Longitudinal study of inflammation and relapse in schizophrenia.

INTRODUCTION: The clinical course of schizophrenia is often characterized by recurrent relapses. Blood inflammatory markers are altered in acute psychosis, and may be state markers for illness relapse in schizophrenia. Few studies have investigated longitudinal, intra-individual changes in inflammatory markers as a predictor of relapse. In the present study, we explored this association in a relapse prevention trial in patients with schizophrenia. METHODS: We analyzed blood inflammatory markers in 200 subjects, with a mean 11 samples per subject, during the 30 month Preventing Relapse in schizophrenia: Oral Antipsychotics Compared to Injectable: eValuating Efficacy (PROACTIVE) trial. Associations between longitudinal changes in inflammatory markers and relapse were analyzed using a within-subjects design. RESULTS: 70 (35 %) of subjects relapsed during the study period. There were no significant differences in mean inflammatory marker levels based on relapse status (yes/no). Baseline levels of inflammatory markers did not predict incident relapse. Among subjects who relapsed, there was a significant decrease in mean blood IL-6 (n = 38, p = 0.019) and IFN-γ (n = 44, p = 0.012) levels from the visit before the relapse to the visit after relapse. CONCLUSION: Although there was some evidence for inflammation as a potential state marker for acute psychosis, we did not find significant evidence for its utility as a relapse-predictive marker.

Predicting relapse in schizophrenia: Is BDNF a plausible biological marker?

Understanding the biological processes that underlie why patients relapse is an issue of fundamental importance to the detection and prevention of relapse in schizophrenia. Brain Derived Neurotrophic Factor (BDNF), a facilitator of brain plasticity, is reduced in patients with schizophrenia. In the present study, we examined whether decreases in plasma BDNF levels could be used as a biological predictor of relapse in schizophrenia. A total of 221 patients were prospectively evaluated for relapse over 30months in the Preventing Relapse in Schizophrenia: Oral Antipsychotics Compared to Injectables: eValuating Efficacy (PROACTIVE) study. Serial blood samples were collected at a maximum of 23 time points during the 30-month trial and BDNF levels were measured in plasma samples by ELISA. Receiver Operating Characteristic (ROC) curve analysis indicated that BDNF was not a significant predictor of relapse, hospitalization or exacerbation. Regardless of treatment group (oral second generation antipsychotic vs. long-acting injectable risperidone microspheres), baseline BDNF value did not differ significantly between those who experienced any of the adverse outcomes and those who did not. While contrary to the study hypothesis, these robust results offer little support for the use of plasma BDNF alone as a biomarker to predict relapse in schizophrenia.

Comparison of Injectable and Oral Antipsychotics in Relapse Rates in a Pragmatic 30-Month Schizophrenia Relapse Prevention Study.

OBJECTIVE: In a pragmatic clinical trial, this study sought to compare relapses among patients receiving either long-acting injectable or oral second-generation antipsychotics. METHODS: PROACTIVE (Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy), a prior 30-month relapse prevention study, compared use of a long-acting injectable second-generation antipsychotic with use of an oral second-generation antipsychotic by 305 patients with schizophrenia or schizoaffective disorder and found similar rates of first relapse between groups (42% with injectable medication, 32% with oral medication). This study examined subsequent relapses among patients who had relapsed in PROACTIVE and who continued in treatment, follow-up, or both. RESULTS: Thirty-two patients (11%) experienced two relapses, and 13 patients (4%) had three relapses. Neither rate of relapse nor time to successive relapses differed between treatment groups. CONCLUSIONS: There was an impressively low rate of subsequent relapses in this pragmatic clinical trial. Because all patients had a clinic visit according to the biweekly long-acting injectable medication administration schedule, frequent contact may have contributed to low relapse rates. Maintaining frequent clinical contact may be a valid psychosocial relapse prevention treatment.

Comparison of SGA oral medications and a long-acting injectable SGA: the PROACTIVE study.

