Problem Gambling Associated With Aripiprazole in First-Episode Psychosis Patients: A Series of 6 Case Reports.

BACKGROUND: Aripiprazole (ARI), an antipsychotic drug used to treat various mental health disorders, has recently been associated with the emergence of problem gambling (PBG). However, few cases have been reported in the schizophrenia-related psychotic disorders population, and even fewer provided sufficient details to systematically assess the causality of the association. METHODS: This article describes 6 cases with first-episode psychosis in whom PBG emerged while on ARI. Detailed information was gathered from clinical staff and patients' families to systematically assess the causal link between ARI and the emergence of PBG using the Naranjo and Liverpool Adverse Drug Reaction scales. FINDINGS: Five of these cases were previously diagnosed with a substance use disorder and/or cluster B personality traits. Five had received a more potent dopaminergic antagonist treatment before being switched to ARI. Two of them had presented PBG before being diagnosed with a psychotic disorder. The level of certainty about the causal role of ARI varied from possible to certain, and in 4 cases, the 2 scales yielded different ratings. IMPLICATIONS: Although these cases suggest that ARI may be associated with the emergence of PBG in the early course of schizophrenia-related psychotic disorders, they cannot prove the causality or the strength of this association. They provide the impetus to perform adequately powered and well-controlled prospective studies to draw more definite conclusion about the causality of this association and, in the meantime, further emphasize the need to carefully assess PBG in this population.

Case Reports of Aripiprazole and Problematic Gambling in Schizophrenia: A Critical Review of the Evidence.

BACKGROUND: Pharmacovigilance studies have reported a higher risk of problematic gambling (PG) in people receiving aripiprazole (ARI), a partial dopamine agonist. This association needs to be specifically assessed in schizophrenia (SZ) given the high prevalence of risk factors for PG in this population (eg, comorbid substance use) and given the nature of the dopamine dysfunction in this disorder. At the present stage, case studies may shed light on such an association. METHODS: All published cases involving SZ patients with PG while on ARI were systematically identified. Two instruments were used to assess causality. RESULTS: We identified 16 published SZ cases exposed to ARI experiencing PG. Half of whom had a gambling history before ARI exposition. Naranjo scores led to the estimation of a possible link between ARI exposition and PG in 15 of 16 cases (average score of 3) and probable (score of 5) in 1 case. More than 50% of items were left unknown owing to the lack of information or scale limitations. Using the Liverpool algorithm, causality estimation was raised to probable in 13 of 16 cases, definite in 1 case, and nonassessable in 2 cases. CONCLUSIONS: The present review confirms that ARI may be involved in the occurrence of PG in some SZ patients. However, important information to assess causality was frequently missing, and the 2 scales used did not yield the same degree of certainty. The current article calls for including more details in future case reports and for well-powered studies carefully assessing factors such as comorbid diagnoses.

Risk of Gambling Disorder and Impulse Control Disorder With Aripiprazole, Pramipexole, and Ropinirole: A Pharmacoepidemiologic Study.

BACKGROUND: Recently, the US Food and Drug Administration issued a warning regarding the potential risk of gambling disorder, but large epidemiologic studies are lacking. METHODS: We used a large health claims database from the United States and conducted a nested case-control study. Cases were defined as subjects newly diagnosed with gambling disorder or impulse control disorder. For each case, 10 controls were selected and matched to cases by age and follow-up time and calendar time. Adjusted rate ratios were computed with conditional logistic regression. RESULTS: There are 355 cases of gambling disorder and 3550 controls along with 4341 cases of impulse control disorder and 43,410 corresponding controls. After adjusting for confounders, users of aripiprazole demonstrated an increased risk of pathologic gambling (rate ratio [RR], 5.23; 95% confidence interval [CI], 1.78-15.38) and impulse control disorder (RR, 7.71; 95% CI, 5.81-10.34). The risk was also elevated for pramipexole or ropinirole for both gambling disorder and impulse control disorder (RR, 7.61; 95% CI, 2.75-21.07; RR, 3.28; 95% CI, 2.31-4.66, respectively). CONCLUSIONS: Our study confirms an association between aripiprazole, pramipexole, or ropinirole and impulse control disorder and gambling disorder.

Partial dopamine agonist-induced pathological gambling and impulse-control deficit on low-dose aripiprazole.

