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.

[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.

Increased risk for developing gambling disorder under the treatment with pramipexole, ropinirole, and aripiprazole: A nationwide register study in Sweden.

Gambling Disorder (GD) has recently been reclassified from an impulse-control disorder to a behavioural addiction and, as in other addictive disorders, the dopaminergic reward system is involved. According to neuroimaging studies, alterations within the striatal dopaminergic signalling can occur in GD. However, the findings to date are controversial and there has been no agreement yet on how the reward system is affected on a molecular basis. Within the last 20 years, there has been growing evidence for a higher risk to develop GD in response to certain dopaminergic medication. Especially the dopamine agonists pramipexole and ropinirole, and the dopamine modulator aripiprazole seem to increase the likelihood for GD. The goal of this study was to examine the association between a prescription for either of the three pharmaceuticals and a GD diagnosis in a large cross-sectional study of the Swedish population. Compared to patients with any other dopaminergic drug prescription (38.7% with GD), the diagnosis was more common in patients with a dopamine agonist prescription (69.8% with GD), resulting in an odds ratio of 3.2. A similar association was found between aripiprazole prescriptions and GD diagnoses, which were analysed within the subgroup of all patients with schizophrenia or a schizotypal, delusional, or another non-mood psychotic disorder. An aripiprazole prescription increased the likelihood of GD (88.8%) in comparison to patients without an aripiprazole prescription (71.2%) with an odds ratio of 3.4. This study contributes to the increasingly reliable evidence for an association between several dopaminergic drugs and a higher risk for developing GD. Therefore, one future research goal should be a better understanding of the neurobiology in GD to be able to design more selective dopaminergic medication with less severe side effects. Additionally, this knowledge could enable the development of pharmacotherapy in GD and other addictive disorders.

Pathological gambling in a patient on piribedil: A case report.

RATIONALE: Piribedil is an orally active dopamine agonist that has been widely used for Parkinson disease (PD), with its partial D2/D3 agonistic functions and alpha2-adrenoreceptor antagonistic effects, piribedil has been proved to be efficacious in the relief of motor symptoms in PD, while it can also lead to impulse control disorders such as pathological gambling due to its dopamine agonistic effects. PATIENT CONCERNS: A 28-year-old Chinese female patient with Parkinson disease and a history of taking piribedil finally developed pathological gambling and depressive episode. DIAGNOSES: After a careful clinical observation and evaluation, the patient met the criteria of severe depressive episode and pathological gambling due to antiparkinson therapy. INTERVENTIONS: We discontinued piribedil and picked bupropion, a dopamine reuptake inhibitor, to alleviate the depressive symptom. Benzhexol and selegiline were also added for the control of motor fluctuations. OUTCOMES: After 3 weeks' treatment, the patient's depressive mood was significantly alleviated and her recurring PD symptoms were also relieved. She was no more addicted to network gambling, and there was no recurrence during the 1-year follow-up. LESSONS: Piribedil-induced problem gambling and impulse control disorders are side effects needed to be evaluated when commencing a patient on piribedil. This case further emphasizes the importance of monitoring and controlling Parkinson symptoms after drug reduction or withdrawal. Anticipation of this risk strengthens the significance of detailed medical history-taking and targeted clinical management.

Pathological Gambling Due to Aripiprazole: Two Cases

ABSTRACT Aripiprazole is an atypical antipsychotic agent which has a partial agonistic effect on dopamine D2 and D3 receptors. It is effective in the treatment of schizophrenia and bipolar disorder. Owing to its partial agonistic effect, hyperactivity of dopamine may occur in the mesolimbic pathway. In the literature, there are few case reports about pathological gambling due to aripiprazole. In this article, there are two case reports of patients who showed pathological gambling behaviour and alcohol abuse and who were under treatment with aripiprazole. The patient had a history of gambling in the past. With the use of aripiprazole, pathological gambling behaviour occurred quickly and with discontinuation of aripiprazole it ended completely. Aripiprazole causes pathological gambling by forming a hyperdopaminergic condition in the mesolimbic dopaminergic pathway. Aripiprazole should be recommended cautiously and carefully to patients who are impulsive and have a history of alcohol/substance abuse.

