Impulse Control Disorders by Dopamine Partial Agonists

[Chip (OP)]

https://academic.oup.com/ijnp/article/25/9/727/6593999

NB: Chipper spent over $50,000 on Meth when court ordered onto Abilify

Impulse Control Disorders by Dopamine Partial Agonists: A Pharmacovigilance-Pharmacodynamic Assessment Through the FDA Adverse Event Reporting System

27 May 2022

Abstract

Background

The dopaminergic partial agonism of the so-called third-generation antipsychotics (TGAs; aripiprazole, brexpiprazole, cariprazine) is hypothesized to cause impulse control disorders (ICDs). Relevant warnings by the Food and Drug Administration (FDA) were posted on aripiprazole (2016) and brexpiprazole (2018). Our study investigated the FDA Adverse Event Reporting System and the pharmacodynamic CHEMBL database to further characterize TGA-induced ICDs.

Methods

We downloaded and pre-processed the FDA Adverse Event Reporting System up to December 2020. We adapted Bradford Hill criteria to assess each TGA’s —and secondarily other antipsychotics’—causal role in inducing ICDs (pathological gambling, compulsive shopping, hyperphagia, hypersexuality), accounting for literature and disproportionality. ICD clinical features were analyzed, and their pathogenesis was investigated using receptor affinities.

Results

A total of 2708 reports of TGA-related ICDs were found, primarily recording aripiprazole (2545 reports, 94%) among the drugs, and gambling (2018 reports, 75%) among the events. Bradford-Hill criteria displayed evidence for a causal role of each TGA consistent across subpopulations and when correcting for biases. Significant disproportionalities also emerged for lurasidone with compulsive shopping, hyperphagia, and hypersexuality, and olanzapine and ziprasidone with hyperphagia. Time to onset varied between days and years, and positive dechallenge was observed in 20% of cases. Frequently, co-reported events were economic (50%), obsessive-compulsive (44%), and emotional conditions (34%). 5-Hydroxytryptamine receptor type 1a agonism emerged as an additional plausible pathogenetic mechanism.

Conclusions

We detected an association between TGAs and ICDs and identified a new signal for lurasidone. ICD characteristics are behavior specific and may heavily impact on life. The role of 5-Hydroxytryptamine receptor type 1a agonism should be further explored.

Introduction

Third-Generation Antipsychotics (TGAs)

In the neuroscience-based nomenclature, aripiprazole, brexpiprazole, and cariprazine are classified together, and separately from other antipsychotics, because of their partial agonism on the dopamine receptors type 2 and 3 (D2/D3) and on the 5-hydroxytryptamine receptor type 1A (5-HT1A). Indeed, due to their unique pharmacodynamic profile, they are referred to as TGAs (Orsolini et al., 2020).

Aripiprazole is considered the prototype of TGAs. First approved for the treatment of schizophrenia (Food and Drug Administration [FDA], 2002; European Medicines Agency [EMA], 2004), it was subsequently extended to the treatment of manic episodes and relapse prevention in bipolar disorders. Cariprazine (FDA 2015; EMA 2017) shares the indications of aripiprazole, while brexpiprazole (FDA 2015; EMA 2018) is approved for schizophrenia and as an adjunctive treatment for major depressive disorder.

TGA-Induced Impulse Control Disorders (ICDs)

While TGAs’ antagonist activity in high dopamine synaptic levels contributes to the therapeutic effect, their peculiar agonism in low levels accounts for a reduced risk of extrapyramidal syndrome (Aringhieri et al., 2018), which is a clinically important adverse event in D2-antagonist first-generation antipsychotics. Nonetheless, this partial agonism could be responsible for the onset of not well-defined behavioral addictions (ICDs), speculatively attributed to D3 agonism (Seeman, 2015) and already acknowledged as adverse reactions to dopamine agonists for Parkinson’s disease (Grall-Bronnec et al., 2018).

ICDs, defined as “the failure to resist an impulse, drive or temptation to perform an act that is harmful to the person or to others” (DSM-5), encompass a group of heterogeneous and not well-defined behaviors, including pathological gambling, hypersexuality, compulsive shopping, and binge eating, but also many other behavioral addictions and stereotypies that are inconstantly considered (Fusaroli et al., 2021). These conditions are often impulsive-compulsive degenerations of previous habits of the patients and can have a serious impact on their life, possibly resulting in family conflicts, divorce, loss of job and money, and legal problems. Therefore, patients should be informed about these side effects before beginning the therapy.

