Cost effectiveness of long-acting risperidone injection versus alternative antipsychotic agents in patients with schizophrenia in the USA

The availability of long-acting risperidone injection may increase adherence and lead to improved clinical and economic outcomes for individuals with schizophrenia. The objective of this study was to assess the cost effectiveness of long-acting risperidone, oral risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and haloperidol depot in patients with schizophrenia over 1 year from a healthcare system perspective. Published medical literature, unpublished data from clinical trials and a consumer health database, and a clinical expert panel were utilized to populate a decision analytical model comparing the seven treatment alternatives. The model captured rates of patient compliance, the rates, frequency and duration of relapse, incidence of adverse events, and healthcare resource utilization and associated costs. Primary outcomes were expressed in terms of percentage of patients relapsing per year, number of relapse days per year (number and duration of relapses per patient per year), and total direct 2003 medical cost per patient per year. On the basis of model projections, the proportions of patients experiencing a relapse requiring hospitalization in 1 year were 66% for haloperidol depot, 41% for oral risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole, and 26% for long-acting risperidone, whereas the proportions of patients with an exacerbation not requiring hospitalization were 60% for haloperidol depot, 37% for oral risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole, and 24% for long-acting risperidone. The mean number of days of relapse requiring hospitalization per patient per year were 28 for haloperidol depot, 18 for oral risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole, and 11 for long-acting risperidone, whereas the mean number of days of exacerbation not requiring hospitalization were eight for haloperidol depot, five for oral risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole, and three for long-acting risperidone. This would translate into direct medical cost savings with long-acting risperidone compared with oral risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and haloperidol depot of US dollars 161, 1425, 508, 259, 1068, and 8224, respectively. These findings were supported by sensitivity analyses. The utilization of long-acting risperidone is predicted to result in better clinical outcomes and lower total healthcare costs than its comparators, oral risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and haloperidol depot. Long-acting risperidone may therefore be a cost saving therapeutic option for patients with schizophrenia.     

Neurologic soft signs in schizophrenic patients treated with conventional and atypical antipsychotics

Neurologic soft signs (NSS) are considered a somatic feature associated with schizophrenia (DSM-IV) that are present in neuroleptic-treated, as well as untreated or first-episode patients. The aim of this study was to determine the incidence and severity of NSS in groups of schizophrenic patients treated with either a conventional neuroleptic medication, haloperidol (n = 37), or atypical antipsychotic medications, risperidone (n = 19), clozapine (n = 34), and olanzapine (n = 18). NSS were assessed with the Neurological Evaluation Scale (NES), whereas extrapyramidal symptoms (EPS), which occur more commonly with conventional neuroleptic treatment, were evaluated using the Simpson-Angus Scale. NES scores were not significantly different between groups. Slight differences were found for 2 items only. The haloperidol group showed higher scores for the "Romberg test," whereas the clozapine group showed higher scores for "short-term memory." There were significant correlations between EPS and NES total score in the haloperidol and risperidone groups. These results demonstrate an overall overlapping of NSS among the groups, confirming their substantial independence from neurologic implications of neuroleptic treatment.     

Striatal dopamine-2 receptor occupancy as measured with [123I]iodobenzamide and SPECT predicted the occurrence of EPS in patients treated with atypical antipsychotics and haloperidol

RATIONALE: Extrapyramidal symptoms (EPS) are common with conventional antipsychotics. Clozapine and other novel antipsychotic substances with lower in vitro affinity for dopamine-2 (D(2)) receptors have a lower propensity to induce EPS. OBJECTIVE: We investigated whether striatal D(2) receptor occupancy predicted the occurrence of EPS with atypical antipsychotics and the typical neuroleptic haloperidol. METHODS: [(123)I]Iodobenzamide (IBZM) and single photon emission tomography (SPECT) were used to quantify receptor occupancy in 71 patients treated with antipsychotics. EPS were rated according to the Simpson-Angus scale (SAS). EPS were deemed clinically relevant, if the SAS score was > or = 5 and/or anticholinergic medication was required. Patients received atypical antipsychotic monotherapy for at least 14 days with amisulpride ( n=2), clozapine ( n=6), haloperidol ( n=10), olanzapine ( n=6), quetiapine ( n=4), risperidone ( n=14), sertindole ( n=13), or zotepine ( n=16). RESULTS: The striatal D(2) receptor occupancy ranged from < 20% to almost saturation. The lowest occupancy was seen with quetiapine and clozapine, the highest with haloperidol. Twenty-two of 71 patients (29%) experienced clinically relevant EPS. These patients displayed significantly higher mean striatal D(2) receptor occupancy (77%) than those without EPS (61%; P=0.002). We found a positive correlation between the percentage of striatal D(2) receptor occupancy and the SAS score ( r=0.28; P=0.02), despite 18 of these patients receiving anticholinergics, thus lowering their SAS score. CONCLUSIONS: Striatal D(2) receptor occupancy as measured with [(123)I]IBZM and SPECT predicted the occurrence of EPS in patients treated with atypical antipsychotics and haloperidol. In vivo imaging of brain receptors with SPECT may provide a useful clinical tool to titrate doses individually and avoid motor side effects in patients treated with novel antipsychotics.     

