Association between benign prostatic hyperplasia and suicide in South Korea: A nationwide retrospective cohort study.

Benign prostatic hyperplasia is a commonly diagnosed disease in elderly men, but elderly men with benign prostatic hyperplasia are more likely to have a lower quality of life and depressive symptoms. This study aims to examine the association benign prostatic hyperplasia patients with suicide death relative to a control group comprising individuals without benign prostatic hyperplasia. We used the Korean National Health Insurance Service-National Sample Cohort from 2006 to 2015 comprising of 193,785 Korean adults ≥40 years old, and followed-up for suicide death during the 8.7 years period. Cox-proportional hazard model was used to estimate hazard ratios for suicide among patients with benign prostatic hyperplasia. From 2006 to 2010, a total of 32,215 people were newly diagnosed with benign prostatic hyperplasia. The suicide rate of people without benign prostatic hyperplasia was 61.6 per 100,000 person-years, whereas that of patients with benign prostatic hyperplasia was 97.3 per 100,000 person-years, 1.58 times higher than the control group (p<0.01). After adjusting for covariates, the hazard ratio for suicide among patients with benign prostatic hyperplasia was 1.47 (95% C.I. = 1.21 to 1.78; p<0.01) compared to people without benign prostatic hyperplasia. For men without mental disorders, the hazard ratio for suicide among patients with benign prostatic hyperplasia was 1.36 (95% CI = 1.05 to 1.76) compared to control group after adjusting for multiple covariates. Our study suggests that men with benign prostatic hyperplasia had a higher probability of suicide compared to men without benign prostatic hyperplasia in South Korea. This study suggests that physicians may be aware that men newly diagnosed with benign prostatic hyperplasia had high probability of suicide.

Introduction

Benign prostatic hyperplasia (BPH) is a common disease in men aged≥40 years old. According to the Olmsted County study, the proportion of patients with a moderate to severe composite of obstructive symptoms increased from 13% in men aged 40–49 years to 28% in men aged >70 years [1]. Debra et al. estimated that about 1.9 billion adults aged ≥20 years experienced symptoms associated with lower urinary tract obstruction worldwide in 2008 [2]. In South Korea, the estimated number of patients with BPH has continuously increased from 894,908 in 2012 to 1,191,595 in 2017 [3]. The number of patients with BPH is expected to increase with the aging population, sedentary life style and increasing obesity.

Major depression is well-known risk factor for suicide [4]. Some epidemiological studies have reported that lower urinary tract symptoms (LUTS), and sexual dysfunction, which are closely related to BPH, contribute to increased probability of depressive symptoms and lower the quality of life (QOL) of patients. Indeed, a cross-sectional study reported that moderate to severe LUTS is associated with decreased QOL in patients with prostate disease [5]. A few studies have also demonstrated that men with LUTS are more likely to have depressive symptoms or suicidal ideation [6-9]. Pietrzyk et al. reported that 22.4% of people treated with BPH had depressive symptoms and prevalence of depressive symptoms were associated with the severity of LUTS, BPH therapy and erectile dysfunction [10]. In United States, Breyer et al. also showed that the odds ratio for suicidal ideation among men with ≥2 LUTS was 3.5 times higher than the control group (≤1 LUTS) [6]. In addition, it was suggested that the 5alpha-reductase inhibitors (5aRI) could lower the quality of life of men with BPH.

However, a recent large retrospective cohort study demonstrated that the use of 5aRI was associated with increased risk of depression or self-harm, but did not increase the risk of suicide [11]. Besides, all men with depression or suicide ideation do not necessarily advance to suicide [12]. To the best of our knowledge, there are barely any studies published examining the association between BPH and risk of suicide death itself.

Therefore, it is necessary to examine whether men diagnosed with BPH have increased probability of suicide death in a real community setting. The present study aimed to evaluate the suicide mortality of Korean men diagnosed with BPH using nationwide representative cohort data of 193,785 men aged ≥40 years.

Material and methods

Study population

This was a retrospective cohort study using the National Health Insurance Service- National Sample Cohort (NHIS-NSC) database. The NHIS-NSC database was obtained from the National Health Insurance Corporation to examine the probability of suicide mortality among patients with newly diagnosed BPH [13]. Everyone living in South Korea is obliged to participate in the National Health Insurance Service. The NHIS-NSC database comprises of data obtained using stratified random sampling based on sex, age, income level and region from the original database of the National Health Insurance Service database and the medical aid database. The NHIS-NSC database includes patients’ information such as age, sex and health insurance cost, health examination data and medical records such as prescription, surgery, disease diagnosis and hospital information. The NHIS-NSC database is also linked to the cause and date of death obtained from Statistics Korea. The last follow-up date for death was December 31, 2015.

Definition of benign prostatic hyperplasia

Patients with BPH were defined by having the primary code “N40” according to the ICD-10 codes [14]. In order to restrict the study population to incident cases (newly diagnosed cases), the washing-out period was set from January 1 2002 to December 31 2005. patients already diagnosed with BPH before year 2006 were excluded and only patients with newly diagnosed with BPH were included from 2006 to 2015.

Suicide mortality

The primary endpoint was death from suicide. Death from suicide was defined by the code “X60-X84” according to the ICD-10 codes [15, 16].

Ethics statement

The study protocol was approved by the Institutional Review Board of National Center for Mental Health (IRB No.116271-2018-32). Our study protocol was exempted from review because it was not a clinical trial, which required contacting the patients, and NHIS-NSC database was anonymized to prevent identification of individuals.

Selection of the study participants

The NHIS-NSC database represents 2.2% of all Korean adults in 2002 who were followed up to 2015.13 We used the NHIS-NSC data from 2006 to 2015, because, there were many missing data points for health insurance premiums before the year 2006. A total of 1,021,208 participants were included in the NHIS-NSC database from 2006 to 2015 (Fig 1).

