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How a risky psychiatric medication became America’s highest-grossing drug.

Photos by Sean Drews.

Photos by Sean Drews.

In 1999, four leading mental health experts published a book, Breakthroughs in Antipsychotic Medications, intended as a guide for doctors, patients and families. Its red and yellow cover depicts a sun rising at the end of a long highway. On the dedication page, Ronald Diamond, M.D., a professor of psychiatry at the University of Wisconsin-Madison, writes alongside his colleagues, “To my parents … who always knew I would eventually write a book.”

On an early page, there’s an image of a key chain with the words “The Keys to Recovery,” followed by this: “Imagine you’re locked in a room with no windows and only one door. You have a ring of keys … That’s how it is with mental illness. The illness locks you in … The only way out is to try every key. Don’t give up if the first medication doesn’t work … There are other medications to try. Medications are the keys to recovery.”

Diamond, still a psychiatrist practicing in Madison, and still a professor at the university, is less than thrilled to look back on Breakthroughs today. In fact, he says, it “oversold” the benefits of the so-called “breakthrough” medications – newer “atypical” antipsychotics such as Seroquel, Zyprexa and Risperdal – all of which are believed to function differently than the older “typical” antipsychotics, including Thorazine and Haldol.

“They’ve been less of a breakthrough than we had hoped for,” he says, in improving the lives of patients who once took the first wave of side effect-heavy antipsychotics. But before Diamond’s skepticism set in, he worked as a paid speaker presenting to colleagues about the new antipsychotic Abilify, which has promoted itself as a kinder and gentler medication set to usher in a new era of safety. Whereas Seroquel, Zyprexa and most second-wave antipsychotics are heavily sedating, Abilify is not. To some, it’s even stimulating.

And its sales have been remarkable. First designed to treat schizophrenia and other psychotic disorders (wherein people may experience hallucinations and powerful delusions), Abilify is now being prescribed for nearly every major mental disorder, especially depression, an illness believed to affect about 7 percent of the U.S. population each year. Between April 2013 and March 2014, Abilify racked up about $6.9 billion in U.S. sales, more than any other prescription drug in the country and enough to eclipse highly lucrative drugs for heartburn, arthritis and high cholesterol. The nearest other psychiatric drug was the antidepressant Cymbalta, which ranked eighth ($4.1 billion), a last gasp before it goes generic. Abilify could go generic this spring and thus make less money for its developer, Japan’s Otsuka Pharmaceutical. But the Tokyo-based drugmaker has fought a last-minute legal offensive aimed at extending its U.S. patent rights until 2021.

Most people are familiar with the Prozac revolution – the wave of new SSRI (selective serotonin reuptake inhibitor) antidepressants that, beginning in the late 1980s, supplanted the older “tricyclic” antidepressants as the first line of depression medications, the first given to new patients before prescribing them more aggressive regimens. A quieter, but no less impactful, reshuffling of medications has centered on antipsychotic drugs, a powerful group of pharmaceuticals that carry not just the risk of temporary side effects but of permanent complications. A handful of companies have pulled off something like a marketing miracle by saturating the national market with a succession of expensive new atypicals.

Overall, they have lower rates of “movement disorders” – uncontrollable jerks, tics and muscle stiffness caused by their suppression of dopamine receptors in the brain. But atypicals also tend to be much worse for weight gain. In the case of Zyprexa, the first to be heavily marketed as a mood stabilizer and depression drug, “About two-thirds of people gain huge amounts of weight,” Diamond says, meaning 20-25 pounds in the first six months. “I’ve had people gain 100 pounds” on Zyprexa and Seroquel, another atypical with wide crossover appeal as a mood stabilizer.

Each successive atypical has attempted to outdo the last: Eli Lilly’s Zyprexa followed Johnson & Johnson’s Risperdal, and then came AstraZeneca’s Seroquel, Pfizer’s Geodon, and finally Abilify, marketed by both Otsuka and Bristol-Myers Squibb of New York. Like Geodon, Abilify doesn’t bind to histamine receptors in the nervous system and so inflicts little sedation. Most importantly, Abilify (scientific name: aripiprazole) isn’t an “antagonist” of dopamine receptors; it’s a “partial agonist” of them. This means that instead of merely suppressing them (or outright deadening them, as was the case with the older “typical” antipsychotics), it attaches to the receptors and lightly stimulates them with something like a safety release valve. In advertisements, this unique chemical structure has been promoted as a “thermostat.”

