abilify and impulsive compulsive behaviour

Aripiprazole and Impulsive-Compulsive Behaviors: A Systematic Review

Abstract

Aripiprazole (ARI) is effective for schizophrenia and as a mood stabilizer, with better tolerability than other antipsychotics.
However, it can cause problem gambling, hypersexuality, obsessive-compulsive symptoms, and other impulsive/compulsive behaviors.
A systematic review of case reports found 35 related records comprising 59 cases after screening over 6000 titles and abstracts.
The majority of cases were male (n=42, 71.18%), with a mean age of 33.83 years ( $\pm$ 13.40), and an average aripiprazole dose of 11.63 mg ( $\pm$ 6.94).
The most frequent impulsivity adverse effect was gambling, followed by hypersexuality, obsessive-compulsive symptoms/disorder, problem eating, trichotillomania, problem shopping, and kleptomania.
Symptoms occurred in patients with and without prior problems in these areas.
Symptoms usually appeared within 30 days of starting aripiprazole and ceased within 30 days of discontinuation or dose reduction.
Clinicians should monitor for impulsivity adverse effects and educate patients and families.

Introduction

Antipsychotics treat mental illnesses like schizophrenia, psychotic disorders, bipolar disorder, and depression.
They are classified into three generations based on their pharmacological target.
First-generation antipsychotics: Act on the dopaminergic system as antagonists for dopamine type 2 (D2) receptors, mainly affecting the positive symptoms of schizophrenia (Li et al. 2016).
Second-generation antipsychotics: Higher affinity for serotonin receptors (5-HT) than for D2 receptors. They are also called dopamine-serotonin antagonists due to their 5-HT 2A/D2 antagonist properties (Pollmächer 2015). They also act on muscarinic cholinergic receptors, histamine receptors, and adrenergic receptors (Endomba et al. 2020).
Third-generation antipsychotics: Aripiprazole, are partial dopamine receptor agonists and also antagonists or weak partial agonists on the serotonin receptors (Kneller et al. 2021).
Aripiprazole acts as an antipsychotic and mood stabilizer (Stajic 2019).
It treats schizophrenia, bipolar-I disorder (McIntyre et al. 2023; Vieta et al. 2005), depression (Furukawa et al. 2022), Tourette syndrome (Cox & Cavanna 2021), behavioral disturbances in dementia (Ambrogio et al. 2019), and in children and adolescents (Lamy & Erickson 2018).
ARI is generally well-tolerated (Stelmach et al. 2023), efficacious in the short and long term (Tien et al. 2022), has a low propensity for extrapyramidal symptoms (Stelmach et al. 2023), a low rate of adverse effects such as weight gain or hyperprolactinemia (Hattori et al. 2023), and a low incidence of metabolic adverse effects (Kane et al. 2002).
Approved in the United States in 2002, in Europe in 2004, and in Japan in 2006 (Kikuchi et al. 2021).
It acts as a partial D2 dopamine and serotonin 5-HT1A receptors agonist as well as a serotonin 5-HT2A receptor antagonist (Hattori et al. 2023).
Less frequent side effects than other antipsychotics (Stelmach et al. 2023), but there have been reports of other adverse drug effects.
Commonly reported adverse effects include headache, agitation, anxiety, insomnia, nausea, vomiting, constipation, dyspepsia, dizziness, and restlessness (Giri & Peteru 2019).