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.

The effects of alcohol on sequential decision-making biases during gambling.

RATIONALE: Gambling and alcohol use are recreational behaviours that share substantial commonalities at a phenomenological, clinical and neurobiological level. Past studies have shown that alcohol can have a disinhibiting effect on gambling behaviour, in terms of bet size and persistence. OBJECTIVES: This study was conducted in order to characterise how alcohol affects biases in judgment and decision-making that occur during gambling, with a focus on sequential decision-making including the gambler's fallacy. METHODS: Sequential biases were elicited via a roulette-based gambling task. Using a standard between-groups alcohol challenge procedure, male participants played the roulette task 20 min after receiving an alcoholic (0.8 g/kg; n = 22) or placebo (n = 16) beverage. The task measured colour choice decisions (red/black) and bet size, in response to varying lengths of colour runs and winning/losing feedback streaks. RESULTS: Across both groups, a number of established sequential biases were observed. On colour choice, there was an effect of run length in line with the gambler's fallacy, which further varied by previous feedback (wins vs losses). Bet size increased with feedback streaks, especially for losing streaks. Compared to placebo, the alcohol group placed higher bets following losses compared to wins. CONCLUSIONS: Increased bet size after losses following alcohol consumption may reflect increased loss chasing that may amplify gambling harms. Our results do not fit a simple pattern of enhanced gambling distortions or reward sensitivity, but help contextualise the effects of alcohol on gambling to research on decision-making biases.

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.

Two Cases of De Novo Pathological Gambling Associated With Aripiprazole.

OBJECTIVES: Pathological gambling can be potentiated by treatment with dopamine agonists. Aripiprazole, bearing a partial agonist activity at dopamine D2 and D3 receptors, has also been linked to such a behavioral aberration, usually on subjects predisposed with tendency of impulsive or addictive behaviors. METHODS: Review of patient's medical records and literature review. RESULTS: Two young patients' pathological gambling emerged simply due to exposure to aripiprazole, neither related to manic or psychotic symptoms nor with history of addictive or impulsive behaviors. Their pathological gambling disappeared soon after switching aripiprazole to other antipsychotics. One patient has tested such a relationship by reexposure to aripiprazole while his compulsion to gamble recurred. CONCLUSIONS: In addition to previously recognized risk factors, pathological gambling might occur in young patients whose history did not reveal an addictive tendency while they were sensitive to the pharmacological effect, as well as adverse effects, of psychotropic agents.

Escalation of Gambling Associated With Aripiprazole: A Case Report and Literature Review.

Impulse-control problems such as gambling, increased spending, hypersexuality, and compulsive eating are thought to be influenced by temperamental, genetic, and physiological risk factors. In addition, dopamine receptor agonists have been implicated in some cases. It is postulated that aripiprazole may cause impulse-control problems because it can produce a hyperdopaminergic state in the mesolimbic pathway (reward system) through its predominant action on dopamine D3 receptors. We present the case of a patient with bipolar disorder and previous gambling behavior, in whom the gambling behavior escalated with the introduction of aripiprazole and its upward titration. The patient's gambling problems were alleviated with a decrease in aripiprazole dosage. Clinicians should be vigilant for possible gambling and other impulse-control behaviors in patients taking aripiprazole. Our literature review suggests cariprazine and brexpiprazole, which have mechanisms of action similar to that of aripiprazole, may also be associated with possible risks of impulse-control problems and pathologic gambling.

Increased motor impulsivity in a rat gambling task during chronic ropinirole treatment: potentiation by win-paired audiovisual cues.

