Asmar Al Hadithy

Association between HTR2C gene polymorphisms and the metabolic syndrome in patients using antipsychotics : a replication study

In two previous studies we found an association between HTR2C polymorphisms and the prevalence of the metabolic syndrome in patients using antipsychotics. In this study, we set out to replicate our findings in a third separate sample of patients. Data for this cross-sectional study came from the ongoing Pharmacotherapy Monitoring and Outcome survey study, investigating the association between schizophrenia and metabolic or cardiovascular risk factors. Primary end point was the prevalence of the metabolic syndrome. Primary determinants were two polymorphisms in the HTR2C gene: rs3813929 (−759 C/T) and rs1414334:C>G. Carriership of the variant rs1414334 C-allele was significantly associated with an increase prevalence of the metabolic syndrome (odds ratio (OR) 3.73; 95% confidence interval (CI) 1.29–10.79, P=0.015). No association was found between the HTR2C −759 C/T polymorphism and the metabolic syndrome. This study confirms previous findings that the variant C-allele of the rs1414334 polymorphism is associated with the metabolic syndrome.

Pharmacogenetics of parkinsonism, rigidity, rest tremor, and bradykinesia in African-Caribbean inpatients: Differences in association with dopamine and serotonin receptors

We studied the association between polymorphisms of genes coding for dopamine D2 (DRD2), dopamine D3 (DRD3), serotonin 2a (HTR2A), and serotonin 2c (HTR2C) receptors and Antipsychotic‐Induced Parkinsonism (AIP), rigidity, bradykinesia, and rest‐tremor in African‐Caribbeans treated with antipsychotics. Polymorphisms of DRD2 (‐141CIns/Del, TaqIA, 957C > T), DRD3 (Ser9Gly), HTR2A (‐1438A > G, 102T > C, His452Tyr), and HTR2C (‐759C > T, Cys23Ser) genes were determined according to standard protocols. The Unified Parkinson Disease Rating Scale was used for the measurement of AIP, rigidity, bradykinesia, and rest‐tremor. Chi‐squared or Fishers exact tests were applied for the association analyses. The t‐test was applied for continuous data. Ninety nine males and 27 females met the inclusion criteria (Schizophr Res 1996, 19:195). In males, but not in females, there were significant associations between ‐141CDel‐allele carriership (DRD2) and rigidity (Fishers Exact Test: P = 0.021) and between 23Ser‐allele carriership (HTR2C) and bradykinesia (P = 0.026, χ2 = 5.0) or AIP (P = 0.008, χ2 = 7.1). Rest‐tremor was not associated with any of the polymorphisms studied. Analyses of the age, chlorpromazine equivalents, benztropine equivalents, the number of patients using anticholinergic medication, and the utilization patterns of the antipsychotic medication did not show statistically significant differences between patients with and without AIP, rigidity, bradykinesia, rest‐tremor. Conducting the analysis without gender stratification did not affect our findings considerably, except for the association between bradykinesia and 23Ser‐allele which failed to reach statistical significance in the total sample (P = 0.0646, χ2 = 3.41). Since AIPs subsymptoms (rigidity, bradykinesia, and rest‐tremor) may differ pharmacogenetically, our data strongly support symptom‐specific analysis of AIP. However, further research is warranted to confirm our findings.

Clinical response to antipsychotic drug treatment: Association study of polymorphisms in six candidate genes

Pharmacogenetic studies have demonstrated significant associations between several candidate genes (DRD2, DRD3, 5HTR2A and 5HTR2C, COMT and MTHFR) and antipsychotic drug response. The present study investigates the effect of nine polymorphisms in these genes for an association with antipsychotic treatment response. 329 Caucasian patients with a non-affective psychotic disorder using antipsychotics were included. All patients participated in the longitudinal GROUP-study in The Netherlands. We genotyped 9 SNPs in 6 candidate genes (DRD2: TaqI_A, -141C; DRD3: Ser9Gly; HTR2A: 102-T/C, His452Tyr; HTR2C: Cys23Ser; COMT: Val158Met; MTHFR: 677-C/T) using standard protocols. Polymorphisms were based on previous studies showing associations with positive symptoms treatment response. The Clinical Global Impression - Improvement (CGI-I) scale was used to assess improvement in positive psychotic symptoms since the start of current antipsychotic treatment. Ordinal regression was used for association analyses. Ninety percent of the patients used second generation antipsychotics, with olanzapine (28%) and risperidone (29%) being the most prescribed drugs. Ser9Gly of the dopamine D3 receptor gene (P value 0.034) and 677-C/T of MTHFR (P value 0.019) were tested statistically significant. Gly-carriers and T-carriers, respectively, showed more clinical improvement on the CGI-I. The other polymorphisms did not show a statistically significant association (P values>0.10). In conclusion, we replicated two out of nine of the previously reported associations between polymorphisms and treatment response. The direction and magnitude of the associations presented here in DRD3 (Ser9Gly) and MTHFR (677-C/T) are in line with previous association studies in Caucasian patients. These polymorphisms may be of value for predicting clinical response.

