The effect of long-term antipsychotic treatment on prolactin

OBJECTIVE: This naturalistic, cross-sectional study was designed to assess the risk of prolactin level elevation and associated side effects in youths taking long-term atypical antipsychotic medication. METHOD: Subjects were enrolled from outpatient child psychiatric treatment settings in upstate New York who were taking risperidone, olanzapine, or quetiapine for at least 6 months. Demographic data, medication history, and side effects were elicited at the initial interview. Two fasting morning serum prolactin levels were obtained 1 month apart, and the results were averaged. RESULTS: Fifty outpatient youths, with a median age of 13 years, were enrolled in the study. The median overall duration of use of an atypical antipsychotic was 22.1 months. The median dose of medication for risperidone was 1.5 mg/day, for olanzapine 10 mg/day, and for quetiapine 200 mg/day. The mean prolactin level among all patients on risperidone was significantly greater than controls, as well as for those on quetiapine or olanzapine. CONCLUSIONS: The risk of hyperprolactinemia with long-term use of risperidone appears to be significantly greater than for olanzapine or quetiapine. Overt side effects were infrequent in the overall sample, but serum prolactin assessment is recommended for youths taking risperidone chronically. Because of variability found in sequential prolactin samples, repeat samples may be warranted.     

Effects of olanzapine, quetiapine, and risperidone on neurocognitive function in early psychosis: a randomized, double-blind 52-week comparison

OBJECTIVE: The authors sought to compare the effects of olanzapine, quetiapine, and risperidone on neurocognitive function in patients with early psychosis. METHOD: In a 52-week double-blind, multicenter study, 400 patients early in the course of psychotic illness (<5 years) were randomly assigned to treatment with olanzapine (2.5-20 mg/day), quetiapine (100-800 mg/day), or risperidone (0.5-4 mg/day). The mean modal daily dose was 11.7 mg (SD=5.3) for olanzapine, 506 mg (SD=215) for quetiapine, and 2.4 mg (SD=1.0) for risperidone. A total of 224 patients completed neurocognitive assessments at baseline and at 12 weeks, and 81 patients also completed them at 52 weeks. Neurocognitive composite scores were calculated from the neurocognitive battery used in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and from the Brief Assessment of Cognition in Schizophrenia. RESULTS: At week 12, there was significant improvement in neurocognition for each treatment (p<0.01), but no significant overall difference between treatments. Composite z score improvements on the CATIE neurocognitive battery were 0.17 for olanzapine, 0.33 for quetiapine, and 0.32 for risperidone. Composite z score improvements on the Brief Assessment of Cognition in Schizophrenia were 0.19 for olanzapine, 0.34 for quetiapine, and 0.22 for risperidone. Statistically significant relationships between improvements in neurocognition and functional outcome were observed at weeks 12 and 52. CONCLUSIONS: Olanzapine, quetiapine, and risperidone all produced significant improvements in neurocognition in early-psychosis patients. Although cognitive improvements were modest, their clinical importance was suggested by relationships with improvements in functional outcome.     

Elevation of prolactin levels by atypical antipsychotics.

OBJECTIVE: Atypical antipsychotics are thought not to elevate prolactin levels. The authors examined data suggesting that atypical antipsychotics do elevate prolactin levels but more transiently than typical antipsychotics. METHOD: Prolactin levels in 18 male patients with schizophrenia who were receiving atypical antipsychotics were monitored over the 24-hour period following administration of their daily oral dose of risperidone, olanzapine, or clozapine. RESULTS: The baseline prolactin levels in patients receiving risperidone (mean=27 ng/ml, SD=14) were abnormally high, but baseline prolactin levels in patients receiving olanzapine (mean=9 ng/ml, SD=5) and clozapine (mean=9 ng/ml, SD=5) were not high. All three atypical antipsychotics caused a doubling of prolactin levels over baseline levels 6 hours after medication administration. CONCLUSIONS: These data suggest that these atypical antipsychotics raise prolactin levels, although the increases with olanzapine did not reach statistical significance. This suggests that the differences in the effects on prolactin levels of atypical and typical antipsychotics are not categorical but lie in the degree and duration of dose-induced prolactin elevation, attributable to the differential binding properties of each drug on pituitary dopamine D(2) receptors.     

