07/7/20

Rebranding Problems With Abilify

Abilify had a profitable and expansive run for Otsuka Pharmaceuticals since it was approved by the FDA for the treatment of schizophrenia in 2002. The FDA then expanded its treatment use to include bipolar disorder in 2005, irritability associated with autistic disorder in 2009 and Tourette’s disorder in 2014. It was also approved by the FDA as an add-on with antidepressants for treatment-resistant depression in 2007. Abilify is used off-label to treat insomnia, delusional disorders and anxiety. In 2013 this enlarged treatment market brought in $7.8 billion in global sales for Otsuka. FiercePharma noted the end of Abilify’s patent exclusivity in April of 2015 left a big revenue hole for Otsuka and Bristol-Myers Squibb, who marketed and promoted it in the U.S. But instead of quietly surrendering to the generic market, Abilify (aripiprazole) was rebranded into three new drug applications with the FDA: Abilify Maintena, Abilify MyCite and Aristada.

Abilify Maintena was approved as an extended-release once-monthly depot shot of aripiprazole for the treatment of schizophrenia in March of 2013. Otsuka said it was a new treatment option to address the need for relapse prevention in patients with schizophrenia. It was the first dopamine D2 partial agonist approved as a once-monthly injection. In July of 2017 its approved use was extended to include maintenance monotherapy treatment of Bipolar I Disorder in adults.

Abilify MyCite has an ingestible sensor embedded in aripiprazole tablets that records that the medication was taken. Approved by the FDA in November of 2017, it is the first drug in the U.S. with a digital tracking system. This was a second try for Otsuka, as the FDA initially failed to approve Abilify MyCite in April of 2016, saying it needs more information about the product’s use, and further human factor investigations. “The goal of human factors testing is to evaluate use-related risks and confirm that users can use the device safely and effectively.”

The pill’s sensor sends a message to a wearable patch that in turn transmits the information to a mobile application that allows the patient to track the ingestion of the medication on their smart phone. Patients can give their caregivers and doctors permission to access the information through a web-based portal. Mitchell Mathis, the director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research, said: “Being able to track ingestion of medications prescribed for mental illness may be useful to some patients.” Actually, the digital tracking capability of Abilify MyCite is a selling point for psychiatrists concerned with patient adherence. Getting people who are prescribed antipsychotics to stay on their drugs can be a challenge. See “Doublespeak With Abilify MyCite” for more information on this.

Aristada (aripiprazole lauroxil) was approved by the FDA as an extended release injectable form of aripiprazole to treat adults with schizophrenia on October 5, 2015. It is a prodrug, meaning it is a biologically inactive compound that is metabolized into a pharmacologically active drug within the body. Unlike Abilify MyCite and Abilify Maintena, its parent company is Alkermes, not Otsuka. Similar to the price of another Alkermes drug, Vivitrol, Aristada costs about $1,500 per month.

According to ProPublica, Alkermes has successfully marketed Vivitrol to the criminal-justice system, emphasizing its use in drug courts. The Atlantic wrote how the relationship between drug companies and the criminal-justice system has expanded in “Marketing Psychiatric Drugs to Jailers and Judges,” as drug companies realized the potential market behind bars. Free samples are distributed to detention facilities; jail and prison doctors attend free luncheons to learn about medications. Payments are made to doctors and criminal-justice employees, such as sheriffs and drug-court judges, to promote certain medications.

Alkermes and other drug companies have marketed not only to jailers but to judges as well. Earlier this year, at a conference for drug- and mental-health-court professionals in Maryland, Alkermes sponsored a closed-door promotional session about using long-acting shots in a court setting. Featured at the session was Richard Jackson, a former psychiatrist at the Women’s Huron Valley Correctional Facility in Ypsilanti, Michigan, and Ernie Glenn, a magistrate in Bexar County, Texas, who had helped defendants in his court get access to long-acting antipsychotic shots. While Glenn had received no payments from Alkermes, the company had paid Jackson more than $250,000 between 2015 and 2018 for speeches, travel and lodging, and meals, according to the Centers for Medicare and Medicaid Services’s open payments database. (Jackson also received $252,608 in payments from Otsuka from 2015 to 2018, and said he has continued receiving payments from drug companies in 2019; it wasn’t immediately clear whether Alkermes was one of them.) The conference program, as in the conference in Nashville, directed people to learn about Aristada at Alkermes’s exhibit booth.

The director of the ACLU’s National Prison Project, David Fathi, expressed concern that the marketing has been aimed at judges and prison officials instead of the incarcerated people themselves. A ProPublica analysis found that doctors who accepted money from pharmaceutical companies were more likely to prescribe those companies’ medications. Incarcerated patients may not feel they have a real ability to choose. In cases where patients choose to take a psychiatric drug, it may be a choice made under duress. “If you know you can be forcibly medicated, can you really make a free and noncoercive choice about medication?”

The makers of drugs like Abilify Maintena and Aristada are banking on long-acting injections as the future of schizophrenia treatment. A 2015 study found that patients who were given injections of long-acting risperidone were more likely to comply with treatment and led to better long-term outcomes. The lead author of the study, Kenneth Subotnik, said, “We know that not taking antipsychotic medication is the single greatest modifiable risk factor for psychotic symptoms returning.” Yet as Max Blau noted in The Atlantic, there is a possibility the side effects will last longer than with the pill form. The most common side effect with Aristada is akathisia (a feeling of inner restlessness and inability to stay still). Other side effects include: Neuroleptic Malignant Syndrome, Tardive Dyskinesia, Diabetes, weight gain and seizures.

In 2016 the FDA published a Safety Communication about impulse-control problems associated with aripiprazole (Abilify, Abilify Maintena and Aristada). They warned of reports of compulsive, uncontrollable urges to gamble, binge eat, shop, and have sex with the use of aripiprazole. The impulse-control problems were rare, but may result in harm to the patient or others. “These uncontrollable urges were reported to have stopped when the medicine was discontinued or the dose was reduced.”