Estradiol gel : review of the pharmacology, pharmacokinetics, efficacy, and safety in menopausal women

Objective: To review the pharmacology, pharmacokinetics, safety, and efficacy of a gel containing estradiol that is applied to the skin. Design: MEDLINE and EMBASE searches were conducted from 1966 to March 2005. Additional references were identified from bibliographies from selected studies in addition to approved product information. Results: Estradiol gel is indicated for the relief of moderate to severe vasomotor symptoms in menopausal women, and moderate to severe symptoms of vulvar and vaginal atrophy. Women who are intolerant of the oral route, have had previous hypersensitivity skin reactions, or have had difficulties with adhesive patches are ideal candidates for estradiol gel. Conclusions: Estradiol gel can effectively reduce menopause symptoms with minimal side effects. Long-term safety data of estradiol gel are required.

Association Between the 1291-C/G Polymorphism in the Adrenergic α-2a Receptor and the Metabolic Syndrome

The prevalence of the metabolic syndrome is increased in patients with schizophrenia compared with the general population. The strong interindividual differences in susceptibility to developing the metabolic syndrome suggests that the genetic makeup is a modulating factor. Part of the genetic puzzle can possibly be explained by variations in the gene coding for the adrenergic &agr;-2a receptor (ADRA2A) because this receptor plays an important role in lipolysis. Three studies have found an association between the &agr;-2a 1291-C/G polymorphism and antipsychotic induced weight gain, with conflicting results between whites and Asians. No studies have been published investigating the association between the 1291-C/G polymorphism and the metabolic syndrome. The primary objective of this cross-sectional study was to investigate the association between the ADRA2A 1291-C/G polymorphism and the metabolic syndrome in 470 patients using antipsychotic drugs. There was no significant association between carriership of the variant 1291-G allele and prevalence of the metabolic syndrome (odds ratio, 0.73; 95% confidence interval, 0.49-1.15). Exploratory analysis showed an association between carriership of the variant 1291-G allele and a reduced prevalence of the metabolic syndrome in patients not currently using antipsychotics (odds ratio, 0.05; 95% confidence interval, 0.003-0.97; P = 0.048). In conclusion, this study shows that the ADRA2A 1291-C/G polymorphism does not seem to be a strong predictor for long-term occurrence of the metabolic syndrome in antipsychotic using patients. Studies investigating this association using a prospective, or retrospective, design, as well as studies investigating this association in a nonpsychiatric population, are warranted.

Antipsychotic-Induced Movement Disorders in Long-Stay Psychiatric Patients and 45 Tag SNPs in 7 Candidate Genes: A Prospective Study

Objective Four types of antipsychotic-induced movement disorders: tardive dyskinesia (TD), parkinsonism, akathisia and tardive dystonia, subtypes of TD (orofacial and limb truncal dyskinesia), subtypes of parkinsonism (rest tremor, rigidity, and bradykinesia), as well as a principal-factor of the movement disorders and their subtypes, were examined for association with variation in 7 candidate genes (GRIN2B, GRIN2A, HSPG2, DRD3, DRD4, HTR2C, and NQO1). Methods Naturalistic study of 168 white long-stay patients with chronic mental illness requiring long-term antipsychotic treatment, examined by the same rater at least two times over a 4-year period, with a mean follow-up time of 1.1 years, with validated scales for TD, parkinsonism, akathisia, and tardive dystonia. The authors genotyped 45 tag SNPs in 7 candidate genes, associated with movement disorders or schizophrenia in previous studies. Genotype and allele frequency comparisons were performed with multiple regression methods for continuous movement disorders. Results Various tag SNPs reached nominal significance; TD with rs1345423, rs7192557, rs1650420, as well as rs11644461; orofacial dyskinesia with rs7192557, rs1650420, as well as rs4911871; limb truncal dyskinesia with rs1345423, rs7192557, rs1650420, as well as rs11866328; bradykinesia with rs2192970; akathisia with rs324035; and the principal-factor with rs10772715. After controlling for multiple testing, no significant results remained. Conclusions The findings suggest that selected tag SNPs are not associated with a susceptibility to movement disorders. However, as the sample size was small and previous studies show inconsistent results, definite conclusions cannot be made. Replication is needed in larger study samples, preferably in longitudinal studies which take the fluctuating course of movement disorders and gene-environment interactions into account.

