The Off-Label Antipsychotic Surge

Tablets of olanzopine, an antipsychotic drug (from Wikimedia Commons)

Tablets of olanzopine, an atypical antipsychotic drug (from Wikimedia Commons)

If you watch enough football games, you might come away with the impression that today’s most profitable drugs are for erectile dysfunction, cholesterol, and allergies. But far less public attention is paid to one of the most expensive classes of drugs : the antipsychotics, drugs designed to treat certain mental disorders. From 1995 to 2006, the number of doctor visits where antipsychotics were prescribed or continued tripled from 6.2 million to 16.7 million, reflecting a nearly $10 billion chunk of the industry. What’s more, the majority of those prescriptions and dollars result from off-label uses of the drugs to treat illnesses where the clinical evidence of their effectiveness and safety is not crystal clear.

Those astonishing figures come from a new study by University of Chicago and Stanford University researchers, published earlier this month in Pharmacoepidemiology and Drug Safety. In the paper, a team led by G. Caleb Alexander, assistant professor of medicine at the University of Chicago Medical Center, used physician survey data to determine the trends and costs of antipsychotic use from 1995 to 2008. The results portray a corner of the pharmaceutical industry that has evolved at a much faster pace than regulatory agencies and the best scientific evidence can keep up with.

The history of antipsychotic medications stretches back more than 50 years to the first wave of agents, now called the “typical” antipsychotics. These drugs, with names such as haloperidol and chlorpromazine (more commonly known as Thorazine), were originally developed to treat the psychotic symptoms of schizophrenia. The typical antipsychotics led the field until the mid-1990’s, when a new class of “atypical” antipsychotics with a slightly different mechanism began to appear on the market for the treatment of schizophrenia, boasting of fewer motor side effects than the older drugs.

Despite the higher cost of atypical agents – typically 5 to 10 times that of the generic, typical agents – they quickly overtook their predecessors despite unconvincing evidence that they were safer or more effective. Though the atypical agents largely avoided the short-term dyskinesia seen with older antipsychotics, longer-term studies found effects upon weight gain and other metabolic conditions, leading to diabetes in some cases. Furthermore, when directly compared against the typical agents for treatment of symptoms such as mania in bipolar syndrome, atypical drugs were no more effective than the cheaper, older medications.

Alexander’s study shows the magnitude of that turnover: in 1995, 84 percent of antipsychotics used were from the typical group; in 2008, just 7 percent were typical therapies. Furthermore, the shift wasn’t simply a one-for-one replacement. From 2002 to 2006, the overall use of antipsychotics soared, with atypical agents leading the expansion into new uses of the drugs. Ironically, there was a return to using typical agents to treat schizophrenia over the 1995-2008 period studied, while atypical antipsychotics became popular for the treatment of bipolar disorder, depression, and other disorders that were beyond the scope of the original FDA approval.

“We saw remarkable changes over time,” Alexander said. “We know from other prescription drugs that uses change or evolve over time, and one reason is clinical innovation, but there’s also substantial over-use and over-adoption of therapies beyond the evidence base.”

That phenomenon was reflected in the study’s findings about off-label uses of antipsychotics. In 1995, nearly three-quarters of all doctor visits involving antipsychotics were for uses other than those indicated by the FDA, even when the 2008 criteria were retroactively applied to the data. That percentage had declined to 60% by 2008, but given that overall use of antipsychotics more than doubled in that time period, the absolute amount of off-label use was still on the rise. It also makes for a big finish to the study: since the overall market for antipsychotics in 2008 was $10 billion, off-label uses accounted for approximately $6 billion of medical costs in the United States.

“It’s a lot of money, particularly if it wasn’t well spent. That’s what we’re trying to emphasize, that we simply don’t have the evidence for a lot of these uses,” Alexander said. “It’s a lot of money for state Medicaid societies struggling to manage prescription benefits, and a lot to the mentally ill, who represent a vulnerable and often economically disadvantaged population.”

Unfortunately, there’s also no simple answer for reforming this practice, Alexander said. Some backlash has already occurred, with four drug companies paying out massive settlements for illegally marketing their antipsychotics. Further remedies might include improved patient and physician education, reforming regulatory policy to put more emphasis on developing higher quality evidence at the time of drug approval, and making changes in payment and reimbursement schemes, with public and private payers declining to pay for drugs that don’t work.

“There’s almost a reflexive tendency to equate newer with better that has to be countered, that has to be resisted,” Alexander said. “We shouldn’t paying for drugs that don’t work, or drug uses that don’t have good evidence to support them.”

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Alexander GC, Gallagher SA, Mascola A, Moloney RM, & Stafford RS (2011). Increasing off-label use of antipsychotic medications in the United States, 1995-2008. Pharmacoepidemiology and drug safety PMID: 21218418

About Rob Mitchum (526 Articles)

Rob Mitchum is communications manager at the Computation Institute, a joint initiative between The University of Chicago and Argonne National Laboratory.

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