Abstract
Objective
The study evaluated trends in the off-label use of second-generation antipsychotics in the Medicare population, a practice that has been identified as lacking adequate supporting evidence for many indications.
Methods
Medicare claims data from 2006–2012 were used to identify beneficiaries who filled at least one prescription for any second-generation antipsychotics. The use of second-generation antipsychotics not associated with any medical claims for approved indications in a given year was classified as off-label use. Rates of off-label use and associated diagnoses were compared over time, and counts and costs were compared between on- and off-label users.
Results
Based on a sample of 490,314 patient-years, the rate of off-label use of second-generation antipsychotics declined from 51% to 45% of users from 2006 to 2012. Fill counts standardized for 30-day supply were 16% lower for off-label user, compared to on-label users. Off-label users had higher out-of-pocket costs but lower total costs for second-generation antipsychotics. Off-label users most commonly had claims related to dementia, minor depression, anxiety disorders, and other psychosis. The proportion of off-label users without any claims for the most common off-label uses of second-generation antipsychotics declined from 45% in 2006 to 30% in 2012.
Conclusions
Off-label use of second-generation antipsychotics has declined over time, especially among those without any of the common off-label conditions. Changes in use based on accompanying diagnoses do not systematically reflect changes in the evidence base for the use of these drugs, suggesting a mismatch between evidence and practice of off-label second-generation antipsychotic prescribing.
Introduction
Once a medication is approved by the Food and Drug Administration (FDA) to enter the US market, providers can prescribe the medication for an unapproved indication or in an unapproved age group, unapproved dosage, or unapproved form of administration. This is referred to as off-label use. Although the FDA follows a set of rigorous criteria in approving new drugs, providers are not regulated for off-label prescribing. Off-label use is common - a 2006 study found that just over one-fifth of prescriptions for commonly used medications were for off-label use (1). Though in some cases off-label use of a drug evolves to become a first-line treatment option, as in the case trazodone for insomnia in elderly patients (2), a potential inconsistency between on-label and off-label prescribing is the evidence corroborating use of the drug. While the efficacy and safety of a drug has typically been rigorously established for on-label conditions, the evidence base for off-label uses of a drug is not subject to the same standards, leading to concerns about medication errors, adverse drug events, and inadequate monitoring (3).
Concerns abound about the off-label use of second-generation second-generation antipsychotics, which are more expensive than their first-generation ‘typical’ counterparts and are associated with a different set of side effects owing to their different chemical structure. There are also a number of recent studies challenging the touted superior efficacy of second-generation antipsychotics (4–6). A 2007 study of Department of Veterans Affairs prescriptions for second-generation antipsychotics found that 60.2% of second-generation antipsychotic use was not associated with approved conditions (7). Another 2007 report by the Department of Health and Human Services on second-generation antipsychotic use among elderly nursing home residents found that 83% of claims for second-generation antipsychotics were for off-label uses, 88% of which were associated with a condition with the FDA’s “black box” warning (8). Specifically, a 2005 black box warning cautioned against the use of second-generation antipsychotics for treating dementia-related psychosis or agitation in the elderly. More broadly, there is concern that these expensive drugs are being used in ineffective ways, resulting in sub-optimal and possibly even harmful treatment of patients at a much higher cost to payers (9, 10).
A 2006 comparative effectiveness review around the off-label use of second-generation antipsychotics was conducted by the Agency for Healthcare Research and Quality (AHRQ), and concluded that there was not sufficiently strong evidence that off-label use was efficacious, but there was strong evidence of increased risk of adverse events associated with such use (11). An updated version of this review, published in 2011, found some evidence that second-generation antipsychotics were effective for specific off-label uses, such as anxiety disorder and obsessive-compulsive disorder, while maintaining a lack of evidence to support other uses such as eating disorders and substance abuse (11).
