Serotonin-1A Receptor Gene HTR1A Variation Predicts Interferon-Induced Depression in Chronic Hepatitis C
2007; Elsevier BV; Volume: 132; Issue: 4 Linguagem: Inglês
10.1053/j.gastro.2007.02.053
ISSN1528-0012
AutoresMichael R. Kraus, Oliver Al‐Taie, Arne Schäfer, M Pfersdorff, Klaus‐Peter Lesch, Michael Scheurlen,
Tópico(s)Tryptophan and brain disorders
ResumoBackground & Aims: Interferon-induced depression is a major complication in antiviral therapy of chronic hepatitis C. Little is known about underlying mechanisms and reliable predictive factors associated with cytokine-induced depressive symptoms. Methods: In a cohort of 139 hepatitis C-infected outpatients treated with interferon alfa-2b, we investigated the impact of functional gene variants of the cerebral serotonin (5-HT) signalling pathway previously implicated in depression risk. Depression was monitored using the Hospital Anxiety and Depression Scale (HADS). All patients were genotyped for functional variations in the 5-HT1A receptor (HTR1A), 5-HT transporter (SLC6A4, 5-HTT), and tryptophan hydoxylase-2 (TPH2). Results: Homozygosity for the HTR1A-1019G variant significantly increased both incidence and severity of interferon-induced depression. Maximum increases in HADS depression scores during antiviral therapy correlated with HTR1A variation (P = .011). Clinically relevant depression was significantly associated with the HTR1A-1019G genotype (P = .017; OR, 2.95). 5-HTT and TPH2 variations did not contribute significantly to the prediction of interferon-induced depression by HTR1A (sensitivity, 35.9%; specificity, 84.0%). Conclusions: Our findings suggest an impact of allelic variation in 5-HT1A receptor expression on the development of interferon alfa-induced depression during antiviral treatment of chronic hepatitis C. Prediction models of interferon-induced depressive symptoms based on HTR1A variation offer a perspective for an antidepressant selective serotonin reuptake inhibitor prophylaxis in patients genetically at risk for interferon-induced depression. Background & Aims: Interferon-induced depression is a major complication in antiviral therapy of chronic hepatitis C. Little is known about underlying mechanisms and reliable predictive factors associated with cytokine-induced depressive symptoms. Methods: In a cohort of 139 hepatitis C-infected outpatients treated with interferon alfa-2b, we investigated the impact of functional gene variants of the cerebral serotonin (5-HT) signalling pathway previously implicated in depression risk. Depression was monitored using the Hospital Anxiety and Depression Scale (HADS). All patients were genotyped for functional variations in the 5-HT1A receptor (HTR1A), 5-HT transporter (SLC6A4, 5-HTT), and tryptophan hydoxylase-2 (TPH2). Results: Homozygosity for the HTR1A-1019G variant significantly increased both incidence and severity of interferon-induced depression. Maximum increases in HADS depression scores during antiviral therapy correlated with HTR1A variation (P = .011). Clinically relevant depression was significantly associated with the HTR1A-1019G genotype (P = .017; OR, 2.95). 5-HTT and TPH2 variations did not contribute significantly to the prediction of interferon-induced depression by HTR1A (sensitivity, 35.9%; specificity, 84.0%). Conclusions: Our findings suggest an impact of allelic variation in 5-HT1A receptor expression on the development of interferon alfa-induced depression during antiviral treatment of chronic hepatitis C. Prediction models of interferon-induced depressive symptoms based on HTR1A variation offer a perspective for an antidepressant selective serotonin reuptake inhibitor prophylaxis in patients genetically at risk for interferon-induced depression. Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, affecting an estimated 170 million people worldwide.1Alter M.J. Epidemiology of hepatitis C.Hepatology. 