OBJECTIVE: To describe a case of aripiprazole-induced problem gambling and impulse-control deficit in a gambling-naïve patient following commencement of low-dose aripiprazole. METHOD: Case report. RESULTS: This case adds to the literature on the dopamine partial agonist aripiprazole causing or exacerbating problem gambling, and extends that literature to low-dose use of aripiprazole in the gambling naïve. CONCLUSIONS: When commencing a patient on aripiprazole the possibility of emergence of problem gambling and other impulse-control deficits should be monitored, even in those with no history of similar behaviours and even on a low dose.

Pathological Gambling Associated With Aripiprazole or Dopamine Replacement Therapy: Do Patients Share the Same Features? A Review.

BACKGROUND: In the last 10 years, dopamine replacement therapy (DRT) has become a well-known risk factor for developing an impulse control disorder, such as gambling disorder (GD). Another medication, aripiprazole (ARI), has been more recently identified as another risk factor. Dopamine replacement therapy and ARI share a dopamine agonist action. Our work aimed at comparing patients with PG according to their treatment with DRT or ARI. METHODS: Two methods were combined-a systematic review concentrated on case reports and the analysis of a French disordered gamblers cohort focused on patients using ARI or DRT at inclusion. RESULTS: We reported 48 cases of GD possibly due to DRT and 17 cases of GD possibly due to ARI. Because of their standardized assessment, only the EVALJEU patients could be compared. Two clinical patterns emerged. Patients in the ARI group were young, impulsive, and high novelty seekers and had a history of substance misuse. Their first gambling experience occurred during adolescence. Conversely, patients in the DRT group were old, and they began gambling late in life. They showed low levels of gambling-related cognition. CONCLUSIONS: Patients in the ARI group seemed to be more severe pathological gamblers than patients in the DRT group. Aripiprazole is a partial D2 receptor agonist, whereas DRT includes full D2 receptor agonist. The trigger mechanism of PG development is complex and cannot only be attributed only to the pharmacodynamic effects of dopaminergic drugs. Indeed, individual vulnerability factors and environmental factors need to be considered.

[Aripiprazole, gambling disorder and compulsive sexuality]. / Aripiprazole, jeu pathologique et sexualité compulsive.

INTRODUCTION: Aripiprazole, an atypical or second-generation antipsychotic, is usually well tolerated. It is an approved treatment for schizophrenia and mania in bipolar disorder type 1. Unlike the other antipsychotics, it has high affinity agonist properties for dopamine D2 and D3 receptors. It has also 5-HT1A partial agonist and 5-HT2A antagonist properties. Aripiprazole is a first or second line treatment frequently used because it has reduced side effects such as weight gain, sleepiness, dyslipidemia, insulin resistance, hyperprolactinemia and extrapyramidal symptoms. CASE-REPORT: We report the case of a 28-year-old male patient diagnosed with schizoid personality disorder. He was a moderate smoker with occasional social gambling habits. After several psychotic episodes, he was first treated with risperidone, but he experienced excessive sedation, decreased libido, erectile dysfunction and was switched to 15 mg aripiprazole. He developed an addiction habit for gambling at casino slot machines. Due to large gambling debts, he requested placement on a voluntary self-exclusion list. Thereafter, he turned his attention towards scratch card gambling. The patient described his experience of gambling as a "hypnotic state". He got several personal loans to obtain money to continue gambling. He was then referred to an addiction unit. Before being treated with aripiprazole, he was an exclusive heterosexual with a poor sexual activity. Under treatment, he switched to a homosexual behavior with hypersexuality, unprotected sex and sadomasochistic practices. The craving for gambling and compulsive sexual behavior ceased two weeks after aripiprazole was discontinued and he was switched to amisulpride. Thereafter, he reported a return to a heterosexual orientation. DISCUSSION: Compulsive behaviors such as gambling, hypersexuality and new sexual orientation are common in patients with Parkinson's disease treated with dopaminergic agonists. These behaviors involve the reward system, with an enhanced dopaminergic activity in the mesolimbic pathways and occur more frequently in young subjects, males with previous gambling habits and tobacco use. A few cases of aripiprazole-induced pathological gambling as well as aripiprazole-induced hypersexuality have been reported. To our knowledge, we are the first to report a case of gambling disorder associated with hypersexuality and change of sexuality orientation. Aripiprazole is the only antipsychotic with agonist properties for the D2 dopamine receptor. It may also act as an enhancer in the mesolimbic dopaminergic pathways. Aripiprazole also has 5-HT1A partial agonist and 5-HT2A antagonist properties that may promote sexual activity. CONCLUSION: Aripiprazole is an antipsychotic associated with reduced side effects compared to other antipsychotics. We report the case of a patient who experienced gambling disorder, hypersexuality and a new sexual orientation under treatment. These side effects are little known. They are usually difficult for patients to mention due to feelings of guilt. The consequences on social life, family and health may be serious. Clinicians and patients should be aware about the possible issue of these behavior disorders with aripiprazole.

