Schizophrenia Bulletin Advance Access originally published online on May 17, 2006
Schizophrenia Bulletin 2006 32(3):403-404; doi:10.1093/schbul/sbj084
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Editorial—Modeling Negative Symptoms: What's Missing?
Keywords: MATRICS / schizophrenia / animal models
Not too long ago, I was sitting at my kitchen table reading an article in the New York Times Magazine written by Charles Siebert entitled "The Animal Self."1 As I read it, I began thinking about the state of animal modeling in schizophrenia research, its relationship to "translational science," and the role of Schizophrenia Bulletin in reporting research findings in preclinical areas.
Few of us would argue with the need to develop heuristic animal models of the accessible domains of psychopathology in schizophrenia or these models' potential for identifying new therapeutic strategies. On the other hand, I wonder how many of my colleagues would agree with the following statement from Siebert's article attributed to Jaak Panksepp: "Every drug used to treat emotional and psychiatric disorders in humans was first developed and found to be effective in animals. This kind of research would obviously have no value if animals were incapable of experiencing these emotional states."1p51 Establishing the face validity of models that seek to recapitulate cognitive deficits and primary negative symptoms already draws heavily on the resemblances between animal and human behavior. As the field begins to reach a consensus view regarding the nature of these impairments, we can reasonably expect that new behavioral endpoints will be developed to evaluate aspects of animal behavior presumed to be homologous to deficits observed in patients and proximate to an identifiable neurobiological pathway, process, or gene. Collaborations between clinical and basic scientists would seem to offer our best hope of "translating" the clinical phenomenology of schizophrenia into heuristic indices of animal behavior. The National Institute of Mental Health MATRICS initiative has succeeded in identifying 7 dimensions of cognitive impairment in schizophrenia,2 at least 5 of which are currently amenable to study in animals.3 The National Institutes of Health has also recognized negative symptoms as an area of unmet therapeutic need and has adopted the MATRICS process to foster debate around phenomenology and treatment development. The Consensus Development Conference on Negative Symptoms, organized by Drs. Steven Marder, Wayne Fenton, William Carpenter, and Brian Kirkpatrick, was held in late January of 2005.4 The Consensus Statement on Negative Symptoms, published in the April 2006 issue of Schizophrenia Bulletin, tentatively identified 5 domains of negative symptoms: blunted affect, alogia, asociality, anhedonia, and avolition.5 Understanding the relationship between these symptom features and the extent to which they share a common neurobiological basis was viewed as critical to the planning of future clinical trials and the development of animal models. Unfortunately, a full agenda and limited time frame precluded formal discussions of the current status of animal constructs, which continue to represent a significant and largely unmet need. As noted recently by Ellenbroek and Cools,6 only 2 of the aforementioned symptom domains (asociality and anhedonia) are suited to modeling in animals using a top-down approach. An alternative strategy recently proposed by Dr. Panksepp is based on the notion that the myriad of complex social behaviors exhibited by mammals derives from a smaller group of core emotional tendencies that are conserved across species and linked to specific neural circuits.7 It is suggested that "a clear taxonomy" of these core tendencies is a necessary prerequisite for understanding higher-level, socially derived emotions that are altered or absent in psychiatric disease. On its face, this approach seems well suited to assessing deficits in animal behavior analogous to negative symptoms in humans, as finding something that has gone missing usually implies an understanding or at least an awareness of what has been lost. A bottom-up approach to modeling complex social behaviors is also likely to result in a more explicit relationship between the behavioral phenomenology and the relevant neurobiological and genetic substrates underlying it. Regardless of the approach used, modeling negative symptoms successfully will require objective measures of animal behavior that are homologous at an evolutionary level with those elements of human behavior that are deficient or altered in the deficit form of schizophrenia. Close collaborative interactions between clinical investigators, animal behaviorists, and behavioral ecologists representing diverse viewpoints on how best to approach this challenge seem the best way forward.
We view Schizophrenia Bulletin as an appropriate forum for publishing discussions between preclinical and clinical scientists, particularly those of a translational nature. As alluded to earlier, "translational" research will not always involve a "bench to bed" approach. Rather, we anticipate that the flow of information will be bi-directional, with clinical findings, particularly those reached through consensus processes like MATRICS, feeding back to inform and influence the design of preclinical studies. To facilitate this exchange, we are introducing a new feature entitled "Schizophrenia in Translation" that will be co-organized by Dr. Tom McGlashan and me and appear in each regular issue of Schizophrenia Bulletin. Half of these articles will be devoted to reviewing a current concept or methodological approach in the neurosciences and describing its relevance to clinical issues in schizophrenia. The remainder will relate a clinical feature, symptom domain, or endophenotype to a molecular, cellular, and/or behavioral finding in contemporary neuroscience. In the first of this series, Henry Holcomb, Jim Gold, and I describe the putative role of the habenula in mediating feedback processing deficits in schizophrenia. In the next issue we will hear from Tom McGlashan. As always, we welcome your suggestions for fostering a lively, productive, and translational scientific debate.
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD
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- Siebert C. The animal self. New York Times Magazine. January 22, 2006:48–55,72,79,86–87.
- Nuechterlein, KH, Barch, DM, Gold, JM, Goldberg, TE, Green, MF, Heaton, RK. Identification of separable cognitive factors in schizophrenia. Schizophr Res 2004; 72:29–39.[CrossRef][Web of Science][Medline]
- Hagan, JJ and Jones, DN. Predicting drug efficacy for cognitive deficits in schizophrenia. Schizophr Bull 2005; 31:830–853.
[Abstract/Free Full Text] - Kirkpatrick, B. Editor's introduction: theme issue on negative symptoms. Schizophr Bull 2006; 32:212–213.
[Free Full Text] - Kirkpatrick, B, Fenton, WS, Carpenter, WT Jr, Marder, SR. The NIMH-MATRICS Consensus Statement on Negative Symptoms. Schizophr Bull 2006; 32:214–219.
[Free Full Text] - Ellenbroek, BA and Cools, AR. Animal models for the negative symptoms of schizophrenia. Behav Pharmacol 2000; 11:223–233.[Web of Science][Medline]
- Panksepp, J. Emotional endophenotypes in evolutionary psychiatry. Prog Neuropsychopharmacol Biol Psychiatry 2006 doi:10.1016/j.pnpbp.2006.01004.
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