Merja Viikki

Gynaecological infections as risk determinants of subsequent cervical neoplasia.

A longitudinal cohort study was carried out to determine whether gynaecological infections other than human papillomavirus (HPV) are also related to the subsequent increased risk of cervical neoplasia. The study comprised 19114 women attending the organized mass screening in Finland in 1985-1990 with cytologically detected HPV, Actinomyces, herpes simplex, Trichomonas vaginalis, or yeast. The women were followed-up for subsequent preinvasive lesions and invasive cancers until the end of 1994 by linkage to the nation-wide Cancer Registry. Standardized incidence ratios (SIR) with rates for the whole of Finland as reference and 95% confidence intervals (CI) were estimated. Trichomonas vaginalis and HPV were associated with a high relative risk of cervical cancer, SIR 6.4 (CI 3.7-10, preinvasive lesion and invasive cancer combined) and SIR 5.5 (CI 4.2-7.2, preinvasive lesion and invasive cancer combined), respectively. Herpes simplex was rarely detected, but the highest and statistically most significant point estimate was observed (SIR 12, CI 2.4-34, preinvasive lesion and invasive cancer combined). Neither Actinomyces nor yeast was associated with a significantly increased risk of cervical cancer. None of these results could be accounted for by the confounding effect of the other infections. Our results, based on a prospective design, lead us to propose that Trichomonas vaginalis and herpes simplex virus are also predictors for cervical neoplasia.

5-HTR1A, 5-HTR2A, 5-HTR6, TPH1 and TPH2 polymorphisms and major depression.

Genes that regulate the serotonin signalling system are potential targets for research in the aetiology of mood disorders and also in the treatment response of serotonin reuptake inhibitors. In this study, we evaluated the association of seven serotonin signal transduction-linked single nucleotide polymorphisms [HTR1A (rs6295), HTR2A (rs6313, rs6311 and rs7997012), HTR6 (rs1805054), TPH1 (rs1800532) and TPH2 (rs1386494)] with major depressive disorder and/or treatment outcome with serotonin reuptake inhibitors. Patients who met the criteria for major depressive disorder were treated for 6 weeks with fluoxetine, paroxetine or citalopram. The treatment response was evaluated with the Montgomery–Asberg Depression Rating Scale, and according to predefined response criteria, the patients were divided into responders, nonresponders, remitters and nonremitters. Altogether, 86 patients completed the entire study according to the study protocol. We had also a control population (N = 395) of healthy blood donors. None of the seven single nucleotide polymorphisms was associated with major depressive disorder or with treatment response in our study population of Finnish individuals.

Vascular endothelial growth factor (VEGF) polymorphism is associated with treatment resistant depression

Antidepressive medication and electroconvulsive therapy (ECT) increase hippocampal neurogenesis by promoting expression of trophic factors, including brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). The aims were to test for an association between the VEGF 2578 C/A polymorphism and major depressive disorder (MDD) in two patient populations compared to controls, and the association between this polymorphism and response to serotonin selective reuptake inhibitors (SSRI) and to ECT. The first patient sample consisted of 119 subjects with treatment resistant major depressive disorder who were treated with ECT and the second of 98 depressive patients treated with SSRI. Treatment response was assessed by the Montgomery and Asberg Depression Rating Scale (MADRS). Patients scoring <8 in post-treatment MADRS were considered remitters. There was a trend that CC genotype of VEGF 2578C/A polymorphism was more common in ECT-treated and SSRI-treated patients than in controls (31.1%, 25.5% and 18.7% respectively; p=0.056). The VEGF 2578 C/A polymorphism was associated with treatment resistant MDD. CC genotype was more common in ECT patients than in controls (31.1% and 18.7% respectively; p=0.015). The VEGF 2578 C/A polymorphism was not associated with treatment response to SSRI or to ECT. The finding suggests an association between VEGF 2578 C/A polymorphism and treatment resistant depression which is reported for the first time. Further studies with larger samples will be required to confirm the results.

Comparison of HPV test versus conventional and automation-assisted Pap screening as potential screening tools for preventing cervical cancer

Objective  To evaluate new techniques in primary cervical cancer screening programmes.