1997; 26: 62S-65SCrossref PubMed Scopus (920) Google Scholar, 2Shepard C.W. Finelli L. Alter M.J. 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Schafer A. Scheurlen M. Paroxetine for the prevention of depression induced by interferon alfa.N Engl J Med. 2001; 345: 375-376Crossref PubMed Scopus (55) Google Scholar Thus, some authors advocate SSRI prophylaxis in all patients before initiating IFN therapy.12Musselman D.L. Lawson D.H. Gumnick J.F. Manatunga A.K. Penna S. Goodkin R.S. Greiner K. Nemeroff C.B. Miller A.H. Paroxetine for the prevention of depression induced by high-dose interferon alfa.N Engl J Med. 2001; 344: 961-966Crossref PubMed Scopus (952) Google Scholar However, this strategy would require subjecting the majority of patients, who will not develop depression, to potential adverse events and for no benefit. It would be preferable to identify those at increased risk for depressive symptoms so that SSRIs would be administered to those who are most likely to benefit from these agents. However, no such predictors are available at present. IFN-induced depression may occur from modulation of the serotonergic system by one or both of the following mechanisms: (1) depletion of the precursor amino acid tryptophan or (2) increased serotonin (5-HT) reuptake by its transporter leading to a relative deficiency of 5-HT.13Hayley S. Poulter M.O. Merali Z. Anisman H. The pathogenesis of clinical depression: stressor- and cytokine-induced alterations of neuroplasticity.Neuroscience. 2005; 135: 659-678Crossref PubMed Scopus (294) Google Scholar, 14Schiepers O.J. Wichers M.C. Maes M. Cytokines and major depression.Prog Neuropsychopharmacol Biol Psychiatry. 2005; 29: 201-217Crossref PubMed Scopus (1017) Google Scholar, 15Valentine A.D. Meyers C.A. Neurobehavioral effects of interferon therapy.Curr Psychiatry Rep. 2005; 7: 391-395Crossref PubMed Scopus (56) Google Scholar, 16Bonaccorso S. Marino V. Puzella A. Pasquini M. Biondi M. Artini M. Almerighi C. Verkerk R. Meltzer H. Maes M. Increased depressive ratings in patients with hepatitis C receiving interferon-α-based immunotherapy are related to interferon-α-induced changes in the serotonergic system.J Clin Psychopharmacol. 2002; 22: 86-90Crossref PubMed Scopus (398) Google Scholar, 17Capuron L. Neurauter G. Musselman D.L. Lawson D.H. Nemeroff C.B. Fuchs D. Miller A.H. Interferon-α-induced changes in tryptophan metabolism: relationship to depression and paroxetine treatment.Biol Psychiatry. 2003; 54: 906-914Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar, 18Morikawa O. Sakai N. Obara H. Saito N. Effects of interferon-α, interferon-γ, and cAMP on the transcriptional regulation of the serotonin transporter.Eur J Pharmacol. 1998; 349: 317-324Crossref PubMed Scopus (159) Google Scholar On the other hand, polymorphisms of genes encoding for several key players of the serotonergic system have been identified to confer an increased risk for depression in the general population. Our hypothesis was that the presence of such polymorphisms might also increase the risk to develop clinically relevant depression in patients receiving IFN-based therapy for chronic hepatitis C. We therefore sought for differences in the distribution of genotypes between subgroups of patients with and without IFN-induced depression. Based on the results of population studies, we selected the following genes and polymorphisms: (1) tryptophan hydroxylase-2 (TPH2), the rate-limiting enzyme in the biosynthesis of 5-HT in the brain (G-703T polymorphism in the transcriptional control region); (2) 5-HT transporter (5-HTT) that terminates 5-HT action at the receptor site (variants: short[s] vs long [l] allele of the 5-HTT gene's transcription initiation site [5-HTTLPR]); and (3) 5-HT1A receptor (HTR1A), the major autoreceptor on serotonergic raphe neurons (C-1019G single nucleotide polymorphism). The polymorphisms