Aripiprazole and Behavioral-Psychological Side Effects

Medication with partial or full dopaminergic agonistic activity, including ARI, can cause hypersexuality, pathological gambling, and compulsive shopping (Fusaroli et al. 2023; Mousailidis et al. 2020; Wolfschlag & Håkansson 2023).
The prevalence rate of such compulsive behaviors ranges from 6 to 24% (Üçok et al. 2007).
Abnormal behaviors usually cease after drug discontinuation (Bulbena-Cabré & Bulbena 2016; Çildir & Kalyoncu 2018; Cohen et al. 2011).
Sexual adverse effects limit antipsychotic use (Das et al. 2017).
Antipsychotics usually reduce libido (Downing et al. 2019), but ARI is a safer option and is often used to alleviate the prolactin-related side effects (Doval et al. 2017). However, it can induce excessive libido and lead to significant relational issues due to hypersexuality (Corbeil et al. 2020; Priya & Moorthy 2021).
ARI can result in more severe pathological gambling than full dopamine agonist agents (Dhillon et al. 2017; Gaboriau et al. 2014), prompting safety alerts from Health Canada and the FDA (Corbeil et al. 2020).
Pathologic gambling is the most common problem, followed by hypersexuality and compulsive shopping, in reports of impulse-control problems associated with ARI (Corbeil et al. 2020).
Other reported impulse-control problems and/or compulsive behaviors include kleptomania (Jones & Shad, (2019), (sleep-related) eating disorder (Kobayashi & Takano 2018), trichotillomania (Naguy & Naguy 2022), compulsive eating (Usmani 2020), and (recurrent episodes of) paraphilic behavior (Stefanou et al. 2020).
While ARI can augment treatment for obsessive-compulsive symptoms (Dold et al. 2015; Thamby & Jaisoorya 2019), contradictory reports show ARI being associated with or worsening obsessive-compulsive symptoms/disorder.
Desarkar and Nizamie (2007) reported ritualistic hand-washing and reassurance-seeking behavior after ARI administration.
Nafisa and Kakunje (2022) reported obsessive-compulsive symptoms after 3 weeks of ARI intake.
Burk et al. (2023) concluded that ARI is most frequently reported for de novo or exacerbated Obsessive Compulsive Symptoms/Obsessive Compulsive Disorder (OCS/OCD) compared to other antipsychotics.
However, there is no published data on how often ARI is associated with de novo or exacerbated OCS/OCD compared to other antipsychotics.

Current Study

There are related case reports and a few systematic reviews in the literature.
Giri and Peteru (2019) focused on gambling associated with ARI and concluded that clinicians should be “vigilant for possible gambling and other impulse-control behaviors in patients taking aripiprazole”.
Lachance et al. (2019) focused on problematic gambling associated with ARI in schizophrenia and concluded that ARI may be involved in the emergence of problematic gambling in some schizophrenic patients.
No systematic review has been conducted on the adverse effects of ARI in the form of various impulsive-compulsive behaviors.
The present study provides a systematic review on impulse-control problems and compulsive behaviors associated with ARI.
The study examines factors like gender, age, diagnoses, psychiatric history, ARI dosage, administration type, and concomitant medications to determine what adverse effects may be more likely under what conditions.

Method

The study is a systematic review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA; Page et al. 2021).

Study Selection

During May–July 2023, four reviewers searched scientific databases (Google Scholar, PubMed, MEDLINE, CINAHL, ScienceDirect, OATD, Embase, APA Psych Info, Cochrane, and clinical trials) without date restriction.
A manual search for reference lists from chosen papers and pertinent reviews of the ARI adverse effects literature was conducted.

Eligible studies for inclusion

The scope of the literature review was restricted using the following criteria:
- Articles focusing on various impulse-control problems and compulsive behaviors
- Articles on aripiprazole
- English-language articles
- Research that reports aripiprazole dosage
- Research that reports the main adverse effect(s)
The scope of our review was not restricted based on any fixed criteria to ensure that all relevant papers were considered.

Search strategy

The search was done using the following keywords for Aripiprazole: “Aripiprazole, Aripiprazole lauroxil, adjunctive Aripiprazole, Abilify, Abilify MAINTENA, Abilify MYCITE, Aristada, dopaminergic, dopamine replacement therapy, DRT, atypical antipsychotic, antipsychotic drug, dopamine agonist, D2 partial agonist, AAPs, aripiprazole augmentation, aripiprazole addition, and dopamine partial agonist”.
A comprehensive list of impulse-control problems and compulsive behaviors was also used.
The full set of search terms related to impulse-control problems and compulsive behaviors is provided in Appendix A.
Using search features specific to each database (e.g., asterisk, quotation mark) in conjunction with the Boolean (“AND” “OR”) operators, the terms were searched both independently and concurrently.

