been proposed as an animal model of depression since several studies have shown that WKY rats exhibit inherent depressive-like behavior in different behavioral tests (Lahmame and Armario, 1996; Pare and Tejani-Butt, 1996; Lahmame et al., 1997; López- Rubalcava and Lucki, 2000; Tejani-Butt et al., 2003; Will et al., 2003). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Wistar Kyoto rat (WKY) has been proposed as an animal model of depression. The noradrenergic nucleus, locus coeruleus (LC) and the serotonergic nucleus, dorsal raphe (DRN) have been widely implicated in the ethiopathology of this disease. Thus, the goal of the present study was to investigate in vivo the electrophysiological properties of LC and DRN neurons from WKY rats, using single-unit extracellular techniques. Wistar (Wis) and Sprague Dawley (SD) rats were used as control strains. In the LC from WKY rats the basal firing rate was higher than that obtained in the Wis and SD strain, and burst firing activity also was greater compared to that in Wis strain but not in SD. The sensitivity of LC neurons to the inhibitory effect of the α2-adrenoceptor agonist, clonidine and the antidepressant reboxetine was lower in WKY rats compared to Wis, but not SD. Regarding DRN neurons, in WKY rats burst activity was lower than that obtained in Wis and SD rats, although no differences were observed in other firing parameters. Interestingly, while the sensitivity of DRN neurons to the inhibitory effect of the 5-HT1 A receptor agonist, 8-OH-DPAT was lower in the WKY strain, the antidepressant fluoxetine had a greater inhibitory potency in this rat strain compared to that recorded in the Wis group. Overall, these results point out important electrophysiological differences regarding noradrenergic and serotonergic systems between Wis and WKY rats, supporting the utility of the WKY rat as an important tool in the research of cellular basis of depression
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 07/2014; 24(7). DOI:10.1016/j.euroneuro.2014.02.007 · 4.37 Impact Factor
  • Source
    • "Moreover, the development of faster and more effective compounds is a slow and often unsuccessful process [4]. Despite the fact that the full spectrum of the depressive symptomatology cannot be replicated in rodents [5], valid and straightforward animal models of depression are still the best tool to gain insight in the pathophysiology of this disease and to lead to the development of the next generation of ADs [6] [7]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The study of depression is facing major challenges: firstly, the need to develop new drugs with a faster onset of action and secondly, fulfilling the unmet needs of treatment resistant patients with more effective compounds. The chronic escape deficit (CED) is a valid and useful model of depression and is based on the induction of an escape deficit after exposure of rats to unavoidable stress. This behavioural model provides a method for evaluating the capacity of a treatment to revert the escape deficit. The majority of antidepressant drugs need to be administered for at least 3-4 weeks in order to revert the escape deficit. A 7-day treatment with escitalopram reverted the stress-induced escape deficit in approximately 50% of the animals. Escitalopram treatment decreased anxiety-related behaviours in stressed animals, by increasing the time spent in the central part of the arena with respect to saline treated stressed animals, without affecting exploratory related behaviours. Gene expression profiling was carried out in the hippocampus to identify new targets associated with the effects of stress or with the different response to escitalopram. By combining a well-validated animal model with gene expression analysis we demonstrated that the CED model may represent a perfect tool for studying treatment-resistant depression.
    Behavioural Brain Research 06/2014; 272. DOI:10.1016/j.bbr.2014.06.040 · 3.03 Impact Factor
Show more