Vicki L. Ellingrod

Clozapine-induced weight gain associated with the 5HT2C receptor −759C/T polymorphism

Weight gain has been documented as a significant adverse effect associated with many of the atypical antipsychotic medications. Several recent reports have linked a −759C/T polymorphism of the 5HT2C receptor gene and obesity as well as chlorpromazine, risperidone, and clozapine induced to weight gain. This aim was to determine the association between changes in body mass index (BMI) during clozapine treatment and the −759C/T polymorphism of the 5HT2C receptor gene. This study included 41 patients with treatment‐refractory schizophrenia (DSM‐IV) who were followed prospectively during treatment with clozapine. Weight and height measurements were obtained prior to starting clozapine and after 6‐months of treatment. Genomic DNA was isolated from a whole blood sample and analyzed for the −759C/T polymorphism of the 5HT2C receptor gene. A χ2 analysis comparing whether or not the subjects carried a −759T allele in subjects grouped as having an increase of more or less than 7% of their baseline BMI during treatment with clozapine found that the presence of the −759T allele was significantly higher in subjects with less than or equal to a 7% increase in baseline BMI compared to those with a greater than 7% increase in BMI. A multiple linear regression analysis showed that both baseline BMI and the presence or absence of the −759T allele had significant effects on 6‐month BMI. The T allele may have a protective function in preventing significant weight gain from clozapine. Subjects without the −759T variant allele were at a greater risk for weight gain from clozapine over 6‐months compared to those with the −759T allele.

Weight gain associated with the −759C/T polymorphism of the 5HT2C receptor and olanzapine

Weight gain from atypical antipsychotic use has become a significant problem. Recent reports have liked the −759 polymorphism of the 5HT2C receptor and obesity as well as weight gain from chlorpromazine, risperidone, and clozapine.

Psychosexual effects of three doses of testosterone cycling in normal men.

BACKGROUND Testosterone is receiving increased attention for contraceptive and therapeutic indications. The potential psychosexual side effects of testosterone therapy and withdrawal are unclear. METHODS Healthy men between the ages of 21 and 40 years were recruited via advertisement for a randomized, controlled, double-blind study of acute and withdrawal effects of three doses of testosterone. Two weeks of placebo injections were followed by one of three randomized weekly doses of testosterone cypionate (100 mg, 250 mg, or 500 mg) for the next 14 weeks. Twelve weeks of placebo injections followed during the withdrawal phase of the study. Psychosexual effects were monitored throughout the study. RESULTS All doses of testosterone demonstrated only minimal effects on measures of mood and behavior during acute and withdrawal phases for all study completers. There were no effects on psychosexual function. There was no evidence of a dose-dependent effect on any measure. One noncompleter on 500 mg of testosterone developed a brief syndrome with symptoms similar to an agitated and irritable mania. CONCLUSIONS Doses of testosterone up to five times physiologic replacement dose appear to have minimal risk of adverse psychosexual effects in the majority of normal men; however, beginning at around 500 mg per week of testosterone cypionate, a minority of normal men may experience significant adverse psychological effects. Because illicit anabolic steroid users may use larger doses of multiple drugs under less restrictive conditions, our study may significantly underestimate the psychological effect of steroid use in the community.

Antipsychotic-induced hyperprolactinemia.

Use of antipsychotic agents has been associated with hyperprolactinemia, or elevated prolactin levels; this hormonal abnormality can interfere with the functioning of repro ductive, endocrine, and metabolic systems. As antipsychotic agents are increasingly used for both United States Food and D rug Administratio n‐a ppro ved and nonapprove d indicatio ns, many individuals are at risk for developing antipsychotic‐induced hyperprolactinemia. First‐generation antipsychotics pose the greatest risk of causing this adverse effect; however, second‐generation antipsychotics, particularly risperidone and paliperidone, also often increase prolactin secretion. Hyperprolactinemia has short‐ and long‐term consequences that can seriously affect quality of life: menstrual disturbances, galactorrhea, sexual dysfunction, gynecomastia, infertility, decreased bone mineral density, and breast cancer. Although many of these are definitively connected to elevated prolactin levels, some, such as breast cancer, require further study. Both clinicians and patients should be aware of hyperprolactinemia‐associated effects. To prevent or alleviate the condition, tailoring an antipsychotic drug regimen to each individual patient is essential. In addition, the risk of hyperprolactinemia can be minimized by using the lowest effective dose of the antipsychotic agent. If the effects of prolactin are evident, the drug can be changed to another agent that is less likely to affect prolactin levels; alternatively, a dopamine agonist may be added, although this may compromise antipsychotic efficacy. Additional research is needed to clarify the appropriate level of monitoring, the long‐term effects, and the optimal treatment of antipsychotic‐induced hyperprolactinemia.