Data collection process

Three reviewers decided on the research eligibility by title screening, abstract screening, and full article screening.
Initially, titles and abstracts were carefully evaluated.
Then, each reviewer independently conducted a thorough review of the articles that appeared relevant.
The reviewers’ disagreements on eligibility were resolved through consensus.
In addition, the reference lists of eligible publications were also checked for potentially relevant studies.
A PRISMA chart is shown in Fig. 1 which illustrates the searching and filtering process.

Quality and risk of bias assessment

In order to assess the quality and risk of bias of the case reports included in the analysis, the JBI Critical Appraisal Checklist for Case Reports (Moola et al. 2017; Fig. 2) was used.
The checklist consists of eight items, with four possible answers for each item: “Yes”, “No”, “Unclear”, or “Not/ Applicable”.
- The items are related to the following areas:
  - 1) clear description of the patient’s demographic characteristics
  - 2) clear description of the patient’s history and its presentation as a timeline
  - 3) clear description of the patient’s current clinical condition
  - 4) clear description of the diagnostic tests or methods and their results
  - 5) clear description of the intervention(s) or treatment procedure(s)
  - 6) clear description of the post-intervention clinical condition
  - 7) identification and description of adverse events (harms) or unanticipated events
  - 8) inclusion of takeaway lessons in the case report
Two of the researchers independently evaluated the quality and assessed the risk bias of eligible case reports, and all disagreements were resolved by consensus.

Data extraction and analysis

From each article, the following were extracted: title, year of publication, authors’ names, number of cases, country and income level, marital status, ethnicity, employment status, education, gender, age (years), medical problem(s), outpatient/inpatient status, substance abuse, psychiatric hospitalization history, suicide attempt(s), primary diagnosis/complaint, other diagnosis(es), ARI daily dose (mg), other medications daily dose (mg), primary impulsivity adverse effect(s), time lapse between taking ARI and appearance of impulsivity adverse effect(s), time lapse between ARI cessation or dose reduction and decrease or cessation of impulsivity adverse effect(s), medication(s) substituting ARI, adverse reaction instrument and its result, and any other measurement tool and its mean score.
All statistical analyses were carried out using SPSS-26 (IBM Corp. Released 2019).

Results

Study characteristics and quality assessment of included case reports

The initial step involved conducting database searches, which yielded 6,851 results.
After removing duplicates (n=543), the remaining records (n=6,308) were screened based on their titles and abstracts.
After excluding irrelevant records based on title/abstract reading (n=5,983), a total of 325 records were assessed for eligibility.
Based on a full-text reading, 292 records were excluded, and 2 new records were identified from a bibliographic search.
Consequently, a total of 35 records representing 59 cases were included in the final review/analysis.
The demographic and clinical information of the studies/cases are presented in Table 1. Supplement A contains further specific details.
Using the JBI Critical Appraisal Tool for Case Reports, the overall quality of the included records was generally good, with>60% records scoring “yes” for most domains (see Fig. 1).
The “diagnostic tests or assessment methods” domain (question #4) was poorly reported across most cases (44 out of 59), followed by “the current clinical condition of the patient” domain (question #3; 18 out of 59), and “the patient’s history” (question #2; 14 cases out of 59).

Patient demographics

The case reports were published between 2007 and 2022.
The total number of cases across these reports was 59.
The total number of males was 42 (71.18%) with a mean age of 31.93 years ( $\pm$ 12.21) and an age range of 9–60 years.
The total number of females was 17 (28.82%) with a mean age of 38.53 years ( $\pm$ 14.60) and an age range of 16–64 years.
Five cases (8.47%) were in the older adult age range (56 years and above), 36 cases (61.01%) were in the adult age range (26–55 years), 14 cases (23.72%) were in the young adult age range (20–25 years), 2 cases (3.38%) were in the adolescent age range (13–19 years), and 2 cases (3.38%) were in the child age range (7–12 years).
The majority of case reports (n=23) were conducted and published before the onset of the COVID-19 epidemic (i.e., before 2020), and 12 case reports were conducted and published during the pandemic (i.e., 2020–2022).
Nine case reports provided information on marital status, indicating that 6 cases (out of nine) were married and 3 cases (out of nine) were single.
The ethnicity of just four cases were reported, 3 Caucasian and 1 Hispanic.
Four case reports provided information on employment status, indicating that all cases were employed.
And, the education levels of just two cases were reported, one 11th grade and one college student.