Fig 1

Flow-chart for selection of study participants.

Of these, 556,724 participants were excluded, because they were younger than 40 years; 241,315 women were also excluded; 9,914 patients diagnosed or treated for BPH in 2006 were excluded, because our study focused only on cases with newly diagnosed BPH. Consequently, 19,470 cancer patients were excluded, because the quality of life of cancer patients is worse than that of general population and cancer patients have a higher risk of suicide. Lastly, 193,785 participants who were not diagnosed with BPH prior to 2007 were included in the final study population.

Covariates

The region was further categorized into cities and provinces according to administrative districts [16]. The income level was classified based on the health insurance premium, and it was divided into high income (9th-10th quartiles of the premiums), middle income (5th-8th quartiles of the premiums), and low income (1st-4th quartiles of the premiums) levels and the medical aid group [16]. Disability was categorized as “People without disability” and “People with disability” according to the disability criteria set by the Ministry of Health and Welfare, and past medical diagnosis by a physician [16]. Co-morbidity was defined among people who had more than one of the 41 pertinent disease categories [17]. The presence of mental disorders was defined by diagnosis with the code “F00-F99” from 2006 to 2015. Unfortunately, the NHIS-NSC considered detailed information about mental disorders as sensitive information and did not provide sub-code of mental disorders to general researchers.

Statistical analysis

In this study, baseline characteristics of patients diagnosed with BPH and the population without BPH were compared using independent t-test for continuous variables and chi-square test for categorical variables. The Cox-proportional hazard model was used to examine the hazard ratio for suicide risk among patients newly diagnosed with BPH compared to the population without BPH. In order to adjust confounding bias, age, region and number of comorbidities were adjusted in model 1 and age, region, number of comorbidities, disabilities, mental disorders and income level were adjusted in model 2. In addition, we conducted stratified analysis by age group (40–59 years/60-69 years/≥70 years) and income level (medical aid/low income level/middle income level/high income level) to examine if there were differences in the association between BPH and rates of suicide by age, income level and previous history of mental health disorder. Interaction effects of age, income level and BPH on risk of suicide were tested using the likelihood ratio test [18]. We performed post-hoc power calculation using the hazard ratio of the Cox-proportional hazard model and the proportion for suicide mortality of BPH group and control group using “powerSurvEpi” package of R program.

P-values less than 0.05 denoted statistical significance. SAS Enterprise Guide ver. 6.1 (SAS Institute Inc., Cary, NC, USA) and R 3.4.0 (R Foundation for Statistical Computing, Vienna, Austria) were used for all statistical analyses.

Results

Baseline characteristics of study participants

The baseline characteristics of patients with BPH and the general population without BPH are presented in Table 1. During the average 8.7-years of follow-up, 32,215 adults aged ≥40 years were newly diagnosed with BPH. Mean age of study participants were 53.2±10.5 years old and all participants were Korean population. Patients with BPH were much older and had higher income level, higher proportion of disabilities and mental disorders compared to those without BPH.

Table 1

Baseline characteristics of patients diagnosed with benign prostatic hyperplasia and general population without benign prostatic hyperplasia.

Characteristics	Overall	People with benign prostatic hyperplasia	People without benign prostatic hyperplasia	p-valuea
	Number (%) or mean (SD)	Number (%) or mean (SD)	Number (%) or mean (SD)
Total number	193,785 (100.0%)	32,215 (100.0%)	161,570 (100.0%)
Age (years)	53.2 (10.5)	59.0 (10.4)	52.1 (10.2)	<0.0001
Region
City	89,243 (46.1%)	15,250 (47.3%)	73,993 (45.8%)	<0.0001
Province	104,542 (53.9%)	16,965 (52.7%)	87,577 (54.2%)
Income level
Medical aid	8182 (4.2%)	1513 (4.7%)	6669 (4.1%)	<0.0001
Low	54173 (27.9%)	8427 (26.2%)	45746 (28.3%)
Middle	75888 (39.2%)	11673 (36.2%)	64215 (39.8%)
High	55542 (28.7%)	10602 (32.9%)	44940 (27.8%)
Disability
No disability	179395 (92.6%)	29247 (90.8%)	150148 (92.9%)	<0.0001
People with disability	14390 (7.4%)	2968 (9.2%)	11422 (7.1%)
Mental disorder
No mental disorder	168802 (87.1%)	24760 (76.9%)	144042 (89.2%)	<0.0001
People with mental disorder	24983 (12.9%)	7455 (23.1%)	17528 (10.8%)
Number of comorbidities	3.71 (2.8)	5.02 (3.1)	3.45 (2.6)	<0.0001

Continuous variables are presented as mean (standard deviation) and categorical variables are presented as numbers (percentage).

aIndependent t-test for continuous variables and chi-square test for categorical variables were used to test difference between men with BPH and men without BPH.

During the follow-up period, we found 1,006 cases of suicide death among a total of 193,785 men (Table 2). Patients with BPH had a suicide rate of 97.3 (95% CI = 82.4 to 114.0) per 100,000 person-years, which was about 1.6 times higher than the suicide rate of those without BPH (61.6 (95% CI = 57.6 to 65.8) per 100,000 person-years).

Table 2

Number of suicide death and suicide rates in patients diagnosed with benign prostatic hyperplasia and general population without benign prostatic hyperplasia.

Categories	Total number	Number of suicide death	Suicide rate per 100,000 person-years (95% CI)a
Patients with benign prostatic hyperplasia	32,215	146	97.3 (95% CI = 82.4 to 114.0)
General population without benign prostatic hyperplasia	161,570	860	61.6 (95% CI = 57.6 to 65.8)

CI: Confidence interval.

aSuicide rates are expressed as incidence density per 100,000 person-years.

