Marcin Olajossy

Polymorphisms of the 5-HT2A receptor gene and clinical response to olanzapine in paranoid schizophrenia.

Background: 5-HT2A receptor is strongly implicated in the mode of action of atypical antipsychotic drugs. The aim of the study was to investigate whether the 5-HT2A receptor gene’s polymorphisms (His452Tyr and T102C) have an influence on the response to olanzapine in patients with schizophrenia. Methods: We studied 99 Caucasian schizophrenia patients treated with olanzapine. Psychopathology was measured before and after 6 weeks of treatment. Clinical improvement was quantified as change in Positive and Negative Syndrome Scale (PANSS) total scores and subscores as shown by percentage improvement below the baseline score. The clinical response to antipsychotic treatment was defined as 30% improvement from baseline in PANSS scores. Results: The His/Tyr polymorphism was significantly associated with a percentage improvement in PANSS positive symptom subscore (better response in His/His homozygotes; p < 0.05) after treatment with olanzapine. As for the T102C polymorphism, a better response in terms of PANSS positive subscore improvement was observed for C/C homozygotes (p < 0.01). A significant association of 5-HT2A genotype distribution of the T102C polymorphism with a categorical measure of response, but only in terms of PANSS positive symptom subscores, was observed (p < 0.01). Conclusions: Variations in the 5-HT2A receptor gene may influence individual and particularly positive symptom response to olanzapine.

Polymorphisms of the histamine receptor (H1HR) gene are not associated with olanzapine-induced weight gain.

To the Editors: W eight gain is an important adverse effect of many atypical antipsychotics (most pronounced with clozapine and olanzapine) with a negative impact on both somatic health and subjective quality of life. Because it occurs in many but not all patients, and to a different degree in individuals, genetic predisposition has been suggested as a plausible underlying mechanism. Most studies to date have focused on genes relevant to the proposed mechanisms of action of antipsychotics (eg, D3 receptor gene) or to obesity (eg, leptin gene). The most consistent positive findings regard the role of the j759C/T variant of the HTR2C (2C serotonin receptor) gene. Another plausible candidate is the histamine H1 receptor (H1HR) gene. A number of studies have linked it with weight gain, showing, for example, a significant correlation between affinity of antipsychotics for H1HR and weight increase (2 meta-analyses),an increase in food intake, and obesity afterH1HR gene knockout in mice and an H1HR antagonist-induced increase and an agonist-induced suppression of food intake associated with a decrease in the receptor’s hypothalamic expression. This down-regulation in H1HR could lead to an increase in histamine levels. Interestingly, histamine may stimulate corticotropin-releasing hormone and activate the hypothalamic-pituitary-adrenal axis, both of which were shown to increase food intake. Although genetic variants of the H1HR gene have been described, genetic studies targeting H1HR gene polymorphisms are scarce. The present study aimed to assess an association between 5 polymorphisms in the coding region (Lys19Asn-rs2067466, Asp349Glu-rs2067467, Phe358

Bipolar affective disorder in a male with a deletion of Y chromosome – a case report