Until relatively recently, long-acting injectable (LAI) formulations were only available for first-generation antipsychotics and their utilization decreased as use of oral second-generation antipsychotics (SGA) increased. Although registry-based naturalistic studies show LAIs reduce rehospitalization more than oral medications in clinical practice, this is not seen in recent randomized clinical trials. PROACTIVE (Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy) relapse prevention study incorporated efficacy and effectiveness features. At 8 US academic centers, 305 patients with schizophrenia or schizoaffective disorder were randomly assigned to LAI risperidone (LAI-R) or physician's choice oral SGAs. Patients were evaluated during the 30-month study by masked, centralized assessors using 2-way video, and monitored biweekly by on-site clinicians and assessors who knew treatment assignment. Relapse was evaluated by a masked Relapse Monitoring Board. Differences between LAI-R and oral SGA treatment in time to first relapse and hospitalization were not significant. Psychotic symptoms and Brief Psychiatric Rating Scale total score improved more in the LAI-R group. In contrast, the LAI group had higher Scale for Assessment of Negative Symptoms Alogia scale scores. There were no other between-group differences in symptoms or functional improvement. Despite the advantage for psychotic symptoms, LAI-R did not confer an advantage over oral SGAs for relapse or rehospitalization. Biweekly monitoring, not focusing specifically on patients with demonstrated nonadherence to treatment and greater flexibility in changing medication in the oral treatment arm, may contribute to the inability to detect differences between LAI and oral SGA treatment in clinical trials.

Evidence for accelerated vascular aging in bipolar disorder.

OBJECTIVE: Persons with bipolar disorder face excess risk of cardiovascular disease, although the biobehavioral mechanisms and time course are unclear. We measured vascular stiffness in a cross-sectional sample of participants with bipolar disorder and compared results to published normative data to assess time-course and relationship to behavioral risk factors. METHODS: 62 individuals with bipolar disorder (33±6.7years; 64% female) underwent non-invasive assessment of arterial stiffness through arterial applanation tonometry. Lifetime tobacco exposure was estimated on clinical interview. Physical activity was assessed using the long-version of the International Physical Activity Questionnaire (IPAQ). A food frequency questionnaire was used to compute Alternate Healthy Eating Index (AHEI), a measure of overall dietary quality. Medication histories were systematically abstracted from pharmacy records. RESULTS: Participants over the age of 32 (median split) had greater arterial stiffness than expected from age-based population norms for pulse wave velocity (PWV) (7.6 vs. 7.0m/s, p=.02) and estimated aortic augmentation pressure (AIx) (14.2 vs. 8.2%, p=.0002). The younger portion of the sample did not differ from population norms on these measures (PWV 6.3 vs. 6.4m/s, p=.45 and AIx 7.6 vs. 7.4%, p=.60). In the older half of the sample, physical activity was inversely associated with AIx and poorer diet marginally associated with PWV. These findings were independent of body mass index (BMI), which was strongly related to arterial stiffness. CONCLUSION: Risk for vascular disease may be acquired over the long-term course of affective illness. This risk appears to reflect maladaptive health behaviors, which may be amenable to intervention.

Feasibility and pilot efficacy results from the multisite Cognitive Remediation in the Schizophrenia Trials Network (CRSTN) randomized controlled trial.

BACKGROUND: The true benefit of pharmacologic intervention to improve cognition in schizophrenia may not be evident without regular cognitive enrichment. Clinical trials assessing the neurocognitive effects of new medications may require engagement in cognitive remediation exercises to stimulate the benefit potential. However, the feasibility of large-scale multisite studies using cognitive remediation at clinical trials sites has not been established. METHOD: 53 adult patients with DSM-IV schizophrenia from 9 university-affiliated sites were randomized to a cognitive remediation condition that included the Posit Science Brain Fitness auditory training program with weekly Neuropsychological and Educational Approach to Remediation (NEAR) "bridging groups" or a control condition of computer games and weekly healthy lifestyles groups. Patients were expected to complete 3 to 5 one-hour sessions weekly for 40 sessions or 12 weeks, whichever came first. The primary outcomes were feasibility results as measured by rate of enrollment, retention, and completion rate of primary outcome measures. The study was conducted from July 2009 through January 2010. RESULTS: During a 3-month enrollment period, 53 (of a projected 54) patients were enrolled, and 41 (77%) met criteria for study completion. Thirty-one patients completed all 40 sessions, and all patients completed all primary outcome measures. Preliminary efficacy results indicated that, after 20 sessions, patients in the cognitive remediation condition demonstrated mean MATRICS Consensus Cognitive Battery composite score improvements that were 3.7 (95% CI, 0.05-7.34) T-score points greater than in patients in the computer-games control group (F(1,46) = 4.16, P = .047). At the end of treatment, a trend favoring cognitive remediation was not statistically significant (F(1,47) = 2.26, P = .14). CONCLUSION: Multisite clinical trials of cognitive remediation using the Posit Science Brain Fitness auditory training program with the NEAR method of weekly bridging groups at traditional clinical sites appear to be feasible. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00930150.

