Ethical Dimensions of Disparities in Depression Research and Treatment in the Pharmacogenomic Era

Dobransky-Fasiska D. Brown C. , and Pincus H. A. , “Developing Community-Academic Partnership to Improve Recognition and Treatment of Depression in Underserved African American and White Elders,” American Journal of Geriatric Psychiatry 17, no. 11 (2008): 953–964; Simpson S. M. Krishnan L. L. Kunik M. E. , and Ruiz P. , “Racial Disparities in Diagnosis and Treatment of Depression: A Literature Review,” Psychiatric Quarterly 78, no. 11 (2007): 3–14.

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In the balance of this paper, we shall adopt the convention of referring to “African Americans” in discussing these disparities and will use the term to refer to the diverse group of “Black” populations in the U.S. We will specify when data or claims refer to specific populations (e.g., Caribbean Blacks) or to older African Americans. Miranda J. and Cooper L. A. , “Disparities in Care for Depression Among Primary Care Patients,” Journal of General Internal Medicine 19, no. 2 (2004): 120–126; see Simpson , supra note 1; Williams , supra note 3.

See Dobransky-Fasiska , supra note 1; Das A. K. Olfson M. McCurtis H. L. , and Weissman M. M. , “Depression in African Americans: Breaking Barriers to Detection and Treatment: Community-Based Studies Tend to Ignore High-Risk Groups of African Americans,” Journal of Family Practice 55, no. 1 (2006): 30–39.

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Id.; see Das , supra note 5.

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On finding a difference, see Poolsup N. Li Wan Po A. , and Knight T. L. , “Pharmacogenetics and Psychopharmacotherapy,” Journal of Clinical Pharmacy and Therapeutics 25, no. 3 (2000): 197–220; on finding a difference on some measures but not others, see Lesser I. M. Castro D. B. , and Gaynes B. N. , “Ethnicity/Race and Outcome in the Treatment of Depression: Results from STAR*D,” Medical Care 45, no. 1 (2007): 1043–1051.

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Jones C. , “Baring Their Souls: More Middle-Class Blacks Are Turning to Therapists,” Detroit Free Press, September 2, 1997, at Accent Section, available at <http://www.africanamerican-therapists.com/middle-class-blacks/>; Whaley A. L. , “Cultural Mistrust: An Important Psychological Construct for Diagnosis and Treatment of African Americans,” Professional Psychology: Research and Practice 32, no. 6 (2001): 555–562.

Hussain-Gambles M. Atkin K. , and Leeseet B. , “Why Ethnic Minority Groups Are Under-Represented in Clinical Trials: A Review of the Literature,” Health & Social Care in the Community 12, no. 5 (2004): 382–388; Rogers W. A. , “Evidence-Based Medicine and Justice: A Framework for Looking at the Impact of EBM on Vulnerable or Disadvantaged Groups,” Journal of Medical Ethics 20, no. 2 (2004): 141–145; Zulman D. M. Sussman J. B. , and Chen X. , “Examining the Evidence: A Systematic Review of the Inclusion and Analysis of Older Adults in Randomized Controlled Trials,” Journal of General Internal Medicine 26, no. 7 (2011): 783–790.

Alvidrez J. Arean P. A. , and Stewart A. L. , “Psychoeducation to Increase Psychotherapy Entry for Older African Americans,” American Journal of Geriatric Psychiatry 3, no. 7 (2005): 554–561.

Cooper L. A. Gonzales J. J. , and Gallo J. J. , “The Acceptability of Treatment for Depression Among African-American, Hispanic, and White Primary Care Patients,” Medical Care 41, no. 4 (2003): 479–489; Kanter J. W. Rusch L. C. , and Brondino M. J. , “Depression Self-Stigma: A New Measure and Preliminary Findings,” Journal of Nervous and Mental Disease 196, no. 9 (2008): 663–670; Rusch L. C. Kanter J. W. Manos R. C. , and Weeks C. E. , “Depression Stigma in a Predominantly Low Income African American Sample with Elevated Depressive Symptoms,” Journal of Nervous and Mental Disease 196, no. 12 (2008): 919–922.

