Somaxon's Silenor: A Case Study in Sleeping Pill Deception

Sometimes, despite neon warning signs and a voice in our head shouting "DON'T DO IT," we go ahead and do stupid things anyway. 

Welcome to the world of Somaxon Pharmaceuticals, unveilers of the new sleeping pill, Silenor. Billed in their press releases as "the first and only non-scheduled prescription sleep aid that is proven to provide patients with a full night's sleep, including sleep into the 7th and 8th hour," Silenor is simply a branded version of doxepin, a tricyclic antidepressant that has been available in the U.S. since the 1960s, and has long been used as a cheap sleeping pill.

A year ago, Somaxon got FDA's permission to market this me-too drug.  All they had to do was to take little pinches of generic doxepin powder, turn them into tablet form, and do some clinical trials to show it works for insomnia (see, for example, Scharf M et al, J Clin Psychiatry 2008;69(10):1557-1564). They now have an FDA indication for insomnia for the 3 mg and 6 mg doses. The lowest dose of generic doxepin in capsule form is 10 mg, so apparently the Somaxon reps will argue that this dose is too strong, and that Silenor's 3 and 6 mg forms are just right. 

A month's supply of Silenor at 3 mg or 6 mg costs $214, according to Boston area pharmacies. On the other hand, a month's supply of doxepin 10 mg costs $4 at Wal-mart. The rare patients who cannot tolerate 10 mg of doxepin can reduce the dose by opening up the capsules and mixing some of the powder in juice. Or, they can try the liquid doxepin elixir if they really need tiny doses. 

Silenor is a blatant get rich quick scheme that appears to be failing miserably. According to The Street, Silenor had total sales of only $1.4 million in the fourth quarter of 2010. At this rate, Silenor drug reps will have to ditch their cars and hike to doctors' offices with samples in their backpacks.

Shrewd analysts were predicting Silenor's early demise soon after it was approved--see for example, Douglas Krohn's June 2010 article, "The Problem With Somaxon's Silenor."  More recently, up and coming psychiatrist/blogger Steve Balt posted a great investigative piece on his Thought Broadcast blog, entitled "Thank you, Somaxon Pharmaceuticals!" Trying to be fair, Balt contacted medical affairs at Somaxon to see if they had any data showing an advantage of Silenor over 10 mg of doxepin. Interestingly, he was sent a document entitled "Is the 10 mg Doxepin Capsule a Suitable Substitute for the Silenor® 6 mg tablet?" Apparently Somaxon was already armed and ready for me-too accusations.

Balt publishes Somaxon's chart comparing blood levels of Silenor 6 mg vs. doxepin 10 mg. At first glance, it appeared that doxepin practically overdoses patients--until Balt realized that the doxepin data was essentially made up. I won't steal any more of his thunder--please jump over to his blog for the entertaining details. 

Dr. Levin, Modern Psychiatrist--Unfulfilled, Bored--But Wealthy

There's been plenty of buzz about Saturday's front page New York Times story, "Talk Doesn't Pay, So Psychiatry Turns Instead to Drug Therapy," by Gardiner Harris. The story is essentially a profile of Dr. Donald Levin, a 68 year old psychiatrist who has a private practice in Doylestown, Pa.

It is a poignant example of a common situation in psychiatry. Older psychiatrists were trained during a time when there were few effective psychiatric medications, so they cut their teeth on training in psychotherapy. Not surprisingly, doing therapy is fun--it's involves getting paid for having interesting and intimate conversations with people, and helping them to become happier as a result.

In the old days, psychiatrists were paid very well for therapy. In part, this was due to the law of supply and demand--until the late 1940s, psychiatrists alone were allowed to do psychotherapy. But with World War 2 came a critical demand for more therapists to deal with the psychological needs of veterans. Over the ensuing decades, the NIMH granted funds to train psychologists and other non-MDs to deal with the growing public demand for therapy. As the supply of therapists rose, reimbursement for therapy plummeted. 

Of course, as any professional guild must do, the American Psychiatric Association fought this trend ferociously, arguing that only professionals who received medical training had the qualifications to do therapy. In 1949, the president of the APA summarized the opinions of a special "Committee on the Relations of Psychiatry and Clinical Psychology" by saying that the "American Psychiatric Association is strongly opposed to independent private practice of psychotherapy by the clinical psychologists; and The Association believes that psychotherapy, whenever practiced, should be done in a setting where adequate psychiatric safeguards are provided."

