Abilify (aripiprazole) is an atypical antipsychotic drug used to treat bipolar disorder and schizophrenia, which is also indicated as adjunctive treatment of major depressive disorder and Tourette’s syndrome (1). Aripiprazole was approved by the U.S. Food and Drug Administration (FDA) for the treatment of acute exacerbations and maintenance therapy of schizophrenia in 2002, and shortly afterward, it was also approved by the European Medicine Agency (EMA) for the same indication (2). In 2009, it was also approved in Canada (3). In the United States, Abilify is jointly marketed by Bristol-Myers Squibb together with the Japanese pharmaceutical company Otsuka.
Abilify (aripiprazole) mechanism of action
Aripiprazole acts by binding to the Dopamine receptor D2 and stimulating it by acting as a partial agonist (4). This mechanism of action is the opposite of all the other atypical antipsychotics such as risperidone, clozapine, and quetiapine, which act by antagonizing this same receptor. Aripiprazole also acts as a partial agonist of the 5-HT1A and 5-HT2C serotonin receptors, and as an antagonist of the 5-HT2A and 5-HT7 serotonin receptors (5). Although its mechanism of action in schizophrenia has never been fully elucidated, Abilify acts on the dopaminergic pathways by modulating neurotransmission. Overactivity of some of these pathways such as the mesolimbic one may, in fact, trigger schizophrenia symptoms such as delusions and hallucinations. On the other hand, the unique activity of aripiprazole as a D2 receptor agonist may increase dopaminergic activity to optimal levels in pathways where it is reduced, such as the mesocortical one (6, 7).
Abilify (aripiprazole) side effects and dangers
Like all the other atypical antipsychotics, aripiprazole is associated with several side effects. The most common among them include weight gain, anxiety, dizziness, sleep disturbances, nausea and headaches (1). However, second-generation antipsychotic medications are associated with other significantly dangerous risks, namely a life-threatening neurological disorder called Neuroleptic malignant syndrome (NMS), and an irreversible form of tardive dyskinesia (a disorder characterized by repetitive, involuntary muscle movements). Also, the weight gain that is common in patients under treatment with these drugs may also increase the risk of cardiovascular accidents in diabetic patients, due to a danger of increased blood sugar and elevated lipids (8). Atypical antipsychotics are also associated with an increased risk of diabetes in otherwise healthy individuals (9)
Although Cochrane and Lancet reviews indicated that aripiprazole side effects and tolerability are in the middle range compared to the other antipsychotic drugs, some concerning adverse reactions do exist for this specific drug (10, 11). In 2008, the FDA updated Abilify’s warning label to include an increased risk of death in the elderly affected by dementia, and of suicidal thoughts in young patients with depression (12). Due to a possible overstimulation of the dopaminergic receptors in the brain, this drug has also been recently associated with other less-known side effects caused by a loss of impulse control ion the subject. Aripiprazole may, in fact, impair the patient’s ability to suppress his urges, leading to aberrant behaviors such as binge eating, compulsive gambling and sex addiction (hypersexuality) (13). Although no extensive studies have been conducted to investigate further this risk specifically with this drug, several case reports highlighted a strong connection between the use of Abilify and compulsive disorders. Many patients who exhibited compulsive gambling and hypersexuality while taking medication saw their symptoms subside shortly after they stopped taking it (14, 15, 16, 17).
Abilify and the off-label prescription scandal and controversial effectiveness
In 2011, the U.S. antipsychotics drug market grew up to immense proportions, with over 3 million U.S. citizens receiving this prescription at a cost of $18,2 billion. From 2013 to 2014, Abilify alone grossed almost $7 billion dollars to its manufacturer, the pharmaceutical giant Bristol-Myers Squibb (18, 19). Although a large portion of these sales came from the widespread habit of prescribing this drug for the treatment of depression, these drugs are often used for off-label indications for which they were never approved for, such as insomnia and anxiety (which are listed among the side effects of these drugs by the way). Yearly antipsychotics prescriptions grew by 93 percent in ten years, from 28 million in 2001 to 54 million in 2011, with aripiprazole and Seroquel (quetiapine) being the two largest players in the marketplace (18, 20). More than the 85 percent of total second generation antipsychotics medication have been prescribed to patients who did not have schizophrenia or bipolar disorder (20, 21). What is even more concerning, is the fact that antipsychotic use increased from 2006 to 2010 for adolescents to limit impulsive and aggressive behavior rather than psychotic symptoms (22).
