The effect of atypical antipsychotic agents on prolactin levels in children and adolescents

This report is a review of the available literature on the effect of atypical antipsychotic agents on prolactin in children and adolescents. Fourteen reports are reviewed. Most reports (79%) have included adolescents. Three reports (21%) consisted of children only, while 7 reports (50%) included only adolescents. A total of 4 reports (29%) included both children and adolescents. The total number of subjects listed in all the reports is 276, while only 49 of the individuals on atypical neuroleptics had prolactin elevations clearly identified as outside of the normal range. The details of the reports are provided by individual atypical antipsychotic agent. Clinical implications, such as the potential impact of hyperprolactinemia on bone density, osteoporosis, gynecomastia, galactorrhea, and weight gain, are presented. Discussion of pertinent medical differential and treatment options are also reported.     

Tardive dyskinesia in children treated with atypical antipsychotic medications.

Recent years have witnessed increased antipsychotic treatment of children despite limited long‐term safety data in children. In this study, motor side effects associated with the use of antipsychotic drugs in children were examined in a sample of pediatric psychiatric patients. Child and adolescent psychiatric patients receiving antipsychotics (most were on atypicals) for 6 months or longer (n = 118) were compared with antipsychotic‐naïve patients (n = 80) with similar age, sex ratio, and diagnoses. Only 19% of patients on antipsychotics had ever experienced psychotic symptoms. Eleven children (9%) on antipsychotics exhibited dyskinesia, when compared with 0 in the naïve group (P = 0.003, Fisher's exact test). Nine of 62 African–American children (15%) on antipsychotics exhibited dyskinesia, when compared with only 4% (2 of 52) of European–American children (P = 0.003, Fisher's exact test). Children treated with antipsychotic drugs might experience a significant risk of dyskinesia even when treated only with atypical antipsychotics. Ethnicity might also be a risk factor for dyskinesia in children. Side‐effect profile of the atypical antipsychotic drugs in children may be much different than that in adults. © 2007 Movement Disorder Society     

Unanswered questions regarding atypical antipsychotic use in aggressive children and adolescents

The aim of this paper was to discuss the arguments for and against the use of atypical antipsychotics in children and adolescents with aggression, and provide recommendations for future research. A MEDLINE search (1985-2004) was performed to identify key literature. Search terms included, but were not limited to, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, children, and adolescents. The search was limited to English-language literature and randomized controlled trials. The use of atypical antipsychotics in children and adolescents has increased significantly over the past few years. Atypical antipsychotics are associated with a more favorable side-effect profile, and growing evidence supports their efficacy for aggression in this population. However, the long-term effects of these agents are unknown. No head-to-head evidence exists to suggest whether pharmacological or nonpharmacological treatments are superior for managing aggression associated with childhood and adolescent psychiatric and behavioral conditions. Future research of atypical antipsychotics in children and adolescents needs to evaluate not only the efficacy but also the effectiveness. Examination of treatment mediators and moderators may help to optimize treatment regimens and improve patient outcomes. Finally, effective interventions require the development and implementation of evidence-based treatment strategies using a multidisciplinary approach.     

Prevalence of hyperprolactinemia in schizophrenia: association with typical and atypical antipsychotic treatment

OBJECTIVE: To evaluate the prevalence and severity of hyperprolactinemia among a large sample of patients with schizophrenia and related psychotic disorders treated with typical and atypical antipsychotic medications. METHOD: Three electronic databases (general medical, psychiatric, and pharmacologic) containing the census data from November 2002 through March 2003 for a state-funded, inpatient hospital serving the chronically mentally ill were merged (N = 470). This database was purged of patient names, while the unique hospital identification number and demographic variables in each record were retained. These records were then screened to exclude patients with medications (except neuroleptics) or medical conditions known to elevate or suppress prolactin, leaving an overall sample (N = 422) in which to evaluate the prevalence of hyperprolactinemia. The sample was composed of patients with DSM-IV schizophrenia (N = 213), other related psychotic disorders (N = 131), mood disorders (N = 44), and other disorders (N = 34). RESULTS: For the overall sample (N = 422), which combined men and women, the mean serum prolactin level was 41.5 ng/mL; 290 of 422 patients were above the normal range. For women (N = 133), the mean serum prolactin level was 57.9 ng/mL, and 67% had levels above normal. For men (N = 289), the mean level was 33.9 ng/mL, with a 70% prevalence of hyperprolactinemia. While age did not influence the prevalence of elevated prolactin among men, age (reflecting reproductive status) was a significant variable in women; older age was associated with lower prolactin levels. For the study sample, a highly significant correlation was observed between neuroleptic dose (chlorpromazine equivalent) and serum prolactin level; however, this relationship was not determined on a medication-by-medication basis. Medications known to elevate prolactin were associated with higher prevalence rates of hyperprolactinemia, and "prolactin-sparing" medications had lower prevalence rates. However, when they were used in combination, the prolactin-elevating medication overwhelmed the effects of prolactin-sparing medication. CONCLUSIONS: This study suggested that neuroleptic treatment of schizophrenia is strongly associated with hyperprolactinemia and showed important differences between prolactin-sparing and prolactin-elevating medications.     