Metabolic Syndrome and Insulin Resistance in Schizophrenia Patients Receiving Antipsychotics Genotyped for the Methylenetetrahydrofolate Reductase (MTHFR) 677C/T and 1298A/C Variants

INTRODUCTION The metabolic syndrome and insulin resistance represent growing concerns related to atypical antipsychotic (AAP) use as their incidence in the schizophrenia population is two-to-four-fold higher than the general population. Reduced methylenetetrahydrofolate reductase (MTHFR) activity, resulting in aberrant folate metabolism and hyperhomocysteinemia, has been linked to cardiovascular disease and is unstudied in relation to AAP associated metabolic complications. PURPOSE To examine the relationship between MTHFR, metabolic syndrome, and insulin resistance in schizophrenia subjects receiving AAPs for >or=12 months. METHODS Fifty-eight subjects were included in this cross-sectional analysis and screened for the metabolic syndrome, insulin resistance and MTHFR 677C/T and 1298A/C genotype. RESULTS Overall, 23 subjects (40%) met metabolic syndrome criteria. There were no differences in age, gender, race, or AAP exposure between genotype groups. For the 677 T allele carriers, 53% met metabolic syndrome criteria, compared to 23% in the CC genotype group, giving an OR=3.7, (95% CI=1.24-12.66, p=0.02). Thus, for T allele subjects, the risk was almost four times greater, despite similar antipsychotic exposure. Both waist circumference and MTHFR genotype significantly predicted insulin resistance (F=8.35, df=5, 51, p<0.0001), with these two terms interacting (F=8.6, df=2, p=0.0006) suggesting that TT subjects are at greater risk for insulin resistance with increasing central adiposity, which is independent of age, gender, BMI, or metabolic syndrome diagnosis. CONCLUSION Results should be taken cautiously due to the small sample size, but suggest the MTHFR 677C/T variant may predispose patients to AAP metabolic complications.

C3435T mutation in exon 26 of the human MDR1 gene and cyclosporine pharmacokinetics in healthy subjects.

To determine the relationship between C3435T mutation in exon 26 of the human multidrug resistant 1 (MDR1) gene and cyclosporine pharmacokinetic parameters among healthy volunteers, the oral cyclosporine pharmacokinetic study was performed for 14 healthy subjects. Blood cyclosporine concentrations were measured by HPLC. Concentration–time data were analyzed by a noncompartmental method using WinNonLin, and the blood samples were genotyped for the C3435T polymorphism of MDR1 gene using the PCR and a restriction digest. Each cyclosporine pharmacokinetic parameter was compared using the Mann-Whitney U test according to his or her P-gp genotype. There were seven (7) homozygous C/C, six (6) C/T, and one (1) homozygous T/T genotypes in these 14 healthy volunteers. According to their genotypes, mean tmax 1.6 ± 0.3 hours, mean Cmax 1337 ± 329 ng/mL, mean Cl/F 66.5 ± 18.3 L/h, and mean AUC 5642 ± 1577 ng·h/mL in C/C group and mean tmax 2.0 ± 0.6 hours, mean Cmax 1540 ± 721 ng/mL, mean Cl/F 55.2 ± 18.9 L/h, and mean AUC 6902 ± 1405 ng·h/mL in C/T+T/T group. Although Cmax and AUC in C/T and T/T group were 15% and 22% larger than those in C/C group, none of these parameter comparisons was statistically significant. There were no statistical differences in cyclosporine pharmacokinetics among different MDR1 genotypes in these 14 healthy subjects.

Serotonin 2A -1438 G/A and G-protein beta3 subunit C825T polymorphisms in patients with depression and SSRI-associated sexual side-effects

The occurrence of sexual side-effects from antidepressants is thought to be mediated through serotonin 2A (5HT2A) receptors. It is currently unknown if functional polymorphisms in the 5HT2A receptor or its G-protein second messenger complex are related to sexual dysfunction in patients taking an selective serotonin reuptake inhibitor (SSRI) for depression. The purpose of this study was to determine the relationship of the 5HT2A −1438 G/A and GNB3 C825T single nucleotide polymorphisms with overall sexual well-being and individual components of sexual health as measured by the Changes in Sexual Functioning Questionnaire (CSFQ). We evaluated 89 outpatients (18–40 years of age) at low risk for other causes of sexual dysfunction who were being treated for depression with an SSRI and did not have sexual difficulties before taking the antidepressant. Outcome measures were stratified by 5HT2A and GNB3 genotypes. After controlling for age, gender, anxiety scale scores, and depression scale scores, persons with a GG genotype of the 5HT2A −1438 single nucleotide polymorphisms (SNP) were significantly more likely to be categorized as having sexual dysfunction than persons with a GA or AA genotype (OR=3.6; 95% CI 1.03, 12.6; p=0.046). Furthermore, the 5HT2A −1438 GG genotype was a significant predictor of lower arousal scores (p=0.022) after accounting for other measures. There was no significant relationship between any outcome measure and GNB3 genotype.

