Dr. Wu is associate director, Mr. Durkin is senior director of outcomes research, and Dr. Canuso is senior director of clinical development at Ortho-McNeil Janssen Scientific Affairs, LLC, in Titusville, New Jersey. Dr. Dickson is professor and past-chairman of the Pharmaceutical and Health Outcomes Sciences Department at the University of South Carolina in Columbia.

Disclosures: Drs. Wu and Canuso own stock in Johnson and Johnson and are employees of Ortho-McNeil Janssen Scientific Affairs, LLC. Dr. Dickson is consultant to Ortho-McNeil Janssen Scientific Affairs, LLC. Mr. Durkin is an employee of Ortho-McNeil Janssen Scientific Affairs, LLC.  This article was funded by Ortho-McNeil Janssen Scientific Affairs, LLC.

Acknowledgments: The authors thank Dr. Victor Navarro for his assistance. Data in this study were presented at the Annual Meeting of the American Psychiatric Association in San Diego, CA, May 19-24, 2007.

Please direct all correspondence to: Jasmanda H. Wu, MPH, PhD, Associate Director, Outcomes Research, Ortho-McNeil Janssen Scientific Affairs, LLC, 1125 Trenton-Harbourton Rd, Titusville, NJ 08560-0200; Tel: 609-730-7718; Fax: 609-730-2411; E-mail: jwu2@omjus.jnj.com.

 


 

Focus Points

• There is a high occurrence of liver diseases observed in patients with mental illness.
• True prevalence of liver diseases may be even higher than that observed.
• Clinicians should consider hepatic issues when treating patients with mental illness. 


 

Abstract

Objective:  To evaluate the percentage of patients with treated liver diseases in patients with schizophrenia or bipolar disorder, compared to a comparison group without mental illness.
Methods: South Carolina State Medicaid program data were analyzed. Patients <65 years of age, with a schizophrenia or bipolar disorder diagnosis from 2002–2003 were identified. A 4–1 frequency-matching algorithm (4 without diagnosis to 1 with diagnosis) was applied. Treated liver diseases were assessed from ambulatory or hospital claims over the 24-month period and compared between the two groups. Direct standardization was used to account for the differences in demographics between the two groups.  
Results: A total of 5,211 patients with schizophrenia and 4,553 patients with bipolar disorder were identified. After standardizing for the differences in age, gender, and race, the percentages of patients with treated liver diseases in patients with schizophrenia (or bipolar disorder) was statistically significantly higher than the non-mentally ill comparison group (schizophrenia versus comparison=4.64% versus 4.14%,
P<.0001; bipolar disorder versus comparison=6.96% versus 2.66%, P<.0001). The percentages observed in the disease group were also higher than the reported prevalence of liver disease from the historic general population (1.3%).
Conclusion: Medicaid recipients with schizophrenia or bipolar disorder have higher percentages of patients with treated liver diseases than non-mentally ill Medicaid recipients. The percentages observed were also higher than the prevalence rate reported for the general population. Clinicians should consider hepatic issues in the management of their patients.

 

Introduction

Schizophrenia and bipolar disorder are severe disorders that usually manifest in late adolescence or early adulthood.1-5 Both conditions involve substantial direct healthcare burden due to early onset, chronicity, and frequent need for repeated hospitalizations.6,7 In addition, patients experience impairments in occupational and social functioning that can result in increased family and societal burden.8,9

It is common for patients with schizophrenia or bipolar disorder to exhibit comorbidities such as substance abuse and hepatic viral infection.10-12 According to the literature, up to 60% of patients with bipolar disorder meet diagnostic criteria for substance abuse.13 Comorbid substance abuse disorder is reported to occur in almost 50% of patients with schizophrenia.13 Patients with alcohol abuse are at particular risk for hepatic impairment.14,15 Increased rates of drug abuse, particularly injection drug use, are likely to contribute to increased risk of hepatitis B virus (HBV) and hepatitis C virus (HCV) in patients with mental illness.16

It has been found that HBV and HCV occur more frequently in patients with severe mental illness than in the general population.17 A 2001 study revealed that the prevalence of HBV (23.4%) and HCV (19.6%), respectively, was 5 and 11 times higher for patients with severe mental illness than in the general population.16 A retrospective database study showed that 9.9% of patients with schizophrenia were infected with HCV.18 Both HBV and HCV are major causes of cirrhosis, hepatic decompensation, and hepatocellular carcinoma.19,20

