Olanzapine treatment in chronic drug-resistant childhood-onset schizophrenia: an open-label study

The use of typical antipsychotics is limited in children with schizophrenia, owing to the high rate of response failure and early appearance of extrapyramidal syndromes as well as tardive and withdrawal dyskinesia. The aim of the present study was to examine the effectiveness of the atypical antipsychotic olanzapine in the treatment of childhood-onset schizophrenia. The study sample included nine children hospitalized for schizophrenia who had proven refractory to treatment with at least two antipsychotic drugs. Olanzapine was administered after a 2-week washout period in gradually increasing doses to a maximum of 5 mg/day on day 5 and 10 mg/day in week 3; six patients received up to 20 mg/day as of week 5. The duration of the study was 12 weeks. Patient psychiatric status was measured with three scales at onset of therapy and thereafter once weekly. Patients also underwent regular blood, laboratory, and liver function tests, and we also monitored their blood pressure and weight and performed electrocardiography and electroencephalography. A reduction in all psychopathology scores was obtained at 12 weeks from baseline. All extrapyramidal symptoms of previous medications resolved, and there were no new incidents. Side effects were mild. There were no adverse changes in blood chemistry, hematological tests, or electrocardiography parameters, but the treatment was associated with a significant weight gain (6.10 +/- 3.25 kg). At 1-year follow-up, the improvement in psychiatric symptoms was sustained in eight children. We conclude that olanzapine may have potential as a first-line drug in the treatment of drug-resistant childhood-onset schizophrenia. Large-scale, double-blind, placebo-controlled comparative studies are needed to clarify the role of the various atypical antipsychotics in both treatment-resistant and treatment-na?ve populations with psychotic symptoms/disorders.     

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.     

Basal ganglia volumes in drug-naive first-episode schizophrenia patients before and after short-term treatment with either a typical or an atypical antipsychotic drug

The present study examined basal ganglia volumes in drug-naive first-episode schizophrenic patients before and after treatment with either a specific typical or atypical antipsychotic compound. Sixteen antipsychotic drug-naive and three minimally medicated first-episode schizophrenic patients and 19 matched controls participated. Patients were randomly assigned to treatment with either low doses of the typical antipsychotic drug, zuclopenthixol, or the atypical compound, risperidone. High-resolution magnetic resonance imaging (MRI) scans were obtained in patients before and after 12 weeks of exposure to medication and in controls at baseline. Caudate nucleus, nucleus accumbens, and putamen volumes were measured. Compared with controls, absolute volumes of interest (VOIs) were smaller in patients at baseline and increased after treatment. However, with controls for age, gender and whole brain or intracranial volume, the only significant difference between patients and controls was a Hemisphere x Group interaction for the caudate nucleus at baseline, with controls having larger left than right caudate nuclei and patients having marginally larger right than left caudate volumes. Within patients, the two medication groups did not differ significantly with respect to volume changes after 3 months of low dose treatment in any of the VOIs. Nevertheless, when medication groups were examined separately, a significant volume increase in the putamen was evidenced in the risperidone group. The altered asymmetry in caudate volume in patients suggests intrinsic basal ganglia pathology in schizophrenia, most likely of neurodevelopmental origin.     

Coagulation and inflammation markers during atypical or typical antipsychotic treatment in schizophrenia patients and drug-free first-degree relatives

BACKGROUND: Clinical studies suggest that the second generation antipsychotics (APs) clozapine and olanzapine and to a lesser extent the typical antipsychotics may be associated with a procoagulant and proinflammatory state that promotes venous thromboembolism. We evaluated here several blood factors associated with coagulation and inflammation in AP-treated schizophrenia patients and their first-degree relatives. METHODS: Procoagulant factors (fibrinogen and plasminogen activator inhibitor [PAI-1]), the anticoagulant factor antithrombin III [AT-III], and inflammation-related factors (C-reactive protein [CRP] and leptin) were assessed in patients chronically treated with clozapine (n=29), olanzapine (n=29), typical APs (n=30) and first degree relatives of clozapine (n=23) and olanzapine subjects (n=11). RESULTS: The typical AP group had the highest CRP level (p=0.013) in spite of having the lowest body mass index (BMI). Patients as a single group had higher CRP levels than relatives (p=0.003). The typical AP group also had the highest AT-III levels (p=0.021). Fibrinogen levels did not differ between the groups (p=0.13). Olanzapine patients displayed the highest PAI-1 and leptin levels among the drug-treated subjects, but values were similar to those observed in their relatives, and were significantly correlated with the BMI. CONCLUSIONS: A homogeneous negative profile of high inflammation and procoagulant factors along with low levels of anticoagulants was not detected in any group. While preliminary, our results suggest that the observed abnormalities were not related to a direct drug effect, but to elevated BMI (high PAI-1 and leptin in olanzapine-treated patients). We speculate that the high CRP in the typical AP group might be related to poor lifestyle habits, but this must we confirmed in future studies.     

