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Hepatitis C–associated late-onset schizophrenia: a nationwide, population-based cohort study

Background: Whether infection with the hepatitis C virus (HCV) causes schizophrenia — and whether the associated risk reverses after anti-HCV therapy — is unknown; we aimed to investigate these topics. Methods: We conducted a nationwide, population-based cohort study using the Taiwan National Health Insurance Research Database (TNHIRD). A diagnosis of schizophrenia was based on criteria from the International Classification of Diseases, 9th revision (295.xx). Results: From 2003 to 2012, from a total population of 19 298 735, we enrolled 3 propensity-score-matched cohorts (1:2:2): HCV-treated (8931 HCV-infected patients who had received interferon-based therapy for ≥ 6 months); HCV-untreated (17 862); and HCV-uninfected (17 862) from the TNHIRD. Of the total sample (44 655), 82.81% (36 980) were 40 years of age or older. Of the 3 cohorts, the HCV-untreated group had the highest 9-year cumulative incidence of schizophrenia (0.870%, 95% confidence interval [CI] 0.556%–1.311%; p < 0.001); the HCV-treated (0.251%, 95% CI 0.091%–0.599%) and HCV-uninfected (0.118%, 95% CI 0.062%–0.213%) cohorts showed similar cumulative incidence of schizophrenia (p = 0.33). Multivariate Cox analyses showed that HCV positivity (hazard ratio [HR] 3.469, 95% CI 2.168–5.551) was independently associated with the development of schizophrenia. The HCV-untreated cohort also had the highest cumulative incidence of overall mortality (20.799%, 95% CI 18.739%–22.936%; p < 0.001); the HCV-treated (12.518%, 95% CI 8.707%–17.052%) and HCV uninfected (6.707%, 95% CI 5.533%–8.026%) cohorts showed similar cumulative incidence of mortality (p = 0.12). Limitations: We were unable to determine the precise mechanism of the increased risk of schizophrenia in patients with HCV infection. Conclusion: In a population-based cohort (most aged ≥ 40 years), HCV positivity was a potential risk factor for the development of schizophrenia; the HCV-associated risk of schizophrenia might be reversed by interferon-based antiviral therapy.


Introduction
Hepatitis C virus (HCV) is a human pathogen responsible for acute and chronic liver disease that infects an estimated 150 million people worldwide, 1 with an estimated global prevalence of 2.8%. 2 HCV infection is considered a systemic disease. In addition to causing hepatic complications such as steatosis, cirrhosis and hepatocellular carcinoma, HCV also causes extrahepatic complications, including mixed cryo globu linemia, renal diseases, 3 hypolipidemia, diabetes melli tus, obesity, cardiovascular disease 1 and neurologic and psychi atric events. 4 Neuropsychiatric disorders have been re ported in up to 50% of patients with chronic HCV infection, independ ent of the severity of the underlying liver disease. 4 Schizophrenia is a debilitating psychiatric illness that affects approximately 1.1% of the world's population, amounting to approximately 51 million people. 5 The lifetime prevalence of schizophrenia is approximately 1%, and it commonly follows a chronic course, with onset in late adolescence. 6 Schizophre nia contributes to a substantial chronic medical burden and a lifespan that is approximately 15 years shorter than the gen eral population. 7 The diverse clinical manifestations of schizo phrenia include cognitive, emotional and behavioural abnor malities. 6 Current treatments for schizophrenia target mainly psychotic symptoms, do little to ameliorate social or cognitive deficits, and come with adverse effects such as weight gain and diabetes; as well, 30% of people do not respond to them. 8 The relationship between schizophrenia and HCV infec tion has been investigated, but findings have been conflict ing. For example, a US study by the Veterans Integrated Services Network showed that patients with schizophrenia had a higher prevalence of HCV infection than the general population (16.5% v. 1.9%). 9 Similarly, reported HCV infec tion rates in patients with schizophrenia are 6.2% in Japan 10 J Psychiatry Neurosci 2021;46(6) and 7.1% and 8.2% in the United States, 11,12 higher than the estimated global HCV prevalence (2.8%). 2 In contrast, a study showed that the seroprevalence of the HCV antibody was 1.9% in institutionalized patients with chronic schizo phrenia, 13 and another case-control study showed that the concurrent HCV infection rate was 2.1% in patients with schizophrenia 14 -both similar to the prevalence of HCV in the general population. The situation is complicated further when the therapeutic effects of antiHCV treatment are con sidered. The combination of pegylated interferon (PEGIFN) and ribavirin has provided a "cure" for a considerable pro portion of patients with chronic HCV infection, particularly patients with the favourable interferon λ 3 (IFNL3) geno type. 15 Cure rates have been further improved by replacing interferonbased therapy with potent directacting antiviral agents (DAAs). 1 The rate of sustained virological response (SVR) to DAAs in HCVinfected patients is approximately 100%. 16 Still, although most HCV infections are currently curable with potent DAAs, not all HCV associated compli cations are reversed after viral clearance. 1,17 Thus, whether HCV infection accelerates the risk of developing schizo phrenia and whether the associated risk is reversed after antiHCV therapy remain crucial issues for public health in an era when HCV infection can be cured using DAAs.
We conducted a nationwide population-based cohort study to investigate the effects of HCV infection on the devel opment of schizophrenia in Taiwan, a country where HCV infection is rampant. 18 We investigated the impact of HCV in fection on schizophrenia by comparing the cumulative inci dence of schizophrenia and of overall mortality among HCV infected people with and without antiHCV therapy, and among people without HCV infection.

