Initial Heritability Analyses of Endophenotypic Measures for Schizophrenia

Greenwood, Tiffany A.; Braff, David L.; Light, Gregory A.; Cadenhead, Kristin S.; Calkins, Monica E.; Dobie, Dorcas J.; Freedman, Robert; Green, Michael F.; Gur, Raquel E.; Gur, Ruben C.; Mintz, Jim; Nuechterlein, Keith H.; Olincy, Ann; Radant, Allen D.; Seidman, Larry J.; Siever, Larry J.; Silverman, Jeremy M.; Stone, William S.; Swerdlow, Neal R.; Tsuang, Debby W.; Tsuang, Ming T.; Turetsky, Bruce I.; Schork, Nicholas J.

doi:10.1001/archpsyc.64.11.1242

Cited by 342 publications

(350 citation statements)

References 81 publications

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“…Swerdlow et al 2008), the basic parametric properties of PPI exhibit striking similarities from rodents to humans (e.g., Swerdlow et al 1994a, b). Furthermore, PPI is under significant genetic control in both rodents (Francis et al 2003) and humans (Greenwood et al 2007).…”

Section: The Evolution Of Prepulse Inhibition As a Validated Animal Mmentioning

confidence: 99%

Animal Models of Deficient Sensorimotor Gating in Schizophrenia: Are They Still Relevant?

Swerdlow

Light

2015

Translational Neuropsychopharmacology

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Animal models of impaired sensorimotor gating, as assessed by prepulse inhibition (PPI) of startle, have demonstrated clear validity at face, predictive, and construct levels for schizophrenia (SZ) therapeutics, neurophysiological endophenotypes, and potential causative insults for this group of disorders. However, with the growing recognition of the heterogeneity of the schizophrenias, and the less sanguine view of the clinical value of antipsychotic (AP) medications, our field must look beyond "validity," to assess the actual utility of these models. At a substantial cost in terms of research support and intellectual capital, what has come from these models, that we can say has actually helped schizophrenia patients? Such introspection is timely, as we are reassessing not only our view of the genetic and pathophysiological diversity of these disorders, but also the predominant strategies for SZ therapeutics; indeed, our field is gaining awareness that we must move away from a "find what's broke and fix it" approach, toward identifying spared neural and cognitive function in SZ patients, and matching these residual neural assets with learning-based therapies. Perhaps, construct-valid models that identify evidence of "spared function" in neural substrates might reveal opportunities for future therapeutics and allow us to study these substrates at a mechanistic level to maximize opportunities for neuroplasticity. Such an effort will require a retooling of our models, and more importantly, a re-evaluation of their utility. For animal models to remain relevant in the search for schizophrenia therapeutics, they will need to focus less on what is valid and focus more on what is useful.

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Section: The Evolution Of Prepulse Inhibition As a Validated Animal Mmentioning

confidence: 99%

Animal Models of Deficient Sensorimotor Gating in Schizophrenia: Are They Still Relevant?

Swerdlow

Light

2015

Translational Neuropsychopharmacology

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“…The COGS chose 6 well-established neurophysiological and neurocognitive measures to be primary endophenotypes. Then, based on initial heritability analyses (8), six Penn Computerized Neurocognitive Battery (CNB) measures were added. All twelve COGS measures show between-site reliability and heritability (3,8,(15)(16)(17).…”

Section: Selection Of Neurophysiological and Neurocognitive Candidatementioning

confidence: 99%

“…Then, based on initial heritability analyses (8), six Penn Computerized Neurocognitive Battery (CNB) measures were added. All twelve COGS measures show between-site reliability and heritability (3,8,(15)(16)(17). In addition, these endophenotypes have significant relationships to functional status and outcome, pointing to possible molecular targets for therapies once association studies identify the molecular deficits underlying these endophenotype abnormalities.…”

Section: Selection Of Neurophysiological and Neurocognitive Candidatementioning

confidence: 99%

Advances in endophenotyping schizophrenia

et al. 2008

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“…For example, menstrual cycle phases are associated with reductions in fear extinction in healthy women (Glover et al 2015;Milad et al 2006). (2) In the context of genetic studies, even relatively "simple" or discrete laboratory-based behaviors do not guarantee greater heritability or simpler genetic architecture than the disorder (Greenwood et al 2007), as would be hoped from an intermediate phenotype or endophenotype. For example, even a behavior as simple as the startle reflex may be modulated by a huge array of biological pathways (Zhang et al 2011).…”

Section: Limitationsmentioning

confidence: 99%

On the Road to Translation for PTSD Treatment: Theoretical and Practical Considerations of the Use of Human Models of Conditioned Fear for Drug Development

Risbrough

Glenn²,

Baker

2015

Current Topics in Behavioral Neurosciences

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The use of quantitative, laboratory-based measures of threat in humans for proof-of-concept studies and target development for novel drug discovery has grown tremendously in the last 2 decades. In particular, in the field of posttraumatic stress disorder (PTSD), human models of fear conditioning have been critical in shaping our theoretical understanding of fear processes and importantly, validating findings from animal models of the neural substrates and signaling pathways required for these complex processes. Here, we will review the use of laboratorybased measures of fear processes in humans including cued and contextual conditioning, generalization, extinction, reconsolidation, and reinstatement to develop novel drug treatments for PTSD. We will primarily focus on recent advances in using behavioral and physiological measures of fear, discussing their sensitivity as biobehavioral markers of PTSD symptoms, their response to known and novel PTSD treatments, and in the case of d-cycloserine, how well these findings have translated to outcomes in clinical trials. We will highlight some gaps in the literature and needs for future research, discuss benefits and limitations of these outcome measures in designing proof-of-concept trials, and offer practical guidelines on design and interpretation when using these fear models for drug discovery.

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Initial Heritability Analyses of Endophenotypic Measures for Schizophrenia

Cited by 342 publications

References 81 publications

Animal Models of Deficient Sensorimotor Gating in Schizophrenia: Are They Still Relevant?

Animal Models of Deficient Sensorimotor Gating in Schizophrenia: Are They Still Relevant?

Advances in endophenotyping schizophrenia

On the Road to Translation for PTSD Treatment: Theoretical and Practical Considerations of the Use of Human Models of Conditioned Fear for Drug Development

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