|
| |
 |
|
| ORIGINAL ARTICLE |
|
| Year : 2022 | Volume
: 36
| Issue : 4 | Page : 182-187 |
|
Protective effect of interferon-based antiviral therapy on risk of bipolar disorder in patients with hepatitis C Virus infection: A nationwide longitudinal study
Mu- Hong Chen M.D., Ph.D 1, Shih- Jen Tsai M.D 1, Tzeng- Ji Chen M.D., Ph.D 2
1 Department of Psychiatry, Taipei Veterans General Hospital; Department of Psychiatry, College of Medicine, National Yang Ming Chiao Tung University; Institute of Brain Science, National Yang-Ming Chiao Tung University, Taipei, Taiwan
2 Department of Family Medicine, Taipei Veterans General Hospital; Institute of Hospital and Health Care Administration, National Yang-Ming Chiao Tung University, Taipei; Department of Family Medicine, Taipei Veterans General Hospital, Hsinchu Branch, Hsinchu, Taiwan
| Date of Submission | 28-Oct-2022 |
| Date of Decision | 18-Nov-2022 |
| Date of Acceptance | 19-Nov-2022 |
| Date of Web Publication | 27-Dec-2022 |
Correspondence Address:
Mu- Hong Chen
No. 201, Shih-Pai Road, Section 2, Taipei 112
Taiwan
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/TPSY.TPSY_37_22
Background: A recent study has shown the beneficial effects of interferon (IFN)-based antiviral therapy (AVT) in reducing the risk of newly diagnosed depression among patients with hepatitis C virus (HCV) infection. But whether IFN-based AVT reduces the risk of bipolar disorder remains unknown. Methods: This is a retrospective study based on the Taiwan National Health Insurance Research Database. From enrollment to the end of 2013, 24,240 patients with HCV infection (4473 treated with IFN-based AVT and 19,767 without such treatment) as well as 96,960 age- and sex-matched controls were included in this study. Time-dependent Cox regression models were used to study the differences in risk of newly-diagnosed bipolar disorder between patients being treated with and without IFN-based AVT and the control participants. Results: Patients with HCV infection who had not yet received IFN-based AVT (hazard ratio = 4.86, 95% confidence interval = 1.87–12.66, p = 0.001), but not those who were receiving IFN-based AVT (1.69, 0.94 - 30.50, nonsignificance) and those who completed the IFN-based AVT (1.77, 0.69 - 4.54, nonsignificance), were significantly more to be diagnosed with bipolar disorder compared with the control group. Conclusion: Our study supports the temporal association between HCV infection and subsequent bipolar disorder, further suggesting that the optimal AVT to eradicate HCV may be associated with a reduced risk of incident bipolar disorder later in life.
Keywords: depression, inflammation, temporal association, the Taiwan National Health Insurance Research Database
How to cite this article:
Chen MH, Tsai SJ, Chen TJ. Protective effect of interferon-based antiviral therapy on risk of bipolar disorder in patients with hepatitis C Virus infection: A nationwide longitudinal study. Taiwan J Psychiatry 2022;36:182-7 |
How to cite this URL:
Chen MH, Tsai SJ, Chen TJ. Protective effect of interferon-based antiviral therapy on risk of bipolar disorder in patients with hepatitis C Virus infection: A nationwide longitudinal study. Taiwan J Psychiatry [serial online] 2022 [cited 2023 Mar 22];36:182-7. Available from: http://www.e-tjp.org/text.asp?2022/36/4/182/365335 |
| Introduction | |  |
Hepatitis C virus (HCV) is a hepatotropic RNA virus that causes progressive liver damage and infects more than 170 million individuals worldwide[1],[2]. Patients with chronic HCV infection are at high risk of developing life-threatening complications. For example, cirrhosis occurs in 20% of cases and hepatocellular carcinoma has an incidence of 4%–5% per year in patients with cirrhosis[2]. In addition to the hepatic complications, HCV infection is also associated with extrahepatic complications, such as insulin resistance, type 2 diabetes mellitus, neurodegenerative disorders, and depression[2],[3],[4].
