From the Editor

Do the pills really work?

It’s a question that we clinicians are repeatedly asked. Antidepressants are widely prescribed, but often doubted – by our patients and by people in general.

This week, we look at an essay penned by Dr. Peter Kramer, an American psychiatrist. Dr. Kramer, you may recall, made a name for himself two decades ago by extolling the super-therapeutic powers of Prozac. Today, he has a more modest goal: explaining the role of antidepressants in the treatment of depression.

Then, looking to The New England Journal of Medicine, we consider a paper that discusses the rise and, perhaps, fall of randomized controlled trials as the “gold standard” of medical research.


Dr. Kramer on Antidepressants

“In Defense of Antidepressants”

Dr. Peter D. Kramer, The Wall Street Journal

27 May 2016


Do antidepressants work? The notion that they don’t—that Prozac, Lexapro and other drugs are little more than placebos with side effects—has become mainstream. “Antidepressant Lift May Be All in Your Head,” a typical headline reads, atop an article citing research from medical journals. With as many as one in eight American adults now taking an antidepressant, the stakes are high.

Concerned about providing effective care to my own patients, I have spent the past five years exploring the evidence on treatment for depression. As I read the formal findings, they jibe with what my clinical work as a psychiatrist had led me to expect. Antidepressants are harmful in a subset of depressed patients but helpful for most. Little of the benefit comes from the classic placebo effect—that is, hopeful expectancy based on the fact of pill-taking. Most of it comes instead from the inherent, chemical properties of the drugs, perhaps through their ability to restore resilience in the brain.

Dr. Peter D. Kramer

So opens an essay by psychiatrist Peter Kramer. (See below for the full text.) This piece ran a few weeks ago, around the time his new book on this topic was published.

The essay hits hard at the argument that antidepressants don’t really work.

Here are a few points he makes:

· “There are reasons beyond the numbers – even beyond the progress of my patients – that make it hard for me to believe that antidepressants do not work.”

· He notes that he used to see many people with “end-stage depression.” In his training years, these cases were common. At the time, psychoanalysis was the standard of care.

· Today, such cases seem to be more rare, based on conversations with colleagues and his own clinical experience.

He goes on to conclude:

Still, my impression is that end-stage depression is less common in part because – haphazardly, with many cases missed altogether – doctors employ antidepressants. They have broad effects, preventing recurrences, improving patients’ quality of life. Even partial successes count.

A few thoughts:

1. Dr. Kramer is always entertaining – and this essay also reads well.

2. I can’t help but feel that the argument overreaches. Dr. Kramer sees less end-stage depression, as he describes it, but he also works in the community. Those of us in hospitals are all too familiar with cases of profound depression.

3. That’s not to argue that antidepressants don’t work; I’m just not so persuaded by this particular argument.

4. For a better review of the literature, I’d suggest taking a look at this blog by Dr. Harriet Hall (at the suggestion of Canadian Journal of Psychiatry editor Scott Patten on his blog):

5. More interesting than Dr. Kramer’s writing, frankly, is his journey. He is the author of Listening to Prozac, the bestselling book that argued that Prozac changes people – giving people more confidence and self-worth. That book, published 23 years ago, seemed to imply that we could all benefit from medications. It was published at the moment when the potential of psychopharmacology seemed unlimited. Dr. Kramer wrote about “cosmetic psychopharmacology” whereby people would be improved, not just treated, by meds – the psychiatric equivalent of a tummy tuck. Today, while there is a recognized role for medications, our collective enthusiasm has waned. Psychiatrists like Dr. Kramer are no longer waxing poetic about the great potential of Prozac and her sister drugs, they are justifying the use of these meds. The pendulum has swung to say the least.

Thoughts on Medicine and Research

“Assessing the Gold Standard — Lessons from the History of RCTs”

Laura E. Bothwell et al., The New England Journal of Medicine

2 June 2016


Over the past 70 years, randomized, controlled trials (RCTs) have reshaped medical knowledge and practice. Popularized by mid-20th-century clinical researchers and statisticians aiming to reduce bias and enhance the accuracy of clinical experimentation, RCTs have often functioned well in that role. Yet the past seven decades also bear witness to many limitations of this new ‘gold standard.’ The scientific and political history of RCTs offers lessons regarding the complexity of medicine and disease and the economic and political forces that shape the production and circulation of medical knowledge.

Laura E. Bothwell

So opens a paper by Bothwell et al. published in The New England Journal of Medicine reviewing the history and prominence of the randomized controlled trial.

Bothwell et al. note the history of the RCT:

“As the role of science in medicine expanded in the late 19th century, physicians approached clinical research with increasing rigor. By the early 20th century, innovators had introduced many clinical-trial techniques to eliminate bias, including blinding, alternate assignment to trial groups, and statistical analysis.”

The British epidemiologist Austin Bradford Hill formalized RCT methods in the 1940s and a war investment in research led to the infrastructure that could support RCTs. Despite this, the early days were marked by “mixed reviews.”

Over time, RCTs grew in prominence. The U.S. National Institutes of Health began funding the work; post-thalidomide, the U.S. F.D.A. used the methodology for drug approval. Not surprisingly, the United States is a major funder of RCTs – see below. And clinical epidemiologists consider them to the “gold standard” of medical research.

The authors note the failings and realities of RCTs:

· “A quick scan of the medical literature reveals that older methods, including case series and even case reports, continue to be valuable.”

· “Even well-conducted RCTs sometimes failed to influence medical practice.” For example, a 2002 RCT showed no benefit of arthroscopic debridement for chronic osteoarthritis of the knee; many orthopedic surgeons dismissed the results and continued using the procedure.

· “Over time, RCTs have become massive bureaucratic and corporate enterprises, demanding costly infrastructure for research design, patient care, record keeping, ethical review, and statistical analysis. By the 21st century, a single phase 3 RCT could cost $30 million or more.”

They conclude:

By the turn of the 21st century, RCTs had achieved the status of gold standard for therapeutic evidence — but one with well-documented limitations. Physicians continue to pursue alternative methods of knowledge production that are faster or less expensive than RCTs, or that claim to answer questions that RCTs cannot.

My final thought: this is a great paper. And while RCTs are likely to remain at the heart of psychiatric research, some very important efforts – think about experimentation with real-time suicide reduction strategies and the incorporation of apps into the care of people with mental health problems, to name two examples – will likely mean that we are less wedded to RCTs in the future.

Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.