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Can a Low Dosage of Aripiprazole Modify Incentive Salience in Naive Bipolar Patients Who Gamble?

Carbone, Manuel G. MD*; Pagni, Giovanni MD*; Tagliarini, Claudia MD*; Maremmani, Icro MD, FISAM†,‡,§

Addictive Disorders & Their Treatment: September 2019 - Volume 18 - Issue 3 - p 134–139
doi: 10.1097/ADT.0000000000000163
Case Report

Gambling disorder is a pathologic condition, resulting from the interaction of multiple risk factors. Among these, dopamine neurotransmission is known for playing a significant role, as seen, for example, in patients using dopamine replacement therapy prescribed for Parkinson disease, in which gambling is considered to be iatrogenic. Considering this, together with the general mechanism of action of antipsychotic drugs, growing attention has recently been dedicated to Aripiprazole and to its partial dopaminergic agonism (reducing D2-receptor hyperactivation in the mesolimbic pathway and improving D2-receptor stimulation in the mesocortical and nigrostriatal pathway). In fact, Aripiprazole has been noticed in several cases to worsen preexisting pathologic gambling and also, in some cases, to precipitate pathologic gambling in those without preexisting pathologic gambling when used at therapeutic doses (10 to 15 mg). Mr F, a bipolar patient under treatment without either personal or family history of gambling, following a low-dose Aripiprazole administration, began displaying gambling behaviors, which immediately ceased after suspension of the drug. Subsequently, after the reintroduction of Aripiprazole, this time at standard dosage, the patient resumed additive behavior of gambling, which in this case also ceased at the time of suspension. It is possible to hypothesize that the dopaminergic agonist activity of low-dose Aripiprazole has influenced the physiological process of salience, leading the patient to give particular attention, through reward circuits, to a specific stimulus, otherwise not relevant. More difficult to explain, on the other hand, is how the standard dosage anti-D2 activity of Aripiprazole, has reactivated gambling behaviors again. According to our hypothesis, it is possible that the administration of standard dose of Aripiprazole has triggered a reward-deficiency syndrome, recalling the gratifying action of the recently experimented gambling to the patient’s memory, bringing him to the relapse.

*Department of Experimental and Clinical Medicine, School of Psychiatry

§Department of Specialty Medicine, Vincent P. Dole Dual Diagnosis Unit, 2nd Psychiatric Unit, Santa Chiara University Hospital, University of Pisa

G. De Lisio Institute of Behavioral Sciences, Pisa

Association for the Application of Neuroscientific Knowledge to Social Aims (AU-CNS), Pietrasanta, Lucca, Italy

I.M., served and/or currently serves as Board Member/Consultant for Indivior, Molteni, Mundipharma, D&A Pharma, CT Sanremo, Lundbeck, Gilead, Merck & Co, and Angelini. The remaining authors declare no conflict of interest.

Reprints: Manuel G. Carbone, MD, Department of Experimental and Clinical Medicine, School of Psychiatry, University of Pisa, Via Roma 67 56100, Pisa, Italy (e-mail:

Gambling disorder (GD) is a pathologic condition characterized by a maladaptive pattern of gambling behavior that persists despite negative consequences in major areas of life functioning. It was recently recategorized as a non–substance-related addiction in the Diagnostic and Statistical Manual of Mental Health Disorders (DSM-5).1 This disorder more frequently occurs in men2 and is often characterized by specific personality traits, high impulsivity levels, and cognitive distortions, such as the illusion of control.3–5 GD is highly comorbid with substance use, mood, anxiety, and personality disorders.6

It is commonly accepted that it results from the interaction of multiple risk factors. Among these, dopamine replacement therapy (DRT) prescribed for Parkinson disease (PD) can be cited.7 PD, which is the most prevalent neurodegenerative disease after Alzheimer disease, maintains close and complex ties with impulse control disorders or behavioral addictions, especially GD. The prevalence of impulse control disorders in PD patients treated with DRT varied between 3.5% and 13.6% and that of GD patients between 2.3% and 8%, which is a significantly higher rate than that of the general population. In the DRT, GD is considered to be iatrogenic on the basis of chronological and pharmacological arguments: GD appeared after the onset of PD and DRT initiation and disappeared after discontinuing DRT; DRT acted on dopamine receptors in the nigrostriatal pathway and in the reward pathway, which plays a role in addiction. The most common medications under investigation are dopamine receptor agonists (pramipexole, ropinirole, pergolide, cabergoline, etc.), but, according to some authors, monotherapy with carbidopa or levodopa could also be considered.8–11