Although pathological gambling is listed as a reported side effect in the current aripiprazole drug labels, this description does not entirely reflect the nature of the impulse-control risk that we identified. In addition, we have become aware of other compulsive behaviors associated with aripiprazole, such as compulsive eating, shopping, and sexual actions. These compulsive behaviors can affect anyone who is taking the medicine. As a result, we are adding new warnings about all of these compulsive behaviors to the drug labels and the patient Medication Guides for all aripiprazole products.

A search of the FDA Adverse Event Reporting System (FAERS) database and the medical literature identified 184 case reports with an association between arpiprazole use and impulse-control problems. Pathological gambling was the most common with 164 cases, “but other compulsive behaviors including compulsive eating, spending or shopping, and sexual behaviors were also reported.” None of the patients had a history of pathological gambling, compulsive sexual behavior, binge eating or compulsive shopping before starting arpiprazole treatment. None of the patients had concurrent substance abuse disorder or symptoms of mania at the time of developing the impulse-control problems.

Despite the problems with Abilify, Otsuka and Alkermes have repackaged it with digital tracking technology and a slow-release, depot injection and then promoted these products as improving treatment adherence, reducing the risk of overdose and improving relapse prevention and reducing rehospitalization rates.

Pharmaceutical companies seem to disregard the problems with antipsychotics like Abilify while they pursue their potential profits. Bristol-Myers Squibb paid $515 million to settle charges it illegally marketed Abilify for children and the elderly. See “Broken Promises with Ability” for more information on this issue. Persistence in addressing problems with nonadherence seems to ignore the larger issue of adverse side effects antipsychotics. See “Abilify in Denial,” “Pick Your Poison: Diabetes and Psych Meds,” “Downward Spiral of Antipsychotics,” “Pros and Cons of Antipsychotics” and “Biomedical Big Brother” for more on concerns with adherence and adverse side effects with Abilify and other antipsychotics. The rebranding Abilify as Abilify Maintena, Abilify MyCite and Aristada does not appear to address the concerns with aripiprazole and other antipsychotics.

10/1/19

Doublespeak with Abilify MyCite

Abilify MyCite was approved by the FDA in November of 2017, but it isn’t being used much. At least one expert said that was because the antipsychotic pill contains a tracking chip the size of a grain of sand that confirms whether or not an individual actually takes the medication. A psychiatrist from Columbia University said people with psychotic disorders often struggle with some degree of paranoia, believing that outside forces are trying to monitor and control them. “The idea that we’re giving this group of patients a pill that, in fact, transmits info about them from inside their body to the people that are involved in their treatment almost seems like a confirmation of the worst paranoias of the worst patients.”

The Daily Mail reported medication nonadherence is a particular problem for doctors treating schizophrenic patients. Otsuka Pharmaceuticals replied that people who are afraid of their medicine, are not likely to be given Abilify MyCite. The medication is supposedly designed for people who ask for it as a way of improving their mental health. A spokesperson for Otsuka said, “It’s really about patients who want to improve their treatment goals. If they have any concerns, it’s probably not the right solution for them.”

Really? A medication that tracks when you have taken your medication is for motivated clients who want to improve their treatment goals, meaning to be more compliant with taking Abilify MyCite? What about patients who seek to minimize or eliminate the adverse side effects from the medication, including weight gain, agitation, unusual urges, akathisia (a feeling of inner restlessness), and more, including thoughts about suicide?

An individual who participated in the clinical trial for Abilify MyCite and who was compliant with his medication hasn’t had paranoid thoughts in a long time. He said that if he had an opportunity to take ‘digital Abilify,’ “I wouldn’t take it.” See, “Biomedical ‘Big Brother’” for more on the adverse side effects of Abilify and other antipsychotics.

The metallic tracking chip contains copper, magnesium and silicon sends a signal to a patch worn on the patient’s arm. It is activated when it becomes immersed in stomach juices, completes a circuit and generates a small electric charge. “The patch then synchronises with a mobile app on the patient’s smartphone or tablet, and sends data to their doctor over the internet to show whether the pill has been taken.” Ingestion is recorded between 30 and 120 minutes after the patient swallows the drug.

The BMJ Evidence-Based Medicine journal published research by Lisa Cosgrove and others that analyzed evidence submitted to the FDA for approval of digital arpiprazole (Abilify MyCite). This was the first such drug-device combination to receive FDA approval, and it “sets a precedent for how technology-enhanced products will be evaluated before marketing.” The authors also said it was important to examine how the clinical trial evidence supporting this approval was represented in news stories and reports. Recent research had documented the presence of ‘spin’ (distorted interpretation of trial evidence) when the results of clinical trials are reported in journals and news reports. This spin gives the impression of there being a greater benefit to the drug than is warranted by the data in both media reports and the scientific literature.

Their review of the clinical trial data submitted to the FDA for the approval of Abilify MyCite revealed the data were limited to trials that “simple assessed whether patients could use the product as intended.” There was no evidence of superiority or non-inferiority compared with non-digital versions of arpiprazole, other antipsychotics or placebo. In the FDA’s clinical review letter, one simulated trial (where the participants did not ingest the drug, but simply placed it in a container to simulate ingestion) provided no additional data about adherence or regarding transmission times. “Considering these limitations, the most accurate statement regarding Abilify Mycite’s capabilities is that ‘Abilify MyCite successfully tracks ingestion of aripiprazole with embedded sensor.’” The lack of even a single comparative trial was said to mean “there is no way to know whether digital aripiprazole improves treatment adherence, quality of life, psychiatric symptoms or remission.”

Patients with serious psychiatric illnesses often suffer from paranoia. An ingestible drug with a sensor brings surveillance to a new level, and the potential negative effects on this patient population merit careful consideration. The potential harm of the surveillance aspect of this technology to the therapeutic alliance and to patients has not been adequately assessed. Thus, it is reasonable to ask if there was a financial rather than a scientific impetus for choosing aripiprazole as the first-ever digital drug.

Before it went off patent in 2015, Abilify made over $7.5 billion. It was the best-selling drug in the US for 2014 with an average cost of $800 for a month’s supply. After the patent expired, sales of arpiprazole dropped to $600 million in 2015, which was when Otsuka and Proteus first submitted an application for market approval for digital arpiprazole. The cost for a month’s supply of the Abilify MyCite is $1,650. In comparison, the generic oral version of arpiprazole costs less than $20 per month. In order to avoid this dramatic loss in revenue, pharmaceutical companies have developed several different schemes.