Systematic Review and Meta-analysis of Pharmacological Interventions for Weight Gain from Antipsychotics and Mood Stabilizers.

Pharmacological treatments for serious mental illness (SMI) can cause weight gain and adverse metabolic effects. Many second generation antipsychotics and mood stabilizers appear to be particularly problematic in this regard. Several studies have investigated interventions for antipsychotic-induced, or less commonly mood stabilizer -induced, weight gain. Both lifestyle and pharmacological interventions have demonstrated effectiveness. We systematically review randomized controlled trials of pharmacological interventions for weight gain related to these medications. We conducted a meta-analysis of clinical trials for the most studied agents to estimate mean weight loss: metformin (2.93 kg, 95% C.I. 0.97-4.89, p=0.003), H(2) antagonists (1.78 kg (95% C.I. -0.50-4.06, p=0.13), topiramate (3.95 kg 95% C.I. 1.77-6.12, p=0.0004), and norepinephrine reuptake inhibitors (1.30 kg (95% C.I. -0.06-2.66, p=0.06). Among the studied options for antipsychotic-related weight gain, metformin has the strongest evidence base and may improve vascular risk factors beyond obesity. The use of topiramate is also supported by the literature and may improve psychotic symptoms in those refractory to treatment. A marginal benefit is seen with norepinephrine reuptake inhibitors, and any vascular benefits from such weight loss may be counteracted by increases in blood pressure or heart rate. Pharmacological therapies may offer benefits as a means of supplementing the effects of lifestyle changes for weight loss. However, the existing evidence provides little evidence of specificity for pharmacological therapies to antipsychotic-induced weight gain and has not studied any connection between benefits and reduced incidence of diabetes mellitus or any vascular outcomes.

Concomitant psychotropic medication use during treatment of schizophrenia patients: longitudinal results from the CATIE study.

OBJECTIVE: This study is a post hoc analysis of additions of antidepressants, anxiolytics, and sedative/hypnotics in treatment of patients randomized to antipsychotic treatment in the CATIE study, which recruited a chronic, "real world" schizophrenia sample and followed patients for up to eighteen months. We examined baseline predictors of initiation, time until initiation, and duration of treatment with antidepressants, anxiolytics, and sedative/hypnotics in CATIE study participants. METHODS: Psychotropic medication use by 1,449 CATIE study participants was documented at each study visit. Baseline demographic and clinical predictors of initiation, of time to initiation, and of duration of treatment of Concomitant Psychotropic Medications (CPMs) in each category (antidepressant, anxiolytic, and sedative/hypnotics) were identified through multiple regression analyses. RESULTS: Initiation of new CPMs post baseline by CATIE clinicians was moderately frequent, with 14.6% of patients receiving antidepressants, 13.7% receiving anxiolytics, and 11.2% receiving sedative/hypnotics. Predictors of antidepressant initiation (14.6% of group) were being female or white, and having a prior diagnosis of depression or symptoms of depression at baseline. Patients with higher positive symptom scores and younger patients were started on antidepressants sooner. Duration of antidepressant treatment was longer in patients with less education and in those with a history of alcohol abuse/dependence. Predictors of anxiolytic initiation (13.7% of group) were not being of African-American race, being separated/divorced, younger age, higher body mass index, and akathisia. Time to anxiolytic initiation was shorter in patients who were separated or divorced and in patients with better neurocognitive functioning. Duration of anxiolytic treatment was shorter for African Americans and longer in patients with better instrumental role functioning. Predictors of sedative/hypnotic use (11.2% of group) were depressive symptoms and prior diagnosis of an anxiety disorder. Time to initiation of sedative/hypnotics was longer for those with depressive symptoms and shorter for those with a history of alcohol abuse/dependence. CONCLUSIONS: Sedative/hypnotics, anxiolytics, and antidepressants were commonly used CPMs in schizophrenia during the CATIE trial, where patients were being seen frequently and antipsychotic treatment was optimized. Randomized, controlled clinical trials examining adjunctive use of antidepressants, anxiolytics and sedative/hypnotics to target symptoms of anxiety, depression, and insomnia in patients with schizophrenia are needed to adequately address the efficacy of these interventions.