The hazard ratio for suicide associated with benign prostatic hyperplasia

The cox-proportional hazard model was used to examine the hazard ratio for suicide among patients with BPH compared to general population without BPH after adjusting for covariates (Table 3). In the unadjusted model, hazard ratio (HR) for suicide among patients with BPH was 1.47 (95% CI = 1.23 to 1.76) compared to general population without BPH. After adjusting for age, geographical location, and comorbidities, patients with BPH had a higher hazard ratio for suicide [HR: 1.54 (95% CI = 1.28 to 1.86)] than general population without BPH. In the final model, the hazard ratio (HR) for suicide among patients with BPH was 1.47 (95% CI = 1.21 to 1.78) compared general population without BPH after adjusting for age, geographical location, comorbidities, disabilities, mental health, and income level. The post-hoc power was 99.9% when the post-hoc power calculation was performed using the hazard ratio for suicide and the proportion for suicide of BPH group and control group.

Table 3

Hazard ratios (95% CI) for suicide among patients with benign prostatic hyperplasia compared to general population without benign prostatic hyperplasia.

Variables	Unadjusted HR (95% CI)	Age, region and comorbidity adjusted HR (95% CI)	Multivariable adjusted HR (95% CI)a
Benign prostatic hyperplasia
No	1.00 (Reference)	1.00 (Reference)	1.00 (Reference)
Yes	1.47 (1.23 to 1.76)	1.54 (1.28 to 1.86)	1.47 (1.21 to 1.78)
Age (years)		1.05 (1.05 to 1.06)	1.04 (1.04 to 1.05)
Region
City		1.00 (Reference)	1.00 (Reference)
Province		1.16 (1.02 to 1.31)	1.12 (0.99 to 1.28)
Number of Comorbidity		0.84 (0.82 to 0.86)	0.82 (0.80 to 0.84)
Income level
Medical aid			1.83 (1.40 to 2.39)
Low			1.56 (1.31 to 1.85)
Middle			1.30 (1.10 to 1.53)
High			1.00 (Reference)
Disability
No			1.00 (Reference)
Yes			1.25 (1.02 to 1.54)
Mental disorder
No			1.00 (Reference)
Yes			3.26 (2.82 to 3.77)

CI: Confidence interval.

aMultivariable model was adjusted for age, geographical location, comorbidities, disabilities, mental health, and income level.

The hazard ratio of suicide associated with benign prostatic hyperplasia by age groups

We performed subgroup analysis to evaluate whether there was as significant difference in HR by age group, because the age was a major confounding variable with the greatest effect on risk of suicide and BPH (Table 4). Among the age group of 40–59 years, HR for suicide among men with BPH was 1.64 times higher (95% CI = 1.20 to 2.22) than that in general population without BPH; the HR for suicide among men with BPH aged more than 60 years was 1.72 times higher (95% CI = 1.24 to 2.40) compared to the control group. However, there was no significant difference in the suicide risk between men with BPH and men without BPH in the >70 years old group.

Table 4

Hazard ratios (95% CI) for suicide among patients with benign prostatic hyperplasia according to different age groups.

Characteristics	Suicide rates (95% CI)	Multivariable adjusted HR (95% CI)a	p for interactionb
40–59 years old			0.78
Without benign prostatic hyperplasia	49.7 (45.7 to 53.9)	1.00 (reference)
With benign prostatic hyperplasia	64.0 (47.9 to 83.9)	1.64 (1.20 to 2.22)
60–69 years old
Without benign prostatic hyperplasia	92.0 (78.7 to 107.0)	1.00 (reference)
With benign prostatic hyperplasia	116.0 (88.0 to 150.2)	1.72 (1.24 to 2.40)
≥ 70 years old
Without benign prostatic hyperplasia	157.8 (132.6 to 186.5)	1.00 (reference)
With benign prostatic hyperplasia	159.3 (116.7 to 212.5)	1.11 (0.77 to 1.60)

Suicide rates are expressed as incidence density per 100,000 person-years.

aMultivariable model was adjusted for age, geographical location, comorbidities, disabilities, mental health, and income level.

bP for interaction was tested using likelihood ratio test.

The hazard ratio of suicide associated with benign prostatic hyperplasia by income level groups

Subgroup analysis was also performed by income levels, because the socioeconomic status is a major health determinant of suicide and BPH (S1 Table). The Cox-proportional hazard model was used in all groups after adjusting for all covariates. Although there was no significant interaction between income level and BPH, there was a small difference in the association between BPH and risk of suicide according to the income level. There was no difference in the risk of suicide in patients with BPH compared to general population without BPH in the medical aid and low income level groups. However, men with BPH had a higher risk of suicide compared to men without BPH in middle and high income groups.

The hazard ratio of suicide associated with benign prostatic hyperplasia by mental health disorder

Mental disorders, especially those related to major depression are a well-known risk factor for suicide (S2 Table). Therefore, we also examined the risk of suicide due to BPH by the presence of the mental disorders. Among men without mental disorders, patients with BPH had about 1.36 (95% CI = 1.05 to 1.76) higher risk of suicide compared to men without BPH after adjusting for multiple covariates. Among men with previous mental disorders, the hazard ratio for men with BPH was 1.66 (95% CI = 1.24 to 2.21) compared to men without BPH using a fully adjusted cox-proportional hazard model.

Discussion

Our findings show that the probability of suicide among patients diagnosed with BPH was about 1.5 times higher than those not diagnosed with BPH. The association between BPH and suicide was similar (HR = 1.66 (95% CI = 1.24 to 2.21)) even in the group without mental disorder. Although previous studies have demonstrated that patients diagnosed with BPH or having LUTS have more depressive symptoms and poorer quality of life compared to controls, the fact that this leads to suicide is rarely known based on our knowledge.

The association between BPH and suicide

The causes of suicide are highly complex ranging from internal factors to external ones, including involvement of genetic, psychological, socio-cultural factors as well as personal experiences like trauma [19]. However, factors such as depression or economic crisis are well-known to increase the risk of suicide [20, 21]. In addition, there is growing evidence that patients diagnosed with diseases that lower the quality of life such as, prostate cancer and asthma also increase the probability of suicide [22, 23].