Drug manufacturers have developed a number of strategies to extend market monopoly after a blockbuster drug (defined as over US $1 billion in yearly revenue) goes off-patent. These are known as ‘evergreening’ strategies, with highly questionable benefit to patients. Evergreening involves the patenting of a slight modification (eg, subtle changes to the medicine’s structure) of an existing drug as a new invention. For the manufacturer, the result is that their product is considered as a new chemical entity that qualifies for market exclusivity (ie, no generic version is available). The possibilities afforded by sensor-based technology make room for a new dimension of practice, an evergreening 2.0. That is, ‘digital evergreening’ may develop as a means whereby manufacturers can gain market exclusivity for a generically available medicine (such as aripiprazole) by combining it with a monitoring technology.

Cosgrove et al added to the growing body of literature documenting the extent and effects of spin in the scientific literature and in media reports by noting the affiliation of authors with the parent pharmaceutical company, Otsuka. Researchers searched the Web of Science to identify all publications in English citing the clinical trials for arpiprazole. Then they reviewed the database NexisUni for all news stories and press releases about the approval of Ability MyCite from January 1, 2015 to January 23, 2018. The researchers defined spin as ‘a specific way of reporting, intentional or not, to highlight that the beneficial effect of the experimental treatment [digital arpiprazole] in terms of efficacy or safety is greater than that shown by the results.’ They identified 70 articles and two press releases which met their inclusion criteria for their study.

Of these, 57% (40/70) did not acknowledge the lack of efficacy data from RCTs [randomly controlled trials], 93% (65/70) did not report on the scarcity of safety data, and no story reported on the absence of a non-digital comparator in clinical trials. Three-fourths (52/70) conveyed an impression of benefit without mentioning the lack of research to support that impression. Most of the news stories (77%, 54/70) cited an expert, and of those 39% (21/54) cited experts who had financial ties to either Otsuka or Proteus.

Not only were some authors of the published studies Otsuka employees, there was evidence of ghost writing in the dissemination of the trial data: “’Editorial assistance was provided by the medical communications company C4 MedSolutions LLC (Yardley, PA, USA), a CHC Group company’, with Otsuka funding.” Both of the positive clinical trial studies were published in the journal Neuropsychiatric Disease and Treatment, whose editor is described as an ‘independent pharma consultant [who] advises and consults worldwide to several pharmaceutical and venture capital organizations’.

Our case study reveals that the approval of this digital drug for marketing in the USA was granted on very limited data. Both the scientific literature and the popular news reports conveyed an unsupported impression of benefit. As a result, the general public and healthcare professionals may be making medical decisions based on industry-friendly, but not necessarily scientifically accurate, information about the efficacy and safety of this new product. Also, if patients are incentivised to take the digital version (eg, by being offered lower copayments or by being offered outpatient treatment—rather than forced inpatient treatment), the line between incentivising and coercion will be blurred. We recommend that other regulatory bodies (eg, the European Medicines Agency) take note of the findings in the current study as well as the medicolegal issues that emerge with the use of digital drugs.

The authors suggested the general public and healthcare professionals may be making medical decisions based on industry-friendly, but scientifically inaccurate, information about the safety and efficacy of Abilify MyCite.

Please do not let the allure of a new pharmaceutical technology seduce you. This doublespeak about how digital arpiprazole will improve your treatment goals, is simple marketing rhetoric. Also do the math, one month of Abilify My Cite is $1,650 and a generic pill will cost you less than $20 per month. The savings leaves you enough to hire a skilled mental health coach and have an even better chance of improving your treatment goals.

01/16/18

Biomedical ‘Big Brother’

The FDA approved a new pharmaceutical product that combines technology and medication: Abilify MyCite, “the first drug in the U.S. with a digital tracking system.” The pill contains a sensor that tracks whether or not a patient has taken their medication. The pill’s sensor sends a message to a wearable patch, which then transmits the information to a mobile app, enabling the patient to track their ingestion of the medication on their smart phone. Patients can also “consent” for others to access the information through a web-based portal. As more than one person observed, the old hide-the-pill-under-your-tongue trick doesn’t work with the new technology.

Science Alert said the sensor, called an Ingestible Event Marker (IEM) is about the size of a grain of sand. It’s made of safe levels of copper, magnesium and silicon. When the pill and IEM are swallowed, stomach acid activates the sensor, which sends an electrical signal to the patch. “The patch records the date and time the pill was ingested, and relays this information to a smartphone app.”

A New York Times article on the approval, “First Digital Pill Approved to Worries About Biomedical ‘Big Brother,’ noted where experts estimate nonadherence or noncompliance with medications costs about $100 billion per year. Much of that cost is said to be due to patients getting sicker and needing additional treatment or hospitalization. Dr. William Shrank said: “When patients don’t adhere to lifestyle or medications that are prescribed for them, there are really substantive consequences that are bad for the patient and very costly.” Ameet Sarpatwari said while the pill has the potential to improve public health, “If used improperly, it could foster more mistrust instead of trust.”

The IEM could be used to monitor medication compliance with post-surgical patients or for individuals required to use a digital medication as a condition for release from psychiatric facilities. “Asked whether it might be used in circumstances like probation or involuntary hospitalization, Otsuka officials said that was not their intention or expectation, partly because Abilify MyCite only works if patients want to use the patch and app.”

Nevertheless, Abilify was said to be an unusual choice for the first sensor-embedded medication. As an antipsychotic or neuroleptic, Abilify is approved for treating schizophrenia, bipolar disorder and as an adjunct for major depression. Some of these individuals may have delusions or become paranoid about their doctor or what the doctor intends. How receptive will they be to using a system that monitors their behavior and then potentially signals their doctor?

Dr Paul Applebaum of Columbia University’s psychiatric department said: “You would think that, whether in psychiatry or general medicine, drugs for almost any other condition would be a better place to start than a drug for schizophrenia.” Dr. Jeffrey Lieberman said many psychiatrists will likely want to try Abilify MyCite, but it has not yet been shown to improve medication adherence. “There’s an irony in it being given to people with mental disorders that can include delusions. It’s like a biomedical Big Brother.”

