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."
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.