Association study of arcuate nucleus neuropeptide Y neuron receptor gene variation and serum NPY levels in clozapine treated patients with schizophrenia.

BACKGROUND: Antipsychotic-induced weight gain (AIWG) leads to metabolic consequences and comorbidity, social stigmatization and nonadherence in patients with schizophrenia. Neuropeptide Y (NPY) has an important role in appetite and body weight regulation. Associations between AIWG and serum NPY levels, and genetic polymorphisms (SNPs) associated with its serum levels have been little studied in these patients. SUBJECTS AND METHODS: Associations between serum NPY concentration and other metabolic and inflammatory markers, and 215 SNPs in 21 genes (NPY gene, NPY receptor genes and genes encoding arcuate nucleus NPY neuron receptors) were studied in 180 patients with schizophrenia on clozapine treatment. RESULTS: The serum levels of NPY correlated with levels of resistin (r=0.31, P<0.001) and age (r=0.22, P=0.003). In the general linear univariate model the best-fitting model with explanatory factors age, serum resistin level, serum insulin level, BMI and gender explained 18.0% (P<0.001) of the variance of serum NPY. Genetic risk score (GRSNPY) analysis found twelve significant (P<0.05) serum NPY concentration related SNPs among α7 nicotinic acetylcholine receptor gene CHRNA7, insulin receptor gene INSR, leptin receptor gene LEPR, glucocorticoid receptor (GR) gene NR3C1, and NPY gene. However, after permutation test of gene score the predictive value of GRSNPY remained non-significant (P=0.078). CONCLUSIONS: Serum NPY level does not seem to be a feasible biomarker of AIWG. Serum NPY level alterations are not significantly associated with the candidate gene polymorphisms studied.

Association study of the HTR2C, leptin and adiponectin genes and serum marker analyses in clozapine treated long-term patients with schizophrenia.

Clozapine treatment is associated with weight gain and cardio-metabolic consequences among patients with schizophrenia. Polymorphisms of leptin, serotonin receptor HTR2C and adiponectin genes have been associated with antipsychotic-induced weight gain and metabolic comorbidity. However, the results of the studies so far are inconclusive. The aim of the present study was first to test for a possible role of serum leptin and adiponectin levels as a marker of weight gain in association with inflammatory cytokines/adipokines (IL-6, IL-1Ra, hs-CRP and adipsin), and second to study associations between SNPs LEP rs7799039 (-2548 A/G), ADIPOQ rs1501299 and HTR2C rs1414334 and weight gain and levels of leptin and adiponectin, in 190 patients with schizophrenia on clozapine treatment, with retrospectively assessed weight change and cross-sectionally measured cytokine levels. A strong association was found between serum levels of leptin and weight gain and cytokines/adipokines related to metabolic comorbidity, especially among female patients (in women leptin vs. weight gain, IL-6 and IL-1Ra, P<0.001; in men leptin vs. weight gain, P=0.026, leptin vs. IL-1Ra, P<0.001). In male patients low adiponectin level was a more specific marker of clozapine-induced weight gain (P=0.037). The results of the present study do not support a major role of SNPs LEP rs7799039, ADIPOQ rs1501299 and HTR2C rs1414334 in the regulation of weight gain or association of serum levels of leptin and adiponectin and corresponding studied SNPs in patients with schizophrenia on clozapine treatment.

Temperament profiles, major depression, and response to treatment with SSRIs in psychiatric outpatients.

OBJECTIVE: The Temperament and Character Inventory (TCI) is commonly used in adult populations. Our aim was to explore: (1) if there are specific differences in temperament dimensions related to depression in comparison with general population, (2) if the treatment response during the acute phase of major depressive disorder (MDD) is predictable by TCI temperament dimensions. METHOD: Temperament profiles in 98 MDD patients were compared with a Finnish community sample. The patients were treated with serotonin selective reuptake inhibitors (SSRIs) for 6 weeks and their temperament profiles were assessed at baseline and endpoint. The harm avoidance (HA) and depression scores at baseline and endpoint were modelled with path analysis. For path modelling, we tested the relationships between different temperament dimensions and depression symptoms and other clinical variables with Mancova model. RESULTS: The HA scores were significantly higher in patients both at baseline and endpoint compared to the Northern Finland 1966 Birth Cohort (NFBC). The patients, and especially males, had slightly higher reward dependency (RD) scores. HA at endpoint explained moderately the Montgomery Åsberg Depression Rating Scale (MADRS) endpoint score. HA endpoint score was strongly explained by HA baseline score. CONCLUSIONS: HA is associated with risk of and treatment response to depression.

Risk of cervical cancer subsequent to a positive screening cytology: follow-up study in Finland.

BACKGROUND: The purpose of the study was to estimate subsequent incidence of cervical cancer among women with positive cytology followed by negative histology. METHODS: This was a longitudinal cohort study involving about 80,000 women with class II, III, IV or V cytology at the organized mass screening in Finland in 1971 1990. Follow-up through the Finnish Cancer Registry started from the fifth month following the initial screening and ended on December 31, 1995. RESULTS: Standardized incidence ratios (SIR) of invasive cervical cancer varied from 2.2 (class II) to 19 (class V), and SIRs of preinvasive lesion varied from 3.0 (class II) to 20 (class V) compared to the risk among the total Finnish female population of same age and calendar period. The relative risk was greatest during first years of follow-up for both preinvasive and invasive cervical lesions, and it remained significantly high over 5 years of follow-up. For women with class II cytology there were peaks in relative risk in the years of subsequent rescreenings. CONCLUSION: Women with positive cytology have a high relative risk of cervical cancer even when excluding the cancers found at screening; the high relative risk is persistent for more than 5 years, and therefore these women should be kept under close surveillance and repeated smears should be taken with relatively short intervals.

