Clinical trial-based cost-effectiveness analyses of antipsychotic use

OBJECTIVE: Second-generation antipsychotics make up one of the fastest growing segments of the rapidly growing pharmaceutical sector. Given limited health care resources, assessment of the value for the cost of second-generation antipsychotics relative to first-generation antipsychotics is critical for resource-allocation decisions. METHOD: With a MEDLINE search, the authors identified eight studies (based on six randomized clinical trials) that analyzed the cost-effectiveness of second-generation antipsychotics relative to first-generation antipsychotics in individuals with schizophrenia disorders. The authors reviewed appropriate methods of measurement, analysis, and design of cost-effectiveness studies in randomized clinical trials and evaluated the validity of economic results derived from the studies in light of appropriate methods. RESULTS: The eight randomized clinical trial-based cost-effectiveness studies of antipsychotic medications faced a variety of threats to validity related to 1) measurement of costs, 2) measurement of effectiveness, 3) analysis of costs, 4) measurement of sampling uncertainty, 5) analysis of incomplete cost data, 6) minimizing loss to follow-up, and 7) threats to external validity. CONCLUSIONS: Economic claims made by the authors of a number of trial-based economic evaluations have generally been favorable to second-generation antipsychotics. However, the methodological issues the authors of the current study identified suggest that there is no clear evidence that atypical antipsychotics generate cost savings or are cost-effective in general use among all schizophrenia patients. Psychiatrists, researchers, and administrators should consider the methodological issues highlighted in interpreting study results. These issues should be addressed in future trial designs.     

Cost-effectiveness of second-generation antipsychotics and perphenazine in a randomized trial of treatment for chronic schizophrenia

BACKGROUND: Second-generation antipsychotics have largely replaced first-generation antipsychotics for the treatment of schizophrenia, but a large-scale cost/effectiveness analysis has not been attempted. METHOD: Patients with schizophrenia (N=1,493) were assigned to treatment with a first-generation antipsychotic (perphenazine) or one of four second-generation drugs (olanzapine, quetia-pine, risperidone, or ziprasidone) and followed for up to 18 months. Patients with tardive dyskinesia were prohibited from assignment to perphenazine. Patients could be reassigned at any time to another second-generation drug, including clozapine, but not to perphenazine. The cost analysis included medications plus health services use. Quality-adjusted life year (QALY) ratings were assessed on the basis of Positive and Negative Syndrome Scale (PANSS) subscale scores and side effects. An intention-to-treat analysis included all available observations, classified by initial drug assignment, and costs of reassignment of most patients to another second-generation drug. The analysis was repeated considering only treatment on initially assigned medications. RESULTS: Although QALY ratings, PANSS scores, and other quality of life measures indicated modest improvement over 18 months, there were no significant differences between perphenazine and any second-generation medication. Average total monthly health care costs were 300 dollars-600 dollars (20%-30%) lower for perphenazine than for second-generation antipsychotics because of lower drug cost. Differences in costs remained when maximally discounted drug prices were used for all patients and when only observations during treatment with the first medication were included. CONCLUSIONS: Treatment with perphenazine was less costly than treatment with second-generation antipsychotics with no significant differences in measures of effectiveness. However, the trial was limited by a high dropout rate, and longer-term neurological and metabolic side effects require further study.     

Second-generation antipsychotics: cost-effectiveness, policy options, and political decision making

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and other recent research suggest that second-generation antipsychotics other than clozapine may offer few, if any, advantages over first-generation antipsychotics, especially agents of intermediate potency. Thus the newer agents are not likely to generate sufficient benefit to justify their $11.5 billion annual cost. Policy approaches for containing drug costs are available and could improve cost-effectiveness by encouraging that second-generation antipsychotics be prescribed more selectively, such as only when clearly indicated. However, restrictions on either drug availability or physician choice are vigorously opposed by professional and consumer advocacy groups as well as by industry, and excessively restrictive approaches could unintentionally reduce access to beneficial treatments. Interventions that directly reduce second-generation antipsychotic prices would increase access for consumers but are inconsistent with broad opposition to government price regulation in the United States. High expenditures on these medications are thus likely to continue without concomitant gains for public health.     

