Sex Differences and Implications for Translational Neuroscience Research Workshop Summary (2011) / Chapter Skim
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3 Studying Sex Differences in Translational Research: Examples from Four Major Disease Areas
3 Studying Sex Differences in Translational Research: Examples from Four Major Disease Areas
Pages 21-54
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From page 21... ...
DEPRESSION Characterization of Sex Differences in Depression In science, we seek to define variables on which populations are similar to and differ from one another, said Katherine Wisner, director of Women's Behavioral HealthCARE at the University of Pittsburgh Medical Center. Two sexes provide a source of "variable partitioning" that creates a natural opportunity for comparative investigation.
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From page 22... ...
Individualized, personalized treatment for depression and other psychiatric illnesses is a primary goal of translational research. In addition to sex and gender, individuals vary with regard to symptoms, comorbidities, clinical factors, personal history, family features, social background, genetic polymorphisms, developmental stage, and characteristics identified from brain imaging or other technologies.
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From page 23... ...
Goldstein and colleagues are currently testing the hypothesis that there are shared etiologies associated with understanding sex differences in depression and cardiovascular disease; that they are initiated during the sexual differentiation of the brain; and that they involve disruption of the fetal hormonal programming of the brain, which leads to endocrine disruptions throughout life, and sex differences in adulthood in these chronic diseases. Throughout life windows of opportunity are available for studying sex differences in these disorders, Goldstein said.
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From page 24... ...
Results showed that the stress response circuitry in the healthy brain activates differently at different points in the menstrual cycle, and those hormonal differences contribute to explaining sex differences in stress response circuitry activation (Goldstein
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Finally, clinical and population-level research is critical for informing the development of basic animal models and vice versa. Sex Differences in Translational Studies of Major Depression Etienne Sibille, associate professor in the Translational Neuroscience Program at the University of Pittsburgh, explained that major depression
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From page 26... ...
Still, the primary pathology of depression is poorly characterized because there are numerous limits with current animal models. The models are often oversimplified; there is poor conceptualization of baseline traits versus induced depressive-like states; conceptualization of syndrome versus single behavior is poor; and little consideration is given to sex differences.
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From page 27... ...
Ultimately, evidence shows sexual dimorphism in the primary pathology of depression in humans. Industry Perspective on the Implications of Sex Differences for Translational Research Carla Canuso, senior director of external innovation, Neuroscience Therapeutic Area at Johnson & Johnson, provided an overview of how and when industry considers sex differences, particularly in antidepressant drug development, during each phase of development, from preclinical through postmarketing.
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From page 28... ...
Canuso concurred with the previous speakers regarding the limitations of animal models, which are necessary for drug development. Animal models show sex differences in depression and stress, and that these differences in stress response are related to differences in corticotropin-releasing factor and serotonin neurotransmission.
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From page 29... ...
• Partner with academia to develop and validate better preclinical animal models that are truly predictive of the diseases, and then study both sexes of the species in those models. • Identify and evaluate sex-specific endophenotypes and other bio markers, such as increased stress sensitivity.
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From page 30... ...
Consideration of comorbid conditions is important. • Current animal models of depressive disorders have significant limitations at the levels of both concept and interpretation.
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From page 31... ...
Berkley also noted that translational research is not unidirectional from animal research to clinical practice, but is really circular, and evidence from human and clinical research should inform animal models. In conclusion, Berkley said that knowledge of statistical sex differences is already beginning to save lives and improve the health of both females and males, but dissemination of this knowledge is key.
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Sometimes sex and gender differences can be studied only in humans, as in the clinical phenotype of IBS, a common persistent pain disorder affecting the gastrointestinal tract. Because no animal models exist that
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Mayer provided several examples of how endophenotypes have been used to deconstruct complex syndromes in pain conditions. In closing, Mayer said that studying endophenotypes in humans and in animals can be productive in understanding sex differences in pain.
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. Open Discussion: Pain and Pain Perception During the open discussion, panelists and participants delved further into the research aspect of sex differences in pain, including animal models and endophenotypes.
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SLEEP MEDICINE Sleep Regulation Although sleep medicine has become a huge field, our understanding of basic sleep regulatory processes and their consequences for disease are still lacking, said Roseanne Armitage, director of the Sleep and Chronophysiology Laboratory at the University of Michigan. Understanding sex differences in any clinical disorder requires knowing about those differences in healthy individuals, and the developmental time course of when those differences emerge.
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From page 36... ...
But this area needs additional focus, Armitage said, to truly appreciate sex differences in sleep regulation and their consequences for disease. Depression is just one model of conditions under which larger sex differences in sleep regulation are observed than in healthy individuals.
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Duffy closed by describing some of the challenges to understanding sex differences in sleep regulation. Similar to other areas of research, many basic studies on sleep and circadian rhythms are done in male animals.
