Ketamine for Depression: Research versus Marketing

Bioethics in the News logoThis post is a part of our Bioethics in the News series

By Arthur Ward, PhD

Just weeks ago, the U.S. Food and Drug Administration approved Ketamine as the first new drug in decades for treatment of depression. Or rather, while the approval for psychiatric treatment was new, the drug itself has been around as an anesthetic since 1970. The story of why it took so long for this well-known and well-tested drug (millions of patients have received ketamine as anesthesia) reveals the complex interplay between medical practice, the economics of pharmaceuticals, and the challenges of research ethics. Ketamine and other psychoactive drugs hold a great deal of promise for the treatment of depression and suicidality, but we need to be measured in our approach. To that end, I recommend an accelerated pace of research, but a slower rate of FDA approval and therapeutic application until more is known about the long-term effects.

What is so special about ketamine? Traditional pharmaceutical treatments for depression such as SSRIs (selective serotonin reuptake inhibitors) work by increasing the levels of the neurotransmitter serotonin in the brain. Ketamine is totally different, acting instead on the neurotransmitter glutamate. While SSRI medications can take weeks or months to become effective, ketamine can sometimes be effective in hours. That is utterly remarkable and groundbreaking, especially given the urgent nature of a depressive crisis. Meta-analyses of recent clinical trials on short term use show clear promise, with as much as a 50% improvement over placebo after 72 hours.

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Image description: a photograph of the sky with rays of sunlight pouring out from behind a dark cloud.

Yet there are reasons to think that Janssen’s esketamine nasal spray needs further research before responsibly coming to market. Double-blind randomized controlled clinical trials (RCTs) on psychoactive substances are very difficult to administer when the experimental drug has known mind-altering properties; in short, those that don’t hallucinate will know they’re in the control group! In the four Janssen phase-three clinical trials, all participants were on SSRI medication (it would not be ethical to give a depressed patient no treatment at all), the experimental group received esketamine nasal spray, while a placebo nasal spray was used in the control group. Despite adding an “embittering agent” to the placebo spray, the control group would likely have known they did not receive the esketamine (which is a hallucinogen), and thus a great deal of scientific rigor of the experiment was lost. In ongoing and future clinical trials, Janssen is using an “active placebo,” combining the placebo nasal spray with midazolam (a benzodiazepine sedative) so that the control group might think they took esketamine. While this would be an improvement in the blinding process, ketamine and midazolam do not feel the same: Midazolam a depressant while ketamine has psychedelic properties.

A second concern with the limited research so far has to do with the unknown long-term effects of ketamine use. Millions have experienced the anesthetic in a single dose, but the effects of long-term use are largely untested. The four clinical trials of Janssen’s esketamine nasal spray lasted only four weeks, and of these, only one showed significant results. Could it cause neurological damage long-term to take many repeated doses of esketamine? We don’t know, because the research hasn’t been done yet.

There are also cautionary signals of over-exuberance in therapeutic application that warrant vigilance. We must be mindful of pharmaceutical economics: capitalism craves returning customers. The market tends to reward expensive treatments for chronic conditions, and stifles cheaper treatments that effect a cure. For use as an anesthetic, Ketamine currently is generic and can be acquired quite cheaply. However, the FDA has only approved Janssen pharmaceuticals to release a nasal spray version of the drug, with esketamine, a closely related chemical. In doing so, the FDA grants esketamine patent protection – guaranteeing that treatment will be upwards of $500 a dose (the recommended treatment is eight doses over a month, totaling $4,720 to $6,785). This price is just for the drug alone, and not the accompanying office visit, which requires several hours of observation by a professional, adding extra expense. Granted, if one is freed from the burden and danger of crushing depression, this is well worth the price! And there are many credible anecdotes of ketamine treatment providing rapid, permanent relief. However, looking at the data, this long-lasting effect does not seem to be the norm. Instead, most people require sustained, periodic maintenance sessions every few weeks or months. This then raises the troubling question of whether we might be cultivating a financially crippling chemical dependence for some patients – rather than a cure.

