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Clinical Markers of Physical Violence in Patients with Bipolar Disorder in Manic States

Authors Li X , Gao Y, Liu Y , Wang Y, Wu Q

Received 21 February 2023

Accepted for publication 13 May 2023

Published 24 May 2023 Volume 2023:16 Pages 991—1000

DOI https://doi.org/10.2147/RMHP.S403170

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Mecit Can Emre Simsekler



Xuelong Li,1– 3 Yakun Gao,4 Yiyi Liu,1– 3 Ying Wang,1– 3,* Qing Wu1– 3,5,*

1School of Mental Health and Psychological Sciences, Anhui Medical University, Hefei, People’s Republic of China; 2Department of Psychiatry, Affiliated Psychological Hospital of Anhui Medical University, Hefei, People’s Republic of China; 3Anhui Mental Health Center, Hefei, People’s Republic of China; 4Affiliated Hospital of Weifang Medical College, Weifang, People’s Republic of China; 5Hefei Fourth People’s Hospital, Hefei, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Ying Wang; Qing Wu, Department of Psychiatry, Affiliated Psychological Hospital of Anhui Medical University, 316 Huangshan Road, Hefei, 230000, People’s Republic of China, Tel +86-13866136686 ; +86-13856919530, Email [email protected]; [email protected]

Purpose: Identifying patients with bipolar disorder (BD) in manic states (BD-M) who are at a high risk of physical violence is a matter of clinical concern. This retrospective institution-based study aimed to identify simple, rapid, and inexpensive clinical markers of physical violence in patients with BD-M.
Patients and Methods: The anonymized sociodemographic variables (sex, age, years of education, marital status) and clinical ones (weight, height, body mass index, blood pressure, the score of BRMS, number of BD episodes, psychotic symptoms, history of violence, biochemical parameters, and blood routine parameters) of 316 BD-M participants were collected, and the risk of physical violence was identified using the Brøset Violence Checklist (BVC). Difference tests, correlation analyses, and multivariate linear regression analysis were performed to identify clinical markers for the risk of physical violence.
Results: The participants were categorized into groups at low (49, 15.51%), medium (129, 40.82%), and high (138, 43.67%) risk of physical violence. The number of BD episodes, serum uric acid (UA), free thyroxine (FT4) levels, history of violence, and monocyte-to-lymphocyte ratio (MLR) differed significantly between groups (all P< 0.05). The number of BD episodes (r=0.152), FT3 (r=0.131) and FT4 (r=0.132) levels, history of violence (r=0.206), and MLR (r=− 0.132) were significantly correlated with the risk of physical violence (all P< 0.05). The existence of history of violence, number of BD episodes, UA, FT4, and MLR were identified as clinical markers of the risk of physical violence in patients with BD-M (all P< 0.05).
Conclusion: These identified markers are readily available at initial presentation and may help in the timely assessment and treatment of patients with BD-M.

Keywords: bipolar disorder, manic states, risk of physical violence, clinical makers

Introduction

Bipolar disorder (BD) is a chronic mental illness with two subcategories: bipolar I disorder, defined as the presence of manic episodes and major depressive episodes (estimated global lifetime prevalence, 0.6−1.0%), and bipolar II disorder, defined as the presence of mild manic episodes and major depressive episodes (estimated global lifetime prevalence, 0.4−1.1%). Most patients with BD have severe disease-related disabilities, reduced psychosocial functioning, and increased financial burden.1 The onset and development of BD may be related to structural and functional brain alterations, genetic factors, social and environmental factors, and metabolic pathways.2 Timely treatment is essential for the prognosis of the disease, while physical violence may delay it.3

The high risk of physical violence in patients with BD, especially in patients with bipolar disorder in manic states (BD-M), has long been a clinical concern. Physical violence is considered a core characteristic of BD-M and refers to non-accidental physical assault that intimidates or harms others and is closely related to hostility and aggression.4,5 Physical violence is common during manic episodes of BD, resulting in a higher rate of violent crime in patients with BD than in the general population and imposes a severe burden on the occupational, social, and family functioning of patients.6 Patients with BD are eight times more likely to engage in physical violence than the general population and are even more likely to engage in physical violence than patients with schizophrenia.7,8 In particular, BD-M is closely associated with physical violence. A prospective study showed that patients with BD-M often exhibited significant hostility and aggression during the acute phase, including aggression toward foreign objects, others, and self. Even after adjusting for demographic and clinical differences between groups, patients with BD-M showed consistently higher levels of violent aggression than non-BD psychiatric patients and the healthy population at the 4-year follow-up.9