Even with its newfangled structure, Abilify still performs suspiciously like an antipsychotic when given to actual human beings. Diamond has witnessed some of these reactions among his own patients, and they’ve tempered his stance toward the drug. One woman he treats who has “very difficult” depression started on a low dose of Abilify a couple years ago as an add-on to her antidepressants, and while it makes her less suicidal, she’s developed a slight case of “tardive dyskinesia” (TD), a potentially permanent condition that causes uncontrollable movements and tremors similar to those in Parkinson’s disease. The condition “scares us both,” says Diamond, but so far, the TD has remained in a common early stage, an involuntary puckering of her lips and twitching of her tongue.

Another woman, one of a “small number” of Diamond’s patients taking Abilify for depression, has recurring major depressive episodes and takes the drug as something like a booster every couple of years to help her through. Each time, some “involuntary movements” start up in her face, he says, but she continues to take the medication anyway, knowing that each time she goes off of it, the tics might not go away.

Although popular as an “adjunctive” (add-on) treatment for depression, doctors are also prescribing Abilify for anxiety disorders, a so-called “off-label” use not specifically approved by the FDA. AstraZeneca’s Seroquel once sought such an “indication” from the FDA for treating anxiety, but it was denied.

“There was a concern that way too many people would start taking it,” Diamond says. As antipsychotics can precipitate long-term complications, doctors have historically restricted their use to the latter stages of treatment – the third and fourth lines of medication – when attempting to alleviate non-psychotic disorders such as depression.

Abilify’s great feat was in moving these lines up and surviving a legal challenge brought by the attorneys general of some 28 states, including Wisconsin. The case, which alleged illegal marketing, relied heavily on anecdotal testimony from a pair of former drug reps-turned-whistleblowers, and in March, a federal judge tossed out most of the charges.

Although the case opened a window into Abilify’s rise, to understand how an antipsychotic became something like a mainstream drug, you have to go all the way back to Prozac.

Photo by Sean Drews.

Photo by Sean Drews.

Michael Oldani, a former drug rep for Pfizer who’s now an associate professor of medical anthropology at UW-Whitewater, promoted Zoloft on the ground in Milwaukee during the early 1990s, extolling to doctors the new SSRI’s benefits. It was an easy sell. Prozac had recently lit the path forward for a vast SSRI marketplace, and it entailed promoting the drugs directly to primary care doctors, who bear the brunt of depression treatment in the U.S.

Psychiatrists were a harder sell. In 1990, Oldani attended a meeting of Wisconsin psychiatrists in the state’s northern reaches, a “continuing medical education retreat” where a “well-known ‘academic’” psychiatrist spoke poorly of Prozac and the SSRIs. According to the ex-drug rep, the doctor told his fellows to “stick with the tried and true” – the broader-acting and cheaply available tricyclic antidepressants, such as amitriptyline and imipramine, that they had long relied upon.

After the lecture, Oldani’s district sales manager declared, with some disgust, that the reps would be “going to primary care” to sell Zoloft.

Curiously, the same doctor who undersold SSRIs became a leading prescriber, Oldani writes in a chapter of the book Killer Commodities, and even a paid speaker for Pfizer. Abilify has followed a similar plan of advancing rapidly on all fronts. “You get primary care writing it,” says Oldani, who’s working on a study of drug rep culture, “and then you get psychiatrists writing it, and after a while, the package insert” – which describes a drug’s warnings and FDA indications – “doesn’t matter.”

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Like Eli Lilly before them, Otsuka Pharmaceutical and Bristol-Myers Squibb understood well that schizophrenia is a miniscule market compared to the one for mood disorders, and pushed for FDA indications to treat major depression and bipolar disorder with Abilify. They won much of what they set out to accomplish, including indications for bipolar disorder in 2004 and 2005 and, in 2007, another to treat schizophrenia in adolescents ages 13-17. Adult depression’s indication as an add-on treatment (something to work alongside a patient’s antidepressants) also arrived in 2007, and two more pediatric approvals, for acute bipolar mania (ages 10-17) and irritability in autistic children (6 and up), followed in 2008 and 2009.

Who’s writing the bulk of Abilify prescriptions? Psychiatrists say primary care doctors must be responsible. The former are too “few in number,” says Richard Friedman, a professor of psychiatry at Weill Cornell Medical College in New York who’s written critically of Abilify’s popularity for The New York Times. In depression treatment, atypicals “are clearly moving into first-line augmentation strategies,” he says, positions historically held by other antidepressants.