Factors associated with the prescribing of olanzapine, quetiapine, and risperidone in patients with bipolar and related affective disorders.

STUDY OBJECTIVE: To identify the factors associated with newly prescribed, first-line, second-generation antipsychotics (SgAs) associated with weight gain-olanzapine, risperidone, and quetiapine. DESIGN: Retrospective medical record review. SETTING: Outpatient and inpatient psychiatry services at a tertiary care, academic medical center. PATIENTS: Three hundred forty consecutive adults who had major depressive disorder with psychotic features, bipolar I, bipolar II, bipolar not otherwise specified, or schizoaffective disorder over two time periods (August 30-October 30, 2009, and April 1-May 31, 2010). MEASUREMENTS AND MAIN RESULTS: Clinical and sociodemographic variables associated with newly prescribed olanzapine, risperidone, and quetiapine were identified by using univariate and multivariate logistic regression. Several clinical factors were individually associated with initiation of these SgAs: mania (odds ratio [OR] 3.6, 95% confidence interval [CI] 1.2-10.8, p=0.02), psychosis (OR 3.3, 95% CI 1.5-6.9, p=0.002), and inpatient treatment (OR 3.8, 95% CI 1.8-7.9, p=0.0005). Prevalent use of lithium (OR 0.3, 95% CI 0.1-0.9, p=0.03) and being married (OR 0.3, 95% CI 0.1-0.8, p=0.02) were inversely associated with new use of an SgA. Mania, psychosis, married status, and lithium use remained independently associated on multivariate analysis. Factors related to metabolic or vascular risk were not associated with SgA initiation. CONCLUSION: Psychiatric clinicians were influenced heavily by clinical features related to mental status and acuity when determining whether to prescribe SgAs. However, factors related to vascular risk were not associated. Future observational studies should consider current clinical status as an important factor in determining propensity to receive antipsychotics or other short-term treatments for bipolar and related disorders.

Predictors of risperidone and 9-hydroxyrisperidone serum concentration in children and adolescents.

INTRODUCTION: Little is known about risperidone metabolism in a clinical sample, where polypharmacy is common. Such knowledge is important since several of its side effects are dose dependent. METHODS: Medically healthy patients aged 7 to 17 years old treated with risperidone for at least 6 months were enrolled. Trough serum risperidone and 9-hydroxyrisperidone concentrations were measured. RESULTS: One hundred seven participants (92% males) were recruited, representing a heterogenous clinical group with attention-deficit/hyperactivity disorder, disruptive behavior disorders, pervasive developmental disorders, anxiety disorders, mood disorders, tic disorders, or psychotic disorders. Risperidone had been used at a mean dose of 0.03 mg/kg, for a mean 2.5 years, predominantly to treat irritability and aggression. Cytochrome CYP2D6 inhibitors were divided into prominent (fluoxetine, bupropion, and lamotrigine), intermediate (sertraline), and weak inhibition groups (citalopram or escitalopram). The concentrations of risperidone and its metabolite were strongly associated with the dose of risperidone and time since the last dose and, to a lesser extent, with male sex. In addition, risperidone concentration increased with pubertal stage (p < 0.05), while body mass index z-score (p = 0.001) predicted a higher 9-hydroxyrisperidone concentration. The use of CYP2D6 inhibitors was much more strongly associated with risperidone concentration (p < 0.0001) than with its metabolite's (p = 0.06). CONCLUSIONS: In chronically treated youths, the metabolism of risperidone depends on the stage of sexual development, whereas that of 9-hydroxyrisperidone varies with body fat. Moreover, CYP2D6 inhibitors more strongly affect risperidone metabolism than that of its metabolite. The clinical implications of these findings, in relation to efficacy and tolerability, deserve further investigation.

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.

Treatment outcomes of patients with tardive dyskinesia and chronic schizophrenia.