Previous studies have proposed several biomarkers of physical violence in patients with BD-M. These include serotonin and dopamine function, nicotinic acetylcholine receptor function, inflammatory markers, the function of the hypothalamic-pituitary-adrenal axis, and cortisol.10–13 In addition, exposure to violence or being a victim of violence increases the risk of physical violence in people with mental illnesses.14 In recent years, several studies have proposed that substance use and childhood trauma also have significant effects on the risk of physical violence.15,16

Previous studies on the risk of physical violence in BD-M relied on complex equipment and cumbersome and time-consuming methods to analyze the markers. Moreover, despite the high specificity of several markers, the high cost of these techniques posed a significant impediment. Therefore, this study aimed to identified inexpensive, accessible, and reproducible clinical markers by analyzing the relationship between variables and the risk of physical violence in patients with acute onset BD-M. Assessing these risks in BD-M patients in a cost-effective and objective manner will help identify the patients at high risk of physical violence in outpatient and inpatient clinics in a timely manner, thus allowing clinicians to implement effective treatment measures.

Materials and Methods

Study Design and Data Sources

This cross-sectional study retrospectively included 316 patients with BD who were admitted to the Anhui Mental Health Center (Hefei, China) from January 2021 to May 2022, with diagnoses of BD-M meeting criteria outlined in the 10th revision of the International Classification of Diseases (ICD-10).17 The diagnoses were confirmed by two psychiatrists. Trained research assistants collected sociodemographic and clinical data from the electronic health records provided by the Anhui Mental Health Center prior to the patients receiving psychiatric medication within 24 hours of admission. The sociodemographic datas included the sex and age of the patients, as well as their years of education, marital status. The clinical data included, weight, height, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), the score of BRMS, number of BD episodes, psychotic symptoms, history of violence, biochemical parameters, and blood routine parameters. The history of violence was provided by the patients and their relatives. The height and weight of all the participants were measured while the patients were standing barefoot on a calibrated electronic scale, and the BMI was calculated by dividing the admission weight by the height squared.

The biochemical parameters included serum uric acid (UA), total triiodothyronine (TT3), total thyroxine (TT4), thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), total cholesterol (TC), high-density lipoprotein (HDL), triglyceride (TG). The blood routine parameters included platelet, lymphocyte, neutrophil and monocyte. The platelet/lymphocyte ratio (PLR), neutrophil/lymphocyte ratio (NLR), and monocyte/lymphocyte ratio (MLR) were calculated manually based on the hemogram results.

The inclusion criteria were: 1) meeting the diagnostic criteria of BD based on the ICD-10, 2) any age, and 3) not receiving psychiatric medication within the last 3 months. The exclusion criteria were: 1) a history of cranial trauma, organic encephalopathy, or other psychiatric disorders (including alcohol and/or substance dependence), 2) serious physical illness, such as cardiovascular disease, 3) pregnant or lactating women, and 4) use of corticosteroids, nonsteroidal anti-inflammatory drugs, or immunosuppressive drugs within the past 2 weeks.

A total of 653 participants were initially selected, and 319 were excluded for not meeting the inclusion criteria. Of these, 236 participants had received psychiatric medication within the last 3 months based on a diagnosis of BD, 43 had severe cardiovascular disease, 26 were diagnosed with comorbid alcohol dependence, 12 had thyroid disease, and 2 were pregnant. Finally, 316 participants were selected for analysis.

Blood Tests

The day after admission, venous blood was collected by nurses between 06:00 and 07:00 after overnight fasting (8−12 hours) and sent to the hospital laboratory within 1 hour of collection for analysis. Plasma biochemical parameters were measured with an automatic biochemistry analyzer (AU480, Beckman Coulter, Brea, CA, USA) using commercial kits (Roche, Basel, Switzerland). Blood routine analysis was performed using an automatic hematology analyzer (Mindray BC-2800, Shenzhen, China).