Patients with schizophrenia and bipolar disorder may be at higher risk for acquiring another spectrum of liver diseases known as non-alcoholic fatty liver disease (NAFLD).21 Among the most common risk factors associated with NAFLD21 are those observed in metabolic syndrome.22 According to the literature, prevalence of metabolic syndrome was 36% for males and 51% for females in patients with schizophrenia. These rates are higher than in the general population (20% males; 25% females).23

Patients with schizophrenia or bipolar disorder commonly receive antipsychotic polypharmacy and pharmacologic add-on therapy for various aspects of their illness.24-27 Unintended interactions between medications may be associated with liver damage. Previous studies have evaluated viral hepatitis in people with severe mental illness.16,17 However, few research articles have been published that address the issue of overall liver diseases in psychiatric patients.

In this study, the authors examined insurance claims data from a State Medicaid program to evaluate the percentages of patients with treated liver diseases in Medicaid recipients with a schizophrenia or bipolar disorder diagnosis, compared to those without mental illness.

 

Methods

Study Cohort

Claims data were analyzed from the South Carolina State Medicaid program database. Approximately 500,000 eligible beneficiaries were identified in 2004 and 2005. Patient identifiers were removed to ensure patient confidentiality. The South Carolina Medicaid Program Committee and the University of South Carolina Institutional Review Board approved the study and did not require informed consent.

Patients <65 years of age who had at least one hospital claim or two ambulatory claims with a diagnosis of schizophrenia or bipolar disorder (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM],28 codes 295.xx, 296.0, 296.1, and 296.4-296.8) during 2002 and 2003 were selected. This method has been used previously for selecting patients with schizophrenia, schizoaffective disorder, or bipolar disorder for examining comorbid conditions, adverse events, and medication compliance.29-32 Diagnosis of schizophrenia included schizoaffective disorder with schizophrenia-spectrum illnesses (ICD-9-CM codes 295.7x). Patients who had skilled nursing home claims during 2002 and 2003 were excluded due to the absence of pharmacy claims records. Those without continuous eligibility during 2004 and 2005 were excluded. The enrollment period (January 1, 2002 to December 31, 2003) differed from the follow-up period (January 1, 2004 to December 31, 2005) to allow focus on liver conditions for existing rather than new schizophrenia or bipolar patients. Temporal sequence between the occurrence of liver disease and schizophrenia/bipolar disorder diagnoses was difficult to establish using claims data and was not required for inclusion. 

The authors of this study separated patients into two cohorts, including those with schizophrenia and those with bipolar disorder. Patients with both conditions were excluded. For each patient in either cohort, four individuals were randomly selected using frequency matching on the age category (age groups of 1–20, 21–40, and 41–64 years) to create the comparison group without mental illness. The authors used medical and pharmacy claims to exclude comparison group subjects who exhibited a diagnosis of mental illness (ICD-9-CM codes 290.xx to 319.xx) or who had received antipsychotics between January 1, 2002 through December 31, 2005. National Drug Codes33 were used to identify the presence of antipsychotics within the comparison group cohort, including aripiprazole, chlorpromazine, clozapine, fluphenazine, haloperidol, loxapine, mesoridazine, molindone, olanzapine, perphenazine, pimozide, promazine, quetiapine, risperidone, thioridazine, thiothixene, trifluoperazine, and ziprasidone.

The four cohorts (schizophrenia and bipolar disorder, and their corresponding comparison group without mental illness) were reviewed for new and existing liver diseases by searching claims for related ICD-9-CM codes occurring between January 1, 2004 and December 31, 2005.

 

