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STAR*D Wars Study Failure on Antidepressants

By Evelyn Pringle  Posted by Evelyn Pringle (about the submitter)       (Page 1 of 2 pages)   1 comment
Message Evelyn Pringle
On March 23, 2006, STAR*D results were major news, front page in the Washington Post. STAR*D, the official acronym for Sequenced Treatment Alternatives to Relieve Depression, was a two-step antidepressant treatment study funded by the National Institute of Mental Health (NIMH), costing U.S. taxpayers $35 million. The NIMH proclaimed that STAR*D showed that “50 percent of people with depression can get better within the two treatment steps using this approach”; and STAR*D researchers declared, “A 50 percent remission rate is extraordinarily good, given the nature of these disorders.” The Associated Press and much of the media simply echoed the enthusiasm of NIMH and STAR*D researchers.

But did -- in a scientific sense -- STAR*D treatment work at all? While the Washington Post did point out that STAR*D reveals, “Antidepressants fail to cure the symptoms of major depression in half of all patients with the disease even if they receive the best possible care,” the following went unreported by all major media outlets:

For STAR*D, NIMH hired researchers with extensive financial ties to the pharmaceutical companies that manufacture the antidepressants that were studied.

STAR*D’s scientific methodology were astonishingly substandard, especially its failure to include a placebo control group. In other antidepressant studies, patients treated with sugar-pill placebos have done as well or better than STAR*D results.

Despite STAR*D’s additional level of drug treatment, if one takes into account depression’s known rate of spontaneous remission (remission of symptoms with no treatment at all), as well as STAR*D’s exclusion of patients less likely to have been cured by it, then STAR*D appears to have worked no better – and conceivably, worse -- than no treatment at all.

There were two levels – or stages -- to STAR*D. In the first stage, all depressed patients received the antidepressant Celexa. In the second stage, Celexa-treated patients who failed to have remission of depression symptoms were assigned to several other treatment modes, including the substitution of Celexa with another antidepressant, either Effexor, Wellbutrin, or Zoloft; or Celexa was augmented with either Wellbutrin or Buspar (an antianxiety drug).

The pharmaceutical companies that manufacture Celexa, Effexor, Wellbutrin, Zoloft, and Buspar were well-acquainted with STAR*D researchers. The two lead STAR*D investigators Dr. A. John Rush and Dr. Madhukar H. Trivedi receive consulting fees from or served on the advisory boards for Forest Pharmaceuticals (Celexa), Wyeth-Ayerst Laboratories (Effexor), and Bristol-Myers Squibb (Buspar); while Dr. Rush has such a relationship with GlaxoSmithKline (Wellbutrin) and Dr. Tiveldi has such a relationship with Pfizer (Zoloft); and Dr. Rush has an equity interest in Pfizer. Both have received speaker fees from Forest Pharmaceuticals; Dr. Rush has received speaker fees from GlaxoSmithKline; and Dr. Trivedi has received speaker fees from Wyeth-Ayerst Laboratories and Bristol-Myers Squibb. The drugs used in STAR*D were furnished at no cost by their manufacturers.

In the first stage of STAR*D, 2876 depressed patients were given high doses of Celexa for 14 weeks, and 790 of them had remission of symptoms -- a success rate of 27.5 percent. The January 2006 American Journal of Psychiatry reports there was no placebo control in this study.

This absence of a placebo control in a treatment effectiveness study is astonishing because it has long been known that sugar pills, other placebos, or any treatment -- including bloodletting -- are routinely reported by some patients as curing their depression. And so by the 1940s, a scientifically respectable investigation of a drug’s effectiveness required a placebo control to which the effects of the hypothesized therapeutic drug could be compared.

Today it is well known in the scientific community from several other antidepressant studies that a placebo does as well or better than Celexa’s 27.5 percent success rate in STAR*D. An April 2002 Journal of American Medical Association (JAMA) study compared the effectiveness of the antidepressant Zoloft, the herb St. John’s wort, and a placebo in depressed patients. In the JAMA study, the placebo-treated patients had a 31.9 percent rate of remission of symptoms (Zoloft’s remission rate was 24.8 percent and St. John’s wort’s remission rate was 23.9 percent). NIMH and STAR*D researchers ignored the superior placebo remission rate in the JAMA study.

Instead, NIMH and STAR*D researchers trumpeted the impressiveness of remission rates given how especially depressed the STAR*D patients were. However, the patients in the JAMA study were actually more depressed then those patients in the STAR*D study. The STAR*D and JAMA studies utilized the identical measure of depression, the Hamilton Rating Scale for Depression (HRSD-17), in which a score can range from 0 to 52, with higher scores indicating more depression symptoms. The criteria for inclusion in the JAMA study was score of 20 or higher, while in STAR*D it was only 14 or higher. (The criteria score for symptom remission was almost the same in both studies, 8 or less in JAMA, 7 or less in STAR*D).

While the Celexa remission rate in the first stage of STAR*D study was highly disappointing compared to placebo results in other antidepressant studies, NIMH (which rounded up the Celexa 27.5 percent remission rate to “about a third”) described it as “particularly good results.” This would be like saying that the New York Knicks had “particularly good results” scoring 88 points while neglecting to say that their opponent scored 100 points, or, even more analogous, staging the basketball game without providing the Knicks an opponent.

The second stage of STAR*D provided a second level of treatment for those depressed patients who failed to respond favorably to Celexa. It lasted 14 weeks and was reported in the March 23, 2006 New England Journal of Medicine. Among Celexa nonresponders, of those assigned another antidepressant, 21 percent had a remission of symptoms; of those who had their Celexa augmented with another drug, 30 percent had a remission of symptoms. As in stage one, there was no placebo control. And again, it is known from other antidepressant studies that had there had been a placebo control in stage two, the control would likely have done as well or better than STAR*D results.

Beyond the lack of a placebo control, there are other reasons that NIMH’s enthusiasm about STAR*D is unjustified. NIMH neglects the well-known phenomenon of spontaneous remission -- the remission of symptoms without any treatment at all. According to a 1994 Canadian Task Force on Preventive Health Care report on depression, “Spontaneous remission can occur over 6 to 12 months in up to 50 percent of affected people.” NIMH’s enthusiasm that 50 percent of depressed people can get better within the two treatment steps in STAR*D neglects the well-known scientific fact that 50 percent of depressed people eventually get better in 6 to 12 months with no treatment at all – and the two stages of STAR*D took slightly over 6 months.

It gets worse. Depressed people who likely would have been uncured by STAR*D were excluded from the STAR*D study. And it is conceivable that had the STAR*D subjects been sampled from the entire population, STAR*D result may have been worse than a 50 percent remission rate.

One important group of excluded subjects was actually discussed in the NIMH press release, “For example, people were not eligible for the study if they had already been treated with an adequate dose for adequate period of time with one or more of the treatments that were part of the first two STAR*D treatment steps.” Thus, NIMH’s 50 percent remission rate is analogous to concluding, “A study shows that X antibiotic is effective for 50 percent of those with Y infection,” when in fact the researchers had excluded from the study all those whom had previously taken X antibiotic for Y infection but had been uncured by it.

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Evelyn Pringle is a columnist for OpEd News and investigative journalist focused on exposing corruption in government and corporate America.
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