Mississippi will receive $18.5 million from drug maker Eli Lilly and Co. as part of a settlement over claims the company promoted the anti-psychotic Zyprexa for ailments it was not federally approved to treat, Attorney General Jim Hood said according to an Associated Press report.

The settlement recovers money the state spent through its Division of Medicaid and the State Insurance Plan, Hood said. The company also will pay $3.7 million in legal fees for the state. Additionally, the company paid a $1.4 billion settlement to the federal government in January 2009 after admitting it had promoted Zyprexa in elderly populations for treatment of dementia between 1999 and 2001.

Zyprexa was approved by the FDA in 1996 to treat symptoms of schizophrenia, bipolar disorder, and psychotic depression.

“Clinicians should consider the potential long-term risks when prescribing to adolescents,” the FDA said in a statement released Friday night. “In many cases, this may lead to prescribe other drugs first,” the statement went on.

The FDA has not approved the marketing of Zyprexa by the drug manufacturer Eli Lilly for use in children under 13 who are diagnosed with schizophrenia or bipolar disorder. But the medication, one of a class of psychiatric medications called the “atypical antipsychotics,” is widely prescribed for young patients, despite growing evidence that call its safety profile into question for this population.

The new warning comes in the wake of the October publication in the Journal of the American Medical Assn., in which a study showed that children and adolescents taking their first-ever course of Zyprexa gained, on average, more than 17 pounds over a 12-week period, as well as dramatic increases in triglycerides and cholesterol levels all factors that put them at higher risk of developing cardiovascular disease.

While two other antipsychotic drugs Seroquel and Risperdal were implicated in significant weight gain and metabolic changes, Zyprexa was found to carry the highest risks of all three.

The government announced a plan to curb overuse of the medicines, including Eli Lilly & Co.’s Zyprexa, Johnson & Johnson’s Risperdal, Bristol-Myers Squibb Co.’s Abilify, AstraZeneca Plc’s Seroquel and Pfizer Inc.’s Geodon. The drugs, designed to treat schizophrenia, are often inappropriately used a first-line therapy to quell behavioral problems in people with dementia, according to the report by Sube Banerjee, professor of mental health at King’s College London Institute of Psychiatry.

An estimated 180,000 elderly people with dementia in England are given the antipsychotic drugs each year, and just 20% improve because of the treatment, Banerjee said at a press conference in London. As many as two-thirds of the patients don’t derive any benefit from the pills, which boost the risk of early death and carry a range of side effects including sedation, stiff muscles, and trouble thinking and speaking clearly, the report found.

“We need to be sure that only the people who benefit from these drugs get them, and they get them at the lowest possible dose for the shortest period of time,” Banerjee said. “It is clear that these medications are being prescribed to deal with behavior and psychological symptoms in dementia rather than just for psychosis,” he wrote in the report.

Behavioral Therapies

All of the medications, including older, generic drugs such as Haldol and Thorazine, have the same effect, Banerjee said. As a result, doctors can’t switch patients from one medication to another to solve the problem.

Instead, they need to focus on basic techniques, such as trying to determine the cause of a patient’s agitation, and behavioral therapies to improve the situation, he said. In some cases, simple problems such as lack of sleep or hunger can be the culprit, he said.

“It is unacceptable that antipsychotic drugs are routinely prescribed to people with dementia,” said Health Minister Phil Hope. “I know we’re not going to reduce the use of these drugs overnight, but it can be done.”

The government accepted the recommendations from Banerjee and plans to hire a national clinical director for dementia to oversee efforts to improve care and reduce unnecessary drug use, Hope said at the press conference.

‘Chemical Restraints’

“The use of these chemical restraints really should be a last resort,” said Neil Hunt, chief executive officer of the Alzheimer’s Society. “We’ve got a culture and an ingrained pattern of care to shift here.”

In 2005, the FDA required makers of antipsychotics to include in dosage instructions a prominent warning surrounded by a black box about the increased risk of premature death in elderly patients with dementia. An English study released two years later found patients getting the drugs die six months earlier than those who don’t receive them.

Weight gain is a known possible side effect of the anti-psychotic drugs which are prescribed for bipolar disorder and schizophrenia, but also increasingly for autism, attention deficit disorders and other behavior problems. The new study in mostly older children and teens suggests they may be more vulnerable to weight gain than adults. The study also linked some of these drugs with worrisome increases in blood fats including cholesterol, also seen in adults. Researchers tie these changes to weight gain and worry that both may make children more prone to heart problems in adulthood.

