General Hospital Psychiatry xxx (2014) xxx–xxx

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Prevalence and associated factors of comorbid skin diseases in patients with schizophrenia: a clinical survey and national health database study Bai-Yao Wu, M.D., M.Sc. a, b, Bo-Jian Wu, M.D. c, Shin-Min Lee, M.D. c, d, Hsiao-Ju Sun, M.D. c, Yun-Ting Chang, M.D., Ph.D. e, f, Ming-Wei Lin, M.P.H., Ph.D. b,⁎ a

Department of Dermatology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan (R.O.C.) Division of Preventive Medicine, Institute of Public Health, National Yang-Ming University, Taipei 112, Taiwan (R.O.C.) Department of Psychiatry, Yuli Hospital, Ministry of Health and Welfare, Hualien 981, Taiwan (R.O.C.) d Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan (R.O.C.) e Department of Dermatology, Faculty of Medicine, National Yang-Ming University, Taipei 112, Taiwan (R.O.C.) f Department of Dermatology, Taipei Veterans General Hospital, Taipei 112, Taiwan (R.O.C.) b c

a r t i c l e

i n f o

Article history: Received 29 September 2013 Revised 9 February 2014 Accepted 11 February 2014 Available online xxxx Keywords: Schizophrenia Skin disease Antipsychotics Prevalence Taiwan

a b s t r a c t Objectives: To examine the epidemiology of and possible risk factors for skin diseases in patients with schizophrenia. Methods: All of 337 patients with schizophrenia were recruited from the therapeutic community of a psychiatric hospital and underwent a detailed skin examination. The National Health Insurance Research Database (NHIRD) was used to compare the prevalence of skin diseases between patients with schizophrenia and those without. Results: In the clinical survey, fungal infection (61.4%) and dermatitis (46.9%) were the most common skin diseases. Clozapine users had a lower risk of fungal infection than those on typical antipsychotics [odds ratio (OR)=0.49, 95% confidence interval (CI)=0.30–0.81]. Obese patients were more likely to have fungal infections than those without (OR=1.93, 95% CI=1.20–3.09), and those with diabetes had an increased risk of bacterial infection than those without (OR=2.0, 95% CI=1.06–3.75). NHIRD revealed that the overall prevalence of skin diseases, including infections, dermatitis, hyperkeratosis, pilosebaceous disease, androgenic alopecia, xerosis and stasis, were higher in patients with schizophrenia than in those without (75.1% vs. 72.6%, P=.01). Conclusions: The prevalence of skin diseases is high in patients with schizophrenia, for whom proper skin care is necessary to improve their life quality. © 2014 Elsevier Inc. All rights reserved.

1. Introduction Most patients with schizophrenia have at least one chronic comorbid medical condition [1] and an overall mortality rate more than twice that of the general population [2]. Most research on comorbidity in schizophrenia has focused on major illnesses that can cause severe morbidity or mortality, such as cardiovascular diseases, neoplasms and infection [1–3]. Although these studies have reviewed comorbidity in schizophrenia, very few have assessed skin diseases in patients with schizophrenia. As the largest organ of the human body, the skin plays an important role in maintaining a patient's well-being. Skin health greatly affects quality of life [4]. Skin diseases may also have adverse effects on psychiatric disorders [5] and may directly or indirectly increase medical expenses [6]. We believe that proper treatment of skin diseases should be regarded as an integral part of the long-term clinical management of schizophrenia. ⁎ Corresponding author. Tel.: +886-2-28267379, fax: +886-2-28210514. E-mail address: [email protected] (M.-W. Lin).

Compared with the general population, patients with schizophrenia have higher prevalence of obstetric complications, cardiovascular disease, obesity, diabetes, dental problems and polydipsia [2]. In addition, one study revealed that comorbid medical conditions such as diabetes, hypertension, dyslipidemia and obesity are underdiagnosed and undertreated in hospitalized psychiatric patients relative to populations without mental health disorders [7]. Likewise, we believe that, relative to populations without schizophrenia, some comorbid skin diseases are more prevalent and more frequently underdiagnosed and undertreated in patients with schizophrenia. Until now, as mentioned above, only a small number of studies have focused on the clinical survey of skin diseases in patients with psychiatric disorders [8–12]. These studies suggested a high prevalence of skin diseases in psychiatric patients. Moreover, obesity, diabetes and female sex were all found to be related to specific skin diseases in psychiatric patients [8,12]. Nevertheless, there were a number of limitations to these studies: (1) inclusion of heterogeneous psychiatric diagnoses that did not focus on schizophrenia alone; (2) inadequate sample size; (3) failure to explore

