J.L. Kennedy

Meta-analysis of two dopamine D2 receptor gene polymorphisms with tardive dyskinesia in schizophrenia patients.

Meta-analysis of two dopamine D 2 receptor gene polymorphisms with tardive dyskinesia in schizophrenia patients

Clinical implications of pharmacogenomics for tardive dyskinesia

INTRODUCTION Spontaneous dyskinetic (or abnormal) movements have been associated with schizophrenia (or to some subforms) independently of the use of antipsychotics. It has been suggested that some forms of dyskinesia may at least partially be intrinsic to the pathophysiology of schizophrenia, perhaps reflecting basal ganglia pathology. However, up to 50% of patients affected with schizophrenia typically develop dyskinesia in combination with long-term exposure (ie months to years) of traditional or ‘typical’ antipsychotics. The term tardive dyskinesia (TD) refers to this potentially irreversible complication that is, by definition, caused by the long-term use of antipsychotic medication. TD consists of hyperkinetic involuntary movements, most commonly characterized by orofacial dyskinesia, but it may include tics, chorea and/or athetosis or a combination of these. For obvious reasons, TD may be extremely distressing to patients as it substantially debilitates motor performances in normal life. Furthermore, TD may lead to social stigmatization or to difficulties in finding employment. The presence of schizophrenia is not necessary to develop antipsychotic induced dyskinesias, as these occur also in patients treated with antipsychotics for other conditions than schizophrenia. A meta-analysis including 76 studies on 39 187 patients with chronic antipsychotic treatment reported TD rates that ranged from 3 to 70% and an overall prevalence of 24.2%. Prevalence rates are, however, difficult to estimate because of the fluctuating course of TD and heterogeneities across studies with respect to study population, diagnostic criteria used, type and dose of (co-)medications, etc. Age, regardless of the duration of treatment, is an important risk factor for TD, as TD is five to six times more prevalent in the elder (445 years) than in younger patients. Even though newer (or ‘atypical’) antipsychotics have a lower or perhaps negligible risk to induce TD, classical (or typical) antipsychotics are, however, currently still prescribed for many reasons: Typical antipsychotics are less expensive than atypical antipsychotics, which may globally be one leading reason. Moreover, some patients do not respond or tolerate treatment with atypical antipsychotics that may cause side effects as weight gain or diabetes mellitus. Finally, if patients are treated by intramuscular application of antipsychotics (ie with depot formula), this particular pharmacopeia is mostly composed of classical antipsychotics. Therefore, TD still represents a serious and prevalent adverse effect. The prevention of TD and the detection of associated risk factors are of great clinical importance as no uniformly safe and effective treatment for TD is available yet. In this review, we retrieved literature with the use of the computerized database MEDLINE (1966 to July 2003), and abstracts that refer to patient samples that were included in a pooled analysis on the dopamine D3 receptor gene by Lerer et al. We do not refer to findings published earlier than 1995 related to the human leukocyte antigen (HLA) and TD, as we wish to focus on more recent findings. To be complete in our coverage of recent data, we refer to three study findings that have not been published yet, which focus on the CYP1A2, NOS1 and DBH genes (see Table 2).

Investigation of polymorphism in the MDR1 gene and antidepressant-induced mania

ABSTRACTThe involvement of the multi-drug-resistant 1 P-glycoprotein gene (MDR1 P-gp) in the transport of antidepressants across the blood–brain barrier makes it a good candidate for the prediction of antidepressant response and side effects. We investigated the role of the MDR1 P-gp gene in predicting the induction of mania in bipolar patients (BP) treated with proserotonergic drugs. Participants met the DSM-IV criteria for BP or BPII and had at least one depressive episode treated with proserotonergic antidepressants. The first group (n=26) included patients with at least one DSM-IV manic/hypomanic episode developed during antidepressant treatment; the second group (N=29) included patients with no antidepressant-induced switches. The common polymorphism of the MDR1 was genotyped for both groups and comparison was made with respect to the presence/absence of induced mania between the two groups. No association between antidepressant-induced mania and the MDR1 alleles or genotypes was found (χ2=1.85, 2 df, P=0.39; χ2=0.13, 1 df, P=0.72).

