Impact of apolipoprotein A5 (APOA5) polymorphisms on serum triglyceride levels in schizophrenic patients under long-term atypical antipsychotic treatment

Abstract

Objectives. Schizophrenic patients treated with clozapine or olanzapine often develop hypertriglyceridemia. The apolipoprotein A5 gene (APOA5), which affects VLDL production and lipolysis, has been implicated in the triglyceride (TG) metabolism. This study examined the association of common APOA5 genetic variants and TG levels in chronically institutionalized schizophrenic patients, on a stable dose of atypical antipsychotic (clozapine, olanzapine or risperidone. Methods. The TG levels in 466 schizophrenic patients treated with clozapine (n = 182), olanzapine (n = 89) or risperidone (n = 195) were measured. Patients were genotyped for the three APOA5 single nucleotide polymorphisms (SNPs) rs662799 (–1131T > C), rs651821 (3A > G) and rs2266788 (1891T > C). Results. A gene × drug interaction with TG levels was observed. In single-marker-based analysis, the minor alleles of the two polymorphisms (–1131C and –3G) were observed to be associated with increased TGs in patients treated with risperidone, but not with clozapine or olanzapine. Haplotype analysis further revealed that carriers of the haplotype constructed with the three minor alleles had higher TG levels than those who did not carry this haplotype in patients taking risperidone (CGC^(+/+) vs. = 125.4 ± 59.1 vs. 82.2 ± 65.8, P = 0.015; CGC^{(–/+ )} vs. CGC^(–/–) = 113.7 ± 80.4 vs. 82.2 ± 65.8, P = 0.012). Conclusions. Our findings extend and add new information to the existing data regarding the association between APOA5 and TG regulation during long-term atypical antipsychotic treatment.     

Association Study of Brain-Derived Neurotrophic Factor Gene Polymorphisms and Body Weight Change in Schizophrenic Patients Under Long-Term Atypical Antipsychotic Treatment

Schizophrenic patients treated with atypical antipsychotics (AAPs) often develop excessive body weight gain, which may lead to further morbidity and poor treatment compliance. This study examined whether genetic variants in the brain-derived neurotrophic factor (BDNF) gene may be associated with body weight change after AAP treatment. The study included 481 schizophrenic patients treated with clozapine (n = 266), olanzapine (n = 79), or risperidone (n = 136) for an average of 49.2 ± 28.2 months. Three common single-nucleotide polymorphisms (SNPs) of the BDNF gene were chosen as tagging SNPs. In single-marker-based analysis, the BDNF rs11030101-T homozygous genotype was found to be associated with significantly increased body weight gain (P = 0.037). The BDNF Val66Met (rs6265) polymorphism was not found to be associated with body weight gain. Haplotype analysis further showed that the rs11030101-T-allele-related haplotype is also associated with increased body weight gain (P = 0.047). Our findings suggest that there is a nominal association with rs11030101 but did not replicate the previously found relationship between the BDNF Val66Met polymorphism and body weight gain during long-term AAP treatment.     

The role of genetic variation across IL-1β, IL-2, IL-6, and BDNF in antipsychotic-induced weight gain

Objectives. Antipsychotics with high weight gain-inducing propensities influence the expression of immune and neurotrophin genes, which have been independently related to obesity indices. Thus, we investigated whether variants in the genes encoding interleukin (IL)-1β, IL-2, and IL-6 and brain-derived neurotrophic factor (BDNF) Val66Met are associated with antipsychotic-induced weight gain (AIWG). Methods. Nineteen polymorphisms were genotyped using Taqman^® assays in 188 schizophrenia patients on antipsychotic treatment for up to 14 weeks. Mean weight change (%) from baseline was compared across genotypic groups using analysis of covariance (ANCOVA). Epistatic effects between cytokine polymorphisms and BDNF Val66Met were tested using Model-Based Multifactor Dimensionality Reduction. Results. In European patients, IL-1β rs16944*GA (P = 0.013, P_corrected = 0.182), IL-1β rs1143634*G (P = 0.001, P_corrected = 0.014), and BDNF Val66Met (Val/Val, P = 0.004, P_corrected = 0.056) were associated with greater AIWG, as were IL-1β rs4849127*A (P = 0.049, P_corrected = 0.784), and IL-1β rs16944*GA (P = 0.012, P_corrected = 0.192) in African Americans. BDNF Val66Met interacted with both IL-1β rs13032029 (Val/Met+ TT, P_Perm = 0.029), and IL-6 rs2069837 (Val/Val+ AA, P_Perm = 0.021) in Europeans, in addition to IL-1β rs16944 (Val/Val+ GA, P_Perm = 0.006) in African Americans. Conclusions. SNPs across IL-1β and BDNF Val66Met may influence AIWG. Replication of these findings in larger, independent samples is warranted.     

