The Newer Atypical Antipsychotic Drug Olanzapine (ZYPREXA) Shows No Advantage Over Haloperidol (HALDOL)

A randomized controlled clinical trial, the “gold standard” for scientific research, published in the November 26, 2003 Journal of the American Medical Association (JAMA) compared the newer top selling atypical antipsychotic drug olanzapine (ZYPREXA) to the much older antipsychotic agent haloperidol (HALDOL) and concluded that this trial:

...found no statistically or clinically significant advantages of olanzapine for schizophrenia on measures of compliance, symptoms, or overall quality of life, nor did it find evidence of reduced inpatient use or total cost.

Haloperidol was first cleared for marketing by the Food and Drug Administration (FDA) 36 years ago in April 1967. According to the authors of the JAMA study 5 milligrams of haloperidol wholesales for $0.02 per tablet. Olanzapine, marketed by Eli Lilly and Company of Indianapolis, was approved by the FDA in September 1996. The authors of the study cited the wholesale cost of olanzapine as $4.84 per 5 milligram tablet. This is a 242-fold difference in cost.

In 2003, about seven million prescriptions were dispensed for olanzapine at a retail cost of over $2.0 billion. This amount placed olanzapine as the seventh largest selling drug in the U.S. during 2003 by retail sales. By contrast, 1.1 million haloperidol prescriptions were dispensed at a retail cost of $30.8 million in 2003.

The JAMA study was conducted in 17 U.S. Department of Veterans Affairs medical centers around the country between June 1998 and June 2000. It involved 309 patients with a diagnosis of schizophrenia or schizoaffective disorder for the two years preceding entry into the study. Patients were randomly chosen to receive either olanzapine or haloperidol. Funding for the study was provided by Eli Lilly, the manufacturer of olanzapine, and the Veterans Administration Cooperative Studies Program.

The study assessed standardized measures of schizophrenia symptoms, quality of life, neurocognitive status, and adverse drug reactions.

The results of this trial were considerably less favorable than previously published studies comparing olanzapine with haloperidol. The authors of the study offered two possibilities for the dissimilar results of this and the previous studies. First, haloperidol patients were initially given benztropine (COGENTIN) to prevent the development of extrapyramidal symptoms (EPS), an adverse effect of haloperidol and other antipsychotic drugs that mimics the movements seen in Parkinson’s disease.

Second, in the comparative studies with haloperidol that were favorable to olanzapine, drugs like benztropine were not given until after the development of EPS.

Waiting until EPS development in a clinical trial would let physicians and patients know that they were taking haloperidol. This could cause patients to drop out of a study and bias the results in favor of olanzapine.

Treatment with olanzapine did result in modestly reduced symptoms of akathisia compared to those patients taking haloperidol. Akathisia is an annoying adverse drug reaction characterized by an inability to remain in a sitting position, restlessness and a feeling of muscular quivering.

The modest benefit of olanzapine over haloperidol with regard to akathisia must be balanced against severe weight gain and the possibility of drug-induced diabetes (see Worst Pills, Best Pills News July 2002). Also in the balance is the exorbitant cost of olanzapine.

The lead author of the JAMA study, a professor of psychiatry from the Yale University School of Medicine and the director of the Veterans Affairs Northeast Program Evaluation Center in West Haven, CT, suggested in a November 26, 2003 Wall Street Journal interview that Eli Lilly tried to influence the results of the study to be more favorable towards olanzapine. He is quoted as saying “They [Eli Lilly] began to suggest things that I did not feel comfortable publishing under my name.” And “When we do research, we generally don’t throw out data.” The Wall Street Journal reported that a Lilly spokeswoman declined to comment.

The author of the study is to be commended for maintaining his scientific integrity.

The results of this should not come as a great surprise for two reasons. First, the standard for drug approval in the U.S. is now over 40 years old and does not require that new drugs coming on the market be either safer or more effective than older drugs such as haloperidol. In fact, new drugs are being approved by the FDA that may be less safe and less effective than existing products.

Second, British physicians developing guidelines for treating schizophrenia with the newer antipsychotic drugs found no clear evidence that they are more effective or better tolerated than older, conventional antipsychotics. The guidelines were developed by systematically reviewing randomized controlled clinical trials and using a statistical technique known as “meta-analysis” to assemble the results of many published studies on the treatment of schizophrenia. The recommendation from this extensive effort — published in the December 2, 2000, British Medical Journal (BMJ) — was that the older, conventional antipsychotics should be tried first (see Worst Pills, Best Pills News February 2001).

The BMJ meta-analysis included randomized trials of the newer antipsychotics clozapine (CLOZARIL), olanzapine, quetiapine (SEROQUEL), and risperidone (RISPERDAL) compared to conventional antipsychotics, usually haloperidol or chlorpromazine (THORAZINE).

The JAMA article directly comparing olanzapine with haloperidol in combination with benztropine answered the question that is most important to patients, physicians, and the healthcare system: is the “newest” high price drug any better or any safer than the less expensive standard treatment?

We, as a country, have been paying whatever a manufacturer demands in the marketplace without demanding comparative information. One is hard pressed to think of another commodity on which so much money is spent, and wherein the decision to buy is based almost entirely on a perception of a new drug’s therapeutic value — a perception that is created by a manufacturer’s advertising.

What You Can Do

If you or a family member is prescribed haloperidol as an anti-psychotic, it should not be considered a cheap low quality treatment used only to save money.