View Full Version : Studies could alter treatment for depression, schizophrenia

07-28-05, 11:05 AM
Wednesday, July 27, 2005
By Leila Abboud, The Wall Street Journal

The results of the largest studies ever conducted of depression and schizophrenia will be released in coming months, potentially transforming the way patients are treated and shaking up some of the drug industry's most lucrative markets.

The federally funded studies are part of a six-year push by the mental-health division of the National Institutes of Health to come up with reliable scientific data on the differences between drugs and treatment strategies for the major psychiatric illnesses. The project comprises four trials, in serious depression, bipolar disorder, schizophrenia and adolescent depression.

The aim is to fill the information gap that plagues psychiatry, and hurts the quality of care given to patients. Clinical trials that companies do to get drugs approved aren't designed to provide the answers that doctors say they really need. For one, these trials don't compare one drug with another, because they are designed to show only whether a particular drug is effective against an illness. Thus, psychiatrists have little guidance on whether one drug works better than another or has fewer side effects than another.

Also, at eight to 12 weeks long, drug-company trials are too short to reveal how patients fare or what side effects crop up long-term. And, in order to stay focused on a drug's efficacy on one illness, they exclude the sickest patients and people with co-existing diseases.

The paucity of quality information about drugs has been a major issue in recent years as concerns have emerged about side effects, and drug companies have been criticized for hushing up unfavorable study results.

So, the NIH-funded trials aim to compare treatments to discover both positive and negative impacts of the drugs, and to mimic the real world with all of its imperfections. All kinds of patients are included and they are followed for years. The trials -- which include thousands of participants, versus the hundreds in a typical drug-company trial -- are conducted all over the country and include community clinics and primary-care offices, not just academic medical centers. As part of the $140 million effort, the NIH is also collecting data on the cost effectiveness of the various treatments and pitting older drugs, which are available as cheaper generics, against newer blockbusters.

Grayson Norquist, a former NIH psychiatrist who played a big role in conceiving the trials, says they aim to answer the main question doctors face every day. "Of the several drugs I have to choose from," says Dr. Norquist, now at the University of Mississippi Medical Center, "which one should I use for the person sitting in front of me?"

Enormous amounts of money are at stake if the trials reveal differences in the safety and efficacy of various drugs. Antidepressants and antipsychotics are the third- and fourth-biggest classes of drugs in the country after cholesterol and heartburn medicines, with U.S. sales of $20.7 billion last year. Much of that cost is borne by government health-care plans. Both health-care payers and Wall Street investors are anxiously awaiting the results of the two trials in coming months. (Results from the first arm of the project, on adolescent depression, came out in August 2004 and showed that a combination of antidepressants and therapy was the most effective treatment. The study of bipolar disorder ends in September, and results will be published after the analysis is completed.)

In addition to comparing drugs, the trials are trying to fill another gap in the scientific literature: what to do with the many patients who don't get better on their first drug. Psychiatrists do a lot of switching patients from one antidepressant to another and tinkering with drug combinations. None of this is backed up with good evidence, and it can take months to find the right regimen. Practices and outcomes vary widely among doctors.

Steve Miller saw a dozen doctors before finding the drugs that alleviated his schizophrenia. The 45-year-old from Cedar Rapids, Iowa, first had hallucinations as a freshman in college, and took haloperidol, an older-generation antipsychotic, for years. He remained so anxious and depressed he contemplated suicide. A newer antipsychotic, Clozaril, worked better. But it was only when his doctor added Zyprexa to the mix that he finally recovered.

"Clinicians are just basically practicing seat-of-their-pants pharmacology based on their experience with patients," said Jeffrey Lieberman, the principal investigator on the schizophrenia study, which is known as CATIE. "When they look for hard data in the scientific literature to base their decisions on, they can't find it."

The problem is especially acute in depression -- about half of patients don't respond to standard antidepressant therapy. The depression study, called STAR.D, tests whether the subsequent treatment strategies doctors typically use for these patients actually work. It included 3,940 patients across the country who were followed for five years.

All of the patients first take the antidepressant Celexa, from Forest Laboratories Inc., which belongs to a class of drugs known as selective serotonin reuptake inhibitors. Those who don't get better can choose whether to try therapy or switch to other antidepressants -- either Pfizer Inc.'s Zoloft, another SSRI, or GlaxoSmithKline PLC's Wellbutrin or Wyeth's Effexor, which work by different mechanisms in the brain. In the third and fourth stages of the study, people who don't get better cycle through various antidepressants and combinations of drugs.

The CATIE schizophrenia study pits eight antipsychotic drugs against each other to determine their comparative effectiveness and safety. About 1,600 patients were enrolled and followed for 18 months.

In the first stage, patients are given either perphenazine (an older, generic antipsychotic medication) or one of four newer drugs: Eli Lilly & Co.'s Zyprexa, Johnson & Johnson's Risperdal, AstraZeneca PLC's Seroquel or Pfizer's Geodon. If they don't get better or encounter side effects, they are switched to other antipsychotics, including the newest, Abilify from Bristol-Myers Squibb Co.

One of the big benefits to patients of the CATIE trial will be high-quality, rigorous information about the comparative side effects of psychiatry medications. Concerns have emerged in recent years that some of the newer medicines, known as atypical antipsychotics, can cause extreme weight gain, worsen cholesterol and lead to diabetes. Although the Food and Drug Administration required that all atypical antipsychotics carry a warning about these side effects, the NIH trial might actually reveal whether certain drugs in the class are worse than others.

The CATIE investigators are now analyzing the results and preparing them for publication in September. But one striking fact has already emerged: nearly 70 percent of patients in the study didn't do well on their first drug, and switched to another.