A randomized, flexible-dose, quasi-naturalistic comparison of quetiapine, risperidone, and olanzapine in the short-term treatment of schizophrenia: the QUERISOLA trial

This was a randomized, flexible-dose, rater-blind, parallel-group, quasi-naturalistic trial comparing the efficacy, safety, and tolerability of quetiapine, risperidone, and olanzapine in patients with schizophrenia hospitalized for severe psychotic symptoms. Seventy-five patients were randomized to quetiapine (n=25), risperidone (n=25), or olanzapine (n=25). Mean doses at Week 8 were: 590.0 mg/day quetiapine; 5.1 mg/day risperidone; 15.1 mg/day olanzapine. Four quetiapine, five risperidone, and five olanzapine patients discontinued prior to Week 8. There were no significant differences between groups in the primary efficacy measures of improvement from baseline in Positive and Negative Syndrome Scale (PANSS) total score at Week 8 in the per protocol (PP) population and the number of completers who experienced >or=40% improvement on the same scale. PP and intent-to-treat analyses showed significant improvement from baseline in each component of a PANSS-derived battery, without significant differences between treatments. No quetiapine patients, one risperidone, and four olanzapine patients reported an adverse event (AE) of moderate intensity; no severe AEs were reported. A linear mixed model for repeated measures showed an effect of treatment on body weight, with significant differences favoring quetiapine over risperidone and olanzapine. Simpson-Angus Scale scores were significantly worse with risperidone compared with both olanzapine and quetiapine at Week 3 and compared with quetiapine thereafter. Use of concomitant medications for anxiety or tension was significantly less frequent with quetiapine. In conclusion, quetiapine, risperidone, and olanzapine have similar efficacy in schizophrenia, but there are drug-specific differences for some AEs and in the use of concomitant medication that differentiate these agents.     

Sexual dysfunction associated with second-generation antipsychotics in outpatients with schizophrenia or schizoaffective disorder: an empirical evaluation of olanzapine, risperidone, and quetiapine

OBJECTIVE: Evaluate sexual dysfunction, as measured by the Arizona Sexual Experience Scale (ASEX), in olanzapine-, quetiapine-, and risperidone-treated outpatients with schizophrenia or schizoaffective disorder. METHOD: The sexual functioning of 238 outpatients (age> or =18 years) with diagnoses of schizophrenia or schizoaffective disorder who took quetiapine (n=57), olanzapine (n=94), or risperidone (n=87) was evaluated with a one-time rating of the ASEX. The dose range for each treatment group was 5 to 40 mg/day (M=16.6 mg/day, SD=7.4) for olanzapine; 1 to 8 mg/day (M=3.9 mg/day, SD=1.6) for risperidone; and 50 to 900 mg/day (M=376.8 mg/day, SD=213.4) for quetiapine. Antipsychotic group designation was based on medication treatment at study entry (i.e., non-random assignment). Participant characteristics were collected to test for treatment group differences and for potential associations with severity of sexual dysfunction. The primary data analysis was a mixed linear model analysis of covariance with age, gender, and presence/absence of antidepressant known to cause sexual dysfunction included as covariates. RESULTS: There was a significant treatment effect on severity of sexual dysfunction, as measured by ASEX total scores (p=.04). The adjusted average ASEX total scores were lower in the quetiapine (M=17.80) than in the risperidone (M=19.69) or olanzapine (M=20.34) groups. Individual comparisons of the treatments on adjusted average ASEX total scores indicated a significant difference between olanzapine and quetiapine (p=.04), but no difference between risperidone and quetiapine (p=.17) or olanzapine and risperidone (p=.76). CONCLUSIONS: Quetiapine was associated with less severe sexual dysfunction than olanzapine and risperidone (albeit the effect between risperidone and quetiapine was not statistically significant). Olanzapine and risperidone were associated with a comparable degree of sexual dysfunction. Patients in all three treatment groups, nonetheless, experienced a moderately high degree of sexual dysfunction. Because the patients were not randomized, conclusions must be interpreted within the context of the quasi-experimental design.     