Evidence accumulated through the FDA Adverse Event Reporting System (FAERS) for aripiprazole-induced ICDs prompted the FDA to issue a relevant warning in 2016 (Moore et al., 2014; Etminan et al., 2017; Lertxundi et al., 2018; Center for Drug Evaluation and Research, 2019), followed by a label update for brexpiprazole in 2018, whereas cariprazine was not considered (Keks et al., 2020). The FAERS, which gathers spontaneous reports of adverse events from the entire world, is particularly suited to investigate rare or unexpected adverse events, such as ICDs, related to recently marketed drugs. It is also extensively used in the psychiatric area as a source of evidence, complementary to clinical trials, for safety profiling of antidepressants and antipsychotics (Poluzzi et al., 2013; Mazhar et al., 2019; Cepaityte et al., 2021; Gastaldon et al., 2021; Zazu et al., 2021) and for generating hypotheses on the underlying mechanisms (Aguiar et al., 2020; Gahr et al., 2021). Given that more than 5 years have passed from the first approval of brexpiprazole and cariprazine, the FAERS should provide enough data for a first in-depth assessment of TGA-related ICDs.

Aim

The scope of this pharmacovigilance study is to extend current knowledge about TGA-induced ICDs, both as specific behaviors and as a unified diagnostic entity. Relying on FAERS spontaneous reports from real-world clinical practice and on CHEMBL pharmacodynamic measures, we aim to characterize ICDs’ clinical features and explore their underlying pharmacological basis. Our focus will be primarily on aripiprazole, brexpiprazole, and cariprazine, including a comparison with other antipsychotics.

METHODS

FDA Adverse Event Reporting System
The FAERS is a freely available spontaneous reporting system that collects worldwide reports of suspected adverse drug reactions. Its raw quarterly data (FDA, 2022) include demographic, therapeutic, and outcome details. Reactions and indications are coded using Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms.

All FAERS Quarterly Data (ASCII files from January 2004 up to December 2020) were downloaded and pre-processed for duplicate removal.

Cases Retrieval

Because the MedDRA is redundant, the use of Standardized MedDRA Queries for case retrieval is advised. In the lack of Standardized MedDRA Queries for ICDs, we used MedDRA queries recently developed by combining a scoping review with pharmacosurveillance analyses (Fusaroli et al., 2021). We focused on the ICDs with the most robust clinical evidence: (1) pathological gambling (“gambling”, “gambling disorder”); (2) hypersexuality (“compulsive sexual behavior,” “sexually inappropriate behavior,” “hypersexuality,” “excessive masturbation,” “excessive sexual fantasies,” “libido increased,” “sexual activity increased,” “Kluver-Bucy syndrome”); (3) compulsive shopping (“compulsive shopping”); and (4) binge eating (“binge eating,” “food craving,” “hyperphagia”). We also extended the search to (5) a broader definition of ICDs, including routine and leisure activities (internet addiction, compulsive hoarding, walkabouts, excessive exercise, overwork), obsessive-compulsive and related disorders (stereotypy, body-focused repetitive behaviors, obsessive-compulsive disorders), conduct disorders (pyromania, kleptomania, aggressivity, paraphilia), drug abuse, and general terms concerning impulsivity and euphoria. Drugs of interest were aripiprazole, brexpiprazole, and cariprazine, but with an extended focus on all the antipsychotics included in the N05A category of the Anatomical Therapeutic Chemical classification updated in 2021.

Although we acknowledge that spontaneous reports do not allow to fully apply diagnostic criteria [in fact the need for diagnostic scales—for both ICDs and the individual behaviors affected—is still largely unanswered (Evans et al., 2019)], we presumed that any suspected adverse drug reaction, to be reported, must have some impact on the quality of life.

Descriptive Analysis

To characterize TGA-related ICDs—both as a single heterogeneous diagnostic construct and as individual behaviors—we compared their demographics (sex, age, outcome, continent, reporter) with 2 Reference Groups (RGs): RG1, all other TGA reports (see Table 1); and RG2, all other ICD reports (see Table 2). Given that the population reporting TGA exposure was not equally split between the sexes and the tendency to report to the FDA is also skewed, even an equal tendency to report the adverse event would not result in equal distribution of cases between the sexes. Therefore, directly comparing the number of men with the number of women in the case group would not be informative. Women tend to report more often than men to the FAERS, and conditions for which a specific drug is prescribed may be distributed asymmetrically between men and women. To consider both reporting biases (e.g., higher reporting by women) and the sex distribution in the underlying indication for use, we chose as comparison the population of non-ICD TGA reports (RG1). In the same way, we compared TGA-related ICD reports with all the other reports of ICDs (RG2) to investigate whether ICDs related with TGAs share their features with other ICDs.

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