The Orexin 1 Receptor (HCRTR1) Gene as a Susceptibility Gene Contributing to Polydipsia-Hyponatremia in Schizophrenia

The underlying pathophysiology of primary polydipsia in schizophrenia (SCZ) is poorly understood. Our previous study, however, suggested that this condition may have a genetic component [Shinkai et al 2003 Am J Med Genet 119B 7–12]. Orexins, also called hypocretins, play an important role in feeding and drinking behavior. Administration of orexin in rats has been shown to induce increased water intake with a longer-lasting effect than angiotensin II, which is also known as a potent dipsogen. Meerabux et al. [2005 Biol Psychiatry 58 401–407] reported an association between the 408Val allele of the orexin 1 receptor (HCRTR1) gene and polydipsia-hyponatremia in a sample of Japanese patients with SCZ. In the present study, we attempted to replicate the findings of Meerabux et al. in an independent Japanese case-control sample. Our sample included 312 patients with SCZ (DSM-IV) (65 with polydipsia and 247 without polydipsia). We also observed an association between the HCRTR1 Ile408Val polymorphism and polydipsia (genotype distribution: χ² = 9.85, df = 2, P = 0.007). Meerabux et al. (2005) previously demonstrated an association between the 408Val allele of the HCRTR1 gene and polydipsia. In contrast with Meerabux et al. study, we found that the 408Ile allele was associated with polydipsia in our sample (χ² = 8.00, df = 1, P = 0.0047; OR = 0.53; 95%CI = 0.34–0.83). How either allele contributes to the development of polydipsia in SCZ is unclear at this stage. It is possible that Ile408Val polymorphism is a non-functional marker that lies in linkage disequilibrium with an as-yet undetected functional variant. In any case, our results support the hypothesis that the HCRTR1 Ile408Val polymorphism may confer susceptibility to polydipsia in SCZ. Further studies examining the association between the orexin system and polydipsia in SCZ are warranted. Yuko Fukunaka and Takahiro Shinkai contributed equally to this work.     

Association study of polymorphisms in leptin and leptin receptor genes with antipsychotic-induced body weight gain

Background

Antipsychotic-induced weight gain (AIWG) is a serious side-effect of antipsychotic medication leading to metabolic syndrome and increased cardiovascular morbidity. Unfortunately, there are still no valid predictors to assess an individual's risk to gain weight. Previous studies have indicated an impact of genetic variation in the genes encoding leptin, LEP, and leptin receptor, LEPR, on AIWG, but results have not been conclusive. Thus, we investigated polymorphisms in both genes for an association with AIWG.

Methods

A total of 181 schizophrenic and schizoaffective patients treated with various antipsychotics were included. In a small subset of patients, leptin plasma levels were additionally obtained. Five polymorphisms in LEP and LEPR (LEP: rs7799039 (-2548G/A polymorphism), rs10954173, rs3828942; LEPR: rs1327120, rs1137101 (Q223R polymorphism) were genotyped using TaqMan assays. Statistical association with % weight change from baseline weight was performed using ANCOVA with baseline weight as covariate.