In the Aftermath of CATIE: How Should Administrators Value Atypical Antipsychotic Medications?

The wide scale use of expensive atypical antipsychotic medications has led to a dramatic increase in the proportion of direct costs schizophrenia being allocated for medications. Although there is evidence that the atypical antipsychotic, clozapine, may lead to cost savings in patients with refractory schizophrenia the cost-effectiveness of the other atypical antipsychotics remains in question. We therefore reviewed the published, long-term randomized, prospective cost-effectiveness treatment studies that compared an atypical to a typical antipsychotic. There were serious methodological problems with all. In general, those that were based on efficacy trials showed an advantage for atypicals while those based on effectiveness studies found the opposite. It appears that to the extent that studies mimic “real world” conditions they fail to support the cost-effectiveness of the atypical antipsychotics.     

Pharmacotherapy and health care costs among patients with schizophrenia and newly diagnosed diabetes

OBJECTIVE: This study investigated how antipsychotic pharmacotherapy and health care costs change after diabetes mellitus is newly diagnosed among patients with schizophrenia. METHODS: Administrative data from the Department of Veterans Affairs were retrospectively reviewed to examine patients with schizophrenia who did not have any history of diabetes and for whom a consistent regimen of antipsychotic monotherapy was prescribed for any three-month period between June 1999 and September 2000. Data for these patients were reviewed through September 2001. Patients who were given a new diagnosis of diabetes were identified, along with a matched comparison group of patients who were not given a diagnosis of diabetes. Medication changes and costs were compared between patients with diabetes and those without and between patients who were taking second-generation antipsychotics and those who were taking first-generation antipsychotics. RESULTS: Of the 56,849 patients who fit the criteria for the study, 4,132 (7.3 percent) were subsequently given a diagnosis of diabetes (7.4 percent were taking second-generation antipsychotics and 7.1 percent were taking first-generation antipsychotics). Differences in the proportions of patients with and without diabetes who switched or discontinued antipsychotics were small and were statistically significant only for patients who were taking risperidone before the diabetes diagnosis date. The average marginal cost of treating a patient with diabetes was 3,104 US dollars over an average follow-up of 15.7 months, or 6.59 US dollars per day. Because the attributable risks of diabetes with second-generation antipsychotics averaged .875 percent, the average additional daily cost per patient that was attributable to each second-generation medication was small, ranging from .003 US dollars for risperidone to .134 US dollars for clozapine. CONCLUSIONS: Surprisingly, a new diagnosis of diabetes did not result in substantial antipsychotic medication changes, even among patients who were taking clozapine or olanzapine. Even though the costs of treating patients with newly diagnosed diabetes were substantial, the increased costs attributable to second-generation antipsychotics were small.     

Atypical antipsychotic medications for borderline personality disorder: What’s the story?

Atypical antipsychotic medications have been approved for treatment of schizophrenia and broad efficacy has led to trials for other illnesses. For borderline personality disorder (BPD), traditional antipsychotics had been demonstrated to reduce symptoms, but were not well tolerated. This paper reviews the new data emerging from trials assessing safety and efficacy of the atypical antipsychotic medications risperidone, olanzapine, and quetiapine (studies of ziprasidone and aripiprazole have not been published). To date, the results of studies with atypical antipsychotics have shown reduction of symptoms from across a broad number of domains. Also, early placebo-controlled trials show an advantage for these agents. Taken together, these new studies are pointing to a positive direction and offer hope for the treatment of BPD.     