Association between the polymorphic GRM3 gene and negative symptom improvement during olanzapine treatment

PURPOSE The excitatory neurotransmitter glutamate has become an important area of focus for schizophrenia researchers. Polymorphisms in the type-three metabotropic glutamate receptor gene (GRM3) have been associated with the pathogenesis of schizophrenia. The purpose of this study was to determine whether a pharmacogenetic relationship exists between six polymorphisms of GRM3 and clinical improvement during olanzapine treatment in persons with schizophrenia. METHOD Forty-two subjects meeting DSM-IV criteria for schizophrenia started olanzapine and were titrated to a fixed dose of 7.5-20 mg/day for 6 weeks. The Brief Psychiatric Rating Scale (BPRS) total score and the Scale for Assessment of Negative Symptoms (SANS) were completed at baseline and then weekly to assess psychopathology. RESULTS The principle finding of this study is that GRM3 polymorphisms were collectively significant predictors of negative symptom improvement in persons with schizophrenia treated with the atypical antipsychotic olanzapine. After controlling for baseline SANS scores, the genotypes as a whole were significant predictors of negative symptom improvement, accounting for approximately 28% of the variance in scores (F = 16.30, df = 29, p < 0.001). The single nucleotide polymorphism SNP1 (rs274622), located in a potential promoter region, had the most significant influence on SANS scores, but the effects of this locus could not be fully separated from the other polymorphisms. The mean decrease in SANS scores was 21% vs. 51% for SNP1 T/T + T/C and SNP1C/C subjects, respectively. CONCLUSION These data suggest that polymorphisms in the GRM3 gene may be useful as predictors of negative symptom improvement in persons with schizophrenia treated with olanzapine.

Risk factors associated with metabolic syndrome in bipolar and schizophrenia subjects treated with antipsychotics: the role of folate pharmacogenetics.

Abstract Folate has been implicated in cardiovascular disease with atypical antipsychotic (AAPs) use, and individuals with methylenetetrahydrofolate reductase (MTHFR) and catechol-O-methyl transferase (COMT) variants are at greater risk. This study examined the relationship between the MTHFR 677C/T, MTHFR 1298A/C, and COMT Val158Met variants; metabolic syndrome; and lifestyle measures in schizophrenia and bipolar subjects. A total of 237 subjects with bipolar or schizophrenia receiving an antipsychotic for at least 6 months were included in this cross-sectional analysis. Subjects were screened for the metabolic syndrome (National Cholesterol Education Program Adult Treatment Panel III criteria) and MTHFR 677C/T, MTHFR 1298A/C, and Val158Met genotypes. In addition, serum folate and homocysteine were measured along with lifestyle factors. The subject’s mean age was 44.7 (SD, 11.7) years; 72% were white, and 51% male; 61% were receiving an AAP; the mean body mass index was 32.6 (SD, 8.2) kg/m2, and 48% were current smokers. Overall, 41% met metabolic syndrome criteria (n = 98). There were no differences in age, sex, AAP exposure, or body mass index between genotype groups. Metabolic syndrome was related to age, smoking, and the MTHFR 677T and COMT 158Val alleles (&khgr;2 = 34.4, P < 0.0001). In addition, AAP use showed a trend association with metabolic syndrome (&khgr;2 = 3.21, P = 0.07). These data support our previous reports and add more data pointing to folate’s role in mediating a link between mental illness and cardiovascular disease. Use of this information clinically may help to reduce the risk for AAP metabolic complications in those whose clinical care necessitates the use of AAPs.

CYP3A5 polymorphism and the ethnic differences in cyclosporine pharmacokinetics in healthy subjects

To determine the relationship between CYP3A5 polymorphism and cyclosporine pharmacokinetic parameters among healthy volunteers, an oral cyclosporine (CsA) pharmacokinetic study was performed in 16 healthy subjects. Blood CsA concentrations were measured by high-performance liquid chromatography. Concentration-versus-time data were analyzed by a noncompartmental method using WinNonLin, and the blood samples were genotyped for the CYP3A5 using the polymerase chain reaction and pyrosequencing. CsA pharmacokinetic parameters were dichotomized and compared using the 1-way ANOVA test according to the CYP3A5*3C genotype. There were 6 homozygous A/A (wild type), 6 homozygous G/G (variant), and 4 heterozygous A/G genotypes for CYP3A5*3 C in these 16 healthy volunteers. All whites were G/G group, and all African Americans except 1 were either A/A or A/G group. The mean AUC (ng·h/mL) of CsA for the 3 genotype groups were 4962 ± 1074 (A/A), 6677 ± 1153 (G/G), and 5416 ± 1817 (A/G), (A/A versus G/G, P = 0.03), and the mean CL/F (mL/min/kg) were 15.6 ± 3.1 (A/A), 12.0 ± 2.3 (G/G), and 14.7 ± 5.9 (A/G), (A/A versus G/G, P = 0.04). None of the other parameters were significantly different among the 3 genotypes. In conclusion, the CYP3A5*3C polymorphism appears to affect AUC and CL/F of oral CsA significantly in healthy subjects, which may partly explain some of the differences of pharmacokinetics in CsA between African Americans and whites.