Friedman’s reaction to antipsychotics is one of categorical caution. “They’re very powerful and have all kinds of side effects,” he says. “The question isn’t if you can get people well. The question is, can you keep them well safely?”

The FDA regulates the sale and marketing of pharmaceuticals in the country but not the practice of medicine, and doctors routinely prescribe medications in dosages, and for disorders, not yet approved by the agency. Such “off-label” sales of Abilify, especially to depression patients and to children, began well before the FDA indicated these consumers and have continued long after. With little sedation and solid efficacy as an antipsychotic, Abilify became one of the hottest off-label scripts in the country, looping in large groups of new patients.

“Abilify is one of the ultimate examples of putting it all together,” says Oldani.

From the start, Otsuka’s novel new drug has presented itself as a cleaner, better antipsychotic, and it was initially promoted as having “almost nil” “extrapyramidal” side effects (which include movement disorders), Oldani says. “The doctor might be skeptical, but he or she keeps hearing that over and over. That’s going to influence prescription writing.”

Testing these claims requires painstaking research, and the number of strictly disinterested studies into psychiatric medications is on the decline. Most major trials are paid for by the drug companies themselves, and company officials may even serve on the research staff, as was the case with Otsuka executive and medical doctor William Carson, a member of a team that evaluated Abilify’s usefulness as an add-on for depression. A copy of the 2009 study funded by Otsuka and BMS, and published in a peer-reviewed journal, is available to read at abilify.com, where a co-pay savings card is said to allow patients to pay as little as “$5 a month for brand-name Abilify.” (Before insurance, a month’s supply has retailed for about $600.)

Even with the paucity of research on Abilify, “Some of the later data is showing that it has far more side effects than previously thought,” says Nicholas Rosenlicht, a California psychiatrist who teaches at the University of California-San Francisco. He cites a 2007 study of Abilify for bipolar depression in which 35 percent of participants developed a condition called “akathisia,” a distressing sensation of inner restlessness and anxiety.

That’s “a whole lot,” he says.

Both Rosenlicht and Oldani point to a subtle redefinition that worked to downplay Abilify’s rates of “extrapyramidal” side effects, including movement disorders. They say its marketing and reports have sometimes used the acronym EPS, but instead of the “S” standing for “side effects,” it stands for “syndrome,” meaning multiple forms of the side effects, a much rarer occurrence.

Rosenlicht and several other researchers conducted a systematic review of all trials and studies that tested the usefulness of Abilify, Zyprexa, Seroquel and Risperdal as add-ons for depression and published their findings in 2013. On a 60-point depression scale – the Montgomery-Asberg Depression Rating Scale, said to be popular with drug companies because it registers small changes – participants in the studies taking Abilify averaged an increase of just 3.15 points, a bump roughly equivalent to a small improvement in functionality. One of these could have been improved sleep, and almost all atypicals help with the insomnia regularly caused by severe depression. “If all Abilify is doing is helping you sleep,” says one of the academics, psychiatrist Alexander Tsai, who teaches at Harvard Medical School, “there are less-dangerous ways of doing that.”

No one questions Abilify’s efficacy for schizophrenia, its first FDA indication. “It’s an antipsychotic,” says Rosenlicht. “It does that. The jury is still out on whether it truly works for depression and bipolar depression.”

 

In 1999, just as Breakthroughs was hitting the presses, Otsuka reached its deal with Bristol-Myers Squibb (BMS) to promote Abilify in the U.S. A large pharmaceutical corporation in Japan, Otsuka is perhaps best known there for its lines of nutrition drinks and dietary supplements (“neutraceuticals”) but has also developed a small portfolio of prescription drugs for treating epilepsy, Parkinson’s disease, stomach ulcers, and, with Abilify, schizophrenia. Under the agreement, BMS would market this last compound in the U.S. and Europe while helping Otsuka perform the clinical trials necessary to gain additional indications from the FDA. In return, BMS would receive about 65 percent of Abilify sales, which, as the years went by, multiplied into the billions of dollars.

Sources: IMS Health and drugs.com;  *no data available; †Estimated

Sources: IMS Health and drugs.com;
*no data available; †Estimated

Although both companies had advertised from the beginning that Abilify was a “potential best-in-class agent,” few analysts foresaw just how successful it would become, and how hearty BMS’ take-home would be. “That was the rip-off of the century,” says Oldani.