The objective of this study is to examine trends in off-label use of second-generation antipsychotics among elderly Medicare beneficiaries since the FDA’s 2005 black box warning. We use Medicare claims data from 2006–2012 to assess trends in second-generation antipsychotic prescribing, identifying users of second-generation antipsychotics and their associated conditions on an annual basis. This study contributes to the literature on the use of second-generation antipsychotics by examining trends in on-label and off-label use, rather than cross-sectional snapshots, allowing us to pinpoint how changes in prescribing patterns reflect changes in the evidence base around the use of this drug class.
Methods
Data source and study sample
We used 2006–2012 Medicare medical and pharmacy claims data from a 5% random sample of Medicare beneficiaries to identify second-generation antipsychotic use and associated medical conditions. The observation of interest was a person-year, so individuals were not tracked longitudinally. In each study year between 2006 and 2012, we identified beneficiaries who were continuously enrolled for twelve months in Parts A, B, and D and filled at least one prescription for second-generation antipsychotics. We included the following second-generation antipsychotics: aripiprazole, asenapine, clozapine, iloperidone, olanzapine, olanzaine/fluoxetine, paliperidone, quetiapine, risperidone, and ziprasidone.
Measure of off-label use
We adopted the approach used elsewhere in this literature to distinguish on-label and off-label prescribing using Medicare data, specifically searching for the presence of any relevant diagnoses in the same calendar year as a prescription fill for an second-generation antipsychotic medication (7, 12). This search was conducted on carrier claim files. First, we used this approach to identify on-label users of second-generation antipsychotics; these users were defined as those with a claim associated with bipolar disorder, schizophrenia or major depressive during the same calendar year as the fill. To be conservative in the determination of off-label use, all available diagnosis codes were included in the search. The remaining observations were then classified as off-label users.
For off-label users, we also identified the off-label conditions for which they had claims during the same calendar year as a prescription fill for an second-generation antipsychotic medication. The conditions were identified based on the literature as well as a series of systematic reviews on antipsychotic use conducted by the Agency for Healthcare Research and Quality (AHRQ) (7, 11, 12), which included a synthesis of the evidence associated with the use of these drugs for each condition and a determination about whether there was solid evidence of a positive impact. The carrier claim files were searched for claims associated with the following conditions and ICD-9 codes: dementia, organic brain syndrome, and Alzheimer’s disease (290*, 293*, 294*, 310*, 331.0); obsessive-compulsive disorder (300.3); post-traumatic stress disorder (309.81); personality disorders (301*); Tourette’s syndrome (307.23); eating disorders (307.1, 307.5*); anxiety disorders (300.0*); hyperkinetic syndromes (314*); insomnia (780.51, 780.52); drug abuse and dependence (292*, 304*, 305.20–305.93); alcohol abuse and dependence (303*, 305.0*); adjustment reaction (309* excluding 309.81); minor depression (296.9*, 300.4*, 311); other psychosis (297*–299*); and personality disorders (301*). Again, all available diagnosis codes were searched as part of this process.
Analysis
After identifying off-label users of second-generation antipsychotics, we compared mean second-generation antipsychotic fills, adjusted for thirty-day supply, and costs (total and out-of-pocket) for off-label and on-label users over time. Gross drug cost and patient pay amount were used to define total and out-of-pocket cost, respectively. We then examined the demographic and health profiles of on-label and off-label users, followed by an exploration of the various conditions associated with off-label use of second-generation antipsychotics. We examined trends in the conditions associated with off-label use over time, and compared these patterns with changes in the evidence base during this period using AHRQ’s evidence assessment (11). To facilitate this comparison, we summarized AHRQ’s findings for each condition as either evidence of efficacy, inefficacy, or both; of note, this determination focuses on efficacy and does not reflect safety. We also identified those off-label users who had no claims in a given year for any of the common off-label conditions associated with second-generation antipsychotics.