Psychometric Scales

Bech-Rafaelsen Mania Scale (BRMS)

The BRMS was used to assess the severity of the patients’ symptoms.18 The BRMS consists of 11 items, with each item being graded on a five-point scale (range, 0−4). The sum of the scores of each item is used as the total score. The higher the total score, the more severe the mania.

Brøset Violence Checklist (BVC)

Data regarding the risk of physical violence were collected within 2 hours of admission using the BVC. This assessment has good reliability and validity and allows for rapid and valid assessment of the risk of violence in a clinical setting.19 The BVC is scored for the following six symptoms: irritability, confusion, physical threats, boisterousness, verbal threats, and attacks on objects. The presence of symptoms is 1, and the absence of symptoms is 0. Finally, the scores of each entry are summed, with a minimum total score of 0 and a maximum score of 6. According to standard guidelines, a total score of 0 suggests a low risk of violence. A score of 1−2 suggests that the risk is moderate and requires preventive measures. A score of ≥3 is considered high risk and requires preventive measures and a plan to manage violent attacks. Based on the BVC scores, the participants were grouped as follows: (1) Low-risk group: 49 individuals with a low risk of physical violence (BVC score, 0); (2) Medium-risk group: 129 participants with a medium risk of physical violence (BVC score, 1−2); and (3) High-risk group: 138 participants with a high risk of physical violence (BVC score, ≥3).

This study was conducted in accordance with the Declaration of Helsinki, which was revised in 1989. Protocols were reviewed and approved by the Institutional Review Board of the Anhui Mental Health Center. The requirement for written informed consent was waived due to the retrospective design of the study.

Statistical Analysis

All statistical analyses were performed using Stata 17.0 (StataCorp LP, College Station, TX, USA). The normality of continuous variables was tested using the Kolmogorov Smirnov test. Continuous variables with a normal distribution are expressed as the mean ± standard deviation (SD), and those with a non-normal distribution are expressed as the median and interquartile range (25th and 75th percentiles). Categorical data are expressed as n(%). One-way analysis of variance or the Kruskal–Wallis H-test was used to analyze intergroup differences in continuous variables, and the chi-squared test was used to analyze intergroup differences in categorical data. Spearman rank correlation coefficients were used to evaluate correlations between the risk of physical violence and sociodemographic and clinical variables. Multiple linear regression analysis was used to identify predictive variables that were significantly correlated with the risk of physical violence. All statistically significant variables were added to the model simultaneously to avoid overlooking any potential associations. All P-values were two-sided, and P-values of < 0.05 were considered statistically significant.

Results

Differences in Baseline Characteristics of Sociodemographic Variables

This study included 316 participants with a mean age of (36.27±13.80) years in the low-risk group, (35.47±12.74) years in the medium-risk group, and (35.53±11.97) years in the high-risk group. There were no significant between-group differences in age, sex, marital status, and years of education (all P>0.05) (Table 1).

Table 1 Comparison of Baseline Characteristics of Sociodemographic Data

Differences in Baseline Characteristics of Clinical Variables

The number of BD episodes, UA, FT4, MLR, and history of violence were significantly different among the three groups (all P<0.05). Among them, the UA and history of violence were significantly different between the low-risk and medium-risk groups (all P<0.05). The UA, MLR, and history of violence were significantly different between the low-risk and high-risk groups (all P<0.05). In addition, the number of BD episodes, FT4, and history of violence were significantly different between the medium-risk and high-risk groups (all P<0.05). However, there were no significant between-group differences in duration of BD, education, TT3, TT4, TSH, FT3, BMRS, age, BMI, SBP, DBP, blood glucose, TC, HDL, TG, NLR, PLR, and psychotic symptoms (all P>0.05) (Table 2)?

Table 2 Comparison of Baseline Characteristics of Clinical Data

Correlation Between Variables and Risk of Physical Violence

All variables were selected for analysis of the correlation with the risk of physical violence after confirming that they have no multicollinearity. The correlation coefficient of the number of BD episodes (r=0.152, P=0.007), FT3 (r=0.131, P=0.019), FT4 (r=0.132, P=0.019), history of violence (r=0.206, P<0.001), and MLR (r=−0.132, P=0.019) were significant in the correlation coefficient matrix (Table 3)?