Samples and measurements
This populationbased retrospective cohort study used nationallevel data from the Taiwan National Health Insur ance Research Database (TNHIRD), including the National Health Insurance (NHI) administrative database, the cancer registry database and the death registry database. The man datory, singlepayer NHI program provides comprehensive coverage of ambulatory care, laboratory tests, hospital ser vices and prescription drugs. More than 99% of the popula tion is enrolled in the program, and approximately 92% of health care organizations are contracted with the NHI ad ministration. We did not enrol patients who had schizophre nia before they started antiHCV treatment in the HCV treated cohort, or before baseline in the other cohorts. Because Taiwan is a hyperendemic area for hepatitis B virus infection, which profoundly affects HCV viral load and bias es the phenotype of HCV infection, 19 we excluded pa tients who were infected with hepatitis B virus during the observation period (2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012). We also excluded patients with cirrhosisrelated complications such as hepatoencepha lopathy, esophageal varices, ascites or hepatorenal syn drome to avoid interference from complications or from as sociated treatments. In particular, given that some infections such as toxoplasmosis, 20,21 Chlamydophila pneumoniae, 22 lym phocytic choriomeningitis virus 23 and herpes simplex virus type 1 24 have been reported to affect the development of schizophrenia, we excluded patients with these infections.
The HCVtreated cohort included patients who had an HCV RNA test and received ribavirin and PEGIFN between 2003 and 2012. The date of their first HCV test was assumed to be the index date of their diagnosis. Baseline for the HCV treated cohort was 6 months after they had completed combi nation therapy, which is the time to ensure SVR. Only those who had undergone antiHCV therapy for 6 months or more were enrolled. The HCVuntreated cohort included patients who had an HCV test (HCV antibody or HCV RNA test; their first HCV test was the index date); were diagnosed with hepatitis C ( ; were prescribed a hepato protective agent (silymarin, liver hydrolysate, choline bitar trate or ursodeoxycholic acid); and did not receive any anti HCV therapy (ribavirin or PEGIFN). The HCV uninfected cohort included those who had no diagnosis of HCV and no HCV test, and who received no hepatoprotective agents or antiHCV therapy. Only those without schizophreniarelated NHI claims at least 2 years before baseline were included in the 3 cohorts.
We matched the HCVtreated cohort with the HCV untreated and HCVuninfected cohorts (1:2:2) using a p ropensity score-matching method that indicated the prob ability of receiving combination therapy and was estimated using a logistic model. Covariates in the model included age group (20-39, 40-49, 50-59, ≥ 60 years), sex (male, fe male), NHI registration location (urban, township, rural), Charlson Comorbidity Index score (0, 1, ≥ 2) 25 and the year of the index date (2003-2006, 2007-2009, 2010-2012). We used this method to ensure that the HCVtreated cohort and their selected counterparts were comparable in terms of ob served characteristics. We assigned the baseline for the HCVuntreated and HCVuninfected cohorts according to the period from the index date to baseline (6 months after treatment completion) for their matched counterparts. The index date for those in the HCVuninfected cohort was the date of a physician visit randomly selected from their claims database. The matching process for the 3 cohorts is shown in Appendix 1, Figure S1, available at jpn.ca. Out comes were the development of schizophrenia or mortality. Schizophrenia was defined as follows: at least 1 hospitaliza tion with a schizophrenia diagnosis (ICD9CM code 295.xx); at least 2 outpatient visits with a schizophrenia diag nosis; or at least 1 outpatient visit with a schizophrenia diagnosis and at least 1 antipsychotic prescription within 1 year. Patients were followed until the date of an event (schizophrenia), death or the end of followup (December 31, 2012), whichever came first. For the HCVtreated group, we recorded only schizophrenia diagnoses or death that occurred more than 6 months after the completion of anti HCV therapy. Dates of death were taken from the death registry database.