Extrapyramidal symptoms during treatment of first schizophrenia episode: Results from EUFEST

The European First Episode Schizophrenia Trial (EUFEST) included first-episode schizophrenia patients, assessing the efficacy of five antipsychotic drugs (haloperidol, amisulpride, olanzapine, quetiapine and ziprasidone) over one year. Baseline frequency of extrapyramidal symptoms (EPS) in this group of patients (n=490) was as follows: parkinsonism 10.8%, akathisia 10.0%, dystonia 1.8%, and dyskinesia 0.6%. The frequency of parkinsonism at baseline was greater in patients with a brief prior exposure to antipsychotics (≤2 weeks) compared with antipsychotic-naïve ones, and was positively correlated with the intensity of negative symptoms and negatively with depressive symptoms. After one month of treatment, the increase of parkinsonism was highest in patients receiving haloperidol (+13%), that of akathisia in patients treated with ziprasidone (+14%), and 10.1% of the patients were taking anticholinergic drugs, most frequently in the haloperidol group (24%). In 291 patients remaining on treatment after one year, both parkinsonism and akathisia had decreased: the frequency of parkinsonism was 3%, highest in the haloperidol group (9.1%), that of akathisia was 3%, highest in the quetiapine group (7.5%), and 4% of patients were taking anticholinergic drugs, most frequently those receiving haloperidol (10.5%). The results obtained suggest that in first-episode schizophrenia patients during the first year of antipsychotic treatment (in this case amisulpride, haloperidol in low doses, olanzapine, quetiapine and ziprasidone), EPS were present as manageable clinical problems.     

Time to all-cause treatment discontinuation of olanzapine compared to other antipsychotics in the treatment of schizophrenia: A systematic review and meta-analysis

Objective: This comprehensive review and meta-analysis compared the effectiveness of olanzapine and other antipsychotics in schizophrenia treatment, defining effectiveness as time to all-cause medication discontinuation (primary) and as all-cause treatment discontinuation rates. This study examined randomized clinical trials (RCTs) and observational non-interventional studies. Experimental procedures: Schizophrenia studies that compared olanzapine with individual first- (FGAs) and/or second-generation antipsychotics (SGAs) were included in the meta-analyses. Hazard ratios (HR), risk ratios (RR), and their associated 95% confidence intervals were extracted for RCTs and observational studies. Sensitivity analyses assessed the impact of sources of funding, dose of olanzapine, and allocation concealment method on final results. Results: There were 60 RCTs (N=33,360) and 27 observational studies (N=202,591) included. On time to all-cause medication discontinuation, olanzapine was significantly better than aripiprazole, quetiapine, risperidone, ziprasidone and perphenazine for RCTs and better than amisulpride, risperidone, haloperidol, and perphenazine for observational studies. There were no significant differences between olanzapine and clozapine in RCTs or observational studies. All-cause discontinuation rates in RCTs were significantly lower for olanzapine compared to all comparators except amisulpride and clozapine. In observational studies, olanzapine was less effective than clozapine. Industry-sponsored studies favored olanzapine when compared to haloperidol and perphenazine; higher dose of olanzapine favored quetiapine and perphenazine when compared to olanzapine; method of allocation concealment did not generally affect the results. Conclusion: Using a global measure of medication effectiveness (time to all-cause medication discontinuation), olanzapine appears to be more effective – in both RCTs and observational studies – than most SGAs and FGAs, except for clozapine.     