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.     

Efficacy and safety of olanzapine, an atypical antipsychotic, in patients with schizophrenia: Results of an open-label multicenter study in Japan

This first clinical study of olanzapine in Japanese patients with schizophrenia was conducted to investigate the efficacy and safety of olanzapine. Eighty-one patients were included in the analysis set. Mean modal dose for those patients were 9.4 +/- 3.6 mg/day. For the primary efficacy measure (Final Global Improvement Rating score), 14.8% of patients had remarkable improvement, 59.3% of patients had moderate improvement or better, and 86.4% of patients had slight improvement or better. Results from the Brief Psychiatric Rating Scale showed improvement from baseline in all clusters including positive psychotic symptoms (thought disturbance) but also against negative symptoms (anergia). The most commonly reported treatment-emergent signs and symptoms with > or =10% incidence, were insomnia, weight increase, excitement, sleepiness, and anxiety. There was a low incidence of extrapyramidal treatment-emergent signs and symptoms, and events reported were tremor (6.2%), muscle rigidity (3.7%), and akathisia (2.5%). The most commonly reported treatment-emergent laboratory changes, with > or = 20% of incidence, were prolactin elevations (24.3%) followed by increases in triglycerides (20.4%). However, mean prolactin values tended to be normalized during the study. This study result suggests that olanzapine is an "atypical" antipsychotic.     

Hormonal side effects in women: typical versus atypical antipsychotic treatment

Neuroleptic-induced hyperprolactinemia can cause menstrual disorders, impaired fertility, galactorrhea, and sexual dysfunction, as well as hypoestrogenism secondary to disruption of the hypothalamic-pituitary-ovarian axis. The development of the prolactin-sparing atypical antipsychotic drugs offers prevention and resolution of these adverse reactions. Thus far, this property of the new medications has received insufficient clinical attention. The authors use case vignettes to discuss assessment and management of clinical situations that arise as a result of antipsychotic-induced endocrine changes.     

传统与新型抗精神病药治疗精神分裂症疗效及诊治费用的比较

目的　了解传统与新型抗精神病药治疗精神分裂症患者的疗效及治疗费用情况。方法将 6 0 0例精神分裂症患者按门诊病历号分为两组 ,奇数为传统抗精神病药组 (服用氯丙嗪、氟哌啶醇等 ,折合氯丙嗪的平均剂量为 4 5 0～ 6 0 0mg/d) ,偶数为新型抗精神病药组 (服用氯氮平 4 5 0～ 6 0 0mg/d、利培酮 4 6mg/d、奥氮平 17 5mg/d)。分别在治疗前及治疗后 2 ,8,12 ,5 0周末采用简明精神病评定量表、临床大体印象表和副反应量表进行评定 ;调查两组患者家庭在一年中因诊治该患者所需的直接、间接和隐性费用。结果　 (1)有效率 :传统药组为 70 7% ,新型药组为 70 3% (P >0 0 5 ) ;(2 )诊治费用 :传统药组的总费用为 (10 372 81± 6 86 2 2 )元 ,直接费用为 (2 795 5 5± 84 6 2 4 )元 ,间接费用为(5 712 32± 977 13)元和隐性费用为 (2 0 36 2 5± 881 6 2 )元 ,均多于新型药组 [分别为 (5 196 4 0±4 5 1 6 4 )元、(380 5 2 2± 989 2 2 )元、(12 5 5 4 1± 5 0 3 13)元和 (15 8 4 9± 2 2 71)元 ],差异均有显著性 (P <0 0 5或P <0 0 1)。结论　新型抗精神病药的疗效与传统抗精神病药相似 ,但较后者更经济 ,更适合大多数患者。     