Otsuka, which describes itself as having fostered Abilify since its discovery in 1988, fielded its own drug reps to promote the new atypical across the U.S. and closely monitored those working for BMS. Two multistate lawsuits have since targeted this endeavor: The first, alleging illegal off-label marketing between 2002 and 2005, ended in the drug companies paying a settlement of $515 million. The second, although greatly deflated, is still ongoing and will consider claims of wrongful termination brought by the whistleblowers. A federal judge threw out charges of illegal marketing in March (a decision that could be reversed on appeal) because the states had failed to link the promotional efforts to actual insurance claims. The joint complaint accused the companies of aggressively promoting Abilify for children and the elderly without first obtaining FDA approval for such uses – and continuing to do so long after the agency had issued warnings of “increased mortality” in elderly patients with dementia and increased “suicidal thinking” in children and young adults taking antidepressants. Another “Black Box” advisory, the FDA’s most severe, followed in 2009 as Abilify became widely popular for depression: “Abilify is not approved for use in pediatric patients with depression.” (It still isn’t.)

As part of the first case’s settlement, both companies signed “corporate integrity agreements” promising to create compliance programs that would somehow stop their drug reps from promoting Abilify for off-label uses. Both multistate cases – which have become something like a rite of passage for the big-name atypicals – alleged violations of the federal False Claims Act. In short, it’s illegal to encourage off-label prescriptions that result in off-label (and technically fraudulent) claims to public insurance programs like Medicare and Medicaid.

The second lawsuit alleged that the companies largely disregarded these agreements and carried on with an aggressive and frequently off-label promotional campaign intent on selling the drug to new markets. The two whistleblowers, a BMS drug rep from the Dayton, Ohio, area and another from Phoenix, Ariz., provided insiders’ accounts of this push and claimed that salespeople from both companies worked in “pods” doing what drug reps do: They called on physicians, psychiatrists, nursing homes, psychiatric facilities and hospitals, and pitched Abilify’s potential benefits. If asked about side effects, the drug reps described only the short-term, and not the long-term, risks. They offered paid speaking gigs to Abilify-friendly doctors, took them out to dinner at their favorite restaurants, and invited them to attend presentations at high-end venues, including the Sanctuary Camelback Mountain Resort and Spa in Scottsdale, Ariz.

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A key outcome of the first lawsuit was a requirement that both companies closely monitor their “call lists” – those used by drug reps to call on physicians and health care facilities – for any obviously off-label targets. But, according to the whistleblowers, these phone lists were never completely cleansed of pediatric doctors and others treating the elderly. In fact, child psychiatrists remained a major target for reps in the years leading up to the FDA’s first indication for children – the one for schizophrenia approved in October 2007. According to the whistleblowers, reps had called on pediatric doctors almost nonstop since 2002 and “sold symptoms” such as agitation, a feature of both schizophrenia and other conditions found in juveniles, including attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder. In a pitch to adolescent providers, reps would ask “if they had female patients who … can’t concentrate in school, are moody, and are preoccupied with their weight.” Abilify was then proposed as a solution to these ills.

At nursing homes and long-term care facilities, reps sold agitation and lethargy, telling medical directors that Abilify would help them to manage their patients’ behavior. One pitch suggested the drug would result in fewer calls from staff in the middle of the night to voice complaints of unruly residents. As an “activating” antipsychotic, Abilify would also liven up their patients instead of sedating them, and provide quick-acting relief from the depression that often plagues the institutionalized elderly. As instructed in their training, the reps asserted that Abilify was “not contraindicated” in the elderly (the lawsuit says geriatric use had not been studied), and if akathisia or other side effects were a concern, then the doctors should “start low, go slow,” break the tablets in half, or even drop the liquid form of Abilify into a resident’s juice.

BMS embarked on various efforts to “clean up” its call lists. In 2007, it removed several doctors treating children under the age of 13, but the lawsuit says the reps – who didn’t want to lose out on the volume-based commission they earned by calling on these prescribers – added many of them back. The company then set a deadline of November 2009 to clean up all lists before porting them into a new call system called “Navigator” to be shared by BMS and Otsuka reps. Employees submitted changes, but they appeared to have been ignored, according to the lawsuit. And in April 2010, a regional business director for BMS sent out a “voice mail blast” to all reps stating that the company was “going to remove 1,300 physicians” from the call lists. But when the next round was released, it still contained many of the old names.