Results
As shown in Table 1, the annual number of beneficiaries in this sample using second-generation antipsychotics grew by approximately 20,000 from 2006 to 2012, with 76,369 beneficiaries filling at least one prescription for this drug class in 2012. Due to comparatively low enrollment in 2006 relative to later years, the proportion of beneficiaries using an second-generation antipsychotic was highest in 2006 at 11%, then stabilized at 8–9% of beneficiaries in ensuing years. Thus, if focusing only on the time period 2007–2012, the annual number of beneficiaries in the sample using second-generation antipsychotics increased by approximately 8,000.
Table 1.
Comparison of on-label and off-label use of second-generation antipsychotics, 2006–2012
| Year | No. of users | Proportion of beneficiaries who are users | No. of off-label users | Proportion of users who are off-label | Mean fill counts per on-label user | Mean fill counts per off-label user |
|---|---|---|---|---|---|---|
| 2006 | 56,787 | .11 | 28,972 | .51 | 11.43 | 9.69 |
| 2007 | 68,778 | .08 | 35,599 | .52 | 11.36 | 9.56 |
| 2008 | 69,547 | .08 | 35,353 | .51 | 11.54 | 9.79 |
| 2009 | 71,217 | .09 | 35,298 | .50 | 11.51 | 9.78 |
| 2010 | 72,534 | .09 | 32,590 | .45 | 11.58 | 9.60 |
| 2011 | 75,082 | .09 | 33,403 | .44 | 11.53 | 9.64 |
| 2012 | 76,369 | .08 | 34,409 | .45 | 11.62 | 9.70 |
Notes: fills are adjusted to reflect a 30-day supply
The proportion of individuals per year engaged in off-label use of an second-generation antipsychotic stayed fairly constant from 2006–2009, representing approximately half of users; the last three years of observation saw a decline in this trend, with a statistically significant decrease to a steady 45% from 2010–2012. Standardized monthly fills of second-generation antipsychotic drug prescriptions are, on average, 16% lower for off-label users throughout the study period, averaging 9.68 monthly fills for off-label users and 11.51 for on-label users.
Costs, shown in Table 2, also differed in a fairly consistent way during this time period, with total annual costs for second-generation antipsychotics on average 42% lower for off-label users. Out-of-pocket costs, however, were higher for off-label users from 2006–2011, with the gap shrinking in 2012. This final year of the analysis saw significant declines in both out-of-pocket and total costs of second-generation antipsychotics for both types of users, with declines anywhere from 17% (out-of-pocket costs of on-label users) to 34% (out-of-pocket costs for off-label users). This sharp decline aligns with patents expiring for four second-generation antipsychotics (Zyprexa in 2011, and Seroquel, Invega and Geodon in 2012). The effect of patent expiration can also be seen in the trend of the ratio of out-of-pocket to total cost of second-generation antipsychotics during this time period.
Table 2.
Annual total costs and patient out-of-pocket costs ($) for second-generation antipsychotics per user for off-label and on-label users, 2006–2012
| Year | Off-label | On-label | Second-generation antipsychotics with patents expiring | ||||
|---|---|---|---|---|---|---|---|
| OOP cost | Total cost | Ratio | OOP cost | Total cost | Ratio | ||
| 2006 | 72 | 2,305 | .031 | 54.28 | 3,852 | .014 | |
| 2007 | 144 | 2,378 | .060 | 106.34 | 4,017 | .026 | |
| 2008 | 148 | 2,612 | .056 | 109.99 | 4,364 | .025 | Risperdal |
| 2009 | 133 | 2,500 | .053 | 105.52 | 4,279 | .025 | |
| 2010 | 137 | 2,512 | .054 | 104.45 | 4,525 | .023 | |
| 2011 | 116 | 2,800 | .042 | 87.28 | 4,981 | .018 | Zyprexa |
| 2012 | 76 | 2,163 | .035 | 72.37 | 3,962 | .018 | Seroquel, Invega, Geodon |
| Average growth rate (%) | 7.81% | −.34% | 10.12% | 1.06% | |||
Notes: OOP=out-of-pocket
Table 3 summarizes the sample characteristics of beneficiaries in this sample using second-generation antipsychotics, broken down by on- and off-label use. Specifically, this table summarizes the person-year observations, the unit of analysis for this paper, and thus individuals may be counted multiple times. Overall, on- and off-label users have different demographic and health profiles. On-label users of second-generation antipsychotics tend to be younger, are more likely to be male, and are less likely to be white than their off-label counterparts. Off-label users have higher rates of most of the chronic conditions shown, as identified by the Chronic Condition Data Warehouse flags. The exceptions are COPD and depression, which are more common among on-label users. The rate of depression among on-label users is almost 14% higher than among off-label users, likely owing to second-generation antispsychotics being approved to treat certain types of depression.
