Psychiatric disorders in female psychosexual disorders—a nationwide, cohort study in Taiwan

We aimed to investigate whether females with psychosexual disorders were associated with the risk of affective and other psychiatric disorders. A total of 2240 enrolled individuals, with 560 patients with psychosexual disorders and 1680 subjects without psychosexual disorders (1:3) matched for age and index year, from the Longitudinal Health Insurance Database, retrieved from the National Health Insurance Research Database (NHIRD), between 2000 and 2015 in Taiwan. The multivariate Cox regression model was used to compare the risk of developing psychiatric disorders during the 15 years of follow-up. There were 98 in the cohort with psychosexual disorders (736.07 per 100,000 person-year) and 119 in the non-cohort without psychosexual disorders (736.07 per 100,000 person-year) that developed psychiatric disorders. The multivariate Cox regression model revealed that the adjusted hazard ratio (HR) was 9.848 (95% CI = 7.298 — 13.291, p < 0.001), after the adjustment of age, monthly income, urbanization level, geographic region, and comorbidities. Female patients with psychosexual disorders were associated with the risk of psychiatric disorders. This finding could be a reminder for clinicians about the mental health problems in patients with psychosexual disorders. Supplementary Information The online version contains supplementary material available at 10.1186/s12888-021-03060-1.

steroids, such as estrogen or progestin, insufficiency may adversely affect central sexual thought processes, and contribute to the female sexual dysfunctions, such as hypoactive sexual desire disorder [8]. Also, gender dysphoria may have several genes involved in the sex hormone-signaling in the brains [9]. Sex hormones such as estrogen have many effects on anxiety and depression [10]. Several studies have found mutual relations between psychiatric comorbidity and psychosexual disorders [11][12][13][14][15][16]. For the clinicians, it is essential to better understand the mutual relationship between female patients with psychosexual disorders and their psychiatric morbidity. And these psychiatric disorders might well contribute to the distress, disability, or an increased risk of suffering death, pain, or disability, and consequent behavioral, psychological, or biological dysfunctions [3,17]. Therefore, several neurodevelopmental, endocrine and psychological factors could be the linkage between psychosexual and psychiatric disorders.
Previous studies have found that depressive disorders are frequently associated with sexual dysfunction, across all the phases of sexual responses [18], and the attention problems related to anxiety might impair sexual motivation even with adequate stimuli [19]. Besides, sexual dysfunction is frequent in patients with posttraumatic stress disorder [20,21]. However, some researchers have revealed that no psychiatric comorbidity was found in female patients with gender identity disorder [22,23]. Furthermore, the relationship between female paraphilia and psychiatric disorders remains unclear, since patients with female paraphilia are rare [24,25]. Therefore, depression, anxiety, and trauma-related disorders are associated with sexual dysfunctions, and also with the association between psychiatric disorders and paraphilia and gender identity disorder. Besides, there is a gap in the literature that no previous cohort studies have been conducted to examine the risk of psychiatric disorders in female patients with psychosexual disorders. We hypothesize that these psychosexual disorders are associated with the risk of psychiatric disorders in a long-term follow-up. We, therefore, conduct the present study, using Taiwan's National Health Insurance Research Database (NHIRD), to investigate the association between psychosexual disorders and psychiatric disorders, in a 15-year follow-up.

Data sources
The National Health Insurance (NHI) Program was launched in Taiwan in 1995, and as of June 2009, including contracts with 97% of the medical providers, with approximately 23 million beneficiaries, or more than 99% of the entire population [26]. The National Health Insurance Research Database (NHIRD) uses the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes to record the diagnoses [27]. The present study has used the NHIRD to identify the inpatients with a discharge diagnosis of psychosexual disorders based on the ICD-9-CM codes, including sexual dysfunctions, paraphilia, and gender identity disorders, during 2000-2015. The paraphilias included the diagnoses as exhibitionism, fetishism, frotteurism, pedophilia, sexual masochism, sexual sadism, transvestic fetishism, voyeurism, other paraphilia, and paraphilia, not otherwise specified [3]. All the ICD-9-CM codes of psychosexual disorders are as listed in Table S1. In this database, all the personal identification data were enciphered, for the protection of the privacy of the patients. The records of ambulatory care visits and inpatient claims periodically were reviewed randomly by the NHI Administration to verify the accuracy of the diagnoses [28]. Several previous studies have documented the details of the program [29][30][31][32][33].