chosen had to fulfil the conditions of being (1) functional and (2) associated with depression and anxiety (as an intermediate phenotype of depression). At present, no additional polymorphisms located on these target genes have been published that fulfil the listed prerequisites. Based on presently published results, we expected, in terms of genetic variation, IFN-induced depression to be associated with the following alleles: TPH2-703T, HTR1A-1019G, and the short (s) variant of 5-HTTLPR. The most promising predictor candidate was hypothesized to be HTR1A, based on previous findings by Cai et al,19Cai W. Khaoustov V.I. Xie Q. Pan T. Le W. Yoffe B. Interferon-α-induced modulation of glucocorticoid and serotonin receptors as a mechanism of depression.J Hepatol. 2005; 42: 880-887Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar who found an impact of IFN alfa action on 5-HT1A expression. Hepatitis C-infected outpatients (18–65 years of age) were consecutively enrolled at our institution (Medizinische Klinik und Poliklinik II, Department of Gastroenterology and Hepatology, University of Würzburg) between 1997 and 2004. All patients gave written informed consent to participation. The study was approved by the Ethics Committee for Medical Research of Würzburg University, Würzburg, Germany (Institutional Review Board for the protection of human subjects), and was carried out in accordance with the Declaration of Helsinki. All patients were anti-HCV positive and had circulating HCV RNA at the time of study entry. Other causes of liver disease had been excluded. Further exclusion criteria were advanced cirrhosis (Child–Pugh stage B or C), coinfections (hepatitis B virus or human immunodeficiency virus), severe internal diseases (eg, cancer, ischemic heart disease, or autoimmune disease), psychiatric illness (severe depression or psychosis), active intravenous drug use or alcohol abuse, or insufficient knowledge of the German language. The trial was a longitudinal and prospective single-center study including 139 patients with chronic hepatitis C infection. During the inclusion period from 1997 to 2004, the German recommendations for antiviral therapy of chronic hepatitis C changed. Every patient was treated according to the recommendations that were effective at the time of study entry. Therefore, IFN medication consisted of either 3 × 3 million units IFN alfa-2b (Intron A; Essex Pharma, Munich, Germany) or a single dose of 1.5 μg/kg pegylated IFN alfa-2b (PegIntron; Essex Pharma) per week; ribavirin (Rebetol; Essex Pharma) was given in a weight-adapted fashion (800–1200 mg daily). Duration of therapy was 24 weeks in genotypes 2 and 3 patients and 48 weeks in genotypes 1 and 4 patients. With respect to the prevalence of clinically relevant depression as an adverse effect, both IFN regimens applied in our study population have been shown to be equivalent in a previous study from our group.20Kraus M.R. Schafer A. Csef H. Scheurlen M. Psychiatric side effects of pegylated interferon alfa-2b as compared to conventional interferon alfa-2b in patients with chronic hepatitis C.World J Gastroenterol. 2005; 11: 1769-1774Crossref PubMed Scopus (59) Google Scholar Patients' emotional state and psychiatric symptoms were monitored repeatedly throughout the study course: once prior to therapy, three times during antiviral treatment (after 4, 12, and 24 weeks of IFN treatment), and once 4 weeks after the end of therapy. Each evaluation time point comprised psychometric monitoring (self-assessment questionnaires, diagnostic interview), medical examination, and laboratory testing (eg, blood count, liver enzymes, HCV RNA). Depression was assessed with the Hospital Anxiety and Depression Scale (HADS; German version, as published by Herrmann et al).21Herrmann C. Buss U. Snaith R.P. HADS-D. Hospital Anxiety and Depression Scale: Deutsche version. Ein Fragebogen