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Please cite this article as: Wu B.-Y., et al, Prevalence and associated factors of comorbid skin diseases in patients with schizophrenia: a clinical survey and national health ..., Gen Hosp Psychiatry (2014), http://dx.doi.org/10.1016/j.genhosppsych.2014.02.008

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B.-Y. Wu et al. / General Hospital Psychiatry xxx (2014) xxx–xxx

risk factors that might be related to skin diseases in schizophrenia, such as psychosocial outcomes of schizophrenia (e.g., psychopathology, cognitive deficits and global function) or types of antipsychotics; and (4) failure to discuss the diagnosis and treatment of skin diseases in patients examined in a face-to-face clinical survey and in population-based data. The aim of this study was (1) to examine the epidemiology of skin diseases, (2) to examine the diagnosis and treatment of skin diseases in clinical survey and population-based data and (3) to explore possible risk factors for skin diseases in patients with schizophrenia. We hypothesized that prevalence of some skin diseases in patients with schizophrenia would be higher than in those without and that skin diseases in patients with schizophrenia would be underdiagnosed or undertreated. 2. Methods 2.1. Clinical data: setting This study was conducted at Yuli Hospital, a government hospital established in 1966 in eastern Taiwan. At the time of this study, a total of 2562 resident psychiatric patients received humanistic and patientcentered professional care at the hospital. Patients were from all areas of Taiwan; over 96% were diagnosed with schizophrenia. The average age of patients was 53.4 years. The therapeutic community (TC) in this hospital accommodates approximately 600 residents diagnosed with psychotic disorders. Compared with patients in other wards or branches of the hospital, the patients in this TC are more stable in terms of psychiatric symptoms and have greater access to occupational rehabilitation outside the hospital. Four certified psychiatrists, a certified neurologist, a family physician and an internist specializing in endocrinology treated psychiatric and general medical conditions; eight certified psychiatric nurses and 30 nurse aides were working in the TC. Three medical and 10 psychiatric outpatient clinics were arranged every week for prescribing medicine for these patients. Skin diseases were diagnosed and treated by psychiatrists or any other physicians. Patients with skin diseases that could not be properly managed within the TC were referred to dermatologists in general hospitals outside the TC (see Table 5). 2.2. Participants A total of 337 patients with schizophrenia spectrum disorders were recruited from the outpatient clinic of TC during July 2011. To be included in the study, TC patients had to meet diagnostic criteria for schizophrenia or schizoaffective disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, Text Revision Fourth Edition. Participants were excluded from the study if they had an acute psychotic episode that necessitated a transfer for hospital admission or were unable to sign the informed consent form. The study was approved by the Institutional Review Board of Yuli Hospital. A written informed consent was obtained after the procedures were fully explained to patients. Demographic and clinical patient data were collected from medical records. 2.3. Measures Global function was evaluated using the Taiwanese Mandarin version [13] of the Personal and Social Performance (PSP) Scale [14]. Psychopathology was assessed using the Chinese version [15] of the Positive and Negative Syndrome Scale (PANSS) [16]. Cognitive function was assessed with the Chinese version of the Mini-Mental State Examination (MMSE) [17,18]. Each patient was rated on the PANSS, PSP Scale and MMSE by board-certified psychiatrists and certified psychiatric nurses. Each patient was rated by the same rater. All raters reached a high standard of inter-rater reliability with gold-