Efficacy and tolerability of quetiapine in patients with schizophrenia who switched from haloperidol, olanzapine or risperidone

A post hoc analysis of the SPECTRUM trial was carried out to evaluate whether the improvements in efficacy and tolerability gained on switching to quetiapine occurred consistently for patients previously treated with either: haloperidol (n = 43); olanzapine (n = 66); or risperidone (n = 55) monotherapy. Patients were initiated with quetiapine to 400 mg/day over 7 days, and then flexibly dosed (300-750 mg/day) for 11 weeks. The mean (SD) modal dose of quetiapine was 501 (138) mg/day in the haloperidol subgroup, 472 (147) mg/day in the olanzapine subgroup and 485 (141) mg/day in the risperidone subgroup at the study endpoint. Switching to quetiapine induced significant improvements from baseline in PANSS scores, with least square mean changes in total scores of -32.5, -15.4, and -18.5 for patients previously treated with haloperidol, olanzapine and risperidone, respectively, (all p < 0.001 vs baseline). Significant improvements were also noted in CDSS scores, particularly for patients clinically depressed at baseline (all p < 0.001 vs baseline). There were significant reductions in EPS on the SAS and BAS for all subgroups (all p < 0.001 vs baseline). Switching to quetiapine produced efficacy and tolerability benefits regardless of whether their previous antipsychotic was haloperidol, olanzapine or risperidone.     

Comparison of risk of cerebrovascular events in an elderly VA population with dementia between antipsychotic and nonantipsychotic users

INTRODUCTION: The credibility of an increased risk of cerebrovascular events (CVEs) in elderly patients with dementia being treated with second-generation antipsychotics (SGAs) is debatable. Although early published and unpublished data indicated a risk, much of the subsequent literature has not supported this initial finding. Previously published studies were flawed in part because they lacked a control group and did not stratify by dementia subtype. This study examined the risk of a CVE in patients diagnosed with Alzheimer or vascular dementia while being treated with SGA, first-generation antipsychotics, or no antipsychotic medication. METHODS: Data from 14,029 patients aged 65 years and older were evaluated using patient information from Veterans Administration and Medicare databases. Patients who received care for dementia were categorized according to dementia subtype (vascular or Alzheimer) and antipsychotic use during an 18-month period. Patients were observed until they were admitted to a hospital for a CVE, stopped taking or switched antipsychotics, died, or until the 18-month observation period ended. RESULTS: Overall, CVE risk did not differ whether patients were receiving a first-generation antipsychotic, SGA, or no antipsychotic therapy. However, patients with vascular dementia had an increased risk in hospitalization for a CVE. There was no increase in risk of a CVE for patients treated with quetiapine, olanzapine, or risperidone relative to haloperidol, or for patients receiving olanzapine or risperidone relative to quetiapine. Stratified subgroup analyses demonstrated no difference in risk for CVE-related admission patients with Alzheimer dementia among individual agents. However, patients with vascular dementia receiving risperidone, but not olanzapine or quetiapine, were found to be at decreased risk for CVE admission relative to haloperidol. CONCLUSIONS: This study found no increase in overall risk for CVE-related hospital admission in patients treated with antipsychotic medications.     

Adverse effects of second-generation antipsychotics in children and adolescents: a Bayesian meta-analysis