Results

ANCOVA showed a non-significant trend for genotype association of the rs7799039 marker (p = .068). No significant association of the other LEP and LEPR SNPs with AIWG was detected. However, we found a significant association between a haplotype of LEP rs7799039G–rs10954173G–rs3828942G (p = .035) and AIWG. The rs7799039 G-allele (p = .042) and G-allele of rs3828942 (p = .032) were associated with higher weight gain.

Conclusion

Our study supports the hypothesis of an impact of LEP gene variation on AIWG. Limitations of our study include heterogeneous samples, short treatment duration and multiple comparisons. Our findings were compared to previous studies in detail in order to provide the readers with a more conclusive picture. However, further studies are warranted including more gene variants and interaction analyses with other genes of the leptin–melanocortin pathway.     

Dopamine D2/3 receptor binding potential and occupancy in midbrain and temporal cortex by haloperidol, olanzapine and clozapine

Aims: Aberrant dopamine transmission in extrastriatal brain regions has been repeatedly illustrated among patients with schizophrenia. Differences between typical and second‐generation antipsychotics in dopamine D₂ receptor modulation within various brain areas remain a topic for debate. The aim of the present study was therefore to investigate dopamine D_2/3 receptor apparent binding potential (BP_app) and occupancy in midbrain and temporal cortex among clozapine‐, olanzapine‐ and haloperidol‐treated schizophrenia patients. Methods: Dopamine D_2/3 binding was studied on single‐photon emission computed tomography ligand [¹²³I]epidepride in 13 schizophrenia patients treated with medication (two with haloperidol, four with olanzapine and seven with clozapine), six drug‐naïve patients and seven healthy controls. Results: Statistically significant differences in midbrain dopamine D_2/3 receptor BP_app (P = 0.015) and occupancy (P = 0.016) were observed between the clozapine, olanzapine and haloperidol groups. The lowest occupancy was found in clozapine‐treated patients (5%), followed by olanzapine‐treated patients (28%), compared to haloperidol‐treated patients (40%). No significant differences were observed in the temporal poles. Occupancy changed substantially depending on the comparison group used (either drug‐naïve vs healthy controls) in the examined brain areas (P = 0.001), showing an overestimation with all antipsychotics when the healthy control group was used. Conclusion: Both typical and second‐generation antipsychotics occupy cortical dopamine D_2/3 receptors, thus mediating therapeutic efficacy. Observed differences in midbrain dopamine D_2/3 occupancy between classical antipsychotics and second‐generation antipsychotics may have clinical relevance by modulating altered nigrostriatal dopamine neurotransmission during the acute phase of schizophrenia.     

The first- and second-generation antipsychotic drugs affect ADP-induced platelet aggregation

Objective. Blood platelets play an important role in haemostasis and their hyperaggregability may lead to thrombosis and cardiovascular diseases. Increased incidence of mortality, caused by cardiovascular disease, and the increased risk of thrombotic complication in schizophrenic patients treated with antipsychotics have been reported. The effects of antipsychotic drugs on blood platelet function are not fully explained, therefore the purpose of the present study was to examine and compare the effects of the second-generation antipsychotic drugs used in schizophrenia (clozapine, risperidone and olanzapine), with the effects of the first generation antipsychotic, haloperidol, on the platelet aggregation induced by ADP in vitro. Methods. Blood obtained from healthy volunteers (n=25) collected into sodium citrate was centrifuged (250×g, 10 min) at room temperature to obtain platelet-rich plasma. Aggregation of blood platelets (10 µM ADP) was recorded (Chrono-log aggregometer) in platelet-rich plasma preincubated with antipsychotic drugs (final concentration: clozapine 420 ng/ml, risperidone 65 ng/ml, olanzapine 40 ng/ml, haloperidol 20 ng/ml) for 30 min. Results. Our results showed that all tested drugs inhibit platelet aggregation induced by ADP in vitro. Among studied antipsychotic drugs clozapine and olanzapine significantly reduced platelet aggregability in vitro. In comparison with control platelets (without the drug), clozapine inhibited ADP-induced platelet aggregation by 21% (P=3.7×10^?6) and olanzapine by 18% (P=2.8×10^?4), respectively. Conclusion. The obtained results indicate that antipsychotic drugs, especially clozapine and olanzapine, contrary to haloperidol, reduced response of blood platelets to ADP measured as platelet aggregation. This suggests that therapy with such antipsychotics, particularly with second-generation antipsychotics, may partly reduce prothrombotic events associated with the increased platelet activation observed in schizophrenic patients. The mechanism of antiaggregatory influence of antipsychotics requires further studies.     

