Unveiling the Burden of Drug-Induced Impulsivity: A Network Analysis of the FDA Adverse Event Reporting System

Abstract

Introduction: Impulsivity induced by dopaminergic agents, like pramipexole and aripiprazole, can lead to behavioral addictions that impact on social functioning and quality of life of patients and families (e.g., resulting in unemployment, marital problems, anxiety). These secondary effects, interconnected in networks of signs and symptoms, are usually overlooked by clinical trials, not reported in package inserts, and neglected in clinical practice.

Objective: This study explores the syndromic burden of impulsivity induced by pramipexole and aripiprazole, pinpointing key symptoms for targeted mitigation.

Methods: An event-event Information Component (IC) on the FDA Adverse Event Reporting System (FAERS) (January 2004 to March 2022) identified the syndrome of events disproportionally co-reported with impulsivity, separately for pramipexole and aripiprazole. A greedy-modularity clustering on composite network analyses (positive pointwise mutual information [PPMI], Ising, Φ) identified sub-syndromes. Bayesian network modeling highlighted possible precipitating events.

Results: Suspected drug-induced impulsivity was documented in 7.49% pramipexole and 4.50% aripiprazole recipients. The highest IC concerned obsessive-compulsive disorder (reporting rate = 26.77%; IC median = 3.47, 95% confidence interval [CI] = 3.33-3.57) and emotional distress (21.35%; 3.42, 3.26-3.54) for pramipexole, bankruptcy (10.58%; 4.43, 4.26-4.55) and divorce (7.59%; 4.38, 4.19-4.53) for aripiprazole. The network analysis identified delusional jealousy and dopamine dysregulation sub-syndromes for pramipexole, obesity-hypoventilation and social issues for aripiprazole. The Bayesian network highlighted anxiety and economic problems as potentially precipitating events.

Conclusion: The under-explored consequences of drug-induced impulsivity significantly burden patients and families. Network analyses, exploring syndromic reactions and potential precipitating events, complement traditional techniques and clinical judgment. Characterizing the secondary impact of reactions will support informed patient-centered decision making.

Fig. 1

Pipeline of the study, showing step-by-step study design. FAERS FDA Adverse Event Reporting System, PPMI positive pointwise mutual information

Fig. 2

Characteristics of the investigated populations. The figure presents information about two populations extracted from the deduplicated FDA Adverse Event Reporting System (FAERS) database—one consisting of reports related to pramipexole and the other consisting of reports related to aripiprazole. Within these populations, cases of pathologic impulsivity were identified. The figure compares drug-induced impulsivity cases and the reference group (other reports recording the drug), considering the indication for use. Only the two most prevalent indications were considered. For each drug and indication, the caption describes the percentage of reports with the specified indication, the percent of reports involving males, and the median and interquartile range of ages. In the drug-induced impulsivity cases sections, green plus signs and red minus signs indicate variables that are respectively higher or lower than expected based on the reference group

Fig. 3

Secondary impact of drug-induced impulsivity. The dendrogram shows the events disproportionally reported with aripiprazole- and pramipexole-related impulsivity. Events are gathered by clinical similarity in alternately colored slices, labeled on the outer border with a name and an icon. Disproportionalities are shown as dots organized in two colored rings, each representing a drug/case population. The dot size is proportional to the percent of reports showing the event, the color is darker for stronger disproportionality (higher median Information Component)

Fig. 4

The secondary impact of aripiprazole-induced impulsivity. The network shows the events disproportionally reported with aripiprazole-related impulsivity and their pattern of co-reporting. Drug-induced impulsivity manifestations are shown as squares and other events as circles. Node colors identify clusters from the Ising estimation, dashed contours for the $\varphi$ estimation, and colored contours for the positive pointwise mutual information (PPMI) estimation. The link width represents the weight of the links of the Ising, here chosen over the others because links are fewer and more conservative. The layout has been manually adjusted to reduce the overlapping. The layout calculated using a spring model with, as weight, the weights from the individual networks and the average of the weights of the three networks, after rescaling them from 0 to 1, is shown in the supplementary material

Fig. 5

The secondary impact of pramipexole-induced impulsivity. The network shows the events disproportionally reported with pramipexole-related impulsivity and their pattern of co-reporting. Drug-induced impulsivity manifestations are shown as squares and other events as circles. Node colors identify clusters from the Ising estimation, dashed contours for the $\varphi$ estimation, and colored contours for the positive pointwise mutual information. (PPMI) estimation. The link width represents the weight of the links of the Ising, here chosen over the others because links are fewer and more conservative. The layout has been manually adjusted to reduce the overlapping. The layout calculated using a spring model with, as weight, the weights from the individual networks and the average of the weights of the three networks, after rescaling them from 0 to 1, is shown in the supplementary material

Fig. 6

The secondary impact of the main manifestations of drug-induced impulsivity, aripiprazole and pramipexole. The subgraphs extracted from the Bayesian Network show the potential direction of the co-reporting relationships between the events, thus providing insight into the direct and indirect impact of drug-induced impulsivity. Nodes linked to hyperphagia, hypersexuality, pathological gambling, and compulsive shopping are represented. Only out-neighbors of order equal or less than 1 are shown here, together with out-neighbors of order 2 considered relevant for clinical interpretation

Fig. 7

Drug-induced impulsivity syndrome, aripiprazole and pramipexole. The main syndrome, representing one or more strongly interconnected central clusters of symptoms and signs identified through network analysis, is depicted as the central figure. Other potential sub-syndromes are shown on the sides highlighted with a colored square