zur Erfassung von Angst und Depressivität in der somatischen Medizin. Huber, Bern, Switzerland1995Google Scholar The HADS is a 14-item questionnaire with the dimensions anxiety and depression. For the purpose of the present study, the analyzed data are based on the 7-item HADS depression subscale. This psychometric instrument was chosen because all of its items solely refer to the emotional state and do not consider somatic symptoms. The cut-off value for clinically relevant depression was set to ≥9.21Herrmann C. Buss U. Snaith R.P. HADS-D. Hospital Anxiety and Depression Scale: Deutsche version. Ein Fragebogen zur Erfassung von Angst und Depressivität in der somatischen Medizin. Huber, Bern, Switzerland1995Google Scholar Venous blood samples of all patients were collected in EDTA-coated tubes. Individuals were then genotyped for 3 polymorphisms as previously described: HTR1A (C-1019G single nucleotide polymorphism [SNP] in the transcriptional control region of the 5-HT1A receptor gene), as described by Strobel et al22Strobel A. Gutknecht L. Rothe C. Reif A. Mossner R. Zeng Y. Brocke B. Lesch K.P. Allelic variation in 5-HT1A receptor expression is associated with anxiety- and depression-related personality traits.J Neural Transm. 2003; 110: 1445-1453Crossref PubMed Scopus (198) Google Scholar; SLC6A4/5-HTT (short[s] vs long [l] allele of the 5-HTT gene's transcription initiation site [5-HTTLPR]), as described by Marziniak et al23Marziniak M. Mossner R. Schmitt A. Lesch K.P. Sommer C. A functional serotonin transporter gene polymorphism is associated with migraine with aura.Neurology. 2005; 64: 157-159Crossref PubMed Scopus (77) Google Scholar and Lesch et al);24Lesch K.P. Bengel D. Heils A. Sabol S.Z. Greenberg B.D. Petri S. Benjamin J. Muller C.R. Hamer D.H. Murphy D.L. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region.Science. 1996; 274: 1527-1531Crossref PubMed Scopus (4470) Google Scholar and TPH2 (G-703T variation in the transcriptional control region of the tryptophan hydroxylase-2 gene), as described by Canli et al25Canli T. Congdon E. Gutknecht L. Constable R.T. Lesch K.P. Amygdala responsiveness is modulated by tryptophan hydroxylase-2 gene variation.J Neural Transm. 2005; 112: 1479-1485Crossref PubMed Scopus (170) Google Scholar and Gutknecht et al).26Gutknecht L. Jacob C.P. Strobel A. Muller J. Reif A. Mossner R. Zeng Y. Gross C. Brocke B. Lesch K.P. Tryptophan hydroxylase-2 gene variation influences personality traits and disorders related to emotional dysregulation.Int J Neuropsychopharmacol. 2006; 19: 1-12Google Scholar Because the HTR1A variation turned out to have a significant effect on IFN-induced depression, we decided to recheck the genotyping results for this polymorphism by DNA sequencing analysis, applying standard protocols. Thus, the distribution of HTR1A genotypes in our study sample could be confirmed. Both applied genotyping methods produced identical results. The Statistical Package for Social Sciences software (SPSS für Windows 12.0.2G; SPSS Inc, Chicago, 2004.) was used for all presented statistical analyses. All performed tests were usually 2-tailed and considered to be statistically significant at P < .050. The character of the presented study was partially explorative; therefore, we did not consider alfa adjustment for multiple comparisons. Moreover, exact calculated P values are usually provided together with statistical analyses for maximum transparency and clarity of the data presentation. We performed t tests (for independent samples) and analysis of variance (1-way ANOVA) to test for differences in continuous variables (eg, depression scores) between patient subgroups, and χ2 tests were used to compare frequencies of categorical variables between patient subgroups (eg, genotype and allele frequencies, depression categories). Testing for deviation from Hardy–Weinberg equilibrium was