Statistical analysis
We performed all statistical analyses using SAS statistical software (version 9.4; SAS Institute Inc.). We estimated cumu lative incidences of outcomes and compared them using the modified Kaplan-Meier method and the Gray method; death was a competing risk event. 26 We used Cox proportional hazards models, taking competing mortality into account, to estimate adjusted hazard ratios for develop ing schizophrenia -adjusting for age; sex; the interaction of age and sex; NHI registration location; Charlson Comorbid ity Index score; year of index date; and the baseline presence of liver cirrhosis, chronic obstructive pulmonary disease, endstage renal disease, diabetes mellitus, hypertension, dys lipidemia, cardiovascular events (including percutaneous coronary intervention, coronary artery bypass graft, myocar dial infarction, heart failure, cardiogenic shock and periph eral vascular disease) and stroke. We checked and confirmed proportionality assumptions using timedependent explana tory variables. We checked for multicollinearity and ex cluded variables that were highly correlated with other vari ables. We conducted a post hoc power analysis to assess the powers of the tests used in this study. Statistical significance was set at 5% based on 2tailed tests of the null hypothesis.

Institutional review board
The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the local institutional review board.

Baseline characteristics
From a total of 19 298 735 patients registered in the TNHIRD database between January 1, 2003, and December 31, 2012, 112 680 patients with HCV infection and 11 686 609 patients without HCV infection were eligible for the study. We en rolled patients in 1 of 3 cohorts: HCVtreated (n = 8931), HCVuntreated (n = 17 862) and HCVuninfected (n = 17 862; Figure 1). The 3 cohorts were matched using propensity scores and did not differ in terms of demographic factors, NHI registration location, Charlson Comorbidity Index score or index year -the covariates used to calculate propensity scores in the models; baseline comorbidities differed. Of the total sample (n = 44 655), 82.81% (n = 36 980) were age 40 years or older (Table 1). Compared to the HCVuntreated cohort, the HCVtreated cohort had higher rates of baseline cirrhosis but lower rates of endstage renal disease, diabetes mellitus, hypertension, dyslipidemia, cardiovascular events and stroke. Compared to the HCVuninfected cohort, the HCVtreated cohort had higher rates of baseline cirrhosis, chronic obstructive pulmonary disease and endstage renal disease, but lower rates of dyslipidemia and stroke. Com pared to the HCVuninfected cohort, the HCVuntreated co hort had higher rates of all baseline comorbidities except stroke. To delineate which complications were associated with HCV infection, we compared baseline factors between an HCVinfected cohort (a combination of the HCVtreated and HCVuntreated cohorts) and the HCVuninfected cohort. The HCVinfected cohort had higher rates of all baseline comorbidities, except for dyslipidemia and stroke (Appendix 1, Table S1).

