J. de Leon

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

The last decade of research into the pharmacogenetics of antipsychotics has seen the development of genetic tests to determine the patients’ metabolic status and the first attempts at personalization of antipsychotic treatment. The most significant results are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects. Patients with genetically determined CYP2D6 poor metabolizer (PMs) status may require lower doses of antipsychotic. Alternatively, CYP2D6 ultrarapid matabolizers (UMs) will need increased drug dosage to obtain therapeutic response. Additionally, polymorphisms in dopamine and serotonin receptor genes are repeatedly found associated with response phenotypes, probably reflecting the strong affinities that most antipsychotics display for these receptors. In particular, there is important evidence suggesting association between dopamine 2 receptor (D2) polymorphisms (Taq I and −141-C Ins/Del) and a dopamine 3 receptor (D3) polymorphism (Ser9Gly) with antipsychotic response and drug-induced tardive dyskinesia. Additionally, there is accumulating evidence indicating the influence of a 5-HT2C polymorphism (−759−T/C) in antipsychotic-induced weight gain. Application of this knowledge to clinical practice is slowly gathering pace, with pretreatment determination of individuals drug metabolic rates, via CYP genotyping, leading the field. Genetic determination of patients’ metabolic status is expected to bring clinical benefits by helping to adjust therapeutic doses and reduce adverse reactions. Genetic tests for the pretreatment prediction of antipsychotic response, although still in its infancy, have obvious implications for the selection and improvement of antipsychotic treatment. These developments can be considered as successes, but the objectives of bringing pharmacogenetic and pharmacogenomic research in psychiatric clinical practice are far from being realized. Further development of genetic tests is required before the concept of tailored treatment can be applied to psychopharmatherapy. This review aims to summarize the key findings from the last decade of research in the field. Current knowledge on genetic prediction of drug metabolic status, general response and drug-induced side effects will be reviewed and future pharmacogenomic and epigenetic research will be discussed.

Suicide attempts and impulsivity.

AbstractImpulsivity in suicidal behavior can describe the attempt (state) or the attempter (trait). There are no studies simultaneously measuring attempt impulsivity and attempter impulsivity in representative samples of suicide attempts. A one–year study of 278 suicide attempts in a general hospital tested the continuous versus dichotomous relationship between attempter impulsivity (Barratt Impulsiveness Scale) and attempt impulsivity (low scores in the planning subscale of Beck’s Suicidal Intent Scale). Attempter impulsivity was not a good predictor of attempt impulsivity independently of how both dimensions were measured (continuous or dichotomous ways). Impulsive attempts were associated with low lethality and lack of depression. Opportunities for prevention of suicide attempts in major depression and some personality traits may exist but require attentive monitoring of suicidal ideation and intent.

Fagerstrom test for nicotine dependence vs heavy smoking index in a general population survey

BackgroundThe Fagerström Test for Nicotine Dependence (FTND) is used for assessing nicotine dependence. A shorter test derived from the FTND used for the general population is the Heavy Smoking Index (HSI) (six questions vs. two). The objective of this study is to compare the validity of the HSI versus the FTND.MethodsA survey of tobacco use in the general population was carried out in the northern Spanish region of Galicia using both the FTND and the HSI to study a representative sample of 1655 daily smokers. The HSI was compared with the FTND, considered the gold standard. Measures of sensitivity, specificity and predictive values were calculated. Concordance between the tests was also established (Cohens kappa).ResultsCohens kappa showed good agreement between measures (Kappa = 0.7); specificity values were also high (Sp = 96.2%). Sensitivity analysis in females (Se = 62.3%) did not show good agreement.ConclusionsThe HSI can be used as a reasonably good screening test in order to identify daily smokers with high nicotine dependence. Nevertheless, for populations or subpopulations having low nicotine dependence, such as women, the FTND is more reliable.

Severity of personality disorders and suicide attempt

Objective:  Severity of personality disorders (PDs) may be more useful in estimating suicide risk than the diagnosis of specific PDs. We hypothesized that suicide attempters with severe PD would present more attempts and attempts of greater severity/lethality.

Pharmacogenomics in Psychiatry: From Therapeutic Drug Monitoring to Genomic Medicine

Psychiatry is increasingly combining new pharmacogenomic findings with therapeutic drug monitoring (TDM) to improve the safety and efficacy of pharmacotherapy. However, a distinction should be made between “nice to know” and “need to know” pharmacogenomic data because many results are statistically significant in meta‐analyses but are not clinically relevant due to their low effect sizes. Some examples will illustrate this integration.

