Too hard a sell?


About a year ago, patients began trooping into the office of UCLA psychiatrist Andrew Leuchter, asking whether an antipsychotic drug called Abilify “might be right for them.” Few appeared to be delusional, plagued by hallucinations or suffering fearsome mood swings. Mostly, they were depressed or anxious, and frustrated by the pace of their recovery.

Leuchter wondered what was up: Depressed patients didn’t usually seek out drugs used to quell psychiatry’s most disturbing symptoms.

What was up, he soon discovered, was spending on a new advertising campaign touting Abilify as an “add-on” treatment for depression. For the first time since the arrival of a new generation of antipsychotic medications -- six drugs called the “atypicals” because they work differently from the earlier generation of antipsychotic drugs -- the makers of one, Abilify, had been granted the legal right to market to a vast new population of patients beyond those with schizophrenia or bipolar disorder.


This week, a Food and Drug Administration advisory panel recommended that the agency should grant the makers of a second atypical antipsychotic drug -- Seroquel XR -- similar latitude. The drug giant AstraZeneca wants permission to market the drug as a treatment for depression or anxiety that has not yielded to antidepressants alone.

But this time, it wasn’t quite so easy a sell. The panel did say the drug was safe and effective for such purposes when used with other drugs, recommending approval for its use as an “add-on” treatment. But the panel recommended against the drug as a stand-alone treatment. And this time, the panel -- echoing an issue expressed by the FDA in convening the meeting -- cited safety concerns about the drugs’ use in a greatly expanded population of patients.

Mounting research has made clear that the atypical antipsychotics are not only less safe than originally thought; they are not, on balance, any safer or more effective than older drugs for schizophrenia. And for the population of depressed or anxious patients that some are now proposed to treat, studies suggest the benefits are extremely modest.

The accumulated findings on the larger group of drugs had prompted the FDA to ask its advisory panel whether expanding the population of patients taking Seroquel XR would be wise. Like other members of this class of drugs, Seroquel has been linked to weight gain extreme enough to cause diabetes and to an often irreversible disorder characterized by involuntary tics and jerking movements.

As for Abilify, Sonia Choi, a Bristol-Myers Squibb spokeswoman, said the company “is continually monitoring the safety of Abilify, including the metabolic data, as part of our regular practice and is committed to disclosing clinical trials results” on the medication as they become available.

The concerns expressed by the FDA and its advisory panel, many public health experts say, come too late. In less than a decade, physicians have embraced the broad use of the atypical antipsychotics to treat mental disorders far less severe than schizophrenia and bipolar disorder -- afflictions such as anxiety, sleep difficulties, depression, attention deficit disorder and autism. First prescribed almost exclusively to adults, the drugs are now often used in the treatment of adolescents and kids as young as 2.


The sales of atypical antipsychotics have skyrocketed in recent years, propelling overall sales of antipsychotic drugs past all other classes, to $14.6 billion in 2008, according to IMS Health, a private firm that tracks drug trends. In 2008, 50 million prescriptions for antipsychotics, mostly the new ones, were filled in the U.S. -- a 5% hike in one year alone.

In the process, the spreading use of these costly drugs is raising -- for the nation as well as individual patients -- the rates and the risks of weight gain, diabetes, strokes, fatal heart attacks, an array of movement disorders and potentially, suicide, according to a wide range of critics.

“This is very worrisome; frankly I have serious concerns about these drugs,” says Dr. Steven Nissen, who is chairman of the Cleveland Clinic’s cardiovascular medicine department and serves as an ad hoc advisor for FDA panels. Studies point to a “very questionable balance between efficacy and safety” for the class, he said. But that message, he said, has been lost in an apparent “marketing bonanza” for the companies that make the medications. A recent report by the consulting firm Decision Resources found the makers of the atypicals spent $993 million in 2006 to promote the drugs to doctors and patients.

That’s not to say the drugs haven’t helped people.

Leuchter, who has prescribed Abilify for some with treatment-resistant depression, says that for certain patients and in certain circumstances, it works. “These are very effective medications, and like all medications, they have side effects,” he says. But he adds: “I wouldn’t want people to think this is the first thing they should reach for when a patient doesn’t respond well to first-line antidepressants.”

Newer drugs ‘safer’

Introduced through the 1990s and early 2000s, the atypical antipsychotics -- drugs marketed as Abilify, Seroquel, Zyprexa, Geodon, Clozaril and Risperdal -- were widely hailed as superior to older schizophrenia drugs such as Thorazine and Haldol, which began to be used in the 1950s and 1960s, respectively. The first-generation antipsychotics could be highly effective at taming hallucinations and delusions. But some studies indicated that as many as 1 in 5 who took them developed involuntary tics and muscle movements called tardive dyskinesia, a condition that frequently cannot be reversed.

The newer drugs were supposed to be safer and more effective. That claim has now been roundly challenged.


