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Issue 346

July 31, 2002

Another $3 Billion Hoax

Antidepressants Work Only Slightly Better Than Placebo

Light Therapy for Eye Injuries

Stealth Antioxidant

When You Can't Juice

Calorie Restriction

Kava-Kava Banned in Europe

Obesity - Cancer Link

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Antidepressants Proven to Work Only Slightly Better Than Placebo

By Dr. Irving Kirsch
E-mail: irving.kirsch@uconn.edu

Although antidepressant medication is widely regarded as effective, a recent meta-analysis of published clinical trials indicates that 75 percent of the response to antidepressants is duplicated by placebo.

The report analyses the data submitted to the U.S. Food and Drug Administration (FDA) for approval of recent antidepressant medications.

We analyzed the efficacy data submitted to the FDA for the six most widely prescribed antidepressants approved between 1987 and 1999:

  • Prozac
  • Paxi
  • Zoloft
  • Effexor
  • Serzone and
  • Celexa.

Results are reported from all well controlled efficacy trials of the use of these medications for the treatment of depression. FDA medical and statistical reviewers had access to the raw data and evaluated the trials independently. The findings of the primary medical and statistical reviewers were verified by at least one other reviewer, and the analysis was also assessed by an independent advisory panel.

More important, the FDA data constitute the basis on which these medications were approved. Approval of these medications implies that these particular data are strong enough and reliable enough to warrant approval. To the extent that these data are flawed, the medications should not have been approved.

In order to generalize the findings of the clinical trial to a larger patient population, FDA reviewers sought a completion rate of 70% or better for these typically 6-week trials. Only 4 of 45 trials, however, reached this objective.

In clinical trials, the effect of the active drug is assumed to be the difference between the drug response and the placebo response.

This report showed that the FDA clinical trials data indicate that 18% of the drug response is due to the pharmacological effects of the medication. Overall, the drug/placebo difference was less than 2 points on the HAM-D, a highly reliable physician-rated scale that has been reported to be more sensitive than patient-rated scales to drug/placebo differences.

Although mean differences were small, most of them favored the active drug, and overall, the difference was statistically significant. There were only 4 trials in which mean improvement scores in the placebo condition were equal to or higher than those in the drug condition, and in no case was placebo significantly more effective than active drug. This may indicate a small but significant drug effect. However, it is also possible that this difference between drug and placebo is an enhanced placebo effect due to the breaking of blind.

These data raise questions about the criteria used by the FDA in approving antidepressant medications. The FDA required positive findings from at least two controlled clinical trials, but the total number of trials can vary. Positive findings consist of statistically significant drug/placebo differences. The clinical significance of these differences is not considered.

To summarize, the data submitted to the FDA reveal a small but significant difference between antidepressant drug and inert placebo. This difference may be a true pharmacological effect, or it may be an artifact associated with the breaking of blind by clinical trial patients and the psychiatrists who are rating the severity of their conditions.

In any case, the difference is relatively small (about 2 points on the HAM-D), and its clinical significance is dubious. Research is therefore needed to assess the additivity of antidepressant drug and placebo effects. If there is a powerful antidepressant effect, then it is being masked by a nonadditive placebo effect, in which case current clinical trial methodology may be inappropriate for evaluating these medications, and alternate methodology need to be developed.

Conversely, if the drug effect is as small as it appears when drug/placebo differences are estimated, then there may be little justification for the clinical use of these medications.

The problem, then, would be to find an alternative, as the clinical response to both drug and placebo is substantial. Placebo treatment has the advantage of eliciting fewer side effects. However, the deception that is inherent in clinical administration of placebos inhibits their use. Thus, the development of nondeceptive methods of eliciting the placebo effect would be of great importance.

Prevention & Treatment, Volume 5, Article 23, July 15, 2002

First Posted in Red Flags Weekly July 17, 2002


This profoundly important study reviews the very foundation that the pharmaceutical companies used to justify to the FDA that their drugs work. There is only a small difference between these drugs and placebo, the review makes clear.

Does this mean the drugs don't work? Absolutely not. These drugs do prevent suicides for many. However, the drug may not be working at the supposed pharmacological or drug level. In many cases, the effect is due to the power of the person's mind in believing that the drug will work. Physicians and patients are quick to discount the placebo effect as due to random chance.

Nothing could be further from the truth.

The placebo effect is indeed quite real and profoundly effective. It really should be renamed as it has such a poor association. It might be more accurate to refer to it as the psychological manifestation effect, which is really the power of one's mind to manifest into reality what one's consistent and persistent thoughts are.