See Cooper , supra note 16; Givens J. L. Katz I. R. Bellamy S. , and Holmes W. C. , “Stigma and the Acceptability of Depression Treatments among African Americans and Whites,” Journal of General Internal Medicine 22, no. 9 (2007): 1292–1297.

Gamble V. N. , “Under the Shadow of Tuskegee: African Americans and Health Care,” American Journal of Public Health 87, no. 11 (1997): 1773–1778; Boulware L. E. Cooper L. A. , and Ratner L. E. , “Race and Trust in the Health Care System,” Public Health Report 118, no. 4 (2003): 358–365.

Roberts D. E. , “Reconstructing the Patient: Starting with Women of Color,” in Wolf S. M. , ed., Feminism and Bioethics: Beyond Reproduction (New York: Oxford University Press, 1996): At 116–143; Gamble (id.).

Brandon D. T. Isaac L. A. , and LaVeist T. A. , “The Legacy of Tuskegee and Trust in Medical Care: Is Tuskegee Responsible for Race Differences in Mistrust of Medical Care?” Journal of the National Medical Association 97, no. 7 (2005): 951–956; Katz R. V. Kegeles S. S. , and Kressin N. R. , “Awareness of the Tuskegee Syphilis Study and the US Presidential Apology and Their Influence on Minority Participation in Biomedical Research,” American Journal of Public Health 98, no. 6 (2008): 1137–1142.

Sanders C. J. , “Religion and Ethical Decision Making in the African American Community: Bioterrorism and the Black Postal Workers,” in Prograis L. Jr. and Pellegrino E. D. eds., African American Bioethics (Washington, D.C.: Georgetown University Press, 2007): At 93–104.

Goldstein A. , “Many Postal Workers Stop Taking Cipro,” Washington Post, December 10, 2001, at B02.

See Sanders , supra note 21.

See Whaley , supra note 13.

Id.; In The Protest Psychosis, Jonathan Metzel details how schizophrenia became a different, socially constructed diagnosis for African-American and white patients, and specifically how its diagnosis in African Americans – both in individual doctor-patient interactions and at a cultural level – rEffects racial tensions, the white establishment's anxieties about racial difference, and fear of African-American rage in response to a racist culture. Metzl J. M. , The Protest Psychosis: How Schizophrenia Became a Black Disease (Boston: Beacon Press, 2009).

See Whaley , supra note 13; Citizens Commission on Human Rights, Creating Racism: Psychiatry's Betrayal (Los Angeles: CCHR International, 2008).

Brunson C. J. , “African Americans and the Mental Health System,” Exodus News, July 27,1999, available at <http://www.exodusnews.com/health/1495-african-americans-and-the-mental-health-system.html> (last visited March 9, 2012).

Gelenberg A. J. Freeman M. P. , and Markowitz J. C. , “Practice Guideline for the Treatment of Patients with Major Depressive Disorder Third Edition,” American Journal of Psychiatry 167, no. 10 (2010): 1–152.

See Alvidrez , supra note 15.

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See Das , supra note 5.

West H. C. Sabol W. J. , and Greenman S. J. , “Prisoners in 2009,” Bureau of Justice Statistics Bulletin, December 21, 2010, available at <http://bjs.ojp.usdoj.gov/content/pub/pdf/p09.pdf> (last visited December 5, 2012).

Indeed, among the arguments made for preservation of the institution of slavery was the need of the American Negro for the protection and structure afforded by being the property of Whites, who considered themselves a superior race.

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See Roberts , supra note 19.

For an example, see Williams D. R. Mohammed S. A. Leavell J. , and Collins C. , “Race, Socioeconomic Status, and Health: Complexities, Ongoing Challenges, and Research Opportunities,” Annals of the New York Academy of Sciences 1186 (2010): 69–101.

See Williams , supra note 3.

Steffens D. C. Artigues D. L. Ornstein K. A. , and Krishnan K. R. , “A Review of Racial Differences in Geriatric Depression: Implications for Care and Clinical Research,” Journal of the National Medical Association 89, no. 11 (1997): 731–736.