Effect of prior authorization of second-generation antipsychotic agents on pharmacy utilization and reimbursements

OBJECTIVE: Medicaid expenditures for antipsychotic medications have risen rapidly, from under $1.0 billion in 1995 to over $5.5 billion in 2005. In response, at least ten states have implemented prior-authorization programs that restrict access to particular second-generation antipsychotic agents (aripiprazole and olanzapine). Twenty-two states restrict particular dosing forms (injections). This study examined the impact of such restrictions. METHODS: The authors used interrupted time-series analysis of quarterly state-level drug utilization data to examine the impact of prior authorization for particular agents in West Virginia and Texas. Changes in market share of nonpreferred medications and total pharmacy costs were compared with changes in states without similar prior-authorization requirements. RESULTS: The West Virginia policy led to an immediate 3.5% reduction in market share level (p<.01) and a 1.3% decrease in trend per quarter in market share (p<.001) for nonpreferred antipsychotics, leading to a 13.9% reduction after two years. In Texas, prior authorization reduced the market share level of nonpreferred agents by 2.6% (p=.055). However, prior authorization did not lead to a significant decrease in pharmacy reimbursements in either state. CONCLUSIONS: Current prior-authorization policies for second-generation antipsychotics do not appear to reduce pharmacy reimbursement, probably because alternative medications are costly. These findings suggest that any cost savings from prior-authorization policies would accrue largely through supplemental rebate agreements with manufacturers, which are likely reduced by the transfer of dually eligible Medicaid enrollees to Medicare Part D plans. Further evaluation of the clinical consequences resulting from such policies is urgently needed to determine whether the minimal cost savings outweigh the potential clinical risks.     

Evoked gamma band synchronization and the liability for schizophrenia

Objective: Electroencephalographic (EEG) synchronization in the gamma band is thought to represent a neuronal mechanism by which the brain integrates information processed in different cortical areas to build a coherent internal representation. Previous studies have reported abnormal gamma range (40 Hz) synchronization in schizophrenic patients. We tested a group of first-degree relatives of schizophrenic probands who have schizophrenia spectrum personality symptoms, and a group of schizophrenic patients, to examine whether individuals with increased liability for schizophrenia have reduced gamma synchronization. Method: A steady-state auditory evoked potential paradigm was used to evaluate the brain's capacity to sustain 20, 30, and 40 Hz EEG synchronization in 11 relatives, 24 schizophrenic patients (11 on conventional, 13 on new generation antipsychotic medications), and 17 normal controls. Results: Relatives with schizophrenic spectrum personality symptoms had reduced power at 40 Hz synchronization compared to normal controls (p=0.022). Previous findings of reduced steady-state gamma band synchronization in schizophrenic patients were not directly replicated in this study. Patients as a group did not significantly differ from controls, but patients taking new generation antipsychotics had significantly enhanced 40 Hz synchronization compared to patients taking conventional antipsychotics (p<0.001). There were no group differences in 20 or 30 Hz synchronization. Conclusions: Gamma band synchronization was found to be reduced in first-degree relatives with schizophrenia spectrum personality symptoms. Patients on new generation antipsychotic medications may exhibit enhanced gamma band synchronization.     

Variations in use of second-generation antipsychotic medication by race among adult psychiatric patients

OBJECTIVE: This study examined variations in the use of second-generation antipsychotic medication among African-American and non-Hispanic white patients in a national sample of adults who were treated by psychiatrists. METHODS: This study used data from studies of psychiatric patients and treatments that were conducted by the American Psychiatric Institute for Research and Education's (APIRE's) Practice Research Network (PRN). Psychiatrists provided detailed clinical data for 126 African-American patients and 574 white patients who were randomly selected and for whom antipsychotic medications were prescribed. The study assessed differences by race in the use of second-generation antipsychotic medication, adjusting for clinical, sociodemographic, and health-system characteristics, including patients' source of payment for treatment. RESULTS: African-American patients were less likely than white patients to receive second-generation antipsychotic medications (49 percent compared with 66 percent). After the analysis statistically adjusted for clinical, sociodemographic, and health-system characteristics, African-American patients remained less likely than white patients to receive second-generation antipsychotics. CONCLUSIONS: Because African Americans tended to receive medications that are not first-line recommended treatments and that have a greater risk of producing tardive dyskinesia and extrapyramidal side effects, African Americans could be expected to suffer diminished clinical status. This disparity may also contribute to lower rates of adherence and to more frequent emergency department visits and psychiatric hospitalizations among African Americans     

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.     

Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs

The treatment of schizophrenia has evolved over the past half century primarily in the context of antipsychotic drug development. Although there has been significant progress resulting in the availability and use of numerous medications, these reflect three basic classes of medications (conventional (typical), atypical and dopamine partial agonist antipsychotics) all of which, despite working by varying mechanisms of actions, act principally on dopamine systems. Many of the second-generation (atypical and dopamine partial agonist) antipsychotics are believed to offer advantages over first-generation agents in the treatment for schizophrenia. However, the pharmacological properties that confer the different therapeutic effects of the new generation of antipsychotic drugs have remained elusive, and certain side effects can still impact patient health and quality of life. Moreover, the efficacy of antipsychotic drugs is limited prompting the clinical use of adjunctive pharmacy to augment the effects of treatment. In addition, the search for novel and nondopaminergic antipsychotic drugs has not been successful to date, though numerous development strategies continue to be pursued, guided by various pathophysiologic hypotheses. This article provides a brief review and critique of the current therapeutic armamentarium for treating schizophrenia and drug development strategies and theories of mechanisms of action of antipsychotics, and focuses on novel targets for therapeutic agents for future drug development.     

Are the second-generation antipsychotics cost-effective? A critical review on the background of different health systems

BACKGROUND: Despite clinical advantages over conventional compounds, second-generation antipsychotics are prescribed less frequently in some European countries than in the United States because of their higher acquisition price and the current cost-containment strategies of many European health systems. This has been criticized on the grounds that the higher acquisition costs of the new antipsychotics might be more than outweighed by savings in other fields, e. g., through a reduction in rehospitalizations or indirect costs. METHOD: In order to create an empirical basis for this discussion, a review of the results of pharmacoeconomic studies (mostly cost-effectiveness studies) comparing second-generation with conventional antipsychotics was undertaken. RESULTS: Of the 35 studies identified, most report at least cost-neutrality of the new antipsychotics (in many cases clozapine) that is due to reductions in hospitalization costs. These results cannot be generalized, however, because of methodological shortcomings such as small patient samples and study designs with low validity, and especially because of a lack of studies performed outside the U.S. It is shown that results from studies in the U.S. cannot be generalized to other health systems in Europe or in developing countries. Furthermore, only a few findings on newer second-generation antipsychotics other than clozapine are reported, and no study investigated indirect costs, which play a major role because of the early onset and chronicity of schizophrenia. CONCLUSION: Until now, there has been no sufficient evidence for the superior cost-effectiveness of atypical antipsychotics in European countries. Considering the importance of this topic for health politics, more cost-effectiveness studies in European countries are urgently needed.But even if economic superiority of the second-generation antipsychotics cannot be demonstrated in such studies, their use is nevertheless indicated with respect to patient's well-being.     

Antipsychotic polypharmacy trends among Medicaid beneficiaries with schizophrenia in San Diego County, 1999-2004

OBJECTIVE: This study examined trends and costs of second-generation antipsychotic polypharmacy among Medicaid beneficiaries with schizophrenia in San Diego County. METHODS: Medicaid data were used to identify 15,962 persons with schizophrenia receiving antipsychotic medications between 1999 and 2004. The yearly proportion of beneficiaries receiving second-generation antipsychotic polypharmacy, duration of polypharmacy, inpatient admissions, and pharmaceutical costs were examined. RESULTS: The proportion of clients receiving second-generation antipsychotic polypharmacy increased from 3.3% in 1999 to 13.7% in 2004, whereas annual antipsychotic medication costs increased from $4,128 to $5,231 (2004 dollars). Among those receiving second-generation polypharmacy, the percentage receiving second-generation polypharmacy for 12 months increased from 5.1% to 14.4%, and the percentage hospitalized increased from 7.2% to 9.0%. CONCLUSIONS: The prevalence of long-term second-generation antipsychotic polypharmacy and its associated costs increased substantially between 1999 and 2004. Prescribing antipsychotic polypharmacy is an unproven and costly strategy that if left unchanged could lead to administrative efforts to cut costs and dictate practice.     