Diagnostic stability and evolution of bipolar disorder in clinical practice: a prospective cohort study

Objective:  To evaluate the long‐term stability of International Classification of Diseases‐10th revision bipolar affective disorder (BD) in multiple settings.

Apolipoprotein-E gene variants associated with cardiovascular risk factors in antipsychotic recipients

Interest exists in identifying the factors that specifically contribute to the increased prevalence of cardiovascular disease observed in psychiatric disease. The apolipoprotein-E (APOE) gene codes for a protein that has a key role in metabolism of cholesterol and triglycerides, with increased levels of apoE found in specific areas of post-mortem schizophrenic brains. This study investigated whether apoE variants influence the prevalence of cardiovascular risk factors (obesity, diabetes and dyslipidaemia), in patients receiving antipsychotic treatment, due to extension of the risk seen in the general population, but also due to the role of the APOE gene in mediating antipsychotic-induced side effects. Seven polymorphisms (rs741780, rs483082, rs429358, rs7412, rs10119, rs439401 and rs405509) were genotyped in 427 American Caucasian patients who were either receiving, or had been prescribed risperidone. Our results support the hypothesis that APOE gene variants influence the prevalence of diabetes and possibly overweight in psychiatric patients. Unfortunately, due to the cross sectional nature of this study, the contribution of antipsychotic treatment was not determined. These associations warrant prospective study to assess interaction between APOE gene variants and the propensity of antipsychotics to induce cardiovascular risk factors.

No association between the Ser9Gly polymorphism of the dopamine D3 receptor gene and schizophrenia in a Spanish sample

This study aims to further evaluate the controversial association between the Ser9Gly polymorphism in codon 9 of the D3 dopamine receptor gene (DRD3) and schizophrenia in psychiatric inpatients acutely hospitalized in two general hospitals in Madrid, Spain. The Ser9Gly polymorphism of the DRD3 was examined in 178 schizophrenic patients, 286 patients with other psychiatric diagnoses, and 132 controls recruited. Genotype frequencies were in Hardy‐Weinberg equilibrium. No association was found between schizophrenia and the Ser9Gly polymorphism of the D3 dopamine receptor gene.

Nicotine addiction in chronic schizophrenic inpatients

27) were adult neuroleptic-medicated inpatients with a DSM-III-R diagnosis of chronic schizophrenia (n = 22) or schizoaffective disorder (n = 5). Paired t tests revealed higher B! than NAART estimates for FSIQ (NAART m =97.2, BI m z 103.8; t[23] 2.63, p < 0.05), VIQ (NAART m -93.7, BI m = 103.2; t[23] =3.5, p < 0.05), but not PIQ. NAART and BI correlations with age, illness duration, education, and mental status (MS) revealed no significant associations. A trend between NAART and MS (r 0.37, p = 0.07) emerged. The possible NAART/MS relation suggested the NAART may be sensitive to cognitive deterioration. One possibility is that the ability to read/retrieve irregular words declines in schizophrenia, consistent with models of left hemisphere dysfunction. Studies with matched controls and nonchronic patients will determine if lower NAART scores reflect lower premorbid IQ or deterioration. As four of six BI components are demographic in nature and relatively independent of schizophrenia disease processes, these results may suggest that the BI is better suited for premorbid IQ estimation in schizophrenia.

P02-40 Searching for variables associated with familial suicide attempts using data mining techniques

Introduction Adoption, twin and family studies suggest that suicide behavior is familial and heritable. Both completed and attempted suicide appear to be transmitted in a familial form. Genetics and environment influences had been detected in various studies. But suicidal behavior suggests to be inherited independently from the mental disorders usually associated with it. While traditional statistics emphasizes inference and estimations, data mining emphasizes the fulfillment of a task such as classification, estimation, or knowledge discovery. Objectives The goal of this study was to determine in a large sample of suicide attempts which variables are associated with family history of attempted suicide. Methods In an emergency room, 539 adult suicide attempters were recruited. The two dichotomous dependent variables were family history of suicide attempt (10%) and of completed suicide (4%). Independent variables were 101 clinical variables explored with two data mining techniques: Random Forest and Forward Selection. Results A model for family history of completed suicide could not be developed. A classificatory model for family history of attempted suicide included the use of alcohol in the intent and family history of completed suicide, provide a sensitivity of 78.4%, a specificity of 98.7% and accuracy of 96.6%. Conclusions A classificatory model for family history of completed suicide could not be developed using data mining techniques. But it suggested that the use of alcohol in the intent and family history of completed suicide may be associated with familial attempted suicide.