anticholinergics antagonize antipsychotic

The first point raised by Singh and Kay (1978) in their rejoinder to Meltzer and Stahl's (1976) criticisms of studies (Singh and Kay 1975a, 19756, and 1975c and Singh and Smith 1973) purporting to demonstrate that anticholinergics antagonize the therapeutic effects of chlorpromazine more so than haloperidol is as follows. They maintain that the suggestion by Meltzer and Stahl of a repeated measures design "violate^] the dictum against applying a treatmentby-subjects analysis where carryover effects may be expected across different treatment conditions" (p. 3) and would test an inapplicable null hypothesis, i.e. that some change would take place over the three treatment periods: neuroleptics alone (period 1), neuroleptics plus anticholinergics (period 2), and neuroleptics alone (period 3). We would suggest their criticism missed the implicit but, to us, obvious point that we were proposing the use of post-hoc tests that would permit a comparison of period 1 vs. period 2, period 2 vs. period 3, and period 1 vs. period 3. The repeated measures design would be applicable to either a two-group or singlegroup study, but we will explain this approach by suggesting how it could have been used in the twogroup study. First, it is necessary to briefly review the single-group research design of Singh and Kay (1975c). A crossover design was used in this study; subjects received 4 weeks of placebo, then 6 weeks on haloperidol or chlorpromazine, followed by 2 weeks of placebo with subsequent crossover to the other neuroleptic for 6 weeks, and finally 2 weeks of neuroleptic of choice. Three 2-week courses of benztropine were given—one in the last 2 weeks of the baseline placebo period and one each in the middle 2 weeks of the two 6-week neuroleptic periods. Combined preand postbenztropine periods vs. neuroleptic alone were used to test for therapeutic reversal by benztropine. Ratings from the first and fifth weeks of treatment with each neuroleptic were used to compare clinical effects of haloperidol and chlorpromazine alone. The clinical rating data were then analyzed by multiple correlated t tests. We suggest that a split-plot, repeated measures ANOVA, as described by Kirk (1968, pp. 245-318) would have offered a more stringent test of the basic anticholinergic therapeutic reversal hypothesis as well as a number of their subsidiary conclusions, e.g., that haloperidol is superior to chlorpromazine. Table 1 outlines the two groups and study periods in our design and provides numbers for each group which will aid our discussion. This split-plot ANOVA design incorporates two independent groups of subjects which differ only in one treatment—the neuroleptic they receive (chlorpromazine or haloperidol). The use of this design allows a test of the following effects simultaneously. First, any differential effect due to chlorpromazine or haloperidol would be exhibited by a significant F ratio for an interaction effect or a main drug effect (chlorpromazine vs. haloperidol). If a significant F ratio for the interaction effect is obtained, then tests for simple main effects are conducted to determine if the anticholinergics, for instance, had a greater impact during the period of chlorpromazine administration than during haloperidol administration. A test for this effect is especially necessary since Singh and Kay (1975a) found a differential effect (chlorpromazine vs. haloperidol) on behavioral responses when anticholinergics were introduced. A significant interaction effect would allow a posteriori tests to be performed between the means (Xi4 vs. XJJ) to compare the effects of benztropine plus each neuroleptic. The effects of the neuroleptics independent of benztropine at different time periods^ could be assessed by comparing Xn vs. "Kn and Xu vs. Xu. Secondly, this design would permit tests for main effects if an interaction F ratio was not significant, but main effect F ratios were. This would allow a posteriori comparisons to be made between the placebo plus benztropine condition (Xi.2) or the neuroleptic plus benztropine condition (X.4) with the appropriate nonbenztropine conditions (i.e., X.I or X.3, X.5). A posteriori tests such as Tukey's HSD test or Scheffe's ratio enable the researcher to make all planned comparisons among means and splits up the level of significance