Id.; Hamilton L. A. Aliyu M. H. , and Lyons P. D. , “African-American Community Attitudes and Perceptions toward Schizophrenia and Medical Research: An Exploratory Study,” Journal of the National Medical Association 98, no. 1 (2006): 1–10.

Faith and spirituality as used by Wittink referred to faith in God and the power of spirituality and prayer to heal. The article does not name a specific god, nor does it refer to organized religion. Various Pentecostal traditions embrace the view of faith as potentially healing and of the ability to heal – by whatever means (i.e., traditional medical or not) – as a gift from God. See Wittink , supra note 6.

See Wittink , supra note 6; Zimmerman R. K. Tabbarah M. , and Nowalk M. P. , “Racial Differences in Beliefs About Genetic Screening among Patients at Inner-City Neighborhood Health Centers,” Journal of the National Medical Association 98, no. 3 (2006): 370–377.

Brown C. Conner K. O. , and Copeland V. C. , “Depression Stigma, Race, and Treatment Seeking Behavior and Attitudes,” Journal of Community Psychology 38, no. 3 (2010): 350–368; Corrigan P. Markowitz F. E. Watson A. Rowan D. , and Kubiak M. A. , “An Attribution Model of Public Discrimination towards Persons with Mental Illness,” Journal of Health and Social Behaviour 44, no. 2 (2003): 162–179.

See Brown , supra note 45, at 352.

See Brown , supra note 45; Pallinkas L. A. Criado V. , and Fuentes D. , “Unmet Needs for Services for Older Adults with Mental Illness: Comparison of Views of Different Stakeholder Groups,” American Journal of Geriatric Psychiatry 15, no. 6 (2007): 530–540.

Corrigan P. W. , “How Clinical Diagnosis Might Exacerbate the Stigma of Mental Illness,” Social Work 52, no. 1 (2007): 31–39.

Bartky S. L. , “Unplanned Obsolescence: Some Refections on Aging,” in Walker M. U. , ed., Mother Time (Lanham: Rowman & Littlefield Publishers, Inc., 1999): At 61–74.

Wendell S. , “Old Women out of Control: Some Thoughts on Aging, Ethics, and Psychosomatic Medicine,” in Walker M. U. , ed., Mother Time (Lanham: Rowman & Littlefield Publishers, Inc., 1999): 133–149; Silvers A. , “Aging Fairly: Feminist and Disability Perspectives on Intergenerational Justice,” in Walker M. U. , ed., Mother Time (Lanham: Rowman & Littlefield Publishers, Inc., 1999): At 203–226.

Black H. K. White T. , and Hannum S. M. , “The Lived Experience of Depression in Elderly African American Women,” Journal of Gerontology 62B, no. 6 (2007): S392–S398.

See Hussain-Gambles , supra note 14.

See Palinkas , supra note 47.

Freimuth V. S. Quinn S. C. , and Thomas S. B. , “African Americans' Views on Research and the Tuskegee Syphilis Study,” Social Science & Medicine 52, no. 5 (2001): 797–808; see Hamilton , supra note 42; Corbie-Smith G. Thomas S. B. Williams M. V. , and Moody-Ayers S. , “Attitudes and Beliefs of African Americans toward Participation in Medical Research,” Journal of General Internal Medicine 14, no. 9 (1999): 537–546; Farmer D. F. Jackson S. A. Camacho F. , and Hall M. A. , “Attitudes of African American and Low Socioeconomic Status White Women toward Medical Research,” Journal of Health Care for the Poor and Underserved 18, no. 1 (2007): 85–99.

See Zimmerman , supra note 44.

Frazier L. Calvin A. O. Mudd G. T. , and Cohen M. Z. , “Understanding of Genetics among Older Adults,” Journal of Nursing Scholarship 38, no. 2 (2006): 126–132, at 130.

Buchanan A. Califano A. , and Kahn J. , “Pharmacogenetics: Ethical Issues and Policy Options,” Kennedy Institute of Ethics Journal 12, no. 1 (2002): 1–15.

