Mental Health Association of Portland

By Joe Rojas-Burke, The Oregonian, Friday, March 23, 2012

(Jamie Francis / The Oregonian)

Published reports on the new drug Fanapt gave it high marks.

One medical journal emphasized its “comparable efficacy” to other drugs used to treat schizophrenia, and prominently noted a lower risk of certain side effects.

There was no mention that competing drugs outperformed it in three of the first clinical trials, or that in one trial a placebo worked just as well. The Journal of Clinical Psychopharmacology‘s summary also made no mention of Fanapt’s tendency to disturb the heart’s electrical activity and increase risk of cardiac arrest.

The one-sided reporting, uncovered by researchers in Oregon, adds to growing evidence that medical journals paint an overly rosy picture of new drugs. The analysis, published this week in PLoS Medicine, found that many unfavorable results on psychiatric drugs never appeared in the articles doctors rely on to learn about trial results.

“It’s unsettling,” says lead author Dr. Erick Turner, a former drug reviewer for the federal Food and Drug Administration and now at the Portland Veteran Affairs Medical Center and Oregon Health & Science University.

The findings do not imply the drugs don’t work. But rather, doctors and consumers don’t get a full, nuanced picture about drugs and can’t make the best decisions without all the facts about safety and effectiveness.

The bias toward publishing positive results is a widespread problem for drug treatments of all kinds.

Trials with favorable outcomes were nearly five times more likely to be published than those without, researchers at the University of California San Francisco found in 2008 when they examined all the new drugs approved by the U.S. Food and Drug Administration in a two-year period. Medical journals frequently reported conclusions more favorable than those in reviews by the FDA.

“And that’s only focusing on half the picture,” says Lisa Bero, the UC professor who led the study. “The other half of that equation is safety. How much information about harm remains unpublished?”

Turner and co-authors obtained 24 clinical trials submitted to the FDA by drug companies seeking approval for eight second-generation anti-psychotic drugs: Abilify, Fanapt, Zyprexa, Invega, Seroquel, Risperdal, Consta, Geodon. The Oregon researchers compared the FDA data – some obtained only after a request under the Freedom of Information Act – with medical journal articles.

Four studies submitted to the FDA were never published. All yielded negative results. In three, the newer anti-psychotic drug worked no better than an inactive placebo. In one, the new drug proved no more effective than an older, cheaper competing drug.

Some journal articles selectively left out unflattering results. Studies showing Fanapt statistically inferior to three competing drugs were not brought up.

The lead author of the Fanapt paper, Dr. Steven Potkin of the University of California at Irvine, was traveling this week, an assistant said, and “unable to respond.”

Study authors who conduct clinical trials with funding from drug companies don’t necessarily have access to all of the data collected or the freedom to independently analyze findings, experts say. Bero, in her 2008 study, did not find any cases in which drug companies prohibited doctors from publishing trial results, but some researchers complained about foot-dragging. “It is clearly important that this should be published,” one clinical trial researcher said. “I have been and continue to be in contact with [the drug company] to see how this can be published.”

Novartis, the maker of Fanapt, in a written statement said it “is committed to transparently disclosing the results of all clinical trials, whatever their outcome, so that healthcare providers can make fully informed treatment decisions for their patients.” The company said safety and efficacy outcomes from all Novartis-sponsored Fanapt trials have been published in peer-reviewed journals or are on the FDA’s website. Novartis said studies finding Fanapt inferior to competing drugs “were not designed as head to head comparisons.”

The extent of bias in anti-psychotic studies was not as severe as Turner and colleagues found for antidepressants in a study they did in 2008. Nearly a third of the clinical trials of antidepressants by drug companies produced questionable or negative results that never appeared publicly in print.

Part of the problem rests with journal editors, who have a long history of favoring studies with positive results and rejecting those showing a treatment doesn’t work. Journals in recent years have tried to correct the bias.

To allow a more complete view of drug trial results, Congress in 2007 mandated a clinical trial database run by the National Institutes of Health. FDA spokeswoman Sandy Walsh said the agency “has initiated a number of transparency programs over the past few years to help inform the public of the agency’s activities while also preserving confidential information.”

Turner, Bero and others who have studied publication bias insist the FDA urgently needs to disclose more information — and make it easier for doctors and consumers to interpret.

“We need access to data that shows all of the outcomes,” Bero says. “Right now, the best place to get that is through regulatory agencies.”

Also see:

The Skanner: Study: Medical Journals Don’t Give Doctors Full Picture on Psychiatric Drugs

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By Sandra G. Boodman, for Kaiser Health News, March 12, 2012

This story was produced in collaboration with The Washington Post.