Table 3.
Descriptive characteristics of on-label and off-label users of second-generation antipsychotics
| Variable - % | On-label (n=254,690) | Off-label (n=235,624) | P-Value |
|---|---|---|---|
| Age, mean (SD) | 52.15 | 66.12 | <.001 |
| Male sex | 44.02 | 35.55 | <.001 |
| Race | <.001 | ||
| White | 74.91 | 79.18 | |
| Black | 15.72 | 12.92 | |
| Hispanic | 6.05 | 4.82 | |
| Other | 3.34 | 3.07 | |
| CMS priority comorbidities | |||
| History of acute myocardial infarction | 1.37 | 3.06 | <.001 |
| Alzheimer’s disease | 5.55 | 20.73 | <.001 |
| Other types of dementia | 15.20 | 36.18 | <.001 |
| Chronic kidney disease | 8.86 | 12.27 | <.001 |
| Congestive heart failure | 16.27 | 26.50 | <.001 |
| COPD | 22.37 | 21.44 | <.001 |
| Depression | 63.82 | 50.59 | <.001 |
| Diabetes | 26.68 | 28.50 | <.001 |
| History of stroke or TIA | 8.18 | 16.84 | <.001 |
Table 4 displays trends in the diagnoses associated with individuals engaged in off-label use of second-generation antipsychotics. The most common condition identified among off-label users was dementia, with claims for this condition arising in 36% in 2006, peaking at 44. % in 2010, and falling to 42% in 2012. Other conditions consistently identified in over 10% of patients designated as off-label users were anxiety disorders (average prevalence of 14%), minor depression (average prevalence of 23%) and other psychosis (average of 15%). The last column of Table 4 identifies the growth in the prevalence of each condition from 2006–2012. The most significant growth was observed in hyperkinetic disorder (136%), anxiety disorder (113%), and insomnia (102%). Of note, drug abuse and alcohol abuse were indicated in 2% and 1% of off-label users in 2006–2011, but in 2012 no off-label users had claims associated with these conditions. Finally, a significant percentage of off-label users did not have claims for any of the common conditions associated with off-label use of second-generation antipsychotics, with the peak of 45% occurring in 2006 and declining to 30% in 2012. This decline was not steady, but rather was spurred by a significant decline from 2009–2010, falling from 44% to 29%.
Table 4.