Study design and sampled participants
Patients with newly diagnosed psychosexual disorders were selected from the 2 million Longitudinal Health Insurance Database (LHID), randomized retrieved from the NHIRD, which covers 99% of the entire population of Taiwan, between January 1, 2000, and December 31, 2015. The patients with psychosexual disorders before 2000 were excluded. Besides, the patients diagnosed with psychiatric disorders before 2000, or before their first visit for any psychosexual disorder, were also excluded. In Taiwan, the legal age of full civil competency is 20 years of age, according to Taiwan's Civil Code [34], therefore, all patients aged < 20, were excluded as well. In this study, 560 patients with the psychosexual disorder and 1680 subjects without psychosexual disorders, were 1:3 matched, for age and index-year control, with a statistic power of 0.72 [35], and little power improvement resulted from increasing the number of controls while the ratio beyond 1:3 or 1:4 [36]. Therefore, the present study is a population-based, matched cohort study.

Covariates
The covariates included age groups (20-49, ≥ 50 years), geographical area of residence (north, center, south, and east of Taiwan), urbanization level of residence (levels 1 to 4), and monthly income (in New Taiwan Dollars [NT$]; < 18,000, 18,000-34,999, ≥35,000). The urbanization level of residence was defined according to the population and various indicators of the level of development. Level 1 was defined as a population of > 1, 250,000, and a specific designation as political, economic, cultural, and metropolitan development. Level 2 was defined as a population between 500,000 and 1,249, 999, and as playing an important role in the politics, economy, and culture. Urbanization levels 3 and 4 were defined as a population between 149,999 and 499,999, and < 149,999, respectively.

Comorbidity
We assessed the comorbidities by using the Charlson Comorbidity Index (CCI), which categorizes comorbidities using the ICD-9-CM codes, and scores each comorbidity category [37][38][39]. The CCI is used for comorbidity adjustment as a useful measure and substitutes for the usage of the individual comorbidity variables in health services research [40]. In CCI, the comorbidities include myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, chronic obstructive pulmonary disease, dementia, paralysis, diabetes mellitus, diabetes with sequelae, chronic renal failure, cirrhosis of the liver, moderate-severe liver disease, peptic ulcers, rheumatoid arthritis, and AIDS [41]. The combination of all the scores was regarded as a single comorbidity score. A score of zero indicates that no comorbidities were found, and higher scores indicate higher comorbidity burdens [42].

Outcome measures
Enrolled individuals in these two cohorts were tracked for 15 years, starting from the index date, to identify those who developed psychiatric disorders, comprising dementia, anxiety disorders, depressive disorders, bipolar disorders, eating disorders, sleep disorders, and psychotic disorders, withdrew from the NHI program, or reached the end of 2015. All the ICD-9-CM codes of psychiatric disorders are as listed in Table S1.

Statistical analysis
All statistical analyses were performed using the SPSS for Windows, version 22.0 (IBM Corp., Armonk, NY). χ 2 and t-tests were used to appraise the distributions of the categorical and continuous variables, respectively. The multivariate regression model was used to determine the risk of psychiatric disorders since death can act as a competing risk factor for psychiatric disorders [43,44]. The results were presented as a hazard ratio (HR) with a 95% confidence interval (CI). Differences in the risk of psychiatric disorders between the study and control groups were estimated using the Kaplan-Meier method with the log-rank test. A 2-tailed p-value < 0.001 was considered to indicate a statistical significance, to minimize the type I error as possible.

Sample characteristics
There was no significant difference between these two cohorts in age, marital status, education, insured monthly premiums, and the CCI scores. The cohort with psychosexual disorders tended to search for medical help in summer, autumn, and winter. Furthermore, the cohort with psychosexual disorders tended to live in the north, and the offshore islands resided more in the region of urbanization level 2 and received their medical treatments in the medical centers ( Table 1).