抗精神病药对男性精神分裂症患者垂体-性腺轴的影响

目的:研究氯丙嗪、利培酮、奎硫平及奥氮平对男性精神分裂症患者垂体性腺轴的影响。方法:88例首发男性精神分裂症患者随机分为氯丙嗪组、利培酮组、奎硫平组及奥氮平组,检测治疗前、治疗4周及8周血清促卵泡素(FSH)、黄体生成素(LH)、催乳素(PRL)、睾酮(T)的水平变化。结果:氯丙嗪组治疗8周后,血清PRL水平显著高于治疗前。利培酮组在治疗4周及8周后PRL水平均显著高于治疗前,治疗8周后T及LH水平显著低于治疗前。奎硫平组在治疗4周及8周后血清PRL、LH、T水平与治疗前比较差异均无显著性。奥氮平组治疗4周后PRL水平显著高于治疗前,治疗8周后即与治疗前差异无显著性。结论:奎硫平对垂体性腺轴激素水平无明显影响。     

New-onset type-2 diabetes associated with atypical antipsychotic medications

PURPOSE: This study compared the one-year incidence of new-onset type-2 diabetes mellitus (DM) and changes in weight in patients with a variety of psychiatric diagnoses prescribed olanzapine, risperidone, or quetiapine, compared to a reference group receiving haloperidol and no other antipsychotic medication. RESEARCH DESIGN AND METHODS: Data was abstracted from charts of subjects newly initiated and then maintained for one year on olanzapine (n=112), risperidone (n=100), quetiapine (n=100), and haloperidol (n=100). Baseline and one-year DM status, height, and weight were collected, as well as concurrent psychotropic medications, medical and psychiatric comorbidities. FINDINGS: Using a multivariate model, logistic regression identified a significant association between olanzapine (but not other atypical agents) and the development of diabetes compared to haloperidol over the one-year period (odds ratio 8.4, 95% CI 1.8-38.7). Baseline obesity was independently associated with new-onset DM, but only marginally greater weight gain was found among olanzapine users. CONCLUSIONS: The middle-aged American veterans in this study cohort were highly vulnerable to the diabetogenic effects of olanzapine, but a close correlation with weight change was not found. Patients administered olanzapine should receive careful laboratory monitoring for elevated plasma glucose in addition to weight measurement.     

Prolactin levels during long-term risperidone treatment in children and adolescents

BACKGROUND: This analysis was designed to investigate prolactin levels in children and adolescents on long-term risperidone treatment and explore any relationship with side effects hypothetically attributable to prolactin (SHAP). METHOD: Data from 5 clinical trials (total N = 700) were pooled for this post hoc analysis. Children and adolescents aged 5 to 15 years with subaverage intelligence quotients and conduct or other disruptive behavior disorders received risperidone treatment (0.02-0.06 mg/kg/day) for up to 55 weeks. Outcome measures analyzed included serum prolactin levels, reported adverse events, and the conduct problem subscore of the Nisonger Child Behavior Rating Form. RESULTS: Mean prolactin levels rose from 7.8 ng/mL at baseline to a peak of 29.4 ng/mL at weeks 4 to 7 of active treatment, then progressively decreased to 16.1 ng/mL at weeks 40 to 48 (N = 358) and 13.0 ng/mL at weeks 52 to 55 (N = 42). There was no relationship between pro-lactin levels and age. Females returned to a mean value within the normal range (相似文献   

Effect of topiramate on plasma concentrations of clozapine, olanzapine, risperidone, and quetiapine in patients with psychotic disorders

OBJECTIVES: To investigate the effect of topiramate on the steady-state plasma concentrations of the second-generation antipsychotics--clozapine, olanzapine, risperidone, and quetiapine--in patients with schizophrenia or bipolar disorder. METHODS: Thirty-eight outpatients on long-term treatment with clozapine (250-500 mg/d, n = 10), olanzapine (10-20 mg/d, n = 12), risperidone (3-6 mg/d, n = 9), or quetiapine (200-600 mg/d, n = 7) received adjunctive topiramate, gradually titrated up to a final dosage of 200 mg/d for 6 weeks. Pharmacokinetic assessments were made at baseline and at the end of treatment weeks 4 and 8 at topiramate dosages of 100 and 200 mg/d, respectively. RESULTS: Plasma concentrations of clozapine and its metabolite (norclozapine), olanzapine, risperidone and its metabolite (9-hydroxy-risperidone), and quetiapine were not significantly modified during concomitant administration of topiramate. Adjunctive topiramate therapy was well tolerated in all groups. CONCLUSIONS: These findings indicate that topiramate, at the dosages recommended for use as a mood stabilizer, does not affect the plasma levels of the new antipsychotics-clozapine, olanzapine, risperidone, and quetiapine.     