The research is the largest in children who had just started taking these medicines, and provides strong evidence suggesting the drugs, not something else, caused the side effects, said lead author Dr. Christoph Correll of North Shore-Long Island Jewish Health System in Glen Oaks, New York.  But because these drugs can reduce severe psychiatric symptoms in troubled children, “We’re a little bit between a rock and a hard place,” he said.

The authors of the study said their results show that children on the drugs should be closely monitored for weight gain and other side effects, and that when possible, other medicines should be tried first.

The study appears in the Journal of the American Medical Association. It involved 205 New York City-area children from 4 to 19 years old who had recently been prescribed one of the drugs; the average age was 14. Depending on which of four study drugs children used, they gained between about 10 and 20 pounds on average in almost 11 weeks; from 10% to 36%t became obese.

The drugs are Abilify, Risperdal, Seroquel and Zyprexa. Of the four, Seroquel and Zyprexa are not yet approved for children, and they had the worst effects on weight and cholesterol. However, a government advisory panel recently voted in favor of pediatric use for the two drugs, and the Food and Drug Administration often follows its advisers’ recommendations.

The drugs’ makers said these problems are known side effects but emphasized the drugs’ benefits in helping patients cope with serious mental illness.

The four drugs have been considered safer than older anti-psychotic drugs, which can cause sometimes permanent involuntary muscle twitches and tics. That has contributed to widespread use of the newer drugs, including for less severe behavior problems, a JAMA editorial said.

The number of children using these drugs has soared to more than 2 million annually, according to one estimate.

Doctors “should not stretch the boundaries” by prescribing the drugs for conditions they haven’t been proven to treat, said Varley, co-author of the editorial.

Why these drugs cause weight gain is uncertain but there’s some evidence that they increase appetite and they may affect how the body metabolizes sugar, said Jeff Bishop, a psychiatric pharmacist at the University of Illinois at Chicago. The drugs also can have a sedation effect that can make users less active.

During a golf game, one doctor agreed to start new patients on Zyprexa for each time a sales representative parred, or put the ball in a hole within a predetermined number of strokes, according to the notes. “I got four pars out of nine holes,” Lilly salesman Vince Sullivan said in a February 2002 note. “I said I wanted my four new patients.”

The notes were made public for the first time in a court hearing in South Carolina in the state’s lawsuit against Lilly over Zyprexa marketing practices. State officials contend Indianapolis-based Lilly marketed the drug for unapproved uses. A trial is set to begin Sept. 14.

South Carolina wants to recoup $200 million it contends it wrongfully spent on Zyprexa prescriptions as a result of Lilly’s push to get doctors to use the medicine, approved only for schizophrenia and bipolar disorder, for other ailments. The state also contends the drug maker withheld information about Zyprexa’s side effects, such as weight gain.

“Call notes are jottings written by sales reps and most reps make hundreds of notes monthly. They are not literal recitations of interactions with physicians,” Marni Lemons, a Lilly spokeswoman, said in telephone interview.

‘Out Of Context’

Lemons said the state’s lawyers took the notes “out of context” and “not one physician employed by the state of South Carolina has testified Lilly promoted off-label to them.”

The notes became public at a hearing in Spartanburg, South Carolina, on Lilly’s motion to have the state’s case thrown out prior to trial.

The state also is seeking a $5,000 fine for each Zyprexa prescription dating back to 1997, according to court filings. That could result in billions of dollars in fines, South Carolina’s lawyers say.

Lilly resolved a marketing investigation over Zyprexa in January with the U.S. Justice Department, promising to pay $1.42 billion, including about $362 million to more than 30 states. South Carolina opted not to join that settlement.

Alaska Settlement

The only trial of a state’s lawsuit ended in March 2008 with an out-of-court settlement in which Lilly agreed to pay Alaska $15 million.

Zyprexa, part of a class of medications called atypical antipsychotics, has been linked to excessive weight gain and diabetes. The lawsuits also claim Lilly failed to properly warn of Zyprexa’s side effects.

Lilly officials have denied the drug maker withheld information about Zyprexa’s side effects or improperly marketed the drug in South Carolina.

Lawyers for the state pointed to a sales note from Sullivan in which he tells another salesman to tie a doctor’s Zyprexa prescriptions to participation in a speakers’ program.

The company paid doctors and psychiatrists to address physician gatherings about the benefits of the antipsychotic. “If his numbers go up, maybe he can talk,” Sullivan said in the August 2001 note.

