Burger, H.

Association of two DRD2 gene polymorphisms with acute and tardive antipsychotic-induced movement disorders in young Caucasian patients (Article)

2012-02-01T00:00:00Z

Rationale: Pharmacogenetic studies on antipsychotic-induced movement disorders (MD) in schizophrenia so far have focused mainly on tardive dyskinesia. Only a few examined the more acute antipsychotic-induced MD such as parkinsonism and akathisia. Notably, all MD relate to deregulation of the dopamine system. Objective: This study aimed to replicate previously reported associations in candidate genes for acute and tardive antipsychotic-induced MD in a young Caucasian sample. Methods: In 402 patients (median age 26 years), a total of 13 polymorphisms were genotyped in eight dopamine-related candidate genes selected a priori from the literature (regarding dopamine and serotonin receptors, dopamine degradation, and free radicals scavenging enzymes pathways). Results: Patients with MD used on average a higher haloperidol dose equivalent when compared to those without MD. The prevalence of MD was high and did not differ between first- and second-generation antipsychotics. Significant associations were found between (a) the TaqI-D polymorphism and akathisia (OR = 2.3, p = 0.001 for each extra C-allele) and (b) the -141C polymorphism and tardive dyskinesia (OR = 0.20, p = 0.001 for each extra Del allele). The other polymorphisms were not significantly associated with an MD. Conclusions: Two associations were found between genetic variation TaqI-D and the -141C polymorphisms in the DRD2 gene and antipsychotic-induced MD; one with acute akathisia and one with tardive dyskinesia. These were previously reported to be associated with tardive dyskinesia and acute parkinsonism, respectively. These results suggest that the contribution of these DRD2 gene variants in the vulnerability of antipsychotic-induced MD takes place in a more general or pleiotropic way.

Long-term response to successful acute pharmacological treatment of psychotic depression (Article)

2010-06-01T00:00:00Z

Background: Data about follow-up after acute pharmacological treatment of psychotic depression are scarce. Methods: A 4 month open follow-up was done, preferentially with same medication as during acute treatment, of patients (n=59) with DSM-IV-TR major depressive disorder with psychotic features, aged 18 to 65 years, who had completed as responders an acute doubleblind 7 week trial with imipramine, venlafaxine or venlafaxine plus quetiapine. Main outcome measures were Hamilton Rating Scale for Depression and Clinical Global Impression Scale. Results: Six patients dropped out during the 4 month follow-up. Almost all patients (86.4%; 51/59) remained responder while remission rate increased from 59.3% (35/59) to 86.8% (46/53), independent of treatment. Relapse rate was low (3.8%; 2/53). Tolerability was good. Weight increased with all treatments. Limitations: Limitations were the limited sample size and consequent limited statistical power. The treatment during follow-up was not double-blind. Conclusions: Continuation treatment with the same medication that was effective in the acute treatment trial, remained effective during the 4 month follow-up in many patients leading to further improvement, and was well tolerated.

Non-right-handedness and mental health problems among adolescents from the general population: The trails study (Article)

2010-05-01T00:00:00Z

To determine whether the association between non-right-handedness and mental problems among adolescents is specific for psychotic symptoms, we included a group of 2096 adolescents with a mean age of 14 years from the general population. Mental health problems were assessed using the parent, self-report, and teacher versions of the Child Behavior Checklist. Internalising problems comprised anxious and depressed, withdrawn and depressed, and somatic complaints. Externalising problems consisted of delinquent behaviour and aggressive behaviour. The remaining problems consisted of social problems, attention problems, and thought problems. The latter were divided into psychotic and non-psychotic items. A total of 14.3% of the adolescents were non-right-handed. We observed positive associations of non-right-handedness with thought problems, social problems, and being withdrawn and depressed. Externalising problems showed no associations with handedness. Within the thought problems subscale, the effect sizes associated with non-right-handedness for psychotic and non-psychotic items were 0.18 (p.005) and 0.04 (p.459), respectively. In conclusion, non-right-handedness is predominantly associated with psychosis-related mental problems as early as in adolescence. Handedness could be taken into account when identifying adolescents at risk for psychosis.