Prospective and randomised public-health trial on neural network-assisted screening for cervical cancer in Finland: results of the first year.

Our objective was to evaluate the feasibility and relative validity of interactive neural network assisted screening (Papnet) in primary mass screening for cervical cancer as a public health policy (routine screening). A randomized, ongoing trial involved 152,969 invitees and 108,686 attendees in the organized mass screening in Finland in 1999. Drawing invitations from the population registry, women were randomized 2:1 at an individual level to have their smear analyzed either conventionally or with Papnet. The distribution of smears to different cytological categories, detection rates of dysplasias, in situ carcinomas and cancers were estimated with smears analyzed either conventionally (72,461) or by Papnet (36,225). A total of 108,686 smears were screened and 449 were histologically confirmed as dysplasias and carcinomas. The detection rates for histologically verified carcinoma in situ/severe dysplasia, moderate and mild dysplasias were 0.14%, 0.14% and 0.13% with conventional and 0.14%, 0.14% and 0.11% with Papnet, respectively. The detection rate of invasive cancer was 0.06‰ (n = 4) with conventional method and 0.08‰ (n = 3) with Papnet. None of the differences were statistically significant (p > 0.05). Papnet was able to identify 92.5% of healthy women (normal cytology), and the specificity of conventional smear was 92.9%. The positive predictive value (Pap Classes III–V) of Papnet was slightly but not significantly better (55% vs. 51%). Papnet screening was feasible as a part of routine screening and performed equally well compared to conventional one methods used in Finland. Organized mass screening was practiced very successfully in the last 38 years. We are going to continue the trial to study the potential trends in cervical cancer incidence in both study arms.

Catechol-O-methyltransferase val108/158met genotype, major depressive disorder and response to selective serotonin reuptake inhibitors in major depressive disorder

The functional val108/158met polymorphism of the COMT gene (rs4680) was evaluated in major depressive disorder (MDD), and in the treatment response to antidepressants in MDD. We could not demonstrate any significant difference in the distribution of this COMT single-nucleotide polymorphism (SNP) in the treatment response to selective serotonin reuptake inhibitors or between patients with MDD and control subjects.

TPH1 218A/C polymorphism is associated with major depressive disorder and its treatment response

The association between the tryptophan hydroxylase 1 (TPH1) 218A/C polymorphism and (1) severity of major depressive disorder (MDD) and (2) response to treatment was studied. There were three study populations, the first consisting of 119 treatment-resistant MDD inpatients treated with electro-convulsive therapy (ECT), and the second of 98 MDD open care patients treated with selective serotonin reuptake inhibitors (SSRI). In addition, there was a control population of 395 healthy blood donors. The first aim of the study was to compare the genotypes of the patient with those of the healthy controls and between patient populations. The second aim was to compare the genotypes of MDD patients achieving remission with basic SSRI treatment (MADRS<8) with the genotypes of non-responders to ECT (defined as MADRS>15). TPH1 218A/C polymorphism was associated with the risk of MDD. CC genotype was significantly more common in patients (including both ECT and SSRI treated patients) than in controls (38.2% and 26.8% respectively; p=0.008), and its frequency was significantly higher in more severe forms of depression, i.e. in ECT treated patients compared with SSRI treated patients (42.0% and 33.7%, p=0.026). CC genotype was also associated with lower probability of achieving remission. It was significantly more frequent among ECT non-responders than among SSRI remitters (53.1% and 23.3%, p=0.049). In this Finnish population TPH1 218A/C polymorphism was associated with the risk of MDD and treatment response; CC genotype was associated with the increased risk of MDD and lower probability of responding treatment. Further studies with larger samples will be required to confirm the results.

Cytokine and adipokine alterations in patients with schizophrenia treated with clozapine.