performed using the correspondent χ2 procedure. Predictive value of chosen polymorphisms was investigated using binary logistic regression analysis (prediction of depression categories). Explanatory variables included in the prediction models were—with respect to the study aims—genetic variations of HTR1A, 5-HTT, and TPH2. Relevant demographic, laboratory, and medical data as well as baseline depression scores (according to the HADS) of patients with chronic hepatitis C enrolled in our study are summarized in Table 1. Data refer to the subgroups stratified for the considered genotypes.Table 1HTR1A, 5-HTT, and TPH2 GenotypesHTR1A GenotypesDemographic and illness-related factorsHTR1A: G/G (n = 35)HTR1A: C/G (n = 64)HTR1A: C/C (n = 40)P valueAge, y (mean ± SD)42.86 ± 10.240.77 ± 10.941.78 ± 8.82.614 Range(18−65)(20−65)(25−65)Gender (%) Women15 (42.9)31 (48.4)22 (55).573 Men20 (57.1)33 (51.6)18 (45)Acquisition mode (%) Unknown10 (28.6)18 (28.1)11 (27.5).501 IVDU20 (57.1)34 (53.1)17 (42.5) Posttransfusion5 (14.3)12 (18.8)12 (30.0)Virus genotype (%)aIn 1 patient, genotype could not be determined. (During antiviral treatment, virus RNA was no longer detectable when we attempted to reidentify the hepatitis C genotype.) Genotype 120 (58.8)35 (54.7)27 (67.5) Genotype 22 (5.9)6 (9.4)6 (15.0) Genotype 312 (35.3)21 (32.8)7 (17.5).304 Genotype 40 (0)2 (3.1)0 (0)HADS depression (T1)4.49 ± 3.33.45 ± 2.925.00 ± 3.57.050 Range(0−14)(0−12)(0−13)5-HTT GenotypesDemographic and illness-related factors5-HTT: ss (n = 18)5-HTT: sl (n = 64)5-HTT: ll (n = 57)P valueAge, y (mean±SD)44.17 ± 10.8441.84 ± 10.0640.47 ± 9.97.389 Range(22−65)(18−65)(21−65)Gender (%) Women10 (55.6)27 (42.2)31 (54.4).340 Men8 (44.4)37 (57.8)26 (45.6)Acquisition mode (%) Unknown8 (44.4)17 (26.6)14 (24.6).498 IVDU7 (38.9)35 (54.7)29 (50.8) Posttransfusion3 (16.7)12 (18.8)14 (24.6)Virus genotype (%)aIn 1 patient, genotype could not be determined. (During antiviral treatment, virus RNA was no longer detectable when we attempted to reidentify the hepatitis C genotype.) Genotype 112 (66.7)39 (61.9)31 (54.4) Genotype 20 (0)8 (12.7)6 (10.5) Genotype 36 (33.3)15 (23.8)19 (33.3).665 Genotype 40 (0)1 (1.6)1 (1.8)HADS depression (T1)4.22 ± 3.103.36 ± 2.965.04 ± 3.48.018 Range(1−13)(0−10)(0−14)TPH2 GenotypesDemographic and illness-related factorsTPH2: GG (n = 93)TPH2: GT (n = 40)TPH2: TT (n = 6)P valueAge, y (mean±SD)42.41 ± 9.8139.58 ± 10.4742.17 ± 12.48.333 Range(21−65)(18−60)(30−65)Gender (%) Women48 (51.6)17 (42.5)3 (50).627 Men45 (48.4)23 (47.5)3 (50)Acquisition mode (%) Unknown25 (26.9)12 (30.0)2 (33.3).847 IVDU46 (49.5)22 (55.0)3 (50.0) Posttransfusion22 (23.7)6 (15.0)1 (16.7)Virus genotype (%)aIn 1 patient, genotype could not be determined. (During antiviral treatment, virus RNA was no longer detectable when we attempted to reidentify the hepatitis C genotype.) Genotype 159 (63.4)20 (51.3)3 (50.0) Genotype 27 (7.5)6 (15.4)1 (16.7) Genotype 325 (26.9)13 (33.3)2 (33.3).661 Genotype 42 (2.2%)0 (0%)0 (0%)HADS depression (T1)4.26 ± 3.183.73 ± 3.375.50 ± 4.09.410 Range(0−14)(0−13)(2−13)NOTE. Important patient characteristics. Continuous variables are presented as mean ± standard deviation (SD). Significance of subgroup differences was evaluated by t test for independent samples (continuous variables) or χ2 test (categorical variables), respectively. Demographic and illness-related data are stratified for genetic variation of HTR1A, 5-HTT, and TPH2.IVDU, intravenous drug use.a In 1 patient, genotype could not be determined. (During antiviral treatment, virus RNA was no longer detectable when we attempted to reidentify the hepatitis C genotype.) Open table in a new tab NOTE. Important patient characteristics. Continuous variables are presented as mean ± standard deviation (SD). Significance of subgroup differences was evaluated by t test for independent samples (continuous variables) or χ2 test (categorical variables), respectively. Demographic and illness-related data are stratified for genetic variation of HTR1A, 5-HTT, and TPH2. IVDU, intravenous drug use. Results from genotyping analysis are presented in Table 2. The genotype and allele frequencies observed in our study sample were in accordance with the Hardy–Weinberg equilibrium with respect to all investigated gene polymorphisms. χ2 Analyses revealed that the observed distributions did not differ significantly from the expected counts (HTR1A: P = .358; 5-HTT: P = .996; TPH2: P = .526).Table 2Results of Genotyping AnalysisGenotypes(HTR1A)AllelesSubjectsNC/CC/GG/GCGTotal sample (%)aTest for Hardy–Weinberg equilibrium: χ21 = 0.844, P = .358.13940 (28.8)64 (46)35 (25.2)144 (51.8)134 (48.2)Genotypes (5-HTT)AllelesSubjectsNs/ss/ll/lslTotal sample (%)bTest for Hardy–Weinberg equilibrium: χ21 = 2.8 × 10−5, P = .996.13918 (12.9)64 (46)57 (41.1)100 (51.8)178 (48.2)Genotypes (TPH2)AllelesSubjectsNG/GG/TT/TGTTotal sample (%)cTest for Hardy–Weinberg equilibrium: χ21 = 0.402, P = .526.13993 (66.9)40 (28.8)6 (4.3)226 (81.3)52 (18.7)NOTE. Genotype and allele frequencies are given as counts and percentages. Correspondence to Hardy–Weinberg equilibrium was tested by means of the χ2 test statistic.a Test for Hardy–Weinberg equilibrium: χ21 = 0.844, P = .358.b Test for Hardy–Weinberg equilibrium: χ21 = 2.8 × 10−5, P = .996.c Test for Hardy–Weinberg equilibrium: χ21 = 0.402, P = .526. Open table in a new tab NOTE. Genotype and allele frequencies are given as counts and percentages. Correspondence to Hardy–Weinberg equilibrium was tested by means of the χ2 test statistic. As known from our previous studies,7Kraus M.R. Schafer A. Faller H. Csef H. Scheurlen M. Psychiatric symptoms in patients with chronic hepatitis C receiving interferon alfa-2b therapy.J Clin Psychiatry. 2003; 64: 708-714Crossref PubMed Scopus (203) Google Scholar, 10Kraus M.R. Schafer A. Faller H. Csef H. Scheurlen M. Paroxetine for the treatment of interferon-alpha-induced depression in chronic hepatitis C.Aliment Pharmacol Ther. 2002; 16: 1091-1099Crossref PubMed Scopus (165) Google Scholar, 20Kraus M.R. Schafer A. Csef H. Scheurlen M. Psychiatric side effects of pegylated interferon alfa-2b as compared to conventional interferon alfa-2b in patients with chronic hepatitis C.World J Gastroenterol. 2005; 11: 1769-1774Crossref PubMed Scopus (59) Google Scholar HADS depression scores increased significantly but reversibly during antiviral treatment. Four weeks after treatment discontinuation, scores were not significantly different from pretreatment levels. Cross-tabs' analyses were performed to assess possible associations between different gene polymorphisms and IFN-induced depression. χ2 Analysis revealed a statistically significant association between HTR1A genotype and clinically relevant depression scores according to the HADS cut-off criterion during antiviral therapy (χ22 = 8.10; P = .017; Table 3). Homozygosity for the HTR1A-1019G allele conferred a significantly higher risk for the occurrence of clinically relevant, treatment-induced depression scores as compared with carriers with at least 1 C allele (odds ratio [OR], 2.95; 95% CI: 1.32–6.56).Table 3Association of HTR1A Genotypes and Cases With Clinically Relevant Interferon-Induced Depression According to HADSHTR1A Genotypesaχ22 = 8.10, P = .017.C/CC/GG/GTotalHADS <922411275HADS ≥918232364Total4064351395-HTT Genotypesbχ22 = 1.77, P = .413.llslssTotalHADS <927381075HADS ≥93026864Total576418139TPH2 Genotypescχ22 = 0.83, P = .660.G/GG/TT/TTotalHADS <94824375HADS ≥94516364Total93406139NOTE. Patients were assigned to the category clinically relevant depression (HADS ≥9) if at least once during antiviral therapy, HADS scores reached or exceeded 9 points on the respective scale. Tested by χ2 analysis.a χ22 = 8.10, P = .017.b χ22 = 1.77, P = .413.c χ22 = 0.83, P = .660. Open