Pharmacoeconomics of quetiapine for the management of acute mania in bipolar I disorder

Bipolar disorder (or manic depression) is a lifelong, severe and complex psychiatric illness characterized by recurrent episodes of depression and mania. The aim of this study is to explore the cost–effectiveness of quetiapine compared with other alternatives for the treatment of acute manic episodes in bipolar I disorder, with a specific focus on serious side effects. Four trials investigating quetiapine monotherapy and adjunctive therapy were performed to investigate the efficacy of quetiapine in patients with bipolar I disorder. Data were derived from The Netherlands Mental Health Survey and Incidence Study and used to construct a study population for the model. To assess the cost–effectiveness of quetiapine in the management of acute mania in bipolar I disorders, a discrete event simulation model of seven monotherapy and combination treatment options was developed. A comparison of the total costs demonstrates that all of the monotherapy options and placebo are more costly than the combination therapy options. The combinations of lithium with risperidone (€2365) and with olanzapine (€2429) are estimated to be less costly per patient than the combination of lithium with quetiapine (€2555). A group of 10,000 patients switching from olanzepine/lithium to quetiapine/lithium would involve extra costs of €1,260,000, but would prevent an estimated number of 362 serious side effects. Switching from risperidone/lithium to quetiapine/lithium would cost an additional €1,900,000 and would prevent 1580 serious side effects. In terms of serious side effects, the combination of lithium/quetiapine was superior to the combination of lithium with olanzapine or risperidone. It must be considered whether the decreased likelihood of developing a severe side effect is worth the extra costs incurred with the combination of quetiapine/lithium.

No involvement of the adenosine A2A receptor in tardive dyskinesia in Russian psychiatric inpatients from Siberia

The adenosine A2A receptor forms a heteromeric complex with the striatal dopamine D2 receptor. We examined whether a specific polymorphism in adenosine A2A receptor (2592 C/Tins) is associated with tardive dyskinesia.

Association between the ROBO1 gene and body mass index in patients using antipsychotics

Background Weight gain is one of the major problems in patients using antipsychotic medication, leading to relevant morbidities and reduced compliance to pharmacotherapy. Recently, an association has been reported between a single nucleotide polymorphism (rs1455832) of the roundabout axon guidance receptor, homolog 1 (ROBO1) gene and body mass index (BMI) in persons younger than 30 years. The aim of this study is to investigate the association between BMI and rs1455832 in patients with a psychotic disorder using antipsychotics. Methods A cross-sectional design was used in a pooled sample of Caucasian psychiatric patients obtained from three comparable Dutch psychiatric populations. Patients were eligible for inclusion in this study if they met the Diagnostic and Statistical Manual of Mental Disorders-IV criteria for a nonaffective psychotic disorder, were 18 years or older, and used one or more antipsychotics. Genotyping was performed according to standard protocols. Linear (for BMI) and logistic (for obesity, defined as BMI>30) regression analyses, corrected for age and sex, were applied in the statistical analyses. Results A total of 435 patients were included in this association analyses. The rs1455832 polymorphism studied was significantly associated with BMI and obesity in female patients. Female patients had a statistically significant (P=0.025) decrease of 1.76 kg/m2 in BMI values per C allele. In contrast to female patients, this association was not exhibited in male patients. Conclusion The rs1455832 polymorphism may play a role in inducing obesity in female patients using antipsychotics.

Dehydroepiandrosterone sulphate as a putative protective factor against tardive dyskinesia

BACKGROUND Tardive dyskinesia (TD) is a potentially irreversible consequence of long term treatment with antipsychotic drugs which is according to a well-known theory believed to be related to oxidative stress induced neurotoxicity. Dehydroepiandrosterone (DHEA) is an endogenous antioxidant with neuroprotective activity. The biosynthesis of DHEA depends upon the activity of cytochrome P450c17α (CYP17). The gene that encodes for CYP17 has a (T34C) single nucleotide polymorphism which enhances CYP17 transcription and expression. OBJECTIVE To test the hypothesis that carriership of a more active CYP17 variant would result in higher DHEA(S) levels and protect against neurotoxicity which results in orofaciolingual TD (TDof), limb-truncal TD (TDlt) or both (TDsum). METHOD Tardive dyskinesia was assessed cross-sectionally in 146 Caucasian psychiatric inpatients from Siberia. RESULTS Patients who are carriers of the Cyp17 genotype CC have less chance of developing TD compared to patients who are carriers of the Cyp17 genotypes TC or TT (p<0.05). However, these carriers have significant lower circulating DHEAS levels compared to carriers of the Cyp17 genotypes TC and TT (p<0.05). Conversely, carriers of the CYP17 T-allele have significant elevated DHEAS levels. After correcting for gender and age no significant relationship between Cyp17 genotype CC, the T-allelle and the C-allele and the DHEAS concentration of patients was observed. CONCLUSIONS Although an association between the CYP17 CC genotype and TD is indicated, our findings do not support the hypothesis that this is mediated through increased DHEA(S) levels. We believe that the relationship between this polymorphism and neuroprotective effects of steroids is more complex and cannot be elucidated without taking the posttranslational regulation of the enzyme into account.