In adults, second-generation antipsychotics (SGAs) have a low frequency of extrapyramidal syndrome (EPS) and a moderate frequency of metabolic adverse effects. Here we aimed to assess short-term adverse effects of SGAs in children and adolescents. We searched for relevant studies in MEDLINE and EMBASE (1996-2010), Food and Drug Administration and European Medicines Agency clinical trial registries, and reference lists of review articles. We found 41 were short-term (3-12 weeks) controlled studies that evaluated SGA adverse effects in youths. Using Bayesian meta-analysis, we analyzed odds ratios (ORs) or mean average effects. Numbers of arms (subjects) in the 41 trials were aripiprazole, 10 (n = 671); olanzapine, 14 (n = 413); quetiapine, 10 (n = 446); risperidone, 25 (n = 1040); ziprasidone, 4 (n = 228); clozapine, 5 (n = 79); and placebo/untreated, 23 (n = 1138), totaling 93 arms (4015 patients). Clozapine was assessed only for weight gain and somnolence. Compared with placebo, significant treatment-related increases were observed for weight gain with olanzapine (mean ± SD = 3.99 ± 0.42 kg; 95% credible interval, 3.17-4.84 kg), clozapine (2.38 ± 1.13 kg; 95% credible interval, 0.19-4.62 kg), risperidone (2.02 ± 0.32 kg; 95% credible interval, 1.39-2.66 kg), quetiapine (1.74 ± 0.38 kg; 95% credible interval, 0.99-2.5 kg), and aripiprazole (0.89 ± 0.32 kg; 95% credible interval, 0.26-1.51 kg); glucose levels with risperidone (3.7 ± 1.36 mg/dL; 95% credible interval, 1.08-6.42 mg/dL) and olanzapine (2.09 ± 1.08 mg/dL; 95% credible interval, 0.13-4.32 mg/dL); cholesterol levels with quetiapine (10.77 ± 2.14 mg/dL; 95% credible interval, 6.6-14.95 mg/dL) and olanzapine (4.46 ± 1.65 mg/dL; 95% credible interval, 1.24-7.73 mg/dL); triglyceride levels with olanzapine (20.18 ± 5.26 mg/dL; 95% credible interval, 9.85-30.53 mg/dL) and quetiapine (19.5 ± 3.92 mg/dL; 95% credible interval, 11.84-27.17 mg/dL); hyperprolactinemia with risperidone (OR, 38.63; 95% credible interval, 8.62-125.6), olanzapine (OR, 15.6; 95% credible interval, 4.39-41.1), and ziprasidone (OR, 9.35; 95% credible interval, 1.24-37.03); and EPS with ziprasidone (OR, 20.56; 95% credible interval, 3.53-68.94), olanzapine (OR, 6.36; 95% credible interval, 2.43-13.84), aripiprazole (OR, 3.79; 95% credible interval, 2.17-6.17), and risperidone (OR, 3.71; 95% credible interval, 2.18-6.02). All SGAs increased the risk of somnolence/sedation. We conclude that short-term metabolic effects and EPS are frequent in children treated with SGAs. Second-generation antipsychotics have distinct profiles of secondary effects, which should be considered in making treatment decisions.     

Cost-utility analysis of treatment with olanzapine compared with other antipsychotic treatments in patients with schizophrenia in the pan-European SOHO study

OBJECTIVE: To determine the cost utility of treating schizophrenic patients with olanzapine compared with other antipsychotics in a naturalistic outpatient setting. METHODS: The pan-European SOHO study is a 3-year, prospective, outpatient, observational study of outcomes associated with antipsychotic treatment, focusing on olanzapine, in ten European countries. For the cost-utility analysis, healthcare resource use (inpatient care, day care, outpatient psychiatric consultations and antipsychotic and concomitant medication use) and EQ-5D data were collected at baseline and at 3, 6 and 12 months. The perspective was that of the health service payer. UK healthcare unit costs (year 2004 values) were applied to the resource use data for the ten countries. UK population tariffs were applied to the EQ-5D data to determine utility values.An Epoch analysis was used to analyze the longitudinal data. Multivariate regression analyses that adjusted for baseline covariates were used to estimate the incremental cost and utility gains for patients treated with olanzapine compared with each of the other antipsychotics (risperidone, quetiapine, amisulpride, clozapine and oral or depot typical antipsychotics). RESULTS: A total of 10 972 patients were enrolled at baseline, of which 9107 completed the 12-month study period. Treatment with olanzapine was more effective in terms of QALYs gained than all of the other antipsychotic treatments. Treatment with olanzapine dominated quetiapine and amisulpride. The incremental cost for olanzapine compared with risperidone was pound sterling 226 per patient over 12 months and the incremental cost per QALY gained was pound 5156, with bootstrap analyses showing 100% of the replications falling below a pound sterling 30 000 per QALY gained threshold. Compared with treatment with clozapine, olanzapine was found to be marginally more effective, at an additional cost of pound sterling 13 per patient over 12 months and to have an incremental cost per QALY gained of pound sterling 775. Bootstrap analyses showed that 81% of replications fell below a pound sterling 30 000 per QALY gained threshold. Comparing olanzapine with oral and depot typical antipsychotics, the incremental cost was pound sterling 849 and pound sterling 1106 per patient over 12 months and the incremental cost per QALY gained was pound sterling 15 696 and pound sterling 23 331, respectively. Bootstrap analyses showed that 98% of the replications fell below a pound sterling 30 000 per QALY gained threshold for the comparison with oral typical antipsychotics, and 79% of replications for the comparison with depot preparations. CONCLUSIONS: Among SOHO patients, if a funding threshold of pound sterling 30 000 per QALY gained is assumed, this analysis suggests that olanzapine has a high probability of being the most cost-effective treatment compared with other antipsychotic treatments. However, comparison of olanzapine with clozapine and typical depot antipsychotics should be viewed with caution because clozapine is a second-line treatment and depot treatment is used for patients who do not adhere to their oral medication.     