Treatment of unipolar psychotic depression: a randomized, double-blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine (Article)

2010-03-01T00:00:00Z

Abstract. OBJECTIVE: It remains unclear whether unipolar psychotic depression should be treated with an antidepressant and an antipsychotic or with an antidepressant alone. METHOD: In a multi-center RCT, 122 patients (18-65 years) with DSM-IV-TR psychotic major depression and HAM-D-17 > or = 18 were randomized to 7 weeks imipramine (plasma-levels 200-300 microg/l), venlafaxine (375 mg/day) or venlafaxine-quetiapine (375 mg/day, 600 mg/day). Primary outcome was response on HAM-D-17. Secondary outcomes were response on CGI and remission (HAM-D-17). RESULTS: Venlafaxine-quetiapine was more effective than venlafaxine with no significant differences between venlafaxine-quetiapine and imipramine, or between imipramine and venlafaxine. Secondary outcomes followed the same pattern. CONCLUSION: That unipolar psychotic depression should be treated with a combination of an antidepressant and an antipsychotic and not with an antidepressant alone, can be considered evidence based with regard to venlafaxine-quetiapine vs. venlafaxine monotherapy. Whether this is also the case for imipramine monotherapy is likely, but cannot be concluded from the data.

Socioeconomic position and mental health problems in pre- and early-adolescents: The trails study (Article)

2009-01-01T00:00:00Z

Background: Family socioeconomic position (SEP) is known to be associated with adolescent mental health. Whether the relationship is different for different mental health dimensions is unknown. Methods: Using a cross-sectional design, we investigated the differential effects of family SEP on multiple mental health dimensions in preadolescents (N = 2230, baseline age 10-12, 49% boys) using reports from multiple informants (parent, self, and teachers). A score equal to or higher than the 85th percentile (averaged across informants) defined mental health problems. Results: SEP was inversely associated with all dimensions. Compared to high SEP, the odds ratios (OR) for externalizing problems were 3.88 (95% confidence interval (CI): 2.56, 5.90) and 2.05 (CI: 1.34, 3.14) for low and intermediate SEP, respectively. For internalizing problems, they were 1.86 (CI: 1.28, 2.70) and 1.37 (CI: 0.94, 2.00), respectively. When adjusted for externalizing problems, SEP effects on internalizing problems materially attenuated (OR: 1.47, CI: 0.78, 1.68 and OR: 1.34, CI: 0.91, 1.96) while the converse was less pronounced (OR: 3.39, CI: 2.24, 5.15) and (OR: 1.91, CI: 1.25, 2.94). Conclusion: In early adolescence, the risk of mental health problems increases with decreasing SEP, particularly for externalizing problems. Further, the SEP-internalizing problems relationship is partly explained by shared aspects with externalizing problems.

Developing a Brief Cross-Culturally Validated Screening Tool for Externalizing Disorders in Children (Article)

2008-03-01T00:00:00Z

Objective: Most screening instruments for externalizing disorders have been developed and validated in Western children. We developed and validated a brief screening instrument for predicting externalizing disorders in native Dutch children as well as in non-Dutch immigrant children, using predictors that can be easily obtained from teachers. Method: Teachers completed the Strengths and Difficulties Questionnaire for an ethnic diverse sample of 2,185 children ages 6 to 10 years. In a stratified subsample, 254 children and their parents were additionally interviewed regarding psychiatric disorders and sociodemographic data. In this group, stepwise logistic regression was used to derive a score from sex and all items of the Hyperactivity and Conduct Problems Scale of the Strengths and Difficulties Questionnaire, for predicting a best-estimate diagnosis of any externalizing disorder. The accuracy of the score was compared between native Dutch and non-Dutch immigrant children. Results: Ninety-one cases of externalizing disorders were identified. An externalizing disorder could be predicted by the items restless, obeys, lies, and concentrates. Sex and ethnicity did not contribute to a prediction of an externalizing disorder. The area under the receiver operating characteristic was 0.84 (95% confidence interval 0.79Y0.89), indicating good discriminatory power with no substantial differences between native Dutch and non-Dutch immigrant children. Conclusions: Externalizing disorders in both native Dutch and non- Dutch immigrant children can be predicted with a scoring rule, based on only four items that can be easily assessed by teachers. Before this internally validated prediction tool can be implemented, external validation in another sample is necessary.

