Baseline evaluation was completed on 619 subjects. Of these, 195 met criteria for persistent TD at baseline (estimated prevalence 31.5%, 95% CI 27.9 to 35.3%) and were ineligible for the incidence analysis. In addition, 23 subjects with negative baseline TD examinations were also not eligible for the incidence sample because of previous Glazer-Morgenstern TD diagnoses. The remaining 401 subjects were free of TD at baseline, of whom 352 were re-examined at least once during follow-up (the study population). Demographic, diagnostic, and treatment characteristics of the study population are shown in . Female gender and longer histories of conventional exposure were more common among subjects receiving conventional antipsychotics at baseline, and histories of atypical exposure were less common in this group. Most of the 352 subjects qualified as at-risk by virtue of both negative clinical histories and negative initial research examinations (81%). The remainder had no clinical history but a positive research examination that was negative on repeat (3%) or a positive clinical history but negative baseline research examination (17%). The distribution of conventional medications at baseline is shown in .
Demographic, diagnostic, and treatment findings by antipsychotic type at baseline.
At-risk individuals underwent 1344 follow-up examinations. There were 52 new persistent cases of TD detected during 783 person-years of follow-up, yielding an average incidence rate of 0.066/year. TD risk (cumulative incidence) after 3.9 years of follow-up was 19.7% (95% CI 15.2 to 25.1%). The average of the four total AIMS scores leading to TD diagnosis in the 52 incident cases was 4.8 (range 3.0 to 8.2).
Estimated Effects of Recent Antipsychotic Type on New Occurrence of TD
Crude analyses revealed that patients receiving conventional antipsychotic alone since the prior visit developed new-onset TD at a rate of 5.6 per 100 patient-years of exposure (8 cases per 141.8 patient-years, 0.056/year), patients receiving atypical antipsychotic alone developed TD at a rate of 0.059/year (28 cases per 475.2 patient-years), and patients receiving both types since the prior visit developed TD at a rate of 0.096/year (16 cases in 166.0 patient-years). Based on crude (unadjusted) analyses, subjects treated with atypical antipsychotics alone since the prior visit developed TD at a similar rate as subjects treated with conventionals alone (crude RR=1.04; 95% CI 0.50 to 2.22). Subjects treated with both types of antipsychotic since the prior visit developed TD at a somewhat higher rate as subjects treated with conventionals alone (crude RR=1.71; 95% CI 0.77 to 3.82).
Based on adjusted results from our core model, subjects treated with atypical antipsychotics alone since the prior visit developed TD at approximately two-thirds the rate as subjects treated with conventionals alone (adjusted RR=0.68; 95% CI 0.29 to 1.64). Subjects treated with both types of antipsychotic since the prior visit developed TD at nearly double the rate as subjects treated with conventionals alone (adjusted RR=1.85; 95% CI 0.72 to 4.75).
Logistic regression models on new TD present at any time during follow-up were also fitted by baseline medication status, employing as a covariate only years of total prior antipsychotic exposure or years of total prior conventional exposure, each expressed as a continuous measure. These analyses produced findings comparable to those of the unadjusted cox regressions: a similar proportion of subjects treated with atypical antipsychotics alone at baseline developed TD as subjects treated with conventionals alone (adjusted RR=1.00, 95% CI 0.48 to 2.08 and 0.94, 95% CI 0.44 to 2.03) and a somewhat higher proportion of subjects treated with both types of antipsychotic at baseline developed TD as subjects treated with conventionals alone (adjusted RR=1.36, 95% CI 0.52 to 3.52 and 1.31, 95% CI 0.50 to 3.41).
AIMS total scores were slightly lower among incident cases appearing after recent atypical only exposure than recent conventional only exposure (mean difference −0.5, 95% CI -1.7 to 0.8). Analyses employing single-visit Glazer-Morgenstern criteria or consecutive-visit Schooler-Kane criteria as alternate definitions of incident caseness produced adjusted RR estimates similar to those for the primary analysis (0.69, 95% CI 0.35 to 1.36 and 0.56, 95% CI 0.21 to 1.48, respectively).
These analyses included clozapine-treated cases in the atypical antipsychotic group, our original intention. Crude analyses showed that 7 incident TD cases occurred among 55 at-risk subjects receiving clozapine who were followed an average of 17.8 months (81.6 person-years, crude TD rate 0.086/year). These results include 5 incident TD cases occurred among 23 at-risk subjects receiving clozapine as their sole antipsychotic followed an average of 23.2 months (44.4 person-years, crude TD rate 0.111/year). Because crude TD rates among clozapine-treated at-risk cases were unexpectedly high, clozapine-treated cases were removed into a separate category. These analyses are shown in .
