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Wednesday, July 18, 2012

Are antipsychotic drugs becoming less effective?

According to a report published today at Reuters, antipsychotic drugs appear to be losing their efficacy. This is supposedly because there is a rise in the affect of the placebo effect.

The Reuters story is well-written (go and read please), but is missing a "Part II." If the data are correct and there is a narrowing gap between drug effect and placebo effect, what are the most likely explanations? Is it true that placebo responses are rising? Or that drugs are becoming less effective?

Let's step back and examine the question being asked, and the possible answers.

When clinical drug trials are done, the drug in question (the test drug) is usually compared to a placebo, an inert substance designed to look, taste and feel the same as the test drug. This is one way of separating the true effect of the drug from other effects, such as simply being involved in a study. Example time (skip if you already know this stuff).

Hypothesis: Oral Wonderflonium increases scrotal volume in human adult males. This is based on a mouse model that showed some promising results. Aspiring Academic Medical Center (AAMC) decides to test the hypothesis. They recruit 400 human adult males and measure their scrotal volumes on entry into the study (up to you to imagine how it's done). They treat the males with Wonderflonium for six months and then re-measure the scrotal volumes. Lo and behold, the average scrotal volume of the group increases by 20%. The folks at AAMC submit the paper to Second Tier Medical Journal.

Two of the reviewers at STMJ love it. Increased scrotal volume! Wonderflonium! Twenty percent! The final reviewer is less enthusiastic. "How do we know it was the Wonderflonium? After all, we're not comparing these people to anyone else. Maybe the drive two and from the center increased their scrotums. Maybe there's something at the coffee cart. Go back and re-work this."

The AAMC folks want to re-do the study, but ran out of money, as Wonderflonium is very hard to come by. But over at Major Academic Medical Center (MAMC), there's a guy with a big grant who grabs the whole idea by the, um, reins and sets up a new study. This time another 400 men are recruited, but half receive Wonderflonium and half receive a placebo that is outwardly identical to Wonderflonium.

This time, the results are published: Wonderflonium increased scrotal volume by 18% over placebo. Woo. Hoo.

The potential market is huge, especially among a certain set of inadequate-feeling, 'roid-raging gym rats. Several more studies are designed by academics and by drug companies (sometimes indistinguishably). Wonderflonium is flying off the shelves as the studies continue to give positive results.

A few years later, someone goes back and looks at the data. The most recent studies are showing that scrotums among gym rats aren't actually getting much bigger, something expected given the wide use of the drug. He goes back and finds recent studies have shown that scrotal size is only up by about 3-4% vs. placebo. WTF?

The researcher notes that scrotums in the placebo groups in the latest study are up more than in the original, and that this increase in placebo response is responsible for what seems like a decrease in the drug's efficacy.

His colleague has a different idea, one examined in detail by Dr. David Gorski at Science-Based Medicine. His colleague looks at the trend, and she sees something familiar: new drugs seem to work better right after their discovery.

She proposes the Scrotum Problem is due to the "decline effect," a mixture of factors that better explains the trend. The early studies of the new drug may have captured a less random moment in time. As more and more people are treated, there is a "regression toward the mean," with more studies giving us more accurate (and less impressive) numbers. There may also have been some publication bias, in which studies with interesting positive results were more likely to be submitted and published.

What is less likely is that something about placebos has changed. While placebo scrotum volumes increased, there may be many explanations for this. Study design can affect placebo response considerably, as can measurement biases. But since placebos don't change, they're not to blame.

So before we all get too excited about the increasing placebo effect killing off new drug development we need to ask smarter questions: Are we looking at the right end points and doing it correctly? Are we allowing expectations to trump good study design? Are we jumping the gun on new drugs by relying on initial small studies? Are we moving the goal posts in our original studies by hunting for statistically significant effects that we didn't lay out in our hypothesis?

All could be true. But a sugar pill is still a sugar pill.

Peter A. Lipson, ACP Member, is a practicing internist and teaching physician in Southeast Michigan. After graduating from Rush Medical College in Chicago, he completed his internal medicine residency at Northwestern Memorial Hospital. This post first appeared at his blog, White Coat Underground. The blog, which has been around in various forms since 2007, offers "musings on the intersection of science, medicine, and culture." His writing focuses on the difference between science-based medicine and "everything else," but also speaks to the day-to-day practice of medicine, fatherhood, and whatever else migrates from his head to his keyboard.