A landmark 2005 study concluded that the drugs have brought marginal improvements at much greater expense than traditional antipsychotics in their primary use of treating schizophrenia. The CATIE study (for Clinical Antipsychotic Trials of Intervention Effectiveness) compared four of the atypicals -- Zyprexa, Geodon, Seroquel and Risperdal -- with the first-generation antipsychotic perphenazine (Trilafon), a drug costing on average a tenth the price of the newer drugs. It found the risk of tremors and tardive dyskinesia to be the same for all. And while all the antipsychotics are associated with weight gain, it was more frequent and more likely to be extreme among patients taking atypicals -- leading many to develop diabetes.

Last December, the British journal Lancet published a comprehensive analysis that further punctured the new drugs’ claims to superiority. A separate study found Seroquel by many measures to be no more effective in treatment of schizophrenia symptoms than Haldol. And a 2008 study on Abilify found it was little better at banishing depressive symptoms than a placebo.

“The results are extremely unimpressive,” said Dr. Daniel Carlat, a Massachusetts psychiatrist who publishes a respected monthly report on psychiatric research. “They just squeak by.”

Many forces -- chief among them medical need and commercial imperatives -- have converged to make the atypical antipsychotics the prescription drug of the moment.

Psychiatrists and patients, disappointed in the effectiveness of antidepressants, have been hungry for treatments capable of curing depression, not just easing its hold on patients. Atypical antipsychotics influence different brain chemicals than do most current-generation antidepressants; their mode of action is thought to complement the ways in which standard antidepressant drugs affect the brain, and boost their effects on mood.

“There certainly is an unmet need out there,” says UCLA’s Leuchter, who has conducted extensive research on antidepressants’ effectiveness. “Only about half the patients [on antidepressant drugs] will improve, and fewer than a third will get well with the first antidepressant they try.”


That “unmet need” represents a potentially huge business opportunity for drug firms. Each year, as many as 10 million to 12 million depressed Americans could still be seeking relief after trying an antidepressant -- many more than the number who suffer from schizophrenia (2.4 million adults) and bipolar disorder (5.6 million adults). About 6.8 million adults suffer from generalized anxiety disorder.

“The story’s pretty clear, and pretty embarrassing for the profession of psychiatry, which has allowed itself to be led by marketing,” says Robert Rosenheck, a psychiatrist at Yale University who has studied the effectiveness and expanded use of the atypical antipsychotics. “We know now what these companies’ strategies are: The number of people with schizophrenia is limited, so the road to profitability goes through soccer moms. They need to market these drugs to ordinary people who have dissatisfactions in life.”

Side effects

In the run-up of use across the nation, weight gain and metabolic changes quickly emerged as a worrisome side effect. And in August 2008, the FDA, responding to a flurry of new research, required all antipsychotics to carry the agency’s most urgent warning: The drugs’ use in geriatric patients with dementia (by then very common) would raise their risk of dying from any cause.

Recent research has darkened the drugs’ safety profile even further.

* Early this year, a Lancet Neurology study concluded that Alzheimer’s disease patients given the drug to control aggression were nearly twice as likely to die of any cause than those not given the drug.

* Another study published in August 2008 -- this one in the British Medical Journal -- concluded that taking any antipsychotic medication raises a patient’s likelihood of suffering a stroke, and added that “the risk of stroke might be higher in patients receiving atypical antipsychotics.”

* Then, in January, the New England Journal of Medicine delivered a further blow to the new class of drugs. A federally funded study compared the rate of fatal heart attacks in patients taking the newer class of antipsychotic drugs, those on the older class, and patients taking neither. Patients on any antipsychotic drug -- new or old -- were twice as likely to die of a heart attack as those not on such medications.


Although drug makers are forbidden to promote, market or advertise drugs for any indication other than those approved by the FDA, that hasn’t stopped physicians from legally writing “off-label” prescriptions. Rosenheck estimates roughly 60% of prescriptions for atypical antipsychotics have been written off-label.

In January, Eli Lilly & Co., which makes the atypical antipsychotic Zyprexa, was ordered by the Justice Department to pay more than $1.4 billion in penalties in connection with alleged illegal off-label marketing efforts. The company admitted no wrongdoing. The attorneys general of several states have sued the makers of Seroquel and Risperdal, alleging they’ve unlawfully marketed their medications to state Medicare and Medicaid agencies. The suits, still pending, allege that widespread prescribing of the drugs, encouraged by pharmaceutical companies that downplayed risks, caused harm to patients and unjustified cost to taxpayers.

One spokesperson for AstraZeneca, which makes Seroquel, says the company “fully supports the work of the FDA” in assessing the drug’s benefits and risks in the treatment of depression and anxiety.

Responding to allegations made in several states’ suits, another spokesman, Tony Jewell, said Seroquel’s detailed package insert “has always provided adequate and appropriate information and warnings based on available data.”

Currently, of all the atypical antipsychotics, only Abilify -- the drug that Leuchter’s patients began asking about -- may legally be promoted as a treatment for psychiatric conditions other than schizophrenia and bipolar disorder. In November 2007, the FDA granted permission to its maker, Bristol-Myers Squibb, to promote the drug as a treatment for depression that has failed to respond to one or more antidepressants.

The FDA’s decision on Abilify came without calling a hearing of its advisory panel on psychopharmacological drugs. In considering AstraZeneca’s petition for Seroquel’s new use, however, the FDA proceeded with greater caution, asking the committee to sift through the evidence and offer its recommendation.