Aripiprazole and Impulse-Control Disorders: A Recent FDA Warning and a Case Report

Rohan Dhillon, MBBS, FRANZCP, MClinSc; Tarun Bastiampillai, MBBS, BMedSc, FRANZCP; Claudia Z. Cao, MBBS; Thomas G. Eckert, MBBS; Prashant Tibrewal, MD, FRANZCP

Prim Care Companion CNS Disord 2017;19(1):16l02003

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To the Editor: Aripiprazole is a unique antipsychotic with partial dopamine agonist properties increasingly linked to pathological gambling. The US Food and Drug Administration (FDA) released in May 2016 a safety announcement in relation to aripiprazole and the induction of impulse-control disorders (ICD), inclusive of pathological gambling, hypersexuality, compulsive shopping, and compulsive eating.

Case report. Mr A, a 35-year-old married man employed as a mechanic, was diagnosed with schizophrenia (as per DSM-IV criteria) in 2007 and commenced on aripiprazole 10 mg/d.

Aripiprazole and Impulse-Control Disorders: A Recent FDA Warning and a Case Report

To the Editor: Aripiprazole is a unique antipsychotic with partial dopamine agonist properties increasingly linked to pathological gambling.1,2 The US Food and Drug Administration (FDA) released in May 2016 a safety announcement3 in relation to aripiprazole and the induction of impulse-control disorders (ICD), inclusive of pathological gambling, hypersexuality, compulsive shopping, and compulsive eating.

Case report. Mr A, a 35-year-old married man employed as a mechanic, was diagnosed with schizophrenia (as per DSM-IV criteria) in 2007 and commenced on aripiprazole 10 mg/d. His past history included attention-deficit/hyperactivity disorder, alcohol abuse, and sporadic use of tetrahydrocannabinol and methamphetamines but no history of significant gambling or compulsive shopping.

Within 4 weeks of commencing aripiprazole, he reported an increased urge to gamble, with weekly spending of US $100 on slot machines. Due to persistent psychosis, Mr A’s aripiprazole dose was increased to 15 mg/d, with an increase in gambling to $200 weekly between 2007 and 2015. Aripiprazole was increased to 20 mg/d in 2012 due to a relapse of psychosis, but there was no change in his level of pathological gambling. Following the increase in aripiprazole dose (15 mg/d to 20 mg/d), Mr A began to compulsively shop, purchasing significant amounts of mechanical work tools, which were never used. He also became hypersexual on treatment with aripiprazole 10 mg, with a dose-dependent increase in symptoms with 15 mg/d, contributing to marital tension. Mr A’s hypersexuality and accumulated losses of $200,000 due to pathological gambling and compulsive shopping resulted in the breakdown of his marriage.

After Mr A’s family discovered that aripiprazole could cause pathological gambling, they informed his general practitioner in 2015, who then ceased aripiprazole treatment. This cessation followed by the commencement of risperidone led to the cessation of his pathological gambling, hypersexuality, and compulsive shopping urges within 2 weeks, without destabilizing his schizophrenia. Importantly, as a result of his ICD resolution, he reunited with his wife with no ongoing relationship or financial difficulties.

Dopamine agonists for patients with Parkinson’s disease are associated with an increased risk of developing ICD.4-6 Of interest, it has been shown that aripiprazole, a partial dopamine agonist, resulted in more severe pathological gambling than full dopamine agonist agents.6 It has been postulated that dopamine agonists with a higher relative affinity for D3 than D2 receptors, such as pramipexole, resulted in significantly higher rates of ICD, thus implicating D3 receptor agonism more specifically with ICD.5,7 Aripiprazole is generally thought to be a partial D2 agonist, but has also been shown to have high affinity for the D3 receptor.8 The D3 receptor is predominantly found in the striatal, prefrontal cortex, and insula limbic circuits involved in key reward pathways, which have been implicated in the development of pathological gambling.9

The FDA, through their Adverse Event Reporting System, identified 184 cases of a possible association between ICD and aripiprazole, with 17 cases published in the medical literature.3 Pathological gambling was the most common, with 164 cases (89%) reported; others included 9 cases of hypersexuality, 4 cases of compulsive buying, 3 cases of compulsive eating, and 4 cases with multiple ICD.3 This case report adds to the existing literature and is one of the few specifically linking aripiprazole with induction of multiple ICD in a single patient with no history of ICD, with complete resolution of these symptoms following its cessation. The FDA safety warning means that clinicians should specifically screen for ICD before prescribing aripiprazole, educate patients about potential risks, and specifically monitor for ICD following commencement or dose increases. More research is required to specifically identify the dopamine receptor pathway and specific dopamine agonists involved in the induction of ICD, which could then lead to more specific therapeutic targets for pathological gambling and ICD.

References

1. Gaboriau L, Victorri-Vigneau C, Gérardin M, et al. Aripiprazole: a new risk factor for pathological gambling? a report of 8 case reports. Addict Behav. 2014;39(3):562-565. PubMed doi:10.1016/j.addbeh.2013.11.005

2. Mété D, Dafreville C, Paitel V, et al. Aripiprazole, gambling disorder and compulsive sexuality. Encephale. 2016;42(3):281-283. PubMed doi:10.1016/j.encep.2016.01.003

3. FDA Drug Safety Communication. FDA warns about new impulse-control problems associated with mental health drug aripiprazole (Abilify, Abilify Maintena, Aristada). US Food and Drug Administration Web site. http://www.fda.gov/Drugs/DrugSafety/ucm498662.htm. Updated May 3, 2016. Accessed May 12, 2016.

4. Clark L, Averbeck B, Payer D, et al. Pathological choice: the neuroscience of gambling and gambling addiction. J Neurosci. 2013;33(45):17617-17623. PubMed doi:10.1523/JNEUROSCI.3231-13.2013

5. Seeman P. Parkinson’s disease treatment may cause impulse-control disorder via dopamine D3 receptors. Synapse. 2015;69(4):183-189. PubMed doi:10.1002/syn.21805

6. Grall-Bronnec M, Sauvaget A, Perrouin F, et al. Pathological gambling associated with aripiprazole or dopamine replacement therapy: do patients share the same features? a review. J Clin Psychopharmacol. 2016;36(1):63-70. PubMed doi:10.1097/JCP.0000000000000444

7. Ahlskog JE. Pathological behaviors provoked by dopamine agonist therapy of Parkinson’s disease. Physiol Behav. 2011;104(1):168-172. PubMed doi:10.1016/j.physbeh.2011.04.055

8. Shapiro DA, Renock S, Arrington E, et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology. 2003;28(8):1400-1411. PubMed doi:10.1038/sj.npp.1300203

9. Potenza MN. Neurobiology of gambling behaviors. Curr Opin Neurobiol. 2013;23(4):660-667. PubMed doi:10.1016/j.conb.2013.03.004

Rohan Dhillon, MBBS, FRANZCP, MClinSca

Tarun Bastiampillai, MBBS, BMedSc, FRANZCPb,c

Claudia Z. Cao, MBBSa

[email protected]

Thomas G. Eckert, MBBSd

Prashant Tibrewal, MD, FRANZCPa

aCramond Clinic, Department of Psychiatry, The Queen Elizabeth Hospital, Adelaide, Australia

bDepartment of Psychiatry, Flinders University, Adelaide, Australia

cSouth Australian Health and Medical Research Institute, Adelaide, Australia

dMedical School, University of Adelaide, Adelaide, Australia

Potential conflicts of interest: None.