General medical and psychological/psychiatric information about patients

Among all 59 cases, eleven cases had no medical problem and 3 cases reported having medical problems (vitamin D deficiency, slight liver damage and hyperlipidemia, head injury).
Seventeen cases were outpatients, seven cases were inpatients, and one case was outpatient then inpatient.
Fifteen cases had substance abuse, and twelve cases did not have substance abuse.
Eight cases had been hospitalized in a psychiatric ward before, and two cases had no psychiatric hospitalization history.
One case had suicidal ideation, three cases had no history of suicide attempt, and one case had a history of three suicide attempts.

Specific psychological/psychiatric information of patients in relation to ARI

The highest frequency of primary diagnosis belonged to schizophrenia (40 cases; including residual schizophrenia [n=13], paranoid schizophrenia [n=10], schizoaffective disorder [n=7], schizophreniform [n=4], initial emergence of psychosis [n=3], unspecified psychosis [n=3]), followed by bipolar disorder (n=9), ADHD (n=3), major depression (n=3), and alcohol abuse, gambling problem, OCD, and mood disorders (one case for each).
Eighteen cases had other diagnoses including OCD, avoidant personality traits, anxiety, and depression in addition to schizophrenia; gambling disorder in addition to schizophrenia; eating disorder and minor OCS in addition to schizophrenia; substance use disorder in addition to bipolar disorder; GAD (Generalized Anxiety Disorder) in addition to bipolar disorder; cluster B personality traits and ADHD in addition to psychosis; bipolar disorder in addition to psychosis; cannabis and cocaine abuse and cluster B personality traits in addition to schizophreniform; alcohol use disorder and cluster B personality traits in addition to schizophreniform; cannabis use and cluster B personality traits in addition to schizophreniform; conduct disorder symptoms in addition to ADHD; ASD (Autism Spectrum Disorder) and mild ID (Intellectual Disability) in addition to ADHD; mood symptoms in addition to ADHD; anorexia nervosa in addition to MDD (Major Depressive Disorder); and GAD and mixed personality disorder (Clusters B & C) in addition to OCD.
The ARI daily dose ranged from 2 to 30 mg, with a mean of 11.63 mg ( $\pm$ 6.94).
In the majority of cases (n=45, 76.27%) just oral administration of ARI was used; in one case (n=1, 1.69%) just long acting injectable (LAI) form of ARI was used; in six cases (10.16%), treatment began with oral administration of ARI and then changed to the LAI form of ARI; and in seven cases (11.86) administration type of ARI was not specified in the article.
In 16 cases, ARI administration substituted risperidone, in 4 cases, it substituted olanzapine, and in 3 cases, it substituted paliperidone.
ARI administration also substituted Haloperidol, Clozapine, Amisulpride, Pimozide, Quetiapine, Cyamémazine, Prazepam, and Ziprasidone, and added to Sertraline, each of these occurred in one case.
The data is summarized in Table 2.