Adriane Fugh-Berman was stunned by the question: Two graduate students who had no symptoms of mental illness wondered if she thought they should take a powerful schizophrenia drug each had been prescribed to treat insomnia.

(Illustration by Richard Borge)

“It’s a total outrage,” said Fugh-Berman, a physician who is an associate professor of pharmacology at Georgetown University. “These kids needed some basic sleep [advice], like reducing their intake of caffeine and alcohol, not a highly sedating drug.”

Those Georgetown students exemplify a trend that alarms medical experts, policymakers and patient advocates: the skyrocketing increase in the off-label use of an expensive class of drugs called atypical antipsychotics. Until the past decade these 11 drugs, most approved in the 1990s, had been reserved for the approximately 3 percent of Americans with the most disabling mental illnesses, chiefly schizophrenia and bipolar disorder; more recently a few have been approved to treat severe depression.

But these days atypical antipsychotics — the most popular are Seroquel, Zyprexa and Abilify — are being prescribed by psychiatrists and primary-care doctors to treat a panoply of conditions for which they have not been approved, including anxiety, attention-deficit disorder, sleep difficulties, behavioral problems in toddlers and dementia. These new drugs account for more than 90 percent of the market and have eclipsed an older generation of antipsychotics. Two recent reports found that children and adolescents in foster care, some less than a year old, are taking more psychotropic drugs than other children, including those with the severest forms of mental illness.

In 2010 antipsychotic drugs racked up more than $16 billion in sales, according to IMS Health, a firm that tracks drug trends for the health-care industry. For the past three years they have ranked near or at the top of the best-selling classes of drugs, outstripping antidepressants and sometimes cholesterol medicines. A study published last year found that off-label antipsychotic prescriptions doubled between 1995 and 2008, from 4.4 million to 9 million. And a recent report by pharmacy benefits manager Medco estimated that the prevalence of the drugs’ use among adults ballooned more than 169 percent between 2001 and 2010.

Critics say the popularity of atypical antipsychotics reflects a combination of hype that the expensive medicines, which can cost $500 per month, are safer than the earlier generation of drugs; hope that they will work for a variety of ailments when other treatments have not; and aggressive marketing by drug companies to doctors and patients.

“Antipsychotics are overused, overpriced and oversold,” said Allen Frances, former chair of psychiatry at Duke University School of Medicine, who headed the task force that wrote the DSM-IV, psychiatry’s diagnostic bible. While judicious off-label use may be appropriate for those who have not responded to other treatments for, say, severe obsessive-compulsive disorder, Frances said the drugs, which are designed to calm patients and to moderate the hallucinations and delusions of psychosis, are being used “promiscuously, recklessly,” often to control behavior and with little regard for their serious side effects. These include major, rapid weight gain — 40 pounds is not uncommon — Type 2 diabetes, breast development in boys, irreversible facial tics and, among the elderly, an increased risk of death.

The Latest Fad?

Doctors are allowed to prescribe drugs for unapproved uses, but companies are forbidden to promote them for such purposes. In the past few years major drugmakers have paid more than $2 billion to settle lawsuits brought by states and the federal government alleging illegal marketing; some cases are still being litigated, as are thousands of claims by patients. In 2009 Eli Lilly and Co. paid the federal government a record $1.4 billion to settle charges that it illegally marketed Zyprexa through, among other things, a “5 at 5 campaign” that urged nursing homes to administer 5 milligrams of the drug at 5 p.m. to induce sleep.

Wayne Blackmon, a psychiatrist and lawyer who teaches at George Washington University Law School, said he commonly sees patients taking more than one antipsychotic, which raises the risk of side effects. Blackmon regards them as the “drugs du jour,” too often prescribed for “problems of living. Somehow doctors have gotten it into their heads that this is an acceptable use.” Physicians, he said, have a financial incentive to prescribe drugs, widely regarded as a much quicker fix than a time-intensive evaluation and nondrug treatments such as behavior therapy, which might not be covered by insurance.

In a series in the New York Review of Books last year, Marcia Angell, former editor in chief of the New England Journal of Medicine, argued that the apparent “raging epidemic of mental illness” partly reflects diagnosis creep: the expansion of the elastic boundaries that define mental illnesses to include more people, which enlarges the market for psychiatric drugs.

“You can’t push a drug if people don’t think they have a disease,” said Fugh-Berman, who directs PharmedOut, a Georgetown program that educates doctors about drug marketing and promotion. “How do you normalize the use of antipsychotics? By using key opinion leaders to emphasize their use and through CMEs (continuing medical education) and ghost-written articles in medical journals,” which, she said “affect the whole information stream.”