standard raters from the research training group at Yuli Hospital (intraclass correlations ranged from 0.86 to 0.95). Antipsychotics were categorized into typical antipsychotics (TAs), non-clozapine atypical antipsychotics (NCAAs) and clozapine [19]. Patients concurrently using TAs and NCAAs or TAs and clozapine were categorized into NCAA or clozapine users. Information on antipsychotic dosages was obtained from medical records and was calculated using the defined daily dose (DDD) of antipsychotics according to the database defined by the World Health Organization (http://www.whocc.no/ atc_ddd_index/). 2.4. Dermatological examination Skin examinations were conducted by one board-certified dermatologist. Before undergoing a skin examination, each patient was asked to remove all clothing and to wear an examination gown. After a brief introduction to the patients and questions about their awareness of their skin condition (yes or no), they were given a thorough skin examination. Any findings of skin diseases were carefully documented. All dermatological diagnoses were based solely on clinical symptoms and signs. 2.5. Population-based database This study used the National Health Insurance Research Database (NHIRD) made available to Taiwan scientists by the Taiwan's National Health Research Institutes. The Ministry of Health and Welfare initiated a single-payer National Health Insurance (NHI) program in 1995, and more than 98% of Taiwan's population of 23 million is included in this program. The NHIRD is composed of original claims data for reimbursement and allows researchers to collect information for all medical services received by enrollees under the NHI program. All records can be linked using internal identification numbers created by NHIRD. The Longitudinal Health Insurance Database 2000, a random sample of 1,000,000 individuals from NHIRD, was used to analyze the distribution and differences of some common and major skin diseases in outpatient service between patients with schizophrenia and age–sex matched control group. Using a ratio of 1:4, we selected 7749 patients with a diagnosis of a schizophrenia spectrum disorder and 30,996 control participants free from schizophrenia. The inclusion criteria included any outpatient visit with the diagnosis of schizophrenia or schizoaffective disorder made by a psychiatrist between January 2000 and December 2010. Following the deduction of cases for 1,000,000 people, the remainder comprised the sampling base of the control group. After selecting the case and control groups, we used specific International Classification of Diseases, Ninth Edition coding to identify any outpatient visits specifically for skin condition. Cases and controls in the NHIRD with skin diseases diagnosed by dermatologists or physicians, regardless of specialty (PROS), were coded in Table 5. 2.6. Statistical analysis Regarding the clinical survey, the differences between subgroups were examined using a two-sample t test for numerical variables and a chi-square test for categorical variables. The outcome variables for the analyses were defined according to the presence of various skin diseases, which were classified into 10 categories, as listed in Table 2. Disease entities for which there were fewer than 10 cases were grouped into an “Other” category and were not included in the regression model analysis. Independent variables included body mass index (BMI), presence of relevant medical conditions (such as diabetes mellitus), patient's awareness of skin condition and schizophrenia-related characteristics (PSP score, PANSS score, MMSE score, types of antipsychotics in use, DDD of

Please cite this article as: Wu B.-Y., et al, Prevalence and associated factors of comorbid skin diseases in patients with schizophrenia: a clinical survey and national health ..., Gen Hosp Psychiatry (2014), http://dx.doi.org/10.1016/j.genhosppsych.2014.02.008

B.-Y. Wu et al. / General Hospital Psychiatry xxx (2014) xxx–xxx

antipsychotics). BMI was transformed into a dichotomous variable using a cutoff point of 24, in accordance with the criteria for being overweight defined by the Department of Health Promotion, Ministry of Health and Welfare, Taiwan. Age, sex and duration of disease were regarded as confounding variables and were included in the multiple logistic regression analysis for adjustment. Crude odds ratios (ORs) were calculated using univariate logistic regression. Adjusted ORs (AORs) were obtained via multivariate logistic regression using the forward selection model. Regarding the NHIRD database, the differences in percentage of participants with skin diseases between patients with schizophrenia and the control group were examined using a chi-square test. SPSS Version 17.0 (Chicago, IL, USA) was used for statistical analysis. The significance level was set at 0.05 (two-tailed). 3. Results 3.1. Clinical survey The majority of patients were male (75.8%). Over 97% of the participants had at least one skin disease. Those patients with skin diseases had an average of 2.24 (S.D.=1.5) skin diseases. Male patients had more skin diseases than female patients [male: 2.37 (S.D.=1.56), female: 1.85 (S.D.=1.20), P=.001; data not shown in the table], but no significant difference remained after removing androgenic alopecia. The basic characteristics are summarized in Table 1. The distribution of skin diseases is presented in Table 2. The most common skin disease was fungal infection, followed by dermatitis, androgenic alopecia, hyperkeratotic disorder, bacterial infection, xerosis, pilosebaceous disease, benign skin tumor, stasis and viral infection, in descending order. As shown in Table 3, in the univariate logistic regression model, patients with a BMI over 24 were more susceptible to fungal infection, and those with diabetes were more likely to have comorbid pilosebaceous disease. Patient awareness of skin problems was strongly associated with dermatitis and stasis. Patients with higher PANSS scores had decreased risk of hyperkeratotic disorder. Compared with patients on TAs, patients using NCAAs had an elevated risk for pilosebaceous disease, and patients on clozapine had lower risk of fungal infection. PSP scores, MMSE scores or DDD of antipsychotics was not significantly associated with any outcomes. As Table 4 shows, after adjusting for age, sex and other covariates, relative to the non-overweight group, overweight patients exhibited a