Dopaminergic Medication in Parkinson's Disease and Problem Gambling.

Studies on Parkinson's disease patients on dopaminergic medication report elevated rates of problem gambling. Results suggest changes in gambling behaviour are associated with the commencement and termination of dopaminergic medication implying a direct causal relationship. However, previous reports have not controlled for possible factors independent of dopamine medication contributing to the onset of problem gambling. This study aimed to explore the temporal relationships between problem gambling and dopamine medication taking into account premorbid gambling risk factors in a sample of Parkinson's disease patients. Twenty patients with Parkinson's disease meeting criteria for moderate risk or problem gambling were compared to twenty patients with Parkinson's disease who did not meet such criteria. The cross-sectional research design compared between group qualitative and quantitative differences. Participants completed an in-depth interview and timeline follow back, and battery of psychometric measures assessing impulsivity, gambling status, affective states, and obsessionality. Results revealed a complex and varied temporal relationship between dopaminergic medication onset and gambling. A small number of participants manifested excessive gambling following dopaminergic medication, with some ceasing on reduction in dosage or change in agonist class. Many demonstrated a range of individual and situational characteristic similar to problem gamblers in the general population, and in older adults with gambling problems. The obtained results provide a better understanding of the role of dopaminergic medication in problem gambling. Such findings have theoretical relevance to the reward deficiency model of gambling and have implications for the treatment of pathological gambling in PD and the general community.

Pathological gambling induced by dopamine antagonists: a case report.

Pathological gambling is defined as inappropriate, persistent, and maladaptive gambling behaviour. It is a non-pharmacological addiction classified as an impulse control disorder. However, pathological gambling has been associated with dopamine agonist use. Here we report of a 28-year-old man with a first major depressive episode and a post-traumatic stress disorder who has been treated with a combination of the serotonine/noradrenaline reuptake inhibitor duloxetine and the tricyclic antidepressant maprotiline. The administration of antipsychotic flupentixole (up to 7 mg) turned this slight online poker gambler into an excessive gambler. Only after the discontinuation of the antidopaminergic agents and the switch to bupropion did this gambling behaviour stop which suggests a causal relationship between dopamine antagonists and pathological gambling.

Citalopram-associated gambling: a case report.

Pathological gambling behaviour is a side effect of dopaminergic drugs used in Parkinson's disease, but has seldom been reported with selective serotonin reuptake inhibitors. A 58-years-old woman with somatisation disorder since the age of 20 and recent-onset major depression (at 54 years) received 40 mg/day intravenous citalopram, thereafter switching to the same dose of oral citalopram to treat her comorbid psychiatric disorders after showing poor response to paroxetine for one year. Her anxious and depressive symptoms were moderately reduced after 7 months of oral citalopram, but simultaneously, the patient admitted gambling. We gradually discontinued citalopram and introduced pregabalin and alprazolam; this was followed by a reduction of gambling compulsions, but the somatisation and depressive symptoms did not further improve. Pathological gambling may be mediated by an interplay of 5-HT1A serotonergic and D2 dopaminergic mechanisms. Citalopram affects both these mechanisms in areas that were shown to be involved in gambling behaviour, but while dopaminergic effects of citalopram appear to be consistent with the induction of gambling, its serotonergic mechanisms are rather inconsistent. In our patient, mood destabilisation induced by citalopram may have contributed to the first onset of pathological gambling.

A single-center, cross-sectional prevalence study of impulse control disorders in Parkinson disease: association with dopaminergic drugs.

