Timothy L. Holman

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.

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.

Bupropion SR vs. Methylphenidate vs. Placebo for Attention Deficit Hyperactivity Disorder in Adults

Despite the increasing recognition of attention-deficit hyperactivity disorder (ADHD) in adults, there are few controlled trials demonstrating the effectiveness of pharmacological treatments, particularly with nonstimulants. One controlled trial found bupropion SR more effective than placebo in the treatment of ADHD adults. We conducted a controlled study to contrast the effectiveness of bupropion SR and methylphenidate to placebo in ADHD adults. A randomized, double-blind, parallel design was used in this study. Following a 7-day placebo lead-in, 30 ADHD (DSM-IV) subjects (18–60 years old) were randomized to bupropion, methylphenidate, or placebo for 7 weeks. Methylphenidate was titrated over 1 week to a maximum dose of 0.9 mg/kg/d divided into 3 doses while bupropion was titrated over 2 weeks to a maximum dose of 200 mg A.M. and 100 mg P.M. Response rates based on Clinical Global Impression improvement ratings in patients receiving bupropion, methylphenidate, and placebo were 64, 50, and 27%, respectively. The difference in response rates between active treatment and placebo was not statistically significant (p = 0.14). Neuropsychological testing demonstrated trends favoring drug treatment on measures of immediate recall and verbal fluency. While bupropion SR may be a viable clinical alternative for adults with ADHD, further investigation is needed.

The association of weight gain and olanzapine plasma concentrations

Abstract: Atypical antipsychotics, including olanzapine, have been associated with clinically significant weight gain in some patients. The purpose of this study was to determine if weight gain was associated with increasing plasma concentrations during olanzapine treatment in subjects with schizophrenia. This study included 39 acutely ill subjects with schizophrenia, schizoaffective disorder, or schizophreniform disorder (DSM-III-R or DSM-IV). Assessments included the Brief Psychiatric Rating Scale (BPRS), the Scale for Assessment of Negative Symptoms (SANS), and weight measurements. Olanzapine was titrated to a dose of 5 to 20 mg/d for 2 to 6 weeks. A 24-hour plasma concentration was obtained after 6 weeks of treatment. Analysis using a receiver operator characteristic curve identified a threshold dose-weighted plasma concentration of 20.6 ng/mL being associated with an increased likelihood of clinically significant weight gain (≥7% baseline weight) during olanzapine treatment. The associations remained significant after adjusting for age, gender, baseline body mass index, baseline symptom severity, and symptom improvement (OR = 10.1; 95% CI, 1.3-75.0; P = 0.024). Similar analysis determined that a threshold olanzapine dose of 13.3 mg/d was associated with ≥7% weight gain. However, after adjusting for potential confounders, the results did not remain significant. The association of weight gain with plasma concentrations during treatment with olanzapine may support the utilization of plasma drug concentration as a marker for antipsychotic-induced weight gain in the treatment of schizophrenia.

Association between type-three metabotropic glutamate receptor gene ( GRM3 ) variants and symptom presentation in treatment refractory schizophrenia

Positive associations between polymorphisms in the type‐three metabotropic glutamate receptor gene (GRM3) and the pathogenesis of schizophrenia as well as response to antipsychotic treatment have been reported. The objective of this study was to determine whether refractory psychiatric symptoms in antipsychotic non‐responders are related to polymorphisms in GRM3.

The Effects of Anabolic Steroids on Driving Performance as Assessed by the Iowa Driver Simulator

The effect of physiologic (100 mg/wk) and supraphysiologic (250 and 500 mg/wk) doses of testosterone cypionate (TC) on automobile driving were studied using the Iowa Driver Simulator. Six normal subject volunteers were studied off TC and on TC once steady-state concentrations were achieved after at least three weeks of dosing. Despite the administration of supraphysiologic testosterone doses, an increase in aggressive driving behavior was not detected. Likewise, corresponding psychometric testing using the Buss-Durkee Hostility Inventory to assess aggression was unable to detect any change in aggression in the test subjects. Although aggressive driving behavior may be increased by testosterone administration, the drug itself may not be responsible for these effects. Supraphysiologic doses greater than 500 mg/wk and a semi-controlled research environment may be necessary to produce this effect since case reports of AAS abuse causing altered driving behavior may be multifactorial in nature.