Is it Prozac? Or Placebo? Part II
WHEN I FILL OUT A treatment report explaining to an insurance company why they ought to pay for someone's therapy, I am asked for a diagnosis. If the patient is depressed and not on antidepressants, I often must explain why not. Were it not for these bureaucratic demands -- and for all the miracle-drug testimony found in advertising and casual talk -- the FDA statistics would hardly be surprising or disturbing, because, like many clinicians, I have come to see that the effects of Prozac and its cousins are just about as pallid as those numbers would predict: The drugs are not panaceas, not solid evidence that depression is a chemical imbalance, but have proved to be moderately useful for some people (and moderately harmful to others). No scientist doubts the existence of the disconnect between the data and the way antidepressants are perceived and used, but Kirsch's theory about it is far from the industry standard. Indeed, some simply dismiss it out of hand -- like Donald Klein, a renowned psychiatry professor at Columbia University's New York State Psychiatric Institute, who thinks that Kirsch's work is so biased against antidepressants that, though asked, he declined to be among the respondents to "The Emperor's New Drugs" -- "for the same reason," he told me, "that I don't argue with creationists."
Klein, who has conducted antidepressant trials for pharmaceutical companies, acknowledges that the data can leave the impression that the drugs don't work very well. But he is among those who think this says more about the trials than the drugs. According to Klein, the FDA standard -- two successful trials without untoward side effects -- won't elicit a full body of knowledge about new drugs, and may even limit what the tests can tell us. "The job of the pharmaceutical company is to get FDA approval," he says. "So you want to go in with a dose which is effective but doesn't create side effects. It's a real problem. Drugs are not being tested for their optimum efficacy." Nor, given this strategy, are they tested for their maximum side effects -- which may be why reports of agitation and suicidal impulses in excess of what the trials found have dogged the Prozac generation of antidepressants since they were introduced.
Clinical trials can become a game for drug companies to win rather than a venue for generating scientific knowledge. And it's a game that establishes perverse incentives, in part because drugs' limited patent lives -- usually 20 years -- begin before clinical trials, which can take a decade, start. "We're talking real money here," says Klein, noting it takes between $300 to $500 million to develop a new drug. Klein told me that within the industry the clinical trial period is thought to cost "a million dollars a day. That adds some pressure for finishing trials fast."
Despite the bottom-line approach, "there are lots and lots of compounds that get evaluated and never approved," notes Lawrence Price, a psychiatrist who directs research at Brown University's Butler Hospital. A more nuanced criterion for a successful trial is possible, but, says Price, "it would just take forever. It's not that there aren't important questions, but you would get so bogged down in trying to nail down the details that you would just never make any progress with newer compounds."
You also might not make any progress if you waited around for severely depressed people to test drugs on. "The problem with antidepressant studies," according to Klein, "is that anything that can be confused with ordinary unhappiness gets in" -- which means that subjects in clinical trials are insufficiently depressed, too close to normal to show dramatic improvement. Price, who has conducted clinical trials of antidepressants for 25 years, points out that recruitment techniques like the one that attracted Janis Schonfeld to UCLA can lead to a skewed sample. "If you go out and advertise in the newspaper for depressed people," says Price, "you are going to get less ill people than if you are taking people who are brought in via the emergency room."
Relatively high-functioning, moderately depressed people, those most likely to enroll in and finish a trial, are, as it happens, more likely to register a high placebo response. There are no biochemical markers of depression, no blood test or X-ray that confirms its presence, so it can be judged only by its appearance -- which means, in trials, by the Hamilton, a test of subjective states scored by clinicians whose employers are paid up to $10,000 for each patient who completes a study. "If the investigator has directed his/her research assistant to rate liberally on the Hamilton," says Price, "then you are going to have more people meeting the entry criterion," typically, at least 17 points -- the line dividing mildly and moderately depressed. (One of Price's colleagues estimates that Hamilton scores are inflated by up to five points for clinical trials.)
The drug companies, of course, want more than speedy trials. They want successful ones. "Placebo is a killer for them," Price explains, "because if they spend $40 million on a trial and get a placebo response rate of 50 percent, then they've just wasted that $40 million. There's a huge interest in trying to address the high placebo response rate in depression. How can it be lowered? How can you identify the sample of people in whom these compounds are really going to work?"
The study in which Janis Schonfeld enrolled may provide some answers to these questions -- although somewhat inadvertently. Hoping to eliminate the trial-and-error method used to match patients with antidepressants, the UCLA doctors were using electroencephalograms to determine if there was some neurochemical difference between the brains of people who respond to Effexor and those who respond to Prozac. The researchers found the differences they were looking for, but they also got a surprise. The EEGs of placebo responders were different from those of the drug responders, and similar to each other, a phenomenon that had never before been observed and that may be the first step to identifying the neurochemistry of the placebo response. This was welcome news to the drug companies, who'd like nothing more than to eliminate placebo responders from their studies.
Take away the people most likely to show a strong placebo effect, include the people most likely to respond to a drug, and the statistics become more favorable for the manufacturers and provide less ammunition for critics like Greenberg and Kirsch. Psychologist David Antonuccio, a professor at the University of Nevada, claims that the deck is already stacked. In addition to publication bias, inflated Hamilton scores, and broken blinds, he points to the placebo washout period that starts every clinical trial: All patients are given a week of placebo treatment, and the strongest responders are eliminated from the study. The idea, of course, is to get a more accurate estimate of the true drug effect, but "if you put everybody on an antidepressant and washed out everyone who responds, people would say, 'That's a very biased strategy against the drugs.' Well, I believe we have a strategy here that's biased against the placebo condition."