However, there were very few studies which have focused on the nature and direction of relationship between BPH and depression. In addition, there are rare studies on the direction and association of BPH, depression, suicide. Interestingly, our study findings showed that patients with BPH have high probability of suicide, regardless of depressive symptoms. Therefore, we were able to infer the two directions from previous study findings and discussion. At first, patients were newly diagnosed with BPH will develop depressive symptoms, and these depressive symptoms may aggravate lower urinary tract symptoms and cause a vicious cycle that aggravates depression and finally leads to suicide [8]. The second hypothesis is that the risk of BPH or LUTS is increased by the dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis due to the predisposing depressive symptoms [24]. People who committed suicide without a diagnosis of depression actually had depressive symptom due to BPH/LUTS but they may don’t want to visit to the psychiatric clinic. Or it is possible that they decided to commit suicide immediately due to uncontrolled or worsening LUTS (Erectile dysfunction, nocturia, urinary dysfunction etc.).

Other biological relevance supporting the association between BPH and suicide

BPH leads to lower urinary tract disease, impairs sexual function, decreases the quality of life and increases the risk of depression or depressive symptoms [5–10, 25]. From this perspective, it was not surprising that patients diagnosed with BPH had a higher probability of suicide compared to control group without BPH. Recent studies have reported that impairment of serotonin (5-HT) synthesis was associated with both urinary dysfunction and depression, suggesting common pathophysiological mechanisms in lower urinary tract symptoms and depression [26, 27]. In addition, some studies have shown that increased adrenergic tone was associated with depressive and voiding symptoms [28] and the corticotropin releasing factor (CRF) pathway leads to changes in stress-related depressive symptoms as well as urinary symptoms [29]. In addition, a recent randomized controlled trial showed that additional anti-depressant therapy not only improved depression, but also reduced symptoms of LUTS and improved quality of life [30]. These pathophysiological studies also support that BPH or its associated lower urinary tract symptoms can increase the risk of depression, leading to suicide.

Strengths and limitations

Some limitations should be considered while interpreting our study’s findings. First, our study design could not account for the severity of BPH, because the NHIS-NSC database was based on secondary data for estimating payments for health insurance. The NHIS-NSC database did not include severity or symptoms of patients with BPH. Second, we defined patients with BPH as those having the code “N40” according to the ICD-10 codes. However, some up-coding or misclassification for the diagnosis for prostatic hyperplasia may exist. Although the use of ICD-10 code "N40" has the potential for misclassification of BPH, it is often used to estimate the national incidence or prevalence of BPH [31]. Third, covariates such as co-morbidities, mental disorders and income levels were adjusted in the Cox-proportional hazard model to minimize the effects of confounding variables. We also performed stratification analysis to exclude the effects of major confounding variables. However, there may be residual confounding factors for suicide such as personal experiences of trauma, cultural factors or severe stress which we could not adjust in this study. Fourth, different types of LUTS may be more likely to be associated with mental health disease [32], however, we could not evaluate the effects of LUTS on depression or suicide in our study. Fifth, 5α-reductase inhibitors, which were mainly used in the medical treatment of BPH, were not reported previously to increase the risk of depression [11], but it may be necessary to consider the effects of medication to more accurately investigate the association between BPH and probability of suicide. Finally, our study findings cannot be easily generalized to other countries. South Korea is considered as a developed country with a very rapid economic growth [33]. At the same time, South Korea has the highest suicide rate among OECD countries [15]. While South Korea has the advantage of physically and economically easy access to medical service, there are cultural barriers that are reluctant to visit psychiatry for mental disorder [34].

Despite these limitations, our study showed meaningful findings that patients with BPH have a higher probability of suicide compared to general population using a large sample cohort data representing South Korea, especially considering the fact that there are barely any studies show an association between BPH and probability of suicide.

Clinical implications

Patients with BPH may complain of sexual dysfunction and dysuria and had lower quality of life. There has been a lot of clinical evidence that these problems among patients with BPH threaten the quality of life, and even lead to depression. Our study findings show that patients with BPH are higher risk for suicide compared to general population and some of them would be necessary for mental health care to prevent suicide. Primary care physicians may have more attention to not only the voiding symptoms related to BPH, but also mood disorders such as anxiety and depression.

Conclusion

Our study suggested that probability of suicide was 1.5 times higher in men with BPH compared to men without BPH among those aged over 40 years in Korea. This close association between BPH and suicide was observed even in people without mental disorder. Further studies are warranted to know high risk group on which BPH patients are at risk for suicide and whether they need transfer and management of mental health.

Hazard ratios (95% CI) for suicide among patients with benign prostatic hyperplasia according to different income levels.

(DOC)

Click here for additional data file.

Hazard ratios (95% CI) for suicide among patients with benign prostatic hyperplasia according to presence of mental disorders.

(DOC)

Click here for additional data file.

10 Sep 2021

PONE-D-21-21842

Risk of Suicide among Patients with Benign Prostatic Hyperplasia in South Korea: a Nationwide Retrospective Cohort Study

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ACADEMIC EDITOR:

Can you with help of the reviewers comments revise thae manuscript. Can you also explain in the manuscript what usually leads th coding BPH, is that 'having lower urinary tract symptoms' or is that based on measuring the size of the prostate. You say in your 'limitations' that you do not know exactly per patient, but you can refer to (a) national (Urologists? GP-PCP?) standard(s). Also can the comparator group can have enlarged prostate without the coding because the prostate was never measured? I also find some (more) reports on relevant medication (5AR and alphablocker) and suicide risk, can you include this? Can you also define 'newly diagnosed' and discuss this in the perspective of your follow up. (and better explain how you excluded patients that were (how?) treated during that follow up).

