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Off-Label Use of Antipsychotic Medications in Medicaid
Douglass L. Leslie, PhD; and Robert Rosenheck, MD

Off-Label Use of Antipsychotic Medications in Medicaid

Douglass L. Leslie, PhD; and Robert Rosenheck, MD
The majority of patients prescribed antipsychotic medications in state Medicaid programs are taking these agents for off-label indications.
Objectives: To determine how often antipsychotics are prescribed off-label to adults without schizophrenia or bipolar disorder who are enrolled in Medicaid, which pays for more than 70% of antipsychotic prescriptions in the United States.

Study Design: Retrospective analysis of 2003 administrative data from 42 state Medicaid programs.

Methods: Continuously enrolled patients with at least 1 prescription for an antipsychotic medication were identified. For these patients, inpatient and outpatient records were checked for any diagnosis of schizophrenia or bipolar disorder; those without any such diagnoses were considered to have received these medications off-label. Offlabel antipsychotic use was compared across sociodemographic groups (age, race/ethnicity, sex). Multivariate logistic regression models identified characteristics associated with off-label use.

Results: Of the 372,038 individuals given an antipsychotic medication, 214,113 (57.6%) received these agents for off-label disorders. Off-label use among patients receiving an antipsychotic was more prevalent among individuals under age 21 years (75.9%) and those 65 years and older (64.8%) than it was among those aged 21 to 64 years (49.0%). Rates of off-label use were relatively high for Hispanics (65.7%) and low for African Americans (52.3%) compared with whites (58.2%). Off-label use was most common among patients receiving risperidone and least common among patients receiving clozapine.

Conclusions: Off-label use of antipsychotic medications is common, particularly among the elderly and children/adolescents. Given that these drugs are expensive, have potentially severe side effects, and have limited evidence supporting their effectiveness off-label, they should perhaps be used with greater caution.

(Am J Manag Care. 2012;18(3):e109-e117)
This study documented rates of off-label use of antipsychotic medications in 42 state Medicaid programs in 2003.

  •  57.6% of patients given an antipsychotic had no diagnoses of schizophrenia or bipolar disorder during the year.

  • Rates of off-label use were higher among children/adolescents and the elderly, among patients given risperidone, and among those diagnosed with depression.

  • Given healthcare reform and widespread crisis in state revenues, state Medicaid programs will be under pressure to serve larger patient populations, increasing their fiscal stress. Reducing off-label antipsychotic use may generate savings with little impact on patient outcomes.
Antipsychotic medications have long been an important component of effective treatment for schizophrenia. They also make up a large and growing share of Medicaid prescription drug programs, which covered nearly 75% of all prescriptions for antipsychotic medications in the United States in 2002,1 although since 2006 the public share of financing for antipsychotic medications has been roughly equally divided between Medicaid and Medicare.2 In addition to schizophrenia, most second-generation antipsychotics have also been approved to treat bipolar disorder. More recently, the Food and Drug Administration (FDA) approved aripiprazole (in 2007) and olanzapine (in 2009) for the adjunctive treatment of major depressive disorder and risperidone (in 2006) and aripiprazole (in 2009) for irritability in children and adolescents with autism. However, once a drug has been approved by the FDA, clinicians are free to prescribe it as they see fit. Because there often is not the same level of high-quality clinical research demonstrating the safety and efficacy of these drugs for non–FDA-approved indications, the benefits of such off-label use are usually unclear. Given that these drugs are expensive and have serious side effects (including weight gain, diabetes mellitus, tardive dyskinesia, and extrapyramidal symptoms), their off-label use may represent significant risk and cost with undemonstrated clinical benefit.