Dopamine receptors D1 and D2 are related to observed maternal behavior.

The dopamine pathway and especially the dopamine receptors 1 and 2 (DRD1 and DRD2) are implicated in the regulation of mothering in rats. Evidence for this in humans is lacking. Here, we show that genetic variation in both DRD1 and DRD2 genes in a sample of 187 Caucasian mothers predicts variation in distinct maternal behaviors during a 30‐min mother–infant interaction at 6 months postpartum. Two DRD1 single‐nucleotide polymorphisms (SNPs rs265981 and rs686) significantly associated with maternal orienting away from the infant (P = 0.002 and P = 0.003, respectively), as did DRD1 haplotypes (P = 0.03). Two DRD2 SNPs (rs1799732 and rs6277) significantly associated with maternal infant‐directed vocalizing (P = 0.001 and P = 0.04, respectively), as did DRD2 haplotypes (P = 0.01). We present evidence for heterosis in DRD1 where heterozygote mothers orient away from their infants significantly less than either homozygote group. Our findings provide important evidence that genetic variation in receptors critical for mothering in non‐human species also affect human maternal behaviors. The findings also highlight the importance of exploring multiple dimensions of the complex human mothering phenotype.

Gender differences in the association between stop-signal reaction times, body mass indices and/or spontaneous food intake in pre-school children: an early model of compromised inhibitory control and obesity.

Background:Poor inhibitory control is associated with overeating and/or obesity in school-age children, adolescents and adults. The current study examined whether an objective and reliable marker of response inhibition, the stop-signal reaction time (SSRT), is associated with body mass index (BMI) z-scores and/or food intake during a snack test in pre-school children.Methods:The current sample consisted of 193 pre-school children taking part in a longitudinal study of early brain development (Maternal Adversity, Vulnerability and Neurodevelopment (the MAVAN project)). Linear mixed-effect models were used to examine whether the SSRT measured at age 48 months associated with BMI z-scores and/or dietary intake during a laboratory-based snack test.Results:After controlling for significant covariates including maternal BMI, there was a significant gender by SSRT interaction effect in predicting 48-month BMI z-scores. Post-hoc analysis revealed an association between longer SSRTs (poor response inhibition) and higher BMIs in girls but not boys. Across both girls and boys, longer SSRTs were associated with greater intake of carbohydrates and sugars during the snack test. The association between SSRT scores and BMI z-scores in girls was not statistically mediated by carbohydrate or sugar intake.Conclusions:At 48 months of age, slower response inhibition on the Stop-Signal Task associates with higher BMI z-scores in girls, and with higher intake of carbohydrates and sugars during a snack test across both genders. Ongoing follow-up of these children will help clarify the implications of these associations for longer term macronutrient intake, eating-related pathology and/or pathological weight gain over time.

Influence of CYP2D6 and CYP2C19 gene variants on antidepressant response in obsessive-compulsive disorder

Numerous studies have reported on pharmacogenetics of antidepressant response in depression. In contrast, little is known of response predictors in obsessive-compulsive disorder (OCD), a disorder with among the lowest proportion of responders to medication (40–60%). Our study is the largest investigation to date (N=184) of treatment response and side effects to antidepressants in OCD based on metabolizer status for CYP2D6 and CYP2C19. We observed significantly more failed medication trials in CYP2D6 non-extensive compared with extensive metabolizers (P=0.007). CYP2D6 metabolizer status was associated with side effects to venlafaxine (P=0.022). There were nonsignificant trends for association of CYP2D6 metabolizer status with response to fluoxetine (P=0.056) and of CYP2C19 metabolizer status with response to sertraline (P=0.064). Our study is the first to indicate that CYP genes may have a role in antidepressant response in OCD. More research is required for a future clinical application of genetic testing, which could lead to improved treatment outcomes.