Prolactin levels in schizophrenia and schizoaffective disorder patients treated with clozapine, olanzapine, risperidone, or haloperidol

BACKGROUND: Prolactin levels are elevated to varying degrees by antipsychotics. Prolactin elevations may result in sexual and other adverse effects, and they may be related to antipsychotic effects. We used the data collected in a trial of antipsychotics to study the differential effect of these drugs on prolactin level, to explore the relation between clinical effects and prolactin level, and to determine the relationship between plasma levels of antipsychotics and prolactin level. METHOD: Treatment-resistant patients (133 men, 24 women) diagnosed with DSM-IV schizophrenia or schizoaffective disorder participated in a double-blind, randomized, 14-week trial comparing clozapine (N = 40), olanzapine (N = 39), risperidone (N = 41), and haloperidol (N = 37). Plasma levels of prolactin and antipsychotics were determined at baseline and at weeks 5, 8, 10, 12, and 14 during the trial. Clinical effects were measured with the Positive and Negative Syndrome Scale and the Extrapyramidal Symptom Rating Scale. Statistical analyses were limited to the 75 men for whom repeated prolactin levels were available. Data were gathered from June 1996 to December 1999. RESULTS: Risperidone caused significant elevation of prolactin levels (p <.05) that appeared to be dose-dependent. Clozapine and olanzapine were associated with decreases of prolactin, whereas haloperidol led to a minor, nonsignificant increase. Plasma olanzapine and prolactin levels were correlated. Prolactin levels were not related to clinical improvement or extrapyramidal side effects. CONCLUSION: Antipsychotics show major differences in their effects on prolactin, and risperidone has clearly the most robust effect.     

Serum leptin and triglyceride levels in patients on treatment with atypical antipsychotics

BACKGROUND: Weight gain is a common adverse effect associated with the use of most antipsychotic drugs. Leptin has been reported to be associated with antipsychotic-induced weight gain. Previous studies have demonstrated a relationship between the atypical antipsychotics clozapine and olanzapine and serum leptin levels. We planned to comparatively investigate the effects of the atypical antipsychotics quetiapine, olanzapine, risperidone, and clozapine on leptin and triglyceride levels and weight gain. METHOD: The study population comprised 56 patients with DSM-IV schizophrenia, who were divided into 4 treatment groups: quetiapine (N = 14), olanzapine (N = 14), risperidone (N = 14), or clozapine (N = 14) monotherapy, and a control group of 11 patients receiving no psychopharmacologic treatment. The patients were evaluated at baseline and at the sixth week according to the Positive and Negative Syndrome Scale (PANSS), body mass index (BMI), weight, and fasting serum leptin and triglyceride levels. Data were gathered in 2001 and 2002. RESULTS: Olanzapine and clozapine caused a marked increase in weight and serum triglyceride and leptin levels, though increases in these variables were modest in the patients receiving quetiapine and minimal in those receiving risperidone. There were positive correlations between serum leptin levels and BMI and triglyceride levels. Clinical efficacy, as indicated by decrease in total PANSS scores, was associated with leptin levels in all atypical antipsychotic groups. CONCLUSION: Our results suggest that leptin may be associated with olanzapine- and clozapine-induced weight gain and that quetiapine appears to have modest influence and risperidone appears to have minimal influence on leptin and triglyceride levels and weight gain compared with olanzapine and clozapine.     

Comparative effectiveness of second-generation antipsychotic medications in early-onset schizophrenia