Table 1 Comparison of patient characteristics between sexes Total (N=337) Male (n=252) Female (n=85) P valuea Gender (%) Numerical variables Age (years) BMI (kg/m2) PANSS score PSP score MMSE score DDD Categorical variables Diabetes Any skin condition Antipsychoticsb TAs NCAAs Clozapine

74.8 54.0 25.3 73.1 52.7 24.7 0.86

(9.8) (4.3) (17.2) (11.6) (8.7) (0.8)

54.0 25.0 72.8 52.8 24.7 0.88

25.2 (9.9) (4.0) (17.2) (11.9) (9.0) (0.8)

52.0 26.3 73.9 52.4 24.9 0.83

(9.4) (4.8) (17.4) (10.7) (7.8) (0.7)

.07 .03 .59 .80 .81 .06

110 (32.6) 329 (97.6)

72 (28.6) 249 (98.8)

38 (44.7) 80 (94.1)

.01 .03

108 (32.0) 112 (33.2) 112 (33.2)

83 (33.0) 84 (33.3) 81 (32.1)

25 (29.4) 28 (32.9) 31 (36.5)

.51 .93 .48

Abbreviation: DDD, DDD of total antipsychotics. Numerical variables are expressed as means and standard deviations, and categorical variables are expressed as numbers of patients (n) and percentages of the total sample. a P values reflect independent t test in numerical variables and chi-square test in categorical variables. b Five patients used no antipsychotics; some patients used more than one type of antipsychotic.

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Table 2 Categories of skin diseases and specific skin diseases observed Category of skin disease

n (%)

Specific skin condition

n (%)

Fungal infection

207 (61.4)

Dermatitis

158 (46.9)

Onychomycosis Tinea pedis Tinea corporis Tinea cruris Tinea versicolor Tinea manuum Seborrheic dermatitis Unspecific eczema Lichen simplex chronica Intertrigo Hand eczema Asteatotic dermatitis Prurigo nodularis Dyshidrosis Male/female androgenic alopecia Palmoplantar keratoderma Corn/callus Folliculitis Paronychia Pitted keratolysis Furuncle Xerosis/ichthyosis Acne vulgaris Rosacea Epidermal cyst, lipoma, angioma, angiokeratoma, neurofibroma, soft fibroma, etc. Varicose vein Stasis dermatitis Viral wart Herpes infection –a

168 (49.9) 125 (37.1) 23 (6.8) 19 (5.6) 5 (1.5) 4 (1.2) 75 (22.3) 57 (16.9) 24 (7.1) 17 (5.0) 11 (3.3) 7 (2.1) 5 (1.5) 4 (1.2) 98 (29.1)

Androgenic alopecia

98 (29.1)

Hyperkeratotic disorder Bacterial infection

86 (25.5)

Xerosis Pilosebaceous disease

57 (16.9) 20 (5.9)

Benign skin tumor

17 (5.0)

Stasis

14 (4.2)

Viral infection

12 (3.6)

Other

28 (8.3)

58 (17.2)

62 (18.4) 30 (8.9) 38 (11.3) 15 (4.5) 5 (1.5) 1 (0.3) 57 (16.9) 15 (4.5) 5 (1.5) 17 (5.0)

9 (2.7) 5 (1.5) 11 (3.3) 2 (0.6) 18 (8.3)

a

Skin diseases in the “Other” category include psoriasis vulgaris, keratosis pilaris, cutaneous amyloidosis, keloid scars, vitiligo, neurotic excoriation, fingernail biting, polymorphous light eruption, fingernail dystrophy, idiopathic telangiectasia, angular cheilitis, urticaria and other diseases of very low incidence.

significantly increased risk of fungal infection (AOR=1.93). Compared with patients without diabetes, those with diabetes showed an increased risk of bacterial infection (AOR=2.00) and pilosebaceous disease (AOR=5.31). In comparison with patients who were unaware of their skin diseases, those with awareness had an elevated risk of dermatitis (AOR=3.09). Those who had higher PANSS scores had a decreased risk of having hyperkeratotic disorder (AOR=0.98). Compared with those using TAs, patients using NCAAs had an increased risk of pilosebaceous disease (AOR=4.35), while using clozapine decreased the risk of fungal infection (AOR=0.49). Detailed data [including 95% confidence intervals (CIs)] are displayed in Table 4. Adjusting for the duration of schizophrenia, age and sex, compared with non-clozapine users, patients on clozapine had a higher risk of benign skin tumors (AOR=3.94, 95% CI=1.24–12.56). In Table 5, regarding the treatment of skin diseases for patients with schizophrenia in the TC during the 12 months prior to the clinical survey, nearly 40% of patients with bacterial infection, 35% of patients with dermatitis, 30% of patients with fungal infection and 20% of patients with hyperkeratotic disorder were treated by physicians in the TC. However, less than 10% of patients with these skin diseases were referred to dermatologists in general hospitals outside the TC. 3.2. Findings of NHIRD Male participants comprised 51.8% of the sample, with a mean age of 46.6 years (S.D.=15.2). As shown in Table 5, for skin diseases diagnosed by dermatologists, patients with schizophrenia had a higher prevalence of hyperkeratotic disorder than the control group in the NHIRD. For skin diseases diagnosed by PROS, patients with schizophrenia had a higher prevalence of fungal and bacterial