My words of caution should not be interpreted as scolding or alarmist. I am a cheerleader for ketamine research. So far, the best evidence is that ketamine and esketamine are able to help some people who found little relief from other antidepressant treatments, and this is a wonderful turn of events. Alternatively, I think we should perhaps slow the pace of how quickly we bring ketamine drugs to market, but accelerate the related research. We need more clinical trials, and not just on ketamine, but on a variety of other psychoactive drugs as well! The culture wars of the 1960s resulted in the shuttering of promising research into LSD, psilocybin, and MDMA, all psychedelics well-recognized to have efficacy for depression treatment. After decades of lost time, clinical trials of all three chemicals are now underway. As the writer Michael Pollan has recently asserted in interviews and in his book, How To Change Your Mind, we are in the midst of a new renaissance of research into psychoactive chemicals. I suggest that we embrace this experimentation momentum, but simultaneously keep watch over our shoulder, both for possible long-term side-effects and for drug marketing’s problematic economic pressures.

Arthur Ward photoArthur Ward, PhD, is a teaching professor of History, Philosophy, and Sociology of Science in Lyman Briggs College at Michigan State University.

Join the discussion! Your comments and responses to this commentary are welcomed. The author will respond to all comments made by Thursday, April 4, 2019. With your participation, we hope to create discussions rich with insights from diverse perspectives.

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Assistant Director Libby Bogdan-Lovis a co-investigator on breastfeeding project

Libby Bogdan-Lovis photoCenter for Ethics Assistant Director Libby Bogdan-Lovis is a co-investigator on the project “Buffers, Barriers, and Resiliency in Breastfeeding Behaviors of Asian American Mothers.” The project is funded by the Trifecta Initiative for Interdisciplinary Health Research, a collaboration between the Colleges of Communication Arts & Sciences, Engineering, and Nursing at Michigan State University.

The interdisciplinary research team includes principal investigator Joanne Goldbort of the College of Nursing, Mary Bresnahan of the College of Communication Arts & Sciences, and Jie Zhuang of the Bob Schieffer College of Communication at Texas Christian University.

Project Summary: While Asian American (AA) mothers are described as high initiators of breastfeeding, no previous studies have conducted a randomized trial of AA mothers’ breastfeeding and formula use behaviors and whether these mothers continue to breastfeed exclusively for the recommended six months. Using an online Qualtrics customized panel, we will conduct a systematic investigation of the breastfeeding behaviors and timing of the introduction of complementary foods, and use of formula of AA mothers over a one-year period. We will recruit 1200 women between the ages of 18 and 35, as follows: 400 AA mothers with children one-year or younger; 400 pregnant AA women; and 400 American mothers from all race/ethnic groups will serve as the control group. This longitudinal study will track pregnant AA women through the birth of their babies, and will assess breastfeeding support and behaviors after the initial data collection, at 3-months, 6-months, and at one-year.

Visit our website to learn more about current research projects in the Center for Ethics and Humanities in the Life Sciences.

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Dr. Kelly-Blake a co-author of new article in ‘Health Services Research and Managerial Epidemiology’

Karen Kelly-Blake photoCenter Assistant Professor Dr. Karen Kelly-Blake is co-author of an article published in Health Services Research and Managerial Epidemiology, “Sex Differences in Statin Prescribing in Diabetic and Heart Disease Patients in FQHCs: A Comparison of the ATPIII and 2013 ACC/AHA Cholesterol Guidelines.”

The team of Michigan State University College of Human Medicine researchers, Nazia Naz S. Khan, Karen Kelly-Blake, Zhehui Luo, and Adesuwa Olomu, found statin underprescribing for both men and women with atherosclerotic cardiovascular disease and diabetes mellitus in Federally Qualified Health Centers.

The full text is available online with open access via Sage Journals.

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Dr. Cabrera co-authors ‘AJOB Neuroscience’ commentary on deep brain stimulation for depression

Laura Cabrera photo“Interpreting Patients’ Beliefs About Deep Brain Stimulation for Treatment-Resistant Depression: The Need for Caution and for Context” is an open peer commentary available in the latest AJOB Neuroscience issue. Michigan State University co-authors Dr. Laura Cabrera, Assistant Professor in the Center for Ethics and Humanities in the Life Sciences and the Department of Translational Science & Molecular Medicine, and Dr. Robyn Bluhm, Associate Professor in the Department of Philosophy and Lyman Briggs College, are currently working on an NIH BRAIN Initiative funded project on a related topic.