Treatment seeking for alcohol and drug use disorders by immigrants to the Netherlands (Article)

2007-05-01T00:00:00Z

Background: We compared risks of first contact with services for an alcohol use disorder (AUD) or drug use disorder (DUD) between the largest immigrant groups to the Netherlands and Dutch nationals. We tested the hypothesis that the ethnic pattern for DUD is similar to the previously demonstrated pattern for schizophrenia. Methods: Retrospective, population-based cohort study of First Admissions to Dutch psychiatric hospitals during the period 1990-1996 (national data) and First Contacts with inpatient or outpatient centres in Rotterdam for treatment of AUD or DUD during the period 1992-2001 (Rotterdam data). Results: In both datasets the risk of service contact for AUD was significantly lower in immigrants from Surinam, Turkey and Morocco than in Dutch nationals. The risk was lower or moderately higher in immigrants from western countries. Analysis of the national data showed that, compared with Dutch males, the risk of first hospital admission for DUD was higher for male immigrants from the Dutch Antilles (RR = 4.6; 95% CI: 4.0-5.3), Surinam (RR = 4.3; 3.9-4.7) and Morocco (RR = 2.3; 2.0-2.6), but not for male immigrants from Turkey (RR = 0.9; 0.7-1.1). A similar pattern was found with the Rotterdam data. Female immigrants from Surinam and the Dutch Antilles had a higher risk for DUD according to the national data, but a lower risk according to the Rotterdam data. Female immigrants from Turkey and Morocco had a lower risk (both datasets). Immigrants from western countries had a higher risk for DUD, but many had developed the disorder before emigrating. Conclusion: Those immigrant groups in the Netherlands that are at increased risk of schizophrenia appear also at increased risk of developing DUD, but not AUD.

Adjacent genes, for collagen type II?1 gene and the vitamin D receptor, are associated with separate features of the radiographic osteoarthritis at the knee (Article)

2000-01-01T00:00:00Z

OBJECTIVE: To study the association of the COL2A1 genotype, in relation to the vitamin D receptor (VDR) genotype, with features of radiographic osteoarthritis (ROA) in a population of elderly men and women. METHODS: In this cross-sectional study, we analyzed a population-based sample of 851 men and women ages 55-80 years from a large cohort study, the Rotterdam Study. We determined the prevalence of ROA of the knee according to the Kellgren/Lawrence (K/L) score and features of ROA (presence of osteophytes and narrowing of the joint space [JSN]) without considering clinical parameters of the disease. Genotypes were determined at a variable-number tandem repeats marker 1 kb downstream of the COL2A1 gene using a newly developed heteroduplexing method. The VDR genotype was previously determined by a direct molecular haplotyping polymerase chain reaction method to establish the phase of alleles at 3 adjacent restriction fragment length polymorphisms for Bsm I, Apa I, and Taq I. RESULTS: We found the COL2A1 genotype to be associated with a 2-fold increased risk for JSN, but not with osteophytes or the K/L score. We had previously found the VDR genotype to be associated with osteophytes and the K/L score, but not with JSN. When the COL2A1 genotype was analyzed in combination with the VDR genotype, we found evidence suggesting that the presence of haplotypes of the 2 genes was associated with increased risk for ROA. CONCLUSION: Our findings demonstrate that both the COL2A1 gene and the VDR gene are involved in ROA, but in separate features. The COL2A1 genotype is associated with JSN, while the VDR genotype is associated with osteophytes.

