About a year ago, patients began marching 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 “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.
Recently, 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 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 cited safety concerns about its 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 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 modest.
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.
The concerns expressed by the FDA 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 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 children 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.
Last year, 50 million prescriptions for antipsychotics, mostly the new ones, were filled in the U.S. – a 5 percent rise in one year alone.
In the process, the spreading use of these costly drugs is raising 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 adviser for FDA panels.
Studies point to a “very questionable balance between efficacy and safety” for atypical antipsychotics, 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.”
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.
The first-generation antipsychotics could be highly effective at taming hallucinations and delusions. But some studies indicated that as many as 1 in 5 people 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, but a landmark 2005 study concluded that they have brought marginal improvements at much greater expense than traditional antipsychotics in their primary use of treating schizophrenia.
In 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.
Many forces 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.
“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 antidepressants) 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 have schizophrenia (2.4 million adults) and bipolar disorder (5.6 million adults). About 6.8 million adults have 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.
“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.”
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 individual physicians from legally writing “off-label” prescriptions for purposes other than those approved by the agency.
Yale’s Rosenheck estimates roughly 60 percent of prescriptions for atypical antipsychotics have been written off-label, based on the doctors’ judgment.
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 of any cause.
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.
Concern also is growing about use of the newer drugs to treat young patients.
Between 1990 and 2000, prescriptions of atypical antipsychotics for children and adolescents grew 160 percent, according to a 2005 study; other studies show they continued to grow briskly through the early 2000s. Virtually all of that prescribing has been off-label.
Among the atypical antipsychotics, only risperidone (marketed as Risperdal) has been approved by the Food and Drug Administration for use by children diagnosed with schizophrenia.
In 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.
“We have optimism based, I think, on intense marketing,” cautions 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,” she says. “But we all need to wake up here and be alert. The problems are real.”