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AlterNet – 28 February 2008

By Bruce E. Levine

While millions of people swear by Prozac, Zoloft, and other antidepressants, do they work any better than a placebo or no treatment at all?

Answering that question would be much easier if: (1) the U.S. Food and Drug Administration (FDA) revealed all drug study findings without requiring a Freedom of Information Act request, (2) drug studies with negative results were routinely published in medical journals, (3) the FDA did not rely on drug company studies employing biased research designs, (4) FDA advisory panels did not include advisers financially connected to drug companies and (5) the National Institute of Mental Health (NIMH) did not fund drug studies by researchers who have financial relationships with drug companies.

The good news? There are antidepressant researchers without ties to drug companies, and there is wisdom about overcoming depression that remains available.

On Jan. 17, 2008, the New England Journal of Medicine analyzed both published and unpublished antidepressant studies registered with the FDA between 1987-2004. Examining 12 antidepressants, Dr. Erick H. Turner, a former FDA medical reviewer, and his research team included data gained via the Freedom of Information Act.

Dr. Turner discovered that most studies with negative results were never published in journals, and so doctors had no way of knowing how poorly antidepressants have actually fared. While 94 percent of antidepressant studies published in journals show antidepressants to be more effective than placebos, only 51 percent of all registered studies were determined by the FDA to show antidepressants superior to placebos.

Why are most negative results not published in journals? Drug studies are routinely funded by the drug’s manufacturer, which has no interest in the publication of negative results. Also, medical journals are increasingly dependent on advertising revenue from drug companies, which results in a disincentive to publish negative results.

Antidepressant advocates point out that when comparing all research subjects, antidepressants retain an advantage — albeit a modest one — over placebos. However, that belief is based on studies funded by drug companies, utilizing research designs biased in favor of antidepressants.

One such research-design bias is the use of depression measurements that weigh heavily depression symptoms most likely to improve with antidepressants (such as sleep problems and agitation), and weigh less heavily depression symptoms not as likely to improve with antidepressants (such as suicidal thoughts and joylessness).

Why does the FDA allow measurement bias and other dice loading that favors antidepressants? Marcia Angell, former editor in chief of the New England Journal of Medicine, concludes that the FDA has been compromised by drug companies. Dr. Angell reports that, for example, in the majority of FDA drug-approval advisory meetings through 2000, half or more of the FDA advisers had conflicts of interest — financial relationships with drug companies.

A critical scientific standard in drug studies is the double-blind control (neither subject nor experimenter knows who is getting the drug and who is getting the placebo), but drug-company antidepressant studies use blinds that can be peeked through. How? Inactive placebos such as sugar pills, which don’t create side effects, are used, and so subjects can more easily guess if they are getting the actual drug. In order to make it more difficult to penetrate the blind, an active placebo, which creates side effects, should be used. In 2000, a Psychiatric Times article concluded: “In fact, when antidepressants are compared with active placebos, there appear to be no differences in clinical effectiveness.”

In addition to biased depression measurements and an absence of a true double blind control, the FDA also accepts antidepressant research in which subjects who respond favorably to placebos are weeded out from final trials.

Thus, it is especially embarrassing for antidepressant manufacturers that despite research-design biases in favor of antidepressants, these drugs achieve superiority to placebos in only 51 percent of the studies.

In a widely covered announcement in March 2006, NIMH reported that 50 percent of depressed people experience remission of symptoms in a two-step treatment study (which ultimately would include four steps) called Sequential Treatment Alternatives to Relieve Depression (STAR*D). Unannounced by NIMH and STAR*D researchers — who had financial relationships with antidepressant manufacturers — was that for each of these antidepressant treatment steps, remission rates were lower than or equal to the customary placebo performance in other antidepressant studies (there was no placebo control in this $35 million U.S. taxpayer-funded STAR*D study).

Moreover, NIMH and STAR*D researchers neglected to mention that in the same time it took to complete steps one and two of STAR*D (slightly over six months), previous research shows that depressed people receiving no treatment at all have a spontaneous remission rate of 50 percent — this identical to STAR*D results over that same time span. Worse yet, by the time all four STAR*D’s treatment steps had been completed, relapse rates were so high that the November 2006 American Journal of Psychiatry calculated the actual cumulative remission rate to be, at best, 43 percent.

The most benign thing that one can say about drug companies’ efforts in creating faith in antidepressants is that faith is a significant reason these antidepressants are effective at all. In 2004, the Journal of Clinical Psychiatry reported that among those depressed patients expecting an experimental antidepressant to be “very effective,” 90 percent had a positive response (not necessarily remission); while among those expecting the medication to be “somewhat effective,” only 33 percent had a positive response. Depressed people with “no faith” in antidepressants were not included in this study, but such nonbelievers rarely tell me about having a positive response with antidepressants. As one might expect, drug companies do nothing to ensure that depressed people who have little or no faith in antidepressants are proportionately included in studies.

More than a century ago, psychologist and philosopher William James understood the importance of belief, faith and expectations, or what scientists now call the “placebo effect.” “Faith in a fact can help create the fact,” James famously observed in his essay, “The Will to Believe.” James was a tough-minded scientist, but when it came to discovering an antidote to his own, often debilitating, states of depression, he came to “believe in belief.” James, however, knew that while any given belief may “work,” it also may have undesirable side effects. So he pragmatically considered many beliefs before choosing to believe that “life shall [be built in] doing and suffering and creating.”

Different faiths fit different temperaments. I know people who have overcome depression with antidepressants, psychotherapy, prayer, philosophy, political activism, dietary supplements, art, exercise and other approaches. Science has no clear favorites and invites pluralism. However, we should not be cavalier in what we choose to believe, because our beliefs determine in no small way what kind of people we are and what kind of effect we have on society.

Bruce E. Levine, Ph.D., is a clinical psychologist and author of Surviving America’s Depression Epidemic: How to Find Morale, Energy, and Community in a World Gone Crazy (Chelsea Green, 2007).

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Opinions expressed are those of the author.