Estrogen receptor polymorphism predicts the onset of natural and surgical menopause (Article)

1999-01-01T00:00:00Z

Age at menopause and risk of hysterectomy have strong genetic components, but the genes involved remain ill defined. We investigated whether genetic variation at the estrogen receptor (ER) gene contributes to the variability in the onset of menopause in 900 postmenopausal women, aged 55-80 yr, of the Rotterdam Study, a population-based cohort study in The Netherlands. Gynecological information was obtained, and if women reported surgical menopause, validation of type and indication of surgery was accomplished by checking medical records. The ER genotypes (PP, Pp, and pp) were assessed by PCR using the PvuII endonuclease. Compared with women carrying the pp genotype, homozygous PP women had a 1.1-yr (P < 0.02) earlier onset of menopause. Furthermore, an allele dose effect was observed, corresponding to a 0.5-yr (P < 0.02) earlier onset of menopause per copy of the P allele. The risk of surgical menopause was 2.4 (95% confidence interval, 1.5-3.8) times higher for women carrying the PP genotype compared to those in the pp group, with the most prominent effect in women who underwent hysterectomy due to fibroids or menorrhagia. We conclude that genetic variations of the ER gene are related to the onset of natural menopause and the risk of surgical menopause, especially hysterectomy.

A polymorphism in the glucocorticoid receptor gene may be associated with and increased sensitivity to glucocorticoids in vivo (Article)

1998-01-01T00:00:00Z

We investigated whether a polymorphism at nucleotide position 1220, resulting in an asparagine-to-serine change at codon 363 in the glucocorticoid receptor (GR) gene is associated with an altered sensitivity to glucocorticoids. In a group of 216 elderly persons, 13 heterozygotes for the N363S polymorphism were identified by PCR/single strand conformation polymorphism analysis. In 2 dexamethasone (DEX) suppression tests (DSTs), using 1 and 0.25 mg DEX, the circulating cortisol and insulin concentrations were compared between N363S carriers and controls. In the 1-mg DST, there were no differences between N363S carriers and controls, with respect to adrenal suppression, but there was a significantly higher (P < 0.05) insulin response in N363S carriers. In the 0.25-mg DST, a significantly larger (P < 0.05) cortisol suppression and higher (P < 0.05) insulin response were seen in N363S carriers. Comparison of blood pressure, body mass index (BMI), and bone mineral density (BMD) between the N363S carriers and controls showed that N363S carriers had a higher (P < 0.05) BMI but normal blood pressure. There was an obvious trend towards lower age-, BMI-, and sex-adjusted BMD in the lumbar spine in N363S carriers. GR characteristics measured in 41 controls and 9 N363S carriers in peripheral mononuclear leucocytes showed no differences between N363S carriers and controls, with respect to GR number and ligand binding affinity. However, there was a trend towards greater sensitivity to DEX in the carriers' lymphocytes, in a mitogen-induced cell proliferation assay. In transfection assays, the capacity of the codon 363 variant to activate mouse mammary tumor virus promotor-mediated transcription in COS-1 cells was unaltered, when compared with the wild-type GR. We conclude that in 6.0% of our study population, a polymorphism in codon 363 of the GR gene was found. Individuals carrying this polymorphism seemed healthy at clinical examination but had a higher sensitivity to exogenously administered glucocorticoids, with respect to both cortisol suppression and insulin response. Life-long exposure to the mutated allele may be accompanied by an increased BMI and a lowered BMD in the lumbar spine but does not affect blood pressure.

Relation of alleles of the collagen type Ialpha1 gene to bone density and the risk of osteoporotic fractures in postmenopausal women (Article)

1998-01-01T00:00:00Z

BACKGROUND: Osteoporosis is a common disorder with a strong genetic component. One way in which the genetic component could be expressed is through polymorphism of COLIA1, the gene for collagen type Ialpha1, a bone-matrix protein. METHODS: We determined the COLIA1 genotypes SS, Ss, and ss in a population-based sample of 1778 postmenopausal women using a polymerase-chain-reaction-based assay. We then related the genotypes to bone mineral density and the occurrence of osteoporotic fractures in these women. RESULTS: As compared with the 1194 women with the SS genotype, the 526 women with the Ss genotype had 2 percent lower bone mineral density at the femoral neck (P=0.003) and the lumbar spine (P=0.02); the 58 women with the ss genotype had reductions of 4 percent at the femoral neck (P= 0.05) and 6 percent at the lumbar spine (P=0.005). These differences increased with age (P=0.01 for modification by age of the effect of COLIA1 on femoral-neck bone density, and P=0.004 for modification of the effect on lumbar-spine bone density). Women with the Ss and ss genotypes were overrepresented among the 111 women who had incident nonvertebral fractures (relative risk per copy of the s allele, 1.5; 95 percent confidence interval, 1.1 to 2.1). CONCLUSIONS: The COLIA1 polymorphism is associated with reduced bone density and predisposes women to osteoporotic fractures.