Association between methylene tetrahydrofolate reductase polymorphisms and risk of ischemic stroke

Abstract

Background: The methylene tetrahydrofolate reductase (MTHFR) is a folate-dependent enzyme which catalyzes the conversion of homocysteine to methionine. Two single nucleotide polymorphisms (SNPs) within this gene namely rs1801133 (C677T) and rs1801131 (A1298C) have been associated with elevated risk of ischemic stroke and total serum homocysteine in some populations.

Aim: To assess associations between MTHFR SNPs and risk of ischemic stroke in Iranian population.

Methods: In the current case-control study, we genotyped rs1801133 and rs1801131 SNPs in 318 Iranian patients with history of ischemic stroke and 400 age- and sex-matched controls using tetra-primer amplification refractory mutation system-polymerase chain reaction method.

Results: The rs1801133 was significantly associated with risk of stroke in recessive model (OR (95% CI) = 1.89 (1.12–3.20), p?=?0.03). The CT haplotype (rs1801131 and rs1801133, respectively) was significantly over-represented in patients compared with controls (OR (95% CI) = 1.71 (0.25–2.32), p?=?0.002).

Conclusion: Consequently, our data demonstrate contribution of MTHFR variants in risk of ischemic stroke in Iranian population.     

Involvement of NRN1 gene in schizophrenia-spectrum and bipolar disorders and its impact on age at onset and cognitive functioning

Objectives Neuritin 1 gene (NRN1) is involved in neurodevelopment processes and synaptic plasticity and its expression is regulated by brain-derived neurotrophic factor (BDNF). We aimed to investigate the association of NRN1 with schizophrenia-spectrum disorders (SSD) and bipolar disorders (BPD), to explore its role in age at onset and cognitive functioning, and to test the epistasis between NRN1 and BDNF. Methods The study was developed in a sample of 954 SSD/BPD patients and 668 healthy subjects. Genotyping analyses included 11 SNPs in NRN1 and one functional SNP in BDNF. Results The frequency of the haplotype C-C (rs645649–rs582262) was significantly increased in patients compared to controls (P?=?0.0043), while the haplotype T-C-C-T-C-A (rs3763180–rs10484320–rs4960155–rs9379002–rs9405890–rs1475157) was more frequent in controls (P?=?3.1?×?10^?5). The variability at NRN1 was nominally related to changes in age at onset and to differences in intelligence quotient, in SSD patients. Epistasis between NRN1 and BDNF was significantly associated with the risk for SSD/BPD (P?=?0.005). Conclusions Results suggest that: (i) NRN1 variability is a shared risk factor for both SSD and BPD, (ii) NRN1 may have a selective impact on age at onset and intelligence in SSD, and (iii) the role of NRN1 seems to be not independent of BDNF.     

Association study between variants of AMP-activated protein kinase catalytic and regulatory subunit genes with antipsychotic-induced weight gain

