Excerpt from Story by ERICA GOODE, New York Times

They were billed as near wonder drugs, much safer and more effective in treating schizophrenia than anything that had come before.

For many years, it seemed that the excitement was fully warranted.

There were remarkable stories of recovery. And the new generation of antipsychotic drugs, called atypicals, seemed to have few of the side effects commonly seen with high doses of older medications for psychosis.

The drugs appeared so successful that doctors began prescribing them for other things, not only for other psychotic illnesses, like manic depression, but also for Alzheimer's, personality disorders and nonpsychotic depression, and for conduct disorder and severe aggression in children. Sales of the drugs soared. More than 15 million prescriptions were written last year for the two leading drugs alone, Zyprexa and Risperdal, industry figures show.

But 14 years after the first of the drugs entered the market, researchers are questioning whether they are quite as miraculous - or benign - as originally advertised.

The first round of antipsychotics had such unpleasant side effects, like dry mouth, stiffness and trembling, that people often just stopped using them. The atypicals are considered by many patients to be more tolerable, and many experts believe they are better than older drugs in treating some aspects of psychosis.

But studies suggest that their superiority is at best modest, specific to certain symptoms and variable from drug to drug. Also, there is increasing suspicion that they may cause serious side effects, notably diabetes, in some cases leading to death.

The issue of risks has become more pressing as the drugs are prescribed for children and for adults with milder conditions. And the states, which pay enormous sums for the atypicals in caring for the severely mentally ill, are questioning whether the benefits of the new drugs are worth their costs.

The drugs, experts say, have now reached a turning point where benefits must be balanced by side effects and cost.

National sales of antipsychotics reached $6.4 billion in 2002, making them the fourth-highest-selling class of drugs, behind cholesterol-lowering drugs, ulcer drugs and antidepressants, said IMS Health, a company that tracks drug sales. According to NDCHealth, another company that tracks the industry, in 2002, more than 7.4 million prescriptions were written for Zyprexa and more than 7.6 million for Risperdal.

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"There has been what I see as a kind of myth-making," said Dr. William Carpenter, a professor of psychiatry and pharmacology at the University of Maryland and the director of the Maryland Psychiatric Research Center. "It's like: `The new generation of drugs is safe, patients like them and they're more effective.' "

"Patients probably do like them a little bit more," Dr. Carpenter said, and therefore might be slightly more likely to keep taking their medication. "But we still have plenty of trouble with the new-generation drugs."

Like other experts, Dr. Carpenter believes that the atypicals have an edge over the older drugs in some areas. He and others said they seem better at easing the emotional blunting, withdrawal and depression often seen in schizophrenia.

Studies have indicated that they are better at preventing relapse and that they carry a lower risk of the most pernicious side effect of older drugs: tardive dyskinesia, a disorder that causes repetitive movements - chewing motions, lip-smacking and contortions of the arms and legs - that sometimes persisted even after the drugs were stopped.

The drugs may help with problems in memory, decision-making and other mental functions that can keep schizophrenia patients from working, but this is still debated.

"I think the new-generation drugs have shown advantages," said Dr. John Kane, the chairman of psychiatry at Zucker Hillside Hospital in Queens and an expert on schizophrenia. "They may not be consistent across every study or every drug, but when you take them in their totality, they are meaningful."

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Some patient-advocacy groups have criticized the study as biased toward the lower-cost, older-generation drugs.

In a telephone interview, Dr. Geddes said that, like other clinicians, he had seen patients improve remarkably on the newer medications. "But I remember over the last 20 years I had quite a lot of people who did really well on the older ones, too," he said.

Part of what gave the older drugs a bad reputation, Dr. Geddes contends, was that in the past they were given in very high doses that may have made them less effective and increased side effects. Too, he said, many atypicals "were quite new, and it's not good to go spraying around new drugs without knowing about the long-term effects."

In a report this month in The Lancet, the medical journal, Dr. Stefan Leucht, a research associate at Zucker Hillside Hospital, and his colleagues found that although most atypicals produced fewer Parkinson's-like side effects than high-potency older drugs like Haldol, when compared with older drugs of lower potency, some of the new drugs were just as likely to cause the side effects.

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The Side Effects`Thorazine Shuffle' Vs. Diabetes

Old antipsychotic drugs were notorious for their side effects, not only tardive dyskinesia but the dull-eyed stare and stiff-legged walk that became known in the back wards of state hospitals as the Thorazine shuffle.

Such problems are less frequent in the newer generation of drugs, but they are not unheard of. If researchers agree on anything, it is that the new medications have side effects of their own, some serious.

Most disturbing are cases of diabetes, Type II and Type I, and hyperglycemia that have been reported in adults and some children taking atypical antipsychotics. A study presented yesterday at the psychiatric meetings by Dr. P. Murali Doraiswamy, chief of the division of biological psychiatry at Duke University, and his colleagues raises the possibility that some newer drugs may also be linked to pancreatitis.

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The F.D.A. is also looking closely at the diabetes issues. A spokeswoman said the agency is waiting for the findings of a large analysis by the Veterans Administration, to be completed this year, before deciding whether to require warning labels on some or all of the atypicals. Some drugs already carry such labels in Japan or Europe, including Zyprexa and Seroquel.

However, psychiatrists say patients taking antipsychotic drugs should be monitored on a regular basis for glucose abnormalities.

Eventually, Dr. Geddes said, the two classes of antipsychotic medication may come down to a tradeoff of side effects: The risk of tardive dyskinesia posed by the older drugs versus the risk of diabetes.

"It's not up to me to say, is it?" Dr. Geddes asked. "It's up to the patient to say."

The FutureCost, Consequences And Patients in Need

Of the billions of dollars spent each year on antipsychotic drugs, a large part comes from government insurance programs.

Dr. Joseph Parks, the medical director of Missouri's Department of Mental Health, said that his state spent $104 million, or 11.6 percent of the total Medicaid payout, on three atypical antipsychotics, Zyprexa, Risperdal and Seroquel, between April 2002 and March 2003. The three drugs topped the list in dollar volume of all drugs covered by the state Medicaid program, including cancer, H.I.V. and heart medications.

"They are good medications," said Dr. Parks, who is also the president of the National Association of State Mental Health Directors' medical directors' council, "and they seriously help a lot of people. I would not want to give up any of them."

But for the price of treating one person with Zyprexa at $303 for a month's prescription, he said, or two on Risperdal, at $159 per month, the state could treat 8 or 10 people with Haldol at $35 per month.

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Advocacy groups like the National Mental Health Association worry that the price difference in the drug classes might cause some states, pressed by shrinking budgets, to include only some atypicals in their formularies or even to eliminate them altogether.

Because different drugs work for different people, said Jennifer Bright, the association's senior policy director for health care reform, forcing people to choose from two or three medications increases the chances that none will work, and increases the risk of hospitalization or other, higher cost care.

"We believe there ought to be open access to all medications," she said.

Whatever the final verdict on the atypicals, many experts believe what is really needed is new and better drugs.

Meanwhile, few psychiatrists - and perhaps even fewer patients - would want to lose any of the newer generation of antipsychotics now on the market. But how they are used and how much value they add, experts say, is ultimately a question for society.

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