Metabolic syndrome is associated with both schizophrenia and antipsychotic medication, especially clozapine, with alterations in inflammatory cytokines and adipokines. However, the data in this field is heterogeneous and the sample sizes of the patients are limited. In this study we assessed the serum levels of cytokines/adipokines IL-6, IL-1Ra, hs-CRP and adiponectin, and components of metabolic syndrome in 190 patients with treatment resistant schizophrenia treated with clozapine. Substantial metabolic comorbidity was found in this patient group; overweight/obesity, smoking, hypertriglyceridemia, low HDL-cholesterol, high HOMA-IR, low adiponectin levels, elevated hs-CRP levels and elevated IL-1Ra levels. Elevated IL-1Ra levels are associated with insulin resistance, obesity and hypertriglyceridemia. Low adiponectin levels were associated with hypertriglyceridemia, low HDL cholesterol and high glucose, and in male patients also with obesity and high IL-1Ra levels. After controlling for confounding factors age and smoking, levels of IL-1Ra and hs-CRP associated with obesity, and the levels of IL-6 associated with obesity in female patients. We conclude that there are partly gender dependent cytokine and adipokine alterations in patients with schizophrenia on clozapine treatment associated with metabolic comorbidity. The genetic background of these cytokine alterations needs to be further investigated.

Prevalence of metabolic syndrome in subjects with melancholic and non-melancholic depressive symptoms. A Finnish population-based study

BACKGROUND We aimed to evaluate the prevalence of the metabolic syndrome (MetS) and its components in subjects with predominantly melancholic or non-melancholic depressive symptoms (DS) in a population-based study evaluating the efficacy of the Finnish diabetes prevention program (FIN-D2D). METHODS Altogether, 4500 randomly-selected Finnish men and women aged 45-74 years were initially enrolled from the National Population Register: 2820 (63%) attended a health examination. Diagnosis of MetS was based on the criteria of the National Cholesterol Education Program (NCEP-ATPIII), and DS on the 21-item Beck Depression Inventory (BDI-21, ≥10 points). A summary score of the melancholic items in the BDI was used to divide the subjects with DS (N=432) into melancholic and a non-melancholic sub-groups. RESULTS The prevalence of MetS was higher among subjects with non-melancholic DS compared to those with melancholic DS (69 % versus 55%, p 0.004). The prevalence of MetS among subjects without DS was 51%. The sex- and age-adjusted odd ratio (OR) for MetS was 2.10 (95%CI 1.62 to 2.73, p<0.001) when comparing the non-melancholic and non-depressed groups, 1.15 (95%CI 0.81 to 1.61, p=0.44) for the melancholic and non-depressed groups, and 1.84 (95%CI 1.20 to 2.80, p=0.005) for the non-melancholic and melancholic groups. LIMITATIONS DS were based on a self-rating scale, and due to the cross-sectional design of our study, we cannot make inferences of causality. CONCLUSIONS Compared to subjects without DS and those with melancholic DS, persons with non-melancholic DS may more frequently suffer from MetS.

P2RX7 polymorphisms Gln460Arg and His155Tyr are not associated with major depressive disorder or remission after SSRI or ECT.

Purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7) gene polymorphism, has been suggested to be associated with major depressive disorder (MDD). The association between P2RX7 gene polymorphism and remission after serotonin selective reuptake inhibitors (SSRI) or electroconvulsive therapy (ECT) has not previously been studied. The aims of the present study were to test for an association between P2RX7 polymorphisms Gln460Arg (rs2230912) and His155Tyr (rs208294) and MDD in two patient populations compared to controls. The first patient sample consisted of 119 subjects with treatment-resistant major depressive disorder, who were treated with ECT and the second of 99 depressive outpatients treated with SSRI. Genotype frequencies were also compared between remitters (Montgomery and Åsberg Depression Rating Scale (MADRS)<8) and non-remitters (defined as MADRS≥8) to SSRI or ECT treatment. There were no differences in allele or genotype frequencies of either rs2230912 or rs208294 between patient groups and controls. Neither rs2230912 nor rs208294 was associated with MDD or remission after SSRI or ECT. The results suggest that P2RX7 gene polymorphisms Gln460Arg (rs2230912) and His155Tyr (rs208294) are not associated with MDD or remission after SSRI or ECT.