Even the same rationale that led to the prescription of antipsychotic drugs in depressed patients is quite controversial. If a patient does not get better with a first antidepressant medication, the psychiatrist may, in fact, increase its dosage or add another similar drug. However, most antidepressants, although much less expensive, may require several weeks to work, and are often associated with detrimental side effects that many patients fail to tolerate. Even though other drugs such as the SSRI antidepressants could be a much safer alternative, many physicians will just catch the shortcut option and end up prescribing antipsychotics for its rapid effects (18).
Second generation antipsychotics such as aripiprazole also failed to prove their effectiveness in the long run, and patients often discontinue them because of the intolerable long-term effects (23, 24). Abilify failed to prove it was able to provide an appreciable improvement of schizophrenic patients’ quality of life, and only small-to-moderate-sized benefits have been shown for adjunctive depression therapy (25). The only trial that extensively investigated the effectiveness of aripiprazole was, in fact, funded by Otsuka Pharmaceutical Co. and Bristol-Myers Squibb, and has been uncritically cited in the subsequent scientific literature despite its evident limitations (26). These medications, other than showing only modest benefits over placebo in the long-term, are not devoid of significant, and often life-threatening side effects (27).
Abilify lawsuits and the Bristol-Myers Squibb $515 million fine
Today several patients filed many Abilify lawsuits to held Bristol-Myers Squibb accountable for the alleged injuries they suffered because of the side effects that the pharmaceutical company failed to warn the public about. In 2008, a retired a Minnesota citizen named Gary Charbonneau filed a lawsuit against Mirapex (pramipexole), a drug that possesses similar dopaminergic effects after he lost $260,000 to compulsive online casino gambling. The court ordered the drug’s manufacturer, Boehringer Ingelheim, to pay Charbonneau $8.3 million dollars for negligence in warning about the risk (28). Back in 2007, Bristol-Myers Squibb already faced a large mass tort litigation, because the company illegally marketed the drug to nursing homes, despite the risk of mortality in elder patients affected by dementia. The U.S. Department of Justice forced the company to pay the amount of $515 million to settle federal charges, as aripiprazole never received approval from the FDA for the treatment of dementia (29).
Article by Dr. Claudio Butticè, PharmD.
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- European Medicines Agency (EMA) – Abilify (aripiprazole). (Accessed March 2016)
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- Jordan S, Koprivica V, Chen R, Tottori K, Kikuchi T, Altar CA (2002). “The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A receptor“. Eur J Pharmacol 441 (3): 137–140. doi:10.1016/S0014-2999(02)01532-7.
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- Brunton LB, Lazo JS, Parker KL, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2010.
- “Abilify”. The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
- Baker RA, Pikalov A, Tran QV, Kremenets T, Arani RB, Doraiswamy PM. Atypical antipsychotic drugs and diabetes mellitus in the US Food and Drug Administration Adverse Event database: a systematic Bayesian signal detection analysis. Psychopharmacol Bull. 2009;42(1):11-31.
- El-Sayeh HG, Morganti C (Apr 19, 2006). “Aripiprazole for schizophrenia.“. Cochrane database of systematic reviews (Online) (2): CD004578.
- Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM (2013). “Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis”. Lancet 382 (9896): 951–62.