table in a new tab NOTE. Patients were assigned to the category clinically relevant depression (HADS ≥9) if at least once during antiviral therapy, HADS scores reached or exceeded 9 points on the respective scale. Tested by χ2 analysis. The classification model resulting from the application of binary logistic regression analysis is shown in Table 4. Homozygosity for the HTR1A-1019G allele is a significant predictor of the occurrence of clinically relevant depression during treatment with IFN alfa, and the prediction could not be improved by the additional consideration of 5-HTT or TPH2 polymorphisms. This finally adopted prediction model on the basis of binary logistic regression analysis yielded a sensitivity of 35.9% and a specificity of 84.0% (Table 4).Table 4Results of Binary Logistic Regression AnalysisPredictedCorrectly classified (%)HTR1AaPrediction model for variable "homozygosity for G allele": B = −1.080 (SE 0.409); Wald statistic 6.983 (df = 1), P = .008. Exp (B) = 0.340 (CI 95%: 0.152–0.757).HADS ≥9HADS <9Observed HADS ≥9234135.9 HADS <9126384.0Total percentage61.9PredictedCorrectly classified (%)5-HTTbPrediction model for variable "5-HTT genotype": B = −0.345 (SE 0.224); Wald statistic 2.367 (df = 1), P = .124. 5-HTT variants were not statistically significant predictors.HADS ≥9HADS <9Observed HADS ≥9303446.9 HADS <9274864.0Total percentage56.1PredictedCorrectly classified (%)TPH2cPrediction model for variable "TPH2 genotype": B = −0.166 (SE 0.174); Wald statistic 0.908 (df = 1), P = .341. TPH2 variants were not statistically significant predictors.HADS ≥9HADS <9Observed HADS ≥93614.7 HADS <937296.0Total percentage54.0NOTE. Included predictor variable is the HTR1A receptor polymorphism ("homozygosity for the HTR1A-1019G allele"). Dichotomous outcome variable is represented by the occurrence of clinically relevant depression scores during interferon treatment.a Prediction model for variable "homozygosity for G allele": B = −1.080 (SE 0.409); Wald statistic 6.983 (df = 1), P = .008. Exp (B) = 0.340 (CI 95%: 0.152–0.757).b Prediction model for variable "5-HTT genotype": B = −0.345 (SE 0.224); Wald statistic 2.367 (df = 1), P = .124. 5-HTT variants were not statistically significant predictors.c Prediction model for variable "TPH2 genotype": B = −0.166 (SE 0.174); Wald statistic 0.908 (df = 1), P = .341. TPH2 variants were not statistically significant predictors. Open table in a new tab NOTE. Included predictor variable is the HTR1A receptor polymorphism ("homozygosity for the HTR1A-1019G allele"). Dichotomous outcome variable is represented by the occurrence of clinically relevant depression scores during interferon treatment. The 1-way ANOVA technique was applied to detect whether changes in depression scores during therapy were significantly different between subgroups according to any of the different genotypes. Our statistical approach was to consider changes in depression scores over time to eliminate the impact of the variability of depression scores at baseline. Both mean (Δmean[HADS] = 1/3*Σ(ti-t1); i = [2, 3, 4]) and maximum (Δmax[HADS] = max (ti-t1); i = [2, 3, 4]) changes in HADS depression scores were chosen as dependent variables for this kind of analysis. Main effect "HTR1A genotype" was statistically significant using 1-way ANOVA for both mean increases (P = .024) and maximum increases (P = .011) of HADS depression scores during antiviral IFN treatment (Figure 1). Post hoc tests revealed that individuals carrying 2 HTR1A-1019G alleles had significantly higher increases in depression scores than the remainder of the study sample. According to this analysis, we found a gene-dose effect of the HTR1A functional polymorphism with respect to the positive link between the increase in depression scores and the number of G alleles (Figure 1). Main effect "5-HTT genot
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