Increasing evidence suggests a relationship between HCV infection and bipolar disorder, which is a recurrent, chronic, and severe affective disorder that manifests as alternating episodes of mania or hypomania and depression[5],[6],[7]. In one study, the investigators assessed the prevalence of HCV infection among 931 patients with severe mental disorders (schizophrenia and bipolar disorder) and found that up to 20% of patients are infected with HCV, which is about 11 times the overall estimated rate among the population[7]. Chong et al. showed that patients with HCV infection only (hazard ratio [HR] = 1.93, 95% confidence interval [CI] = 1.07–3.48) or with HCV and HIV coinfection (HR = 3.22, 95% CI = 1.64–6.32) are more likely to develop the bipolar disorder during follow-up than those without diagnoses of viral hepatitis and HIV infection[8]. A meta-analysis of 28 studies on 14,888 patients with severe mental disorders for HCV showed a prevalence of 17.4% in North America and 4.4% in Asia, being higher than the 1% prevalence seen in the general population[2]. However, most previous studies are cross-sectional, thus confounding the investigation of the temporal association between HCV infection and bipolar disorder.
In current clinical practice, interferon (IFN)-based antiviral treatment (AVT) is a standard treatment for HCV infection, being able to reduce HCV-related intra- and extrahepatic complications, including stroke and Parkinson's disease[9],[10],[11]. Hsu et al. compared the risk of ischemic stroke between patients with HCV being treated with and without IFN-based AVT and found that AVT is associated with a lower risk of ischemic stroke (HR = 0.62; 95% CI = 0.46 - 0.83)[9]. Lin et al. demonstrated that among patients with HCV infection, IFN-based AVT reduced the risk (HR = 0.75; 95% CI = 0.59 - 0.96) for Parkinson's disease at the 5-year follow-up[11]. However, IFN-related treatment can be a double-edged sword with having benefits and risks for mood disorders[12],[13]. Assessing 200 HCV-infected patients starting IFN-based AVT for 24 weeks, Su et al. found that 59 (30%) patients have developed IFN-α-induced depression during the IFN-based AVT[12]. They further found that IFN-α-induced depression is associated with more somatic symptoms and fewer symptoms of mood, anxiety, and negative cognition[12]. A murine BV-2 microglia cell line study showed that IFN-α induces nitric oxide synthase expression and haem oxygenase-1 down-regulation, which may play a crucial rôle on the development of IFN-α-induced depression[14]. On the contrary, Sun et al. revealed that the HR for incident depressive disorder is 0.79 (95% CI = 0.72 - 0.87) for patients with HCV treated with IFN-based AVT compared with untreated patients[10]. But whether IFN-based AVT reduces the risk of bipolar disorder among patients with HCV infection remains unknown.
Based on the evidence of an association between HCV infection and bipolar disorder as well as the potential neuroprotective effect of IFN-based AVT, we used the Taiwan National Health Insurance Research Database (NHIRD) with a large sample size and a longitudinal study design and intended to study the risk of newly diagnosed bipolar disorder after HCV infection. We also intended to clarify whether IFN-based AVT reduces this risk. We hypothesized that HCV infection would be related to an elevated likelihood of subsequent bipolar disorder and that this risk could be reduced through the administration of the optimal IFN-based AVT.
| Methods | | |
Data source for study patients
In the current study, we analyzed the data from the Taiwan National Health Insurance Research Database (NHIRD), i.e., the Longitudinal Health Insurance Database. Established for research purposes and audited by the Ministry of Health and Welfare and the Bureau of the NHI program, the NHIRD contains comprehensive medical information between 1996 and 2013 about the insured patients, including demographics (birthdate, sex, residential location, and income status), clinical visits (dates and diagnoses), medical assessment (laboratory examination), and interventions (prescriptions). Each patient is assigned a unique and anonymous identifier upon enrollment by the NHI, which allows researchers to follow their diseases and outcomes. Claims data of subjects included in the NHIRD are anonymous to protect individual privacy. Diagnoses were captured using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). The NHIRD has been used extensively for epidemiologic studies[15],[16],[17],[18]. The study protocol was approved by the Taipei Veterans General Hospital institutional review board (IRB protocol number = 2018-07-016AC and date of approval = July 23, 2021) with the waiver of the requirement for any informed consents.