Impulsivity adverse effect(s) of ARI and the related data

Gambling was the most frequent published impulsivity adverse effect among the cases (n=34; 57.64%), followed by hypersexuality (n = 12; 20.33%), obsessive–compulsive symptoms/disorder (n=7; 11.86%), problematic eating (n=3; 5.08%), problematic shopping (n=2; 3.38%), trichotillomania (n = 2; 3.38%), and kleptomania (n = 1; 1.69%).
Twenty-one cases (35.59%) had a positive history of experiencing the primary impulsivity adverse effect in the past, i.e., experienced some problems in that field before ARI administration; 31 cases (52.54%) experienced the primary impulsivity adverse effect for the first time only after ARI administration.
In the majority of cases (n = 29; 49.15%), the ARI impulsivity adverse effect emerged within 30 days of its administration.
In 17 cases (28.81%), the ARI impulsivity adverse effect emerged within 31–181 days (and above) of its administration.
And 13 case reports (22.03%) lacked the relevant data regarding the impulsivity adverse effect emergence time after ARI administration.
Also, in the majority of cases (n=30; 50.84%), the ARI impulsivity adverse effect ceased within 30 days after its discontinuation; in 8 cases (13.55%), the ARI impulsivity adverse effect ceased within 31–181 days (and above) of its discontinuation; and 21 case reports (35.53%) lacked the relevant data about the impulsivity adverse effect cessation time after ARI discontinuation.
Overall, 18 case reports (30.50%) contained exact data on both time to emergence and time to cessation of ARI impulsivity adverse effects after its administration and discontinuation, respectively.
The correlation coefficient between the emergence time and cessation time of impulsivity adverse effects in these 18 cases was 0.386 (p=0.113).
In 14 cases, an instrument was used to assess the ARI impulsivity adverse effect and its score was reported.
- The instruments were “checking criteria of DSM-IV pathological gambling section” (8 cases), the South Oaks Gambling Screen (3 cases), the Yale-Brown Obsessive–compulsive Scale (Y-BOCS; 2 cases), and the Massachusetts Gambling Screen & Gambling Craving Scale adapted from the Penn Alcohol Craving Scale (1 case).
The Naranjo Adverse Reaction Probability Scale was completed by 17 cases with the following results: reaction of one case as “definite”, reaction of seven cases as “probable”, reaction of eight cases as “possible”, and reaction of one case as “doubtful”.
The data is summarized in Table 3.

Daily dosage (mg) and impulsivity adverse effect(s) of ARI

The three most frequently published impulsivity adverse effects (i.e., gambling, hypersexuality, and OCS/OCD) were related to a wide range of ARI daily dosage, from 2-30 mg for gambling, 3-30 mg for hypersexuality, and 5-30 mg for OCS/OCD.
For problem shopping also the daily dosage ranged from 3-20 mg.
However, for problem eating, trichotillomania, and kleptomania, there was a narrower daily dosage range of ARI: 3-15 mg, 2.5-5 mg, and 2 mg respectively.

Primary diagnosis and/or chief complaint and impulsivity adverse effect(s) of ARI

The most frequently published impulsivity adverse effect of ARI among cases who suffered from any form of psychosis, bipolar disorder, and depression was gambling (n=26, n=4, n=2 respectively).
Gambling was also the only impulsivity adverse effect reported by cases with alcohol/substance abuse or gambling as their primary diagnosis and/or chief complaint (n=1 for each).
Among cases with any form of psychosis, gambling was followed by hypersexuality (n=8), OCS/OCD (n=6), problem shopping (n=1), and problem eating (n=1).
Among cases with bipolar disorder also gambling was followed by hypersexuality (n=2), OCS/OCD (n=1), and problem shopping (n=1).
Among cases with ADHD and/or behavioral problems, the only impulsivity adverse effects of ARI were either trichotillomania (n=2) or problem eating (n=1).

Age (category), gender, and impulsivity adverse effect(s) of ARI

Among child cases, just two adverse effects (problem eating, trichotillomania) were reported with the same frequency (n=1 for each one).
Among adolescent cases, trichotillomania (n=2), OCS/OCD (n=1), and problem eating (n=1) were reported.
Gambling was the most frequently published impulsivity adverse effect of ARI among young adults (n=10), followed by OCS/OCD (n=2) and hypersexuality (n=2).
Among adult cases, the most frequently published impulsivity adverse effect of ARI was gambling (n=2), followed by hypersexuality (n=8), OCS/OCD (n=3), problem shopping (n=2), problem eating (n=1), and kleptomania (n=1).
Among old adult cases, gambling (n=2) and hypersexuality (n=2) were the most frequently published impulsivity adverse effects, followed by OCS/OCD and problem eating (n=1 for each one).
Among female cases, the most frequently published impulsivity adverse effects were gambling (n=6) and OCS/OCD (n=6), followed by hypersexuality (n=3), problem shopping, problem eating, and kleptomania (n=1 for each one).
For male cases also, the most frequently published impulsivity adverse effect was gambling (n=28), followed by hypersexuality (n=9), problem eating and trichotillomania (n=2 for each one), and OCS/OCD and problem shopping (n=1 for each one).
Among female cases and across all age categories, the most frequently published impulsivity adverse effects were OCS/OCD (n=6) and gambling (n=6), followed by hypersexuality (n=3).
Considering the age category, three kinds of impulsivity adverse effects were most frequently published among adult female cases: gambling (n = 4), OCS/OCD (n = 3), and hypersexuality (n = 2).
Among male cases and across all age categories, the most frequently published impulsivity adverse effect was gambling (n=28), followed by hypersexuality (n=9), problem eating (n=2), and trichotillomania (n =2).
Considering the age category, gambling was the most frequently published impulsivity adverse effect among adolescent, young adult, and adult male cases (n=2, n=8, and n=18 respectively).
Hypersexuality was the second most frequently published impulsivity adverse effect among adult male cases (n=6) and the only impulsivity adverse effect reported by older adult male cases.
Trichotillomania was only reported by male cases – one case in child age category and one in adolescent age category; kleptomania was only reported by an adult female case; and problem shopping was only reported by an adult male case.

