Status Quo Bias Resulting from Consistently Positive Messaging
Psychiatrist discussants indicated that at the time of the CATIE trial, the belief in the superiority of atypicals was nearly universal, for at least four reasons. First, the majority of trials preceding CATIE were funded by the pharmaceutical industry, and they consistently concluded that second-generation antipsychotics were superior. It was only following CATIE that critiques of these trials emerged in the peer-reviewed literature. Experts highlighted the fact that first-generation comparators were used at high doses, often without adjuvant therapies designed to control extrapyramidal side effects; statistical analyses used inferior methods; and superiority claims were often based on statistical significance rather than clinical significance (Carpenter and Buchanan, 2008). Second, industry detailers were highly effective in disseminating early findings that supported atypical antipsychotics and motivating their widespread use in the years preceding CATIE. The labeling as second-generation medications implied that they offered an improvement over first-generation medications. As one discussant noted, “We didn’t call beta-blockers second-generation antihypertensives.” When CATIE’s findings were released, there was a “significant effort [by industry detailers] to counter-detail the trial’s findings” according to one discussant. Third, key thought leaders, many of whom had received industry funding, reinforced these messages within both the academic community and the larger provider community. Fourth, medical education may have helped to promote the use of atypicals over first-generation medications. The consistently positive messaging about the superiority of second-generation medications raised expectations about them (particularly since there had been few advances in antipsychotic therapy over the previous several decades) and appears to have prompted many psychiatrists to view the unexpected results from CATIE with skepticism. Widespread belief about the status quo (i.e., the effectiveness of atypical antipsychotics) appears to have been one of the strongest barriers to changing prescribing practices.
Criticism of the Study Design
Possible weaknesses in CATIE’s design and its potentially limited generalizability were widely debated in the peer-reviewed literature. While many experts defended the trial, the funder (NIMH) did not participate directly in these exchanges. Three points were frequently raised. First, there were concerns that medication doses were not equivalent across treatment groups (Dettling and Anghelescu, 2006), and in some cases, the doses used were not those in standard practice. For example, olanzapine doses were higher than average, while doses of risperidone and ziprasidone were lower. Second, patients with tardive dyskinesia were excluded from receiving perphenazine, and this caused many psychiatrists to criticize the common interpretation of the trial results—i.e., that first- and second-generation medications are equivalent—because it seriously downplayed the risks of tardive dyskinesia for patients taking perphenazine. Third, some experts argued that longer-term follow-up data were needed and that the 18-month study design did not answer key long-term questions, in particular, whether the incidence of tardive dyskinesia and diabetes differed across classes. Many stakeholders felt that these critiques were intended to draw attention away from the main results of the trial, and subsequent empirical studies debunked many of them. The consensus among our discussants was that the critiques were unlikely to have affected the decisionmaking of the average physician.
Prior Experience with Tardive Dyskinesia
Psychiatrists with prior experience managing the adverse effects of first-generation medications, particularly tardive dyskinesia, may have been less likely to embrace CATIE’s findings. Physician discussants impressed upon us how debilitating and potentially irreversible this side effect can be. One physician commented, “It’s a reality for those of us who grew up in that era and had severe experiences with first-generation drugs. . . . You would try to get the patient down on the lowest dose [possible] . . . to control their psychosis.” In the past, before psychiatrists ever initiated therapy using first-generation medications, they would have to warn patients about these side effects in writing in order to protect themselves from malpractice lawsuits. Tardive dyskinesia may therefore remain a key concern for many in the psychiatric community, and CATIE did not directly address this issue, since patients with tardive dyskinesia were excluded from receiving perphenazine.
Lack of Positive Messaging from Professional Societies About Changing Practice
Discussants indicated that one of the chief concerns of the American Psychiatric Association (APA), the largest professional society of psychiatrists, was the preservation of physician autonomy—potentially motivated by the historic lack of insurance coverage for mental health services (an issue that has only begun to be addressed in recent years). Lack of parity between mental and nonmental healthcare coverage was mainly attributable to the limited evidence base in psychiatry. One common interpretation of CATIE’s results was that neither first- nor second-generation antipsychotics were effective, and psychiatrists might have perceived this interpretation as a threat to their autonomy if the results were to be used by payers and purchasers to limit access to certain medications. The APA argued that antipsychotics were not interchangeable and that an individualized treatment approach was appropriate, which implied unlimited access to these medications despite their higher costs (Duckworth and Fitzpatrick, 2008).
Limited Impact of Changes to Guidelines
In 2009, the APA published a Guideline Watch, which updated its pre-CATIE guidelines. It stated that the “distinction between first- and second-generation antipsychotics appears to have limited clinical utility” (Dixon, Perkins, et al., 2009). The new guidelines also recommended the use of low-dose medications when first-generation agents were selected. This change was a watershed in that it was the first instance of APA guidelines explicitly stating that, as a group, second-generation medications offered no advantages over first-generation medications. This contrasts with the Schizophrenia Patient Outcomes Research Team (PORT) guidelines, which consistently acknowledged the relative equivalence of first- and second-generation medications despite the fact that it was an unpopular view within the community (Buchanan, Kreyenbuhl, et al., 2010). Neither of these guidelines appears to have had a substantial impact on clinical practice.
Limited Leverage of Payers
Given the cost differential between first- and second-generation antipsychotics, one might have expected payers to modify prescribing formularies or introduce other restrictions on the use of the latter, but public payers did not adopt stricter formularies following the trial, causing some researchers to lament that state Medicaid agencies have been “largely silent” following the release of CATIE’s results (Rosenheck, Leslie, et al., 2008). One discussant referred to the failure by payers to more actively encourage use of first-generation medications as a “lost opportunity.” A total of 21 states had introduced prior authorization programs for one or more atypicals at the time CATIE began, but only four more did so by June 2006 (Polinski, Wang, et al., 2007).
In general, payers run the risk of being shamed by advocacy organizations when they attempt to implement policies that restrict access to medications. In their messaging, advocacy groups have stressed the vulnerability of patients and their extreme price-sensitivity. Following CATIE, some experts advocated step therapy—starting initial treatment with equivalent but less-expensive drugs—with prior authorization for any deviation (Rosenheck and Sernyak, 2009), while others argued against it citing the risks of homicides or suicides as potential unintended consequences of treatment failure for this population. There is little empirical evidence about the impact of step therapy on health outcomes for patients with schizophrenia. Many payers may view formulary policy as the “third rail” of state Medicaid policy and avoid using it as a potential policy lever (Rosenheck, Leslie, et al., 2008).
While step-therapy programs might have saved states considerable sums of money, Medicaid programs have typically relied on bulk purchasing with the use of preferred drug lists as a way to control their pharmacy budgets. A discussant from an advocacy organization noted that the National Association of State Mental Health Policy Directors successfully disseminated a preferred drug list template for antipsychotics that promoted access to different types of second-generation antipsychotics because of their distinct side-effect profiles as demonstrated in CATIE. While we do not know the impact of this template, it may have preserved relatively open access to second-generation medications in many states. Private payers, particularly small payers, may have had some success in implementing step therapy, according to one government expert.
Quality Measures Favored Second-Generation Antipsychotics
Prior to the release of CATIE, SAMHSA used a performance indicator as part of its reporting requirements. The measure appears to have assessed the rate at which second-generation medications were prescribed (Covell, Finnerty, et al., 2008) and continued to be used in the years following CATIE.