‘So Much Money’

A year later, Sullivan noted in sales records that he was pressing a doctor to write more Zyprexa prescriptions “because we’re paying him so much money” to participate in the speakers’ program, according to a call note made public.

Lilly also offered other inducements to doctors who prescribed Zyprexa, such as deep-sea fishing trips and Palm- Pilot devices, said John Simmons, a Columbia, South Carolina- based lawyer representing the state.

The sales notes show that many of those prescriptions were for unapproved or so-called off-label, uses, Simmons told Judge Roger Couch.

The FDA regulates what drugs can be used to treat specific ailments. Drug makers can only promote their medicines for FDA-specified illnesses.

Faced with the loss of patent protection for its Prozac antidepressant, Lilly officials pushed salespeople to market Zyprexa for a host of ailments, including depression, agitation and anger, Simmons said. The FDA hadn’t approved the drug for any of those uses, he added.

‘Diamond’

Company officials said in a memo that they were “betting the farm on Zyprexa” to replace Prozac, Simmons said.

In internal memos, Lilly officials used the word “diamond” as a code for talking about their Zyprexa off-label marketing campaign, he said.

He cited notes from visits with doctors in 2000 and 2001 where sales reps reported talking about older patients being treated with Zyprexa for agitation and declining mental acuity.

Simmons noted the drug maker already pleaded guilty to a criminal charge over its off-label promotion of Zyprexa for use with elderly patients.

In that plea, Lilly officials acknowledge that the company illegally pushed the drug’s off-label use by older patients from Sept. 1, 1999, to March 31, 2001.

The company also pushed primary-care physicians to use the antipsychotic medication on children, Simmons said. One of the notes indicated salespeople said the drug is ‘for kids whose parents have to shove the pills down their throat every day.”

‘In His Tea’

Another note shows that one doctor told Lilly he was prescribing Zyprexa for a 13-year-old, whose mother “puts it in his tea.”

Besides illegally marketing its drug, South Carolina officials contend Lilly violated the state’s unfair trade practices law by mishandling Zyprexa and unjustly enriched itself at the state’s expense.

The 36-week trial included 421 outpatients with Alzheimer’s disease who were treated for delusions and aggression. The average patient age was 78 years and 56 % were female. The findings are reported in the online edition of the American Journal of Psychiatry.

Seventy-two patients had no exposure to the study drugs, while the remaining subjects were assigned to treatment with Zyprexa (generic: olanzapine), Seroquel (generic: quetiapine), and Risperdal (generic: risperidone); and they could switch antipsychotic medication during the trial.

Female subjects gained an average of 0.14 pounds per week and body mass index increased by 0.03 per week, Dr. Lon S. Schneider at the University of Southern California, Los Angeles, and associates report. Changes in weight and BMI among males were not statistically significant.

The duration of antipsychotic use by women was significantly associated with weight gain. “The prevalence of significant weight gain was 10 percent, 17 percent, and 20 percent among patients with less than 12 weeks, 12 to 24 weeks, and greater than 24 weeks of use compared to 7 percent with no use,” Schneider’s team reports.

The effect on weight was significant for olanzapine and quetiapine, but less so for risperidone. Olanzapine was also significantly associated with increased waist circumference and decreased HDL cholesterol, the “good” cholesterol.

The metabolic changes that correlated with treatment with a second-generation antipsychotic drug were of similar magnitude to those observed in younger people with schizophrenia, the team notes.

The results from a previous analysis of the CATIE-AD data indicated that the drugs did not improve patients’ function and quality of life and did not decrease their need for care.

The worsening cardiac and metabolic risks among these Alzheimer’s patients are “particularly concerning,” they add, and likely explain the increased risk of mortality seen with these drugs.

Nearly all of that prescribing has been for off-label uses. Of all the atypical antipsychotics on the market only Risperdal (generic: risperidone) has been approved by the FDA for use by children diagnosed with schizophrenia. This June, the FDA will consider a petition by AstraZeneca for permission to promote the use of Seroquel by adolescents (ages 13 to 17) with schizophrenia and younger kids (11 to 17) with bipolar disorder. As the drugs have become more widely prescribed, however, many physicians have become increasingly alarmed.

“We have optimism based, I think, on intense marketing,” says Julie M. Zito, a University of Maryland researcher who has led several studies documenting the growth of antipsychotic use in children. “We’re all searching for better drugs, all searching for magic bullets. But we all need to wake up here and be alert. The problems are real.”