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Blog log

Members of the American College of Physicians contribute posts from their own sites to ACP Internistand ACP Hospitalist. Contributors include:

Albert Fuchs, MD
Albert Fuchs, MD, FACP, graduated from the University of California, Los Angeles School of Medicine, where he also did his internal medicine training. Certified by the American Board of Internal Medicine, Dr. Fuchs spent three years as a full-time faculty member at UCLA School of Medicine before opening his private practice in Beverly Hills in 2000.

And Thus, It Begins
Amanda Xi, ACP Medical Student Member, is a first-year medical student at the OUWB School of Medicine, charter class of 2015, in Rochester, Mich., from which she which chronicles her journey through medical training from day 1 of medical school.

Auscultation
Ira S. Nash, MD, FACP, is the senior vice president and executive director of the North Shore-LIJ Medical Group, and a professor of Cardiology and Population Health at Hofstra North Shore-LIJ School of Medicine. He is Board Certified in Internal Medicine and Cardiovascular Diseases and was in the private practice of cardiology before joining the full-time faculty of Massachusetts General Hospital.

Zackary Berger
Zackary Berger, MD, ACP Member, is a primary care doctor and general internist in the Division of General Internal Medicine at Johns Hopkins. His research interests include doctor-patient communication, bioethics, and systematic reviews.

Controversies in Hospital Infection Prevention
Run by three ACP Fellows, this blog ponders vexing issues in infection prevention and control, inside and outside the hospital. Daniel J Diekema, MD, FACP, practices infectious diseases, clinical microbiology, and hospital epidemiology in Iowa City, Iowa, splitting time between seeing patients with infectious diseases, diagnosing infections in the microbiology laboratory, and trying to prevent infections in the hospital. Michael B. Edmond, MD, FACP, is a hospital epidemiologist in Richmond, Va., with a focus on understanding why infections occur in the hospital and ways to prevent these infections, and sees patients in the inpatient and outpatient settings. Eli N. Perencevich, MD, ACP Member, is an infectious disease physician and epidemiologist in Iowa City, Iowa, who studies methods to halt the spread of resistant bacteria in our hospitals (including novel ways to get everyone to wash their hands).

db's Medical Rants
Robert M. Centor, MD, FACP, contributes short essays contemplating medicine and the health care system.

Suneel Dhand, MD, ACP Member
Suneel Dhand, MD, ACP Member, is a practicing physician in Massachusetts. He has published numerous articles in clinical medicine, covering a wide range of specialty areas including; pulmonology, cardiology, endocrinology, hematology, and infectious disease. He has also authored chapters in the prestigious "5-Minute Clinical Consult" medical textbook. His other clinical interests include quality improvement, hospital safety, hospital utilization, and the use of technology in health care.

DrDialogue
Juliet K. Mavromatis, MD, FACP, provides a conversation about health topics for patients and health professionals.

Dr. Mintz' Blog
Matthew Mintz, MD, FACP, has practiced internal medicine for more than a decade and is an Associate Professor of Medicine at an academic medical center on the East Coast. His time is split between teaching medical students and residents, and caring for patients.

Everything Health
Toni Brayer, MD, FACP, blogs about the rapid changes in science, medicine, health and healing in the 21st century.

FutureDocs
Vineet Arora, MD, FACP, is Associate Program Director for the Internal Medicine Residency and Assistant Dean of Scholarship & Discovery at the Pritzker School of Medicine for the University of Chicago. Her education and research focus is on resident duty hours, patient handoffs, medical professionalism, and quality of hospital care. She is also an academic hospitalist.

Glass Hospital
John H. Schumann, MD, FACP, provides transparency on the workings of medical practice and the complexities of hospital care, illuminates the emotional and cognitive aspects of caregiving and decision-making from the perspective of an active primary care physician, and offers behind-the-scenes portraits of hospital sanctums and the people who inhabit them.

Gut Check
Ryan Madanick, MD, ACP Member, is a gastroenterologist at the University of North Carolina School of Medicine, and the Program Director for the GI & Hepatology Fellowship Program. He specializes in diseases of the esophagus, with a strong interest in the diagnosis and treatment of patients who have difficult-to-manage esophageal problems such as refractory GERD, heartburn, and chest pain.