Weight gain and metabolic syndrome are the most common deleterious side effects following treatment with second generation antipsychotic drugs such as clozapine and olanzapine. However, the mechanisms underlying these negative effects of second generation antipsychotic drugs are not fully understood. In this study we investigate whether variants in the genes coding for the α-catalytic (PRKAA1, PRAKAA2) and the β regulatory subunits (PRKAB1 and PRKAB2) of the cellular energy sensor AMP-activated protein kinase (AMPK) are associated with antipsychotic-induced weight gain. To accomplish this, ten polymorphisms in 208 schizophrenia or schizoaffective disorder patients treated with clozapine, haloperidol, risperidone or olanzapine for up to 14 weeks were analyzed. Significant association was observed between rs3766522 in PRKAB2 (AA vs. AT + TT; p = 0.022) and rs10789038 in PRKAA2 (GG + GA vs. AA, p = 0.023) with weight change (%) in patients of European ancestry following treatment with clozapine or olanzapine. Allelic association of the T-allele of rs3766522 (p = 0.019) and the G-allele of rs10789038 (p = 0.041) with weight change (%) was also observed. Analysis of raw weight gain revealed that carriers of the T-allele of rs3766522 (AT + TT, 4.3 kg ± 3.7) gained more weight than the AA-genotype carriers (2.5 kg ± 4.5, p = 0.042). Similarly, carriers of the G-allele of rs10789038 (GG + GA, 4.2 kg ± 4.5) gained more weight than AA-homozygotes (1.5 kg ± 2.9, p = 0.014) under antipsychotic treatment. In conclusion, we observed significant associations between polymorphisms in AMPK subunit genes and weight gain induced by clozapine and olanzapine.     

Association study in a Sardinian sample between bipolar disorder and the nuclear receptor REV‐ERBα gene,a critical component of the circadian clock system

Objective: The aim of our study was to investigate the association between REV‐ERBα gene (NR1D1) single nucleotide polymorphisms (SNPs) and bipolar disorder (BP) in a case‐control sample of Sardinian ancestry and evaluate its effect on age at onset (AAO) of BP. Methods: We genotyped SNPs rs12941497 (SNP1) and rs939347 (SNP2), located, respectively, in the first intron and in the 5′UTR region of the gene, in a sample comprised of 300 bipolar patients and 300 healthy controls of Sardinian ancestry. We also studied AAO by means of admixture analysis, obtaining a cutoff point of age 22 and then carrying out association analysis between the two AAO groups. Results: In the case‐control comparison, single marker analysis showed no association for any of the SNPs tested. Haplotype analysis showed a nominally significant association for two haplotypes of SNPs 1‐2. Comparing the early‐ and later‐onset groups, nominal association was found for SNP1. Haplotype analysis showed that one haplotype was nominally associated with the later‐onset group. Conclusions: Our results, indicating a nominal association of the REV‐ERBα gene with BP, suggest a possible role of REV‐ERBα in the pathogenesis of BP. Further investigation of larger independent samples and different populations is warranted.     

Leukoaraiosis is associated with genes regulating blood–brain barrier homeostasis in ischaemic stroke patients

Background: The biologic agents causing leukoaraiosis are unknown. Our aim was to study the genetic basis of leukoaraiosis. Methods: We analyzed 212 single nucleotide polymorphisms (SNPs) in 142 patients with ischaemic stroke, generating a total of 30 104 genotypes. Seventy‐nine subjects (55.6%) presented leukoaraiosis measured by the Fazekas scale and 69 (48.6%) by ARWMC scale. We analyzed the presence of synergic associations between SNPs using the hfcc software. Finally, functional studies were performed in 56 subjects. The Ingenuity Pathways software (ipa ) was used to examine the role of the identified genes. Results: Six SNPs were associated with leukoaraiosis using both measuring scales. After logistic regression adjusted for leukoaraiosis risk factors, the rs2252070 of MMP13 (OR = 4.9, 95%CI: 1.34–17.9, P = 0.016), rs662 of PON1 (OR = 0.37, 95%CI: 0.15–0.87, P = 0.024) and rs1800779 of NOS3 (OR = 3.9, 95%CI: 1.38–11.38, P = 0.01) were independently associated with leukoaraiosis under a dominant/recessive model and the rs2290608 of IL5RA (OR = 0.46, 95%CI: 0.25–0.85, P = 0.013) and rs669 of A2M (OR = 2.5, 95%CI: 1.36–4.83, P = 0.004) under an additive model. Computational analysis showed a synergic association of rs10497212‐AA of ITGB6 and rs2290608‐GG of IL5RA with leukoaraiosis using both scales. (i) ARWMC (P = 1.3 × 10⁻⁴) and (ii) Fazekas (P = 4.5 × 10⁻⁵). Functional studies showed that the rs669 SNP was associated with plasma levels of A2M (P = 0.012) and A2M levels with leukoaraiosis in Fazekas scale (P = 0.02). ipa analysis revealed that the genes associated with leukoaraiosis were involved in blood–brain barrier (BBB) homeostasis. Conclusions: Amongst patients with ischaemic stroke, several genes associated with BBB homeostasis could be involved with a higher risk of leukoaraiosis.     

