The study examined the question of whether a person's response to these anti-depressant medications was dependent on how depressed the patients were before they received treatment for their depression. All four medications studied are the so-called selective serotonin reuptake inhibitors—commonly known as SSRIs—and were specifically Eli Lilly and Company’s Prozac, which is also known as fluoxetine; Wyeth's Effexor, which is also called venlafaxine; GlaxoSmithKline's Paxil, which goes by both Seroxat and paroxetine; and Bristol-Myers Squibb Company’s drug Serzone, which is also called nefazodone. Bristol-Meyer’s Serzone is no longer marketed in the United States.
The research group discovered that when compared with placebo, these new-generation SSRI antidepressant medications did not provide any measurable, clinically significant improvements in depression in those patients who initially suffered from moderate or even very severe depression. The study did reveal, though, that the most significant benefits occurred only in the very severely of depressed patients. "Drug-placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication," the researchers wrote.
As part of their study, the researchers also obtained data on all of the clinical trials submitted to the U.S. Food and Drug Administration (FDA) for the licensing of the four antidepressant SSRI drugs. "Although patients get better when they take antidepressants, they also get better when they take a placebo, and the difference in improvement is not very great. This means that depressed people can improve without chemical treatments," Kirsch said in a statement concerning the findings of the study. But, Mary Ann Rhyne, a spokeswoman for Paxil maker GlaxoSmithKline, argued that the study only looked at data submitted prior to the drug's U.S. approval. "The authors have failed to acknowledge the very positive benefit these treatments have provided to patients and their families who are dealing with depression and they are at odds with what has been seen in actual clinical practice," Rhyne said. "This analysis has only examined a small subset of the total data available, while regulatory bodies around the world have conducted extensive reviews and evaluations of all of the data available," she added.
Doug Petkus, a spokesman for Wyeth, the maker of Effexor, said he had not yet seen the recent study and could not comment on its contents.
The overwhelming amount of published research on antidepressants show that these drugs are effective in treating depression and other psychological problems. But according to an article in the New England Journal of Medicine, these published studies don’t tell the whole story. According to a data review submitted to the Food & Drug Administration (FDA), the vast majority of unpublished antidepressant studies found the drugs to be less effective than those that made it into medical journals.
According to the New England Journal of Medicine, of 74 antidepressant studies reviewed, 38 were deemed favorable to antidepressants. Of those favorable studies, all but one where published. Of the unfavorable studies, 22 of 36 where never published. Even more outrageous, of the 14 unfavorable studies that were published, at least 11 mischaracterized the results and presented a negative study as positive.
The antidepressant studies that the New England Journal of Medicine looked at involved some of the most popular drugs on the market. For example, in five clinical trials done on the Pfizer drug Zoloft, two published studies showed Zoloft appeared to work better than the placebo. But in three other Zoloft trials, the placebo did just as well at reducing indications of depression. Pfizer never published the three unfavorable studies, and the company discusses only the positive results in Zoloft's literature for doctors.
Even when studies where published, researchers found that drug companies found ways to manipulate them to make findings appear more favorable to an antidepressant than they really where. For example, sometimes drug makers ignore or downplay a negative finding for the "primary outcome" -- the main question the study was designed to answer -- and highlight a positive secondary outcome. In nine of the negative studies that were published, the authors simply omitted any mention of the primary outcome, the researchers said.
According to The Wall Street Journal, sales of antidepressants total about $21 billion a year. Considering this, it is understandable that drug makers would want to protect these sales. But suppressing the results of unfavorable studies affects more than antidepressant sales. Doctors unaware of the unpublished data are making inappropriate antidepressant prescribing decisions that aren't in the best interest of their patients. Sales of antidepressants are so huge because doctors and patients have been given the wrong impression about their effectiveness. "There is a view that these drugs are effective all the time," Dr. Erick Turner, a lead researcher on the study, told the Wall Street Journal. "I would say they only work 40% to 50% of the time."
Effexor XR is an extended version of the original Effexor. Effexor is the top selling anti-depressant in the world, according to Wyeth, and Effexor drugs reaped sales of $958 million in the third quarter of 2007 alone.
Effexor and Effexor XR work by increasing the brain’s uptake of the neurotransmitters serotonin and norepinephrine, both of which effect mood. But both drugs are known to have dangerous side effects, including an increased risk of suicidal thoughts and behavior when used in children and adolescents, as well as hypertension and serious withdrawal symptoms. Despite such serious side effects, Effexor and Effexor XR are marketed by Wyeth as better alternatives to antidepressants like Paxil, Prozac and Zoloft.