COVID-19 pandemic and impulsivity adverse effect(s) of ARI

Gambling was the most frequently published impulsivity adverse effect of ARI in both studies conducted/published before COVID-19 pandemic (n=22) and studies conducted/ published during COVID-19 pandemic (n=10), followed by hypersexuality (n=8 for pre-COVID; n=3 for during- COVID) and OCS/OCD (n=2 for both pre- and during- COVID pandemic).

Marital status, employment, and impulsivity adverse effect(s) of ARI

For nine cases, marital status was reported.
Among the six cases who were married and/or in a relationship, the most frequently published impulsivity adverse effects were gambling (n=3) and hypersexuality (n=3), followed by problem shopping (n=1) (one case reported more than one impulsivity adverse effect).
Among the three cases who were single, the most frequently published impulsivity adverse effect was hypersexuality (n=2), followed by gambling (n=1).
In just four cases, employment status was reported.
They were all employed and the most frequently published impulsivity adverse effects were gambling (n=2), followed by hypersexuality (n=1), problem shopping (n=1) and OCS/OCD (n=1) (one case reported more than one impulsivity adverse effect).

Other medications and impulsivity adverse effect(s) of ARI

In twenty cases, it was reported that in addition to ARI, what other medication was used by the patient.
Among cases who had gambling problems, two cases used ARI plus valproic acid, and one case used ARI plus valproic acid, lithium, risperidone, clonazepam.
In two other cases, ARI was used in addition to amisulpride, alone or with diazepam.
Gambling problems were also reported in patients who used ARI plus carbamazepine, premazepam, lisdexamfetamine, haloperidol, delorazepam, alprazolam.
Among cases suffering from hypersexuality, ARI was used with fluoxetine, risperidone, lithium, carbamazepine, citalopram, chlorprothixene, lamotrigine, venlafaxine, risperidone, and clonazepam.
Problem eating emerged in patients who used ARI plus methylphenidate, lithium, and perphenazine.
OCD was observed in a case who used ARI with zolpidem, and trichotillomania was observed in a case who use ARI plus methylphenidate.

Substituted antipsychotics and impulsivity adverse effect(s) of ARI

In 31 cases (52.54%), ARI substituted another medication in the treatment process of the case.
In the majority of cases, ARI substituted risperidone (n=16; 27.11%), followed by olanzapine (n=4; 6.7%), and paliperidone (n=3, 5.08%).
Further analysis indicated that in cases for whom ARI substituted risperidone, the reported impulsivity adverse effects were hypersexuality (n=8; 13.55%), gambling (n=7; 11.86%), and OCS (n=1, 1.69%); in cases for whom ARI substituted olanzapine, the reported impulsivity adverse effects were gambling (n=2; 3.38%), hypersexuality (n=1; 1.69%), and OCS (n=1, 1.69%); and in cases for whom ARI substituted paliperidone, gambling was the only reported impulsivity adverse effect of ARI.