Many patients aren’t compliant with neuroleptics because of the side effects. These side effects can include: weight gain, diabetes, pancreatitis, gynecomastia (abnormal breast tissue growth), hypotension, akathesia (a feeling of inner restlessness), cardiac arrhythmias, seizures, sexual dysfuntion, tardive dyskinesia, anticholinergic effects (constipation, dry mouth, blurred vision, urinary retention and at times cognitive impairment). For more on the adverse effects with Abilify and other antipsychotics, see (“Abilify in Denial,” “Broken Promises with Abilify,” “Antipsychotic Big Bang,” “Wolves in Sheep’s Clothing,” and “Downward Spiral of Antipsychotics”).

Otsuka, the pharmaceutical company with the patent rights to distribute Abilify MyCite, has not set a price for the drug yet. Although Abilify alone is now off patent, Otsuka will have a new patent time frame for Abilify MyCite. Here may be the reason that Otsuka invested so much capital into Proteus Digital Health, the California company that developed the IEM technology. Profits from Abilify will continue to be made by Otsuka with the newly patented formula.

The labeling information for Abilify MyCite notes the ability of the product to improve patient compliance hasn’t been demonstrated yet. Additionally, it should not be used to track drug ingestion in “real-time” as detection may be delayed or may not occur. Robert McQuade, an executive vice president for Otsuka, confirmed the company does not have current data to say it will improve adherence. But they will likely study that after sales begin.

How patients themselves view Abilify MyCite is mixed. One person who takes Abilify for schizoaffective disorder participated in the clinical trial for Abilify MyCite. Compliant with his medication, he doesn’t think he needs digital monitoring. He hasn’t had paranoid thoughts for a long time. If he had a chance to take ‘digital Abilify,’ “I wouldn’t take it.” Another person who sometimes will stop taking his medication thought the idea behind Abilify MyCite was “overbearing.”

A third person reported his use of Abilify for 16 years to prevent recurrence of episodes of paranoia. He thought some people might use the new drug to avoid the injections of Abilify if they were noncompliant with their pills. But he said he would not use the digital Abilify. He didn’t want an electrical signal, strong enough for his doctor to read, coming out of his body. “But right now, it’s either you take your pills when you’re unsupervised, or you get a shot in the butt. Who wants to get shot in the butt?”

The above are the milder responses to the FDA’s news about Abilify MyCite. What follows are the thoughts of Michael Cornwall. He is a Jungian/Langian psychotherapist who specializes in providing psychotherapy for people in psychotic states (which he refers to as ‘extreme states’) without the use of medication. He has his own website and commented there how digital Abilify “can now automatically send signals to your doctor, family members and the courts, to show them when you comply and swallow the pill.” Not one to pull punches, his article on Mad in America was titled: “The Orwellian New Digital Abilify Will Subjugate Vulnerable People across the US.”

He predicted there will be tragic personal injury coming from the use of Abilify MyCite to control people’s dosing compliance, “something that I believe would even make dystopian visionaries George Orwell and Aldous Huxley shudder.” Singling out California as an example, he said the state was ripe for an even more oppressive mental health “best practice” service model and standard of care for people in “extreme states” who are receiving forced in-home treatment. Like California, most states now have some version of in-home compulsory court-ordered medication treatment. Research has shown that 74% of people prescribed antipsychotic medications who are in extreme state stop taking their medications by 18 months. Pro-medication people find this unacceptable.

Tremendous pressure, I believe, will also be exerted by mental health care providers for people to voluntarily accept taking the new digital Abilify. I see that pressure being put on people seeking discharge from in-patient units, and pressure will be put on people in extreme states or with such histories, who will be involved anywhere on the spectrum of community mental health services and in jails and prisons too. In both mental health and penal systems, medication compliance, not providing humanistic care, is clearly the highest priority.

Yet there is reliable evidence suggesting long-term use of antipsychotics like Abilify is not necessary. Robert Whitaker wrote a paper, “The Case Against Antipsychotics” where he critiqued the research cited by psychiatry as evidence for long-term use of antipsychotics. Additionally, he presented a history that tells how antipsychotics, on the whole have actually worsened long-term outcomes. Whitaker described a long-term study by Harrow that followed an original group of patients for 20 years (and counting) after their initial hospitalization for schizophrenia.

Harrow discovered that patients not taking medication regularly recovered from their psychotic symptoms over time. Once this occurred, “they had very low relapse rates.” Concurrently, patients who remained on medication, regularly remained psychotic—even those who did recover relapsed often. “Harrow’s results provide a clear picture of how antipsychotics worsen psychotic symptoms over the long term.” Medicated patients did worse on every domain that was measured. They were more likely to be anxious; they had worse cognitive functioning; they were less likely to be working; and they had worse global outcomes. Also see “Worse Results With Psych Meds” for more on the Harrow study.

Returning to the thoughts of Michael Cornwall, he said treatment with Abilify MyCite was “a morally bankrupt approach that ensures a soul-numbing, hi-tech compliance-monitoring device be in the digestive tract of every DSM-labeled person in an extreme state, in order to keep them in line.” It places the controlling impulse of psychiatric care “within our very guts.” To the uninitiated, Cornwall’s rhetoric may sound extreme. But I suspect that for individuals wanting to cope with their “extreme state” without medication or struggling to live with the side effects from antipsychotics, it is spot on. Clearly as the technology behind the IEM improves, it will be used to “convince” individuals that using a digital antipsychotic like Abilify MyCite is in their best interests, particularly if they want to be discharged from a psychiatric facility, or to continue living outside of one. The first Biomedical Big Brother has arrived.

03/17/17

Broken Promises with Abilify

Based upon sales data for the world’s 15 top selling drugs, Abilify was ranked fourth, with $9.3 billion of sales in 2014. Reflect for a moment what this means; an antipsychotic drug had greater worldwide sales than Nexium (for acid reflux) and Crestor (for high cholesterol). While it is an approved medication in the US for bipolar 1 and schizophrenia, it is likely these sales figures reflect it use as an adjunct medication for major depression. Oh, and along with other antipsychotics, it is used off label to treat several other behavioral disorders such as Tourette’s and irritability associated with autism. This popularity is despite the reality that antipsychotics have a high incidence of negative side effects—greater than antidepressants and anti-anxiety medications.

