An open-label trial of aripiprazole in the treatment of aggression in male adolescents diagnosed with conduct disorder.

BACKGROUND: The adverse effect profiles of typical and atypical antipsychotics are problematic because of their extrapyramidal and endocrine adverse effects, respectively. METHODS: Ten adolescent male patients diagnosed with conduct disorder received aripiprazole in doses of ≤20 mg/d in an open-label, intent-to-treat design to establish and characterize the efficacy of the drug in reducing aggressive behavior. RESULTS: Based on clinician and parent observations, aripiprazole was effective in reducing aggressive behavior in adolescent boys. The change in clinician-observed aggression ratings appears to have been driven by a decrease in physical aggression, whereas the change in parent-observed aggression ratings appears to have been driven by a decrease in verbal aggression and aggression against objects and animals. CONCLUSIONS: Aripiprazole was an effective and relatively well-tolerated treatment for overall aggression in adolescent males with conduct disorder, in the view of both clinicians and parents. Depending on the observer, aripiprazole improved aggression categorized as physical aggression, verbal aggression, and aggression against objects and animals.

Diabetes prevalence estimates in schizophrenia and risk factor assessment.

BACKGROUND: Atypical antipsychotics have been indirectly associated with the diagnosis of type 2 diabetes mellitus (T2DM) in patients with schizophrenia. The purpose of this cross-sectional study was to determine the prevalence of T2DM and to examine the risk factors associated with T2DM among outpatients diagnosed with schizophrenia. The study also sought to determine which risk factors are of particular screening importance in monitoring the metabolic status of these patients. METHODS: This study included 202 patients diagnosed with schizophrenia. Data on a number of known and hypothesized risk factors for T2DM were collected. RESULTS: Risk factors for T2DM identified by bivariate analyses in this sample included older age, waist-to-hip ratio >1.0, sedentary lifestyle, number of hours worked per week, hyperlipidemia, previous screening for T2DM, higher random blood glucose, and number of years on atypical antipsychotics risperidone or olanzapine. However, further scrutiny using multiple logistic regression identified only sedentary lifestyle, waist-to-hip ratio ≥1.0, and a diagnosis of hyperlipidemia as significant risk factors in these patients. Similar to other studies, there was an 11.5% (22/192) lifetime prevalence rate of diabetes among this population. CONCLUSIONS: Risk factors traditionally associated with T2DM, as well as waist-to-hip ratio, are the factors most strongly associated with increased risk of diabetes in patients with schizophrenia.

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

OBJECTIVE: 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. METHODS: Ninety-five treatment refractory schizophrenia participants were enrolled. Prior to a medication switch, global psychopathology and negative symptoms were rated. These participants were genotyped for seven markers in GRM3. Genotype associations with symptoms were assessed. RESULTS: Two markers in GRM3 (rs1989796 and rs1476455), were associated with the presence of refractory global symptoms as measured by the Brief Psychiatric Rating Scale (BPRS) Total scores. Participants with an rs1476455_CC genotype had significantly higher BPRS scores than A-carriers (55.1±10.4 vs. 48.3±9.2; F=7.6, p=0.0071). Additionally, participants with the rs1989796_CC genotype had significantly higher BPRS scores than T-carriers (50.1±5.7 vs. 55.8±10.5, F=7.1, p=0.0091). No evidence for significant associations with negative symptoms was observed. CONCLUSIONS: Polymorphisms in the GRM3 gene may be associated with refractory global psychosis symptoms but not negative symptoms in persons with schizophrenia.

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.

Testosterone therapy in late-life major depression in males.

BACKGROUND: Major depression associated with aging in males may improve with anabolic/androgenic steroid therapy. The efficacy and safety of testosterone therapy in the treatment of depression in elderly hypogonadal males is inconclusive. The following study identifies a subgroup of elderly depressed males who may benefit from testosterone therapy. METHOD: Participants included 16 elderly eugonadal males with major depressive disorder (DSM-IV criteria) and a Hamilton Rating Scale for Depression (HAM-D) score > 18. Following a single-blind 2-week placebo lead-in, patients were randomly assigned to treatment with either a physiologic dose of testosterone cypionate (TC), 100 mg/week, or supraphysiologic dose of 200 mg/week IM for 6 weeks. Psychometric testing was carried out at entry into the study, at the TC injection baseline, and every 2 weeks thereafter. Tests included an objective measurement, the HAM-D, and the Buss-Durkee Hostility Inventory. RESULTS: One patient meeting inclusion criteria responded during the placebo lead-in; thus, 15 patients were randomly assigned to treatment (100 mg/week, N = 8; 200 mg/week, N = 7). There was a 42% decrease in the mean HAM-D scores from 20.1 to 11.9 (p <.0001). However, the majority of the change was due to improvement in the 10 late-onset (< or = 45 years old) depression patients, whose mean HAM-D score decreased from 19.8 to 9.3 (53%), versus the 5 early-onset depression patients, whose mean HAM-D score decreased from 20.8 to 17.0 (18%) (p =.0110). The TC dose did not affect the response. Similar HAM-D decreases of 43% and 41% occurred for the respective 100- and 200-mg/week doses. The HAM-D responder analysis found that none of 5 early-onset patients had HAM-D response, whereas 6 (60%) of 10 late-onset patients responded (p =.025). Similarly, none of the early-onset patients experienced a remission whereas 5 (50%) of the late-onset patients were categorized as remitters (p =.053). Correlations between the peak and mean total testosterone concentrations and HAM-D change scores suggested that only minimal TC doses were required to produce an antidepressant effect. CONCLUSION: These data suggest that testosterone therapy would best be limited to men with late-onset depression. The findings suggest that short-term therapy with TC is safe. Long-term treatment safety is unknown. Psychiatrists using testosterone therapy should ascertain that patients have been recently valuated for prostate cancer. If testosterone therapy is initiated, serial serum prostate-specific antigen sampling should be used for monitoring patients' prostate status.