The current study aimed at establishing the prevalence of impulse control disorders (ICDs) in patients with Parkinson disease (PD) and their association with demographic, drug-related, and disease-related characteristics. We performed a single-center cross-sectional study of 805 PD patients. Impulse control disorders were investigated with the Questionnaire for Impulsive Compulsive Disorders in Parkinson's Disease; also comorbid neuropsychiatric complications (dementia, delusions, visual hallucinations) were investigated with clinical interviews and ad hoc instruments (Parkinson Psychosis Questionnaire and Neuropsychiatry Inventory). Impulse control disorders were identified in 65 patients (prevalence, 8.1%), with pathological gambling and hypersexuality the most frequent. Impulse control disorders were present in 57 of 593 cognitively preserved patients (prevalence, 9.6%) and in 8 of 212 demented patients (prevalence, 3.8%). Impulse control disorders were significantly associated with dopamine agonists (odds ratio [OR], 5.50; 95% confidence interval [CI], 2.60-12.46; P < 0.0001) and levodopa (OR, 2.43; 95% CI, 1.06-6.35; P = 0.034). Impulse control disorders frequency was similar for pramipexole and ropinirole (16.6% vs 12.5%; OR, 1.45; 95% CI, 0.79-2.74; P = 0.227). Additional variables associated with ICDs were male sex and younger age. These findings suggested that dopaminergic treatments in PD are associated with increased odds of having an ICD, but also other demographic and clinical variables are associated with ICDs, suggesting the multifactorial nature of the ICD phenomenon in PD.

Drug-Induced Gambling Disorder: Epidemiology, Neurobiology, and Management.

Problematic gambling has been suggested to be a possible consequence of dopaminergic medications used mainly in neurological conditions, i.e. pramipexole and ropinirole, and possibly by one antipsychotic compound, aripiprazole. Patients with Parkinson's disease, restless legs syndrome and other conditions potentially treated with dopamine agonists, as well as patients treated for psychotic disorders, are vulnerable patient groups with theoretically increased risk of developing gambling disorder (GD), for example due to higher rates of mental ill-health in these groups. The aim of the present paper is to review the epidemiological, clinical, and neurobiological evidence of the association between dopaminergic medications and GD, and to describe risk groups and treatment options. The neurobiology of GD involves the reward and reinforcement system, based mainly on mesocorticolimbic dopamine projections, with the nucleus accumbens being a crucial area for developing addictions to substances and behaviors. The addictive properties of gambling can perhaps be explained by the reward uncertainty that activates dopamine signaling in a pathological manner. Since reward-related learning is mediated by dopamine, it can be altered by dopaminergic medications, possibly leading to increased gambling behavior and a decreased impulse control. A causal relationship between the medications and GD seems likely, but the molecular mechanisms behind this association have not been fully described yet. More research is needed in order to fully outline the clinical picture of GD developing in patient groups with dopaminergic medications, and data are needed on the differentiation of risk in different compounds. In addition, very few interventional studies are available on the management of GD induced by dopaminergic medications. While GD overall can be treated, there is need for treatment studies testing the effectiveness of tapering of the medication or other gambling-specific treatment modalities in these patient groups.

Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson's patients with medication-induced pathological gambling: a [11C] FLB-457 and PET study.

Impulse control disorders such as pathological gambling (PG) are a serious and common adverse effect of dopamine (DA) replacement medication in Parkinson's disease (PD). Patients with PG have increased impulsivity and abnormalities in striatal DA, in common with behavioural and substance addictions in the non-PD population. To date, no studies have investigated the role of extrastriatal dopaminergic abnormalities in PD patients with PG. We used the PET radiotracer, [11C] FLB-457, with high-affinity for extrastriatal DA D2/3 receptors. 14 PD patients on DA agonists were imaged while they performed a gambling task involving real monetary reward and a control task. Trait impulsivity was measured with the Barratt Impulsivity Scale (BIS). Seven of the patients had a history of PG that developed subsequent to DA agonist medication. Change in [11C] FLB-457 binding potential (BP) during gambling was reduced in PD with PG patients in the midbrain, where D2/D3 receptors are dominated by autoreceptors. The degree of change in [11C] FLB-457 binding in this region correlated with impulsivity. In the cortex, [11C] FLB-457 BP was significantly greater in the anterior cingulate cortex (ACC) in PD patients with PG during the control task, and binding in this region was also correlated with impulsivity. Our findings provide the first evidence that PD patients with PG have dysfunctional activation of DA autoreceptors in the midbrain and low DA tone in the ACC. Thus, altered striatal and cortical DA homeostasis may incur vulnerability for the development of PG in PD, linked with the impulsive personality trait.