Electrocardiographic changes in children and adolescents treated with ziprasidone: a prospective study

OBJECTIVE: To assess the electrocardiographic safety profile of low-dose ziprasidone (< or =40 mg/day) among pediatric outpatients treated for up to 6 months. METHOD: This was a prospective, open-label trial involving 20 subjects with a mean age of 13.2 +/- 3.0 years. Subjects received a mean ziprasidone dose of 30 +/- 13 mg/day and were followed for 4.6 +/- 2.0 months, receiving a median of nine electrocardiograms each (range 2-11; total, 176). RESULTS: There were statistically significant changes from baseline to peak values in heart rate, PR, and QTc intervals, but not in QRS complex width. The mean QTc prolongation was 28 +/- 26 milliseconds and not related to dose (r = 0.16, p = .07). The peak QTc of three subjects reached or exceeded 450 milliseconds; one subject experienced a 114-millisecond prolongation. There was poor agreement (kappa = 0.25) between automated and manual identification of long QTc intervals (> or =440 milliseconds). CONCLUSIONS: These preliminary findings, occurring at doses low by current treatment standards, suggest that close electrocardiographic monitoring is warranted when prescribing ziprasidone to children, particularly at higher doses or when combined with other QTc-prolonging agents.     

Effect of hyperprolactinemia during development in children and adolescents

Increased levels of prolactin associated with some antipsychotic treatment can potentially lead to serious adverse events including gynecomastia, galactorrhea, oligomenorrhea, amenorrhea, and pituitary tumors. Clinicians may need to employ pharmacotherapeutic interventions such as reducing dosage, switching antipsychotics, or prescribing adjunctive agents to minimize or prevent these negative side effects and improve patients' outcomes.     

Prolactin-related and metabolic adverse effects of atypical antipsychotic agents

While there are many effective antipsychotics available to clinicians for treating schizophrenia or bipolar mania, the onset of antipsychotic-associated prolactin-related and metabolic adverse effects can diminish the effectiveness of treatment. Increased levels of prolactin (hyperprolactinemia) associated with some antipsychotics raises the risk of sexual side effects. The increased appetite and/or sedation (reduced activity levels) induced by other antipsychotics can lead to weight gain, dyslipidemia, and high blood pressure and, if unchecked, ultimately to cardiovascular disease, diabetes, and metabolic syndrome. Clinicians should take steps to help their patients avoid unnecessary risks associated with antipsychotic use. These steps include monitoring risk factors for developing these illnesses by taking careful patient histories and baseline measurements of patients' weight and blood chemistry. Patients should be made aware of potential metabolic and prolactin-related side effects, and periodic checks should also be made to watch for changes in weight, body mass index, waist size, blood pressure, fasting glucose, or lipid levels that could be harmful and may increase risk for cardiovascular disease.     