The problems with antipsychotics have been known for a few years. As far back as 2010, Robert Field wrote: “Antipsychotic Medications Are Spelling Legal Trouble for Drugmakers” for the journal Pharmacy and Therapeutics. In 2007, Bristol-Myers Squibb paid $515 million to settle charges of illegally marketing Abilify for children and the elderly, “In contravention of FDA-approved labeling.” But that hasn’t been the end of legal troubles regarding Abilify. On May 3, 2016, the FDA published a safety announcement warning that Abilify (aripiprazole) can trigger impulse-control problems such as “compulsive or uncontrollable urges to gamble, binge eat, shop, and have sex.” These urges reportedly stop when the drug is discontinued or the dose reduced.

These compulsive behaviors can affect anyone who is taking the medicine. As a result, we are adding new warnings about all of these compulsive behaviors to the drug labels and the patient Medication Guides for all aripiprazole products.

The mechanism of action for Abilify is not clearly understood, but researchers think it over-stimulates dopamine 3 (D3) reward receptors, which are mainly located in the limbic system. This in turn triggers the compulsive behaviors. Gaboriau et al. reviewed case reports in Addictive Behaviors and indicated that pathological gambling (PG) appeared as quickly as a few days after Abilify was started; sometimes after an increase in dosage with 7 of the 8 case reports. PG then decreased after Abilify treatment was stopped or decreased; again sometimes as soon as a few days afterwards.

Limitations on the Gaboriau et al. findings included that most of the patients were already gambling before starting with Abilify. Several patients also had a history of substance use disorders. However, the authors noted that the same D3 receptor was implicated in another study by J. E. Ahiskog of the dopamine agonist medications, pramipexole and ropinirole, which are commonly used to treat Parkinson’s disease.

This hyperstimulation would apparently be particularly enhanced in cases of a previous treatment by antipsychotics acting as a dopaminergic receptors antagonist, owing to the up-regulation and the dopaminergic receptor hypersensitivity processes. The partial agonist action of aripiprazole then causes stronger effects. Moreover, the intrinsic dopamine pharmacodynamic activity of aripiprazole imparts it less action agonist than a complete agonist, which could explain why the occurrence of PG is sometimes late or due to dosage increase.

The above concern with Abilify was also supported by the findings of a study by Moore, Glenmullen and Mattison reported in JAMA Internal Medicine. Adverse drug event reports received by the FDA from 2003 to 2012 were reviewed for the six dopamine receptor agonist drugs marketed in the U.S. The review identified 1580 reports of impulse control disorder events, including pathological gambling, hypersexuality, compulsive shopping and others. They also detected weaker signals for antidepressants and antipsychotics.

The Daily Beast reported on a massive tort lawsuit being filed against Otuska and Bristol-Myers Squibb charging that Abilify created a compulsion for sex and gambling. Moreover, the suit claims the drug makers knew of the serious side effects because of required changes in Canadian and European warning labels, but waited for years to warn U.S. consumers. Thomas Moore of the Institute for Safe Medication Practices explained the drug triggers an urge to gamble constantly, sometimes with people with no prior interest. “It might be people starting to spend $300 a week on lottery tickets, and in other cases people will gamble away tens of thousands of dollars.” Moore went on to say:

We live in a society whose rules and laws assume people are responsible for their actions, including running up a large gambling debt. . . But we have scientific evidence that sometimes a drug can trigger a pathological urge to gamble so severe it can ruin someone’s life.

A woman who began using Abilify to aid in treating her PTSD developed a compulsive gambling problem. She used up her unemployment checks, pawned her husband’s automotive tools, and lied about needing money for baby formula. “Nothing was off-limits when it came to getting the money I needed to keep up the ruse.” She’d stuff her bed at night in order to fool her husband into thinking she was asleep when she was actually at the casino playing the slot machines.

Another woman developed hypersexuality. She started with online chatting with men. She became obsessed with sexual fantasies and took sexualized pictures of herself and sent them to select ‘friends.’ “I just couldn’t stop with the pictures and fantasies.” She also went on shopping sprees. Then her husband caught her. “The drug has destroyed my life, my reputation, and the lives of those I love.”

The website RxISK has multiple reports on adverse events with Abilify. “Abilify from the Inside Out” described bouts of akathisia (a state of agitation, distress, and restlessness), unusual aggression or anger, first time episodes of psychosis, suicidality, at least three confirmed suicides, movement disorders such as tremors, and (of course) compulsive gambling. The author said the reports were hard for him to read. Since most of the patients were on several meds, some patients couldn’t be sure that Abilify alone caused the problem. Even stopping Abilify was related to adverse drug events.

The above noted 2007 lawsuit, where Bristol-Myers Squibb paid $525 million to settle charges of illegal marketing, unveiled some of the marketing records for Abilify. Remember, one of the concerns was that it was illegally marketed for use with the elderly. The sales reps for Abilify would invite nursing home staff to picture a new resident, hunched in their chair, staring off into space because of ‘depression.’ “’Who wants to see that when they come to visit Mom on a Saturday?’ the reps would ask. ‘Wouldn’t we like to see her up and about, looking lively?’” The sale pitch worked. One woman wrote the following to RxISK:

I have seen many commercials about how drugs like Abilify can perk people right up. . . So I was not only disappointed and frightened by the results, but felt once again tricked and exploited by the big promises that drug companies make but never seem to keep.

I wish the above concerns weren’t true. But I’ve known individuals whose experiences on Abilify are consistent with the above discussion of its adverse effects. Sadly, even when sanctions are in the millions of dollars, the profits are higher. And it seems the cards are stacked against pharmaceutical companies being held accountable financially. So consumers have to fight against this by refusing to use Abilify and telling others what you have read here. If you are interested in other articles on the problems with Abilify and the other antipsychotics, try: “Antipsychotic Big Bang” or “Abilify in Denial” on this website.