OBJECTIVE: We compared the response to antipsychotic treatment between patients with and without tardive dyskinesia (TD) and examined the course of TD. METHOD: This analysis compared 200 patients with DSM-IV-defined schizophrenia and TD and 997 patients without TD, all of whom were randomly assigned to receive one of 4 second-generation antipsychotics. The primary clinical outcome measure was time to all-cause treatment discontinuation, and the primary measure for evaluating the course of TD was change from baseline in Abnormal Involuntary Movement Scale (AIMS) score. Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to compare treatment discontinuation between groups. Changes in Positive and Negative Syndrome Scale (PANSS) and neurocognitive scores were compared using mixed models and analysis of variance. Treatment differences between drugs in AIMS scores and all-cause discontinuation were examined for those with TD at baseline. Percentages of patients meeting criteria for TD postbaseline or showing changes in AIMS scores were evaluated with χ(2) tests. Data were collected from January 2001 to December 2004. RESULTS: Time to treatment discontinuation for any cause was not significantly different between the TD and non-TD groups (χ(2)(1) = 0.11, P = .743). Changes in PANSS scores were not significantly different (F(1,974) = 0.82, P = .366), but patients with TD showed less improvement in neurocognitive scores (F(1,359) = 6.53, P = .011). Among patients with TD, there were no significant differences between drugs in the decline in AIMS scores (F(3,151) = 0.32, P = .811); 55% met criteria for TD at 2 consecutive visits postbaseline, 76% met criteria for TD at some or all postbaseline visits, 24% did not meet criteria for TD at any subsequent visit, 32% showed a ≥ 50% decrease in AIMS score, and 7% showed a ≥ 50% increase in AIMS score. CONCLUSIONS: Schizophrenia patients with and without TD were similar in time to discontinuation of treatment for any cause and improvement in psychopathology, but differed in neurocognitive response. There were no significant differences between treatments in the course of TD, with most patients showing either persistence of or fluctuation in observable symptoms. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00014001.

Pharmacogenetics and schizophrenia.

The wide interindividual variability in clinical response and tolerability of antipsychotic medications has led investigators to postulate that these variabilities may be under genetic control. Although not always consistent, there are promising indications from emergent pharmacogenetic studies that efficacy of antipsychotic medications for the various symptom domains of psychopathology in schizophrenia may be genetically regulated. This is an encouraging approach. Moreover, there are also suggestive findings that the side-effect profiles of second-generation antipsychotic medications and their propensity to cause weight gain and glucose and lipid abnormalities as well as tardive dyskinesia may be related to pharmacogenetic factors in this patient population. Ultimately, such approaches could drive choices of antipsychotic medication based on the likelihood of clinical response and development of side effects in light of a particular patient's genetic profile. In the future, this targeted approach (personalized medicine) may become informative for clinicians choosing an antipsychotic medication for an individual patient with schizophrenia.

Population pharmacokinetics of perphenazine in schizophrenia patients from CATIE: impact of race and smoking.

The goal of the study was to characterize population pharmacokinetics (PPK) for perphenazine in patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Patients (n = 156) received 8 to 32 mg of perphenazine daily for 14 to 600 days for a total of 421 plasma concentrations measurements. Nonlinear mixed-effects modeling was used to determine PPK characteristics of perphenazine. One- and 2-compartment models with various random effect implementations and mixture distributions were evaluated. Objective function values and goodness-of-fit plots were used as model selection criteria. Age, weight, sex, race, smoking, and concomitant medications were evaluated as covariates. A 1-compartment linear model with proportional error best described the data. The population mean clearance and volume of distribution for perphenazine were 483 L/h and 18 200 L, respectively. Race and smoking status had significant impacts on perphenazine clearance estimates. In addition, the estimated population mean clearance was 48% higher in nonsmoking African Americans than in nonsmoking other races (512 L/h vs 346 L/h). Active smokers eliminated perphenazine 159 L/h faster than nonsmokers in each race. Clearances for smoking African Americans versus smokers in other races were 671 L/h versus 505 L/h, respectively.

Antipsychotic dose equivalents and dose-years: a standardized method for comparing exposure to different drugs.