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Reviewer #1: The important massage from the study is that patients with BPH and without history of mental disorders have increased risk of suicide. This should be presented in the abstract and perhaps in the title.

Please consider a subanalysis after exclusion of subjects with mental disorders.

Surprisingly the analysis shows that the number of comorbidities is increasing the risk for suicide. Perhaps the authors should look for the 41 disease categories and identified the risk factors. In addition it would be wise to analyze multimorbidity as a risk factor.

Introduction

Pietrzyk et al. do not present suicidal ideation. They demonstrate that occurrence of depressive symptoms in patients with BPH is independently associated with severity of LUTS [OR 1.1 (95%CI: 1.09-1.13), BPH therapy (polytherapy, history of TURP), erectile dysfunction and comorbidities.

Discussion

Discussion need to be improved incorporating new data from additional analyses.

The authors extensively discuss biological relevance supporting the association between BPH and risk of suicide, but they do not have anything to add in this point. This part should be more consist.

Clinical implications are nonrealistic. I can’t believe that urologists can be more holistic. But it might be a place for general practitioners to look for depressive symptoms in their patients treated for BPH/LUTS.

The conclusion should be based on the risk in patients without mental disorders.

Reviewer #2: Congratulation to the authors to look into the relation between benign prostatic hyperplasia and suicide. Due to it is a retrospective study, the title and conclusion should be suggestive of suicide and not risk of suicide.

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27 Oct 2021

Manuscript ID: PONE-D-21-21842

Original title:

Risk of Suicide among Patients with Benign Prostatic Hyperplasia in South Korea: a Nationwide Retrospective Cohort Study

Revised title:

Association between Benign Prostatic Hyperplasia and Suicide in South Korea: a Nationwide Retrospective Cohort Study

To the Editors and Reviewers:

We thank you for careful reading of the manuscript and helpful comments and suggestions from reviewers. We are submitting reviewers’ comments together, and plan how we revised our paper according to the reviewers’ suggestions and comments. Changes made to the text are marked with highlights changes and track change mode in the revised manuscript.

Comments from Academic Editor:

1. Can you with help of the reviewers’ comments revise the manuscript? Can you also explain in the manuscript what usually leads th coding BPH, is that 'having lower urinary tract symptoms' or is that based on measuring the size of the prostate?

Answer: Thanks for your thoughtful comments. We believe that we have faithfully answered the reviewers' questions, and reviewer and editor’s comments have improved the quality of our research.

As the Editor pointed out, the definition of benign prostatic hyperplasia (BPH) is a very important issue for this study. Generally, the diagnosis of lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) is established by the presence of storage, voiding, and/or irritative urinary symptoms in the absence of history, examination or laboratory findings suggesting of non-BPH causes of lower urinary tract symptoms.

However, we used data from the Health Insurance Corporation, which is a secondary source of data. Although ICD-10 code for BPH (“N40”) used as the main diagnosis may have some degree of misclassification, it is believed to have a considerable degree of validity for real (true) lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH).

Indeed, the previous studies using data from the National Health Insurance Corporation also defined that BPH as ICD-10 code “N40”. The national incidence rate for benign prostatic hyperplasia (BPH) is also estimated using ICD-10 code “N40”.

Reference) Kim SH, Kwon WA, Joung JY. Impact of Benign Prostatic Hyperplasia and/or Prostatitis on the Risk of Prostate Cancer in Korean Patients. World J Mens Health. 2021;39(2):358-365. doi: 10.5534/wjmh.190135 [doi].

Lee YJ, Lee JW, Park J, Seo SI, Chung JI, Yoo TK, Son H. Nationwide incidence and treatment pattern of benign prostatic hyperplasia in Korea. Investig Clin Urol. 2016;57(6):424-430. doi: 10.4111/icu.2016.57.6.424.

Also, in the national patient registry of denmark, ICD-10 code "N40" was found to have a positive predictive value (PPV) of 95% (95% CI: 89–98%) for benign prostatic hyperplasia (BPH). (Of course, since this case is a disease registry, the accuracy is thought to be higher than our data.)

Reference) Bengtsen MB, Heide-Jørgensen U, Blichert-Refsgaard LS, Hjelholt TJ, Borre M, Nørgaard M. Positive Predictive Value of Benign Prostatic Hyperplasia and Acute Urinary Retention in the Danish National Patient Registry: A Validation Study. Clin Epidemiol. 2020;12:1281-1285. doi: 10.2147/CLEP.S278554.

2. You say in your 'limitations' that you do not know exactly per patient, but you can refer to (a) national (Urologists? GP-PCP?) standard(s).

Answer: There is no established diagnostic standard for benign prostatic hyperplasia (BPH). However, the International Prostate Symptom Score (IPSS) questionnaire was adopted as a basic questionnaire standard at the International Council of BPH organized by the World Health Organization in 1993, and various studies on epidemiology and therapeutic efficacy have been done using the IPSS [7]. The IPSS is used to assess the severity of storage symptoms and voiding symptoms with one additional quality of life question.

However, because our data is consisted of secondary database (the National Health Insurance Service- National Sample Cohort (NHIS-NSC) database) rather than clinical chart review, it is impossible to use IPSS questionnaire or uroflowmetry or measurement of postvoid residual volume (PVR).

However, ICD-10 code of “N40” is often used to measure the nationwide incidence rate for benign prostatic hyperplasia (BPH).

Reference) Kim SH, Kwon WA, Joung JY. Impact of Benign Prostatic Hyperplasia and/or Prostatitis on the Risk of Prostate Cancer in Korean Patients. World J Mens Health. 2021;39(2):358-365. doi: 10.5534/wjmh.190135 [doi].

Lee YJ, Lee JW, Park J, Seo SI, Chung JI, Yoo TK, Son H. Nationwide incidence and treatment pattern of benign prostatic hyperplasia in Korea. Investig Clin Urol. 2016;57(6):424-430. doi: 10.4111/icu.2016.57.6.424.