Inclusion criteria for patients with hepatitis C virus
We included adolescent patients aged between 10 and 19 years and adult patients ≥ 20 years who were diagnosed with HCV (ICD-9-CM codes: 070.41, 070.44, 070.51, 070.54, V02.62) given by board-certified physicians after the real-time PCR HCV genotyping test between January 1, 1997, and December 31, 2012, and those without any history of major psychiatric disorder (ICD-9-CM codes: 295 for schizophrenia, 296 for affective disorder) before their HCV diagnoses in this HCV cohort. Excluded from this study cohort were patients with a diagnosis of hepatitis B virus (HBV) infection (ICD-9-CM: 070.2, 070.3, V02.61), human immunodeficiency virus (HIV) infection (ICD-9-CM: 042–044, V08).
Interferon-based antiviral therapy
The regimen of IFN-based AVT is a combination of pegylated IFN α-2b and ribavirin[11],[19]. The adequate IFN-based AVT was defined as receiving at least a 16-week course AVT in this study. The duration of IFN-based AVT ranged from 16 to 48 weeks. In clinical practice, the duration of IFN-based AVT mainly depends on the serum virologic response and the adverse effects of treatment. Less than 16 weeks of an IFN-based AVT has been suggested as inadequate and premature termination of therapy[11],[19].
Selection of matched controls
Exact matching was used to match this cohort in a 1:4 fashion to controls without diagnoses of neither HCV, HBV, and HIV nor major psychiatric disorder before the enrollment on the bases of age (±1 year), sex, enrollment time, medical comorbidities, income level, and urbanization level of residence (levels 1-5, most to least urbanized), a proxy for health-care availability in Taiwan[20]. Medical comorbidities, such as hypertension, dyslipidemia, diabetes mellitus, obesity, smoking, alcohol use disorder, substance use disorder, and cerebrovascular diseases, were assessed[21],[22],[23],[24]. In addition, Charlson Comorbidity Index (CCI) and all-cause clinical visits were provided for the HCV and the matched-control cohorts. CCI consisting of 22 physical conditions was also assessed to determine the systemic health conditions of all enrolled subjects[25]. All-cause clinical visits (the numbers of clinical visits per year) for the HCV cohort and the matched-controls cohort were included to account for potential detection bias.
Outcome assessment
Diagnosis of bipolar disorder (ICD-9-CM codes: 296 except 296.2x, 296.3x, 296.9x, and 296.82) was given by board-certified psychiatrists at least twice during the follow-up period (from enrollment to December 31, 2013, or until death).
Statistical analysis
For between-group comparisons, the F-test was used for continuous variables and Pearson's chi-square test for nominal variables. Stratified Cox-regression analyses on each matched-pair (the patient and their four matched controls in a 1:4 ratio) with adjustment for age, CCI score, and all-cause clinical visits were applied to investigate the bipolar disorder risk between HCV and control groups. In order to avoid the immortal time bias, IFN-based AVT was treated as a time-dependent variable in the regression models: before or never IFN-based AVT, during IFN-based AVT, and after IFN-based AVT. In addition, the sex effect was also clarified in our study.
Data processing and statistical analyses were done with Statistical Analysis System (version 9.1, SAS Institute, Cary, North Carolina, USA). Statistical significance was set at two-tailed p ≤ 0.05.
