Network analysis of comorbid aggressive behavior and testosterone among bipolar disorder patients: a cross-sectional study

Liu, Yi; Cai, Hong; Han, Tian; Wang, Yi-Fan; Li, Juan; **e, **ao-meng; Ji, **ao

doi:10.1038/s41398-024-02957-1

Network analysis of comorbid aggressive behavior and testosterone among bipolar disorder patients: a cross-sectional study

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Published: 29 May 2024

Volume 14, article number 224, (2024)
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Translational Psychiatry

Network analysis of comorbid aggressive behavior and testosterone among bipolar disorder patients: a cross-sectional study

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Abstract

Testosterone has complex effects on psychological traits and behavior; it is associated with social dominance and competition and is a potential human sex pheromone. This study aimed to investigate the associations between testosterone levels, aggressive behavior, and manic symptoms using a network analysis among bipolar disorder (BD) patients in psychiatric emergency departments (PED). Data from January 2021 and March 2022 BD patients in PED were analyzed. Manic symptoms were assessed using the Young Mania Rating Scale (YMRS). Aggression was assessed with subscale of the PANSS scale (PANSS-AG). The undirected network structures of testosterone levels, aggressive behavior, and manic symptoms were estimated, and centrality and bridge centrality indices were examined. Network stability was examined using the case-drop** procedure. The Network Comparison Test (NCT) was conducted to evaluate whether network characteristics differed by gender. We recruited a total of 898 BD patients, with the mean YMRS score as 13.30 ± 9.58. The prevalence of level II aggression was 35.6% (95%CI = 32.5%–38.7%), level III aggression was 29.5% (95%CI = 26.3%–32.6%), and level VI aggression was 7.0% (95%CI = 5.4%–8.8%). The male participants had a mean testosterone level of 391.71 (Standard Deviation (SD):223.39) compared to 36.90 (SD:30.50) for female participants in the whole sample. Through network analysis, “Increased motor activity-energy” emerged as the central symptom, with the highest centrality expected influence, followed by “Emotional Instability” and “Disruptive/aggression behavior”. Notably, “Emotional Instability” appeared to be the bridge symptom linking manic symptoms to aggressive behavior. Within the flow network model, “Speech rate and amount” exhibited the strongest positive correlation with testosterone levels, followed closely by “Disruptive/aggression behavior”. The constructed network model demonstrated robust stability, with gender showing no significant impact on the structure. In this study, “Increased motor activity-energy” stood out as the most influential symptom, and “Speech rate and amount” acted as the main bridge symptom linking testosterone levels, aggressive behavior, and manic symptoms. Targeting the central and bridge symptoms may improve the outcomes of aggression interventions implemented among BD patients in psychiatric emergency care.

Comorbidity of anxiety and depression disorder among clinical referral patients: a longitudinal study based on network analysis

Article 01 April 2024

Gender differences in aggression of borderline personality disorder

Article Open access 09 April 2015

Correlates of Aggression in Personality Disorders: an Update

Article 21 July 2018

Introduction

Bipolar disorder (BD) is a potentially lifelong condition characterized by extreme changes in mood with high incidences of hyperactivity, irritability, grandiosity, poor judgment, and other symptoms, all of which are highly likely to lead to aggressive behavior [1]. Impulsive aggression is common amongst BD patients. Notably, aggressive behavior in BD patients show a direct prognostic value, which links to suicidal behaviors, more frequent hospitalizations, higher severity of mania symptoms, mixed symptoms, and comorbid borderline personality disorder [2]. A characteristic of BD emerges as hindrance towards an individual’s ability to perceive risk and protect themselves, which make them vulnerable to physical assault [3]. Given the risk of hurting others and self-harm, patients with BD have profound effects on society and family numbers.

The etiology of BD is unknown; however, factors such as genetics, biological traits, and environment have been proposed for consideration in the pathogenesis of BD [4]. For patients with BD who are experiencing disease episode, emergency departments or psychiatric emergency department (PED) are often their preferred choice for medical treatment. The highest prevalence of aggressive behavior occur in acute care settings (12.5–61.8%) [5, Full size image

Node-specific predictive betweenness measure

Researchers have found that “Testosterone” plays an important role in aggressive behavior in previous studies [22]. Figure 4 shows the node-specific predictive betweenness values for each node in the network. The white dots represent the node-specific predictive betweenness in the study sample, while the black lines represent the variability of the measure across 1000 nonparametric bootstrap iterations. YMRS6 (“Speech–rate and amount”) has the highest node-specific predictive betweenness score, followed by YMRS5 (“Irritability”). This finding suggests that “Speech–rate and amount” and “Irritability” may be the main bridge symptoms between testosterone levels, manic symptoms, and aggression (Fig. 4).