A more definite shift occurred after November 2007, when the FDA awarded the much sought-after indication for depression in adults. Immediately, BMS and Otsuka revised their marketing plans. A Nov. 17, 2009, memo to the national sales force instructed it to promote “MDD [major depressive disorder] all the time,” and a few months later, another memo declared “Adult Adjunctive MDD as the #1 opportunity.” The problem was, as the whistleblowers complained, their call lists still contained many child and adolescent providers, and to meet their quotas, they couldn’t afford to skip them. They were effectively forced to show up and deliver some kind of MDD pitch, they said, even though pediatric depression remained well off-label.

The lawsuit also claims that BMS and Otsuka deliberately set out to elevate Abilify from a third- or fourth-line treatment for depression, something to try after several other medications have failed, to a drug of second resort. Ads have shown a muted-looking woman who says, “I’ve been taking an antidepressant, but my depression was still creeping up on me.” One print ad in particular personifies the disorder as a shadowy bathrobe that chases a well-dressed women down the street. “The one glaring omission in these ads is that they’re antipsychotics,” says Friedman. “They’re leaving out a piece of information that consumers ought to have.”

Also involved in promoting Abilify as a second-line treatment were the BMS and Otsuka drug reps. One of the whistleblowers paraphrased a district business manager at BMS as having said, during a 2008 sales meeting, “If every physician augmented in the third or fourth position, the company would go out of business.” He also told the reps that “he didn’t want to see any physicians prescribing beyond the second augmentation position,” so that few other augmenters (including additional antidepressants) would first be given a chance to work.

Otsuka eventually broke free of its marketing pact with BMS in 2012, and the former’s U.S. patent for Abilify, originally set to expire in October 2014, could win an extension until 2021. Apparently hoping to stave off generics, Otsuka applied for and won approval to treat pediatric Tourette syndrome in 2014 and then sued the FDA in March, claiming protection under the Orphan Drug Act. This federal law awards seven years of exclusive sales to companies that develop new medications for obscure conditions such as, Otsuka claims, pediatric Tourette syndrome.

BMS didn’t respond to a request for comment, and Otsuka sent a short statement saying Abilify “has helped more than 7 million patients” who fall under five different FDA indications. “The decision to treat with Abilify should be made between health care providers and patients only after a thorough discussion of both the benefits and risks associated with the treatment.”

 

The onus is on doctors to continually educate themselves by reading published research, attending medical conferences and networking with colleagues. Not all accept visits from drug reps, a fourth conduit of information. “It’s really up to individuals to be lifelong learners,” says Harvard’s Tsai, who declines visits from reps. “I’m perfectly capable of reading medical journals myself.”

Antipsychotics have fallen out of favor before. More than one psychiatrist interviewed for this story expressed an aversion to prescribing Zyprexa, the Abilify of its day, because of its reputation for weight gain. Seroquel, Zyprexa’s immediate successor, has had “staying power,” according to Rosenlicht, but he says that these days, most experts only agree that one antipsychotic – the oldest atypical, clozapine – has clearly demonstrated itself as being more effective at treating psychosis than the rest. It’s rarely prescribed because it can lead to dire side effects, such as a decimation of white blood cell counts. Patients taking it are carefully monitored.

Depression studies have had a bit more success in establishing a hierarchy of effective treatments. The “STAR*D” trials (Sequenced Treatment Alternatives to Relieve Depression), completed by the National Institute of Mental Health in 2006, are the best-known example but included no antipsychotic drugs in the medications tested, only the mood stabilizer lithium. One of the best-performing regimens for stubborn depression was a combination of the antidepressants mirtazapine (Remeron) and venlafaxine (Effexor).

So far, there’s been no such research comparing antipsychotics head-to-head in depression treatment, only a smattering of independent clinical trials. The data generated is hard to stack up, unlike studies of blood pressure medications or cholesterol drugs. “Psychiatry,” as Rosenlicht says, “is a bit fuzzier.”

Matt Hrodey is a senior editor at Milwaukee Magazine. Write to him at matthew.hrodey@milwaukeemag.com.

Hear more about the story from Matt Hrodey on WUWM’s “Lake Effect.”

‘The Selling of Abilify’ appears in the May, 2015, issue of Milwaukee Magazine.
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