Cumulative incidence of schizophrenia and associated risk factors
We followed the 3 cohorts (HCVtreated, HCVuntreated and HCVuninfected until death, for a duration of up to 9.5 years). The results of the post hoc power analysis for the various comparisons were greater than 0.8 (Appendix 1, Table S2). Of the 3 cohorts, the HCVuntreated cohort had the highest cumulative incidence of schizophrenia ( Figure 2, Table 2). However, we observed no difference in cumulative incidence of schizophrenia between the HCVtreated and HCVuninfected cohorts. Multivariate analysis of the 3 co horts showed that the HCVuntreated cohort had a higher risk of developing schizophrenia than the HCVtreated and HCVuninfected cohorts, and that patients with baseline stroke had borderline higher risk than those without baseline stroke (Appendix 1, Figure S2).
Because the HCVtreated and HCVuninfected cohorts showed similar risks of developing schizophrenia, we com bined these cohorts into an HCVnegative cohort to explore the effect of HCV on the development of schizophrenia. Compared to the HCVnegative cohort, the HCVpositive (i.e., HCVuntreated) cohort had a higher risk of incident schizophrenia (p < 0.001; Appendix 1, Table S3). Multivariate analyses of these 2 cohorts showed that HCV positivity (haz ard ratio 3.469, 95% confidence interval [CI] 2.168-5.551) was an independent risk factor for the development of schizo phrenia (Figure 3).

Discussion
The differences in baseline comorbidities between the HCV treated and HCVuntreated cohorts coincided with the fact that only patients with significant hepatic fibrosis were re imbursed for antiHCV therapy, and those with severe comorbidities were ineligible for interferonbased therapy. The differences in comorbidities between the HCVinfected and HCVuninfected cohorts reflected the fact that HCV is associated with cardiometabolic complications and that people infected with HCV are less likely to have dyslipid emia. 1 Thus, our baseline comparisons of the 3 cohorts sup ported the reliability of the results from the TNHIRD.

