From 1995 to 2008, there was a pronounced shift in the use of atypical antipsychotic drugs. Based on nationally representative serial, cross-sectional data from U.S. outpatient physician practices, we found a 45% decrease in the proportion of use for schizophrenia, for which most drugs were initially labeled, and a nearly seven-fold increase in use for bipolar affective disorder, representing a third of all uses with atypical agents in 2008. Rates of atypical use for depression did not change substantially over the period examined. Significant divergence in the application of typical and atypical agents was evident, with the small residual use of typical agents concentrated in prescribing for schizophrenia.
Antipsychotic medications are one of the most common and costly classes of prescription drugs in the U.S. While their increasing use has been widely reported, far less is known regarding the evolution of their clinical uses. While others have noted the shift towards antipsychotic use for mood disorders (19
), our report reinforces the magnitude of this shift using with national U.S. data collected over an extended observation period with clinician-reported diagnoses.
Previous studies have demonstrated a substantial replacement of typical antipsychotics with their newer counterparts following the market release of the first atypical agent in 1989. This increase has occurred despite a lack of definitive advantages of the atypical agents over their typical predecessors in their efficacy and adverse effect profiles. Recent trials (22
) failing to demonstrate clinically significant differences in the effectiveness of these two classes in schizophrenia raise the question of whether typical antipsychotics should be reconsidered as a first line therapy, given that the superiority of atypical agents has yet to be established. Such a shift in practice, however, is unlikely given the potency of a variety of non-clinical factors that shape prescribing, including clinical inertia and the continued marketing of atypical agents. This is especially important given the small share of all antipsychotic use accounted for by typical agents, as well as the divergence in the use of typical and atypical antipsychotic medications.
Prescription drugs vary in their clinical and biochemical innovation, and in many cases important discoveries regarding therapies are made only after market release, often to treat conditions distinct from those initially targeted. The effectiveness of selective serotonin reuptake inhibitors (SSRIs) to treat anxiety, and the use of angiotensin converting enzyme-inhibitors (ACE inhibitors) in congestive heart failure, are but two examples where drugs approved for one use were subsequently found to have other important clinical applications. Although typical and atypical antipsychotics were not initially developed for use in bipolar affective disorder, subsequent evidence suggests their efficacy in treating mania associated with this disease (24
). While increasing antipsychotic use since 1995 reflects clinical innovation and other factors, it has led to clinical use where regulatory scrutiny has not occurred and where the supporting evidence is less certain.
Innovation in clinical practice necessarily involves the use of therapies that are not well studied. When the application of therapies for new and largely untested clinical indications reaches a substantial volume, however, there should be a corresponding obligation to generate evidence that demonstrates the safety and efficacy of the new uses. This is especially important in clinical settings where alternatives to the innovative therapies are already available, as with mood stabilizers (e.g., divalproex) for bipolar affective disorder and antidepressants (e.g., selective serotonin reuptake inhibitors) for the treatment of depression. Further scrutiny of widespread psychotropic medication use for scientifically unsupported off-label indications is needed, especially among those patient subpopulations and clinical applications where such uses are most common.
Our study has several important limitations. First, because the NDTI is a visit-based sample of outpatient office practices, it oversamples those with greater comorbid illness compared with population-based samples. Nevertheless, visit-based samples are commonly used for this type of analysis, and the NDTI provides data congruent with the National Ambulatory Medical Care Survey conducted by the U.S. government (14
). Second, as with many other data sources, NDTI lacks information that would be useful in understanding the choice of off-label use, such as data regarding patient non-response to FDA approved therapies and detailed comorbid histories. Third, since there is no single source that includes summary information on drug safety and effectiveness, drug compendia vary in their assessments of the levels of evidence supporting different clinical applications (25
). Despite its limitations, Drugdex® serves as a key source of information that is updated regularly, commonly used in clinical practice, and recognized in U.S. reimbursement regulations, including Medicaid evaluation of coverage for off-label uses (26
). As with any method of determining levels of evidence, our estimates are subject to imprecision due to these limitations of drug compendium data and NDTI's sparse clinical detail. Even if significant misclassification were to have occurred, however, our results would still suggest a substantial exposure to therapies for clinical indications that have not received regulatory scrutiny and where the evidence base is uncertain. If only 30% of all atypical uses in 2008 were to have uncertain evidence (a conservative estimate compared with our derived estimate of 54%), this would translate into an estimated 3.8 M prescriptions at a cost of $3.0 billion.
Antipsychotic medications have important known benefits and risks. Our data suggest substantial growth of atypical antipsychotics beyond their substitution for older, typical antipsychotics. Patterns of clinical use have diverged for typical and atypical agents. The use of typical agents has declined, but continues predominantly for schizophrenia. In contrast, atypical agent use has dramatically increased, both substituting for typical agents and expanding into new indications, such as bipolar disorder and depression. Despite the value of innovation, expansion of clinical practice beyond FDA approved indications raises significant concerns. Further expansion of atypical antipsychotics should be approached with caution while awaiting new evidence evaluating their comparative benefits. This information is important not only for non-elderly adults who comprise the majority of atypical use, but also for children and the elderly, vulnerable populations where increasing rates of atypical use are also noted.