EEG abnormalities associated with antipsychotics: a comparison of quetiapine, olanzapine, haloperidol and healthy subjects

In this study the effects of the atypical antipsychotics quetiapine and olanzapine, and the typical antipsychotic haloperidol on EEG patterns were retrospectively investigated in 81 patients under stable monotherapy with either drug (quetiapine: n=22, olanzapine: n=37, haloperidol: n=22). These three subgroups were compared with a control group of healthy subjects (n=30) which were matched regarding sex and age. Diagnoses of patients were schizophrenia (DSM-IV 295.xx, n=61), brief psychotic disorder (DSM-IV 298.8, n=9), schizoaffective disorder (DSM-IV 295.70, n=8) and delusional disorder (DSM-IV 297.1, n=3). There were no statistically significant differences regarding demographic characteristics between the groups. Digital EEG recordings were retrieved from a database and visually assessed by two independent investigators, and one blinded regarding medication. One patient from the quetiapine group (5%), 13 olanzapine patients (35%), five of the haloperidol patients (23%) and two subjects of the control group (7%) had an abnormal EEG. Epileptiform activity was observed in four patients (11%) of the olanzapine group, and none in the others. EEG abnormalities were statistically significantly increased with dose in the olanzapine group, in contrast to patients treated with haloperidol, quetiapine or healthy subjects. In conclusion, EEG abnormalities seem to occur rarely in patients treated with quetiapine comparable to the control group, but significantly more often with haloperidol and olanzapine, possibly due to different receptor profiles of these substances. To our knowledge, this is the first electrophysiological investigation comparing the new atypical antipsychotics quetiapine, haloperidol, olanzapine with healthy subjects.     

Olanzapine. A pharmacoeconomic review of its use in schizophrenia.

Olanzapine is an atypical antipsychotic agent which is at least as effective as the conventional agent haloperidol and the atypical agent risperidone. Olanzapine may be superior to haloperidol in some respects, including treatment of negative symptoms. A major advantage of olanzapine over haloperidol is its lower risk of extrapyramidal symptoms. Olanzapine improves quality of life and other aspects of functioning to a greater extent than haloperidol, and improves quality of life to at least the same extent as risperidone. However, olanzapine has a high acquisition cost compared with conventional antipsychotics. Despite this, most pharmacoeconomic analyses indicate that treatment with olanzapine does not significantly increase, and may even decrease, the overall direct treatment costs of schizophrenia, compared with haloperidol. Total direct medical costs calculated from prospective resource utilisation data were lower with olanzapine than with haloperidol by $US388 (1995 values) per patient over 6 weeks and by $US55 per patient per month during 46 weeks extended treatment. In a mixed effects linear model of the same data, total costs over 1 year were $US10,301 (1996 values) per patient lower with olanzapine than haloperidol, and olanzapine was associated with 18.3 more symptom-free days per patient. Compared with risperidone, mean total direct medical costs over 28 weeks were $US493 (1995 values) per patient lower with olanzapine. In a Markov model of 5 years' treatment, olanzapine was associated with more time in a disability-free state than haloperidol at a total cost per patient that was lower by $US1539 (1995 values), 816 Pounds (1995/1996 values), 977 Dutch guilders (NLG; 1995 values) and 2296 Deutschmarks in US, UK, Dutch and German analyses, respectively. In a similar Spanish analysis, the overall total cost was higher with olanzapine, giving an incremental cost effectiveness for olanzapine of 32,516 pesetas (1995 values) per month of disability-free time gained. When risperidone was a comparator, the total cost per patient was $US1875 and NLG202 lower with olanzapine in US and Dutch analyses, respectively. CONCLUSIONS: The high acquisition cost of olanzapine is offset by reductions in other treatment costs in patients with schizophrenia. Compared with haloperidol, the drug improved patient outcome and quality of life, while overall direct treatment costs were generally not increased, or even decreased. Olanzapine has also been reported to decrease overall treatment costs compared with risperidone, but confirmation is required. Olanzapine is a cost-effective alternative to conventional agents for the treatment of moderately to severely ill patients with longstanding schizophrenia.     