J Psychiatry Neurosci 2021;46(6)
Although high HCV infection rates have been noted in patients with schizophrenia, the data are conflicting, [9][10][11][12][13][14] and high comorbidity with intravenous substance use 11 or old age 10 in patients with schizophrenia has been thought to account for the high HCV prevalence in this population.
The present study clearly demonstrated that HCV infec tion increased the risk of incident schizophrenia: the HCV untreated cohort had the highest cumulative incidence of schizophrenia of the 3 cohorts, and multivariate analyses showed that HCV infection was positively associated with  E587 the development of schizophrenia. Previous findings that pa tients with schizophrenia had a higher prevalence of chronic liver disease than the general population, and comorbidity with diabetes was the primary risk factor for patients with schizophrenia to develop chronic liver disease, 9,27 endorse a causal relationship between HCV infection and schizophre nia, because HCV infection is a main cause of both chronic liver disease and diabetes. 1 Although schizophrenia is a psychi atric disorder with high heritability, the etiology of schizophrenia is complex and involves a complicated inter play of genetic and environmental factors. 28 Infection, obstet ric complications, urbanicity, cannabis and trauma have all been shown to interact with genetic risk. 29 With respect to in fection, associations between schizophrenia and toxoplasmo sis, herpes or influenza have been reported, [20][21][22][23][24]28 and we eliminated patients with these infections to avoid any con founding effects. Interestingly, 8% of the human genome consists of human endogenous retroviruses (HERVs) and a specific HERV -HERVW -has been linked with schizo phrenia. 28 A lifelong scenario of a detrimental interaction be tween infectious agents and HERVW genes may cause the development of schizophrenia. 29 The evidence of direct neuro invasion of HCV, particularly in cells of the macro phage or monocyte lineage, 30 suggest the possibility that HCV interacts with HERVW in initiating the development of schizophrenia. As well, inflammation, oxidative stress 31 and disturbances in neurotransmitter, metabolism, immunity and adipokine homeostasis 32 may play important roles in eliciting schizophrenia. HCV infection consistently causes significant alterations in metabolism, 1,33,34 neurotransmitter, 34 immunity, adipokine 15 and oxidative stress profiles 1,33,34 in the hosts, reflecting the potential link between HCV and schizo phrenia. It is important to note that the typical age of onset for schizophrenia is late adolescence or the early 20s, 6 whereas most of the patients in our study (82.81%) were aged 40 years or older. That is, most of the diagnoses of schizo phrenia in the present study occurred after age 40 years, be cause only those with no schizophreniarelated claims at least 2 years before baseline were enrolled. This finding was in line with the fact that the HCV infection rate is highest for adults older than 35 years, 35 because the present study was based on propensity score-matched HCVpositive and HCVnegative cohorts. The late onset of schizophrenia in these patients thus might not be generalizable for patients with schizophrenia and requires further investigation. Although interferonbased antiHCV therapy in patients with schizophrenia has yielded negligible worsening psychi atric symptoms and the therapeutic response rate for people with schizophrenia is similar to that of the general popula tion, 36 schizophrenia is still a predictive factor for not treating  HCV infection because of concerns about interferonrelated neuropsychiatric adverse effects. 37 We stress that the HCV associated risk in incident schizophrenia might be reversed by interferonbased antiHCV therapy, because the cumula tive incidence of schizophrenia in the HCVtreated cohort was lower than that of the HCVuntreated cohort and similar to that of the HCVuninfected cohort. However, whether the reversal of HCVassociated risk in schizophrenia is universal for all antiHCV regimens (including DAAs) or is specific to interferonbased therapy requires further investigation. Moreover, the HCVuntreated cohort in the present study had the highest risk of overall mortality among the 3 cohorts. It is likely that this finding was at least partly attributable to HCVassociated systemic complications. [1][2][3][4] As well, people with schizophrenia are at greater risk for morbidity and mor tality as a result of cardiovascular disease 38 and stroke 39 than the general population. Thus, mortality is high for those with schizophrenia and HCV infection. 40 These findings point to the importance of prescribing antiHCV therapy in all HCV infected patients regardless of schizophrenia status (unless contraindicated), particularly in the era of DAAs, which can cure HCV infection. In addition to HCV infection, stroke was borderline positively associated with the development of incident schizophrenia. Schizophrenialike psychosis after stroke is common and severely affects quality of life. 41 Pre existing subcortical atrophy and a lesion location in the right hemisphere 42 -particularly in the frontal, temporal and pari etal regions and the right caudate nucleus 41 -are risk factors for poststroke schizophrenialike psychosis.

Limitations
The current study had several limitations. First, because the TNHIRD did not contain direct laboratory results, it was im possible to explore a correlation between schizophrenia and SVR to antiHCV therapy. However, we were confident of anti viral efficacy in the HCVtreated cohort because interferonbased therapy generally achieves a high SVR in Taiwan (up to 82.7%), 15 where a favourable IFNL3 genetic variation for interferonbased therapy response is prevalent. 15 Second, there might have been some patients with undiag nosed HCV infection in the HCVuninfected cohort. How ever, given that reimbursement for antiHCV therapy is nationwide and only 2.7% of the Taiwanese were likely to be  infected with HCV, 43 the rate of undiagnosed HCV infection in the HCVuninfected cohort was probably negligible and likely would not bias our results. Third, information about important risk factors for schizophrenia, including genetic susceptibility, were lacking in the TNHIRD and the effect of these risk factors on schizophrenia could not be assessed. Fourth, we were un able to determine the precise mechanism of the increased risk of schizophrenia in patients with HCV infection. Future pro spective studies in other independent cohorts with identifiable SVR following DAAbased antiHCV therapy, comprehensive surveys of risk factors, wellstratified patient subpopulations and sophisticated molecular or animal investigations are needed to elucidate the fundamental mechanisms that under lie the findings described here.

Conclusion
Taken together, the findings of the present study confirmed that in a population aged mostly 40 years and older, HCV positivity is a positive risk factor for incident schizophrenia, and that the risk may be reversed with interferonbased anti viral therapy. In the era of DAAs to eliminate HCV infection, antiHCV therapy should be prescribed for all people infected with HCV to reduce the risk not only of hepatic com plications, but also of extrahepatic complications, includ ing schizophrenia.