Measures of aggression and mood changes in male weightlifters with and without androgenic anabolic steroid use.

Supraphysiologic doses of testosterone are associated with increased aggression that is hypothesized to be a function of testosterone serum concentrations, mood, and personality. The study attempted to characterize this relationship among weightlifters who were users (n = 10) and nonusers (n = 18) of anabolic steroids. Participants were interviewed using the Modified Mania Rating Scale and Hamilton Rating Scale for Depression to assess mood, the Buss-Durkee Hostility Inventory (BDHI) and Point Subtraction Aggression Paradigm (PSAP) to assess aggression, and the Personality Disorder Questionnaire (PDQ-R) to assess personality. Blood samples were obtained for the determination of total, free, and weakly bound testosterone. Comparisons of continuous variables between testosterone users and non-users were performed with a parametric (unpaired t-test) or non-parametric (Mann-Whitney) test where appropriate. Correlations with testosterone were examined separately for testosterone users and non-users, using Spearman rank correlation. The subjective (BDHI) and objective (PSAP) assessments of aggression found that supranormal testosterone concentrations were associated with increased aggression. However, the PDQ-R results suggest that this finding was confounded by the personality disorder profile of the steroid users, because steroid users demonstrated Cluster B personality disorder traits for antisocial, borderline, and histrionic personality disorder.

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 chi(2) 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.

BACKGROUND: 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. AIM: To determine associations between weight gain during olanzapine treatment and the -759C/T polymorphism of the 5HT2C receptor gene. METHODS: This study included 42 acutely ill patients with schizophrenia (DSM-IV). Weekly assessments included Brief Psychiatric Rating Scale (BPRS), Scale for Assessment of Negative Symptoms (SANS), and weight measurements. Olanzapine was titrated to a fixed dose (7.5-20 mg/day) for 2-6 weeks. A 24 hr plasma level was obtained at the endpoint visit. Genomic DNA was isolated from a whole blood sample and analyzed for the -759C/T polymorphism of the 5HT2C receptor. RESULTS: A chi-square analysis was conducted comparing the distribution of T and C alleles in subjects grouped as gaining more or less than 5, 7, and 10% of their baseline weight during treatment with olanzapine. A threshold of 10% was found to be significant. The distribution of T alleles was higher in subjects not gaining 10% of more of their body weight compared who did gain significant weight (11/27 (40.7%) vs. 0/15 (100%), chi2 = 11.805, P = 0.0035). CONCLUSIONS: Subjects with a T allele of the 5HT2C receptor -759C/T polymorphism may have a lower incidence of weight gain from olanzapine over a 6 week period compared to those with the C allele. These results need to be replicated.

The association of weight gain and olanzapine plasma concentrations.

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 (> or =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 > or =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.

5-HT2A receptor promoter polymorphism, -1438G/A and negative symptom response to olanzapine in schizophrenia.

The 5-HT2A receptor promoter -1438G/A polymorphism, which is in complete linkage disequilibrium with the 5-HT2A 102T/C polymorphism, may be related to antipsychotic response. The aim of this paper is to determine relationships between the -1438G/A polymorphism and olanzapine negative symptom response. DNA from 41 subjects with schizophrenia (as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) was analyzed for the -1438G/A polymorphism. Olanzapine (7.5-20 mg/day) was given for 6 weeks and response was assessed using the Scale for Assessment of Negative Symptoms (SANS). A linear regression used a dependent variable of percent change in SANS. Independent variables included 5-HT2A polymorphisms and interactions. The -1438G/A polymorphism and percent change in SANS showed a significant trend (P=.0542). The A/A genotype group had a 45% reduction in SANS compared with 19% in the other groups. We conclude that the A/A genotype may be associated with olanzapine negative symptom response, seen as a 2-fold greater percent reduction in SANS, and may be clinically relevant.