| Results | | |
We included 24,240 patients with HCV infection and 96,960 demographic characteristics- and comorbidities-matched controls in the current study, with a mean age of 55 years and equal sex distribution [Table 1]. Among patients with HCV infection, 4,473 (18.5%) were ever treated with IFN-based AVT and 19,767 (81.5%) were not [Table 1]. Compared with the control group, patients with HCV infection significantly had a higher incidence of subsequent newly diagnosed bipolar disorder (0.42% vs. 0.04%, p < 0.001), higher CCI scores (3.82 ± 2.60 vs. 2.36 ± 2.29, p < 0.001), and greater numbers of all-cause clinical visits (23.68 ± 19.35 vs. 15.75 ± 14.75, p < 0.001) [Table 1]. | Table 1: Demographic data and incidence of bipolar disorder among patients with hepatitis C virus and control group
Click here to view |
Stratified Cox-regression analyses with adjustment of age, CCI score, and all-cause clinical visits and with IFN-based AVT as time-dependent variable showed that only patients with HCV infection who have not yet received IFN-based AVT (HR = 4.86, 95% CI = 1.87-12.66) were significantly more been diagnosed with bipolar disorder compared with the control group [Table 2]. Patients with HCV infection who were receiving IFN-based AVT (HR =1.69, 95% CI = 0.94-30.50) and those who completed the IFN-based AVT (1.77, 0.69-4.54) were not associated with the risk of newly-diagnosed bipolar disorder [Table 2]. Findings of an association between before/never IFN-based AVT and bipolar disorder risk were consistent in HCV-infected men (HR = 3.90, 95% CI = 1.17-13.01) and women (HR = 8.09, 95% CI = 1.53- 42.94) [Table 2]. | Table 2: Risk of developing bipolar disorder among patients with hepatitis C virus and controls
Click here to view |
| Discussion | | |
Our findings support the study hypotheses that patients with HCV infection are more likely to develop the newly-diagnosed bipolar disorder later in life than are the control group [Table 1]. This increased risk of bipolar disorder may be neutralized through the administration of the optimal IFN-based AVT [Table 2].
The prevalence of HCV infection and comorbid severe mental disorders, such as schizophrenia and bipolar disorder, is high (up to 20%)[5],[6],[7]. A recent study examined 34,459 patients with HBV infection, 9,893 patients with HCV infection and 3,863 patients with HBV/HCV coinfection and determined that patients with HBV/HCV coinfection had the highest risk (HR = 3.22, 95% CI = 1.64–6.32) of incident bipolar disorder, patients with HCV infection had the second highest risk (HR = 1.93, 95% CI = 1.07–3.48), and those with HBV infection had the lowest risk (HR = 1.95, 95% CI = 1.09 - 2.25) compared with non-HBV/HCV comparison group[8]. Our findings corroborate the findings of Chong et al.[8] and support the relationship between HCV infection with an increased risk of incident bipolar disorder. Neuroimaging studies of patients with HCV infection may have found a partial explanation of the temporal association between HCV infection and subsequent development of bipolar disorder[26],[27]. McCready et al. used functional magnetic resonance imaging (fMRI) and evaluated reward-related functioning, which is commonly impaired in bipolar disorder, to investigate brain activation; the delay discounting task (DDT) was done by patients with HCV infection, and in fMRI, those with HCV infection exhibited less activation in the superior frontal cortex and precuneus than did the controls[26]. Moreover, patients with HCV with high viral loads were more impulsive in the DDT than those with low viral loads, which indicated that HCV-related impulsivity was negatively related to activation in brain regions important for cognitive control, such as the frontal cortex[26]. Hjerrild et al. compared the cortical thickness of 43 patients with HCV but without liver fibrosis, substance abuse, or comorbid HIV or HBV infection and 43 controls; they reported that areas of reduced cortical thickness have particularly been found in the left frontal lobe[27]. A perfusion-weighted MRI study has further confirmed the neurotoxicity of HCV toward the frontal cortex; patients with HCV infection have shown significantly lower relative cerebral blood volume values within the frontal cortex[28]. The frontal cortex, which works as a modulator of affective and cognitive functioning, has been regarded as the core region involved in the neuropathophysiology of bipolar disorder[29],[30]. We suggest that HCV infection takes time to impair the specific brain function and neural circuitry involved in emotional regulation and cognition, especially in the frontal cortex, which may explain the sequential phenomenon of HCV infection being followed by bipolar disorder.
