The first antipsychotic medication, chlorpromazine, was introduced in 1954. A major side effect of this and other “first-generation” drugs was the development of extrapyramidal symptoms, including several serious movement disorders such as tardive dyskinesia. In 1990, the Food and Drug Administration (FDA) approved clozapine for a limited set of indications (limited because of the risk of serious, life-threatening side effects), ushering in the second generation of antipsychotic medications. The fundamental clinical difference between the first- and second-generation antipsychotics was the lower risk of extrapyramidal symptoms in the latter. The second-generation medications came to be known as “atypical” antipsychotics. The mechanism of action for these agents and the reasons for individual differences in response are still not completely understood.
The introduction of the atypical antipsychotics was heralded by the medical industry and others as the first breakthrough in the treatment of schizophrenia in nearly 40 years, and their use increased rapidly. Many prescribers came to believe that these medications had cognitive-enhancing properties and were effective in controlling positive, negative, and mood symptoms. In addition, they had enhanced tolerability (Lewis and Lieberman 2008). Prescribing practice prior to the CATIE trial may also have been influenced by treatment guidelines and performance measures that emphasized the superiority of the atypical antipsychotics (Owens 2008). For example, one of the performance indicators within the Substance Abuse and Mental Health Services Administration’s (SAMHSA’s) Uniform Reporting System was a measure of the rate at which second-generation antipsychotics were prescribed (Covell, Finnerty, et al., 2008).
In 2003, the results of two key studies called into question beliefs about the superiority of the atypical antipsychotics. The first was a trial funded by the Department of Veterans Affairs (VA) health system that compared a first-generation and a second-generation antipsychotic medication and found that they had comparable efficacy and risk of extrapyramidal symptoms and their use resulted in comparable quality of life (Rosenheck, Perlick, et al., 2003). A meta-analysis published the same year showed that optimal dosing for conventional antipsychotics might avoid the high rates of extrapyramidal symptoms typically seen with first-generation medications (Leucht, Wahlbeck, et al., 2003). Neither of these studies caused the psychiatric community (except for a few dissenters) to doubt the superiority of second-generation medications. However, the VA study did highlight the risk of metabolic side effects from them, and these concerns quickly gained recognition by many physicians. According to one discussant, the pharmaceutical industry had attempted to suppress information on the metabolic side effects of second-generation medications.
In addition, insurers were becoming concerned about the cost of atypical antipsychotics, which constituted a significant share of the total pharmaceutical expenditures of Medicaid budgets in many states (Parks, Radke, et al., 2008). Advocates for parity in mental health insurance coverage worried that questions about the effectiveness or side effects of atypical antipsychotics might be seized upon by insurers to curtail access to them for a population that was already struggling to obtain adequate coverage and access to therapy.