ABILIFYand

COMPULSIVE GAMBLING

• An antipsychotic drug approved by the FDA to treat bipolar disorder, major depression, and schizophrenia

• Often used in tandem with other medications to treat major depression

• Emerged on U.S. market in 2002

• Developed by Otsuka Pharmaceutical and marketed in collaboration with Bristol Myers Squibb Co.

• Top-selling pharmaceutical drug in the U.S. in 2013 and 2014

• Generic version approved on April 28, 2015

On May 3, 2016 the FDA required that a warning be added to the Abilify label in the U.S. directing patients and caregivers to monitor experiences of uncontrollable behavior, such as compulsive gambling, while taking Abilify. The warning also specifies that doctors should notify patients of these additional risks and specifically ask about any new or increasing urges while they are being treated with the drug.

FDA REQUIRES COMPULSIVE GAMBLING WARNING

What is Abilify (aripiprazole)?

What’s the problem?Abilify manipulates dopamine levels in the brain. This can lead to uncontrollable and compulsive behaviors such as: • Gambling• Shopping• Sexual behaviors• EatingWhy focus on gambling?Losses from gambling are both quantifiable and catastrophic/life altering: • Drained bank accounts and 401ks• Marital and family problems• Home foreclosures• Bankruptcies

Warnings in Canada and EuropeIn 2011 both Canada and Europe added a warning to Abilify’s label regarding the drug’s potential to cause compulsive gambling after health agencies in both locations found a positive link between aripiprazole and possible compulsive gambling. Otsuka’s report submitted to the European Medicines Agency acknowledged a total of 23 “serious” reports of pathological gambling while taking Abilify. In the medical assessment of the reported pathological gambling cases, defendants concluded that “a casual role of aripiprazole [Abilify] could not be excluded.”Abilify September 2011 6-Month Periodic Safety Update Report, p. 149.

Unapproved in Europe as add-on treatment for depression

The European Medicines Agency declined to approve Abilify as an add-on treatment for depression because of concerns about its efficacy for that indication.European Medicines Agency, Withdrawal Assessment Report for Abilify (Jan. 20, 2010), available at: http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessment_report/2010/02/WC500074519.pdf.

According to a rigorous study by the Cochrane Collaboration, there is limited evidence that Abilify leads to symptom reduction when added to antidepressants, and side effects are more frequent under Abilify augmentation treatment.K. Komossa et al., Second-Generation Antipsychotics for Major Depressive Disorder and Dysthymia (Review), THE COCHRANE COLLABORATION, Issue 2 at 2 (John Wiley & Sons, 2012), available at http://www.updatesoftware.com/BCP/WileyPDF/EN/CD008121.pdf.

How does Abilify work?Abilify is chemically classified as a partial and full dopamine agonist. Agonists activate receptors in the brain, whereas antagonists block receptors. Aripiprazole is different from other antipsychotics because it is the only approved antipsychotic that augments dopamine levels in the brain through agonism instead of antagonism.

Dopamine is a neurotransmitter that plays a large role in the brain’s reaction to reward and pleasure. When a drug such as Abilify changes dopamine levels by either blocking or allowing receptors to take in dopamine, compulsive behaviors can result if over-stimulation of a reward pathway occurs.

Scientific literature has identified dopamine as a potential cause of pathological gambling for years.

See, e.g., Chau et al., The Neural Circuitry of Reward and Its Relevance to Psychiatric Disorders, CURR. PSYCHIATRY REP. 2004 Oct;6(5):391-9; Dodd et al., Pathological Gambling Caused by Drugs Used to Treat Parkinson Disease, ARCH NEUROL. 2005;62(9): 1377-1381.

Key Concept – Challenge, De-challenge, Re-challenge

FDA, Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiological Assessment, at 6 (Mar. 2005), available at http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126834.pdf; Federal Judicial Center, Reference Manual on Scientific Evidence, at 605 (Nat’l Academies Press ed., 3d ed. 2011), available at http://www.fjc.gov/public/pdf.nsf/lookup/SciMan3D01.pdf/$file/SciMan3D01.pdf.

CHALLENGE Patient begins taking Abilify as part of their medication regimen

ADVERSE EXPERIENCE Patient experiences compulsive gambling behaviors that are atypical of his/her personality

DECHALLENGE Patient stops taking Abilify

+ DECHALLENGE Compulsive gambling fades or disappears once the patient stops taking Abilify

RECHALLENGE Following the fading or disappearance of compulsive gambling behavior, thepatient begins taking Abilify again

+ RECHALLENGE Patient experiences similar compulsive gambling behaviors once he/she begins taking Abilify again

*Both a + DECHALLENGE and + RECHALLENGE are considered evidence that a drug caused a particular effect.

Our CriteriaCLIENT HISTORY:• Cannot have a history of problematic gambling habits prior to

taking Abilify

• The patient cannot also have taken other dopamine agonists which cause compulsive behavior (e.g., Mirapex or Requip, which are often prescribed for treatment of Parkinson’s or Restless Leg Syndrome)

GAMBLING:• Must have lost at least $30,000 while gambling and taking

Abilify• Gambling losses must be traceable – (see next page for

details)• Must have experienced compulsive gambling while taking

Abilify• Urge to gamble must have faded or stopped after

discontinuing Abilify within a couple months at most (challenge, de-challenge, and possibly re-challenge)

USAGE:• Took Abilify for at least three months

• Most or all Abilify use occurred after 2006: obtaining records that are more than 10 years old is often difficult

• If taken after April 28, 2015, cannot be generic

Traceable Gambling Losses

Casino statements and player’s card statements

Credit card/ PayPal charges at online casinosBank transfers to online gambling sites

ATM withdrawals, credit card cash advances, etc. at casinos

Actual lottery tickets/scratch-offs

ATM withdrawals at the same gas station/establishment where always purchase lottery tickets

Leas

t des

irabl

efo

rms o

f pro

of

Mos

t des

irabl

efo

rms o

f pro

of