Crude (unadjusted) and adjusted estimated effects (rate-ratio, RR; and 95% CI) of antipsychotic type and other covariates in the core model on the incidence rate of persistent tardive dyskinesia.
Based on adjusted results from the core model, subjects treated with atypical antipsychotics alone (excluding clozapine) since the prior visit developed TD at slightly over half the rate as subjects treated with conventionals alone (adjusted RR=0.55, 95% CI 0.23 to 1.36). The adjusted RR for combined AT and CV antipsychotics (excluding clozapine) was 2.21 (95% CI 0.85 to 5.80).
Based on adjusted results, the TD incidence rate was also associated with age and years of previous conventional antipsychotic use (). Being African American was only weakly associated with TD, and the association with recent antipsychotic dose was not monotonic. None of the remaining planned covariates appear to have appreciably confounded individual antipsychotic effects.
The adjusted RR for atypicals vs conventionals (0.55) was lower than the crude RR (0.94) in due to apparent confounding by years of conventional antipsychotic exposure. Subjects receiving atypicals had shorter durations of prior (TD-free) conventional exposure than subjects receiving conventionals (), and shorter durations of prior TD-free
conventional exposure were associated with a higher rate of TD (), as in our prior report.4
Thus adjusting for this confounder lowered the RR for atypicals. When this variable was omitted from the core model, the otherwise-adjusted RR for atypical antipsychotic was very similar to the unadjusted RR. The relative effect of atypicals vs conventionals did not appear confounded by years of previous lifetime atypical exposure when this variable was added to the model. None of the remaining planned covariates, including gender, appreciably changed antipsychotic effects on TD incidence after adjustment for core model variables.
The overall modest advantage of atypical antipsychotics (excluding clozapine) since the prior visit on TD incidence was stronger among affective disorder subjects (RR=0.15, 95% CI 0.03 to 0.71) than among schizophrenia subjects (RR=0.97, 95% CI 0.31 to 3.04, p for interaction term 0.050). The stronger advantage among affective patients appeared partly due to lower risk among affective patients exposed to atypicals (crude rate 0.028/year, 4 cases in 142.5 person-years) and partly due to higher risk among affective patients exposed to conventionals (crude rate 0.100/year, 3 cases in 29.9 person-years). None of the remaining variables appreciably modified the estimated atypical antipsychotic effect on TD incidence.
Results for individual atypical antipsychotics are shown in . Estimates were imprecise in this analysis, since fewer subjects had received one atypical only for the entire time since the prior visit.
Estimated crude and adjusted rate-ratio (RR, 95% CI) for tardive dyskinesia comparing each atypical antipsychotic with conventional antipsychotic since the prior visit.
Estimated Effects of Duration of Antipsychotic Use by Type
Only 26 subjects were naïve to conventional exposure over their lifetimes. Among these, two incident cases of persistent TD appeared during 51.3 years of atypical exposure (crude rate 0.039/year). Comparing that rate to the crude rate for conventionals only yields a crude rate-ratio of 0.69 (95% CI 0.15 to 3.25).
Models focusing on lifetime duration of antipsychotic use at the current visit by drug type revealed estimated antipsychotic effects similar to those from the recent exposure analyses (available on request from SWW).
Loss to Follow-Up
Among 401 TD-free subjects enrolled, 49 (12%) were never re-examined and 133 (33%) withdrew sometime later during follow-up before developing TD. Analyses omitting the partial data for dropouts produced results that were not appreciably different from the primary analysis.
We identified nine previous studies in adult patients that reported TD incidence with atypical compared to conventional antipsychotics.33–41
shows the mean age, design, TD acquisition methods, baseline TD prevalence, average antipsychotic doses, incident cases, mean follow-up time, patient-years of exposure, annual incidences, and the atypical/conventional RRs and 95% CIs for each study, as well as for the nine studies taken together and the present study. The 7 randomized and 2 cohort studies together reported 123 incident cases of TD among 2287 patient years of conventional antipsychotic exposure (0.085/year) and 247 incident cases of TD among 12,018 patient years of atypical antipsychotic exposure (0.031/year, RR 0.24, 95% CI 0.12 to 0.48). About three-quarters of the exposure time was accounted for by the two large cohort studies.37, 38
The present study reports on more atypical antipsychotic exposure time than any of the previous studies except the two previous cohort studies and one of the seven randomized studies.36
Average length of follow-up in the previous studies was about one-third that for the present study.
Previous studies comparing newly identified tardive dyskinesia in atypical- and conventional-treated groups, compared to current study.