Network comparison tests by gender

The comparison of the network model by gender did not reveal significant differences in network global strength (network strength: 11.37 in female participants; 11.40 male participants; M = 0.214, P = 0.571) and edge weights (S = 0.026, P = 0.969, Supplementary Figs. S1–S4).

Discussion

The study is the first network analysis of the association between testosterone levels and aggressive behavior among patients with BD in China PED. Within the assessed network model, “Increased motor activity-energy”, “Emotional instability” and “Disruptive/aggressive behavior” stood out as the most influential symptoms. Notably, “Speech rate and amount” acted as the main bridge symptom linking testosterone levels, manic symptoms, and aggression, followed by “Elevated Mood” and “Difficulty in delaying gratification”.

Our network analysis highlighted “Increased motor activity-energy” and “Emotional instability” as central symptoms in patients arriving at the emergency room due to aggressive tendencies. Patients with BD often displays alcohol or substance abuse, which can increase behavioral activity, leadings to an increased prevalence of aggressive behavior possibly up to 12% [27]. Consistent with previous findings, aggression was associated with more severe manic symptoms, as measured by the YMRS in acute manic episodes [28]. People in the manic phase are often highly motivated to engage in goal-oriented activities. However, due to lack of insight, patients may not realize their behavior is abnormal and prone to harmful consequences. Patients become extremely aggressive and irritable, and are more likely to harm themselves or others and destroy property through verbal or physical aggression [29]. This observation also shed light on the identification of “Difficulty in delayed gratification” as another bridge symptom. Previous functional magnetic resonance imaging (fMRI) studies have observed responses in the amygdala, periaqueductal gray matter, and the prefrontal lobe when BD patients were frustrated by the denial of a reward. This neural response can potentially stimulate aggressive impulses, transforming unfulfilled desires into the urge to attack [30].

“Speech–rate and amount” acted as the main bridge symptoms linking testosterone levels, manic symptoms, and aggression, succeeded by “Elevated Mood”. “Speech–rate and amount” and “Elevated mood” are typical symptoms of manic episodes, and previous imaging studies have shown abnormalities in neuronal coupling in the sensory-motor subcortical-cortical circuit in patients with highly excited brains, compared to healthy controls [31]. Testosterone may act through receptors located in key regulatory regions to increase the connectivity between subcortical regions of the brain while weakening connections between the cortex and subcortical regions [32], causing the patient in highly excited state. Abnormal regulation of the HPG axis is critical for homeostatic regulation of synthesis and secretion of testosterone and the most potent androgen dihydrotestosterone (DHT) by the testis [33]. Dysregulation of the HPG axis may cause depressive symptoms, which are associated with high cortisol inhibition [34]. Moreover, compared to bodybuilders who did not take exogenous testosterone, there was a higher rate of hypomanic episodes among those who did [35]. The release of testosterone will increase the motivation of BD patients to seek dominance and take impulsive risks, which are often poorly thought-out and prone to adverse consequences [36]. High levels of testosterone have been found to reduce activity and functional connectivity in the prefrontal cortex, altering the function of prefrontal-mediated emotion regulation, thereby impairing the ability to control aggressive impulses [37].

Regarding the gender for the network model of comorbid aggression severity, manic symptoms, and testosterone levels among patients with BD, there were none significant differences shown in this study. The existing evidence suggests that testosterone concentrations in early life influence the development of some human behaviors, with certain gender differences [38]. One study from community recruiters suggested that adolescent males with higher plasma testosterone levels were more irritable and likely to overreact to provocation and threats [39]. Previous studies on depressive episode status in patients with BD have found that male patients have significantly lower testosterone levels, while female patients have significantly higher levels [40].