Our study [Table 2] is the first to suggest a beneficial effect of IFN-based AVT on the risk of newly-diagnosed bipolar disorder among patients with HCV infection. Furthermore, our study results indicate that HCV patients being treated with IFN-based AVT exhibit a similar likelihood of newly-diagnosed bipolar disorder during follow-up as the control group. By assessing the neurocognitive and neurostructural changes among patients with HCV infection before and after IFN-based AVT, Kuhn et al. found that patients with HCV infection experience improvements in cognitive functioning following eradication of HCV, which is related to positive changes in white matter integrity of the superior longitudinal fasciculus[31]. Bladowska et al. further indicated that AVT improves the integrity of bilateral inferior fronto-occipital fascicles and increases the cerebral perfusion in bilateral basal ganglions among patients with HCV infection, which may explain the improved functioning of frontostriatal regions after AVT[32]. In addition to the normalization of neurofunctioning in the frontal cortex and basal ganglion region after HCV eradication therapy, IFN-based AVT may neutralize the pro-inflammatory cytokine storm caused by HCV infection, which is also commonly observed in major depressive disorder and bipolar disorder[33],[34],[35]. Our pro-inflammatory cytokine study of 130 patients with bipolar disorder, 149 patients with unipolar depression, and 130 healthy comparison controls revealed that both patients with bipolar disorder and those with unipolar depression had higher levels of pro-inflammatory cytokines, such as C-reactive protein, soluble interleukin-6 receptor, and soluble tumor necrosis factor (TNF) receptor type 1, compared with the control group, and further suggested a more severe inflammatory dysregulation in bipolar disorder than in unipolar depression[36]. Huang et al. reported that high-sensitivity C-reactive protein serum levels were significantly decreased in patients with HCV after IFN-based AVT, particularly among those achieving a sustained virological response[33]. Torre et al. found that early reduction of soluble TNF-α receptor levels on the 3rd after IFN-based AVT is related to virus decay on day 30[34]. A decrease in TNF-α level after 12 weeks of HCV eradication therapy has been observed by Esquivel et al.[35]. Based on these studies, we hypothesized that the positive synergic effect of IFN-based AVT in the neurofunctioning of the frontal cortex and in anti-inflammatory modulation could neutralize the risk of newly diagnosed bipolar disorder among patients with HCV infection. However, the pathophysiology of HCV infection and bipolar disorder and the exact underlying mechanisms of how IFN-based AVT reduces the risk of bipolar disorder among patients with HCV infection need further investigation.
Study limitations
- Study limitations reflect those shared by other registry-based analyses.
- The incidence of bipolar disorder may be underestimated because only those who sought medical help and consultation were identified in the database. But the diagnosis of bipolar disorder was made by board-certified psychiatrists, improving the diagnostic validity.
- The NHIRD does not provide some information, such as psychosocial stresses, family history, personal lifestyle, and environmental factors. Without this information, we were unable to examine their influence.
Summary
Patients with HCV infection, particularly those who had not yet received IFN-based AVT, were prone to developing newly-diagnosed bipolar disorder later in life compared with the control participants. IFN-based AVT may neutralize the risk of newly-diagnosed bipolar disorder among patients with HCV infection. The mental health of patients with HCV infection should be closely monitored in regular clinical practice. In addition, the optimal treatment for HCV infection can be beneficial for the long-term mental health among patients with HCV infection.
| Acknowledgment | | |
We would like to thank I-Fan Hu for his support.
| Financial Support and Sponsorship | | |
The study was supported by grant from Taipei Veterans General Hospital (V111C-010, V111C-040, V111C-029), Yen Tjing Ling Medical Foundation (CI-109-21, CI-109-22, CI-110-30) and Ministry of Science and Technology, Taiwan (MOST110-2314-B-075-026, MOST110-2314-B-075-024 -MY3, MOST 109-2314-B-010-050-MY3, MOST111-2314-B-075 -014 -MY2, MOST 111-2314-B-075 -013). The funding source had no rôle in any process of our study.
| Conflicts of Interest | | |
All authors have no financial relationships relevant to this article to disclose.