Second-generation antipsychotic medications in children and adolescents

OBJECTIVE: We reviewed available pediatric literature on second-generation antipsychotic medications to assess current evidence of efficacy and safety. METHOD: An English language MEDLINE search (1974-2003) was conducted using key words-atypical antipsychotics, children and adolescents, toxicity, clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. Additional efficacy and safety data were obtained from drug manufacturers. RESULTS: We identified 176 reports, including 15 double-blind, controlled trials, 58 openlabel studies, 18 retrospective chart reviews, and 85 case series/reports. The majority of these studies (43%) were of risperidone. Evidence suggests that second-generation antipsychotics are efficacious in the treatment of psychosis, bipolar disorders, pervasive developmental disorders, and Tourette's Disorder, and are potentially useful in mental retardation, conduct disorder, and severe attention deficit hyperactivity disorder (ADHD). The most frequently reported side effects included cardiovascular effects, weight gain, sedation, sialorrhea, extrapyramidal signs, and hyperprolactinemia, although the relative frequencies of these untoward effects vary among medications. CONCLUSION: Although the evidence base for pediatric use of second-generation antipsychotics is expanding, the majority of available studies are anecdotal, or short-term, openlabel trials. Reports suggest that these compounds are effective for a variety of psychiatric disorders in children and adolescents, but additional double-blind, controlled studies are required to establish definitive efficacy. Although these medications appear to be well tolerated in short-term studies, long-term follow-up investigations and ongoing clinical monitoring are necessary to confirm their safety in this age group.     

A prospective study of bipolar disorder in children and adolescents from India

Bipolar disorder in adults is known to run an episodic course. However, little information exists on the long-term naturalistic course of bipolar disorder in juvenile populations. The present study was undertaken with the objectives of (i) documenting the rates of recovery and relapse, (ii) identifying the predictors of recovery and relapse and (iii) assessing the rates of comorbid conditions. A total of 30 subjects with onset of bipolar illness (according to DSM-III-R criteria) in childhood and adolescence were assessed systematically at baseline and 4 to 5 years later. All 30 subjects (100%) had recovered from their index episodes and none had exhibited chronicity. Twenty of the 30 subjects (67%) had relapsed, with most relapses occurring within 2 years of recovery from index episodes. No predictors of recovery and relapse could be identified. Conduct disorder was the only comorbid diagnosis in two subjects (7%). The main implication of our study, in view of the high rates of relapse in the crucial developmental phase of a young individual, is that long-term maintenance medication should be considered in juvenile bipolar patients, even if it is a first episode.     

Amoxapine shows atypical antipsychotic effects in patients with schizophrenia: results from a prospective open-label study

OBJECTIVE: Amoxapine is marketed as an antidepressant. However, its receptor occupancy, in vitro and in vivo, and its effects in pre-clinical models are very similar to atypical antipsychotics. To examine if this leads to an atypical antipsychotic effect in the clinical context, the authors examined the antipsychotic and side-effect profile of amoxapine in acutely psychotic patients with schizophrenia. METHODS: Seventeen patients were enrolled and 15 completed a prospective open-label 6-week study of amoxapine starting with a fixed-starting dose (150 mg/h) with standardized titration up to 250 mg/h, if required. Positive, negative, affective symptoms and side-effects were monitored using standardized weekly assessments. RESULTS: Amoxapine (median final dose 210 mg/h) was well-tolerated and showed significant improvement in positive and negative symptoms (both p<0.001), with a trend towards improvement in mood symptoms and no treatment-emergent extrapyramidal side-effects, akathisia or weight gain. Prolactin elevation was observed. CONCLUSION: These clinical data lend support to the pre-clinical suggestions that amoxapine may be an atypical antipsychotic. Given its lack of weight gain and that it is considerably less expensive than current options, amoxapine could be a valuable alternative for some patients. These considerations strongly call for more systematic, double-blind studies of amoxapine as an atypical antipsychotic.     

Pregnancy outcome of women using atypical antipsychotic drugs: a prospective comparative study

BACKGROUND: A substantial number of women of childbearing age suffer from schizophrenia and other mental illnesses that require the use of antipsychotic drugs. Atypical antipsychotics have been on the market since the mid-1990s, and to date there are no prospective comparative studies regarding use during pregnancy. OBJECTIVES: (1) To determine whether atypical antipsychotics increase the rate of major malformations above the 1% to 3% baseline risk seen in the general population. (2) To examine rates of spontaneous and therapeutic abortions, rates of stillbirths, birth weight, and gestational age at birth. METHOD: The cohort was composed of pregnant women who contacted the Motherisk Program in Canada or the Israeli Teratogen Information Service in Israel and women who were recruited from the Drug Safety Research Unit database in England. Women who had been exposed to atypical antipsychotics were matched to a comparison group of pregnant women who had not been exposed to these agents. RESULTS: Data were obtained on 151 pregnancy outcomes that included exposure to olanzapine (N= 60), risperidone (N = 49), quetiapine (N = 36), and clozapine (N = 6). Among women exposed to an atypical antipsychotic, there were 110 live births (72.8%), 22 spontaneous abortions (14.5%), 15 therapeutic abortions (9.9%), and 4 stillbirths (2.6%). Among babies of women in this group, there was 1 major malformation (0.9%), and the mean +/-SD birth weight was 3341 +/-685 g. There were no statistically significant differences in any of the pregnancy outcomes of interest between the exposed and comparison groups, with the exceptions of the rate of low birth weight, which was 10% in exposed babies compared with 2% in the comparison group (p = .05), and the rate of therapeutic abortions (p = .003). CONCLUSION: These results suggest that atypical antipsychotics do not appear to be associated with an increased risk for major malformations.     

