Dose trends for second-generation antipsychotic treatment of schizophrenia and bipolar disorder

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Abstract

Background

Antipsychotic dosing used in clinical practice can differ from dosing originally recommended in product labeling. This has been reported for olanzapine and quetiapine, where higher doses are commonly used. This may be the case for ziprasidone as well.

Method

To characterize changes over time in dosing for the initial and subsequent prescriptions of first-line second-generation antipsychotics used during treatment episodes for outpatients with schizophrenia and bipolar disorder, the 2001–2005 Thomson MarketScan Medicaid Database (Medicaid) and the 2001–2006 MarketScan Commercial Claims and Encounters Database (Commercial) were analyzed. Dose trends were evaluated using autoregressive time-series models.

Results

Data were available for 49 180 treatment episodes of schizophrenia (4683 Commercial and 44 497 Medicaid) and 83 289 treatment episodes of bipolar disorder (57 961 Commercial and 25 328 Medicaid). The initial prescription mean daily and overall mean daily doses of ziprasidone in schizophrenia episodes significantly increased across the Medicaid and Commercial populations, with similar trends observed for bipolar episodes. The first (May 2001) and last (December 2005) observed 3-month mean daily doses for ziprasidone were 112 mg/d and 138 mg/d for patients with schizophrenia and 93 mg/d and 113 mg/d for those with bipolar disorder in the Medicaid cohort, with similar findings for the Commercial cohort. Consistently significant trends in dose changes were not observed for the other medications, although quetiapine and olanzapine doses generally increased while aripiprazole and risperidone doses generally decreased.

Conclusions

There remains a need for controlled randomized clinical trials that test fixed doses of antipsychotics to ascertain the dose–response relationship within the dose range used in contemporary clinical practice.

Introduction

When new medications become commercially available, clinicians rely on the dosing instructions contained in the product labeling. This has led to initial practices such as titrating risperidone from 2 mg/d to 6 mg/d by day 3, with subsequent increases to a maximum of 16 mg/d, or if prescribing quetiapine, going no higher than 500 mg/d (Citrome et al., 2005a). Ziprasidone, when launched for the treatment of schizophrenia, was recommended to be started at a dose of 20 mg twice daily to initiate symptomatic control, with the patient evaluated for an undetermined period of time prior to dose adjustments within the broad range of 40 to 160 mg/d. After gaining clinical experience with new medications, clinicians may modify their prescribing practices, with some antipsychotics being prescribed at much lower or at much higher doses than originally anticipated, such as observed for risperidone, olanzapine, and quetiapine in hospitalized patients (Citrome et al., 2005a).

Dosing recommendations contained in product labeling may differ from dosing implemented in clinical practice because the recommendations reflect the design and results of registration studies. These studies may be designed without the benefit of complete knowledge of dose–response relationships, and implemented in study subjects who may differ from the patients who will generally receive these medications in the “real world.” Examples of these differences include disease severity, chronicity, and the presence of comorbid psychiatric and medical conditions. Moreover, in the absence of knowledge about the dose–response relationship, study design for registration protocols may err on the side of caution when selecting doses or timing of titration to maximum dose, with the unintentional consequence of sacrificing efficacy, such as possibly evidenced by quetiapine (Citrome, 2008).

Although “prescribing-based evidence” is not a substitute for “evidence-based prescribing,” fixed-dose studies of second-generation antipsychotics to clearly elucidate dose–response relationships are generally lacking (Citrome and Volavka, 2002, Davis and Chen, 2004). It remains important to update dose trend information to highlight the need for controlled clinical trials to test the utility of different dose strategies.

The purpose of the present study was to evaluate the mean daily doses of the first-line second-generation antipsychotics used in clinical practice for the treatment of schizophrenia and bipolar disorder. We hypothesized that there was a measurable change in mean daily dosing for aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone over the period of time of 2001 through 2005 (Medicaid) and 2006 (Commercial).

Section snippets

Design

This was a retrospective cohort study using health care claims databases to evaluate dosing of antipsychotics during discrete treatment episodes for patients with schizophrenia, schizoaffective disorder, or bipolar disorder receiving prescriptions for aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone.

Data sources

Two databases were used. The first is the MarketScan Medicaid Database which is comprised of health care claims from 9 state Medicaid programs, with data available from January

Demographics and descriptive data

A total of 49 180 schizophrenia episodes (4683 Commercial and 44 497 Medicaid) in 28 434 patients (2776 Commercial and 25 658 Medicaid) and 83 289 bipolar treatment episodes (57 961 Commercial and 25 328 Medicaid) in 49 157 patients (33 043 Commercial and 16 114 Medicaid) were evaluated from the Commercial and Medicaid populations over the 5-year study period. Among patients with schizophrenia, the mean age was 38.5 years with 52.4% male in the Medicaid population and 40.2 years with 49.7% male in the

Overview

In this analysis, drug-specific trends in doses of second-generation antipsychotics for the treatment of schizophrenia and bipolar disorder were evaluated between 2001 through up to 2006. The initial prescription mean daily doses and overall mean daily doses of ziprasidone increased significantly during the study period in both schizophrenia and bipolar disorder populations and across payor segments. The changes translate into an annual increase up to 10.5% for the initial prescription and up

Role of funding source

Funding for this study was provided by Pfizer, Inc. Employees of Pfizer, Inc. were involved in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Editorial support was provided by Annie Neild, PhD, of PAREXEL and was paid by Pfizer Inc.

Contributors

Brian Cuffel and Thomson Reuters designed the study and wrote the protocol. Christopher Reist reviewed the initial data and was involved in the preparation of the poster presentation that preceded the paper. Leslie Citrome, Liisa Palmer, Leslie Montejano and Greg Lenhart managed the literature searches and analyses. Greg Lenhart undertook the statistical analysis, and Leslie Citrome and James Harnett wrote the first draft of the manuscript. All authors contributed to and have approved the final

Conflicts of interest

Leslie Citrome, is a consultant for, has received honoraria from, or has conducted clinical research supported by the following: Abbott Laboratories, AstraZeneca Pharmaceuticals, Avanir Pharmaceuticals, Azur Pharma Inc, Barr Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Forest Research Institute, GlaxoSmithKline, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Pfizer Inc, and Vanda Pharmaceuticals.

Christopher Reist has received research support from Astra Zeneca Pharmaceuticals,

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