Gender-specific relationship between serum free and total IGF-I and bone mineral density in elderly men and women (Article)

1998-01-01T00:00:00Z

OBJECTIVE: Little is known about the association between free IGF-I levels and bone mineral density (BMD). DESIGN: A cross-sectional study of 218 healthy subjects (103 men, 115 women, age 55-80 years) was carried out. METHODS: Fasting serum free IGF-I, total IGF-I, estradiol and sex hormone-binding globulin (SHBG) levels were measured. The ratio of estradiol to SHBG was used as an index of free estradiol. BMD measurements were performed by dual-energy X-ray absorptiometry of the lumbar spine and the proximal femur. RESULTS: In multivariate analyses with BMD of the lumbar spine as the dependent variable and serum free IGF-I, age, body mass index (BMI) and the free estradiol index as independent variables, the free IGF-I was positively related to the BMD of the lumbar spine in men (P = 0.02) but not in women. When the same analyses for the lumbar BMD were performed with total serum IGF-I the association was also only statistically significant in men (P = 0.05). In multivariate analyses with the trochanter BMD as the dependent variable and serum free IGF-I, total IGF-I, age, BMI and the free estradiol index as independent variables, the associations between (free and total) IGF-I and the trochanter BMD in men was of borderline significance. CONCLUSIONS: In elderly men free and total IGF-I were positively related to lumbar BMD, while (free and total) IGF-I was borderline positively related to trochanter BMD. As these relationships were not observed in elderly women, we suggest a weak gender-specific anabolic effect of IGF-I on BMD on trabecular bone.

Vitamin D receptor genotype is associated with osteoarthritis (Article)

1997-01-01T00:00:00Z

Osteoporosis and osteoarthritis are age-related disorders of the skeleton with genetic components. Low bone density is a risk factor for osteoporotic fracture while osteoarthritis is associated with increased bone density. The 1,25-dihydroxy-vitamin D3 receptor (VDR) gene locus was previously found to be associated with bone density. We therefore studied the relationship between radiographic osteoarthritis at the knee and VDR genotype in a population-based sample (n = 846), using molecular haplotyping of anonymous intragenic DNA polymorphisms. Radiographic osteoarthritis was defined using the Kellgren score, which is based on the assessment of osteophytes and joint space narrowing (JSN). We show that one VDR haplotype allele is significantly overrepresented in individuals with knee osteoarthritis and associated with a 2.27-fold increased relative risk (95% confidence interval 1.46, 3.52). Adjustment for bone density at the femoral neck did not change these results, indicating that the association is not mediated by bone density. The association appeared to be largely explained by the presence of osteophytes rather than JSN. Our results indicate a role of the VDR gene in the pathogenesis of osteophytes while linkage disequilibrium with another nearby gene, i.e., the collagen type IIa1 gene encoding the most abundant protein in cartilage, might contribute to the association.

Epidemiologic studies on bone mineral density and fractures (Doctoral Thesis)

1995-12-06T00:00:00Z

Osteoporosis is currently defined as a systemic skeletal disease characterized by low bone mass and microarchitectnral deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. The burden of fractures is substantial, both in terms of individual and public health. The most serious fracture, i.e. hip fracture, is associated with a high mortality rate of approximately 25 % within one year and a considerable decline of physical and social functions. Hip fracture is not a rare event. On average, the lifetime risk of a hip fracture for a 50 year old woman is approximately 16 % 4. The total number of incident hip fractures in the Netherlands was 10360 in 1987 and it is expected that, partly as a consequence of aging of the population, this number will have exceeded 20000 by the year of 2010. The general aim of the thesis is to study determinants of bone density and consequences of vertebral fractures or deformities.