Moreover, because of pleiotropy, a genetic variation associated with drug response may be found also to be associated with an increased disease risk. The NAT2 enzyme, involved in detoxification of many carcinogens and the metabolism of many common drugs, is an example. Genetic variation in NAT2 may predict toxic effects of drugs and “may contribute to racial and ethnic variation in the incidence of environmentally induced cancers.” Burchard E. G. Ziv E. Coyle N. , and Gomez S. L. , “The Importance of Race and Ethnic Background in Biomedical Research and Clinical Practice,” New England Journal of Medicine 348, no. 12 (2003): 1170–1175, at 1173.

Slightly different definitions abound with some commentators abandoning, and others maintaining, a distinction between pharmacogenetics and pharmacogenomics. P-genetics investigates the relationship between individuals' drug metabolism and genetic polymorphisms, while p-genomics uses genome-wide studies to develop new drugs using information about genetic polymorphisms and gene expression ( Morley K. I. and Hall W. D. , “Using Pharmacogenetics and Pharmacogenomics in the Treatment of Psychiatric Disorders: Some Ethical and Economic Considerations,” Journal of Molecular Medicine 82, no. 1 (2004): 21–30). In relation to drug response, p-genetics focuses on genotypic variations that are not tissue-specific, while p-genomics focuses on gene expression in cells of particular tissues (see Buchanan , supra note 57). Because our concerns about research participation apply to both domains, however they are defined, and because our focus is on the eventual clinical use of all such research to reduce health disparities, we employ the term “pharmacogenomics” to refer to the generation and clinical translation of information about genetic variation and treatment response. Rothstein and Epps ( Rothstein M. A. and Epps P. G. , “Pharmacogenomics and the (Ir)relevance of Race,” Pharmacogenomics Journal 1, no. 2 (2001): 104–108) define pharmacogenetics as the study of inherited genetic Influences on drug response, a conception that may resonate negatively with older adults whom Frazier et al. identified as reluctant to participate in genetic research for fear of learning they have passed on a condition to offspring (see supra note 56).

Some include a fourth phenotype: intermediate metabolism (between slow and rapid). See Poolsup , supra note 9.

Foster M. W. and Sharp R. R. , “Beyond Race: Towards a Whole-Genome Perspective on Human Populations and Genetic Variation,” Nature Reviews Genetics 5 (2004): 790–796, at 792.

For example, see Tang H. Quertermous T. , and Rodriguez B. , “Genetic Structure, Self-Identified Race/Ethnicity, and Confounding in Case-Control Association Studies,” American Journal of Human Genetics 76, no. 2 (2005): 268–275.

Bamshad M. , “Genetic Influences on Health: Does Race Matter?” JAMA 294, no. 8 (2005): 937–946.

See Poolsup , supra note 9.

Nanda R. Schumm L. P. , and Cummings S. , “Genetic Testing in an Ethnically Diverse Cohort of High-Risk Women: A Comparative Analysis of BRCA1 and BRCA2 Mutations in American Families of European and African Ancestry,” JAMA 294, no. 15 (2005): 1925–1933, at 1925.

Id., at 1930.

Olopade O. I. Fackenthal J. D. , and Dunston G. , “Breast Cancer Genetics in African Americans,” Cancer 97, no. 1, Supp. (2003): 236–245.

Tate S. K. and Goldstein D. B. , “Will Tomorrow's Medicines Work for Everyone?” Nature Genetics 36, no. 11 supplement (2004): S34–42.

This finding has been disputed by other studies and also has been attributed to Differences in clinicians' attitudes and prescribing practices, rather than to African Americans' response to anti-psychotic medications. See Poolsup , supra note 9.

Frackiewicz E. J. Sramek J. J. Herrara J. M. Kurtz N. M. , and Cutler N. R. , “Ethnicity and Antipsychotic Response,” Annals of Pharmacotherapy 31, no. 11 (1997): 1360–1369.

An additional burden for the elder African-American population is the fact that depression is associated with these conditions or treatment for them, and African Americans experience these conditions at disproportionate rates. Establishing the efficacy of antidepressants in African Americans, especially those middle-aged and older, is thus a necessary feature of adequately addressing multiple health problems facing an aging African-American population and providing them non-disparate care.

See Williams , supra note 39, at 91.