| References | | |
| 1. | Li HC, Lo SY: Hepatitis C virus: Virology, diagnosis and treatment. World J Hepatol 2015; 7: 1377-89.  |
| 2. | Manns MP, Buti M, Gane E, et al.: Hepatitis C virus infection. Nat Rev Dis Primers 2017; 3: 17006. |
| 3. | Chiu WC, Lu ML, Chang CC: Mental disorders and interferon nontreatment in hepatitis C virus infection-a population based cohort study. Psychiatry Investig 2020; 17: 268-74. |
| 4. | Choi HY, Mai TH, Kim KA, et al.: Association between viral hepatitis infection and Parkinson's disease: a population-based prospective study. J Viral Hepat 2020; 27: 1171-8. |
| 5. | Bauer-Staeb C, Jörgensen L, Lewis G, et al.: Prevalence and risk factors for HIV, hepatitis B, and hepatitis C in people with severe mental illness: A total population study of Sweden. Lancet Psychiatry 2017; 4: 685-93. |
| 6. | Hughes E, Bassi S, Gilbody S, et al.: Prevalence of HIV, hepatitis B, and hepatitis C in people with severe mental illness: a systematic review and meta-analysis. Lancet Psychiatry 2016; 3: 40-8. |
| 7. | Rosenberg SD, Goodman LA, Osher FC, et al.: Prevalence of HIV, hepatitis B, and hepatitis C in people with severe mental illness. Am J Public Health 2001; 91: 31-7. |
| 8. | Chong LW, Hsu CC, Lee CY, et al.: Association of viral hepatitis and bipolar disorder: a nationwide population-based study. J Transl Med 2018; 16: 173. |
| 9. | Hsu YC, Ho HJ, Huang YT, et al.: Association between antiviral treatment and extrahepatic outcomes in patients with hepatitis C virus infection. Gut 2015; 64: 495-503. |
| 10. | Sun CF, Chiu WC, Chen PC, et al.: Depression-free after interferon-α exposure indicates less incidence of depressive disorder: a longitudinal study in Taiwan. Brain Behav Immun 2020; 88: 125-31. |
| 11. | Lin WY, Lin MS, Weng YH, et al.: Association of antiviral therapy with risk of Parkinson disease in patients with chronic hepatitis C virus infection. JAMA Neurol 2019; 76: 1019-27. |
| 12. | Su KP, Lai HC, Peng CY, et al.: Interferon-alpha-induced depression: Comparisons between early and late-onset subgroups and with patients with major depressive disorder. Brain Behav Immun 2019; 80: 512-8. |
| 13. | Su KP: Nutrition, psychoneuroimmunology and depression: the therapeutic implications of omega-3 fatty acids in interferon-α-induced depression. Biomedicine (Taipei) 2015; 5: 21. |
| 14. | Lu DY, Leung YM, Su KP: Interferon-α induces nitric oxide synthase expression and haem oxygenase-1 down-regulation in microglia: Implications of cellular mechanism of IFN-α-induced depression. Int J Neuropsychopharmacol 2013; 16: 433-44. |
| 15. | Cheng CM, Chang WH, Chen MH, et al.: Co-aggregation of major psychiatric disorders in individuals with first-degree relatives with schizophrenia: a nationwide population-based study. Mol Psychiatry 2018; 23: 1756-63. |
| 16. | Chen MH, Lan WH, Hsu JW, et al.: Risk of developing Type 2 diabetes in adolescents and young adults with autism spectrum disorder: A nationwide longitudinal study. Diabetes Care 2016; 39: 788-93. |
| 17. | Chen MH, Pan TL, Li CT, et al.: Risk of stroke among patients with post-traumatic stress disorder: nationwide longitudinal study. Br J Psychiatry 2015; 206: 302-7. |
| 18. | Chen MH, Hsu JW, Huang KL, et al.: Sexually transmitted infection among adolescents and young adults with attention-deficit/hyperactivity disorder: A nationwide longitudinal study. J Am Acad Child Adolesc Psychiatry 2018; 57: 48-53. |