Olanzapine in Chinese treatment-resistant patients with schizophrenia: an open-label,prospective trial

The role of olanzapine in treatment-resistant schizophrenia has still not been clearly resolved. In addressing this issue, the current report presents an open-label, prospective, 13 week trial with olanzapine use in Chinese schizophrenic patients who were resistant to more than two different classes of antipsychotics during a minimal 4 week treatment period for each antipsychotic drug at adequate dosage. Fifty-one inpatients were recruited after a cross-titration period and given 10-25 mg of olanzapine daily, without any concomitant antipsychotic medication. Patients were evaluated with the Brief Psychotic Rating Scale (BPRS), the Positive and Negative Symptoms Scale, the Clinical Global Impression Scale (CGI), the Abnormal Involuntary Movement Scale, the Simpson-Angus scale, and the Barnes Akathisia Scale. The olanzapine-treated patients showed significant improvement in both the positive and negative symptoms of schizophrenia by the end of the study. Overall, 20 of 51 (39.2%) responded to 10-25 mg of olanzapine per day as measured by the BPRS and CGI scores. Five patients dropped out due to the worsening of their psychotic symptoms, two patients discontinued owing to poor drug compliance, and the remaining patient complained of a lack of efficacy. Extrapyramidal side-effects were mild, and anticholinergic medications required has decreased. The present open study suggests that olanzapine may be effective and well-tolerated in Chinese treatment-resistant schizophrenic patients. Further double-blinded trials are needed to confirm this result.     

A longitudinal study on the effects of typical versus atypical antipsychotic drugs on hippocampal volume in schizophrenia

BACKGROUND: Previous studies have reported that hippocampal volumes correlate with symptom severity in schizophrenia. This longitudinal study measured changes in symptoms and hippocampal volume in patients switched from typical antipsychotics to olanzapine. METHODS: MRI scans were acquired from patients with chronic schizophrenia (n=10) and healthy volunteers (n=20). At baseline, patients were treated with typical antipsychotics for at least one year, then switched to olanzapine, and rescanned approximately one year later. RESULTS: Olanzapine treatment resulted in no significant change in right or left hippocampal volume. Individual changes in right hippocampal volume correlated significantly with changes in symptoms. CONCLUSIONS: Hippocampal volume change may serve as a marker of symptom change in patients on olanzapine.     

Olanzapine for the treatment of chronic refractory schizophrenia: a 12-month follow-up naturalistic study

OBJECTIVE: The aim of this study is to provide long-term data on the effectiveness and safety of olanzapine in a group of patients with severe refractory schizophrenia. GENERAL METHODS: Twenty patients who had previously received treatment with typical antipsychotic agents and who met the DSM-IV criteria of schizophrenia and refractoriness to treatment were evaluated in a 1-year prospective study after switching to olanzapine. The Positive and Negative Symptoms Scale (PANSS) and the Brief Psychiatric Rating Scale (BPRS) were used to measure effectiveness. The extrapyramidal symptoms were also recorded. Serial laboratory tests, electrocardiograms and body weight measurements were also performed. Longitudinal statistical analyses were performed on the global changes in the scores of the scales by means of a repeated measures analysis of variance. RESULTS: Significant reductions in the global scores from baseline in the PANSS, as well as in the BPRS, were observed. Furthermore, these reductions were also significant when considered only from Week 12. Olanzapine was, in general, well tolerated; a weight gain was observed between baseline and Month 4.5, but, interestingly, it decreased again from this time point to Month 12. CONCLUSION: Olanzapine was shown to be a suitable treatment for refractory schizophrenia in this series of seriously ill patients. Although most of the effects were observed before Week 12, improvement persisted after 1 year. Weight gain stopped or even regressed when the treatment was prolonged. Large controlled clinical trials to define the role of atypical antipsychotics for the management of treatment-refractory schizophrenia are necessary.     