Now, the FDA is charging that an ad which appeared in a medical journal makes “unsubstantiated superiority” claims about Effexor XR. The FDA criticized several claims in the ad, including citation of a study claiming that said Effexor XR prevented a depressive episode in 92 percent of cases, versus 55 percent for a placebo. The agency said that claim is "based on a study that is inadequate."
The FDA also faulted Wyeth's claim that 20 million people have been treated with the Effexor XR, a statistic the FDA said is based on suspect data. Because people may associate the number of people treated with quality, this claim "may mislead consumers and healthcare providers," FDA wrote.
This is not the first time Wyeth has been accused of making misleading Effexor claims. Last month, Dr. Daniel Carlat recounted his experiences as a Wyeth-paid Effexor lecturer in the New York Times. According to Dr. Carlat, the Effexor information Wyeth instructed him to convey during visits to physician offices was often incomplete, downplayed risks, and was skewered to favor Effexor over other drugs. When Dr. Carlat, uncomfortable with the Wyeth-provided script, altered it to include more complete data on hypertension, he was visited by a district manager, who expressed concern that the doctor was not exhibiting enough “enthusiasm” in his talks. Dr Carlat quit lecturing for Wyeth shortly after that episode.
The FDA has ordered Wyeth to cease running ads for Effexor XR that make misleading claims in medical journals. The company must also provide the FDA with a list of other Effexor XR marketing materials that make similar claims, as well as a detailed plan for discontinuing the use of such materials. Wyeth has until December 21 to respond to the FDA Effexor XR warning letter.
The Effexor XR ads in question are no longer running, but a spokesperson for Wyeth told Reuters that the company believes they were “responsible.”
According to Dr. Carlat, a psychiatrist with a specialty in psychopharmacology, Wyeth first approached him in 2001, asking if he would be willing to give talks to primary care physicians about Effexor XR, a drug used in treating depression. Effexor XR was being marketed by Wyeth as a better alternative to antidepressants like Paxil, Prozac and Zoloft. Effexor XR works by increasing the brain's uptake of the neurotransmitters serotonin and norepinephrine, both of which effect mood. Traditional antidepressants like Paxil only increase serotonin uptake. Dr. Carlat was familiar with some positive studies involving Effexor XR, and had prescribed it to his patients. Wyeth's offer of a $500-$750 stipend for each Effexor XR talk he gave helped convince Dr. Carlat to take the company up on its offer.
Dr. Carlat and was first sent by Wyeth to a conference in New York City, where the doctor would receive "education" on Effexor XR. The drug company put Dr. Carlat and his wife up in a posh Manhattan hotel, provided the couple with tickets to a Broadway Show, and paid him $750 just for attending the conference. At the Effexor XR "education classes", prominent scientists - all paid by Wyeth --touted the drug as a big improvement over other medications. One researcher emphasized Effexor XR's remission rate - complete cure -which the company said was 10% better than other antidepressants. This bothered Dr. Carlat somewhat, as antidepressant effectiveness is usually measured by response rate, which is defined as a 50% improvement in symptoms. In his New York Times piece, Dr. Carlat admits that he wondered if Wyeth had chosen to emphasize remission in order to make Effexor XR look better than it truly was.
Another researcher spent much of his lecture downplaying Effexor XR's association with high blood pressure - a side effect not shared by other antidepressants. According to the speaker, Effexor XR only had a slight chance of elevating blood pressure. The conference also downplayed problems experienced by people who stopped taking the drug - including dizziness, mood changes, and even nervous breakdowns - that where more serious than those associated with other antidepressants.
At the end of the conference Dr. Carlat went home to begin with his new role as "Dr. Drug Rep." But as month's passed, he became increasing uneasy serving as an Effexor XR cheerleader. For one thing, Dr. Carlat kept up with Effexor XR developments, and as more research became available, it was clear that Effexor was not significantly better than other antidepressants. He also learned that some of the Wyeth studies cited at the Effexor XR conference had been conducted in a way that was beneficial to Effexor. Dr. Carlat also became aware of studies that showed Effexor XR's risk of hypertension was greater than previously thought.
Still, Dr. Carlat continued giving Effexor talks, downplaying risks and highlighting benefits. Finally, during one of his Effexor lectures, Dr. Carlat was challenged by a doctor over Wyeth's hypertension data. This bothered him enough that he altered his lectures from the approved Wyeth format, and decided to begin ending his Effexor talks with the caveat that the Effexor studies he cited were mainly short-term, and that there was a possibility that other antidepressants were just as effective as Effexor. The first lecture he gave with this warning resulted in Dr. Carlat receiving a visit from a Wyeth district manager, concerned that the doctor was not exhibiting enough "enthusiasm" in his talks. According to Dr. Carlat, he decided then and there to end his association with Wyeth.