11/4/15

Abilify in Denial

Modern Healthcare reported that Proteus Digital Health, a California company, is partnering with Otusuka Pharmaceuticals to approve an Abilify “smart pill.” When a medication embedded with a sensor reaches the stomach, it sends a signal to a wearable sensor patch. The patch records and time-stamps the information and other information such as rest and activity patterns. Then the information can be relayed to patients on their phones or other Bluetooth-enabled devices; or it can be forwarded to physicians or caregivers.

It was just in July of 2015 that Proteus announced that the FDA had expanded the Indications for Use statement for its Ingestible Sensor technology to be used as an aid in measuring medication adherence. At this point in time, it seems to be the only device with an FDA-sanctioned claim for measuring medication compliance. Proteus and Modern Healthcare pointed to findings from a 2014 article in Risk Management and Healthcare Policy that estimated avoidable healthcare costs from poor medication adherence as between $100 to $300 billion annually in the U.S. That represents 3% to 10% of total U.S. healthcare costs.

Dr. George Savage, the co-founder and chief medical officer of Proteus, said the company hopes to give patients feedback on their adherence so they can improve their health and avoid adverse medication events. Dr. William Carson, the president and CEO of Otsuka Pharmaceuticals said: “We believe this new digital medicine could revolutionize the way adherence is measured and fulfill a serious unmet medical need in this population.” They expect a response from the FDA by April of 2016.

There is reportedly a widespread problem of with non-adherence to taking medications as prescribed, especially with individuals with mental illness. So the FDA suggested to Proteus that the need for an ingestible sensor was most needed by mental health patients. It seems to have been rushed through the approval process, with about nine months from the FDA approved expansion of the Indications for Use statement for Proteus’s Ingestible Sensor to the expected response by the FDA approving the Abiliy “smart pill.” So there are two questions to ask about this. Why the rush? Why is the greatest need for a smart pill with antipsychotics like Abilify?

Abilify went off of patent in October of 2014 and was made available as a generic in April of 2015. The Abilify smart pill would probably be a new molecular entity (NME) and thus eligible for a new patent. While aripiprazole (Abilify) will be available as a generic, only Otsuka and Proteus will be able to sell the smart pill version. Otsuka and its former distribution partner, Bristol-Myers Squibb, grossed $5.5 billion in Abilify sales for 2014.

The pressing need for a smart pill with psychiatric medications to help counter non-adherence issues is because there are serious, and sometimes debilitating side effects from taking them. Here is a link to an advertisement for Abilify as an add-on medication with antidepressants to treat depression. Most of the audio in the 90-second commercial is describing the potential side effects.

The side effects from antipsychotics can include: weight gain, diabetes, pancreatitis, gynecomastia (abnormal breast tissue growth), hypotension, akathesia (a feeling of inner restlessness), cardiac arrhythmias, seizures, sexual dysfuntion, tardive dyskinesia, anticholinergic effects (constipation, dry mouth, blurred vision, urinary retention and at times cognitive impairment). Read more about these and other side effects at: “Side Effect of Atypical Antipsychotics: A Brief Overview”; “Antipsychotic Drugs, Their Adverse Effects”; “Adverse Effects of Antipsychotic Medications”; and “An Overview of Side Effects Caused by Typical Antipsychotics.”

The website RxISK described some of the reports and first-hand accounts about individuals who had used Abilify in: “Abilify From the Inside Out.” Out of 34 who had used Abilify, only five had taken it for a “psychotic” diagnosis. Fourteen were taking it for depression. Six used it for bipolar disorder; three for other diagnoses; two for “stress”; and three for unknown reasons. Fifteen individuals were taking Abilify in conjunction with antidepressants.

Most patients were on more than one medication, so they could not be sure that if Abilify alone caused these adverse effects. Nevertheless, there were three confirmed suicides and several episodes of severe emotional stress or physical misery. Eight people reported akathisia and six reported unusual anger or aggression. Two of the aggression episodes were violent physical attacks on family members. One woman assaulted her husband when she had “bizarre and frightening thoughts.”

At the other extreme, 14 people reported over-sedation and cognitive slowing, with memory, concentration and word-finding problems. About half felt a profound emotional numbing, an inability to feel pleasure or care about anything. One man regretted this state, but felt it was better than his prior severe depression. For the rest, however, it brought new or worse depression. Three felt trapped at home by “total lack of interest in life” along with anxious depression; loss of the ability to pursue, or even care about, formerly cherished goals was painful for others. Most reported suicidal thoughts of varying intensity.

Three people had tremors, but of these cases cleared up when they stopped the drug. Four others had tardive dyskinesia. Their symptoms started after using Abilify for at least a year; and they continued despite stopping the drug. “They found their condition painful, debilitating, disfiguring and socially isolating.” Four men reported sexual dysfunction. One man had a gambling problem that began two months after starting Abilify. “Eight people had their worst problems on stopping Abilify.”

Johanna Ryan, who wrote the article on RxISK, said that most antidepressants are metabolized in the liver by the same enzymes that process Abilify. So the resulting “traffic jam” will effectively raise the level of Abilify in your blood. Some SSRIs have also a stronger effect than others on this issue. “Your actual Abilify levels might be 150% to 300% of your official dose.” Side effects such as agitation, anxiety, insomnia and nervousness commonly occur with antidepressants and can increase your chances of akathisia with Abilify.

In other words, the “little baby dose” was an illusion. Even 2 mg was bigger than it seemed – and doses over 5 mg could put you on a par with patients taking Abilify for psychosis. (Those patients may be taking excessive doses as well: Two patients with psychotic symptoms in the RxISK group found they did better on half the dose their doctor initially prescribed.)

In “Dodging Abilify” on RxISK, Johanna Ryan related how a psychiatrist had tried to convince her once to try Abilify for her depression. He told her “these drugs” (referring to Abilify) weren’t really antipsychotics since they were used to treat several kinds of things. “’Oh, come on,’ he coaxed. ‘We’re talking about little baby doses here, just a fraction what they give people for schizophrenia.’” Like other antipsychotics, it blocks certain dopamine receptors. Unlike them, it is a “partial agonist,” meaning it activates others.