Normal P50 suppression in schizophrenia patients treated with atypical antipsychotic medications

OBJECTIVE: Patients with schizophrenia have deficits in attention, cognition, and information processing. Measures such as P50 suppression are used to study cognitive and attentional dysfunction among these patients. P50 suppression is an operational measure of sensory gating that can be assessed by averaging electroencephalographic responses to multiple pairs of auditory clicks separated by 500 msec. Normally, the P50 response to the second click is smaller than the response to the first click. Many studies have demonstrated that schizophrenia patients have deficient P50 suppression, meaning that the difference between the first and second clicks is not as large as normal. Atypical antipsychotic medications may have superior clinical efficacy for negative symptoms and cognitive deficits. It is important, therefore, to evaluate the effects of atypical antipsychotic medications on measures such as P50 suppression. METHOD: P50 suppression of 13 patients with schizophrenia receiving clinically effective doses of clozapine, olanzapine, or risperidone (classified as atypical antipsychotic medications) was compared to that of 13 patients receiving conventional antipsychotic medications. RESULTS: The patient groups did not differ on clinical or demographic measures. The patients receiving atypical antipsychotic medications had normal-range P50 suppression (mean=72%). In contrast, the patients receiving typical antipsychotic medications had dramatically lower P50 suppression (mean=27%). CONCLUSIONS: The results support the hypothesis that patients treated with atypical antipsychotic medications have normal P50 measures of sensory gating. Longitudinal within-subjects studies are warranted to clarify the mechanisms mediating this effect.     

A randomized, double-blind, placebo-controlled trial of metformin treatment of weight gain associated with initiation of atypical antipsychotic therapy in children and adolescents

OBJECTIVE: Second-generation, or atypical, antipsychotics effectively treat psychiatric illness in children and adolescents. However, weight gain and abnormalities in insulin sensitivity, including diabetes, complicate this therapy. METHOD: A 16-week double-blind, placebo-controlled trial was conducted to evaluate the effectiveness of metformin in managing weight gain in 39 subjects, ages 10-17, whose weight had increased by more than 10% during less than 1 year of olanzapine, risperidone, or quetiapine therapy. Body weight, body mass index (kilograms per square meter of height), and waist circumference were measured regularly, as were fasting insulin and glucose levels. RESULTS: Weight was stabilized in subjects receiving metformin, while those receiving placebo continued to gain weight (0.31 kg/week). Because the study was conducted with growing children, metformin treatment resulted in reduction in z scores for both weight and body mass index. The homeostasis model assessment, a surrogate indicator of insulin sensitivity, decreased in treated subjects. Overt diabetes was diagnosed in two subjects before treatment (elevated baseline fasting glucose and insulin values) and in two placebo-treated subjects (one at week 12 and the other after study completion). One subject taking placebo developed impaired fasting glucose. Placebo treatment was associated with the need to perform oral glucose tolerance testing upon study completion, by which three additional subjects were identified with impaired glucose tolerance. No serious adverse events resulted from metformin treatment. CONCLUSIONS: Metformin therapy is safe and effective in abrogating weight gain, decreased insulin sensitivity, and abnormal glucose metabolism resulting from treatment of children and adolescents with atypicals.     