Genome-wide association study on antipsychotic-induced weight gain in the CATIE sample

Antipsychotic-induced weight gain (AIWG) is a common side effect with a high genetic contribution. We reanalyzed genome-wide association study (GWAS) data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) selecting a refined subset of patients most suitable for AIWG studies. The final GWAS was conducted in N=189 individuals. The top polymorphisms were analyzed in a second cohort of N=86 patients. None of the single-nucleotide polymorphisms was significant at the genome-wide threshold of 5x10−8. We observed interesting trends for rs9346455 (P=6.49x10−6) upstream of OGFRL1, the intergenic variants rs7336345 (P=1.31 × 10−5) and rs1012650 (P=1.47 × 10−5), and rs1059778 (P=1.49x10−5) in IBA57. In the second cohort, rs9346455 showed significant association with AIWG (P=0.005). The combined meta-analysis P-value for rs9346455 was 1.09 × 10−7. Our reanalysis of the CATIE GWAS data revealed interesting new variants associated with AIWG. As the functional relevance of these polymorphisms is yet to be determined, further studies are needed.The Pharmacogenomics Journal advance online publication, 1 September 2015; doi:10.1038/tpj.2015.59

Lack of association between polymorphism of the human cyclic GMP-dependent protein kinase gene and obesity

OBJECTIVE:To investigate whether genetic variation in the cyclic GMP-dependent protein kinase gene (PRKG1) is associated with obesity.METHODS:The study included 143 individuals from New York City area, NY, USA. The subjects were sampled on the basis of body mass index (BMI): obese (BMI ranging from 33.8 to 89.5 kg/m2), and nonobese (BMI ranging from 16.0 to 29.4 kg/m2). The association between C2276T polymorphism in PRKG1 gene and obesity was tested using linear regression analysis.RESULTS:BMI levels were predicted by linear regression models adjusted for demographic factors. An analysis was performed twice: in individuals of all ethnical backgrounds and in European-Americans only. In both cases, genotype did not have a significant effect.CONCLUSION:We found no evidence that the C2276T polymorphism in the PKRG1 gene is associated with obesity.

The role of the ITIH3 rs2535629 variant in antipsychotic response.

INTRODUCTION There is mounting evidence that schizophrenia risk variants influence response to antipsychotic medication. Common single nucleotide polymorphisms (SNPs) in or near the inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) gene have been repeatedly associated with schizophrenia and related psychiatric disorders in genome-wide association studies. Here, we provide the first study to assess the relevance of the ITIH3 rs2535629 SNP in response to antipsychotic medication. METHODS The rs2535629 SNP was genotyped in N=256 patients receiving various antipsychotics for up to 26weeks. Treatment response was assessed using the Brief Psychiatric Rating Scale (BPRS) including its positive and negative subscales. Follow-up analyses were performed after stratifying for ethnicity and medication. RESULTS We found significant association of rs2535629 with improvement of negative symptoms in patients of European ancestry after six months of clozapine treatment (F1,87=8.8, pcorr=0.032). Patients homozygous for the minor A-allele showed the best improvement of negative BPRS scores. However, we observed no association between rs2535629 and changes in total BPRS score in the entire sample or the clozapine-treated subgroup. DISCUSSION Although there was no association of genotype with overall changes in BPRS scores, the greater improvement of negative symptoms in minor allele carriers indicates that rs2535629 may help to identify a subset of schizophrenia patients with better treatment response to clozapine. Therefore, our findings provide the first suggestive evidence that rs2535629 is relevant in antipsychotic response.

Association of ethnicity with antipsychotic dosage using STRUCTURE analysis.

Several studies have examined whether ethnicity as an independent factor can influence the individuals dosage of antipsychotics. However, there has been inconsistency in the results of these studies, particularly between white and non-white populations. This retrospective study tests the hypothesis of different dosing of antipsychotics in white Europeans vs. non-white Europeans considering both the self-reported ethnicity and the geographical ancestry calculated using 196 DNA markers.We collected self-reported ethnicity and DNA samples from 209 schizophrenia patients. We tested the association between self-reported and genetically-determined ethnicity with the chlorpromazine equivalent dose of each antipsychotic prescribed at the time of the assessment.We did not find any significant difference between self-reported white European -ethnicity and chlorpromazine equivalent doses (p=0.972). Furthermore, when we considered the geographical ancestry determined by the 196 SNPs, we could not find any correlation between the European ancestry and chlorpromazine equivalent dose.Our preliminary analysis shows that there is no evidence that different ethnic groups receive different dose of antipsychotics.