Dr. Cabrera and Dr. Bluhm focus on two points raised by the Lawrence et al. paper. First, they discussed a couple methodological decisions made by the authors which may have had an important influence on the results presented in the article. The second point relates to the work of Dr. Cabrera and Dr. Bluhm, examining differences in the bioethics literature’s discussion of deep brain stimulation and public comments on newspaper and magazine studies covering the intervention; this part of the open peer commentary shows how their findings can help to deepen the analysis by Lawrence et al.

The full text is available online via Taylor & Francis Online (MSU Library or other institutional access may be required to view this article).

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Bioethics for Breakfast: Addressing Maternal Mortality in the Childbearing Year

Bioethics for Breakfast Seminars in Medicine, Law and SocietyEvery woman who dies during or after pregnancy has a story to tell, a story that can teach us how to prevent other maternal deaths.

Renée Canady, PhD, MPA, and Cheryl Larry-Osman, RN, MS, CNM, presented at the February 21st Bioethics for Breakfast event, offering perspectives and insight on the topic “Just Caring for All Michigan Mothers: Addressing Maternal Mortality in the Childbearing Year.” Drawing from the 2018 Michigan Maternal Mortality Surveillance report, the speakers reminded the audience that “every woman who dies during or after pregnancy has a story to tell, a story that can teach us how to prevent other maternal deaths.” The presenters introduced the session with compelling personal experiences, illustrating the scope and scale of the problem. Using an ethics yardstick Dr. Canady then invited the 33-member audience to respond to graphic depictions of the U.S. maternal mortality death rate – the highest rate within the developed world. Those numbers give evidence of a profound social injustice and a need to modify resource allocation accordingly.

Yet as in much of the U.S., evidence suggests that Michigan has not met the mark. As the speakers noted, race matters – a lot. From 2011-2015 Black women in Michigan were found to be three times more likely than white women to die of a pregnancy-related cause; upon review nearly half (44%) were considered preventable. Black mothers in Michigan were twice as likely to die from a pregnancy-associated cause; upon review, 39% were deemed preventable. Social and medical advances have disproportionately failed to address pregnancy needs for Black mothers. Sociodemographic variables do not fully explain the observed gap – the disparities are rooted in multilevel (system, practitioner, patient) inequalities including place, communication, and discrimination. A health equity approach recognizes that one must comprehensively address institutional racism, class oppression, and exploitative gender discrimination.

As a just and caring society we have an obligation to ensure safe and healthy pregnancy and birth experiences for all mothers. Ms. Larry-Osman noted that a virtue ethics approach leans on the character of health professionals to engage compassion, reason and discipline in the interest of maternal well-being. In concert, a communitarian ethics approach emphasizes shared values, ideals and goals to identify barriers to care as well as interventions and solutions. As reported by attendee Lynette Biery, Maternal Child Health Director at the Michigan Department of Health and Human Services, maternal mortality reviews such as the Michigan Maternal Mortality Surveillance Program provide data necessary to address changes that would improve women’s health before, during and after pregnancy. Michigan has seen some improvement after the 2016 implementation of hemorrhage and hypertension “safety bundles” and the MI-AIM (Alliance for Innovation on Maternal Health) is now working on opioid bundles as well. But given the scale of the problem, are such efforts enough?

Approximately 50% of Michigan women rely on Medicaid for prenatal care and give birth in a Medicaid supported hospital, but that program is targeted for cuts under the current federal administration. What is the state/physician obligation to address this? Should the state ensure the availability of labor support “doulas” as part of standard maternity care as is being done in other states? Mortality reviews help, but are they sufficient to raise awareness and address the multilevel problems? What structural strategies might best pave the way for continuity of care and community care? How can solutions avoid racist calls for “personal responsibility for heath”? What are the effects of pervasive racism and how might the state best address them? Many in audience lingered past the session’s end to continue discussing these questions. Our thanks to health law firm Hall, Render, Killian, Heath & Lyman for generously supporting these important conversations.

Renée Canady
Renée Canady, PhD, MPA, is Chief Executive Officer of the Michigan Public Health Institute. She is a nationally recognized thought leader in health disparities and inequities, cultural competence, and social justice. She additionally is Assistant Professor in MSU’s Division of Public Health within the College of Human Medicine. In her scholarly work, she emphasizes the social context of mental and physical health, and the pregnancy experiences of African-American women.