Are patients with schizophrenia under-treated with second-generation antipsychotics? A pilot study of the prescription practices of German psychiatrists

INTRODUCTION: Patients' and relatives' associations, psychiatrists, and pharmaceutical companies are complaining about a deficiency in the care of psychiatric patients with innovative medications in Germany. They estimate that only about 10- 30 % of all patients with schizophrenia receive second-generation antipsychotics, a figure that lies significantly below the international average. METHODS: In order to determine the frequency of use of second-generation antipsychotics in the actual care of schizophrenic patients, we conducted the following investigations:--Discharge papers of schizophrenic inpatients from a university hospital and from a district hospital were studied with regard to the antipsychotic discharge medication.--Practicing psychiatrists were contacted and asked whether during the first 3 months after discharge they had continued the antipsychotic discharge medication that was proposed by the hospital. RESULTS: The investigation of a total of 200 discharge papers and the subsequent questioning of the psychiatrists who carried out the follow-up treatment showed that 166 patients (83 %) received a second-generation antipsychotic upon discharge. Only 5 % of these patients were switched to conventional antipsychotics in the outpatient treatment. Thus, contrary to our expectations, there was no noteworthy change from second-generation to classical antipsychotics. DISCUSSION: Therefore, in the sample analyzed the second-generation antipsychotics were far more frequently prescribed than would have been expected according to general estimates, and it was not possible to verify the often-heard complaints of an under-treatment with second generations in this study. Our findings suggest, however, that only 60 % of the patients still receive their discharge medication 3 months after discharge from the hospital. This raises the important question as to how continuity of the antipsychotic treatment could be better ensured.     

High-cost use of second-generation antipsychotics under California's Medicaid program

OBJECTIVE: The high costs associated with second-generation antipsychotic medications raise concerns that prior-authorization restrictions may be implemented to restrict use. This study assessed patterns of antipsychotic use to identify uses that are associated with high economic cost but for which there is no documented efficacy. METHODS: California Medicaid fee-for-service pharmacy claims were analyzed from May 1999 through August 2000 for patients who received risperidone, olanzapine, or quetiapine. RESULTS: Of the 116,114 patients who received at least one of these agents, 4.1 percent received a combination regimen. Polypharmacy was the most expensive form of second-generation antipsychotic use, costing up to three times more per patient than monotherapy. CONCLUSION: Restricting polypharmacy may reduce costs and prevent the need for prior-authorization restrictions.     

First- v. second-generation antipsychotics and risk for diabetes in schizophrenia: systematic review and meta-analysis

BACKGROUND: The increased prevalence of diabetes in schizophrenia is partly attributed to antipsychotic treatment, in particular second-generation antipsychotics, but the evidence has not been systematically reviewed. AIMS: Systematic review and meta-analysis comparing diabetes risk for different antipsychotics in people with schizophrenia. METHOD: We searched MEDLINE, PsycINFO, EMBASE, International Pharmaceutical Abstracts, CINAHL and Web of Knowledge until September 2006. Studies were eligible for inclusion if the design was cross-sectional, case-control, cohort or a controlled trial in individuals with schizophrenia or related psychotic disorders, where second-generation antipsychotics (defined as clozapine, olanzapine, risperidone and quetiapine) were compared with first-generation antipsychotics and diabetes was an outcome. Data were pooled using random effects inverse variance weighted meta-analysis. RESULTS: Of the studies that met the inclusion criteria (n=14), 11 had sufficient data to include in the meta-analysis. Four of these were retrospective cohort studies. The relative risk of diabetes in patients with schizophrenia prescribed one of the second-generation v. first-generation antipsychotics was 1.32 (95% CI 1.15-1.51). There were insufficient data to include aripiprazole, ziprasidone and amisulpride in this analysis. CONCLUSIONS: There is tentative evidence that the second-generation antipsychotics included in this study are associated with a small increased risk for diabetes compared with first-generation antipsychotics in people with schizophrenia. Methodological limitations were found in most studies, leading to heterogeneity and difficulty interpreting data. Regardless of type of antipsychotic, screening for diabetes in all people with schizophrenia should be routine.