Measurements

Liver Diseases
Individuals were identified as having liver diseases (acute and chronic), viral hepatitis, or chronic cirrhosis if they had at least one hospital claim or two ambulatory claims for the ICD-9-CM codes listed in Table 1.28 The method using two separate outpatient visits to help increase the diagnostic specificity has been used previously to examine medical comorbidities in patients with bipolar disorder.29 Patients were identified as having NALFD if they had at least one hospital claim or two ambulatory claims for the ICD-9-CM codes listed in Table 1 and had a diagnosis of diabetes (the ICD-9-CM codes 250.xx), obesity (278.0), hyperlipidemia (272.0, 272.1, 272.2, 272.3, and 272.4), or hypertension (401.xx–405.xx). NAFLD patient selection also required the absence of specific ICD-9-CM codes in their claim history, including 571.0, 571.1, 571.2, 571.3, 573.1, 070, and V02.6. Ascertaining diagnosis of NAFLD generally is to rule out co-existent or alternate liver diseases and to evaluate the presence of metabolic syndrome and insulin resistance in patients.21 Determination of specific ICD-9-CM codes was based on hepatologist consultation and published literature.34 Absence of clinical details in the claims forms and different coding practice in different clinics may have compromised classification of specific types of liver diseases from these claims. The authors of this study intended to focus on the overall liver diseases as the primary outcome of interest.

 

 

Comorbid Conditions
The four study cohorts were evaluated for comorbid conditions (January 1, 2002–December 2003), which included hypertension (ICD-9-CM codes 401.xx–405.xx), hyperlipidemia (272.0, 272.1, 272.2, 272.3, and 272.4), diabetes (250.xx), obesity (278.0), human immunodeficiency virus (HIV) infection (042, 795.71, and V08), and substance abuse (291.xx, 292.xx, 303.xx–304.xx, and 305.xx).

Percentage of Patients with Treated Liver Diseases
The percentage of patients with treated liver diseases for 2004–2005 were computed using the number of new and existing liver disease cases divided by the total number of individuals in the schizophrenia, bipolar disorder, and comparison (individuals without mental illness) groups.

Direct Standardization
The adjusted percentages of patients with treated liver diseases were computed using direct standardization to account for the differences in age, gender, and race between the schizophrenia (or bipolar disorder) and the comparison without mental illness groups. The adjusted percentages were computed for the comparison group based on the age, gender, and race distribution of the schizophrenia (or bipolar disorder) cohort. The detailed formula for the computation is displayed in Table 2. For illustration purpose, only the age group between 36 and 50 is included in Table 2.

 

 

 

Sub-Analysis on Schizoaffective Disorder

The study authors also performed a subgroup analysis to evaluate demographic characteristics and outcomes of interest for schizoaffective disorder patients with schizophrenia-spectrum illnesses (ICD-9-CM codes 295.7x). 

 

Statistical Methods

Statistical analyses were performed using Statistical Analysis System (version 9.1.3). Standard descriptive statistics summarized the data in the schizophrenia, bipolar disorder, schizoaffective disorder with schizophrenia-spectrum illnesses, and comparison groups. The mean, median, standard deviation, minimum, and maximum were provided for continuous variables. Frequency distributions were provided for categorical variables, including gender, race, and comobid conditions. The differences in the categorical variables between the schizophrenia (bipolar disorder or schizoaffective disorder with schizophrenia-spectrum illnesses) and the comparison groups were assessed using a Chi-square test for independent samples. The differences in the continuous variables were assessed using a t-test. A two-sided 5% significance level was used for all tests.

 

Results

Baseline Characteristics

Patients with schizophrenia were identified (n=5,211; n=20,844 comparison group without mental illness). Baseline characteristics (Table 3) indicated that age distribution was similar between the two groups as expected using frequency matching. There was a higher proportion of male patients in the schizophrenia group compared to the comparison group without mental illness. By race, black patients represented the highest proportion of patients in the schizophrenia cohort as compared to the comparison group.

 

For comorbid conditions, 19.2% of schizophrenia patients had substance abuse. Patients with schizophrenia were more likely to have HIV infection, hypertension, diabetes, hyperlipidemia, and obesity than the comparison group without mental illness.

The mean age of patients with bipolar disorder was 33.0. By race, white patients represented the highest proportion of patients in the bipolar cohort as compared to the comparison group without mental illness. Approximately 29.3% of patients with bipolar disorder had substance abuse, and patients with bipolar disorder were more likely to have HIV infection, hypertension, diabetes, hyperlipidemia, and obesity than the comparison group without mental illness.

 

Treated Liver Diseases

The percentage of patients with treated liver diseases in patients with schizophrenia were statistically significantly higher than the comparison group after standardizing the age, gender, and race distribution of the two groups (in schizophrenia versus comparison without mental illness, overall liver diseases was 4.64% versus 4.14%, P<.0001) (Table 4). The majority (80%) of these cases were coded using the liver disease-related ICD-9-CM codes other than abnormal liver function test (ICD-9-CM codes 790.4 and 794.8). Schizophrenia patients also had higher percentages of various liver diseases, except for NAFLD.