Scant information exists to guide pharmacological treatment of early-onset schizophrenia. We examine variation across commonly prescribed second-generation antipsychotic medications in medication discontinuation and psychiatric hospital admission among children and adolescents clinically diagnosed with schizophrenia. A 45-state Medicaid claims file (2001-2005) was analyzed focusing on outpatients, aged 6-17 years, diagnosed with schizophrenia or a related disorder prior to starting a new episode of antipsychotic monotherapy with risperidone (n = 805), olanzapine (n = 382), quetiapine (n = 260), aripiprazole (n = 173), or ziprasidone (n = 125). Cox proportional hazard regressions estimated adjusted hazard ratios of 180-day antipsychotic medication discontinuation and 180-day psychiatric hospitalization for patients treated with each medication. During the first 180 days following antipsychotic initiation, most youth treated with quetiapine (70.7%), ziprasidone (73.3%), olanzapine (73.7%), risperidone (74.7%), and aripirazole (76.5%) discontinued their medication (χ(2) = 1.69, df = 4, P = .79). Compared with risperidone, the adjusted hazards of antipsychotic discontinuation did not significantly differ for any of the 4-comparator medications. The percentages of youth receiving inpatient psychiatric treatment while receiving their initial antipsychotic medication ranged from 7.19% (aripiprazole) to 9.89% (quetiapine) (χ(2) = 0.79, df = 4, P = .94). As compared with risperidone, the adjusted hazard ratio of psychiatric hospital admission was 0.96 (95% CI: 0.57-1.61) for olanzapine, 1.03 (95% CI: 0.59-1.81) for quetiapine, 0.85 (95% CI: 0.43-1.70) for aripiprazole, and 1.22 (95% CI: 0.60-2.51) for ziprasidone. The results suggest that rapid antipsychotic medication discontinuation and psychiatric hospital admission are common in the community treatment of early-onset schizophrenia. No significant differences were detected in risk of either adverse outcome across 5 commonly prescribed second-generation antipsychotic medications.     

Safety and tolerability of antipsychotic treatment in young patients with schizophrenia

Antipsychotics have proven efficacy for treating patients with early-onset schizophrenia, and aripiprazole, olanzapine, quetiapine, and risperidone have FDA approval for treating adolescents aged 13 to 17 years. Children and adolescents appear to have a higher risk than adults for experiencing adverse events such as extrapyramidal symptoms, prolactin elevation, weight gain, and metabolic effects when taking antipsychotic medications. Pediatric studies indicate that adverse effect profiles differ among commonly used antipsychotics. Clinicians should consider the differing adverse effect profiles when choosing medications for young patients.     

Effects of short- and long-term risperidone treatment on prolactin levels in children with autism.

BACKGROUND: The effects of short- and long-term risperidone treatment on serum prolactin were assessed in children and adolescents with autism. METHODS: Patients with autism (N = 101, 5-17 years of age) were randomized to an 8-week trial of risperidone or placebo and 63 then took part in a 4-month open-label follow-up phase. Serum samples were obtained at Baseline and Week-8 (N = 78), and at 6-month (N = 43) and 22-month (N = 30) follow-up. Serum prolactin was determined by immunoradiometric assay; dopamine type-2 receptor (DRD2) polymorphisms were genotyped. RESULTS: Baseline prolactin levels were similar in the risperidone (N = 42) and placebo (N = 36) groups (9.3 +/- 7.5 and 9.3 +/- 7.6 ng/ml, respectively). After 8 weeks of risperidone, prolactin increased to 39.0 +/- 19.2 ng/ml, compared with 10.1 +/- 8.8 ng/ml for placebo (p < .0001). Prolactin levels were also significantly increased at 6 months (32.4 +/- 17.8 ng/ml; N = 43, p < .0001) and at 22 months (N = 30, 25.3 +/- 15.6 ng/ml, p < .0001). Prolactin levels were not associated with adverse effects and DRD2 alleles (Taq1A, -141C Ins/Del, C957T) did not significantly influence baseline levels or risperidone-induced increases in prolactin. CONCLUSIONS: Risperidone treatment was associated with two- to four-fold mean increases in serum prolactin in children with autism. Although risperidone-induced increases tended to diminish with time, further research on the consequences of long-term prolactin elevations in children and adolescents is needed.     

Clinical drug monitoring in child and adolescent psychiatry: side effects of atypical neuroleptics