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.

Risk of cervical cancer after a negative Pap smear.

OBJECTIVE: To evaluate whether five years is an appropriate screening interval for cervical cancer for the improvement of public health. SETTING: Finland. METHODS: 45,572 women with a cytological class I smear attending the mass screening programme organised every five years in Finland during 1971 to 1976 and followed up until the end of 1994. The data from the Nationwide Mass Screening Registry were linked to the Finnish Cancer Registry. Standardised incidence ratios of preinvasive and invasive cervical cancer with 95% confidence intervals (CI) were estimated, with rates for the total Finnish population as reference. RESULTS: The standardised incidence ratio estimates were low initially after screening and then gradually increased up to the time of the next smear five years later. This pattern was repeated after each screening. The risk was persistently low for invasive cervical cancer even after 10 years of follow up, whereas the low risk for preinvasive lesions was of a shorter duration. The low risk associated with a negative smear became even lower with advancing age. CONCLUSIONS: Women who attend organised screening programmes and have a negative smear have a low risk of cervical cancer for over 10 years. Also, the relative risk of a preinvasive lesion after an initial negative smear is decreased for more than five years. Therefore, the five year screening interval in Finland is appropriate and effective in reducing the risk of invasive cervical cancer.

Risk of endometrial, ovarian, vulvar, and vaginal cancers after a positive cervical cytology followed by negative histology.

OBJECTIVE: To estimate the subsequent incidence of cancers of endometrium, ovary, vulva, and vagina among women with positive cytology at screening for cervical cancer followed by negative histology. METHODS: This was a longitudinal cohort study involving women attending the organized mass screening in Finland from 1971-1990 with class II, III, IV, or V cytology followed by negative histologic confirmation, and a sample of 42,844 women attending the organized mass screening in Finland in 1971-1976 with cytologic class I smears without any gynecologic symptoms or infections. Follow-up on the women to the end of 1994 for subsequent cancers was maintained by linkage to the national cancer registry. Standardized incidence ratios with 95% confidence intervals (CI), with rates for all of Finland as reference, were estimated. RESULTS: The standardized incidence ratios after negative class I smears of all the cancers studied were between 0.9 and 1.0. Ovarian cancer was not associated with positive cervical cytology. After positive class III-V cytology, the standardized incidence ratio of endometrial carcinoma was 1.6 (CI 1.0, 2.2) and that of vulvar carcinoma was 5.8 (CI 2.3, 12). The standardized incidence ratios of vaginal cancer after class II and III-V cytological smear were 2.7 (CI 1.7, 4.1) and 16.4 (CI 7.1, 32), respectively. The relative risks of all the cancers studied were greatest during the first year of follow-up and persisted for more than 5 years for vulvar and vaginal cancers. CONCLUSION: Although the Papanicolaou smear is poor in detecting cancers other than cervical, in clinical practice, the possibility of other gynecologic cancer has to be considered in surveillance after positive cervical cytology is followed by negative histology.

Bleeding symptoms and subsequent risk of gynecological and other cancers.

BACKGROUND: The purpose of our study was to find out whether bleeding symptoms are predictive factors of subsequent gynecological or urinary cancers among women screened negative. METHODS: The data stemmed from the Finnish Mass Screening Registry, and were linked to the National Cancer Registry: 37,596 screening negative women in the nationwide population-based mass screening program for cervical cancer were classified by their bleeding symptom (bloody discharge, coital bleeding, irregular bleeding, postmenopausal bleeding) at the time of screening (1985-1990) and followed up (1985-1994) in order to assess the subsequent risk of cancer. RESULTS: Bleeding symptoms with prevalence of 5.9% were more likely to be signs of preinvasive than invasive cervical cancer with the exception of coital bleeding, nevertheless relative risk of cervical cancer (SIR 1.1, 95% CI 0.8-1.4) was not significantly increased during the total follow-up of maximum 10 years. Women with any bleeding symptom had increased risk of cancer of the corpus uteri (SIR 2.1, 95% CI 1.6-2.6), postmenopausal bleeding was the strongest symptom (RR 3.6, 95% CI 2.0-6.0). None of the bleeding symptoms increased subsequent risk of ovarian, vaginal or vulvar carcinoma. The risk of kidney cancer was increased (SIR 1.7, 95% CI 1.0-2.6). CONCLUSIONS: The prevalence of bleeding symptoms was small and relative risks for cancers were low for them to be suitable as predictive factors of cancer neither in clinical practice nor for public health purposes, e.g. in developing selective screening based on this high risk group. Only 34 gynecological cancers during 220,000 person-years in women with bleeding symptoms were attributable to bleeding. Relative risks remained increased only for a short time after screening. Therefore, short term surveillance is important, but due to the fact that relative risks approached unity during the follow-up, reassurance of a woman that she is cancer-free should be emphasized more in the long term after the bleeding symptoms.