Please cite this article as: Wu B.-Y., et al, Prevalence and associated factors of comorbid skin diseases in patients with schizophrenia: a clinical survey and national health ..., Gen Hosp Psychiatry (2014), http://dx.doi.org/10.1016/j.genhosppsych.2014.02.008

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B.-Y. Wu et al. / General Hospital Psychiatry xxx (2014) xxx–xxx

Table 3 Univariate logistic regression results (in OR) of predict factors associated with various specific skin diseases Outcome variable

Age

Gender (M/F)a

BMI

Diabetes (Y/N)b

Awareness (Y/N)c

PSP score

PANSS score

MMSE score

DDD

NCAAd

Clozapined

Any skin condition Fungal infection Dermatitis Androgenic alopecia Hyperkeratotic disorder Bacterial infection Xerosis Pilosebaceous disease Benign skin tumor Stasis Viral infection

1.13⁎⁎ 1.03⁎⁎ 1.02 1.03⁎⁎ 1.00 0.94⁎⁎ 1.03⁎ 0.92⁎⁎ 1.00 1.04 0.97

5.19⁎⁎ 1.41 0.99 25.54⁎⁎ 1.26 1.20 1.17 0.39⁎⁎ 1.61 2.08 0.66

0.87 1.69⁎⁎ 0.96 0.83 0.82 1.82⁎ 0.93 2.89⁎ 1.27 2.60 2.11

1.47 1.29 1.08 0.88 0.69 1.45 0.77 2.69⁎⁎ 1.90 0.82 1.03

4.82 1.63 2.79⁎⁎ 1.36 1.55 1.39 1.00 1.14 0.59 3.66⁎⁎ 1.53

0.97 1.00 1.00 0.99 1.01 1.00 1.00 1.02 1.01 1.01 1.01

0.99 1.00 1.00 0.99 0.98⁎⁎ 1.00 1.01 1.00 1.01 1.02 0.97⁎

0.97 0.99 1.00 1.01 0.99 1.01 1.00 1.00 1.06 1.00 1.00

0.82 1.08 0.76 0.95 0.76 1.05 1.05 1.06 1.05 0.91 0.89

0.85 1.49 1.22 0.82 0.89 0.95 1.11 2.55⁎⁎ 0.41 1.24 0.73

0.50 0.45⁎⁎ 0.84 0.87 1.26 1.37 0.92 0.83 2.32⁎ 0.87 1.67

Abbreviations: DDD = DDD of total antipsychotics. a Female as reference. b Non-diabetes as reference. c Awareness of skin problems. Non-awareness as reference. d Typical antipsychotics as reference. ⁎ Pb.1, by univariate logistic regression. ⁎⁎ Pb.05, by univariate logistic regression.

infections, dermatitis and hyperkeratotic disorder than the control group. The overall prevalence of skin diseases listed in Table 5 diagnosed by PROS was 75.1% in patients with schizophrenia and 72.6% in those without (P= .01).

4. Discussion Our study revealed a high prevalence of skin diseases in patients with schizophrenia. Compared with patients treated with TAs only, those treated with NCAAs had a fourfold risk of pilosebaceous disease. In contrast, patients treated with clozapine seemed to have a reduced risk of fungal infection. Patients with higher PANSS scores were less likely to have hyperkeratotic disorders. We also found that patients with diabetes and high BMI had a higher risk of bacterial and fungal infections. The high prevalence of skin diseases (97.6%) in the study population was far beyond our expectations. Even when we restricted our analysis to dermatitis and infectious skin diseases, which have a major impact on the patient's quality of life and could cause other complications, the percentage of affected patients remained as high as 83.7%. Among the patients with skin diseases, only 21.2% were aware of their skin conditions. This discrepancy may be due to the cognitive deficits of patients with schizophrenia, which could in turn affect symptom recognition [20]. Previous studies have revealed that patients with schizophrenia have higher pain thresholds; thus, they