Several previous studies have investigated off-label use of antipsychotic medications.3,4 A recent study using data from the US Department of Veterans Affairs (VA) found that 60.2% of veterans who had a prescription for an antipsychotic medication in fiscal year 2007 did not have a diagnosis of either schizophrenia or bipolar disorder in the same year.5 Two reports by the Agency for Healthcare Research and Quality (AHRQ) found that off-label use of second-generation antipsychotics is common, especially in the treatment of agitation in dementia, depression, obsessive-compulsive disorder, posttraumatic stress disorder (PTSD), personality disorders, Tourette’s syndrome, and autism; however, there was moderate to strong evidence of efficacy in the literature for only a few of the drugs and for only a small number of the off-label indications. 6,7 Another study by Walton and colleagues8 found that several of the second-generation antipsychotics (quetiapine, risperidone, and olanzapine) had a high rate of offlabel prescribing in the absence of good evidence of effectiveness.

Medicaid is the primary payer for patients with schizophrenia in the United States, with over a third of individuals with schizophrenia receiving their care through state Medicaid programs.9 Hence, antipsychotic medications make up a considerable share of Medicaid prescriptions and pharmacy budgets. 1,2,10 It is unknown, however, how much of antipsychotic use in Medicaid is off-label. The objective of the current study was to determine the prevalence of off-label use of antipsychotic medications in state Medicaid plans and to explore patient sociodemographic and clinical characteristics associated with off-label use of these drugs.


Sources of Data

Medicaid Analytic eXtract (MAX) data for 2003 were obtained from the Centers for Medicare & Medicaid Services (CMS) for 42 states. MAX files were developed by CMS to support research and policy analysis on Medicaid populations. MAX files include person-level data with information on Medicaid eligibility, service utilization, and payments. They are organized into 5 files: a Personal Summary File (which contains enrollment information) and 4 claims files (Inpatient, Other Therapy, Long Term Care, and Prescription Drug). The claims files represent final action claims, and have undergone extensive edit checks.

The states studied include the District of Columbia and all but the following 9 states: Colorado, Delaware, Michigan, Montana, North Dakota, South Dakota, Tennessee, Utah, and Washington. These states were excluded because they had a relatively high proportion of managed care enrollees during the study period. Medicaid claims information for managed care enrollees is typically not as complete as that for fee-for-service enrollees.11

The study was approved by the Institutional Review Board of the Penn State College of Medicine.


First, all Medicaid patients who were continuously enrolled for the entire year in a fee-for-service plan and who were not dually enrolled in Medicare were identified. For these patients, all prescriptions for antipsychotic medications were identified and categorized as aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and first-generation antipsychotics considered as a class. Next, inpatient and outpatient records were examined to determine whether patients who received these medicationshad any visits or hospitalizations with a diagnosis of either schizophrenia (International Classification of Diseases, Ninth Revision, Clincial Modification [ICD-9-CM] code 295) or bipolar disorder (ICD-9-CM codes 296.0, 296.1, 296.4- 296.8). Patients without any diagnosis of schizophrenia or bipolar disorder during 2003 who received an antipsychotic medication were considered to have received these medications off-label. Although some of these drugs are now approved for treatment of other disorders (eg, autism, depression), we considered only schizophrenia and bipolar disorder since they were the only approved indications in 2003.

Among these patients, the average daily dose was computed for the first prescription of the year by multiplying the number of pills by the strength per pill and dividing by the number of days of supply. Dosages of first-generation antipsychotics were converted to chlorpromazine equivalents. Patients without a diagnosis of schizophrenia or bipolar disorder were assigned to the following diagnostic groups based on whether they had any visits with the corresponding nonexclusive ICD-9-CM codes: adjustment reaction (309, excluding 309.81), alcohol abuse/dependence (303, 305.00), anxiety disorder (300, excluding 300.4), autism spectrum disorder (299, excluding 299.9), conduct disorder (309.3, 309.4, 312.0-312.9, 313.3-313.9), drug abuse/dependence (292, 304, 305.2-305.9), major depression (296.2-296.3), minor depression (300.4, 296.9, 311, 301.1), organic brain syndrome/Alzheimer disease (290, 293-294, 331.00, 310), other psychosis (297-299), PTSD (309.81), other mental disorder (290-319, excluding 305.1, not elsewhere specified), and no mental disorder. Patients could belong to more than 1 mental disorder diagnostic group.