-rs2067469, A1068G-rs2067468, andLeu449Ser-rs2067470) and a polymorphism in the promoter (C-17TY rs901865) of the H1HR gene and weight gain after 6 weeks of monotherapy with olanzapine. Ninety healthy subjects were genotyped to control for differences in allelic distribution between the groups. The study included 90 patients with schizophrenia and 90 sexand age-matched healthy individuals. Patients (44 women) with the diagnosis of paranoid schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, were inpatients of the Department of Psychiatry of the Medical University of Lublin. All patients were of white (Polish) background. Exclusion criteria were comorbid mental disorder, somatic illness, addiction, concomitant treatment with psychiatric medications other than benzodiazepines, a history of atypical antipsychotics treatment, or resistance to drugs. All patients were on the same hospital diet (exact caloric intake was impossible to establish because families were allowed to bring in food, sweets, etc) and had a comparable exercise level (all patients were in the ward and some took part in offered exercises such as walks or gym classes but not to the extent that it would allow weight loss). Among 90 patients, 61 had a history of multiple episodes and treatment with typical but not atypical antipsychotics (switch to olanzapine mainly because of adverse effects); 29 were drug-naive first-episode patients (mean [SD] age, 23.9 [4.7] years). All patients and healthy controls gave written consent to the study. All the procedures were approved by the local ethical committee. Patients were treated with 20 to 25 mg/d of olanzapine in monotherapy (titrated up from 10 mg daily)Vonly benzodiazepines were permitted in the first 2 weeks of the treatment. Weight was measured on the first and 42nd day of the treatment. The coding region polymorphisms were analyzed by polymerase chain reactionrestriction fragment length polymorphism method using primers and protocols described by Mancama et al; the H1-17C/T polymorphism was analyzed by polymerase chain reaction-single strand conformation polymorphism using the customized method (Supplementary Table A, Supplemental Digital Content 1, http://links.lww.com/JCP/A176). All samples were genotyped twice. Distribution of genotypes was assessed using W test. Stepwise regression analysis and 1-way analysis of variance were performed to assess the influence of baseline variables on body mass index (BMI) change. One-way analysis of variance and independent-samples t tests were used to assess the association between polymorphisms and BMI change. A 2-tailed P value of less than 0.05 was considered significant. All analyses were performed using SPSS 16.0 (SPSS Inc, Chicago, IL). At baseline, mean (SD) age was 29.1 (9.7) years (women, 31.7 [11.8]; men, 26.7 [6.9]); mean (SD) age at onset, 23.5 (6.3) years; mean (SD) preolanzapine treatment duration, 5.3 (6.8) years; mean (SD) positive and negative syndrome scale (PANSS) score at baseline 103.80 (15.9); mean (SD) weight, 69.6 (14.4) kg; and mean (SD) BMI, 23.6 (4.5) kg/m. The polymorphisms were in the HardyWeinberg equilibrium (P 9 0.05). Stepwise regression analysis showed that only baseline BMI and baseline total PANSS score had a significant effect on BMI change (P = 0.001, A = j0.338 and P = 0.018, A = j0.239, respectively), and the influence of sex, age, age at onset, and duration of preolanzapine antipsychotic treatment were excluded. The H1-17C/T variant was the only polymorphism with minor allele frequency high enough to allow statistical analysis (alleles: T 0.16, C 0.84; genotypes: CC 0.71, CT 0.26, TT 0.03); the frequencies of minor alleles of other single-nucleotide polymorphism were considered too low: 0.016 for the 358

P.3.a.036 Association between polymorphisms of the 5HT2A receptor gene and positive symptom response to olanzapine treatment in patients with schizophrenia

allele of the Phe358

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polymorphism (3 Phe358/Phe358

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subjects, no Phe358

Contents Vol. 64, 2011

/Phe358

D3 receptor gene polymorphism and the results of Trial Making Test in patients with schizophrenia

homozygotes), 0.011 for the G allele of the A1068G polymorphism (2 A/G subjects and no G/G homozygotes); there was no statistical difference in genotype and allele distribution between patients and healthy controls (P 9 0.5). The Lys19Asn, the Asp349Glu, and the Leu449Ser presented with only 1 allele (LysLys, AspAsp, and LeuLeu genotypes, respectively, in both groups. There was no significant effect of the C-17T variant on olanzapine-associated weight gain after 6 weeks of the treatment, both when genotypes and the presence of the alleles in the genotype were considered (Table 1). The results remained nonsignificant when baseline BMI and PANSS total were included or when analysis was restricted to drug-naBve patients (results not shown). There was no significant difference in age, age at onset, preolanzapine treatment duration in previously treated patients, baseline weight, baseline BMI, and baseline psychopathology (PANSS scale) between these genotype variant groups (results not shown). Genetics of the H1HR gene has attracted surprisingly little attention given quite convincing data pointing at the possible role of this receptor in susceptibility to weight increase (presented briefly previously). To date, only 3 studies investigated an association between its polymorphic variants and weight gain, with only negative results. No association was found between weight gain and the H1-17-C/T polymorphism after LETTERS TO THE EDITORS