To the modern eye it seems absurd that intelligent people could believe that you had to go to medical school to do psychotherapy, but the potential for loss of income often confuses the mind. From the 1950s until the 1980s, the APA continuously lobbied state legislatures to prevent independent credentialing for non-MD therapists, but they eventually lost in every state.

Ironically, many within the APA were eventually happy to off-load their therapy tasks to psychologists and social workers, because a plethora of psychotropic drugs were introduced in the 1980s and 1990s. Psychiatrists no longer needed to do therapy to make good money. But this forced a decision point for many psychiatrists, like Dr. Levin, who loved doing psychotherapy. Would they continue to do psychotherapy--thereby diminishing their incomes--or would they become psychopharmacologists, lucratively churning through patients in 15 minute increments? Dr. Levin chose the latter, and sadly, he is unfulfilled.

Quoting from the New York Times article: “I miss the mystery and intrigue of psychotherapy,” he said. “Now I feel like a good Volkswagen mechanic.” “I’m good at it,” Dr. Levin went on, “but there’s not a lot to master in medications. It’s like ‘2001: A Space Odyssey,’ where you had Hal the supercomputer juxtaposed with the ape with the bone. I feel like I’m the ape with the bone now.”

Many psychiatrists will recognize the sense of tedium and boredom described by Dr. Levin. He went through psychiatric training to do therapy and is now a pill-pusher. 

Of course, one can argue that he is simply living with the consequences of that age-old decision: the choice of  higher income, but less fulfilling work. The world is filled with realtors, lawyers, marketers, managers, etc..., who wish they could make their current income doing watercolors or teaching elementary school or writing novels.

If Levin wanted to do therapy, he could, but, as he said in the article, "Nobody wants to go backwards, moneywise, in their career." We all make our decisions.

Are Dr. Levin's patients happy? Harris interviewed six of them who said they were satisfied with his care--but these were presumably chosen by Dr. Levin and may not be representative of his caseload of 1200. This brings up a host of issues that I'll discuss in a future post. 

New Drug Approved for the Annoyingly Cheerful

FDA Rejects Contrave for Obesity--Big Mistake

As you can read from various sources, including the NY Times, the LA Times, and the Washington Post, the FDA has rejected another anti-obesity drug, Contrave, because of concerns that it might cause heart attacks in patients who take it for years.

FDA's excessive caution was motivated by its experience having been burned by the Fen-Phen fiasco. This was a weight loss drug widely prescribed in the 90s that was pulled from the market after studies showed it caused fatal lung and heart valve problems. 

This new drug, however, is a combination of two medications that have already been widely prescribed and are fairly safe: Wellbutrin and naltrexone. Psychiatrists are familiar with both of them. We prescribe Wellbutrin for depression and smoking cessation, (and off-label for weight loss, for which it has shown efficacy as a stand alone), and we prescribe naltrexone for alcoholism.

As you can see from information published on Clinicaltrials.gov, Contrave is simply a combination of Wellbutrin 400 mg with Naltrexone at a couple of different doses, 48 mg and 16 mg. Clinical trials showed that Contrave helped 50% of obese patients lose 5% of their body weight, while only 10% of patients on placebo lost that much weight. The FDA's advisory panel voted to recommend approval, but the FDA demurred, saying that the company, Orexigen, will have to conduct a huge placebo-controlled long term study to make sure the drug doesn't cause heart attacks (one of Wellbutrin's well-known side effects is a slight increase in pulse and blood pressure, although there were no heart attacks in the Contrave clincial trials).

In my opinion, the FDA made the wrong decision. Obesity is a public health catastrophe, and Contrave's approval would have been predicated on conducting post-marketing safety studies anyway. The good news is that patients can ask doctors to prescribe them the constituents of Contrave, both of which are available in generic form--burpropion and naltrexone. Presumably, this generic combination will be much cheaper than Contrave's pricing anyway!

Anatomy of an Epidemic: The Carlat Take, Part 2

In my last post, I critiqued one aspect of Robert Whitaker's endlessly fascinating book, Anatomy of an Epidemic. Now I'll do yet some more critiquing.

To recap, his book consists of two general arguments:

1. Rates of psychiatric disability have soared during the period when many new psychiatric medications have been introduced--contrary to what you would assume should happen if the drugs worked so well.
2. Long-term studies actually comparing patients on meds vs. those off meds have yielded an apparently paradoxical result: patients not taking meds end up doing better over the years than those taking meds.