James H. Scully Jr., medical director of the American Psychiatric Association, sees the situation differently. He agrees that misuse of the drugs is a problem and says that off-label prescribing should be based on some evidence of effectiveness. But Scully suggests that a key factor driving use of the drugs, in addition to “intense marketing and some effectiveness,” is the growing number of non-psychiatrists prescribing them. Many lack the expertise and experience necessary to properly diagnose and treat mental health problems, he said.

Among psychiatrists, use of antipsychotics is rooted in a desire to heal, according to Scully. “All of the meds we use have their limits. If you’re trying to help somebody, you think, ‘What else might I be able to do for them?’”

Since 2005, antipsychotics have carried a black-box warning, the strongest possible, cautioning against their use in elderly patients with dementia, because the drugs increase the risk of death. In 2008 the Food and Drug Administration reiterated its earlier warning, noting that “antipsychotics are not indicated for the treatment of dementia-related psychosis.” But experts say such use remains widespread.

In one Northern California nursing home in 2006 and 2007, 22 residents, many suffering from dementia, were given antipsychotics for the convenience of the staff or because the residents refused to go to the dining room. In some cases the drugs were forcibly injected, state officials said. Three residents died.

A 2011 report by the Inspector General of the Department of Health and Human Services found that in a six-month period in 2007, 14 percent of nursing home residents were given antipsychotics. In one case a patient with an undetected urinary-tract infection was given the drugs to control agitation.

“The primary reason is that there’s not enough staff,” said Toby S. Edelman, senior policy attorney for the Center for Medicare Advocacy, a Washington-based nonprofit group, who recently testified about the problem before the Senate Special Committee on Aging. “If you can’t tie people up, you give ‘em a drug” she said, referring to restrictions on the use of physical restraints in nursing homes.

Drugs At 18 Months

Nursing home residents aren’t the only ones gobbling antipsychotics.

Mark E. Helm, a Little Rock pediatrician who was a medical director of Arkansas’s Medicaid evidence-based prescription drug program from 2004 to 2010, said he had seen 18-month-olds being given potent antipsychotic drugs for bipolar disorder, an illness he said rarely develops before adolescence. Antipsychotics, which he characterized as the fastest-growing and most expensive class of drugs covered by the state’s Medicaid program, were typically prescribed to children to control disruptive behavior, which often stemmed from their impoverished, chaotic or dysfunctional families, Helm said. “Sedation is the key reason these meds get used,” he observed.

More than any other factor, experts agree, the explosive growth in the diagnosis of pediatric bipolar disorder has fueled antipsychotic use among children. Between 1994 and 2003, reported diagnoses increased 40-fold, from about 20,000 to approximately 800,000, according to Columbia University researchers.

That diagnosis, popularized by several prominent child psychiatrists in Boston who claimed that extreme irritability, inattention and mood swings were actually pediatric bipolar disorder that can occur before age 2, has undergone a reevaluation in recent years. The reasons include the highly publicized death of a 4-year-old girl in Massachusetts, who along with her two young siblings had been taking a cocktail of powerful drugs for several years to treat bipolar disorder; the revelation of more than $1 million in unreported drug company payments to the leading proponent of the diagnosis; and growing doubts about its validity.

Helm said that antipsychotics, which he believes have become more socially acceptable, serve another purpose: as a gateway to mental health services. “To get a child qualified for SSI disability, it is helpful to have a child on a medicine,” he said, referring to the federal program that assists families of children who are disabled by illness.

Ask Your Doctor

Psychiatrist David J. Muzina, a national practice leader at pharmacy benefits manager Medco, said he believes direct-to-consumer advertising has helped fuel rising use of the drugs. As former director of the mood disorders center at the Cleveland Clinic, he encountered patients who asked for antipsychotics by name, citing a TV commercial or print ad.

Some states are attempting to rein in their use and cut escalating costs. Texas has announced it will not allow a child younger than 3 to receive antipsychotics without authorization from the state. Arkansas now requires parents to give informed consent before a child receives an anti-psychotic drug. The federal Centers for Medicare and Medicaid Services announced it is summoning state officials to a meeting this summer to address the use of antipsychotics in foster care. And Sens. Herb Kohl (D-Wis.) and Charles E. Grassley (R-Iowa) introduced legislation that would require doctors who prescribe antipsychotics off-label to nursing home patients to complete forms certifying that they are appropriate.

Medco is asking doctors to document that they have performed diabetes tests in patients taking the drugs. “Our intention here is to get doctors to reexamine prescriptions,” Muzina said.

“In the short term, I don’t see a change in this trend unless external forces intervene.”