BACKGROUND: A standardized quantitative method for comparing dosages of different drugs is a useful tool for designing clinical trials and for examining the effects of long-term medication side effects such as tardive dyskinesia. Such a method requires establishing dose equivalents. An expert consensus group has published charts of equivalent doses for various antipsychotic medications for first- and second-generation medications. These charts were used in this study. METHODS: Regression was used to compare each drug in the experts' charts to chlorpromazine and haloperidol and to create formulas for each relationship. The formulas were solved for chlorpromazine 100 mg and haloperidol 2 mg to derive new chlorpromazine and haloperidol equivalents. The formulas were incorporated into our definition of dose-years such that 100 mg/day of chlorpromazine equivalent or 2 mg/day of haloperidol equivalent taken for 1 year is equal to one dose-year. RESULTS: All comparisons to chlorpromazine and haloperidol were highly linear with R(2) values greater than .9. A power transformation further improved linearity. CONCLUSIONS: By deriving a unique formula that converts doses to chlorpromazine or haloperidol equivalents, we can compare otherwise dissimilar drugs. These equivalents can be multiplied by the time an individual has been on a given dose to derive a cumulative value measured in dose-years in the form of (chlorpromazine equivalent in mg) x (time on dose measured in years). After each dose has been converted to dose-years, the results can be summed to provide a cumulative quantitative measure of lifetime exposure.

Genomewide association study of movement-related adverse antipsychotic effects.

BACKGROUND: Understanding individual differences in the development of extrapyramidal side effects (EPS) as a response to antipsychotic therapy is essential to individualize treatment. METHODS: We performed genomewide association studies to search for genetic susceptibility to EPS. Our sample consisted of 738 schizophrenia patients, genotyped for 492K single nucleotide polymorphisms (SNPs). We studied three quantitative measures of antipsychotic adverse drug reactions-the Simpson-Angus Scale (SAS) for Parkinsonism, the Barnes Akathisia Rating Scale, and the Abnormal Involuntary Movement Scale (AIMS)-as well as a clinical diagnosis of probable tardive dyskinesia. RESULTS: Two SNPs for SAS, rs17022444 and rs2126709 with p = 1.2 x 10(-10) and p = 3.8 x 10(-7), respectively, and one for AIMS, rs7669317 with p = 7.7 x 10(-8), reached genomewide significance (Q value < .1). rs17022444 and rs7669317 were located in intergenic regions and rs2126709 was located in ZNF202 on 11q24. Fourteen additional signals were potentially interesting (Q value < .5). The ZNF202 is a transcriptional repressor controlling, among other genes, PLP1, which is the major protein in myelin. Mutations in PLP1 cause Pelizaeus-Merzbacher disease, which has Parkinsonism as an occurring symptom. Altered mRNA expression of PLP1 is associated with schizophrenia. CONCLUSIONS: Although our findings require replication and validation, this study demonstrates the potential of genomewide association studies to discover genes and pathways that mediate adverse effects of antipsychotics.

A candidate gene study of Tardive dyskinesia in the CATIE schizophrenia trial.

Tardive dyskinesia (TD) is a movement disorder characterized by involuntary oro-facial, limb, and truncal movements. As a genetic basis for inter-individual variation is assumed, there have been a sizeable number of candidate gene studies. All subjects met diagnostic criteria for schizophrenia and were randomized to receive antipsychotic medications as participants in the Clinical Antipsychotic Trials of Intervention Effectiveness project (CATIE). TD was assessed via the Abnormal Involuntary Movement Scale at regular intervals. Probable TD was defined as meeting Schooler-Kane criteria at any scheduled CATIE visit (207/710 subjects, 29.2%). A total of 128 candidate genes were studied in 710 subjects-2,580 SNPs in 118 candidate genes selected from the literature (e.g., dopamine, serotonin, glutamate, and GABA pathways) and composite genotypes for 10 drug-metabolizing enzymes. No single marker or haplotype association reached statistical significance after adjustment for multiple comparisons. Thus, we found no support for either novel or prior associations from the literature.

Variants of the dopamine D2 receptor gene and risperidone-induced hyperprolactinemia in children and adolescents.