In recent years, Aripiprazole has received growing attention. It is an atypical antipsychotic drug prescribed for the treatment of adult patients with schizophrenia, bipolar disorder I (acute treatment of manic and mixed episodes, maintenance treatment of bipolar I disorder), in major depressive disorder (as an adjunctive therapy to an antidepressant), and in irritability associated with autistic disorder and Tourette’s disorder. Finally, Aripiprazole injection is prescribed for the acute treatment of agitation associated with schizophrenia or bipolar disorder. Aripiprazole has a unique mechanism of action as a dopamine D2 and D3 partial agonist (as opposed to a full dopamine antagonist like an atypical antipsychotic), serotonin 5-HT(1A) partial agonist, and serotonin 5-HT(2A) antagonist. As a partial agonist, Aripiprazole acts as a functional antagonist in conditions of high dopamine concentrations and as a functional agonist in conditions of low dopamine concentration. This partial agonist can reduce D2 hyperactivation in the mesolimbic pathway, thus alleviating positive symptoms of schizophrenia, but providing enough D2-receptor stimulation in the mesocortical pathway and the nigrostriatal pathway to prevent, respectively, negative symptoms and extrapyramidal side effects12; at same time, it is a well-tolerated drug, especially with regard to metabolic side effects.13

Aripiprazole has been noted to adversely modify preexisting pathologic gambling, and, in all of these cases, the dose was 10 to 30 mg, except for 1 reported case of a patient diagnosed with bipolar disorder, whose preexisting gambling was adversely modified 2 years after commencing Aripiprazole at a low dose of 5 mg. Aripiprazole has also been noted in several cases to precipitate pathologic gambling in those without preexisting pathologic gambling when used at therapeutic doses of 10 to 15 mg. Only therapeutic doses of ≥10 mg have been reported in the literature as causing problem gambling in those with no history of problem gambling, to our knowledge.14–19

In the present case report, we describe the case of a gambling-naive patient who quickly exhibited problem gambling behaviors on only a low dose of Aripiprazole (5 mg), who stopped gambling when Aripiprazole was removed, and returned to gambling when a standard dosage was successively reintroduced.

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Mr F was a 40-year-old man, employed in a public office, with an early-onset Bipolar I disorder (DSM-5) that started at the age of 15. He presented at our department as a result of the reappearance of a hypomanic episode with the elevation of anxiety levels.

The patient suffered from mild degree arterial hypertension and denied the use of substances and alcohol.

On psychic examination, the patient was alert, lucid, mnesic, and was oriented in space and time and toward things and people. Mime and gesticulation during the interview were hyperrepresented and lively, at times, expressing internal tension. The mood was oriented toward the expansive pole with high levels of energy, reduction of the need for sleep, and high hedonic-volitional thrust. The anxiety levels were high, mainly in the evening hours. Emotional-verbal acceleration emerged. The patient’s ability to conceive the future was good. There were no abnormalities of sense perceptions. There was a slight increase in appetite.

His longitudinal evaluation revealed family loading for psychiatric illnesses, with no complications at birth, pregnancy, and delivery. No developmental disorder or delays were referred. Mr F had never previously been interested in gambling and had no history of other impulse control disorders, remembering that the loss of control of the impulses is one of the typical features of the bipolar spectrum, but it is not a predominant characteristic.

The onset was with a manic episode characterized by elevation of mood, increase in energy levels, visual and somatic misperceptions, motor restlessness, elevation of anxiety levels with panic attacks for which he made access to the emergency room and was then sent to the psychiatric ward. He was discharged with a psychopharmacological therapy based on Haloperidol and Ademetionine with clinical benefit.

Mr F in the following years enjoyed a fair psychoaffective compensation with a discrete functioning in the social and working environment, although he presented periodic oscillations of the mood in both polarities with increases in the anxiety share in the absence of psychotic symptoms. During this period, he was followed-up by different psychiatric specialists who imposed, in relation to the various manifestations of the clinical picture, multiple psychopharmacological associations based on mood stabilizers (valproic acid, lithium salts, lamotrigine), atypical antipsychotics (Olanzapine, Quetiapine, and Perphenazine), antidepressants (fluoxetine, escitalopram, duloxetine, amitriptyline, venlafaxine, ademetionine, and vortioxetine), and Benzodiazepines (Delorazepam, Lorazepam) with partial clinical benefit.

In these years, he has had 3 inpatient admissions, most recently in May 2018, with relapse of a hypomanic episode, which, as mentioned earlier, brought him to our attention.

In September 2017, in relation to a hypomanic episode, his specialist psychiatrist stated a therapy with valproic acid: 1500, Quetiapine: 300, and Aripiprazole: 5 mg per day.

After only a few days on Aripiprazole 5 mg, Mr F felt a strong desire to gamble. He attended slot machines and scratch cards every night for several days. He decided spontaneously to suspend Aripiprazole, and, within 1 week of cessation, he lost the urge to gamble.