Last time, I rebutted the disability argument, pointing out that the skyrocketing rates of psychiatric disability have to do with increasing enthusiasm for diagnosing psychiatric illness and for increasing government financial incentives that encourage people to seek a psychiatric diagnosis.

In this post I'll consider his second argument. Whitaker argues that essentially all classes of psychiatric drugs are harmful in the long-term--including antidepressants, anti-anxiety drugs, and ADHD drugs--but I'll focus on antipsychotics, because this seems to be his main focus.

Before beginning, as anybody who has followed my blog knows, I readily acknowledge that psychiatrists over-rely on drug treatment of mental illness and should be doing more therapy. In order to maximize profits, drug companies consistently downplay the side effects of their medications. It's not that I believe drug treatment worsens conditions--rather, that our obsession with psychopharmacology has deprived many patients of integrative treatment, which combines the judicious use of medications (when needed) with the right kind psychotherapy (also, when needed). Thus, while both Whitaker and I end up with a similar conclusion--that psych meds are inappropriately used in the U.S--we arrive at that conclusion in very different ways and we mean different things by "inappropriate use."

On his website, Whitaker has posted a useful page in which he provides links to the studies he mentions in his book. He lists 34 studies, including links and brief summaries. Don't worry, I won't go through all 34, I'll just make two general observations.

1. The studies cited by Whitaker are old, and the patients who were diagnosed with "schizophrenia"often did not have that illness. 

Most of the long-term outcome studies in the literature were published in the 60s, 70s, 80s, and early 90s. But they are actually even older than that, because these studies often describe people who were diagnosed with "schizophrenia" 10 to 20 years before the date of the publication. For example, the Vermont longitudinal study was published in 1987, while is already pretty old, but the study describes patients who were originally diagnosed with schizophrenia in the late 1950s and early 1960s.

Why does this matter? Because before DSM-III was published in 1980, American psychiatrists had a bad habit of vastly over-diagnosing "schizophrenia." Patients who would now be labeled with bipolar disorder, borderline personality disorder, depression, and various other problems, were, in the 60s and 70s, likely to be diagnosed "schizophrenic."

The classic study to demonstrate American psychiatry's historic infatuation with the schizophrenia diagnosis was published in 1971.  The researchers showed videotapes of 8 patient interviews to a few hundred psychiatrists in both Britain and the U.S. After viewing the videotapes, the doctors were asked to make a diagnosis. The disagreements were glaring--and were somewhat embarrassing for the Americans. For example, in one case, "Patient F," the patient was a man from Brooklyn who had hysterical paralysis of one arm and a history of mood fluctuations associated with alcohol abuse. The diagnosis? According to 69% of American psychiatrists, the man had schizophrenia, whereas only 2% of the British psychiatrists favored that diagnosis. Most of the British psychiatrists diagnosed the patient with "hysterical personality disorder."

The point is that most of the long term outcome data Whitaker cites is based on unreliable and very broad conceptions of schizophrenia. While he accurately describes studies showing that schizophrenic patients who were not on medications often did very well, I'll bet you a dime to a dollar that many of these high functioning schizophrenics never had schizophrenia in the first place, at least not according to current DSM-IV criteria. They did perfectly well off antipsychotics for the same reason somebody without diabetes would do well off insulin--they didn't actually have the disease.

2. Most of the studies Whitaker cites are observational studies--which are suggestive, but not definitive. 

The best way to figure out if a medication is helpful or harmful for schizophrenia is to conduct a placebo-controlled study. You randomly assign patients to two treatments: an antipsychotic or a sugar pill placebo. A recent meta-analysis of 38 such randomized studies of second generation antipsychotics, which pulled together data from 7323 patients, found that antipsychotics outperform placebo with a response rate of 41% vs. placebo's 24%. These were mainly short term studies, lasting a couple of months or so. Thus, we know that antipsychotics are moderately effective in the short term, although they can have some nasty side effects. 

In order to convincingly show that antipsychotics improve (or worsen) schizophrenia over the long term, you would have to do a placebo controlled trial lasting many years. That has not been done--not through some conspiracy of the pharmaceutical industry, but because it would be extremely hard to conduct such a trial. Imagine if you were schizophrenic and a researcher asked you to be in a 10 year long study in which you might get an active medication or a sugar pill. Schizophrenia is a serious, like threatening condition.  Would you roll the dice with your life, taking the chance that you would be on a sugar pill for 10 years? Probably not. Furthermore, even if you agreed, chances are good that you would drop out of the study before the 10 year mark--for any number of reasons, such as moving away, worsening mental or physical illness, side effects etc.... 