OBJECTIVE: To investigate the association between hyperprolactinemia and variants of the dopamine D2 receptor (DRD2) gene in children and adolescents in long-term treatment with risperidone. METHODS: Medically healthy 7 to 17-year-old patients chronically treated with risperidone but receiving no other antipsychotics were recruited in a cross-sectional study. Four DRD2 variants were genotyped and prolactin concentration was measured. Medication history was obtained from the medical records. The effect of the TaqIA variants of the DRD2 on the risk of risperidone-induced hyperprolactinemia was the primary outcome measure. RESULTS: Hyperprolactinemia was present in 50% of 107 patients (87% males) treated with risperidone for an average of 2.9 years. Age, stage of sexual development, and the dose of risperidone independently predicted a higher prolactin concentration, whereas the dose of psychostimulants was negatively correlated with it. However, these four predictors became nonsignificant when risperidone serum concentration was entered into the model. Adverse events potentially related to hyperprolactinemia were more common in participants with elevated prolactin concentration and in girls (45%) compared with boys (10%). After controlling for risperidone concentration and the dose of psychostimulants, the TaqIA A1 and the A-241G alleles were associated with higher prolactin concentration, whereas the -141C Ins/Del and C957T variants had no significant effect. In addition, adverse events potentially related to hyperprolactinemia were four times more common in TaqIA A1 allele carriers. CONCLUSION: Prolactin concentration is closely related to central DRD2 blockade, as reflected by risperidone serum concentration. Furthermore, the TaqIA and A-241G variants of the DRD2 gene could be useful in predicting the emergence of hyperprolactinemia and its potential adverse events.

Extrapyramidal side-effects of antipsychotics in a randomised trial.

BACKGROUND: There are claims that second-generation antipsychotics produce fewer extrapyramidal side-effects (EPS) compared with first-generation drugs. AIMS: To compare the incidence of treatment-emergent EPS between second-generation antipsychotics and perphenazine in people with schizophrenia. METHOD: Incidence analyses integrated data from standardised rating scales and documented use of concomitant medication or treatment discontinuation for EPS events. Mixed model analyses of change in rating scales from baseline were also conducted. RESULTS: There were no significant differences in incidence or change in rating scales for parkinsonism, dystonia, akathisia or tardive dyskinesia when comparing second-generation antipsychotics with perphenazine or comparing between second-generation antipsychotics. Secondary analyses revealed greater rates of concomitant antiparkinsonism medication among individuals on risperidone and lower rates among individuals on quetiapine, and lower rates of discontinuation because of parkinsonism among people on quetiapine and ziprasidone. There was a trend for a greater likelihood of concomitant medication for akathisia among individuals on risperidone and perphenazine. CONCLUSIONS: The incidence of treatment-emergent EPS and change in EPS ratings indicated that there are no significant differences between second-generation antipsychotics and perphenazine or between second-generation antipsychotics in people with schizophrenia.

Population pharmacokinetic analysis for risperidone using highly sparse sampling measurements from the CATIE study.

AIMS: To characterize pharmacokinetic (PK) variability of risperidone and 9-OH risperidone using sparse sampling and to evaluate the effect of covariates on PK parameters. METHODS: PK analysis used plasma samples collected from the Clinical Antipsychotic Trials of Intervention Effectiveness. A nonlinear mixed-effects model was developed using NONMEM to describe simultaneously the risperidone and 9-OH risperidone concentration-time profile. Covariate effects on risperidone and 9-OH risperidone PK parameters were assessed, including age, weight, sex, smoking status, race and concomitant medications. RESULTS: PK samples comprised 1236 risperidone and 1236 9-OH risperidone concentrations from 490 subjects that were available for analysis. Ages ranged from 18 to 93 years. Population PK submodels for both risperidone and 9-OH risperidone with first-order absorption were selected to describe the concentration-time profile of risperidone and 9-OH risperidone. A mixture model was incorporated with risperidone clearance (CL) separately estimated for three subpopulations [poor metabolizer (PM), extensive metabolizer (EM) and intermediate metabolizer (IM)]. Age significantly affected 9-OH risperidone clearance. Population parameter estimates for CL in PM, IM and EM were 12.9, 36 and 65.4 l h(-1) and parameter estimates for risperidone half-life in PM, IM and EM were 25, 8.5 and 4.7 h, respectively. CONCLUSIONS: A one-compartment mixture model with first-order absorption adequately described the risperidone and 9-OH risperidone concentrations. Age was identified as a significant covariate on 9-OH risperidone clearance in this study.