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A better understanding of sex differences in sleep has implications for many of the other sex-related health disorders. Sex Differences in Subjective and Objective Measures of Sleep Rachel Manber, director of the Stanford Sleep Medicine Clinic at Stanford University, expanded on the discussion of sex differences in the objective and subjective measures of sleep.
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From page 39... ...
In summary, Manber reiterated the need to better understand sex differences in the discrepancy between objective and subjective sleep; the need to understand sex differences in the presentation, course, and treatment of specific sleep disorders; and the need to have sufficiently large samples to allow examination of the interaction between moderators and sex in treatment outcomes research. Health Consequences of Sex Differences in Sleep and Circadian Rhythms Although one can argue that sleep is of, by, and for the brain, the brain sits in a corporeal body, and the body is essential for the brain's continued adventure throughout life, said Martica Hall, associate professor of psychiatry, psychology, and clinical and translational studies at the University of Pittsburgh School of Medicine.
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Open Discussion: Sleep Medicine Animal models were once again a topic of much interest during the open discussion. Panelists and participants also discussed sleep patterns in adolescents, and how subjective and objective measures factor into the drug development process.
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From page 41... ...
Although animal neurophysiologists have worked on sleep studies for years, few have included both sexes of rodents in their studies. A participant raised the issue of the disconnect between objective and subjective measures of sleep in humans and pointed out that there are no animal models that can take this into consideration.
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From page 42... ...
• Comprehending sex differences in any clinical disorder requires an under standing of sex differences in healthy individuals, and the developmental time course of when those sex differences emerge. • Baseline sleep studies of the organization of sleep are important, but challenge studies are necessary for understanding risk factors for certain diseases that are sex specific, either in their prevalence or in a variety of conditions within the disorder.
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From page 43... ...
Sex Differences in Multiple Sclerosis Fox reviewed the current knowledge about sex differences in MS based on clinical observations, imaging, histopathology, and clinical trials. Overall, MS is two to three times more common in women than in men (Alonso and Hernán, 2008; Orton et al., 2006)
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Although a sex difference is prominent in the incidence in neuromyelitis optica, no sex differences have been observed in progression. With regard to the role of sex hormones in MS, from the clinical point of view it is clear and widely accepted that relapse rate decreases during pregnancy, particularly the third trimester.
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From page 45... ...
That does not mean, however, that consideration of sex differences should not be included in planning future studies. MuLTIPLE SCLEROSIS AND NEuROINFLAMMATION: CONSIDERING SEx DIFFERENCES IN DESIGNING THERAPEuTIC AGENTS Multiple sclerosis is just one of a list of autoimmune diseases that show sex differences.
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. One study connected the increase in the sex differences to vitamin D, suggesting that higher levels of vitamin D are associated with a lower incidence of multiple sclerosis only in women (Kragt et al., 2009)
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Therefore, preclinical studies should always include both sexes. Studying Sex Differences from Bedside to Bench to Bedside When discussing sex-based disparities in health, separating incidence from progression is important.
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Based on this clinical observation, and the subsequent results from animal models, estriol was then administered in pill form to people with MS in a Phase I trial, and reduction in the number and size of lesions was observed. A multicenter Phase II trial is under way.
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From page 49... ...
Open Discussion: Multiple Sclerosis and Neuroinflammation In the open discussion, panelists further considered the implications of sex differences in MS, and how MS is different from the other diseases discussed so far. Participants were interested in further information on the studies discussed, and raised issues about approaches to research.
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From page 50... ...
In the community, there are large sex differences in pain, but within the tertiary care setting there are not many differences between males and females. OvERARCHING DISCuSSION Following the disease-specific panel discussions of issues related to sex differences in translational research, the four panel moderators and the workshop cochairs assembled to consider overarching issues across major disease areas.
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From page 51... ...
A company usually has a very strong rationale, and has met certain criteria, before moving a drug from early phase into the later phases of development. Data from animal models are considered in these decisions, but experience has shown that some animal models that were relied on failed, in the sense that they did not predict the outcomes later observed in humans.
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From page 52... ...
Nakamura added that over the past few years, there has been discussion that the business model for CNS disorder medication development is basically failing, and that many pharmaceutical firms are leaving this therapeutic area. Studying sex differences, to the extent that they are a complicating factor, adds costs when developing a profitable drug.
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From page 53... ...
There could be a study section, or similar alternative mechanism, for vetting which sex differences in human conditions and diseases should be funded. A participant added that, as a previous recipient of NIH funding, he believed that forcing researchers to include both sexes in animal research was a bit unpalatable, but that it would be reasonable to ask them to justify why they use one sex or another, or both.
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From page 54... ...
SEX DIFFERENCES AND IMPLICATIONS Interdisciplinary Collaboration As the panel presentations demonstrated, there are commonalities and shared factors across different clinical conditions with respect to sex differences. Given limited funds, participants suggested that one way to have a greater impact is to target funding toward those commonalities.
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