Selecting comparable doses of antipsychotic medications is an important challenge in the design of clinical trials. Ideally, studies that compare efficacy and side effects of two or more drugs should be based on some objective measure of the “best dose” so that drugs can be compared on a “level playing field.” This requires creating an empiric quantitative metric that can be used to make doses equivalent, and yet no such metric exists. Furthermore, because schizophrenia is usually a chronic illness, many patients are maintained on antipsychotic medications for long periods. A quantitative measure of the amount of medication exposure over long time durations is also useful to address a variety of other research questions, such as the relationship between long-term treatment and medication side effects (e.g., tardive dyskinesia). Previously, we developed a method to quantify cumulative antipsychotic drug exposure through calculation of dose-years (1
). A dose-year is defined as the product of the dose of a particular antipsychotic (converted into equivalents of a “standard” medication such as chlorpromazine or haloperidol) and the time on that dose expressed in years. This concept is akin to “pack-years,” in which lifetime exposure to smoking is calculated by multiplying the packs of cigarettes smoked per day by the years spent smoking.
The first step in meeting the dual goals of choosing comparable doses for clinical trials and measuring long-term drug exposure is to develop a method for determining dose equivalents. A traditional approach has been to use the concept of chlorpromazine equivalents. The earliest method for determining equivalents, developed by Davis, was based on double-blind studies reported in the literature that used chlorpromazine as the comparator; this method provided data about comparable doses chosen by clinicians to achieve a therapeutic effect and identified dose ratios in relation to 100 mg of chlorpromazine (3
). Using this method, haloperidol, for example, was found to have a ratio of 1.6 (SEM .4). As “second-generation” or “atypical” antipsychotics became available, however, a need arose to determine chlorpromazine equivalents for these as well. Woods (4
) developed equivalents for the newer antipsychotics using minimum effective dose data drawn from fixed-dose placebo-controlled trials conducted in drug development programs.
Defining equivalents on the basis of clinical trials has a variety of limitations, however. Most clinical trials recruit relatively chronic patients, and therefore they do not necessarily generalize more broadly to community or acute treatment settings. Furthermore, as Woods reported, only a few studies were available to derive most of his data; additionally, in most cases, the identified studies were early studies that might have reflected different dosing from what has become more common in current clinical practice.
Using expert clinical consensus concerning dose equivalence offers an alternative approach that may be more valid. In 2003, Kane et al.
) conducted a survey of experts to address questions concerning “medication selection, dosing and dose equivalence, and the management of inadequate response, compliance problems, and relapse.” Their survey included 60 questions and 994 options, which were sent to 50 national experts on pharmacologic treatment of psychotic disorders; 47 (94%) completed it. Guidelines derived from this survey were published as the “Expert Consensus Guideline Series. Optimizing Pharmacologic Treatment of Psychotic Disorders” (5
). Guideline 5A consists of a table comparing several antipsychotic medication doses to their equivalent haloperidol doses. To determine these comparisons, mean and standard deviations of survey responses were used “to generate real-world doses rounded to currently available pill strengths.” Guideline 5B used the same approach to define equivalent doses of risperidone. The authors noted that the responses “followed a very linear pattern” and proposed “it would probably be possible to use linear formulas to calculate dose equivalency.”
Therefore, in developing an up-to-date and optimally accurate measure of dose equivalents and lifetime antipsychotic exposure expressed as dose years, we chose to use the charts from these guidelines. These doses were used to derive new chlorpromazine equivalency values for antipsychotic medications in our dose-year calculations. However, because many clinicians no longer use chlorpromazine and are unfamiliar with its dosing strategies, we also derived haloperidol equivalents. In addition, in the process we went further to develop a new and more direct way to calculate a standard drug comparator equivalency by using regression equations. This approach has several advantages that enhance validity. First, it is empirically and statistically based. Second, it is based on evaluations from 47 experts; this is a far larger number of evaluations than have been used in other efforts to identify dose equivalents, and it therefore contributes maximal variance and enhances generalizability across diverse populations of patients, ranging from acute to chronic.