Selective IGT decision-making impairment in a patient with juvenile Parkinson's disease and pathological gambling: a role for dopaminergic therapy?

The orbitofrontal cortex and the dopaminergic system are structures involved in managing impulsivity and sensibility to reinforcements, and both are typically impaired in Parkinson's disease (PD). Also, l-DOPA treatment can contribute to the development of the 'Dopamine Dysregulation Syndrome', a syndrome that can influence the patients' personality and lead to risk-taking behaviors. In this study, we describe the case of a 42-year-old woman (LT) affected by juvenile PD, treated with both l-DOPA and dopamine agonists, who showed a sudden onset of pathological gambling (PG), as the only neuropsychiatric symptom. We assessed LT with a full neuropsychological battery and the Iowa Gambling Task (IGT), in order to describe her specific failure in decision making. LT's performance on the IGT is compared with that of 15 non-demented PD patients under therapy with dopamine agonists and no behavioral dysregulations and with that of 16 age- and education-matched healthy subjects. Results showed fully preserved memory, executive functions, and reasoning abilities for LT, but a remarkable and stable impairment in the IGT. Performance of LT on the IGT is significantly lower than that of both control groups. This case shows, for the first time, that high cognitive functioning and preserved executive functions are no guarantee for advantageous decision making, and that the onset of PG is consistent with selective orbitofrontal disruption and side-effects of dopamine agonist therapy. It is also showed that the IGT is a useful neuropsychological device to detect specific risk-taking behaviors, which compromise functioning in real life.

[Gambling addiction as a side effect of low dose pramipexole in the treatment of restless legs syndrome].

Pathologic gambling is a rare but severe side effect of dopamine agonists (DA). Low dosage DA, as given when treating restless legs syndrome (RLS), has been thought only to have mild side effects. This case report describes two patients with low dosage pramipexole for RLS, who developed gambling addiction for a decade, highly affecting their quality of life. After stopping the treatment, the patients' gambling addiction ceased. Even though this is a very rare side effect, patients prescribed a DA should be informed of the risk of gambling addiction, independently of dosage.

Pramipexole modulates the neural network of reward anticipation.

Pramipexole is widely prescribed to treat Parkinson's disease. It has been found to cause impulse control disorders such as pathological gambling. To examine how pramipexole modulates the network of reward anticipation, we carried out a pharmacological functional magnetic resonance imaging study with a double-blind, within-subject design. During the anticipation of monetary rewards, pramipexole increased the activity of the nucleus accumbens (NAcc), enhanced the interaction between the NAcc and the anterior insula, but weakened the interaction between the NAcc and the prefrontal cortex. These results suggest that pramipexole may exaggerate incentive and affective responses to possible rewards, but reduce the top-down control of impulses, leading to an increase in impulsive behaviors. This imbalance between the prefrontal-striatum connectivity and the insula-striatum connectivity may represent the neural mechanism of pathological gambling caused by pramipexole.

Pathological gambling in Parkinson's disease--a review of the literature.

The prevalence of pathological gambling is 3.4% to 6% in treated Parkinson's disease, which is higher than the background population rate. In this review we discuss current evidence to indicate that dopamine agonists are much more likely to trigger this behavior than either L-dopa or selective monoamine oxidase B inhibitor monotherapy. New insights from recent behavioral and functional imaging studies and possible treatment approaches are also covered. A PubMed literature search using the terms "gambling" and "Parkinson's disease," "impulse control disorder," "impulsive compulsive behaviour," "dopamine agonist," of individual dopamine agonists, and of ongoing drug trials, using http://www.clinicaltrials.gov, was carried out for the period up to January 2011.

Pathological gambling plus hypersexuality in restless legs syndrome: a new case.

Emerging clinical data indicate that dopaminergic agonists used to treat restless legs syndrome may be associated with dopamine dysregulation syndrome, particularly pathological gambling. We report a new case with pathological gambling plus hypersexuality and impotence in an old patient treated with a small dose (0.18 mg daily at bedtime) of pramipexole for restless legs syndrome for 5 months. The time relationship and the resolution upon discontinuation of dopaminergic agonists suggest a causative association. Our new case confirms that restless legs syndrome patients should be cautioned about potential dopamine dysregulation syndrome coinciding with dopaminergic agonists, as it can be reversed by drug withdrawal.