 

 

The differences in the percentages of patients with treated liver diseases were even greater between patients with bipolar disorder and the comparison group without mental illness after standardizing the age, gender, and race distribution of the two groups. In bipolar disorder versus comparison without mental illness, the percentage of overall liver diseases was 6.96% versus 2.66%, P<.0001; acute liver disease was 5.47% versus 2.00%, P<.0001; chronic liver disease was 6.94% versus 2.66%, P<.0001; viral hepatitis was 2.99% versus 0.73%, P<.0001; chronic cirrhosis was 2.09% versus 0.84%, P<.0001; and NAFLD was 1.89% versus 1.05%, P<.0001.

For various subgroup analyses, the percentage of patients with treated liver diseases were higher in females than males (eg, bipolar disorder, male [4.53%] versus female [8.21%], P<.0001). “Other” race had the highest prevalence of overall liver diseases, followed by white, then black (eg, bipolar disorder, white [7.59%] versus black [4.33%] versus “other” [8.67%], P=.0007). The group 31–50 years of age had the highest percentage of patients with treated liver diseases (eg, bipolar disorder, age <30 [2.97%] versus 31–50 years of age [10.76%], versus >50 [7.38%], P<.0001).

 

Schizoaffective Disorder Group

A total of 2,056 schizoaffective disorder patients with schizophrenia-spectrum illnesses were identified, along with 8,224 subjects in the comparison group without mental illness. The mean age was 42.1 years in these patients and a higher percentage of male patients in the schizoaffective disorder group were observed. In the schizoaffective versus comparison group, the male percentage was 42.7% versus 25.3%. Approximately 19% of schizoaffective disorder patients with schizophrenia-spectrum illnesses had substance abuse, and these patients were more likely to have hypertension, diabetes, hyperlipidemia, and obesity than the comparison group without mental illness. In the schizoaffective versus comparison without mental illness, hypertension was 35.5% versus 32.8%, P=.0214; diabetes was 20.5% versus 18.6%, P=.0515; hyperlipidemia was 17.7% versus 15.4%, P=.0141; and obesity was 8.6% versus 6.0%, P<.0001.

Schizoaffective disorder patients with schizophrenia-spectrum illnesses had higher percentages of patients with various treated liver diseases, except for NAFLD, compared to the comparison group without mental illness after standardizing the age, gender, and race distribution of the two groups. In the schizoaffective versus comparison without mental illness, overall liver disease was 4.62% versus 4.12%, P<.0001; acute liver disease was 3.84% versus 3.37%, P<.0001; chronic liver disease was 4.57% versus 4.11%, P<.0001; viral hepatitis was 1.70% versus 1.27%, P<.0001; chronic cirrhosis was 1.12% versus 1.06%, P<.0001; and NAFLD was 1.31% versus 1.55%, P<.0001.

 

Discussion

In this study, claims data from the South Carolina State Medicaid program were used to evaluate the percentages of patients with treated liver diseases in Medicaid recipients with the diagnosis of schizophrenia (including schizoaffective disorder patients with schizophrenia-spectrum illnesses) or bipolar disorder as compared to those without diagnosis of mental illness. Results indicate that 4.64% of patients with schizophrenia and 6.96% with bipolar disorder had a diagnosis of liver disease, which is statistically significantly higher than Medicaid recipients without mental illness. Although the absolute difference in the prevalence rates observed between Medicaid recipients with schizophrenia and Medicaid recipients without mental illness is small, bias may be introduced when using Medicaid recipients without mental illness as the comparison group. The percentages of patients with treated liver diseases observed in Medicaid recipients with schizophrenia or bipolar disorder are approximately three to five times higher than the 1.3% reported prevalence of liver disease in the general population (National Health Interview Survey)35 and are more than 10 times higher than the 0.2% reported in the non-Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,36 disorder control group in a study by Carney and Jones.29 The percentages of patients with treated liver diseases found in this study are slightly <7.4%, as reported from a claim-based study which evaluated comorbid conditions among patients with schizophrenia in the Veterans Health Administration database.30

The authors of this study also found that the differences in the percentages of patients with treated liver diseases between the disease group and the comparison group without mental illness were larger for patients with bipolar disorder than those with schizophrenia. Higher percentages of patients with substance abuse and viral hepatitis observed in patients with bipolar disorder may account for this finding. The percentages of patients with NAFLD were also higher in the bipolar disorder group than the comparison group. Most patients with NAFLD are female and obesity is present in >50% of these patients.21 The bipolar cohort reflected higher percentages of female patients and obesity and may partially explain the observation.