In November 2008, an expert panel advising the FDA on pediatric drug safety sounded the alarm over the rising use of atypical antipsychotic drugs among kids, and faulted the FDA for failing to issue warnings.

Dr. Leon Dure, a pediatric neurologist from the University of Alabama’s School of Medicine, complained that physicians prescribing the drugs to children may not appreciate the side effects, including weight gain and movement disorders. “This committee is frustrated,” Dure said. “And we need to find a way to accommodate this concern.”

Documents ranging from unpublished study results to earlier undisclosed depositions are among more than 100 the British drug manufacturer agreed to unseal on February 26, 2009; in lawsuits brought by plaintiffs who allege they were harmed by the multibillion-dollar antipsychotic drug. Many of the cases have been consolidated in the U.S. District Court for the Middle District of Florida.

In an August 15, 2005, voicemail message addressed to company salespeople, an AstraZeneca employee named Christine Ney followed up on a “weight and diabetes sell sheet” they had recently been sent. The sales representatives should assuage doctors’ fears about their patients’ weight gains, she said in the voicemail, by telling them that data showed no causal link between diabetes and the drug.

“Our objective is to neutralize customer objections to Seroquel’s weight and diabetes profile,” Ms. Ney said, according to a transcript of the voicemail message. She then instructed representatives to “refocus the call” away from diabetes to the drug’s tolerability, the transcript shows.

The voicemail to the sales representatives raises questions about whether there was a contradiction between Ms. Ney’s instructions and an AstraZeneca drug-safety expert’s own assessment of Seroquel’s link to diabetes years earlier. In a 2000 position paper about the safety of Seroquel sent to Dutch regulatory authorities, an AstraZeneca doctor named Wayne Geller wrote that there was a relationship between the drug and diabetes.

“There is reasonable evidence to suggest that Seroquel therapy can cause impaired glucose regulation including diabetes melliutus in certain individuals,” Dr. Geller wrote.

AstraZeneca acted “responsibly and appropriately as it developed and marketed Seroquel,” company spokesman Tony Jewell says. “From the time it was first approved, the Seroquel labeling alerted physicians that diabetes mellitus, hyperglycemia and weight gain had been observed in clinical trials. We’ve continued to update the label as the findings have developed.”

Mr. Jewell says the document written by Dr. Geller doesn’t accurately reflect the company’s position in 2000. “In fact, it was not Dr. Geller’s ultimate view either. It was an initial draft for discussion purposes. After rigorous discussion of the scientific evidence, Dr. Geller and his colleagues concluded the evidence did not establish that Seroquel causes diabetes.”

Dr. Geller retracted his statement in a May 2008 deposition with plaintiffs’ attorneys. In response to a plaintiffs’ attorney’s question, Dr. Geller responded that the statement was “an artifact of an earlier discussion document.” AstraZeneca declined to make Dr. Geller and Ms. Ney, who are both still employed by the company, available for comment. Neither could be reached for comment.

AstraZeneca had argued that the documents should remain under seal because they contained proprietary information that could hurt the company if it was revealed to competitors and could harm the public if interpreted out of context. But the company agreed to make public most of the documents following negotiations with plaintiffs’ attorneys that concluded in the early hours of February 26, 2009.

“AstraZeneca believes communications from the FDA [Food and Drug Administration] to doctors is the appropriate way to notify patients and the public about a medicine’s benefits and risks, not a court proceeding,” Mr. Jewell says.

Makers of antipsychotic drugs have come under intense scrutiny over whether they knew early on that the powerful psychiatric medicines which are used to treat schizophrenia and bipolar disorder caused serious side effects such as diabetes. Most of the drugs were approved for sale in the 1990s, but their side effects didn’t become widely known until earlier this decade. The drug makers have also been accused of marketing the drugs outside of their approved indications, which is against U.S. law.

Internal company documents proved damaging to Eli Lilly & Co., which agreed to pay $1.4 billion to settle off-label promotion claims last month with the U.S. attorney for the Eastern District of Pennsylvania. Company e-mails and memos leaked in 2006 showed that Lilly played down the health risks of its antipsychotic drug, Zyprexa.

In 2007, Bristol-Myers Squibb Co. agreed to pay $515 million to settle another federal investigation over its marketing practices for its antipsychotic drug, Abilify.

AstraZeneca faces more than 9,000 lawsuits from patients who allege they have been harmed by Seroquel. Most of the cases have been consolidated into one group being heard in the Florida federal court. The first two of these cases, considered bellwethers that would have helped predict the outcomes of the remaining lawsuits, were supposed to have been tried earlier this month, but the judge dismissed them on the grounds that the evidence failed to prove that Seroquel had caused their diabetes.