Quetiapine, clozapine, and olanzapine in the treatment of tardive dyskinesia induced by first-generation antipsychotics: a 124-week case report

Our report of a patient with severe tardive dyskinesia (TD) who has been exposed to both typical antipsychotic and clozapine, olanzapine and quetiapine during a 124-week follow-up period supports the possible beneficial effect of atypical antipsychotics on pre-existing symptoms of TD. Persistently high AIMS scores during all the periods of treatment with typical antipsychotics contrast strongly with the drop in scores that occurs in strict chronological sequence after switching to both clozapine (45%), olanzapine (27.8%) and quetiapine (85%). Since the reversal to haloperidol from the three atypical agents was systemically associated with a return to high AIMS scores, it seems likely that the improvement noted with clozapine, olanzapine and quetiapine represents a temporary symptomatic effect rather than a sustained resolution of the disorder. The olanzapine-clozapine-quetiapine rank order of increasing effectiveness against TD symptoms suggests that this property, although shared by the atypical antipsychotics, is to some degree drug-specific. Patient- and/or drug-dependent mechanisms may be involved in this gradient of effect.     

Pharmacy cost evaluation of risperidone, olanzapine, and quetiapine for the treatment of schizophrenia in acute care inpatient settings

OBJECTIVE: This study examines total pharmacy cost and usage patterns of schizophrenic patients in acute mental health inpatient settings for three atypical antipsychotics -- risperidone, olanzapine, and quetiapine. Despite the readily available unit cost information for drugs, actual pharmacy costs may deviate significantly from 'labeled costs'. Recent research findings indicate the need for more robust evaluation of such pharmacy costs. RESEARCH DESIGN AND METHODS: This study used data from non-randomized inpatient retrospective charts from three acute care inpatient mental health facilities. The final pooled sample included 327 patients, of which 120 received risperidone, 153 received olanzapine, and 54 received quetiapine. Medication cost was defined as the average wholesale price (AWP) as listed in the 2001 'Red Book'. Propensity scoring methodology and multinomial regression were employed to reduce treatment selection bias. RESULTS: The observed mean daily antipsychotic drug doses were 4.45 mg (SD 2.44) for risperidone, 14.04 mg (SD 5.55) for olanzapine, and 350.33 mg (SD 228.24) for quetiapine. The corresponding mean daily drug costs were $7.66(SD $4.20) for risperidone, $8.11 (SD $5.29) for quetiapine and, $12.10 (SD $4.79) for olanzepine. Numbers adjusted for treatment selection bias show that the average daily total pharmacy cost of risperidone was $4.35 lower than olanzapine (p < 0.001) and $1.41 lower than quetiapine (p = 0.38). The adjusted average daily pharmacy cost of olanzapine was $4.02 higher than quetiapine (p < 0.001). After statistical adjustment there were no significant differences between study drugs in terms of length of stay or patient functioning. CONCLUSION: This study provides the first US comparison of medication utilization patterns and pharmacy costs for olanzapine, risperidone, and quetiapine administered in acute mental health care inpatient settings. While this study did not estimate the full economic value of the three antipsychotics in these inpatient settings, it demonstrated that the mean daily costs for risperidone were lower than the mean daily costs for olanzapine (p < 0.001) and quetiapine although the later difference was not statistically significant (p = 0.38).     

Atypical antipsychotic drugs: current issues of safety and efficacy in the management of schizophrenia

This review focuses on the comparative safety and efficacy profile of nine atypical antipsychotic drugs (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone and zotepine), which may ultimately affect the therapeutic options available for patients with schizophrenia. These antipsychotic compounds differ markedly in their potential to impact a number of quality-of-life measures. Furthermore, their differential effects on anxiety disorders, treatment-resistant depressive illness, cognitive functions and manic disorders may influence the selection of atypical antipsychotics for conditions associated with schizophrenia. The possible relevance of these parameters in evaluating the risk/benefit equation and probable involvement of varying receptor mechanisms is also discussed.     

The new generation of antipsychotic drugs: how atypical are they?

The cardinal feature of traditional neuroleptic drugs is extrapyramidal symptoms (EPS), such as parkinsonism, akathisia, and dystonia. Irrespective of the autonomic nervous system side-effect profile of a specific neuroleptic, the entire class produces EPS. Therefore, EPS and antipsychotic activity were once thought to be inextricably linked. However, with the discovery of clozapine, this concept was no longer defensible. Clozapine produced antipsychotic actions without associated EPS or increases in serum prolactin levels, and the term 'atypical' was coined to differentiate its actions from those of the traditional agents. Later, the definition of atypical was expanded to encompass clozapine's unique clinical spectrum of activity, including its effectiveness in treating some patients unresponsive to traditional neuroleptics. Clozapine thus became the archetype for a new generation of antipsychotic drugs, which now includes quetiapine, olanzapine, risperidone, sertindole, ziprasidone, zotepine and amisulpride. This paper will review the pharmacological actions that contribute to the unique features of clozapine, focusing on receptor profile and activity in animal models used for evaluations of antipsychotic activity and EPS. Similarities and differences amongst the new agents will also be discussed. Although conclusions regarding atypicality require controlled clinical trials in addition to preclinical and animal models, it is apparent from this review that not all agents match the profile of clozapine.     