The cumulative incidence of psychiatric disorders
There were 98 in the cohort with psychosexual disorders and 119 in the comparison cohort that developed psychiatric disorders (3444.66 vs 736.07 per 100,000 person-year). Figure 1 depicts that the difference was statistically significant in the Kaplan-Meier survival analysis (log-rank, p < 0.001).
Changes of psychosexual disorders in the follow-up period, 2000-2015 Figure 2 reveals that there was no significant difference between the beginning and the end-point of the followup in all these psychosexual disorders, between 2000 and 2015. Besides, the treatment prevalence of the female psychosexual disorders was 0.007% of the sexual dysfunctions, paraphilias were around 0.004%, and the female-to-male (FTM) gender identity disorder was 0.017%, during the 15-year follow-up.

HR analysis of psychiatric disorders in patients with psychosexual disorders
The multivariate Cox regression model showed that the adjusted HR of the psychosexual disorders cohort in the development of psychiatric disorders was 9.848 (95% CI = 7.298-13.291, p < 0.001), after adjustment for age, marital status, education, comorbidity (CCI scores), urbanizations/areas of residence, insurance premiums, seasons of visits, and levels of medical facilities, as compared to the control group ( Table 2). Table 3 depicts that the cohort with psychosexual disorders, including sexual dysfunctions, paraphilias, and gender identity disorders, were associated with the risk of psychiatric disorders.

Types of psychiatric disorders in female patients with psychosexual disorders
Also, there were no significant differences in the times of the psychiatric visits between the two cohorts, even though the cohort with psychosexual disorders had more psychiatric visits than the comparison cohort (3.82 [standard deviation (SD) ± 4.06] vs 3.15 [SD ± 3.97]), without a statistical difference (p = 0.001) (Table S2).

Association between psychosexual disorders and the risk of psychiatric disorders
The adjusted HR was 9.848 (95% CI = 7.298-13.291, p < 0.001) in the association between the psychosexual disorders and psychiatric disorders, and the female patients with psychosexual disorders had a 9.8-fold increase in the risk of psychiatric disorders, after the adjustment of age, monthly income, urbanization level, geographic region, and comorbidities. The Kaplan-Meier analysis demonstrated that the cohort with psychosexual disorders had a significantly higher 15-year psychiatric disorders cumulative incidence than the comparison cohort. To the best of our knowledge, this is the first study on the topic of an association between female patients with psychosexual disorders and the risk of psychiatric morbidity. This finding could serve as a reminder for the clinicians to pay much more attention to these patients because of the issues about psychiatric disorders.

Comparison of this study to previous literature
Previous studies have shown the association between psychosexual disorders and psychiatric disorders that included antidepressant-related sexual dysfunctions in patients with depressive or anxiety disorders [16,[45][46][47], female paraphilia focused and the personality disorders on the forensic psychiatric topics [14,15], and the FTM gender disorders and depression, posttraumatic stress disorder, anxiety disorders and suicides [12,13,48]. However, these studies were mostly conducted in cross-section methods, and our study is unique for the retrospective cohort design, from a larger population-based database. Besides, male patients with psychosexual disorders have been associated with an increased risk of anxiety disorders, depressive disorders, bipolar disorders, sleep disorders, and psychotic disorders, respectively [33]. There were several differences in the risk of different psychiatric disorders in these two studies. The underlying reasons for the difference of risk for psychiatric disorders, between female patients with psychosexual disorders, needs further studies.