OBJECTIVE: The aim of this study was to improve and evaluate the practibility of a method for the assessment of drug-associated side effects, and we implemented a clinical drug monitoring for atypical neuroleptics. METHODS: Side effects of initially hospitalized patients treated with clozapine (n = 16), olanzapine (n = 16), and risperidone (n = 19) were prospectively monitored on a weekly basis for the first 3 weeks. In the case of stable medication, measurements of all variables were made every 4 weeks or upon discharge. We used the Dosage Record Treatment Emergent Symptom Scale (DOTES) in a supplemented version to measure the presence and severity of side effects. RESULTS: Drowsiness and decreased motor activity were common, especially in the first 2 weeks. Orthostatic hypotension, increased salivation, constipation, and nasal congestion were seen in more than 30% to 60% of patients treated with clozapine and were less common in adolescents treated with olanzapine and risperidone. Rigidity, tremor, and dystonia were seen in 5% to 15% of patients treated with risperidone and olanzapine. The average weight gain after 6 weeks of treatment with the atypical neuroleptics was significantly higher for the olanzapine group (4.6 +/- 1.9 kg) than for the risperidone (2.8 +/- 1.3 kg) and clozapine (2.5 +/- 2.9 kg) groups. CONCLUSIONS: The authors' supplemented DOTES version is generally applicable to clinical use in mental health centers. The differences among the side effects of these three agents may affect compliance with medication and medical risks of metabolic syndrome, diabetes, and cardiovascular disease. More research on the short- and long-term safety of psychotropic drugs in children and adolescents, using standardized methods, should be considered.     

Different patterns of longitudinal changes in plasma levels of catecholamine metabolites and brain-derived neurotrophic factor after administration of atypical antipsychotics in first episode untreated schizophrenic patients

In the present study, we longitudinally investigated the effects of risperidone, olanzapine, and aripiprazole on plasma levels of catecholamine metabolites and brain-derived neurotrophic factor (BDNF) in first-episode unmedicated schizophrenic patients. The subjects were 59 Japanese schizophrenic patients (35 males and 24 females; age range: 18–46 years; mean±SD: 25±16 years). The patients were treated with risperidone (n=32) in a dose range of 2–6 mg/day (mean±SD=3.4±1.9), olanzapine (n=18) in a dose range of 5–20 mg/day (mean±SD=12.1±5.8), or aripiprazole (n=9) in a dose range of 12–30 mg/day (mean±SD=22.8±10.1). All three drugs significantly decreased plasma homovanillic acid (HVA) levels within 8 weeks, although aripiprazole transiently raised this level before 8 weeks. All three drugs also significantly increased plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels within 8 weeks. On the other hand, none of them altered plasma BDNF levels. These results indicate that risperidone, olanzapine, and aripiprazole affect catecholaminergic systems in the brain, that the effects of aripiprazole on the dopaminergic systems seem to slightly different than those of risperidone and olanzapine, and that these atypical antipsychotic drugs might not alter BDNF levels, at least within 8 weeks of treatment.     

The PsyCoLaus study: methodology and characteristics of the sample of a population-based survey on psychiatric disorders and their association with genetic and cardiovascular risk factors

Background

How long an antipsychotic is effective in maintaining response is important in choosing the correct treatment for people with schizophrenia. This post-hoc analysis describes maintenance of response over 24 or 28 weeks in people treated for schizophrenia with olanzapine, risperidone, quetiapine, ziprasidone, or aripiprazole.

Methods

This was a post-hoc analysis using data from 5 double-blind, randomized, comparative trials of 24 or 28 weeks duration in which olanzapine was compared to risperidone (1 study; N = 339), quetiapine (1 study; N = 346), ziprasidone (2 studies; N = 548 and 394) or aripiprazole (1 study; N = 566) for treatment of schizophrenia. For each study, time to loss of response in patients who met criteria for response at Week 8 and the proportion of patients who lost response following Week 8 were compared by treatment group. The number needed to treat (NNT) with olanzapine rather than comparator to avoid loss of one additional responder over 24 or 28 weeks of treatment was calculated for each study.

Results

Time maintained in response was significantly longer (p < .05) for olanzapine compared to risperidone, quetiapine, and ziprasidone. Olanzapine did not significantly differ from aripiprazole. The proportion of patients who lost response was significantly lower for olanzapine versus risperidone, quetiapine, and ziprasidone (p < .05). NNTs to avoid one additional patient with loss of response with olanzapine versus risperidone, quetiapine and ziprasidone were favourable, ranging from 5 to 9.

Conclusion

During 24 and 28 weeks of treatment, the antipsychotics studied differed in the time that treated patients with schizophrenia remained in response and the proportion of patients who lost response. Olanzapine treatment resulted in a consistent and statistically significant advantage in maintenance of response compared to treatment with risperidone, quetiapine and ziprasidone; but not compared to treatment with aripiprazole.     