Clinical and economic outcomes of olanzapine compared with haloperidol for schizophrenia. Results from a randomised clinical trial.

OBJECTIVE: The purpose of this study was to compare, from the payor perspective, the clinical and economic outcomes of olanzapine to those of haloperidol for the treatment of schizophrenia. DESIGN AND SETTING: Clinical, quality-of-life and resource utilisation data were prospectively collected for US-residing patients with schizophrenia who were participating in a multicentre, randomised, double-blind clinical trial comparing olanzapine and haloperidol. Direct medical costs were estimated by assigning standardised prices (1995 values) to the resource utilisation data. PATIENTS AND PARTICIPANTS: 817 patients with schizophrenia who had a baseline Brief Psychiatric Rating Scale score (BPRS) > or = 18 (items scored 0 to 6) and/or were no longer tolerating current antipsychotic therapy. INTERVENTIONS: Olanzapine 5 to 20 mg/day (n = 551) or haloperidol 5 to 20 mg/day (n = 266) for 6 weeks. Patients showing a predefined level of clinical response entered a 46-week maintenance phase. MAIN OUTCOME MEASURES AND RESULTS: After acute treatment, BPRS-based clinical improvements were seen in 38 and 27% of olanzapine and haloperidol patients, respectively (p = 0.002). Clinically important improvements on the Quality of Life Scale were achieved during acute treatment in 33% of olanzapine recipients and 25% of haloperidol recipients (p = 0.094). Olanzapine treatment in the acute phase led to significantly lower inpatient ($US5125 vs $US5795, p = 0.038) and outpatient ($US663 vs $US692, p = 0.001) costs, resulting in a significant overall reduction in mean total medical costs of $US388 (p = 0.033). This significant reduction in total costs was found despite olanzapine mean medication costs being significantly greater than haloperidol medication costs ($US326 vs $US15, p < 0.001). No significant differences in clinical improvement were observed in the maintenance phase. Maintenance phase olanzapine mean total medical costs were $US636 lower than haloperidol total costs (p = 0.128). Although olanzapine medication costs were significantly higher than haloperidol medication costs ($US3461 vs $US95, p < 0.001), this difference was offset by significantly lower inpatient ($US8322 vs $US10,662, p = 0.044) and outpatient ($US3810 vs $US5473, p = 0.038) costs. CONCLUSIONS: In this study, olanzapine treatment was more effective than haloperidol in producing clinical response in the acute phase. In addition, olanzapine treatment led to reductions in inpatient and outpatient costs that more than offset olanzapine's higher medication costs relative to haloperidol.     

Stimulus properties of the "atypical" antipsychotic zotepine in rats: comparisons with clozapine and quetiapine

The stimulus properties of the "atypical" antipsychotic zotepine were assessed in three studies in rats. In Study 1, the ability of zotepine to generalise to clozapine was studied. Two groups of rats were trained to discriminate clozapine at 2 and 5 mg/kg. Clozapine induced full generalisation in both groups, with the generalisation curves shifted significantly to the left in the low dose group. In generalisation tests clozapine did not suppress responding. Zotepine induced dose-related generalisation in both groups, with full generalisation in the low dose group and 50% maximal generalisation in the high dose group at the highest dose that could be tested. In contrast to clozapine, zotepine induced substantial (50% or more) substitution for clozapine only at doses which suppressed responding. In Study 2 zotepine was investigated in rats trained to discriminate quetiapine (10 mg/kg). Quetiapine induced full generalisation and zotepine only induced 54% generalisation at the highest dose that could be tested. Generalisation was accompanied by response suppression induced by both quetiapine and zotepine. In Study 3 an attempt was made to train a zotepine discrimination (1 mg/kg increased to 2 mg/kg). Even after 150 training sessions it proved impossible to obtain reliable discriminative responding with zotepine. These data suggest that: (i) The actions of zotepine in discrimination assays are similar to, but not identical with, those of clozapine and quetiapine; (ii) The differences among the actions of clozapine, quetiapine and zotepine may be related to either the unique ability of zotepine to block noradrenaline (NA) uptake, or to its more marked affinity for D(2) receptors; (iii) The finding that zotepine only mimicked quetiapine up to a level of 54% was unexpected, since quetiapine and clozapine generalise reciprocally and zotepine generalised fully to (low dose) clozapine. This finding may also be related either to zotepine's ability to inhibit NA uptake or its relatively high D(2) affinity; (iv) Although zotepine clearly possesses discriminative properties, it is not possible to train it as a reliable stimulus, in contrast to clozapine and quetiapine. This may be due to its more marked D(2) receptor affinity. Collectively, these data demonstrate both similarities and differences between zotepine and other novel atypical antipsychotics in drug discrimination assays.     