Treatment prevalence of psychosexual disorders in this study
Previous studies revealed that the prevalence of female sexual dysfunctions was 30-60%, in different countries [49][50][51][52], but we found that there was 0.007% of sexual dysfunctions in this sample of 15year of follow-up. In the present study, there were 70 paraphilia patients from the database, and the treatment prevalence of female paraphilias was around 0.004% in this LHID. The prevalence of the female paraphilias were 2% in exhibitionistic behaviors in previous studies [25,53], 4% in voyeuristic behaviors [25,53], 0.4% in transvestic fetishism [54], and 1% in sadomasochistic activity [55], from surveys in the population of Sweden [25,53], and Australia [55]. Previous reports have shown that there were 0.003% in Belgium, [56], 0.82% in Japan [57], and 0.023-0.058% in the United States veteran's populations [12,58] of FTM gender identity disorder. Furthermore, the present study found that the treatment prevalence of FTM gender identity disorder, was 0.017%, in the duration of the 15 years of follow-up. The discrepancy of the prevalence might be the difference of studies from a claims database or the survey. Cultural differences might also contribute to this difference: previous studies have shown that females have more difficulties in their help-seeking for sex-related problems in Asian countries [59,60]. However, the PYs Person-years, Adjusted HR Adjusted Hazard ratio: Adjusted for the variables listed in Table 1, CI Confidence interval present study is the first one for females with psychosexual disorders and the risk of psychiatric disorders in an Asian country.

Possible mechanisms for the increased risk of psychiatric disorders in patients with psychosexual disorders
In the present study, female patients with sexual dysfunctions were associated with psychiatric disorders. There are several neurodevelopmental, endocrine, and psychological factors related to the linkage between these two groups of disorders. The stress from the suffering of sexual dysfunction [61,62], paraphilias [63,64], and gender identity disorders [65][66][67], might well contribute to the association between these psychosexual disorders and the risk of psychiatric disorders, such as anxiety, depressive, or sleep disorders. One study has found that hyperprolactinemia seems to play a role in the pathogenesis of hypoactive sexual desire disorder, one of the female sexual dysfunctions [68], and hyperprolactinemia might induced psychiatric disorders, such as depression and anxiety [69][70][71][72]. Evidence suggests that female and male brains are different in the mean volumes of the hippocampus, amygdala, and thalamus [73], the concentration of estrogen or androgen receptors [74], and the total brain, cerebrum, and cerebellum volumes [75]. Thus, the difference in the brain anatomy and neuronal signaling pathways are more closely aligned with a person's perceived gender identity, and individuals with discordant gonadal and brain developments might experience psychological challenges for the generalized dissatisfaction with their biological sex [76]. Besides, paraphilias and depression might share a common dysregulation of this monoaminergic pathway in these patients [11,77].
Psychological, social, and cultural factors might also contribute to both psychosexual disorders and psychiatric disorders. Previous studies have shown that patients with paraphilias might suffer emotional distress, social embarrassment [4], and stigma [5]. For example, a study from Turkey has found that patients with vaginismus have higher levels of depression and anxiety [78]. Phobic defense mechanisms [79], the rejection of the female role, and religious orthodoxy which regards sex as dirty or shameful [80] are the psychosocial factors that contribute to vaginismus, depression, and anxiety [78].

Limitations
The present study has several limitations that warrant consideration. First, similar to previous studies using the NHIRD on psychosexual disorders [32,[81][82][83], we were unable to evaluate the severity, weakness severity, laboratory parameters, or psychological assessments in the patients with psychosexual disorders, since the data were not recorded in the NHIRD. Second, the genetic, psychosocial, and environmental factors, were not included in the dataset. Third, even though we have excluded the patients diagnosed with psychiatric disorders before 2000, or before their first visit for any psychosexual disorders, there is the possibility of the protopathic bias, in which some patients could have been introduced into this study by subjects who have an undiagnosed disease. Fourth, although paraphilias and gender dysphoria are distinct categories, there is some evidence for an overlap between paraphilias and gender dysphoria [84]. The combination of distinct entities, in a single heterogeneous category of psychosexual disorders, is a limitation when discussing the results of the data analysis. Fifth, there is a possibility that the high prevalence of psychiatric disorders, among female patients with psychosexual disorders, is due to the high utilization of psychiatric services. However, as shown in Table S2, there were no significant differences in the times of psychiatric visits between the two cohorts.

Conclusion
Female patients who suffer from psychosexual disorders have a 9.8-fold increase in the risk of psychiatric disorders, and this finding should serve as a timely reminder for the clinicians to pay much more attention to these patients because of their mental health issues.
Additional file 2: Table S2. Frequency of psychiatric service.