Table 4 Multiple logistic regression results of predict factors associated with specific skin diseases Variables Fungal infection Dermatitis Hyperkeratotic disorder Bacterial infection Pilosebaceous disease

AOR

95% CI

P value

Clozapine BMIb Awareness of skin problems (Y/N) PANSS

0.49 1.93 3.09

0.30–0.81 1.20–3.09 1.68–5.66

b.01 b.01 b.01

0.98

0.97–0.99

.02

Diabetes (Y/N) NCAAa Diabetes (Y/N)

2.00 4.35 5.31

1.06–3.75 1.56–12.13 1.73–16.30

a

.03 b.01 b.01

Variables included in the model for forward selection were awareness of skin problems, PANSS, PSP, MMSE, DDD of antipsychotics, NCAAs vs. typical antipsychotics, clozapine vs. typical antipsychotics, diabetes and BMI. Each model has been adjusted for age and gender. Only variables with significant results are presented. a Typical antipsychotics as reference. b BMI was transformed into a dichotomous variable with a cutoff point of 24.

may be less likely to report physical symptoms until they become severe [21]. In our study, the most common skin disease was fungal infection. This warrants particular attention because it could lead to secondary acute bacterial cellulitis [22–24], which affected up to 61.4% of our patients. Nearly 50% of the study population had onychomycosis, which is the most common condition in this category. Dermatitis was the second most prevalent skin disease. Approximately half of the study population had some type of eczema. In a study using data from the National Hospital Discharge Survey in the US, the proportional morbidity ratio of contact dermatitis and other eczema in psychiatric patients was 2.9 compared to the general US population [25]. Data from the NHIRD of Taiwan indicate high comorbidity of atopic dermatitis and asthma, with evidence of these conditions in 20.2% patients with schizophrenia [26]. The precise relationship between schizophrenia and dermatitis remains unclear, but these conditions are likely to aggravate each other, forming a vicious cycle.

4.1. Effects of antipsychotics on skin diseases Compared with patients treated only with TAs, patients treated using NCAAs had a much higher risk of pilosebaceous disease. Acne was the major disease in this entity and made the greatest contribution to statistical differences, as confirmed by subgroup analysis. Another study has suggested that patients with schizophrenia have more problems with acne [27]. TAs and some atypical antipsychotics, such as risperidone and amisulpride, can induce hyperprolactinemia [28,29]. An elevated prolactin concentration can induce relatively high androgenic activity and make patients prone to acne and mild hirsutism [30]. Atypical antipsychotics are also more likely to cause patients to be overweight or obese and may thus increase the risk of acne in this group [31]. However, the explanation for the increased risk of pilosebaceous disease in the NCAA group remains unclear. Interestingly, clozapine appeared to have a protective effect against fungal infection. Clozapine has an immunomodulatory effect by inducing multiple cytokines [32] such as IL-6 [33,34] and TNF-α [35]; both cytokines are crucial mediators of inflammation. This immunomodulatory effect may modify the patient's immune response against fungal infection, thus producing a protective effect. Although the mechanism remains unclear, this finding is unprecedented and interesting and warrants further exploration in the future. Conversely, after adjusting for the duration of schizophrenia, patients

Please cite this article as: Wu B.-Y., et al, Prevalence and associated factors of comorbid skin diseases in patients with schizophrenia: a clinical survey and national health ..., Gen Hosp Psychiatry (2014), http://dx.doi.org/10.1016/j.genhosppsych.2014.02.008

B.-Y. Wu et al. / General Hospital Psychiatry xxx (2014) xxx–xxx

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Table 5 Skin diseases in patients with schizophrenia and control participants in the TC and the NHIRD Skin diseases

1. Dermatitis 2. Fungal infection 3. Pilosebaceous disease 4. Bacterial infection 5. Viral infection 6. Hyperkeratotic disease 7. Androgenic alopecia 8. Xerosis 9. Stasis Overall prevalence

SCH in TC

SCH with SD in TC

SCH with SD in TC

SCHa in NHIRD

Controla in NHIRD

(n=337)

Treated by non-DTs in TC

Refer to DTs outside TC

(n=7749)

(n=30,996)

n (%)

n (%)

n (%)

n (%)

n (%)

158 (46.9) 207 (61.4) 20 (5.9) 58 (17.2) 12 (3.6) 86 (25.5) 98 (29.1) 57 (16.9) 14 (4.2) –