Genetic Polymorphisms in Pre-microRNAs and Risk of Ischemic Stroke in a Chinese Population

Ischemic stroke is considered to be a complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. MicroRNAs participated in various physiopathological processes; common single-nucleotide polymorphisms (SNPs) in pre-miRNAs have been shown to be associated with susceptibility to several human diseases. We evaluated the associations of the hsa-mir-196-a2/rs11614913 T/C, hsa-mir-146a/rs2910164 C/G, and hsa-mir-499/rs3746444 A/G polymorphisms in pre-miRNAs with the risk of ischemic stroke in a Chinese population. The three polymorphisms were identified in 296 ischemic stroke patients and 391 healthy controls using polymerase chain reaction–restriction fragment length polymorphism. The frequency of the allele G of hsa-mir-499/rs3746444 A/G showed significant association with ischemic stroke when compared with controls (OR?=?1.509, 95%CI?=?1.151–1.978, P?=?0.003). Increased ischemic stroke risks were associated with rs3746444 A/G genotypes in different genetic model (homozygote comparison: P?=?0.045, OR?=?2.084, 95%CI?=?1.019–4.262; heterozygote comparison: P?=?0.024, OR?=?1.489, 95%CI?=?1.063–2.087; dominant genetic model: P?=?0.007, OR?=?1.563, 95%CI?=?1.135–2.153). Similar results were obtained by adjusted fully risk factors. However, we failed to find any association between the alleles and genotypes of rs2910164 C/G and rs11614913 T/C SNPs and ischemic stroke, respectively (p?>?0.05). The present study provided evidence that hsa-mir-499/rs3746444 A/G polymorphism might be associated with a significantly increased risk of ischemic stroke in a Chinese population, indicating that the common genetic polymorphism in pre-microRNAs contributed to the pathogenesis of ischemic stroke.     

HTR2C polymorphisms,olanzapine-induced weight gain and antipsychotic-induced metabolic syndrome in schizophrenia patients: A meta-analysis

Objective. To conduct meta-analyses of all published association studies on the HTR2C -759C/T (rs3813829) polymorphism and olanzapine-induced weight gain in schizophrenia patients and on the HTR2C -759C/T, -697G/C (rs518147) and rs1414334:C> G polymorphisms and olanzapine/clozapine/risperidone-induced metabolic syndrome in schizophrenia patients. Methods. Eligible studies were identified by searching PubMed and Web of Science databases. Meta-analyses were performed using Cochrane Review Manager (RevMan, version 5.2) to calculate the pooled odds ratio (OR) and its corresponding 95% confidence interval (CI). Results. Our meta-analyses revealed both a significant positive association between the rs1414334 C allele and olanzapine/clozapine/risperidone-induced metabolic syndrome and a marginally significant positive association between the -697C allele and the induced metabolic syndrome in schizophrenia patients, but no significant association between the -759C/T polymorphism and the induced metabolic syndrome in schizophrenia patients. Our analysis further revealed a pronounced trend toward a significant negative association between the -759T allele and high olanzapine-induced weight gain and a trend toward a significant positive association between the -759C allele and high olanzapine-induced weight gain in Caucasian schizophrenia patients. Conclusions. Our results support that HTR2C polymorphisms play a role in antipsychotic-induced metabolic disturbance. More association studies are needed to further elucidate association of different HTR2C polymorphisms and antipsychotic-induced metabolic disturbance.     

