PHARMA: The Industry Veteran on Polypharmacy in Psychiatry

Yesterday’s WSJ had an article on the increasing use of polypharmacy in psychiatric treatment of bi-polar disorder, depression and schizophrenia. It’s controversial because there have been no clinical trials to prove its value, and due to the nature of those conditions it can be hard to measure outcomes which in any case may vary dramatically between different patients. As the article is behind a firewall I’m going to quote somewhat liberally from it:

Psychiatrists are increasingly crafting drug cocktails of multiple medicines to treat depression, bipolar disorder and schizophrenia. The approach, called polypharmacy," aims to help people who don’t respond to a single drug by putting them on several drugs that target different brain chemicals. The approach — driven in part by the shortcomings of many available medications — is psychiatry’s answer to HIV/AIDS drug cocktails and combinations of cancer drugs. But there are some key differences. Unlike HIV and cancer — whose underlying cell biology is fairly well understood and that have been the subject of clinical trials involving drug combinations — the causes of mental illness remain largely a mystery. Little research has been done about how to administer polypharmacy or whether it even works in some cases. Multiple drugs also mean multiple side effects — and multiple prescription bills. Doctors arrive at the right mix by tinkering with a sequence of different drugs based on past experiences, word of mouth and drug-company marketing that informs them about the strengths and weaknesses of each drug.


Some psychiatrists question whether more drugs are necessarily better. Gabor Keitner, professor of Psychiatry and Human Behavior at Brown University in Providence, R.I., thinks polypharmacy has gone too far. Patients are plied for years with a dizzying sequence of drugs that have side effects ranging from insomnia to lack of libido to weight gain. "I think we are overmedicating people," he says. Dr. Keitner, who directs the inpatient mood-disorder clinic at Rhode Island Hospital, also worries that patients are getting the false hope that some magic combination of drugs will cure them. It may be better, Dr. Keitner says, to teach patients how to manage their conditions and emphasize continuing therapy. "This is leading us down a path that may not be good for patients or the profession," he says.

Still, for many, the cocktails provide long sought-after relief. Noreen Fraser, a 50-year-old mother of two from Los Angeles, was treated for depression with multiple drugs during her three-year battle with breast cancer. The powerful cancer drugs she took abruptly halted her body’s production of estrogen, sending the normally animated television producer into a deep depression. "I couldn’t even help my children with their homework," Ms. Fraser said. Her psychiatrist, Andy Leuchter of the UCLA Neuropsychiatric Institute, tried combining two antidepressants. That worked only for a while. Then last fall, Dr. Leuchter added a low dose of the antipsychotic medication, Zyprexa, into the mix. Within two days, Ms. Fraser felt better than she had in years. "It was like a cloud lifted," she said.


Using multiple drugs to treat mental illnesses has become controversial partly because of the cost involved — especially with schizophrenia. The standard therapy for schizophrenia today is the use of "atypical" antipsychotics, which have milder side effects than older drugs, but are relatively expensive. A month’s worth of Bristol-Myers Squibb Co.’s atypical antipsychotic Abilify, for instance, costs $352 whereas generic clozapine, an older drug, costs $152. If a schizophrenic patient doesn’t improve on one drug alone, doctors may add another atypical antipsychotic or one of the older "typical" drugs. In some states, public-health programs have balked at paying for combinations of psychiatric drugs without evidence that the treatment actually works.

Insight on how to use combinations of drugs to treat resistant cases of depression may be provided by a large government-funded trial just completed that tested various prescribing strategies. But results of the trial, conducted with 4,000 depressed people in 13 states, aren’t expected until May 2005.

Given his moderate and understated views on the medical profession and its relationship with pharma manufacturers, regular THCB readers may be surprised to know that Industry Veteran has his suspicions about the science and the marketing behind the new polypharmacy.

    1. The cocktail approach to therapy represents an emerging paradigm in psychiatry that a growing number of clinicians do not reserve as merely a last measure. At a recent meeting of the American Psychiatric Association, a clinical investigator gave me a synopsis of his thinking. "In neuropsychiatry," he explained, "since anything can cause anything, it’s wise to use everything for everything." In other words, throw as much s- – – on the wall as you can and see what sticks.
    2. Advocates of early cocktailing not only lack an understanding of the pharmacological basis for their polypharmacy regimens, some even disparage such basic science and consider it an after-thought or a fig leaf. At various times, cocktailing exponents have told me that medical science need not advance "in textbook fashion" by moving from basic scientific understanding to clinical applications. If a drug or a drug combination appears to offer clinical benefit, according to this worldview, then the bench science guys can retrofit a mechanism to provide a soothing rationale for the clinicians.
    3. More than a few colleagues have whispered to me their opinions that the cocktail approach in psychiatry represents a combined effort by psychiatrists and drug companies to grow their businesses. Entrepreneurial psychiatrists, frustrated by limited reimbursements and a median income that lags behind most of other specialties, promote cocktailing to create a niche for themselves as "medication specialists" (they actually use that term on their business cards). The drug companies subsidize this effort as a means of developing new, frequently off-label markets for their products.

It’s doubtlessly true that some desperate souls have received substantial benefits from psychiatric drug cocktails after failing to obtain relief from more conventional therapies. I am always suspicious, however, when bald-faced greed concocts a new therapy in an environment where no one guards the guardians.

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  1. Complex drug cocktails might be justified if they evovle slowly-one drug at a time and with adequate interludes to assess the efficacy of the preceding medication regimen. Does anyone think this is happening on inpatient services with short lengths of stay and pressure to stabilize patients rapidly? Lets not kid ourselves we are overmedicating patients, increasing the probability of iatrogenic harm, nonadherence and grossly diminishing our capacity to figure out what is causing what. Reform in practice and education are needed. Is our field ready to accept this?