Correlation of antipsychotic and prolactin concentrations in children and adolescents acutely treated with haloperidol,clozapine, or olanzapine

Patients with a Diagnostic and Statistical Manual of Mental Disorders (third edition, revised) diagnosis of schizophrenia or psychotic disorder not otherwise specified with onset of psychosis before the age of 13 participated in 6- to 8-week open or double-blind trials of haloperidol (n = 15, mean dose 15.4 +/- 8.1 mg/day [0.27 +/- 0.15 mg/kg/day]), clozapine (n = 30, mean dose 269.9 +/- 173.3 mg/day [4.4 +/- 2.6 mg/kg/day]), or olanzapine (n = 12, mean dose 17.5 +/- 2.8 mg/day [0.30 +/- 0.13 mg/kg/day]). Blood samples were obtained at 6 weeks for evaluation of haloperidol, reduced haloperidol, clozapine, desmethylclozapine, and olanzapine plasma concentrations and serum prolactin concentrations. No gender differences were noted for antipsychotic dose or concentration within each treatment group. Correlations between antipsychotic plasma concentration and serum prolactin concentration were significant only for the olanzapine treatment group (r = 0.80, p = 0.002). Separate correlations for gender were significant only for females receiving olanzapine (r = 0.91, p = 0.03); the patient with the highest serum prolactin experienced galactorrhea. Further studies evaluating the prolactin-elevating properties of antipsychotics are warranted in this population.     

Neurological adverse events associated with antipsychotic treatment in children and adolescents

A retrospective cohort design using medical and pharmacy claims from one state's Medicaid program compared incidence rates for neurological adverse events associated with antipsychotic use in 4140 youths prescribed antipsychotic medications and an untreated sample of 4500 youths, January 1998 to December 2005. The treated cohort evinced a higher prevalence of involuntary movements, sedation, and seizures. The odds of incident involuntary movements were significantly higher for those taking aripiprazole, risperidone, haloperidol, and multiple antipsychotics. The odds of incident seizures were greater for those taking risperidone, multiple antipsychotics, and serotonin-specific reuptake inhibitors. The odds of incident sedation were greater for those taking ziprasidone, risperidone, quetiapine, multiple antipsychotics, and serotonin-specific reuptake inhibitors. Exposure to risperidone, multiple antipsychotics, and serotonin-specific reuptake inhibitors consistently confers a higher risk of developing a range of neurological adverse events in young patients, especially those with preexisting central nervous system, mental retardation, or cardiovascular disorders.     

Glucose metabolism in patients with schizophrenia treated with atypical antipsychotic agents: a frequently sampled intravenous glucose tolerance test and minimal model analysis

BACKGROUND: While the incidence of new-onset diabetes mellitus may be increasing in patients with schizophrenia treated with certain atypical antipsychotic agents, it remains unclear whether atypical agents are directly affecting glucose metabolism or simply increasing known risk factors for diabetes. OBJECTIVE: To study the 2 drugs most clearly implicated (clozapine and olanzapine) and risperidone using a frequently sampled intravenous glucose tolerance test. DESIGN: A cross-sectional design in stable, treated patients with schizophrenia evaluated using a frequently sampled intravenous glucose tolerance test and the Bergman minimal model analysis. SETTING: Subjects were recruited from an urban community mental health clinic and were studied at a general clinical research center.Patients Fifty subjects signed informed consent and 41 underwent the frequently sampled intravenous glucose tolerance test. Thirty-six nonobese subjects with schizophrenia or schizoaffective disorder, matched by body mass index and treated with either clozapine, olanzapine, or risperidone, were included in the analysis. MAIN OUTCOME MEASURES: Fasting plasma glucose and fasting serum insulin levels, insulin sensitivity index, homeostasis model assessment of insulin resistance, and glucose effectiveness. RESULTS: The mean +/- SD duration of treatment with the identified atypical antipsychotic agent was 68.3 +/- 28.9 months (clozapine), 29.5 +/- 17.5 months (olanzapine), and 40.9 +/- 33.7 (risperidone). Fasting serum insulin concentrations differed among groups (F(33) = 3.35; P = .047) (clozapine>olanzapine>risperidone) with significant differences between clozapine and risperidone (t(33) = 2.32; P = .03) and olanzapine and risperidone (t(33) = 2.15; P = .04). There was a significant difference in insulin sensitivity index among groups (F(33) = 10.66; P<.001) (clozapineolanzapine>risperidone) (clozapine vs risperidone, t(33) = 2.94; P = .006; olanzapine vs risperidone, t(33) = 2.42; P = .02). There was a significant difference among groups in glucose effectiveness (F(30) = 4.18; P = .02) (clozapine相似文献