More than 2,300 other cases have also been dismissed. A separate tranche of state cases is also working its way through the courts, with the first set to go to trial in Delaware, where AstraZeneca has its U.S. headquarters. The company says it will defend itself vigorously against the suits.

Pennsylvania, Montana, Arkansas and South Carolina have all sued AstraZeneca, alleging that they were bilked into paying for the medicine for off-label usage and seeking reimbursement for alleged injuries sustained by individuals as a result of the drug. AstraZeneca acknowledges that the U.S. attorney for the Eastern District of Pennsylvania, Laurie Magid, is investigating Seroquel but wouldn’t say when the investigation started or what it involves. A spokeswoman for Ms. Magid declined to comment.

When Seroquel was approved in 1997, it contained information in the “adverse reactions” section of the product label concerning diabetes, hyperglycemia and weight gain that had been observed in clinical trials, says Mr. Jewell. In 2003, the FDA mandated a stricter precaution, upgrading the diabetes risk to the label’s “warnings” section -even though the agency said at the time that it wasn’t certain that a causal relationship existed.

Last month Seroquel’s label was updated to include data on children and adolescents, including blood-glucose levels, cholesterol, weight gain and increased appetite. It also voluntarily agreed to move information about increased blood sugar to the “warnings” section of the label, according to a company lawyer’s testimony in court .

Among the unsealed documents, another set goes back to the late 1990s and raises further questions about whether AstraZeneca kept a lid on unflattering Seroquel studies.

A document dated Feb. 12, 1997, describes internal company deliberations over how to report “Study 15,” a study comparing Seroquel to Haldol, an older-generation psychiatric drug. In the document, an AstraZeneca employee named Richard Lawrence writes to his team that one of his colleagues had done a great “smoke and mirrors job,” and another had suggested an approach that “should minimize (and dare I venture to suggest) could put a positive spin (in terms of safety) on this cursed study.”

It isn’t clear what Mr. Lawrence’s comments were referring to. He couldn’t be reached, and AstraZeneca declined to discuss the emails.

In a series of emails in 1999, AstraZeneca executives discuss withholding the results of another Seroquel study, known as COSTAR. That study compared Seroquel to Risperdal, another antipsychotic drug made by Johnson & Johnson.

On Dec. 6, 1999, an AstraZeneca employee named John Tumas, the publications manager for Seroquel, wrote to his colleagues, “There is growing pressure from outside the industry to provide access to all data resulting from clinical trials conducted by industry. Thus far, we have buried” certain studies. Referring to COSTAR, he added: “We must find a way to diminish the negative findings. But in my opinion we cannot hide them.”

Mr. Tumas couldn’t be reached late Thursday. AstraZeneca’s Mr. Jewell declined to comment about the 1990s e-mails and documents other than to note that the FDA “vetted and substantiated the safety data for Seroquel,” including the data from both Study 15 and COSTAR. “The FDA has approved the medicine as a safe and effective treatment for schizophrenia and bipolar disorder,” he says.

The drug maker’s settling lawsuits brought by the Justice Department and the U.S. Attorney for the Eastern District of Pennsylvania over past marketing and promotions of Zyprexa, its top-selling drug. Eli Lilly (LLY) has agreed to plead guilty to one misdemeanor violation of the Food, Drug and Cosmetic Act.

The Justice Department pegged the size of the fine that the company’s paying at $515 million, saying it was the largest individual corporate criminal fine in history. Some $800 million will be used to settle civil charges, with $432 million going to the federal government and up to $362 million to individual states.

There had been worries that a felony conviction would put Eli Lilly’s Medicare business at risk.

While it’s not illegal for doctors to prescribe medications for uses that the FDA has not specifically approved -so-called “off- label” uses it is illegal for companies to market drugs for those purposes.

“Off-label promotion of pharmaceutical drugs is a serious crime because it undermines the FDA’s role in protecting the American public by determining that a drug is safe and effective for a particular use before it is marketed,” said Gregory Katsas, the assistant attorney general for the Justice Department’s civil division.

Eli Lilly took a charge of nearly $1.42 billion, or $1.29 a share, against results for the third quarter of 2008 in connection with this investigation. The company is finalizing the tax treatment.

“We deeply regret the past actions covered by the misdemeanor plea,” said John Lechleiter, chairman, president and chief executive of Eli Lilly.