Because these gold-standard long term studies do not exist, we are forced to fall back on much less convincing evidence--observational studies. This is where researchers enroll, say, 200 patients with schizophrenia and ask them to agree to periodic evaluations. The patients can get their care wherever they want, they can continue to see their doctors, take or not take medications, seek enlightenment in the Himalayas, or go to Lourdes. It's all up to them. Every few years, the researchers contact them and ask them how they are doing. Are they taking meds? Are they having psychotic symptoms? Do they have a job? And so on.

You can immediately see why such observational (also termed "naturalistic") studies are suboptimal. If, 10 years after the study starts, the patients who are not taking meds anymore are doing better than the patients who are taking meds, how do you interpret this? You could conclude that antipsychotics worsen schizophrenia. Or, you could conclude that the patients who are not on meds after 10 years simply were blessed with a milder version of schizophrenia, such that they recovered after a few years and didn't need meds anymore.

This inherent weakness of observational studies is why the Harrow study is so hard to interpret. Whitaker and Andrew Nierenberg debated this study on Radio Boston recently.  In this study, Harrow and colleagues identified 64 patients with schizophrenia and reinterviewed them five times over the next 15 years. At the final 15 year follow up, 64% of the patients who were taking antipsychotics still had psychotic symptoms, whereas only 28% of those not taking antipsychotics had such symptoms. What does this mean? Whitaker sees this as evidence that antipsychotics worsen mental illness. I see it differently. I suspect that the patients still taking antipsychotics after 15 years had more severe cases of schizophrenia to begin with, and therefore required more prolonged treatment with medications. The medication didn't cause the psychosis--the psychosis caused patients to still need the medications. 

Over the last few days, I've spent many hours thinking and writing about Anatomy of an Epidemic. Mostly, I've chipped away at its central thesis, and yet the fact that this powerful book has riveted my attention for so long means something. It's fascinating. It's enthralling. And it is the work of a highly intelligent and inquiring mind--a person who is struggling to understand the nature of psychiatric treatment.  Put it on your reading list, and join the debate.

Robert Whitaker's Anatomy of an Epidemic: The Carlat Take

I haven't reviewed Anatomy of an Epidemic until now, partly because I once shared a meal with the author, Robert Whitaker. It's hard to be objective reviewing the work of someone you know, whether you like him or dislike him.

As it happens, I quite like Robert Whitaker. We had dinner at a Chinese Restaurant in Harvard Square last June just before I gave a book talk for my book Unhinged. Over wonton soup and kung pao chicken, we chatted pleasantly about our work. He's an extremely intelligent and devoted journalist who really cares about the treatment of the mentally ill.

I had read parts of his book before we met, and told him that I disagreed with various aspects of it. He understood my points, saw their merits, but cordially held fast to his own convictions. I haven't spoken with Bob since then. I continue to respect him and I'm sure our paths will cross again.

Generally, I don't think it's great practice to review books when you know the author, and most mainstream publications prohibit it. But hey, this is a blog and I think we can be a bit less "ruley" in this context.

My overall take is that Whitaker has his basic facts right, and that he communicates them in a compelling style that I envy. But I disagree with his interpretation of the facts.

My argument is not all that different from the MGH/Andy Nierenberg rebuttal that was beautifully covered by Carey Goldberg in the CommonHealth Blog. You gotta check her post out--it includes video clips of Whitaker's brave grand rounds talk at MGH and captures the atmospherics of the ether dome, where I often went to grand rounds when I was a psych resident there.

Before I offer my rebuttal, here is Whitaker's overall argument:
1. Over the past couple of decades, many new and supposedly more effective psychiatric drugs have been introduced.
2. If these drugs were so effective, you'd think rates of psychiatric disability would have declined over this period, but in fact, rates of psychiatric diagnosis and disability have skyrocketed.
3. There are some poorly publicized studies suggesting that patients with serious mental illness actually do better when they do not take drugs.
4. Therefore, it's reasonable to conclude that psychiatric drugs are actually bad for many people, at least when taken for more than a short period of time.

This is obviously a simplified version of a long book that makes several other points as well, but this is pretty much the arc of his argument.

