Schizophrenia Drugs Still Fall Short

A long-awaited government trial, by far the largest of its kind, has not managed to clear up the prescription picture for schizophrenia, a severe and debilitating mental illness.

According to the $44 billion study, first-generation drugs are essentially as effective as the newer, more expensive second-generation drugs.

In an illustration of the difficulty doctors have had in prescribing the right treatment for this illness, 74 percent of study participants discontinued their original treatment either because of side effects or lack of effectiveness, the researchers found.

Olanzapine -- brand name Zyprexa -- may have been the closest thing to a winner with better effectiveness, which was somewhat balanced by severe side effects.

"The medications work, but there were substantial limitations," said study leader Dr. Jeffrey A. Lieberman, chairman of psychiatry at Columbia University's College of Physicians and Surgeons.

"When it comes to the treatment of patients with chronic schizophrenia, the glass is only half full. Patients and their doctors are looking for more in the way of symptom relief and to enable recovery, and they want this with fewer side effects," he said.

Lieberman emphasized, however, that these treatments are "far better than no treatment at all."

The study appears in the Sept. 22 issue of the New England Journal of Medicine. It was released early to coincide with a Monday press conference on the findings, hosted by the National Institute of Mental Health, which had sponsored the study.

"We don't have a magic bullet for the treatment of schizophrenia and clinicians are struggling every day to find a medication that will work for individual patients," said Dr. Leslie Citrome, a professor of psychiatry at New York University School of Medicine in New York City, who was not involved with the study.

"The interesting finding that about three-quarters of patients did not stick to the medicines they were assigned to really speaks to the inter-individual differences. Response and tolerability vary a great deal among patients. The treatment of schizophrenia is really sequential trials of different medication until one finds one that patients find really satisfactory. There is no cure," Citrome added.

Schizophrenia is a chronic mental illness in which the hallmark symptoms include hallucinations, delusions and disordered thinking. The disease affects about 3.2 million Americans, only about 15 percent of whom are employed at any given time and only 10 percent to 15 percent who are married.

The advent of antipsychotic drugs such as Haldol 50 years ago meant that many people with schizophrenia could move from institutions into the community. While these medications seemed effective, they were handicapped by severe side effects, including Parkinson's-like symptoms such as tremors and muscle rigidity.

The second generation of antipsychotic drugs reached the market in the 1990s and supposedly had fewer of the movement side effects, although they were often associated with severe weight gain and metabolic problems. There are now six of these drugs on the market, representing 90 percent of antipsychotic prescriptions (the fourth-largest group of medications prescribed in the United States), and about $10 billion in sales in 2005.

Despite their leap to the forefront of the market, it has been unclear which of the second-generation drugs were the most effective, and whether the second-generation drugs surpassed the older drugs in effectiveness and side-effects profile.

Enter the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial, launched in 1994, which compared perphenazine, a first-generation antipsychotic, with four of the newer drugs.

In all, 1,493 patients with schizophrenia were randomly assigned to receive various doses of perphenazine (a first-generation drug), olanzapine, quetiapine, risperidone or ziprasidone (all second-generation drugs) for up to 18 months.

Almost three-quarters (74 percent) of patients discontinued their original medication before the 18 months were up: 64 percent of those assigned to olanzapine (Zyprexa); 74 percent of those assigned to risperidone (Risperdal); 75 percent of those assigned to perphenazine; 79 percent of those assigned to ziprasidone (Geodon); and 82 percent of those assigned to quetiapine (Seroquel).

The 74 percent discontinuation rate, Lieberman said, "was not that high or dissimilar compared to what we've seen in other trials." Switching medications, he added, is the "undeniable fact of clinical treatment of this patient population at this point in time with this class of medication."

People who volunteer for study trials also tend to have a higher switching rate because they are looking for something different, Rosenheck added.

Not only were patients who started on olanzapine more likely to stay on their medication longer, they were also less likely to be hospitalized for a psychotic relapse. On the other hand, patients on olanzapine had substantially more weight gain and metabolic changes associated with an increased risk of diabetes than study participants taking the other drugs.

"The biggest surprise was that the older medication was comparably effective to at least three of the new medications and not much worse than the newer drug that did the best," Lieberman said.

While the similarities between old and new drugs could argue for more use of older drugs, which are cheaper, Dr. Robert Rosenheck, study co-investigator and professor of psychiatry at Yale University Medical School, pointed out that the lower hospitalization rate seen with olanzapine might offset the cost of the medication.

But perphenazine "is clearly an effective treatment and should not be disregarded just because it is older," Lieberman said.

Unexpectedly, the movement side effects were similar in the new and old classes of drugs. "We believe this is due to the fact that we administered lower potency first-generation drugs," Lieberman said.

"This isn't a horse race -- in a horse race there is one winner," Rosenheck said. "This is about a series of drugs with complex benefits and side effects. No one drug was hands-down superior to all the others. The information we learn from this study does not tell us what is the best drug to start with but, rather, that we need to look at the situation of the patients. Which drug best fits the situation of that patient, like fitting the pieces of a puzzle together which has multiple factors that have to fit."

Dr. Thomas R. Insel, director of the National Institute of Mental Health, said, "One of the things we'll get out of this [study] for the first time is enough information to help us tailor treatments for individual patients. There may not be a magic bullet for schizophrenia. For hypertension, most people end up on multiple agents. That may be where we end up in five years for schizophrenia. We may need to combine treatments to get maximum impact."

Many involved with the study felt this may already be happening. "I would say the majority [of individuals with schizophrenia] benefit from treatment substantially, and can find a treatment to stay on," Lieberman said, HealthDay News reported.

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