I'm dok
Mike Aref, MD, PhD, FACP, is an academic hospitalist with an interest in basic and clinical science and education, with interests in noninvasive monitoring and diagnostic testing using novel bedside imaging modalities, diagnostic reasoning, medical informatics, new medical education modalities, pre-code/code management, palliative care, patient-physician communication, quality improvement, and quantitative biomedical imaging.

Informatics Professor
William Hersh, MD, FACP, Professor and Chair, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, posts his thoughts on various topics related to biomedical and health informatics.

David Katz, MD
David L. Katz, MD, MPH, FACP, is an internationally renowned authority on nutrition, weight management, and the prevention of chronic disease, and an internationally recognized leader in integrative medicine and patient-centered care.

Just Oncology
Richard Just, MD, ACP Member, has 36 years in clinical practice of hematology and medical oncology. His blog is a joint publication with Gregg Masters, MPH.

KevinMD
Kevin Pho, MD, ACP Member, offers one of the Web's definitive sites for influential health commentary.

MD Whistleblower
Michael Kirsch, MD, FACP, addresses the joys and challenges of medical practice, including controversies in the doctor-patient relationship, medical ethics and measuring medical quality. When he's not writing, he's performing colonoscopies.

Medical Lessons
Elaine Schattner, MD, FACP, shares her ideas on education, ethics in medicine, health care news and culture. Her views on medicine are informed by her past experiences in caring for patients, as a researcher in cancer immunology, and as a patient who's had breast cancer.

Mired in MedEd
Alexander M. Djuricich, MD, FACP, is the Associate Dean for Continuing Medical Education (CME), and a Program Director in Medicine-Pediatrics at the Indiana University School of Medicine in Indianapolis, where he blogs about medical education.

More Musings
Rob Lamberts, MD, ACP Member, a med-peds and general practice internist, returns with "volume 2" of his personal musings about medicine, life, armadillos and Sasquatch at More Musings (of a Distractible Kind).

Prescriptions
David M. Sack, MD, FACP, practices general gastroenterology at a small community hospital in Connecticut. His blog is a series of musings on medicine, medical care, the health care system and medical ethics, in no particular order.

Reflections of a Grady Doctor
Kimberly Manning, MD, FACP, reflects on the personal side of being a doctor in a community hospital in Atlanta.

The Blog of Paul Sufka
Paul Sufka, MD, ACP Member, is a board certified rheumatologist in St. Paul, Minn. He was a chief resident in internal medicine with the University of Minnesota and then completed his fellowship training in rheumatology in June 2011 at the University of Minnesota Department of Rheumatology. His interests include the use of technology in medicine.

Technology in (Medical) Education
Neil Mehta, MBBS, MS, FACP, is interested in use of technology in education, social media and networking, practice management and evidence-based medicine tools, personal information and knowledge management.

Peter A. Lipson, MD
Peter A. Lipson, MD, ACP Member, is a practicing internist and teaching physician in Southeast Michigan. The blog, which has been around in various forms since 2007, offers musings on the intersection of science, medicine, and culture.

Why is American Health Care So Expensive?
Janice Boughton, MD, FACP, practiced internal medicine for 20 years before adopting a career in hospital and primary care medicine as a locum tenens physician. She lives in Idaho when not traveling.

World's Best Site
Daniel Ginsberg, MD, FACP, is an internal medicine physician who has avidly applied computers to medicine since 1986, when he first wrote medically oriented computer programs. He is in practice in Tacoma, Washington.

Other blogs of note:

American Journal of Medicine
Also known as the Green Journal, the American Journal of Medicine publishes original clinical articles of interest to physicians in internal medicine and its subspecialities, both in academia and community-based practice.

Clinical Correlations
A collaborative medical blog started by Neil Shapiro, MD, ACP Member, associate program director at New York University Medical Center's internal medicine residency program. Faculty, residents and students contribute case studies, mystery quizzes, news, commentary and more.

Interact MD
Michael Benjamin, MD, ACP member, doesn't accept industry money so he can create an independent, clinician-reviewed space on the Internet for physicians to report and comment on the medical news of the day.

PLoS Blog
The Public Library of Science's open access materials include a blog.

White Coat Rants
One of the most popular anonymous blogs written by an emergency room physician.

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