Here is my basic rebuttal: Correlation does not imply causation. In other words, yes, many more people take psych drugs, and yes, many more people are psychiatrically disabled. But the med use has not caused the disability. Instead, the skyrocketing disability rates are caused by several other factors, having almost nothing to do with any putative toxic effects of long-term medication use.

In my opinion, the apparent rise in psychiatric disability has three major causes.

Cause #1: There are more disorders to diagnose. 

The number of official DSM diagnoses has grown from about 100 in 1952 to about 300 today--see the table below.

Version	Year Published	Number of Pages	Number of Diagnoses
DSM-I	1952	130	106
DSM-II	1968	134	182
DSM-III	1980	494	265
DSM-III-R	1987	567	292
DSM-IV	1994	886	297
DSM-IV-TR	2000	886	297

Each time a new version of the DSM is published, clinicians get trained in how to recognize the new categories of disorders. There's plenty of room for debate about whether all these "new" disorders are truly new or valid, but my point here is that, valid or not, the rise in diagnosis has been largely driven by changes in disease classification and subsequent training--not by toxic medications.

Cause #2: There are more treatments available, so clinicians have a greater incentive to look for diseases.

Unless there is a treatment for a disease, doctors have little incentive to take the extra time required to diagnose it. Not only has there been an explosion of new psychiatric drugs, but there are many more types of targeted psychotherapies as well. New drugs and therapies have motivated psychiatrists, psychologists, and social workers to ask more questions to discover newly treatable disorders.

Again, one can argue that drug companies have practiced "disease mongering" and have unethically persuaded doctors to recognize questionable disorders simply in order to make money. This has certainly happened at times, as I document in Unhinged. Sure, drug companies have revved up the diagnosis of disorders, but their drugs haven't actually caused the disorders.

In addition, it's certainly true that psych drugs have many side effects, and that side effects can cause certain disabilities. But this is true for all drugs in all fields of medicine. Antipsychotics are effective at reducing delusions and hallucinations, but they can also cause weight gain, diabetes, tremor, etc.... It's up to the doctor and the patient to decide together whether the side effects are so disabling as to overwhelm the benefits. But this does not mean that psych drugs cause worsening psychiatric disabilty, any more than blood pressure drugs cause worsening blood pressure.

Cause # 3: Changes in federal law have encouraged more people to seek disability status.

To understand the ins and outs of Supplemental Security Income (SSI), you must read an outstanding recent series in the Boston Globe, called The Other Welfare: A Legacy of Unintended Side Effects.The short version of these articles is that SSI is a well-intentioned program to provide income and insurance for disabled citizens. But over the years, it has expanded to include various psychiatric disorders that are difficult to diagnose and that can be easily faked, such as ADHD and PTSD. Indigent people have realized that it's not too hard to get a psychiatric diagnosis and a medication, and once you have these you can apply for SSI benefits. The application is an arduous process, with no guarantee of success, but the numbers cited in the Globe tell the story (the Globe article focuses on children). In 1990, only 24,000 children qualified as psychiatrically disabled under SSI; by 2009, 640,000 children had qualified, a 26-fold increase.

Okay--I'm running out of steam and this post is already too long. Bottom line: Whitaker does a great job documenting an astonishing rise in psychiatric disability, but he erroneously blames the drugs, when the actual causes are more nuanced and multifactorial.

Next time I'll get into some of the studies he cites in support of the idea that psychiatric drugs can worsen mental illness. I believe he is on shaky ground here as well.

So, You Want to be a Health and Science Blogger? Get Some Tips.

On Wednesday, January 19, I'll be part of a panel of experts on blogging about health and science for an event at the Harvard Faculty Club in Cambridge, Mass, sponsored by the the New England Science Writers. You can hear all about how I've channeled my outrage about medical education corruption into blog form. It's a relatively mature defense mechanism that we shrinks call "sublimation."

I'm flattered to be invited to join such talents as Gary Schwitzer, whose Health News Review blog was named best medical blog of 2009 by Epocrates; Ivan Oransky, the Executive Editor of Reuters Health who blogs at Embargo Watch and Retraction Watch; and former Wall Street Journal reporter Rachel Zimmerman, who writes the CommonHealth blog for Boston's NPR station, WBUR.

The event's moderator will be Alison Bass, the author of Side Effects: A Prosecutor, a Whistleblower, and A Bestselling Antidepressant on Trial, and a blogger herself, at her eponymous blog.

It's sure to be an interesting discussion.You can learn more about the panel on the New England Science Writers' website.