Prevalence of common off-label conditions associated with second-generation antipsychotic use, 2006–2012 (%)
| Year | 2006 | 2007 | 2008 | 2009 | 2010 | 2011 | 2012 | Growth, 2006–2012 | AHRQ review efficacy determination(11) |
|---|---|---|---|---|---|---|---|---|---|
| Dementia | 35.8 | 35.7 | 35.3 | 34.6 | 44.1 | 43.8 | 41.9 | 17 | +− |
| Minor depression | 17.5 | 18.1 | 19.5 | 20.5 | 27.0 | 28.9 | 29.0 | 66 | |
| Other psychosis | 13.7 | 13.4 | 13.7 | 13.5 | 17.3 | 18.2 | 18.0 | 31 | |
| Anxiety disorder | 9.2 | 10.2 | 11.2 | 12.1 | 16.3 | 17.8 | 19.7 | 113 | +− |
| Insomnia | 3.8 | 4.1 | 4.5 | 5.1 | 6.6 | 7.3 | 7.6 | 102 | − |
| Adjustment reaction | 2.4 | 2.3 | 2.4 | 2.5 | 3.3 | 3.1 | 3.0 | 26 | |
| Drug abuse | 1.7 | 1.8 | 2.0 | 2.3 | 2.8 | 3.1 | 0 | −100 | − |
| Personality disorder | 1.4 | 1.3 | 1.4 | 1.2 | 1.6 | 1.6 | 1.5 | 6 | +− |
| Alcohol abuse | 1.3 | 1.3 | 1.2 | 1.4 | 1.7 | 1.7 | 0 | −100 | − |
| OCD | 1.2 | 1.1 | 1.1 | 1.1 | 1.6 | 1.6 | 1.7 | 40 | +− |
| PTSD | .9 | .9 | .9 | 1.0 | 1.2 | 1.4 | 1.4 | 63 | +− |
| Hyperkinetic disorder | .5 | .5 | .6 | .6 | .8 | 1.0 | 1.1 | 136 | + |
| Eating disorder | .3 | .3 | .3 | .3 | .3 | .3 | .3 | 27 | − |
| Tourette’s | .1 | .1 | .1 | .1 | .2 | .2 | .2 | 47 | +− |
| None of the above | 45.4 | 45.4 | 44.8 | 44.2 | 29.3 | 28.0 | 29.7 | −35 |
Notes: OCD = Obsessive-compulsive disorder; PTSD = Post-traumatic stress disorder
A “+” indicates evidence of efficacy, while “−” indicates evidence of inefficacy. Conditions not included in the AHRQ review are left blank.
Discussion
The trend analysis of second-generation antipsychotic use showed persistence in the off-label use of these drugs in the Medicare population from 2006–2012. During this time period, off-label use increased from 45% to 51% of beneficiaries using second-generation antipsychotics, a 13% increase. This somewhat modest change belied the more dramatic shifts in the conditions associated with this off-label use: anxiety, hyperkinetic disorder, and drug and alcohol abuse saw swings of more than 100% in magnitude during this time. second-generation However, these changes in the associated indications did not necessarily reflect changes in the evidence base around the efficacy and safety of these drugs for off-label indications. For example, while the increase in the use of second-generation antipsychotics among beneficiaries diagnosed with anxiety disorder is consistent with the emerging evidence during this time, the similar growth in the use of these drugs among beneficiaries diagnosed with insomnia is not supported by evidence (11). One of the more notable surges in off-label use was the increasing prevalence in the use of second-generation antipsychotics among those with dementia, despite the black box warning from the FDA warning of increased mortality in elderly patients with dementia related-psychosis. These findings are consistent with those from studies evaluating second-generation antipsychotic usage in other populations, which generally find a lack of evidence supporting a large proportion of their use (7, 9).
A normative view of this increase in off-label use depends on the value that use is perceived to bring to patients, as well as its effect on broader utilization and cost outcomes. For example, an AHRQ review found evidence supporting the use of second-generation antipsychotics for hyperkinetic disorder, suggesting that this somewhat ‘sanctioned’ off-label use is beneficial to patients. What is less clear, however, is the relative value of using second-generation antipsychotics for treating anxiety compared with other, potentially less expensive or more efficacious traditional treatments, and thus this supporting evidence opens the door for further research as to the allocative efficiency of this use. On the other hand, there is a very different takeaway from the preponderance of second-generation antipsychotic users with insomnia, for which AHRQ concludes there is an absence of evidence; in this case, it speaks to a need to understand what, if anything, is driving the continued and intensified use of these drugs for these conditions. These sub-themes create ambiguity when interpreting the overall increase in off-label use during the time period of this study, while also raising further questions about whether this is a substantial or surprising increase given the patent expiration, and thus broader appeal, of many of these drugs that occurred during this time frame.