(Discussion, Page 16, Line 314-315) Although the use of ICD-10 code "N40" has the potential for misclassification of BPH, it is often used to estimate the national incidence or prevalence of BPH [31].

31. Lee YJ, Lee JW, Park J, Seo SI, Chung JI, Yoo TK, Son H. Nationwide incidence and treatment pattern of benign prostatic hyperplasia in Korea. Investig Clin Urol. 2016;57(6):424-430. doi: 10.4111/icu.2016.57.6.424.

3. Also can the comparator group can have enlarged prostate without the coding because the prostate was never measured?

Answer: Of course, there is a probability that some very small number of control groups have enlarged prostate. Some patients with mild BPH may don’t want to go hospital due to fear of treatment or financial difficulties. However, it is practically impossible to find such a case with hospital patient-control study. BPH is very difficult to detect without a doctor's diagnosis, unless there was a large survey using IPSS questionnaire.

4. I also find some (more) reports on relevant medication (5AR and alphablocker) and suicide risk, can you include this?

Answer: Whether 5-a reductase or alpha blocker increases the risk of suicide in patients with benign prostatic hyperplasia (BPH) is a very important and controversial issue [1-3]. However, our study has a slightly different scope from this topic (the association between medication (5AR and alphablocker) and suicide risk).

At first, the control group in our study was the general population without a diagnosis of BPH. However, to evaluate the association between medication (5AR and alphablocker) and suicide risk, the control group must also be patients with BPH. This is, because BPH itself can reduce sexual dysfunction and quality of life due to its symptoms.

Second, we do not have information about the medication (5AR and alphablocker). Of course, the National Health Insurance Service- National Sample Cohort (NHIS-NSC) database has information about the medication (5AR and alphablocker). If we ask NIHS to reuse the data for further analysis (information on the medication), we may have to wait to use after one year. So, we would be very grateful if the editor could understand our situation.

Perhaps, we cannot be completely excluded the effect of medication such as 5AR or alpha blocker on the increased risk of suicide among people newly diagnosed with benign prostatic hyperplasia. However, it was not possible the effects of medication on the risk of suicide in our study finding.

Moreover, we thought that depressive symptoms and BPH are interactively influenced by each other [4-5] (bidirectional relationship), it is difficult to say that the increased risk of suicide in patients with BPH in our study is simply due to medication (5AR and alphablocker).

Reference)

1. Irwig MS. Depressive symptoms and suicidal thoughts among former users of finasteride with persistent sexual side effects. J Clin Psychiatry. 2012;73(9):1220-3.

2. Welk B, McArthur E, Ordon M, Anderson KK, Hayward J, Dixon S. Association of suicidality and depression With 5alpha-Reductase Inhibitors. JAMA Intern Med. 2017;177:683-91.

3. Nguyen DD, Marchese M, Cone EB, Paciotti M, Basaria S, Bhojani N, Trinh QD. Investigation of Suicidality and Psychological Adverse Events in Patients Treated With Finasteride. JAMA Dermatol. 2021;157(1):35-42.

4. Dunphy C, Laor L, Te A, Kaplan S, Chughtai B. Relationship between depression and lower urinary tract symptoms secondary to benign prostatic hyperplasia. Rev Urol. 2015;17:51-7.

5. Huang CL, Wu MP, Ho CH, Wang JJ. The bidirectional relationship between anxiety, depression, and lower urinary track symptoms: A nationwide population-based cohort study. J Psychosom Res. 2017;100:77-82.

5. Can you also define 'newly diagnosed' and discuss this in the perspective of your follow up. (and better explain how you excluded patients that were (how?) treated during that follow up).

Answer: Our focus was on people newly diagnosed with BPH. We were concerned that if people with existing BPH (prevalent cases) were included in this study, a selective survival bias would occur, in which those diagnosed with BPH who had already committed suicide were excluded. Therefore, we have set washing period of 4 years from 2002 to 2006. Patients diagnosed with or treated for BPH during the washing out period were excluded from the study participants, and the starting point was from January 1, 2006. From January 1, 2006 to December 31, 2015 (during study period), patients newly diagnosed with BPH were classified as BPH patients, and the rest were classified as control group. Please see the below figure.

We also slightly revised the method part to make it easier for editors and readers to understand as follows:

(Method, Page 6, Line 107-111) Patients with BPH were defined by having the primary code “N40” according to the ICD-10 codes [14]. In order to restrict the study population to incident cases (newly diagnosed cases), the washing-out period was set from January 1 2002 to December 31 2005. patients already diagnosed with BPH before year 2006 were excluded and only patients with newly diagnosed with BPH were included from 2006 to 2015 (Figure 1).

Comments from Reviewer #1:

Reviewer #1:

1. The important message from the study is that patients with BPH and without history of mental disorders have increased risk of suicide. This should be presented in the abstract and perhaps in the title.

Answer: Thanks for your thoughtful comments. As reviewer has commented, we added the association between BPH and suicide among people without mental disorder in the abstract as follows:

(Page 3, Abstract, Line 52-54) For men without mental disorders, the hazard ratio for suicide among patients with benign prostatic hyperplasia was 1.36 (95% CI=1.05 to 1.76) compared to control group after adjusting for multiple covariates.

2. Please consider a subanalysis after exclusion of subjects with mental disorders.

Answer: We also examined the risk of suicide due to BPH by the presence of the mental disorders. Among men without mental disorders, patients with BPH had about 1.36 (95% CI=1.05 to 1.76) higher risk of suicide compared to men without BPH after adjusting for multiple covariates. Please see the supplementary table 2.

Supplementary Table 2. Hazard ratios (95% CI) for suicide among patients with benign prostatic hyperplasia according to presence of mental disorders

3. Surprisingly the analysis shows that the number of comorbidities is increasing the risk for suicide. Perhaps the authors should look for the 41 disease categories and identified the risk factors. In addition it would be wise to analyze multimorbidity as a risk factor.