AFTER JANIS SCHONFELD was debriefed, she was given her reward for participating in the study: a one-year supply of Effexor. She didn't consider not taking the drug. "They told me that I'd gotten a good start, that if I'd done well on placebo, I'd probably do better on the drug." And so she did. "After about a week or maybe two weeks it was like a fog was lifted from my eyes. I realized I had spent much of the last 20 years in that fog." Schonfeld took Effexor for two and a half years and then "one day I just thought, 'You know, I don't think I need this medication anymore.' I spent three weeks weaning off of it. That was about a year and a half ago, and I haven't really felt that I needed it since." She emphatically rules out the possibility that her improvement was a result of placebo effects, amplified or otherwise.
To Kirsch, Schonfeld's is a case of lost opportunity. "Why not say to her, 'You did this'? People respond the way they were expecting to respond, so why not work on that expectation? Why not teach her the strategies that she can use to make herself feel better?" Antonuccio says, "Placebo is a valid intervention in and of itself," adding that people like Schonfeld have ample contact with trained staff during trials, which may itself be what accounts for the high placebo rates. "It's possible that psychological treatments are mostly placebo as well," he says -- not, as he is quick to add, that there's any- thing wrong with that. "We just ought not to see the placebo effect as some sort of inferior response or condition."
But even though, as Kirsch notes, "more placebos have been administered to research participants than any single experimental drug," they remain poorly understood and used, for the most part, only inadvertently and haphazardly. The discovery of biological underpinnings of the placebo effect may change this, as drug researchers grasp the potential of turning yet another neurochemical pathway into a pharmaceutical market by developing a placebo drug. Bizarre as this sounds, it may be the only incentive that will lead a profit-driven health care industry toward an understanding of humanity's oldest means of healing.
Gary Greenberg is a psychotherapist and professor of psychology. His writing on medicine and science has appeared in the New Yorker, Discover, Rolling Stone, and McSweeny's, and is featured in Best American Science and Nature Writing 2002.
We read them the way sailors and farmers read the weather reports. Our very lives can depend on the information. I am referring to those ubiquitous announcements of clinical drug trial results. Invariably, the new drug's efficacy is compared to that mysterious entity known as the "placebo group."
The placebo effect is very real. The Baltimore Sun cited these examples in a 1999 article:
* Patients who were taken off blood-pressure medicine for three weeks so they could try a new drug saw their blood pressure drop to normal in the period when they were taking no drug at all.
* Thousands of elderly Chinese Americans in California born in years with bad astrological qualities died sooner from cancer than Chinese Americans with the same disease who were born in good astrological years. A study of whites with the disease revealed no similar correlation of cancer deaths and astrological signs in birth years.
* A pilot study of pretend knee surgery on ten Houston veterans hospital patients produced such startling results that doctors launched a larger study.
* A saline injection was enough to kill the pain in 30 to 40 percent of people who got their wisdom teeth out, according to one study at the University of Maryland. A symbolic injection stimulated patients' production of morphine endorphins in a 20-year-old California study.
* In a classic 1958 study, patients underwent sham surgery for angina (pain due to a constricted blood supply). They got local anesthesia and were cut slightly, but they did better than patients who actually had the surgical procedure.
A 2001 Swedish study of brain scans reported in The Scientist suggest the placebo effect and opioid analgesia "may have a common neural mechanism," and a 2002 University of Toronto study of brain scans revealed that Prozac and a placebo worked on similar areas of the brain (Prozac, though, worked on more areas of the brain). With antidepressant drug trials, the placebo effect is high enough to cause a full half of these studies to end in failure, which has set off fierce debate over whether an antidepressant is little more than a placebo with side effects. The focal point of the controversy are two studies by Irving Kirsch PhD of the University of Connecticut:
A meta-analysis of nineteen double-blind antidepressant trials published in the American Psychological Association's online publication, Prevention and Treatment (Guy Sapirstein PhD of Westwood Lodge Hospital, Needham, MA, co-author) in 1998 caused an uproar in professional circles when it was revealed that the placebo effect accounted for a mind-boggling 75 percent of an antidepressant's result - any antidepressant, you name it. Four years later, the July 2002 Prevention and Treatment published another study by Dr Kirsch that analyzed the FDA database of 47 placebo-controlled short-term clinical trials involving the six most widely prescribed antidepressants approved between 1987 and 1999. These included "file drawer" studies, ie trials that failed but were usually never published.
What Dr Kirsch and his colleagues found was that 80 percent of the medication response in the combined drug groups was duplicated in the placebo groups, and that the mean difference between the drug and placebo was a "clinically insignificant" two points on both the 17-item and 21-item Hamilton Depression Scale, regardless of the size of the drug dose. The placebo factor ranged from a high of 89 percent for the Prozac response, according to the study, and a low of 69 percent for the Paxil response. In four trials, the placebo equaled or achieved marginally better results than the drug. In the nine expert commentaries published with the study, none of the commentators disputed the study's main findings.
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Omega 3 Oils as Effective as Antidepressants and Are Non-Toxic
In September 1998 the National Institute of Health conducted a seminar on the effectiveness of Omega 3 oils in combating manic depression, schizophrenia, depression, hyperactivity, PMS, etc. Now a new study supports those reports.
In a new book called “The Omega-3 Connection,” Andrew Stoll argues that fish oils—with their high content of polyunsaturated, omega-3 fatty acids—may help a range of psychiatric disorders. The brain is an astonishing 60 percent fat, and it needs omega-3s to function properly. In the last century, however, Americans have drastically reduced their intake of these oils, as we moved to diets based on processed foods.