While the conditions associated with off-label use of second-generation antipsychotics changed during the period 2006–2012, the usage and cost patterns of off-label relative to on-label use were fairly consistent. It may not be surprising that off-label users have on average two fewer monthly fills per year than on-label users, on average, given that they may have less of a chronic need for an second-generation antipsychotic. Fewer fills not surprisingly translates to lower total costs for off-label users of second-generation antipsychotics, while the higher out-of-pocket costs may reflect the lower proportion of dual-eligibles among off-label users.
Another clear area for further study is the off-label use of second-generation antipsychotics among those without any of the common conditions associated with these drugs. This description characterized a significant proportion of the off-label users in this sample; while this type of usage declined by about one-third during the study period, it still represented almost 30% of off-label use as of 2012. This unexplained usage is concerning from both financial and clinical perspectives. Second-generation antipsychotics are significantly more expensive than their typical counterparts, which has led to measures such as prior authorization being applied in Medicaid. In addition, there are significant safety risks associated with the use of second-generation antipsychotics, suggesting that in the cost-effectiveness spectrum these drugs may be dominated by other therapeutic alternatives. This ongoing usage in the face of less expensive and/or more effective alternatives again speaks to the problem of intransigence of prescribing behaviors in the face of emerging evidence.
Our classification of drug use as on-label or off-label involved assumptions that serve as limitations of this study. We are unable to observe the true medical reason for prescribing of second-generation antipsychotics, and instead identify conditions associated with claims in the same calendar year as a prescription. This will mischaracterize second-generation antipsychotic use if, for example, a ‘true’ on-label user does not have any claims for bipolar disorder, schizophrenia or major depressive disorder in a calendar year. We attempted to reduce the likelihood of this misidentification by using the calendar year as our reference period. Furthermore, this analysis of all claims within a one-year time frame also complicates assigning off-label use to a specific diagnosis; we are limited to merely identifying the conditions that also appeared during that calendar year, but cannot make any more concrete link between drug use and a specific diagnosis. Finally, our conclusions about trends in the off-label use of second-generation antipsychotics are specific to the Medicare population, and may differ from patterns of use in the broader United States population.
It is difficult to say whether this approach over- or under-estimates the rate of off-label usage of second-generation antipsychotics in the Medicare population. Off-label usage will be overestimated if individuals with bipolar disorder, schizophrenia or major depressive disorder commonly go one year or longer without an inpatient stay or outpatient visit related to these conditions. On the other hand, it will be underestimated if individuals with on-label conditions use these drugs for other indications, or initiate their use for an off-label condition and are later diagnosed with an on-label condition later in the calendar year.
Conclusions
The advent of second-generation antipsychotics was intended to offer a safer, albeit more expensive alternative for the treatment of specific psychiatric disorders (13). Despite evidence and policy efforts to the contrary, these drugs have been used to treat a wide variety of conditions. From 2006–2012, the proportion of Medicare beneficiaries engaged in on-label use of second-generation antipsychotics declined slightly, as did the proportion of off-label users without any of the common off-label conditions. Nonetheless, given the significant proportion of users of second-generation antipsychotics without evidence of the approved conditions, and the known higher cost of these drugs, further investigation and policy action are warranted into the continued non-evidenced base use of this expensive and at times risky therapeutic option.
Acknowledgments
We acknowledge funding from the National Institute of Mental Health (Nos. R21 MH100721 and RC1 MH088510), the Commonwealth Foundation and Institute of Medicine.
Footnotes
Conflicts of interest and financial disclosure: None.
Contributor Information
Julia Driessen, Email: driessen@pitt.edu, University of Pittsburgh - Health Policy & Management, Pittsburgh, Pennsylvania.
Seo Hyon Baik, National Library of Medicine - Lister Hill National Center for Biomedical Communications, Bethesda, Maryland.
Yuting Zhang, University of Pittsburgh - Health Policy & Management, A653 Crabtree Hall 130 DeSoto Street, Pittsburgh, Pennsylvania 15261.
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