The percentages of patients with treated liver diseases found in the two different samples of the comparison groups without mental illness were different (eg, the adjusted percentages of patients with treated liver diseases were 4.14% versus 2.66%). Since the percentages in the comparison groups were adjusted based on the demographic distribution of the disease groups, the differences observed are likely related to the differences in demographic distribution of these two samples.

It is surprising that the percentages of patients with substance abuse in schizophrenia patients (19.2%) and bipolar disorder patients (29.3%) was much lower than those reported in the literature.13  However, substance abuse is often underreported and underdiagnosed and may not be fully represented in claims data since treatment may be bundled and not readily recognized in the claims history.

The authors of this study found a higher proportion of male and black patients in the schizophrenia group, and a higher proportion of female and white patients in the bipolar disorder group. Some evidence suggests that clinicians may have a tendency to overdiagnose schizophrenia in some ethnic groups.36 It is unknown whether the differences in the diagnosis of schizophrenia and bipolar disorder observed in our study represent true differences among gender and race groups or if it results from clinician bias or cultural insensitivity. In addition, since the Medicaid population has a higher proportion of minority groups compared to the general population, the differences observed among gender and race groups in this study may be larger than other studies due to overrepresentation of minority population.

The true prevalence of liver diseases may be higher due to failure of asymptomatic cases to present for care. For example, HBV and HCV do not have subjective symptoms in most instances and many people may be unaware that they are infected with HBV and HCV.37 Cases with symptoms may be under-recognized because common complaints are often nonspecific (eg, fatigue, muscle ache, headache, abdominal discomfort).38 Seroprevalence rates of HBV and HCV have been reported16 and the prevalence of HBV (23.4%) and HCV (19.6%) found in that study was nearly 10 times higher than those observed in this study.

The findings of this research may have important implications for the management of mentally ill patients. Clinicians should consider hepatic issues when treating patients with mental illness who are at higher risk for liver disease. In addition to addressing treatment issues such as psychotic symptoms, clinicians could better serve their patients by evaluating and monitoring risk factors and clinical indications of liver disease. Clinicians should be aware that hepatic disease may impair the liver’s synthetic function, resulting in alterations in the protein binding and the bioactivity of various treatments. Further, when severe, hepatic compromise may also affect drug metabolism. As a result, dose adjustment of most antipsychotics is often necessary in these patients. Liver diseases may reduce antipsychotic treatment options for these patients and clinical consideration of medications that place a lower metabolic burden on the liver may present a viable treatment option for some patients.

This study has some limitations. Claims database are not well suited to address epidemiology questions, and the true prevalence rate of liver diseases was not evaluated in the study. Medicaid data are confounded by people moving in and out of the system who may not be fully captured. In addition, some individuals at high risk for medical comorbidities, such as those who are homeless, may not have acquired Medicaid coverage. Further, the findings of this study were based on data from the South Carolina State Medicaid program and may not be generalizable. Similar studies in different populations or study settings would be useful to provide context for these findings. Because the data were collected for reimbursement rather than clinical purposes, it is possible that some diseases experienced by the members may be misclassified or omitted from the database. The authors’ strategy of using at least one hospital claim or two ambulatory claims for liver disease-related ICD-9-CM codes to identify study participants was aimed toward minimizing misclassification of liver conditions. Finally, claims databases generally lack clinical details, and the classification of various types of liver diseases may not be accurate.

 

Conclusion

In this study, Medicaid recipients with schizophrenia or bipolar disorder showed higher percentages of treated liver diseases than non-mentally ill Medicaid recipients, and the percentages observed were also higher than the prevalence rate reported for the general population. The differences in the percentages of patients with treated liver diseases between the disease group and the comparison group without mental illness were larger for patients with bipolar disorder than with schizophrenia. The true prevalence of liver diseases may be higher than that observed due to failure of asymptomatic cases to present for care. Clinicians should consider hepatic issues when treating patients with mental illness who are at higher risk for liver disease. PP

 

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