Risk of discontinuation of atypical antipsychotic agents in the treatment of schizophrenia

OBJECTIVES: To compare discontinuation rates of atypical antipsychotic agents in patients with schizophrenia. METHOD: Adult Maryland Medicaid patients with schizophrenia were categorized based on initial atypical antipsychotic drug received: aripiprazole (n=446); olanzapine (n=1705); quetiapine (n=1467); risperidone (n=1580); and ziprasidone (n=700). Discontinuation was measured using refill patterns, allowing 14-day gaps between refill dates. Using olanzapine as the reference drug, the hazard of discontinuation within the first year of follow-up was compared across atypicals using Cox proportional hazard models adjusted for demographic and clinical covariates. Sensitivity analysis tested the robustness of results by using different definitions of the index date. RESULTS: At one-year follow-up, most patients discontinued their antipsychotic medication (90.4% adjusted mean discontinuation). The hazard ratio (HR) for discontinuing therapy in patients starting treatment on aripiprazole, risperidone, or ziprasidone was not significantly different from olanzapine [HR 1.047, 0.973 and 0.990, respectively]. Quetiapine was associated with significantly higher hazard of discontinuation [HR 1.130] than olanzapine. Covariates associated with significantly lower discontinuation were being male [HR 0.899], older age [HR 0.997] and being on concurrent medication when initiating therapy [HR 0.225]; having a previous hospitalization was associated with significantly higher discontinuation hazard [HR 1.276]. Results were robust in the sensitivity analysis. CONCLUSIONS: Discontinuation rates were high at one-year follow-up and did not differ significantly for patients on aripiprazole, olanzapine, risperidone, or ziprasidone. The higher hazard of discontinuation associated with quetiapine when compared to olanzapine is consistent with that observed in Phase I of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE).     

Risperidone-induced prolactin elevation in a prospective study of children, adolescents, and adults with mental retardation and pervasive developmental disorders

OBJECTIVE: Risperidone is widely prescribed for aggression and self-injury in children, adolescents, and adults with mental retardation (MR) and pervasive developmental disorders (PDD). Risperidone elevates prolactin more than other atypical antipsychotic medications. Females may show greater prolactin elevation than males. METHOD: In this relatively long-term study of risperidone efficacy and safety for aggression and self-injury in children, adolescents, and adults with MR and PDDs, serum prolactin was measured in a 21-subject subset during the course of a double-blind, placebo-controlled trial. Prolactin was measured in ng/mL at baseline, once during acute treatment, and once during maintenance. RESULTS: In children and adolescents (n=10), mean age of 12.5 years, prolactin increased from mean 13.2+/-8.6 at baseline to 31.0+/-11.6 acutely and remained elevated at 37.9+/-10.4 in maintenance. In adults, mean age of 35.3 years, prolactin increased more markedly from 11.6+/-7.4 baseline (n=11) to 93.3+/-54.2 acutely but decreased to 67.8+/-62.9 in maintenance (n=7). Prolactin remained significantly elevated above normal in all subjects for at least 26 weeks. Mean prolactin of adult females, while similar to that of adult males at baseline, was 2.2 times male levels acutely and 3.7 times greater in maintenance. CONCLUSION: In this small subset, mean prolactin elevation persisted for at least 26 weeks. In adults, females showed significantly greater elevations than males.     

Predominant role of the 9-hydroxy metabolite of risperidone in elevating blood prolactin levels

OBJECTIVE: The atypical antipsychotic risperidone significantly raises plasma prolactin levels in patients, but clozapine, olanzapine, and quetiapine do not. The differences in neuroendocrine response may be connected with the metabolism of the medications. The authors examined the contributory role of risperidone's active metabolite 9-hydroxy-risperidone by measuring plasma concentrations of risperidone, 9-hydroxy-risperidone, and prolactin. METHOD: Blood samples taken from 25 patients with psychotic disorders following 6 weeks of treatment with risperidone (mean dose=3 mg/day) were examined. Mean plasma concentrations of risperidone, 9-hydroxy-risperidone, and prolactin were 4.6, 19.4, and 49.3 ng/ml, respectively. RESULTS: The oral dose of risperidone correlated significantly with plasma concentrations of risperidone, 9-hydroxy-risperidone, active moiety, and prolactin. The plasma concentration of 9-hydroxy-risperidone, but not of risperidone, correlated significantly with increases in plasma prolactin. CONCLUSIONS: These data suggest that the 9-hydroxy metabolite plays a predominant role in risperidone's effect on prolactin release.