58 (36.7) 66 (31.8) 0 24 (41.3) 0 17 (19.7) 0 0 0 –

13 (8.2) 9 (4.3) 5 (25) 5 (8.6) 0 3 (3.4) 0 3 (5.2) 0 –

3057 (39.5) 1419 (18.3) 1116 (14.4) 981 (12.7) 634 (8.2) 259 (3.3) 63 (0.8) 48 (0.6) 4 (0.1) 3913 (50.5)

13,159 5452 5225 3668 3612 874 264 201 22 16,737

c

(42.5)⁎⁎ (17.6) (16.9) ⁎⁎ (11.8) (11.7) ⁎⁎ (2.8) ⁎ (0.9) (0.6) (0.1) (54.0)⁎⁎

SCHb in NHIRD

Controlb in NHIRD

(n=7749)

(n=30,996)

n (%)

n (%)c

4879 (63.0) 2129 (27.5) 1339 (17.3) 3047 (39.3) 968 (12.5) 373 (4.8) 71 (0.9) 59 (0.8) 12 (0.2) 5819 (75.1)

18,754 (60.5)⁎⁎ 7169 (23.1)⁎⁎ 5981 (19.3)⁎⁎ 9458 (30.5)⁎⁎ 5083 (16.4)⁎⁎ 1271 (4.1)⁎⁎ 294 (0.9) 245 (0.8) 59 (0.2) 22,503 (72.6)⁎⁎

Note: SCH, patients with schizophrenia; SD, skin disease; DTs, dermatologists; non-DTs, non-dermatologist physicians; Control, control group. a Skin diseases diagnosed by dermatologists. b Skin diseases diagnosed by physicians regardless of specialty. c Comparison between SCH and Control group in the NHIRD. ⁎ Pb.05. ⁎⁎ Pb.01 by chi-square test.

treated with clozapine had an increased risk of benign skin tumors, which is compatible with findings from another study [8]. 4.2. Psychopathology and hyperkeratosis The PANSS score was the only psychosocial outcome related to a specific skin condition, namely hyperkeratotic disorder. Palmoplantar keratoderma and corn/callus conditions were included in this category. The PANSS score had a negative association with hyperkeratotic disorder. One possible explanation may be that medical staffs were likely to contact patients with prominent psychosis more frequently in order to stabilize their psychiatric symptoms. During common interventions such as interviewing, administering intramuscular injections or physical restraint, conditions might garner attention from the medical team for early detection of hyperkeratosis and result in the prescription of proper medication and referral to dermatologists, thus reducing the risk of a diagnosis of hyperkeratosis in the current study. In addition, in this TC, relative to severely psychotic patients, patients in remission from psychiatric symptoms are much more likely to receive labor-related rehabilitation programs such as document delivery, gardening or household cleaning. Pressure on the feet related to long-distance walking and long-term standing may precipitate the onset of hyperkeratosis. 4.3. Influence of diabetes mellitus and overweight on skin infection Prior studies have revealed a higher prevalence of dermatophyte infection in the skin of patients with diabetes than in people without, but this difference did not reach a significant level [36], and nursing home residents with diabetes did not have higher rates of fungal skin infection than those without [37]. However, our study showed that patients with diabetes or obesity had a significantly increased risk of bacterial or fungal infection. This finding was consistent with the results of previous studies in which overweight chronic psychiatric patients or those with diabetes were predisposed to infectious skin diseases [8,12]. Compared with the general population, the seemingly greater difference in skin infection rates between patients with schizophrenia having diabetes and those without (twice as likely in our study and 10 times more likely in another [8]) could be attributed in part to various reasons. First, the monocytic system (the proinflammatory immune response in particular) was found to be impaired in patients with schizophrenia [38]. Second, reduced natural killer cytotoxicity and lymphocyte proliferation in psychiatric patients increased susceptibility to infectious skin diseases [39]. All of these