First, the number and proportion of off-label users who received each drug was determined. Second, all patients belonging to any of the 13 diagnostic groups listed above (excluding those with any comorbid diagnosis of schizophrenia or bipolar disorder) were identified. The proportion of patients in each of these diagnostic groups who received a prescription for an antipsychotic medication was determined, along with the average daily dose of each antipsychotic among users of that medication.

In order to identify patient-level factors associated with off-label use of these agents, logistic regression models were then estimated in which off-label use of antipsychotic medications was the dependent variable and the independent variables included the following: age group, female sex, black race, Hispanic ethnicity, other/missing race, and diagnostic group. Because these models intended to predict off-label use, the sample was again restricted to all individuals without any diagnoses of schizophrenia or bipolar disorder. Separate models were run using receipt of the following antipsychotic drugs as the dependent variable: aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, and first-generation antipsychotics. Because so few patients received clozapine off-label, a separate model was not estimated for clozapine. A final model was estimated for receipt of any antipsychotic medication off-label. In each of the models, standard errors were adjusted to account for the clustering of individuals within states.


Off-Label Use

We identified 372,038 unique patients who were continuously enrolled in a fee-for-service Medicaid program and received a prescription for an antipsychotic medication across all 42 states in 2003. Of these patients, 214,113 (57.6%) did not have a diagnosis of schizophrenia or bipolar disorder during the year and were considered to have received these drugs off-label. Characteristics of off-label users of antipsychotic medications are presented in Table 1. The average age was 30.5 years and they were evenly divided by sex. Whites were the most common racial group (53.1%), with blacks comprising 22.4% of off-label users.

The diagnostic breakdown of off-label users is also presented in Table 1. The most common diagnostic group was other mental disorder (35.0%), followed by minor depression (25.4%), major depression (23.2%), no mental disorder (18.8%), conduct disorder (18.8%), and anxiety disorder (16.2%). Very few off-label users were diagnosed with PTSD (5.6%) or alcohol abuse (5.0%). There was a considerable degree of comorbidity among these disorders, as evidenced by the fact that the proportions of patients in these diagnostic groups sum to more than 100%.

Risperidone was the most commonly prescribed medication among those given antipsychotic medications off-label (41.4%), followed by olanzapine (25.2%) and quetiapine (23.1%). First-generation antipsychotics were also fairly common (20.9%), while relatively few patients were given aripiprazole (6.2%), ziprasidone (4.1%), or clozapine (0.3%) off-label. Table 2 shows rates of off-label use as a percentage of antipsychotic users by age, sex, and race/ethnicity. Among antipsychotic users, off-label use was most common in patients younger than 21 years (75.9%), followed by patients 65 years and older (64.8%). Off-label use among antipsychotic users was only slightly more common among males (58.7%) than females (56.4%). In addition, there were substantial differences by race/ethnicity, with off-label use among antipsychotic users being most common among Hispanics (65.7%) and least common among blacks (52.3%).

Off-Label Use Among Diagnostic Groups

Table 3 shows the use of antipsychotic medications and average daily doses among patients with specific mental illness diagnoses, exclusive of comorbid schizophrenia or bipolar disorder. In contrast to Tables 1 and 2, in which the sample consists only of patients receiving antipsychotics off-label (N = 372,038), Table 3 includes all patients who did not have schizophrenia or bipolar disorder (N = 5,888,286). Rates of antipsychotic use were highest among patients diagnosed with other psychosis (62.7%), followed by autism spectrum disorder (39.2%), organic brain syndrome/Alzheimer disease (36.5%), PTSD (35.0%), and major depression (34.0%). Relatively few patients diagnosed with no mental disorder (0.8%), adjustment reaction (13.1%), other mental disorder (14.5%), or alcohol or drug abuse (16.9% and 18.5%, respectively) received an antipsychotic medication.

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