Now let’s go back to the cute Abilify commercials. This one includes a woman and her umbrella. Listen to see if Abilify is ever referred to as an antipsychotic or neuroleptic. As a matter of fact, it wasn’t. The same is true for the link to the commercial above. Admittedly, these commercials were pushing Abilify as an add-on to antidepressants. But now download the FDA Medication Guide for Abilify, and search through it. You won’t find the word “antipsychotic.” The word “neuroleptic” appears once within the listing of a side effect: neuroleptic malignant syndrome. Abilify is described and presented as an “antidepressant medicine” throughout the medication guide. There were other antipsychotics that seemed to also minimize using these two words (neuroleptic and antipsychotic) in referring to their drug, but not to the same extent as noted for Abilify. My thought is Otusuka decided that referring to Abilify as an antipsychotic or neuroleptic was bad for business.

So Abilify is a neuroleptic that apparently wants to be known as an antidepressant and absolutely HATES to be referred to as an antipsychotic. Yet it has the same kinds of adverse side effects as other neuroleptics. (If it walks like a duck and talks like a duck …) And of all the current antipsychotics on the market, Proteus partnered with Otsuka first to create an Abilify smart pill to facilitate medication compliance with its drug. To borrow a phrase from addiction recovery, it sounds like Abilify is in denial about being an antipsychotic.

10/14/15

Antipsychotic Big Bang

Duff Wilson wrote in “Side Effects May Include Lawsuits” that antipsychotics were a niche product for decades. Yet they have recently generated sales that have surpassed that of “blockbusters like heart-protective statins.” In the 1990s, pharmaceutical companies began marketing them for much broader uses than the original FDA approved uses for more serious mental illnesses, like schizophrenia and bipolar disorder. A Scientific American article reported that pediatric prescriptions for atypical antipsychotics rose 65%—from 2.9 million to 4.8 million—between 2002 and 2009. And a New York Times article noted that federal investigators have found widespread overuse of psychiatric drugs by older Americans with Alzheimer’s disease.

There are two more facts to introduce you to about neuroleptics or atypical antipsychotics. First, in 2008, antipsychotics sales reached $14.6 billion, making them the biggest selling therapeutic class of drugs in the U.S. Second, each of the following pharmaceutical companies that marketed antipsychotics has been investigated for misleading marketing under the False claims Act. All their neuroleptics—Risperdal (risperidone; Johnson & Johnson), Zyprexa (olanzapine; Eli Lilly), Seroquel (quetiapine; AstraZeneca), Geodon (ziprasidone; Pfizer), and Abilify (aripiprazole; Bristol-Myers Squibb and Otsuka)—are now off patent.

The primary use off-label use of neuroleptics for the elderly and with children has been for behavioral control. A recent study commissioned by the Pennsylvania Department of Human Services found that children between the ages of 6 and 18 who were in foster care was four times higher than other youth in Medicaid. More than half of these youth had a diagnosis of ADHD. “This is concerning, as the majority of these youth did not have another diagnosis that clinically indicated the use of antipsychotics.” Risperidone was the most frequently prescribed antipsychotic medication among the youth. However, Abilify and Seroquel grew to exceed risperodone over the course of the study. Zyprexa was the least commonly used antipsychotic among all youth.

A trade group for nursing homes, The American Health Care Association, indicated that while antipsychotics helped some dementia patients who have hallucinations or delusions, “They also increase the risk of death, falls with fractures, hospitalizations and other complications.” The American Psychiatric Association, among others pointed to a JAMA Psychiatry study that showed mortality risks increased in patients given antipsychotics to reduce their symptoms of dementia. Another study published in Health Policy said the benefits and harms of using antipsychotic medications in nursing homes should be reviewed.

Antipsychotic medication use in nursing home residents was found to have variable efficacy when used off-label with an increased risk of many adverse events, including mortality, hip fractures, thrombotic events, cardiovascular events and hospitalizations.

Another “add on” area for neuroleptic use is when it is used with an antidepressant for “treatment resistant” depression. On BuzzFeed, Cat Ferguson reported how the sale of antipsychotics such as Abilify, and Zyprexa “skyrocketed” as they were approved to treat depression as an add-on medication. Seroquel is not FDA approved to treat major depression, but along with Abilify and Zyprexa is approved to treat bipolar depression in adults. Zyprexa and Seroquel are approved for some indications of bipolar disorder in adolsecents, but Abilify is only used off label with bipolar children, having “low or very low evidence of efficacy.” See the Psychopharmacology Institute for more information on these drugs and their approved and off-label uses.

Ferguson quoted a few psychiatrists expressing concern about the antipsychotic boom, and there are some surprises given other stands they’ve taken. Allen Frances, the former chair for the DSM-IV, agreed there has been heavy marketing of antipsychotics. He thought they are prescribed too quickly for depression and without clear indication of their efficacy. He added there seemed to be pressure from the pharmaceutical companies. He said: “These drugs should have a narrow indication, and instead they’ve become the highest revenue-producing drugs in America.”

Over the past few years Allen Frances has become an outspoken critic of some psychiatric practices, including the overuse of antipsychotics and antidepressants. He’s also been critical of the DSM-5. He’s even written Saving Normal to address his concerns with psychiatry and psychiatric practice. Search for his name here to find several articles where he is mentioned.

I was surprised and encouraged to see Jeffrey Lieberman, the chair of psychiatry at the Columbia University College of Physicians and Surgeons express concern with the over prescribing of antipsychotics. Lieberman has positioned himself as defender of psychiatry and psychiatric practice, recently publishing Shrinks. You can also search his name here to see other articles interacting with his book and position on psychiatry. Lieberman said that antipsychotic medication should be used sparingly in treating nonpsychotic disorder, including depression. He said: “I think there’s the possibility that antipsychotics are overprescribed, not just for depression, but in other areas.”

My point is that when two prominent psychiatrists with opposing views on many areas of psychiatry and psychiatric practice agree that antipsychotics are overused, pay attention. Both Frances and Lieberman have pointed out elsewhere how pharmaceutical marketing strategies contribute to this problem, but some pharma companies and representatives put the blame back on doctors. An Eli Lilly spokesperson said pharmaceutical companies aren’t responsible for how their drugs are used by doctors. “Physicians make prescribing decisions, not pharmaceutical companies. . . . While certainly we inform doctors of the benefits and risks of our medicine, it’s really up to physicians to prescribe the right medicine.”