Answer: We totally agree with the opinion of reviewers, the number of comorbidities may increase the risk of depression and suicide. Many previous reports and studies have already shown that the presence of mental or physical comorbidities increases the risk of suicidal ideation and suicide [1-4]. One of the reasons for conducting this study is that it has been frequently reported previously that the prevalence of depression among BPH patients is high and that the symptom severity of LUTS is closely related to the prevalence, severity of depressive symptoms, and lower quality of life. However, there have been no reports on the association between BPH and the risk of suicide.

We have requested for permission for remote to the NHIS for revision of the current manuscript, but we heard that there are too many users currently, so we may have to wait for about a year. However, we have excluded 19,470 cancer patients with high suicide risk before the study, and the number of comorbidities and disability were adjusted in multivariate analysis. We would be very grateful if the reviewer could understand our situation.

Reference)

1. Pompili M, Bonanni L, Gualtieri F, Trovini G, Persechino S, Baldessarini RJ. Suicidal risks with psoriasis and atopic dermatitis: Systematic review and meta-analysis. J Psychosom Res. 2021 Feb;141:110347.

2. Alias A, Bertrand L, Bisson-Gervais V, Henry M. Suicide in obstructive lung, cardiovascular and oncological disease. Prev Med. 2021 Nov;152(Pt 1):106543.

3. Bulotiene G, Pociute K. Interventions for Reducing Suicide Risk in Cancer Patients: A Literature Review. Eur J Psychol. 2019 Sep 27;15(3):637-649.

4. Wu JJ, Penfold RB, Primatesta P, Fox TK, Stewart C, Reddy SP, Egeberg A, Liu J, Simon G. The risk of depression, suicidal ideation and suicide attempt in patients with psoriasis, psoriatic arthritis or ankylosing spondylitis. J Eur Acad Dermatol Venereol. 2017 Jul;31(7):1168-1175.

4. (Introduction) Pietrzyk et al. do not present suicidal ideation. They demonstrate that occurrence of depressive symptoms in patients with BPH is independently associated with severity of LUTS [OR 1.1 (95%CI: 1.09-1.13), BPH therapy (polytherapy, history of TURP), erectile dysfunction and comorbidities.

Answer: Thank you for kind and detailed comments. The contents of the bibliography have confused. We changed the sentence pointed out as follows:

(Page 4, Introduction, Line 75-77) Pietrzyk et al. reported that 22.4% of people treated with BPH had depressive symptoms and prevalence of depressive symptoms were associated with the severity of LUTS, BPH therapy and erectile dysfunction [10].

5. (Discussion) Discussion need to be improved incorporating new data from additional analyses. The authors extensively discuss biological relevance supporting the association between BPH and risk of suicide, but they do not have anything to add in this point. This part should be more consist.

Answer: Thank you for comments. In fact, there was no previous study on the association between BPH and suicide among people without depression. To our best knowledge, this study is the first paper to report the association between BPH and suicide risk. Therefore, it was difficult to develop the contents of the discussion based on our study finding alone. Please understand this difficult point.

As reviewer suggested, we added the following contents to the discussion and conclusion about the increased risk of suicide in people without mental disorders:

(Discussion, page 14 Line 262-264) The association between BPH and suicide was similar (HR=1.66 (95% CI=1.24 to 2.21)) even in the group without mental disorder.

(Discussion, page 14 Line 268-page 15, Line 288)

(Conclusion, page 17, Line 343-344) This close association between BPH and suicide was observed even in people without mental disorder.

6. Clinical implications are nonrealistic. I can’t believe that urologists can be more holistic. But it might be a place for general practitioners to look for depressive symptoms in their patients treated for BPH/LUTS.

Answer: Thank you for comments. I understood that these parts are the role of the general practitioner or primary care physician rather than the role of urologists. So, we revised the part of clinical implications as follows:

(Page 17, Clinical implications, Line 337-338) Primary care physicians may have more attention to not only the voiding symptoms related to BPH, but also mood disorders such as anxiety and depression.

7. The conclusion should be based on the risk in patients without mental disorders.

Answer: Thank you for comments. As mentioned above, the absence of a mental disorder is just that people (who maybe have depressive symptoms) has not been diagnosed with an affecting disorder in a mental clinics. People who have attempted suicide may have depressive symptoms, although they have not been diagnosed with a mental disorder in the hospital.

However, in our study finding, the suicide risk was significantly higher even in people without depression, so we agreed that it should be mentioned in the conclusion as the reviewer has commented.

(Page 3, Abstract, Line 52-54) For men without mental disorders, the hazard ratio for suicide among patients with benign prostatic hyperplasia was 1.36 (95% CI=1.05 to 1.76) compared to control group after adjusting for multiple covariates.

(Conclusion, page 17, Line 343-344) This close association between BPH and suicide was observed even in people without mental disorder.

Comments from Reviewer #2:

1. Congratulation to the authors to look into the relation between benign prostatic hyperplasia and suicide. Due to it is a retrospective study, the title and conclusion should be suggestive of suicide and not risk of suicide.

Answer: Thank you for comments. We fully agree with the reviewer's opinion. Our study cannot establish a causal relationship, only suggests a possibility between BPH and suicide. Therefore, the title and conclusion have been revised as follows according to the reviewers' opinions:

(Page 1, title): Association between Benign Prostatic Hyperplasia and Suicide in South Korea: a Nationwide Retrospective Cohort Study

(Page 3, Abstract, Line 40-42) This study aims to examine the association benign prostatic hyperplasia patients with suicide death relative to a control group comprising individuals without benign prostatic hyperplasia.