Cheryl Larry-Osman
Cheryl Larry-Osman, RN, MS, CNM, is a Perinatal Clinical Nurse Specialist at Henry Ford Hospital (Detroit). She additionally is trained as a Healthcare Equity Ambassador for the hospital and serves as a cultural competency and healthcare equity expert within that system. She has over 18 years of experience in obstetrics and is a passionate advocate for the optimal and equitable care of women and children.

About Bioethics for Breakfast:
In 2010, Hall, Render, Killian, Heath & Lyman invited the Center for Ethics to partner on a bioethics seminar series. The Center for Ethics and Hall Render invite guests from the health professions, religious and community organizations, political circles, and the academy to engage in lively discussions of topics spanning the worlds of bioethics, health law, business, and policy. For each event, the Center selects from a wide range of controversial issues and provides two presenters either from our own faculty or invited guests, who offer distinctive, and sometimes clashing, perspectives. Those brief presentations are followed by a moderated open discussion.
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What social and ethical challenges are presented by female cosmetic genital surgery?

bbag-blog-image-logoFemale Cosmetic Genital Surgery: Social and Ethical Considerations

Event Flyer

In recent years, there has been an upsurge in plastic surgery for women who wish to alter the look and feel of their genitalia. The women who undergo these procedures claim they are empowering, but critics worry such surgeries pathologize normal genital appearance. Several surgeons are also using social media to document these surgeries, granting them greater visibility and legitimacy. This talk will discuss the latest innovations in female cosmetic genital surgery, the history behind the medical community’s involvement in defining women’s sexuality, and the ethical and social challenges these surgeries present.

March 13 calendar iconJoin us for Dr. Stahl’s lecture on Wednesday, March 13, 2019 from noon until 1 pm in person or online.

Dr. Devan Stahl is an Assistant Professor of Clinical Ethics in the Center for Ethics and Humanities in the Life Sciences at Michigan State University. She received her Ph.D. in Health Care Ethics from St. Louis University. Dr. Stahl teaches medical students and residents in the College of Human Medicine and performs ethics consultation services at hospitals in Lansing, Michigan. Her research interests include medicine and the visual arts, theological bioethics, and disability studies. Dr. Stahl’s recent book, Imaging and Imagining Illness: Becoming Whole in a Broken Body, examines the power of medical images and their impact on patients and the wider culture.

In person: This lecture will take place in C102 Patenge Room in East Fee Hall on MSU’s East Lansing campus. Feel free to bring your lunch! Beverages and light snacks will be provided.

Online: Here are some instructions for your first time joining the webinar, or if you have attended or viewed them before, go to the meeting!

Can’t make it? All webinars are recorded! Visit our archive of recorded lecturesTo receive reminders before each webinar, please subscribe to our mailing list.

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What happens when people express hope for a miracle in the context of medicine?

No Easy Answers in Bioethics logoNo Easy Answers in Bioethics Episode 12

How do patients, their families, or their caregivers express hope for a miracle in the clinical setting? How can medical professionals respond to these desires for a miracle to occur?

Guests Dr. Devan Stahl, Assistant Professor in the Center for Ethics and Humanities in the Life Sciences and Department of Pediatrics and Human Development at Michigan State University, and Dr. Trevor Bibler, Assistant Professor in the Center for Medical Ethics and Health Policy at Baylor College of Medicine, have written on this topic, with articles published in the American Journal of Bioethics and the Journal of Pain and Symptom Management. In this episode they discuss the framework for categorizing the various ways in which people hope for a miracle, while also drawing from experiences they have had as clinical ethicists. They also discuss the importance of not making assumptions when miracle language is used, emphasizing the need for all religious beliefs to be respected by medical professionals.

Ways to Listen

This episode was produced and edited by Liz McDaniel in the Center for Ethics. Music: “While We Walk (2004)” by Antony Raijekov via Free Music Archive, licensed under a Attribution-NonCommercial-ShareAlike License. Full episode transcript available.

About: No Easy Answers in Bioethics is a podcast series from the Center for Ethics and Humanities in the Life Sciences in the Michigan State University College of Human Medicine. Each month Center for Ethics faculty and their collaborators discuss their ongoing work and research across many areas of bioethics—clinical ethics, evidence-based medicine, health policy, medical education, neuroethics, shared decision-making, and more. Episodes are hosted by H-Net: Humanities and Social Sciences Online.

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