Serum levels of second-generation antipsychotics are associated with cognitive function in psychotic disorders

Objectives: Antipsychotics are effective in treating psychosis and mood episodes; however, the effect on cognition is less known. We investigated the association between serum levels of second-generation antipsychotics (SGAs) and cognitive performance in psychosis spectrum disorders in a naturalistic setting.

Methods: A total of 495 patients with a DSM-IV Schizophrenia and Other Psychotic Disorders (SCZ, n?=?373) or Bipolar Disorder (BD, n?=?122) diagnosis treated with olanzapine, quetiapine, aripiprazole or risperidone were tested neuropsychologically with concurrent measurement of the serum concentration of the drug. Linear regression was used for association analyses.

Results: Attention was positively associated with the olanzapine concentration (standardised beta (β) coefficient =?0.19, P?=?.006), and short-term verbal memory and verbal fluency were negatively associated with the quetiapine (β?=?–0.24, P?=?.004) and risperidone (β?=?–0.37, P?=?.007) concentrations respectively.

Conclusions: The present results suggest that SGA serum concentration is associated with better attention (small effect size), and worse verbal memory (small effect size) and verbal fluency (medium effect size). These findings are in line with the notion that SGAs affect aspects of cognitive function, and suggest careful dosing in patients with severe memory and executive problems.     

Clozapine/olanzapine-induced recurrence or deterioration of binge eating-related eating disorders

Summary Objective. To explore the association between eating disorders (EDs) prior to the use of clozapine/olanzapine (pre-clozapine/olanzapine EDs) and after initiation of these antipsychotics (post-clozapine/olanzapine EDs). Method. Sixty-four consecutively admitted patients receiving clozapine/olanzapine were screened using the M-Composite International Diagnostic Interview (M-CIDI) to identify subjects with pre-clozapine/olanzapine EDs (DSM-IV criteria). We investigated post-clozapine/olanzapine EDs and binge eating behavior using the Questionnaire on Eating and Weight Patterns (QEWP) and used the Naranjo probability scale as objective causality assessment. Results. Post-clozapine/olanzapine EDs were significantly more frequent in patients with pre-clozapine/olanzapine EDs (5 of 6) when compared to patients without pre-clozapine/olanzapine EDs (4 of 58) [χ² = 26.29; df = 1; p < 0.001] [odds ratio (OR) 67.5; 95% CI: 6.3–725.8]. According to the Naranjo probability scale, recurrence or deterioration of EDs in patients with prior EDs was definitely (n = 1) or probably (n = 4) related to the intake of clozapine/olanzapine. Conclusion. Clozapine/olanzapine may induce recurrence or deterioration of binge eating symptomatology or full-blown EDs in patients with prior EDs.     

Association of DRD2 and ANKK1 polymorphisms with prolactin increase in olanzapine-treated women

Dopamine D2 receptors, encoded by DRD2, play a role in regulating serum prolactin concentration. Single nucleotide polymorphisms (SNPs), rs2734842(C), rs6275(T), and rs6279(C) located within DRD2, have been shown to be associated with prolactin increase in olanzapine/fluoxetine combination (OFC)-treated women. The present analyses seek to replicate these results and test other SNPs in DRD2 and neighboring gene ANKK1 for associations with prolactin increase in women, using data from 3 pooled studies of olanzapine, and 2 previously examined studies OFC. An ANCOVA was used to test whether change from baseline in the natural log of prolactin concentration (ln[prolactin]) was associated with SNPs in the pooled olanzapine studies. A meta-analysis was also performed using the inverse chi-square method, pooling p-values from the 2 previously examined studies and the 3 olanzapine studies. Negative strand alleles rs2734842(C), rs6275(T), and rs6279(C) were significantly associated with increased prolactin in olanzapine-treated women, replicating previous results. These SNPs also showed moderate association with increased prolactin in olanzapine-treated and OFC-treated women in the meta-analysis, as did rs4938016, rs2734848, rs2734841, rs1124493, and rs1076562. Five of these SNPs fall in or are adjacent to an LD block spanning DRD2 intron 7, exon 7, 5' untranslated region and ANKK1. Clinical trial Registration: www.clinicaltrial.gov.