- Food and Drug Administration (FDA). Safety – Abilify (aripiprazole) Tablets August 2008. (Accessed March 2016)
- Moore TJ, Glenmullen J, Mattison DR. Reports of Pathological Gambling, Hypersexuality, and Compulsive Shopping Associated With Dopamine Receptor Agonist Drugs. JAMA Intern Med. 2014;174(12):1930-1933. doi:10.1001/jamainternmed.2014.5262
- Neil Smith, Nathan Kitchenham, Henrietta Bowden-Jones. Pathological gambling and the treatment of psychosis with aripiprazole: case reports. The British Journal of Psychiatry Jul 2011, 199 (2) 158-159; DOI: 10.1192/bjp.bp.110.084996
- Roxanas, M.G. . Pathological Gambling and Compulsive Eating Associated with Aripiprazole. Aust N Z J Psychiatry March 2010 44: 291.
- Schlachetski, J. et al. Aripiprazole induced hypersexuality in a 24-year-old female patient with schizoaffective disorder? Journal of Clinical Psychopharmacology: October 2008 – Volume 28 – Issue 5 – pp 567-568 doi: 10.1097/JCP.0b013e31818582de
- L. Gaboriau, C. Victorri-Vigneau, M. Gérardin, G. Allain-Veyrac, P. Jolliet-Evin, M. Grall-Bronnec. Aripiprazole: A new risk factor for pathological gambling? A report of 8 case reports. Addictive Behaviors, Volume 39, Issue 3, Pages 562-565
- Richard A. Friedman, M.D. A Call for Caution on Antipsychotic Drugs. New York Times, September 24, 2012. (Accessed July 2016)
- Art Levine. Abilify Is Top-Selling U.S. Drug — But New Reports Question Long-Term Antipsychotic Use, Cite Need for Personalized Services. The Huffington Post, December 12, 2014. (Accessed April 2016)
- Alexander, G. Caleb et al. “INCREASING OFF-LABEL USE OF ANTIPSYCHOTIC MEDICATIONS IN THE UNITED STATES, 1995-2008.” Pharmacoepidemiology and drug safety 20.2 (2011): 177–184. PMC. Web. 9 Mar. 2016.
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- Olfson M, King M, Schoenbaum M. Treatment of Young People With Antipsychotic Medications in the United States. JAMA Psychiatry. 2015;72(9):867-874. doi:10.1001/jamapsychiatry.2015.0500.
- Thomas Insel. Director’s Blog: Antipsychotics: Taking the Long View. National Institute of Mental Health (NIMH), August 28, 2013. (Accessed March 2016)
- Jeffrey A. Lieberman, et al. Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia. N Engl J Med 2005; 353:1209-1223, DOI: 10.1056/NEJMoa051688
- Spielmans GI, Berman MI, Linardatos E, Rosenlicht NZ, Perry A, Tsai AC (2013) Adjunctive Atypical Antipsychotic Treatment for Major Depressive Disorder: A Meta-Analysis of Depression, Quality of Life, and Safety Outcomes. PLoS Med 10(3): e1001403. doi:10.1371/journal.pmed.1001403
- Tsai AC, Rosenlicht NZ, Jureidini JN, Parry PI, Spielmans GI, Healy D (2011) Aripiprazole in the Maintenance Treatment of Bipolar Disorder: A Critical Review of the Evidence and Its Dissemination into the Scientific Literature. PLoS Med 8(5): e1000434. doi:10.1371/journal.pmed.1000434
- Anthony P. Morrison, Paul Hutton, David Shiers, Douglas Turkington. Antipsychotics: is it time to introduce patient choice? The British Journal of Psychiatry Aug 2012, 201 (2) 83-84; DOI: 10.1192/bjp.bp.112.112110
- Jane Akre. $8.2 Judgment Against Parkinson’s Drug Mirapex. Northwest Parkinson’s Foundation. August 06, 2008. (Accessed March 2016)
- Department of Justice. (2007). Bristol-Myers Squibb to pay more than $515 million to resolve allegations of illegal drug marketing and pricing. (Accessed March 2016)
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