Comorbidity and impulsivity adverse effect(s) of ARI

For seventeen cases, detailed information about comorbidity was provided.
Analysis revealed that when the primary diagnosis is bipolar disorder, the presence of GAD or substance use disorder results in the appearance of gambling problems.
Conduct disorder symptoms and ADHD might lead to trichotillomania.
Furthermore, it seems that existence of cluster B personality traits and/or alcohol/drug abuse in addition to psychosis, may make patients more susceptible to problem gambling.

Discussion

Among the 59 cases, the total number of males was more than twice the number of females (42 versus 17).
The mean age of male cases (31.93 $\pm$ 12.21 years) was lower than that of female cases (38.53 $\pm$ 14.60 years).
However, the difference was not statistically significant (p=0.204).
One possibility is that ARI is prescribed more for males than females.
Another is that male patients suffer from impulsivity adverse effects of ARI more than female patients.
However, Montero et al. (2008) could not ascertain the possible differences between men and women in the therapeutic response or in the impulsivity adverse side effects of treatment with ARI which was due to “failure to conduct analyses stratified by sex” (p.40).
Since the number of male and female cases was not the same, it is not possible to say which gender is more susceptible to ARI impulsivity adverse effects.
The same is true for different age categories.
Another possibility is that among male patients, ARI is prescribed for a wider range of disorders than among female patients.
As seen in Table 1, among female patients ARI is prescribed for schizophrenia, schizoaffective disorder, and mood disorders while among male patients ARI is prescribed not only for these disorders, but also for alcohol abuse, gambling disorder, ADHD, and OCD.
It has been found that the prevalence of both gambling/problem gambling (Hing et al. 2016) and alcohol abuse (Goh et al. 2022) among men is higher than that of women.
A review by Faheem et al. (2022) showed sufficient evidence of gender differences in adult ADHD prevalence.
Regarding OCD, it may be more common among males in childhood, but is more common among females in adolescence and adulthood (Mathes et al. 2019).
And since the most effective drugs for OCD are serotonin reuptake inhibitors (Kopelman 2020), ARI may not be a first line OCD treatment.
In addition to epidemiological differences, another explanation is that ARI has been found to be a more effective medication and therefore, prescribed more frequently.
For example, Derakhshanpour et al. (2022) found that the score of the aripiprazole group on ADHD-RS was significantly less than the score of the risperidone group.
ARI is also used as an antipsychotic augmentation in the treatment of obsessive–compulsive disorder (Thamby & Jaisoorya 2019).
Or for alcohol use disorder as well, Martinotti et al. (2016) found that ARI would promote alcohol abstinence and reduce alcohol-seeking behavior.
The most frequently published impulsivity adverse effects were gambling (n=34; 57.64%), followed by hypersexuality (n=12; 20.33%).
This is consistent with previous reports (for example, Ceylan et al. 2021; Kozian 2019).
Other compulsive behaviors like binge/compulsive eating and excessive/compulsive shopping, which were reported in 4 cases (6.77%), can also be accounted for here since the mesolimbic dopaminergic circuit acts as a reward system for sex, food, and drugs of abuse and may be involved in such behaviors (Bulbena-Cabré & Bulbena 2016).
There are some hypotheses underlying the possible mechanisms of this association.
For example, Moore et al. (2014) suggest that these behaviors are reward-based and therefore reinforced by dopaminergic stimulation, specifically by the dopamine D3 receptor.
Padala and colleague (2007) also suggest that the combined antagonism of 5-HT1A and partial agonist of D2 receptors of ARI could cause frontal dopamine release, especially in patients with chronic exposure to D2 antagonists.
This may predispose them to such behavior.
The important point to consider is that the positive history of problem gambling does not seem to play a role here since 13 cases had no history of problem gambling, compared to 17 cases who had it.
The same pattern was observed for other impulsivity adverse effects; for example, hypersexuality emerged in just one case who had positive history of it and 6 cases who did not.
This however needs further investigation since in this review, the relevant data for 18 cases was not reported in the studies.
The last point in this part is that among the seven cases for whom either just the LAI form of ARI was used (n=1, 1.69%) or oral administration of ARI and then the LAI form of ARI was used (n=6, 10.16%), gambling (n=6) and hypersexuality (