All-cause treatment discontinuation in schizophrenia during treatment with olanzapine relative to other antipsychotics: an integrated analysis

OBJECTIVES: Treatment continuation, as measured by time to all-cause treatment discontinuation, is a broad measure of overall treatment effectiveness. This integrated analysis compared the likelihood of discontinuation from olanzapine treatment versus other antipsychotics among patients with schizophrenia. METHODS: Clinical trials of all sponsors were included if they met the following criteria: double-blind, randomized, comparative; duration of 12 weeks or longer; no mandatory discontinuation before 12 weeks; and schizophrenia-spectrum disorders; 20 patients or more per treatment. Weighted mean hazard ratios and 95% confidence intervals were calculated from discontinuation time. Meta-analyses were performed for the following comparators that had at least 2 studies: haloperidol (5 studies), risperidone (5 studies), ziprasidone (2 studies), clozapine (3 studies), and perphenazine (2 studies) (13 studies in total; 3 included more than 1 comparator). Only 1 eligible published study was found for fluphenazine, amisulpride, and quetiapine; therefore, meta-analyses could not be performed for these comparators. RESULTS: Significantly (P < 0.05) greater likelihood of discontinuation relative to olanzapine treatment (hazard ratio [95% confidence interval]) was observed for haloperidol (1.4 [1.2-1.7]), risperidone (1.3 [1.1-1.6]), ziprasidone (1.6 [1.4-2.0]), and quetiapine (1.4 [1.1-1.9]), but not clozapine (1.2 [0.9-1.6]), fluphenazine (1.8 [0.8-4.3]), perphenazine (1.3 [0.7-2.1]), or amisulpride (1.1 [0.8-1.6]). CONCLUSIONS: These data suggest that patients with schizophrenia and related disorders may continue olanzapine treatment longer than haloperidol, risperidone, ziprasidone, or quetiapine treatment.     

Interactions between antiepileptic and antipsychotic drugs.

Antiepileptic and antipsychotic drugs are often prescribed together. Interactions between the drugs may affect both efficacy and toxicity. This is a review of human clinical data on the interactions between the antiepileptic drugs carbamazepine, valproic acid (sodium valproate), vigabatrin, lamotrigine, gabapentin, topiramate, tiagabine, oxcarbazepine, levetiracetam, pregabalin, felbamate, zonisamide, phenobarbital and phenytoin with the antipsychotic drugs risperidone, olanzapine, quetiapine, clozapine, amisulpride, sulpiride, ziprasidone, aripiprazole, haloperidol and chlorpromazine; the limited information on interactions between antiepileptic drugs and zuclopenthixol, periciazine, fluphenazine, flupenthixol and pimozide is also presented. Many of the interactions depend on the induction or inhibition of the cytochrome P450 isoenzymes, but other important mechanisms involve the uridine diphosphate glucuronosyltransferase isoenzymes and protein binding.There is some evidence for the following effects. Carbamazepine decreases the plasma concentrations of both risperidone and its active metabolite. It also decreases concentrations of olanzapine, clozapine, ziprasidone, haloperidol, zuclopenthixol, flupenthixol and probably chlorpromazine and fluphenazine. Quetiapine increases the ratio of carbamazepine epoxide to carbamazepine and this may lead to toxicity. The data on valproic acid are conflicting; it may either increase or decrease clozapine concentrations, and it appears to decrease aripiprazole concentrations. Chlorpromazine possibly increases valproic acid concentrations. Lamotrigine possibly increases clozapine concentrations. Phenobarbital decreases clozapine, haloperidol and chlorpromazine concentrations. Phenytoin decreases quetiapine, clozapine, haloperidol and possibly chlorpromazine concentrations. There are major gaps in the data. In many cases there are no published clinical data on interactions that would be predicted on theoretical grounds.