The strengths of this study include a substantial sample size, the utilization of standardized assessment instruments, and the employment of network analysis techniques. These techniques were tailored to investigate the structure of the model assessing testosterone levels and aggressive behavior in patients with BD. Such insights may pinpoint potential targets for treatment and prevention measures, particularly for patients with BD in psychiatric emergencies exhibiting these problems. Nonetheless, several methodological limitations in our study warrant attention. First, the cross-sectional design precludes establishing causal relationships between variables, and there was an absence of a control/naive group. Future longitudinal research is essential to elucidate the time-bound causal links between testosterone levels and aggressive behavior in patients with BD. Secondly, though routine blood collections were performed for clinical evaluations during psychiatric emergency visits, additional measurements, such as thyroxine, should be added to the study analysis. Subsequently, we hope to carry out relevant radiological research to further explore the specific relationship between testosterone levels and aggressive behavior in BD patients. Lastly, our sample was consecutively drawn from one major psychiatric emergency department (PED) in China, which may limit the generalizability of our findings in other psychiatric contexts.

To summarize, within the aggression-bipolar disorders network model, as well as the association with testosterone levels, “Increased motor activity-energy,” “Emotional instability,” and “Disruptive/aggressive behavior” were the most pivotal symptoms among BD patients in PED. Our study showed no significant gender differences in testosterone levels observed in BD patients during the manic episode phase. These specific symptoms, which are potential intervention targets, should be at the forefront of physicians’ evaluation protocols.

Data availability

The data of the investigation will be made publicly available if necessary.

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Funding

The study was supported by the National Clinical Key Specialty Construction Project Fund (3-2-2021-PT40).

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Authors and Affiliations

Bei**g Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Bei**g Anding Hospital, & the Advanced Innovation Center for Human Brain Protection, Capital Medical University, Bei**g, China
Yi Liu, Tian Han, Yi-Fan Wang, Juan Li, **ao-meng **e & **ao Ji
Unit of Psychology Medicine and Behavior Medical, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
Hong Cai

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Yi Liu
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Hong Cai
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Tian Han
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Juan Li
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**ao-meng **e
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Contributions

(I) Conception and design: **ao Ji, **ao-meng **e. (II) Administrative support: **ao Ji, Yi Liu, Yi-Fan Wang. (III) Provision of study materials or patients: Cai Hong, Yi Liu, Tian Han, Juan Li. (IV) Collection and assembly of data: Yi-Fan Wang, Yi Liu, Tian Han, Juan Li. (V) Data analysis and interpretation: Yi-Fan Wang, **ao-meng **e, Cai Hong. (VI) Manuscript writing: All authors. (VII) Final approval of manuscript: All authors.

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Correspondence to **ao-meng **e or **ao Ji.

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Ethics approval

This study involving human participants was reviewed and approved by the Human Research and Ethics Committee of Bei**g Anding Hospital, Capital Medical University. All the study procedures were carried out in accordance with relevant guidelines. The approval number is 2022(163)-202314FS-2.

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Liu, Y., Cai, H., Han, T. et al. Network analysis of comorbid aggressive behavior and testosterone among bipolar disorder patients: a cross-sectional study. Transl Psychiatry 14, 224 (2024). https://doi.org/10.1038/s41398-024-02957-1

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Received: 09 January 2024
Revised: 15 May 2024
Accepted: 21 May 2024
Published: 29 May 2024
DOI: https://doi.org/10.1038/s41398-024-02957-1
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Network analysis of comorbid aggressive behavior and testosterone among bipolar disorder patients: a cross-sectional study

Abstract

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Comorbidity of anxiety and depression disorder among clinical referral patients: a longitudinal study based on network analysis

Gender differences in aggression of borderline personality disorder

Correlates of Aggression in Personality Disorders: an Update

Introduction

Node-specific predictive betweenness measure

Network comparison tests by gender

Discussion

Data availability

References

Funding

Author information

Authors and Affiliations

Contributions

Corresponding authors

Ethics declarations

Competing interests

Ethics approval

Additional information

Supplementary information

supplementary materials

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About this article

Cite this article

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Network analysis of comorbid aggressive behavior and testosterone among bipolar disorder patients: a cross-sectional study

Abstract

Similar content being viewed by others

Comorbidity of anxiety and depression disorder among clinical referral patients: a longitudinal study based on network analysis

Gender differences in aggression of borderline personality disorder

Correlates of Aggression in Personality Disorders: an Update

Introduction

Node-specific predictive betweenness measure

Network comparison tests by gender

Discussion

Data availability

References

Funding

Author information

Authors and Affiliations

Contributions

Corresponding authors

Ethics declarations

Competing interests

Ethics approval

Additional information

Supplementary information

supplementary materials

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