Terms of the settlement also stipulate that Eli Lilly enter a “corporate integrity agreement” with the inspector general of the Department of Health and Human Services. It provides for an independent third-party review organization to assess and report on the company’s systems, processes, policies, procedures and practices.

Zyprexa brought in more than $37 billion in sales for Eli Lilly since its U.S. approval in 1996, according to calculations made by The Wall Street Journal.

The findings, which run contrary to a long-standing belief, add to a growing drumbeat of criticism about this class of drugs, known as atypical antipsychotics. Zyprexa, Risperdal and Seroquel are among the 10 most commonly prescribed medications in the world, with annual sales estimated at $14.5 billion.

Researchers are especially concerned about the rising use of atypical antipsychotics in the elderly and the young both groups that are fragile and more susceptible to adverse effects of powerful medications.

Last week British researchers reported in the journal Lancet Neurology that Alzheimer’s patients given the drugs to control aggression were nearly twice as likely to die from any cause as patients who did not receive them.

Some studies have shown that as many as 40% of Alzheimer’s patients in nursing homes receive the drugs for unapproved use. The number of prescriptions for the drugs written for children and adolescents doubled to 4.4 million from 2003 to 2006, in part because of increases in diagnoses of bipolar disorder. Their efficacy in children and Alzheimer’s patients has never been demonstrated, experts said.

Eli Lilly & Co., the manufacturer of Zyprexa, settled a lawsuit with the federal government on January 15, 2009, paying a record $1.4 billion in civil and criminal charges to resolve complaints about the marketing of Zyprexa for unapproved uses. The company has already paid nearly $1.3 billion to states and consumers to settle other complaints about marketing and side effects.

“I am, and have been, very concerned about these drugs,” said Dr. Ian Cook, a psychiatrist at UCLA’s Geffen School of Medicine who was not involved in the new study. “These are powerful medications that affect the brain and the body, and we need to be very thoughtful in their use.”

No one, however, is urging abandonment of the atypical antipsychotics. The nub of the matter is that there are no other drugs with the same beneficial effects.

“The antipsychotics are a godsend,” said Dr. Alan Manevitz, a psychiatrist at Lenox Hill Hospital in New York who was not involved in the study. “They have taken people and unchained them from walls. We don’t want to throw out the baby with the bathwater.”

The drugs are approved only for treatment of schizophrenia and bipolar disorder in the general population. But their use has been expanding to treat aggression in young people and dementia in the elderly.

“We use them because they are somewhat useful in some patients and because we have no alternative,” said Dr. Dilip V. Jeste of UC San Diego.

Researchers already knew that atypical antipsychotics could produce excessive weight gain, increase the risk of diabetes and induce strokes and heart problems in the elderly. The Food and Drug Administration requires both conventional and atypical antipsychotics to carry a so-called black-box warning the strongest warning possible informing patients and physicians that the drugs are associated with increased risk of death in elderly patients treated for dementia.

In their federally funded study, published in the New England Journal of Medicine, the researchers analyzed Tennessee Medicaid records for the 15 years ending in 2005. They identified 44,000 users of conventional antipsychotics and 46,000 of atypical antipsychotics. They compared them with 186,600 matched patients taking neither.

The scientists found that patients taking either type of drug were about twice as likely to die of a heart attack as those not taking the drugs, with the risk of death increasing with dose and the length of time on the medication. There were about 3.3 excess deaths per year for every 1,000 patients taking the drugs.

The prescribing of drugs “is a balancing of risks and benefits. Our study gives more information on the risk side of things,” said study leader Dr. Wayne A. Ray of the Vanderbilt University School of Medicine.

Conventional antipsychotics, such as haloperidol (Haldol) and chlorpromazine (Thorazine), were stumbled on by chance in the 1950s and were found to have a powerful calming effect on psychotic patients, but also a number of side effects. Among the most disturbing was tardive dyskinesia, characterized by tremors and other movement disorders that are often irreversible.

The atypical antipsychotics, which also include Clozaril, Geodon and Abilify, were designed to avoid tardive dyskinesia, which is why they were perceived as safer, Ray said. “Today, nearly all people taking antipsychotics are taking the atypical ones,” he said.

In an editorial accompanying the paper, Dr. Sebastian Schneeweiss and Dr. Jerry Avorn of Brigham and Women’s Hospital in Boston argue that the danger can be mitigated by assessing patients’ cardiovascular risk before treatment and after a month on the drugs. Patients with a heightened risk could be counseled on ways to lower it, such as modifications of diet and exercise.