RATIONALE: Chronic administration of D2/3 receptor agonists ropinirole or pramipexole can increase the choice of uncertain rewards in rats, theoretically approximating iatrogenic gambling disorder (iGD). OBJECTIVES: We aimed to assess the effect of chronic ropinirole in animal models that attempt to capture critical aspects of commercial gambling, including the risk of losing rather than failing to gain, and the use of win-paired sensory stimuli heavily featured in electronic gambling machines (EGMs). METHODS: Male Long-Evans rats learned the rat gambling task (rGT; n = 24), in which animals sample between four options that differ in the magnitude and probability of rewards and time-out punishments. In the cued rGT (n = 40), reward-concurrent audiovisual cues were added that scaled in complexity with win size. Rats were then implanted with an osmotic pump delivering ropinirole (5 mg/kg/day) or saline for 28 days. RESULTS: Chronic ropinirole did not unequivocally increase preference for more uncertain outcomes in either the cued or uncued rGT. Ropinirole transiently increased premature responses, a measure of motor impulsivity, and this change was larger and more long-lasting in the cued task. CONCLUSIONS: These data suggest that explicitly signaling loss prevents the increase in preference for uncertain rewards caused by D2/3 receptor agonists observed previously. The ability of win-paired cues to amplify ropinirole-induced increases in motor impulsivity may explain why compulsive use of EGMs is particularly common in iGD. These data offer valuable insight into the cognitive-behavioral mechanisms through which chronic dopamine agonist treatments may induce iGD and related impulse control disorders.

Drug-induced gambling disorder: A not so rare but underreported condition.

The widespread use of dopaminergic agents for the treatment of Parkinson's disease has revealed the presence of gambling disorder (GD) as an uncommon, but serious, adverse reaction to these agents. We describe the main characteristics of drug-induced GD reports received by the Spanish Pharmacovigilance System during the period from 1983 to 2016. Fifteen reports of GD have been identified. Dopaminergic agonists, especially pramipexole, are the main drugs involved in inducing GD. Physicians prescribing these drugs should warn patients and families about this disorder. Knowledge of this disorder will encourage early diagnosis, treatment, and reporting of this clinically and socially relevant 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.

Effects of acute and chronic caffeine on risk-taking behavior in children and adolescents.

Consumption of caffeinated beverages is associated with increased risk-taking behavior. The purpose of this study was to determine if acute caffeine administration influences risk-taking behavior in a dose-dependent manner. Participants were pre- (ages 8-9) and post-pubertal (ages 15-17) children who visited the laboratory three times and consumed a beverage containing 0, 1, or 2 mg/kg of caffeine. Thirty minutes later, participants completed the balloon analogue risk task (BART), the Iowa gambling task (IGT), and a delay discounting task. The number of balloons exploded on the BART task was significantly increased after 2 mg/kg of caffeine in moderate caffeine consumers, but was decreased after 2 mg/kg of caffeine in high caffeine consumers. There were no main effects of caffeine dose on the delay discounting task or on the IGT. Post-pubertal participants showed reduced delay discounting compared with pre-pubertal participants. Finally, average daily caffeine use was significantly, positively correlated with scores on a risk-taking questionnaire. These data suggest that caffeine dose-dependently influences decision making and risk taking. More research is needed to determine the mechanism of this difference as well as the extent to which sex and pubertal phase influence these relationships.

Gambling disorder: a side effect of an off-label prescription of baclofen-literature review.

The use of high-dose baclofen emerged in 2008 in the treatment of alcohol-use disorders. Its prescription is still off-label in France, but recent trials have suggested the interest of using high doses for alcohol dependence, so we have to deal with an increase in its use. However, we still have few data about the adverse effects of a high-dose baclofen prescription, especially in complex addictive disorders. We present a case of a 32-year-old man who sought treatment for gambling disorders (GDs). He had complex addictive disorders, including alcohol-use disorders and GDs. He developed a severe GD, after treatment with a high dose of baclofen. The maximum dose was 160 mg/day, prescribed for his alcohol-use disorders. According to the Naranjo algorithm, the score was +7, it enabled to conclude that problem of gambling was probably imputable to baclofen. We discuss this case with reference to literature.

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.