(Page 3, Abstract, Line 54-57) Our study suggests that men with benign prostatic hyperplasia had a higher probability of suicide compared to men without benign prostatic hyperplasia in South Korea. This study suggests that physicians may be aware that men newly diagnosed with benign prostatic hyperplasia had high probability of suicide.

(Page 17, Conclusion, Line 342-343) Our study suggested that probability of suicide was 1.5 times higher in men with BPH compared to men without BPH among those aged over 40 years in Korea.

Submitted filename: Response to the Reviewers Comments (211025).doc

Click here for additional data file.

27 Dec 2021

8 Feb 2022

Manuscript ID: PONE-D-21-21842.R1

Original title:

Association between Benign Prostatic Hyperplasia and Suicide in South Korea: a Nationwide Retrospective Cohort Study

To the Editors and Reviewers:

We thank you for careful reading of the manuscript and helpful comments and suggestions from reviewers. We are submitting reviewers’ comments together, and plan how we revised our paper according to the reviewers’ suggestions and comments. Changes made to the text are marked with highlights changes and track change mode in the revised manuscript.

Comments from Academic Editor:

1. Can you add explanation about what the reviewer considers a limitation of the generalisability of the findings?

Answer: In my opinion, reviewer is pointing out that we have to consider the specific situation of South Korea – South Korea has the highest suicide rate among OECD country, although South Korea has achieved remarkable success in combining rapid economic growth with significant poverty reduction. There are unique cultural and social background behind this highest suicide rate in South Korea [1-2].

In addition, there is a cultural barrier that are reluctant to visit psychiatry for mental disorder. In particular, there were severe stigma and prejudice toward patients with mental disorders such as depression [3]. In addition, physical illness is common cause for suicide among elderly people [4].

Considering these points, depression due to BPH may be relatively undiagnosed or untreated, and can easily lead to suicide compared to the other countries. These cultural differences (stigma, cultural barrier to visit psychiatry) can lead to difficulties in generalization of our study findings to the situation of other country.

1. Lee SU, Park JI, Lee S, Oh IH, Choi JM, Oh CM. Changing trends in suicide rates in South Korea from 1993 to 2016: a descriptive study. BMJ Open. 2018;8(9):e023144.

2. Hong J, Knapp M. Impact of macro-level socio-economic factors on rising suicide rates in South Korea: panel-data analysis in East Asia. J Ment Health Policy Econ. 2014;17(4):151-62.

3. Park J, Jeon M. The stigma of mental illness in Korea. Journal of Korean Neuropsychiatric Association. 2016;55(4):299-309.

4. https://www.statista.com/statistics/1230755/south-korea-number-of-suicides-by-reason/

Comments from Reviewer #3:

1. South Korea has one of the world's highest suicide rates per capita. The reasons for this are not clear, but are likely to be multifactorial. As such, the findings in the authors' manuscript may not be generalizable to a different country with lower per capita suicide rates. I would add this as a limitation.

Answer: Thank you for comments. We fully agree with the reviewer's opinion that our study finding are generally applicable to other countries. Therefore, the following sentence has been added to the limitation part of the discussion:

(Page 16, Line 326- Page 17, Line 331) Finally, our study findings cannot be easily generalized to other countries. South Korea is considered as a developed country with a very rapid economic growth. At the same time, South Korea has the highest suicide rate among OECD countries. While South Korea has the advantage of physically and economically easy access to medical service, there are cultural barriers that are reluctant to visit psychiatry for mental disorder.

Submitted filename: Response to the Reviewers Comments (220131).doc

Click here for additional data file.

10 Feb 2022

21 Feb 2022

Manuscript ID: PONE-D-21-21842.R2

Original title:

Association between Benign Prostatic Hyperplasia and Suicide in South Korea: a Nationwide Retrospective Cohort Study

To the Editors and Reviewers:

We thank you for careful reading of the manuscript and helpful comments and suggestions from reviewers. We are submitting reviewers’ comments together, and plan how we revised our paper according to the reviewers’ suggestions and comments. Changes made to the text are marked with highlights changes and track change mode in the revised manuscript.

Comments from Academic Editor:

1. Can you please add the (new) reference(s), that you provided in your answer regarding the limitations for generalizability, in the text of the manuscript as well?

Answer: As the editor suggested, we have added new references (no.33- no.34) to the limitation part of external generalization as follows:

(Page 16, Line 326 – Page 17, Line 2) Finally, our study findings cannot be easily generalized to other countries. South Korea is considered as a developed country with a very rapid economic growth [33]. At the same time, South Korea has the highest suicide rate among OECD countries [15]. While South Korea has the advantage of physically and economically easy access to medical service, there are cultural barriers that are reluctant to visit psychiatry for mental disorder [34].

References)

33. Hong J, Knapp M. Impact of macro-level socio-economic factors on rising suicide rates in South Korea: panel-data analysis in East Asia. J Ment Health Policy Econ. 2014;17:151-162.

34. Park JI, Jeon M. The Stigma of Mental Illness in Korea. J Korean Neuropsychiatr Assoc. 2016:55:299-309.

Paper of Hong J et al (No.33) pointed out that suicide rate in South Korea especially higher compared to other Asian countries, despite of similarities in geography and culture. The findings highlight the differential associations between social changes and suicide rates at various stages over a person's life course.

Paper of Park JI (No.34) discussed the stigma of psychiatric disorders in Korea and the reluctance to visit a psychiatric clinic/hospital.

2. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Answer: We checked all references and confirmed that they are correct.

Submitted filename: Response to the Reviewers Comments (220221).doc

Click here for additional data file.

23 Feb 2022

Association between Benign Prostatic Hyperplasia and Suicide in South Korea: a Nationwide Retrospective Cohort Study

PONE-D-21-21842R3

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Reviewers' comments:

28 Feb 2022

PONE-D-21-21842R3

Association between Benign Prostatic Hyperplasia and Suicide in South Korea: a Nationwide Retrospective Cohort Study

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