mechanisms could aggravate the severity of skin infections caused by diabetes. These findings support the idea that, relative to the general population, patients with schizophrenia are more liable to suffer from the complication of diabetes [8]. Likewise, similar mechanisms might intensify the severity of obesity-related infectious skin disease in this population. 4.4. Skin diseases in the TC and NHIRD As shown in Table 5, the prevalence of diagnosis of skin diseases by PROS was higher than the prevalence of diagnosis by dermatologists in patients with schizophrenia. These conflicting results may be a function of the limited availability of medical resources for patients with schizophrenia [40–42]. In general, there is a barrier to direct referral to a dermatologist for patients with schizophrenia having skin diseases, unless the skin disease is too severe for non-dermatologist physicians to manage in psychiatric or medical institutions. In Taiwan, many patients with schizophrenia in psychiatric wards, general hospitals, rehabilitation centers, nursing homes or therapeutic communities who suffer skin diseases are primarily treated by psychiatrists or family physicians in these units. Some psychiatrists are asked to prescribe medication for skin diseases during psychiatric outpatient visits. Thus, there is a selection bias if we focus only on skin diseases diagnosed or treated by dermatologists in the NHIRD while exploring the prevalence of skin diseases in patients with schizophrenia. For this reason, treatment of skin diseases by PROS seems to be more consistent with the actual situation when examining at the prevalence of skin diseases in population-based data. In the NHIRD, the overall prevalence of skin diseases diagnosed by PROS in patients with schizophrenia was higher than in those without. Some skin diseases, including fungal and bacterial infection, dermatitis and hyperkeratosis, were more prevalent in patients with schizophrenia than in those without. It is noteworthy that patients with schizophrenia have more limited access and greater barriers to medical care than those without [40], the number of skin diseases which are more prevalent in the former than that of the latter is possible to be underestimated. Our finding is in part consistent with the result of a study recruiting 300 patients with psychiatric disorders and 300 patients without, which indicated that the prevalence of fungal infection of the former was significantly higher than in the latter [9]. The occurrence of several of skin diseases in patients of schizophrenia was higher in the face-to-face clinical survey than those in the NHIRD. The difference in frequencies between these two

Please cite this article as: Wu B.-Y., et al, Prevalence and associated factors of comorbid skin diseases in patients with schizophrenia: a clinical survey and national health ..., Gen Hosp Psychiatry (2014), http://dx.doi.org/10.1016/j.genhosppsych.2014.02.008

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samples is expected due to inconsistencies in demographic data between these two groups, selection bias caused by limited access to NHI and other potential confounding factors. Only 20–40% of some skin diseases were diagnosed and treated by physicians in the TC, and less than 10% of patients with skin diseases were referred to certified dermatologists. Our findings indicate that a number of skin diseases in patients with schizophrenia were underdiagnosed and undertreated. Possible explanations include patients' unawareness of skin problems, their under-reporting of skin problems to caregivers [8] and the negligence of medical staffs. Moreover, we found that comorbidity of skin diseases was independent of patients' global function and cognitive function after adjusting for confounding factors. This indicates that no matter how well patients with schizophrenia function, comprehensive examination of skin diseases on a regular basis by caregivers or medical staffs is of paramount importance.

4.5. Strengths and limitations As previously discussed, this is the first study to use a populationbased database and clinical survey to explore the prevalence of skin diseases and treatment in patients with schizophrenia. In addition, the sample size of patients with schizophrenia in the current study was larger than those of prior studies. However, there are several limitations in our study. First, generalization of the findings may be restricted to similar populations, such as institutionalized, stable patients with schizophrenia, predominantly males. Moreover, in the analysis of population-based data, we excluded inpatient data, focusing on outpatient data alone. The second limitation is that our study is cross-sectional; therefore, causal inference between risk factors or concerns and outcomes should be made with caution. Third, some skin diseases possibly greatly affected by seasonal variation might not have been observed in our current clinical survey. Additionally, a selection bias for skin diseases diagnosed by dermatologists and the accuracy of diagnosis by PROS in the NHIRD are limitations with respect to the evaluation of the precise prevalence of specific skin diseases. Finally, we did not include people without schizophrenia for comparison with our patients in this clinical survey. In conclusion, our findings revealed a high prevalence of skin diseases among stable patients with schizophrenia and a higher prevalence of some skin diseases in patients with schizophrenia than in those without. Diabetes, obesity, severity of psychopathology and type of antipsychotics were found to be associated with skin diseases. It is important to use these predictors to single out potential risk factors for skin diseases and provide proper treatment to patients with schizophrenia. As a number of skin diseases in patients with schizophrenia are underdiagnosed and undertreated, it is important to encourage caregivers and medical professionals in psychiatric institutions to familiarize themselves with these skin diseases and seek adequate consultation with dermatologists as necessary. To prevent severe complications and disability induced by cutaneous problems, comprehensive, prompt and timely dermatological intervention is mandatory for maintaining well-being and quality of life in these patients.

Acknowledgments This work was supported in part by the University System of Taiwan–University of California, San Diego International Center of Excellence in Advanced Bioengineering sponsored by the Taiwan National Science Council I-RiCE Program under Grant Number NSC 102-2911-I-009-101 and a grant from The Ministry of Education, Taiwan, Aim for the Top University Plan.

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