During the last admission in our ward in the month of May, not being aware of this problem with gambling, we decided to reintroduce, in association with valproic acid, Aripiprazole 20 mg per day with resolution of hypomanic symptoms.

The patient, on the basis of the DSM-5 criteria assessed with SCID 5, was found to be suffering from a hypomanic episode in bipolar disorder 1.

After about 1 week of discharge, Mr F decided to contact us, informing us that he restarted playing slot machines and scratch cards with financially hard expenses.

He tells us that he already had a similar episode in relation to the first introduction of 5 mg Aripiprazole. We decided to immediately stop Aripiprazole and replace it with Quetiapine. In a few days from the suspension (<10 d), the patient does not report episodes of pathologic gambling.

During the check-up carried out in July, about 50 days after the suspension of the Aripiprazole, Mr F no longer presented pathologic gambling behaviors.

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Emotional instability, in its various expressions within the bipolar spectrum, shares with drug and not related drug addictions a common substrate. The predisposition to develop emotional instability and the sensitivity to the addictive effects of some substances ensue in convergent dysfunctions impinging the same brain metabolic system, highlighting the close relationship between bipolar spectrum disorders and substance and nonsubstance dependence.20 Furthermore, both emotional instability and sensitivity to developing addictive behaviors are closely associated with the concept of salience. It is already known that salience is an integration process that allows to give attention to internal or external stimuli, which grow in relevance, becoming able to influence thoughts and behaviors. The neurobiological substrate that underlies this process finds its place in the mesolimbic dopaminergic system, which is also involved in reward regulation. The existence of this common substrate explains how minimal changes in dopaminergic activity within this pathway can result in an alteration of the salience mechanism and, consequently, the development of addictive behaviors.

In May 2016, the US Food and Drug Administration (FDA) released a safety communication warning patients and doctors that Aripiprazole may cause uncontrollable urges to gamble, binge eat, have sex, and shop. According to the agency, the urges stopped after patients reduced their dose of the drug or stopped taking it. The agency reported about 184 cases of impulsive behaviors associated with the drug in the FDA Adverse Event Reporting System (FAERS) since its approval in 2002 through January 2016. Of those reports, 167 were in the United States and affected adults and children, and gambling accounted for 164 cases. The FDA reported that none of the patients suffered from substance abuse disorders or mania when they developed impulsive behavior symptoms after taking Aripiprazole. Although previous cases have mostly demonstrated such behaviors on therapeutic doses of Aripiprazole, often in patients with a history of problem gambling, in the literature, there is just one case of Aripiprazole-induced problem gambling on a low dose in the gambling naive.21,22

Our case suggests that low dose of Aripiprazole could lead to an increasing of the “physiological” process of salience: in this new condition, the patient is more predisposed to develop addiction behavior toward new stimuli, to which he did not attribute particular significance before.

The mechanism by which pathologic gambling is precipitated may be attributable to Aripiprazole’s partial dopamine agonist activity in reward circuits, which are hypothesized as being regulated ultimately by the mesolimbic pathway.23

The potential causality of Aripiprazole in the occurrence of GD is strengthened by several pharmacological hypotheses. Some authors indicated that there is an abnormal catecholaminergic neurotransmitter activity underlying GD. Addictions result in part from an abnormal brain activation in mesocorticolimbic pathways, dopamine being the cornerstone of this reward system. Aripiprazole acts as a partial agonist at the D2 and 5-HT1A receptors and as an antagonist at the 5-HT2A receptor. Partial agonist activity at dopamine D2 receptors has been associated with stabilization of the dopamine system (ie, functional antagonism in hyperdopaminergic states and functional agonism in hypodopaminergic states), which provides therapeutic action.

Its action at the D3 receptor is still unknown.23 Some authors, therefore, assume that Aripiprazole has an agonist action at the D3 receptor, which is mainly present in the limbic system, hence stimulating in an unusually strong manner the reward system.7,15 This includes the nucleus accumbens, an area involved in reward processing to attain reinforcing stimuli including natural reinforcers, such as food, or synthetic reinforcers, such as drugs. The same D3 receptor was incriminated in cases of GD inducted by DRT.7 This hyperstimulation would apparently be particularly enhanced in cases of a previous treatment with antipsychotics acting as a dopaminergic receptor antagonist, owing to the upregulation and the dopaminergic receptor hypersensitivity processes. A hyperdopaminergic state within the mesolimbic system has been heavily implicated in developing maladaptive behaviors such as GD. To exemplify dopamine’s mesolimbic role in reward processing, pramipexole was found to increase nucleus accumbens dopaminergic activity to larger than to smaller rewards and to the anticipation of receiving a reward compared with no reward. The affinity of pramipexole and ropinirole for the D3 receptors is much greater than the D2 receptor (100 and 25 times, respectively) as well as for the D1 receptor (>1000 and 300 times, respectively). The D3 receptors are thought to be involved in GD; when activation of D3 receptors was lessened by eliminating the agonist or dose reduction, gambling behavior ceased. Moreover, the intrinsic dopamine pharmacodynamic activity of Aripiprazole imparts its less agonist activity with respect to that of a complete agonist, which could explain why the occurrence of GD is sometimes late or due to dosage increase.16,24–30