| 19. | Omata M, Kanda T, Yu ML, et al.: APASL consensus statements and management algorithms for hepatitis C virus infection. Hepatol Int 2012; 6: 409-35. |
| 20. | Liu CY, Hung YT, Chuang YL, et al.: Incorporating development stratification of Taiwan townships into sampling design of large scale health interview survey. J Health Manage (Chin) 2006; 4: 1-22. |
| 21. | Tsao YC, Chen JY, Yeh WC, et al.: Association between visceral obesity and hepatitis C infection stratified by gender: a cross-sectional study in Taiwan. BMJ Open 2017; 7: e017117. |
| 22. | White DL, Ratziu V, El-Serag HB: Hepatitis C infection and risk of diabetes: A systematic review and meta-analysis. J Hepatol 2008; 49: 831-44. |
| 23. | Liao CC, Su TC, Sung FC, et al.: Does hepatitis C virus infection increase risk for stroke? a population-based cohort study. PLoS One 2012; 7: e31527. |
| 24. | Butt AA, Evans R, Skanderson M, et al.: Comorbid medical and psychiatric conditions and substance abuse in HCV infected persons on dialysis. J Hepatol 2006; 44: 864-8. |
| 25. | Charlson ME, Pompei P, Ales KL, et al.: A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40: 373-83. |
| 26. | McCready H, Kohno M, Kolessar M, et al.: Functional MRI and delay discounting in patients infected with hepatitis C. J Neurovirol 2018; 24: 738-51. |
| 27. | Hjerrild S, Renvillard SG, Leutscher P, et al.: Reduced cerebral cortical thickness in Non-cirrhotic patients with hepatitis C. Metab Brain Dis 2016; 31: 311-9. |
| 28. | Bladowska J, Zimny A, Knysz B, et al.: Evaluation of early cerebral metabolic, perfusion and microstructural changes in HCV-positive patients: A pilot study. J Hepatol 2013; 59: 651-7. |
| 29. | Cattarinussi G, Di Giorgio A, Wolf RC, et al.: Neural signatures of the risk for bipolar disorder: a meta-analysis of structural and functional neuroimaging studies. Bipolar Disord 2019; 21: 215-27. |
| 30. | Lu X, Zhong Y, Ma Z, et al.: Structural imaging biomarkers for bipolar disorder: meta-analyses of whole-brain voxel-based morphometry studies. Depress Anxiety 2019; 36: 353-64. |
| 31. | Kuhn T, Sayegh P, Jones JD, et al.: Improvements in brain and behavior following eradication of hepatitis C. J Neurovirol 2017; 23: 593-602. |
| 32. | Bladowska J, Pawłowski T, Fleischer-Stępniewska K, et al.: Interferon-free therapy as the cause of white matter tracts and cerebral perfusion recovery in patients with chronic hepatitis C. J Viral Hepat 2019; 26: 635-43. |
| 33. | Huang CF, Hsieh MY, Yang JF, et al.: Serum HS-CRP was correlated with treatment response to pegylated interferon and ribavirin combination therapy in chronic hepatitis C patients. Hepatol Int 2010; 4: 621-7. |
| 34. | Torre F, Rossol S, Pelli N, et al.: Kinetics of soluble tumour necrosis factor (TNF)-alpha receptors and cytokines in the early phase of treatment for chronic hepatitis C: Comparison between interferon (IFN)-alpha alone, IFN-alpha plus amantadine or plus ribavirin. Clin Exp Immunol 2004; 136: 507-12. |
| 35. | Alvarado Esquivel C, Elewaut A, Philippé J, et al.: Evolution of hepatitis C virus-specific T cell responses and cytokine production in chronic hepatitis C patients treated with high doses of interferon-alpha. Rev Invest Clin 2002; 54: 41-50. |
| 36. | Bai YM, Su TP, Li CT, et al.: Comparison of pro-inflammatory cytokines among patients with bipolar disorder and unipolar depression and normal controls. Bipolar Disord 2015; 17: 269-77. |
[Table 1], [Table 2]
|
Search Pubmed for