But this attempt to deflect responsibility onto physicians is a cop out when you consider the marketing done by pharmaceutical companies for their products. In this YouTube advertisement for Abilify as an antidepressant add-on, you see how Bristol-Myers Squibb actively encouraged individuals to “ask your doctor if Abilify is right for you.” Pay attention to the fact that the first thirty seconds verbally describes how Abilify can help, while the rest of the 90-second commercial has the woman and her family going on a picnic while the adverse side effects are described.

Another problem is that all clinical trials for drug approval are done over short periods of time—six or eight weeks—antipsychotics included. But what are the long-term consequences of antipsychotics? As Dan Iosifescu, the director of the Mood and Anxiety Disorders Program at Ichan School of Medicine at Mount Sinai Hospital said, “It’s just a fallacy to take short-term data and extrapolate it for long term.” His bottom line is that antipsychotics tend to be helpful in the short term, but can have major consequences in the long term.

Thomas Glasen, writing in Schizophrenic Bulletin, weighed the pros and cons of medication treatment for psychosis. In the case for medication, he noted that the benefits of medication were profound. The therapeutic power of antipsychotic medication had been validated in countless studies and was now the primary treatment of schizophrenia. “In today’s climate, treating schizophrenia without medication mobilizes high anxiety among treaters for the safety of their patients from irrationality and for the safety of themselves from litigation.” However, in the case against medication, Glasen said:

Antipsychotics obscure the pathophysiology of psychosis by altering the neurobiology of the brain and the natural history of [the] disorder. . . . Medication can be lifesaving in a crisis, but it may render the patient more psychosis-prone should it be stopped and more deficit-ridden should it be maintained.

So how do individuals on long-term antipsychotics do? In Anatomy of an Epidemic, Robert Whitaker described Martin Harrow’s presentation of a long-term study funded by NIMH on sixty-four individuals diagnosed as schizophrenic between 1975 and 1983. Whitaker had just reviewed a series of studies questioning whether there was a long-term benefit to the use of antidepressants before discussing the Harrow study. He then said: “If the conventional wisdom is to be believed, then those who stayed on antipsychotics should have had better outcomes.” Harrow found that after two years, there was evidence that the off-med group was doing slightly better than the group on drugs.

Then, over the next thirty months, the collective fates of the two groups began to dramatically diverge. The off-med group began to improve significantly, and by the end of 4.5 years, 39 percent were “in recovery” and more than 60 percent working.

The outcomes for the medication group worsened and this divergence continued. At the fifteen-year follow up, 40 percent of those off drugs were in recovery and more than half were working; only 28 percent suffered from psychotic symptoms. “In contrast, only 5 percent of those taking antipsychotics were in recovery, and 64 percent were actively psychotic.” The 2007 Harrow study can be found here. Harrow said that not only was there a significant difference in global functioning between the two groups, 19 of the 23 (83%) schizophrenic patients with uniformly poor outcome after fifteen years were on antipsychotics.

Harrow et al. (2014) continued his study and reported data in Psychological Medicine at the twenty-year stage of his follow-up schedule. Here he investigated whether multi-year treatment with antipsychotics reduced or eliminated psychosis; and whether the results were superior to individuals in the non-medicated group. The data showed that the pattern noted above by Whitaker in Harrow’s 2007 report continued: “A surprisingly high percentage of SZ prescribed antipsychotic medications experienced either mild or more severe psychotic activity.” The figure to the left, originally from the 2014 Harrow et al. report, shows that 68% of the medication group experienced psychotic activity, while only 8% of the off-med group experienced any psychotic activity. The source of the figure was a slide reproducing the Harrow data in a presentation by Robert Whitaker at the “More Harm than Good” conference sponsored by the Council for Evidence-Based Psychiatry (CEP). The slides and videos of the presentation can be found here.

Harrow et al. thought the high percentage of the medication group experiencing psychotic activity was influenced by two factors. One was the high vulnerability to psychosis of many schizophrenic patients, leading to a high risk of psychosis. But that begs the question of how the medication group in the study had such a high number of patients “at risk of psychosis.” Given the above data, their second factor seems to have been the more important factor: prolonged use of antipsychotics (or partial dopamine blockers) may produce a medication-generated build-up of supersensitive dopamine receptors or excess dopamine receptors.

The production of excess or supersensitive dopamine receptors would then be an iatrogenic, drug induced effect from the long-term use of antipsychotics. The brain increases or sensitizes the receptors, thus compensating for the blockade of original receptors in the postsynaptic neuron. Again, drawing from Whitaker’s presentation slides at the CEP conference, it would look like this:

The above presentation of Harrow’s data and the discussion from Whitaker’s CEP presentation seem to affirm Glasen’s thesis that antipsychotics could alter the neurobiology of the brain. Antipsychotics reduce the activity of dopamine systems, stimulating the increase of receptors. When the antipsychotic is tapered or withdrawn, this would not immediately diminish the number of additional dopamine receptors produced by the brain to compensate for the dopamine blocking action of the antidepressant. With decreased antipsychotic levels, the result would be increased activation of the postsynaptic neurons because of the greater number receptors to absorb dopamine.

The person’s symptoms could intensify through the increased absorption of dopamine because of this disregulation of the dopamine system. In other words, tapering off of antipsychotics could activate symptoms like mania, paranoia and hallucinations because of the chemical imbalance produced by the medication. The experience of mania from a too sudden withdrawal of an antipsychotic is in this view, likely a withdrawal or discontinuation symptom instead of proof that the person needs to remain on an antipsychotic because they have a chemical imbalance. Robert Whitaker’s conclusion in Anatomy of an Epidemic was:

What the scientific literature reveals is that once a person is on an antipsychotic, it can be very difficult and risky to withdraw from the medication, and that many people suffer severe relapses. But the literature also reveals that there are people who can successfully withdraw from the medications and that it is this group that fares best in the long term.

Faith Seeking Understanding

Charles Sigler, D.Phil.

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