Weight change and atypical antipsychotic treatment in patients with schizophrenia

Schizophrenic patients who have been prescribed atypical antipsychotics have a potential risk of gaining weight. The implications of weight gain for clinical care may differ depending on whether a patient is underweight or overweight at baseline. The exact mechanism for weight gain is not known, but several factors have been identified that can help predict which patients are at risk for gaining weight. These factors include better clinical outcome, increased appetite, and low baseline body mass index. In patients treated with olanzapine for up to 3 years, weight gain trended toward a plateau at approximately 36 weeks. Weight gain interventions, including behavioral modifications, show promise in controlling or reducing weight in patients treated with antipsychotics.     

A comparison of long-term outcome in first-episode schizophrenia following treatment with risperidone or a typical antipsychotic

BACKGROUND: Most reports assessing the efficacy and tolerability of risperidone have involved patients previously treated with typical antipsychotics. Such patients are more likely to have a greater resistance or intolerance to treatment, thus restricting our interpretation of the impact a new treatment might have on the course of schizophrenia and possibly biasing the results. The present study examines the relative effectiveness of risperidone and typical antipsychotics in patients being treated for their first episode of schizophrenia. METHOD: From a cohort of 126 patients, 2 groups of 19 first-episode DSM-III-R/DSM-IV schizophrenia patients matched for age, gender, length of illness, and length of treatment and treated with either a typical antipsychotic or risperidone for a minimum of 1 year were compared on a number of outcome dimensions during their course of treatment and at follow-up. Treatment allocation was not random, and patients were judged to be compliant with medication. Patients treated with typical antipsychotics were followed up for a statistically nonsignificantly longer time (mean = 2.7 vs. 1.9 years). RESULTS: Six patients (31.6%) from the typical antipsychotic group were admitted to the hospital within the first year following the index admission compared with 1 patient (5.3%) in the risperidone group (admitted at month 14). Patients in the risperidone group showed a statistically significantly lower length of first hospitalization (p < .01), utilization of inpatient beds during the course of treatment (p < .001), and use of anticholinergic medication (p < .05). There were no statistically significant differences in symptom levels, either during the course of treatment or at follow-up; in the use of antidepressant, antianxiety, or mood-stabilizing drugs; or in changes in living circumstances or employment. CONCLUSION: These findings confirm at least equal long-term efficacy of typical antipsychotics and risperidone, but a possible advantage for risperidone in decreased service utilization and decreased use of anticholinergic drugs.     

Comparison of withdrawal of typical and atypical antipsychotic drugs: a case study

Haloperidol and clozapine were rapidly withdrawn from a schizophrenic patient on separate occasions several months apart. Mental status changes and fluctuations in involuntary movements were carefully observed under both conditions. Although little change in either mental status or involuntary movements was observed within the 3 weeks following the withdrawal of haloperidol, marked deterioration in mental status and involuntary movements occurred within 1 week of withdrawal of clozapine. Implications of this differential response to withdrawal of antipsychotic medications are discussed.     

Amisulpride,an atypical antipsychotic,in the treatment of acute episodes of schizophrenia: a dose-ranging study vs. haloperidol

This 4-week, double-blind, randomized study was undertaken to determine the dose-response relationship of amisulpride in 319 patients with acute exacerbation of schizophrenia. Fixed doses of amisulpride (400, 800 and 1200 mg/day) and haloperidol (16 mg/day) were compared to amisulpride, 100 mg/day, as a potentially subtherapeutic dose. Efficacy data (BPRS total score and PANSS positive subscale) in the amisulpride groups generated a bell-shaped dose-response curve, with 400 mg/day and 800 mg/day being the most effective treatments for positive symptoms. Parkinsonism did not increase significantly between baseline and endpoint with amisulpride 400, 800 and 1200 mg/day compared to the amisulpride 100 mg/day group, whereas the difference was significant for haloperidol (P<0.05). It is concluded that amisulpride 400 mg and 800 mg/day is highly effective in treating the positive symptoms of schizophrenia, with less extrapyramidal side-effects than haloperidol 16 mg/day.     

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).