In Mr F’s case, cessation of Aripiprazole completely resolved his gambling behaviors, and this is consistent with the above-cited case reports, in which lowering or ceasing Aripiprazole resolved the impulse control dysregulation.14,15,19,27 The possibility that Mr F’s behavior change was due to emerging mania was considered, but, in any case, Mr F had never practiced pathologic gambling behaviors. Furthermore, due to the close temporal relationship of initiation of symptoms to the beginning of treatment with Aripiprazole, the rapid resolution of those symptoms on cessation of Aripiprazole and the lack of other features of mania were felt to be more consistent with a medication side effect.

Mr F was not a gambler, having therefore never presented an alteration of the specific salience for gambling. This leads us to think that probably the urge to play when exposed to gambling stimuli did not occur, at least initially, for a reward mechanism, but for an alteration of the general process of salience. In fact, probably, in a hypersensitive dopaminergic system, which characterizes patients with symptoms of the bipolar spectrum and therefore with emotional dysregulation, the D3 stimulation at low dosage modifies the salience and therefore the process of attribution of importance to external stimuli: this justifies the development of reward mechanisms concerning situational stimuli initially considered to be nonspecific. It is possible to hypothesize that this dysregulation of the salience in these subjects is induced and maintained by Aripiprazole. A proof supporting this hypothesis is given by the cessation of addictive behavior concomitantly with the suspension of drug intake.

The reintroduction of Aripiprazole therapy at the standard dosage (20 mg) led Mr F to a resumption of addictive behavior. This can also be explained by the different action of Aripiprazole corresponding to the different dosages: a standard dose, acting in an antagonistic manner on the reward system’s D2 receptors, stimulates again the craving for gambling in an already sensitized system, in which salience was previously dysregulated.

It is more difficult to explain why a standard anti-D2 dosage has reactivated the desire for gambling. Considering that, in the SUD, the use of drugs with anti-D2 action exacerbates the craving for the primary substance of abuse, it is probable that a reward-deficiency syndrome (RDS) will occur.

Some psychoactive substances and medications like anti-D2 antipsychotics can be related to “reward-deficiency syndrome,” which is closely related to the postwithdrawal syndrome, described by Martin et al32 as an enduring pathologic state in abstinent detoxified opiate addicts.31 From a withdrawal-related point of view, through each detoxification cycle, the patient passes from the acute withdrawal state (counter polar to intoxication—psychomotor retardation in case of cocaine acute withdrawal) to a later and enduring drug-free state featuring symptoms of hypophoria, looming as acquired discomfort related to the absence of drug-related stimulation. Hypophoria includes somatic, vegetative (sleep), mood, and anxiety symptoms such as susceptible or irritable (depressed) mood, amplified pain perception, inability to perform simple tasks and make normal efforts, and inability to experience reward in any way other than substance use. This syndrome closely resembles the subthreshold symptoms of dysthymia and the residual symptoms of chronic bipolar disorder.33,34 This is one of the possible ways of relapsing behavior.

In this case, in reality, the subject had not become an inveterate player; however, as a bipolar patient, he had been treated with anti-D2 drugs, favoring an RDS, and, as in SUD patients, a mild RDS caused by the dosage full of Aripiprazole could have recalled the gratifying action of the game, experimented in the recent past, bringing it, in a certain sense, to the relapse.

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It could, therefore, be assumed that our patient with a partial dopamine agonist dose of Aripiprazole has crossed the threshold to become a significant “nonsignificant salience,” starting to be a gambler. Once this dose was interrupted, the patient stopped playing because the salience not supported by the dopaminergic agonist action was not sufficient to induce him to play. When, however, the patient was subjected to an anti-D2 dosage of Aripiprazole, the RDS returned active, and the memory of the past gratification led him to a kind of relapse.

This case provides further support to the importance of screening for the emergence of SUDs when commencing a patient on Aripiprazole and extends the ambit of this vigilance to those who are commenced even on a very low dose also where the patients are substance use disorder and/or gambling naive.

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Aripiprazole; gambling; incentive salience; relapse; bipolar disorder

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