Table 3 Correlation Between Variables and Risk of Physical Violence

Potential Clinical Markers for Risk of Physical Violence in Patients with BD-M

All statistically significant variables were added to the model of multivariate linear regression analysis after confirming that they have no multicollinearity. The following variables were found to be statistically significant: the existence of history of violence (B=0.278, β=0.194, P<0.001, 95% CI 0.125−0.431), number of BD episodes (B=0.019, β=0.115, P=0.035, 95% CI 0.001–0.037), UA (B=0.001, β=0.136, P=0.012, 95% CI 0.000−0.002), FT4 (B=0.017, β=0.122, P=0.026, 95% CI 0.002−0.033), and MLR (B=−0.002, β=−0.111, P=0.041, 95% CI −0.003−0.000) (Table 4)?

Table 4 Multivariate Logistic Regression Analysis of Variables Associated with the Risk of Physical Violence

Discussion

In the current study, we evaluated easily obtainable clinical markers of risk of physical violence in patients with BD-M, which can facilitate the follow-up and observation of these patients. There were significant differences in the history of physical violence, number of BD episodes, UA, FT3, FT4, TT4, and MLR in patients with BD-M with different levels of risk of physical violence. Additional analysis of the above factors revealed that the presence of a history of violence, more frequent episodes of BD, and higher serum UA levels were associated with a higher risk of physical violence in all patients with BD-M, regardless of sex. In contrast, there was an inhibitory effect of MLR on the risk of physical violence.

Physical violence is considered a serious public health problem with negative effects on individuals and society and can even result in crime.20,21 BD-M is a recurrent disease; therefore, timely assessment of the patient’s risk of physical violence is of great importance for treatment and prognosis. However, the complex assessment process and the stigma associated with the disease can delay the identification of patients at high risk of physical violence to some extent, thus preventing their timely and effective treatment.22,23 Moreover, physical violence is notoriously difficult to predict in clinical settings, and it may be difficult for staff to know what a patient is thinking or trying to do if the patient is intellectually disabled or motivated by an internal logic known only to themselves.4 To help meet these challenges, we analyzed rapidly available clinical data to explore easily obtainable clinical markers of the risk of physical violence. Our findings may help develop a method for the timely assessment of the risk of physical violence in acute patients with BD-M.

We found that a history of violence was a risk factor for physical violence in patients with BD-M, which is consistent with the results of previous studies.18 Previous study have found that patients with acute psychiatric disorders with history of physical violence (especially within 1 month) exhibit significant rates of violent behavior after hospitalization, and researchers hypothesize that history of violent behaviors reflected significant hostility of patients, predisposing the patients to resort to violent behaviors in resistance.19 A recent study found that patients with BD experience difficulties in identifying, expressing, and processing their negative states, and therefore it is difficult to effectively comply with their emotions and relate them to behaviors that are consistent with their goals. For this reason, they may tend to express their thoughts and emotions through violent behavior toward others.24 Based on these factors, we hypothesized that a history of physical violence reflects the high risk of physical violence in patients with BD-M.

The increased number of BD episodes was associated with a higher risk of physical violence in patients with BD-M. This association may be related to abnormalities in the nervous and endocrine systems of patients. A neuroanatomical study has found that the greater the number of manic episodes, the greater the degree of prefrontal cortex thinning in patients and may lead to emotional dysregulation.25 The relationship between the prefrontal cortex and the risk of physical violence revealed that aggression can be modulated by stimulating the ventral lateral prefrontal cortex.26 In addition, several studies in recent years have reported alterations in the functional connections between the anterior cingulate gyrus and the amygdala and caudate nucleus during the first manic episode.27,28 Patients with multiple episodes of BD exhibit hypoactivation in areas, such as the bilateral ventral lateral prefrontal cortices and amygdala networks in the prefrontal-striatal-amygdala circuit.29 Abnormalities in the amygdala and prefrontal cortical connectivity are closely associated with the regulation of irritability, which in turn promotes the emergence of physical violence.30,31 Thus, we hypothesized that as the number of BD episodes increases, the risk of physical violence may increase due to a decline in the patient’s ability to control physical violence.