Griffith D. M. Mason M. , and Yonas M. , “Dismantling Institutional Racism: Theory and Action,” American Journal of Community Psychology 39, nos. 3–4 (2007): 381–392.

See Williams , supra note 39.

This recommendation is made by Brody with regard to other types of research that affect health disparities. Parker L. S. and Brody H. , “Comparative Effectiveness Research and Health Reform: Ethical Issues,” Health Progress 92, no. 5 (2011): 64–71.

Department of Health and Human Services, HHS Action Plan to Reduce Racial and Ethnic Health Disparities, 2011, at 12, available at <http://minorityhealth.hhs.gov/npa/files/Plans/HHS/HHS_Plan_complete.pdf> (last visited December 5, 2012).

Forrow L. Arnold R. , and Parker L. S. , “Preventive Ethics: Expanding the Horizons of Clinical Ethics,” Journal of Clinical Ethics 4, no. 4 (1993): 287–294.

Wolf S. M. Lawrenz F. P. , and Nelson C. A. , “Managing Incidental Findings in Human Subjects Research: Analysis and Recommendations,” Journal of Law, Medicine & Ethics 36, no. 2 (2008): 219–248.

Office of Human Research Protections, IRB Guidebook, 1993, available at <http://www.hhs.gov/ohrp/archive/irb/irb_guide-book.htm> (last visited December 5, 2012).

See Buchanan , supra note 57.

Brody H. and Hunt L. M. , “BiDil: Assessing a Race-Based Pharmaceutical,” Annals of Family Medicine 4, no. 6 (2006): 556–560.

In the 1980s two trials of BiDil (a combination of isosorbide and hydralazine) failed to establish that its effect was comparable or superior to that of an ACE inhibitor, enalapril, for the treatment of heart failure. Most of those enrolled in the 2001 African-American Heart Failure Trial (A-HeFT) were also using ACE inhibitors or betablockers, or both, so that A-HeFT studied and established the effectiveness of BiDil as an addition to standard therapies, which is not the same question the 1980s trials had examined. Whether adding a combination of isosorbide and hydralazine to the current treatment regimens of non-African-American heart failure patients would be beneficial has not been studied in an all-race trial. Evidence that BiDil works well in African-Americans, but not in Whites, is at best ambiguous. Ellison G. T. H. Kaufman J. S. Head R. F. Martin P. A. , and Kahn J. D. , “Flaws in the U.S. Food and Drug Administration's Rationale for Supporting the Development and Approval of BiDil as a Treatment for Heart Failure Only in Black Patients,” Journal of Law, Medicine & Ethics 36, no. 3 (2008): 449–457.

See Ellison , supra note 84.

Such sentiments were expressed, for example, at the April 7, 2006 conference, Race, Pharmaceuticals, and Medical Technology, sponsored by the Center for the Study of Diversity in Science, Technology, and Medicine of the Massachusetts Institute of Technology, as reported by University of California Hastings College of Law professor, Obasogie Osagie K. , available at <http://www.biopoliticaltimes.org/article.php?id=2018> (last visited December 5, 2012).

There are apparent incentives not to conduct such a study: BiDil is currently approved for marketing to African-American patients, and other patients may be prescribed BiDil on an of-label basis, thereby expanding its market. The generation of evidence that the combination is beneficial in other populations would actually undermine the rationale for FDA approval of BiDil, its patented status, and its marketing strategy. Ironically, showing that BiDil is suitable for the majority of genotypes – or that genotype is largely irrelevant to its effectiveness – would reduce its profitability.

U.S. Department of Health and Human Services, Pharmacogenomics Knowledge Base, PharmGKB, available at <http://www.pharmgkb.org/resources/forGeneralUsers/pharmacogenetics_pharmacogenomics_anpersonalized_medicine.jsp> (last visited March 9, 2012); also quoted, for example, in Khoon C. C. , Genomics and Population Health: A Social Epidemiology Approach, in Genomics and Bioethics: An Interdisciplinary Perspectives, Technologies, and Advancements, ed. Hongladarom Soraj (Hershey, PA: Medical Information Science Reference, 2011.)