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By Nick Budnick, The Oregonian, Friday, March 02, 2012

Psychiatrist Curt Sturos tends to troubled kids in southern Oregon and considers himself part of a growing awareness that mental health drugs may be overused.

So it was a surprise to find himself exhibit A in a recent letter from a powerful U.S. Senator, demanding to know what Oregon is doing to crack down on doctors who overprescribe.

State Medicaid records show Sturos authorized more of the mental health drug Abilify for the last three years than any other Oregon doctor. A letter to the Oregon Health Authority from Sen. Chuck Grassley, R-Iowa, who wants to curb Medicaid spending nationwide, called the rate “shocking.”

While Sturos calls the letter unfair, and an Oregon Health Authority review found nothing wrong, his situation shows how psychiatrists and other doctors face increasing scrutiny of their prescribing, particularly when it comes to children. Yet doctors in Oregon say the state lacks options beyond drugs to treat severely troubled children.

Ajit Jetmalani, M.D.

Young brains are considered more vulnerable and few drug safety studies exist due to ethical concerns about testing children, said Dr. Ajit Jetmalani, director of the Oregon Health & Science University’s Child Psychiatry Program. He also believes the mental health system needs more non-drug alternatives.

“If we’re all expecting medical providers to write prescriptions – and are not willing to invest in alternatives – then we’re going to get more prescriptions,” he said. “I think that is a duty of medical providers to push back.”

Pushing Begins

Earlier this week, the American Academy of Child and Adolescent Psychiatry issued cautious new prescribing guidelines for child welfare agencies. And a December federal report found that foster kids in five states, including Oregon, were more likely to be prescribed psychiatric medication — including at levels not considered safe.

Sturos cares for 250-300 People — about 200 are children or teens, he said. Many are foster kids and autistic with significant behavioral problems. He favors Abilify, a drug the Food and Drug Administration has approved for children 10 and above with bipolar disorder and other mental health conditions, because of fewer side effects than comparable drugs, including less weight gain.

In 2009, Sturos wrote 1,104 prescriptions costing Oregon’s Medicaid program $457,335, nearly twice the next highest prescriber, records show. In 2010 he wrote more than 1,000 compared to 666 for No. 2. In 2011, his total grew to 1,243 prescriptions, though Sturos says some of these were written to help a colleague in training.

“On a weekly basis I am working with our teams to try to provide the best access to non-medication treatments for kids with various conditions such as depression, schizophrenia, PTSD, bipolar disorder,” he said.

Prompted by Grassley’s letter – versions of which went to other states – the Oregon Health Authority in January reviewed Sturos’ numbers. “We do not feel this doctor’s prescribing practices are out of line,” wrote Tom Burns, director of pharmaceutical programs for the Oregon Health Authority, in a Feb. 9 reply.

Little Tested

Last year, Harvard researchers evaluating the scientific evidence for long-term use of Abilify for bipolar disorder essentially found only one clinical trial met scientific standards but a design flaw may have made the drug appear more effective.

“Frankly, I think it’s an embarrassment to the profession that (Abilify) has been accepted so uncritically for this indication,” one of the professors told CNN.

Terry Lee, an instructor at the University of Washington, treats kids in the state’s foster care and the juvenile justice systems. He often weans his less-troubled kids off Abilify and other medications, finding psychotherapy, anger management and social skills training is what’s needed. “They lose weight, they report feeling more alert, more awake and less sedated,” he said.

Similarly, psychologist Peter Sprengelmeyer says children often improve with scaled-back medications.

“I think sometimes what we’re doing is medicating for a chaotic environment,” says Sprengelmeyer, who heads OSLC Community Programs, a Eugene nonprofit that provides mental health care to kids in foster homes and the juvenile justice system.

Other states do more than Oregon to oversee prescribing to kids, experts say.

In Illinois, for instance, youths in foster care or state custody receive an independent medication review by a state psychiatrist, and the drugs’ effects are tracked over time, says Dr. Michael Naylor, who heads the program. He says medication should be only part of treatment — but qualified people to provide psychotherapy for kids are hard to find.

Jetmalani of OHSU says good things are happening in Oregon, including a new hotline to help primary care physicians make better prescribing decisions for children. And state health reform could result in a better, team-based approach to children’s mental health.

Meanwhile, though Sturos was supported by the state, his prescribing practices are now being reviewed by Jefferson Behavioral Health, which manages prescribing practices for Jackson County and several others. Sturos says it’s good to ask questions, and he has nothing to hide.

“If Senator Grassley or any state officials wish to come and look at the details of what we’re doing I’d be happy to show them,” he says.

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