Your subconscious is completely neutral with respect to whatever you believe in. If you continually focus your attention on the belief that very powerful pills will work in your brain to make you feel better, they will indeed frequently do just that.

Many would view that as a beneficial effect, but your mind could just as easily manifest the opposite effect if you believed that the pills would not work.

There are numerous studies documenting the effect that the color or shape of the pill has on the response. This is obviously unrelated to the biochemical effect, but still, it makes a major difference in the outcome of the response. This is further proof of the psychological manifestation principle.

So what does this mean for you?

You don't have to rely on expensive and possibly toxic pills to relieve your depression or anxiety. You can use simple targeted techniques like psychological acupressure, of which EFT is a preferred technique. If you are challenged implementing the technique yourself, you can consult with one of the many well-trained clinicians across the country. I also have a 9-hour video set that was recently updated and has an entire new 45-minute section on how you can actually use psychological acupressure to implement positive goals in your life.


Fisher, S., & Greenberg, R. P. (1993). How sound is the double-blind design for evaluating psychotropic drugs. Journal of Nervous and Mental Disease, 181, 345-350.

Hamilton, M. A. (1960). A rating scale for depression. Journal of Neurology, Neurosurgery, and Psychiatry, 23, 56-61.

Hull, J. G., & Bond, C. F. (1986). Social and behavioral consequences of alcohol consumption and expectancy: A meta-analysis. Psychological Bulletin, 99, 347 360.

Hunter, J. E., & Schmidt, F. L. (1990). Methods of meta-analysis: Correcting error and bias in research findings. Newbury Park, CA: Sage.

Khan, A., Warner, H. A., & Brown, W. A. (2000). Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: An analysis of the Food and Drug Administration database. Archives of General Psychiatry 57, 311-317.

Kirsch, I. (2000). Are drug and placebo effects in depression additive? Biological Psychiatry 47, 733-73.

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Kirsch, I., & Sapirstein, G. (1998). Listening to Prozac but hearing placebo: A meta analysis of antidepressant medication. Prevention & Treatment, 1, Article 0002a. Available on the World Wide Web: http://www.journals.apa.org/prevention/ volume1/pre0010002a.html.

Klein, D. F. (1998). Listening to meta-analysis but hearing bias. Prevention & Treatment, 1, Article 0006c. Available on the World Wide Web: http://www.journals.apa.org/prevention/ volume1/pre0010006c.html.

Laughren, T. P. (1998, March 26). Recommendation for approvable action for Celexa (citalopram) for the treatment of depression. Memoradum: Department of Health and Human Services, Public Health Service, Food and Drug Administration, Center for Drug Evaluation and Research, Washington, DC.

Leber, P. (1998, May 4). Approvable action on Forrest Laboratories, Inc. NDA 20-822 Celexa (citalopram HBr) for the management of depression. Memoradum: Department of Health and Human Services, Public Health Service, Food and Drug Administration, Center for Drug Evaluation and Research, Washington, DC.

Lyerly, S. B., Ross, S., Krugman, A. D., & Clyde, D. J. (1964). Drugs and placebos: The effects of instructions upon performance and mood under amphetamine sulphate and chloral hydrate. Journal of Abnormal and Social Psychology, 68, 321 327.

Marlatt, G. A., & Rohsenow, D. J. (1980). Cognitive processes in alcohol use: Expectancy and the balanced placebo design. In N. K. Mello (Ed.), Advances in substance abuse: Behavioral and Biological Research, (pp. 159 199). Greenwich, CT: JAI Press.

Murray, E. J. (1989). Measurement issues in the evaluation of pharmacological therapy. In S. Fisher & R. P.Greenberg (Eds), The limits of biological treatments for psychological distress: Comparisons with psychotherapy and placebo (pp. 39-67). Hillsdale, NJ: Erlbaum.

Rabkin, J.G., Markowitz, J. S., Stewart, J. W., McGrath, P. J., Harrison, W., Quitkin, F. J., & Klein, D. F. (1986) How blind is blind? Assessment of patient and doctor medication guesses in a placebo-controlled trial of imipramine and phenelzine. Psychiatry Research, 19, 75-86.

Ross, S., Krugman, A. D., Lyerly, S. B., & Clyde, D. J. (1962). Drugs and placebos: A model design. Psychological Reports, 10, 383 392.

RxList: The Internet Drug Index. (1999). The top 200 prescriptions for 1999 by number of U.S. prescriptions dispensed. Retrieved November 19, 2001, from http://www.rxlist.com/99top.htm

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