Furthermore, we identified serum UA level as a clinical marker for the risk of physical violence in patients with BD-M; precisely, patients with a higher risk of physical violence exhibited higher serum levels of UA. A previous study proposed an association between BD-M and high levels of UA, showing that serum UA levels were significantly lower in patients in remission than in those not in remission.32 Meanwhile, serum UA was higher in patients before and after treatment than in healthy controls, suggesting that serum UA levels may be a potential marker for patients with BD-M.33 Abnormal serum UA levels in patients with BD-M are thought to be associated with purinergic system dysfunction and adenosine neurotransmission. This hypothesis is supported by the effectiveness of allopurinol treatment in alleviating manic symptoms in patients with BD in the acute phase.34,35 One study reported an association between UA levels and the risk of physical violence in patients with BD-M.36 A follow-up study reported that serum UA levels were positively associated with physical violence in patients with BD-M, and the levels decreased with improvement in manic symptoms.37 Based on these findings, UA is thought to be an effective predictive marker of physical violence in patients with BD-M.38

In recent years, several studies have validated the inflammatory mechanisms involved in the pathophysiology of BD-M. Accordingly, low-cost, highly reproducible, and easily accessible markers of inflammation (such as NLR, PLR, and MLR) are increasingly being used in the study of BD.39 Growing evidence suggests that patients with BD-M have higher values of NLR, PLR, and MLR and lower levels of lymphocytes than the healthy population and patients with other types of mental illnesses, implying a more pronounced level of inflammation in BD-M.40,41 After analyzing the three inflammatory markers, we found that MLR may be an independent protective factor against the risk of physical violence in patients with BD-M. In contrast, NLR and PLR had negligible effects on this risk. The severity of BD-M has been shown to be strongly correlated with abnormal MLR values.42 Monocytes are an important component of the innate immune response and play a regulatory role in the production and release of inflammatory factors (such as interleukin 1 and TNF-α).43 Elevated serum TNF-α levels are also closely associated with high levels of aggression in patients with mental disorders.44 However, although patients with BD-M exhibited elevated MLR, their increased dopamine function may also downregulate the functional activity of monocytes and macrophages and inhibit TNF-α production.45,46 Taken together, MLR may play a protective role in the risk of physical violence in patients with BD-M by inhibiting the release of pro-inflammatory cytokine.

Similar to previous studies, the present study found serum FT4 levels to be a risk factor for physical violence in patients with BD-M. A positive correlation between serum T3 and T4 levels and physical violence has also been demonstrated in several studies.47,48 Acar et al explored thyroid hormone levels in 208 prisoners and found that higher T3 and T4 levels were associated with a tendency to commit violent crimes among manic patients.49 They suggested that stressful environmental conditions may affect the hypothalamic-pituitary-thyroid axis and lead to aggression through the increase of thyroid hormone levels.

Limitations

This study had some limitations. First, due to its cross-sectional nature, the present study could not elucidate a temporal causal relationship between clinical markers and the risk of physical violence in patients with BD-M. Second, blood indicators may be influenced by other factors that we could not consider, such as the patients’ cardiovascular status and dietary patterns. Third, the study did not distinguish BD-I and BD-II types, which may affect the accuracy of the study. Finally, the effect of harmful substance abuse on the risk of violence has been described.50 The limitations of this retrospective study left patients’ smoking and drinking histories under-collected, which may have biased the assessment of physical violence risk. This needs to be considered, collected, and analyzed in future studies.

Conclusion

Physical violence seriously affects the diagnosis and treatment of patients with BD-M. The potential clinical markers reported in this study, including a history of physical violence, number of BD episodes, UA levels, FT4 levels, and MLR, may be predictive of a high risk of physical violence in patients with BD-M. These data are reliable and inexpensive to obtain in most clinical settings. As such, the early collection of these data may help identify BD-M patients (in both outpatient and inpatient settings) who are at high risk of physical violence, thus allowing clinicians to implement effective treatment measures in a timely manner.

Acknowledgments

We would like to thank the Anhui Mental Health Center for providing data support for this study. Without the support of the hospital, this work would not have been possible.

Funding

This research was funded by the Hefei Health Applied Medicine Research Project (grant number Hwk2021yb015) and the Hospital Project of Hefei Fourth People’s Hospital (grant numbers 2019001, HFSY2022YB08 and HFSY2022ZD11). The funders had no role in the study design; in the collection, analysis, or interpretation of the data; in the writing of the manuscript; or in the decision to submit the article for publication.

Disclosure

The authors report no conflicts of interest in this work.

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