There are several broad limitations of our methodology for describing all-causes discontinuation. For example, it might be expected that discontinuation rates would increase in proportion to the duration of the trial (i.e., higher all-causes discontinuation rates would be expected in longer trials), although, interestingly, this was not the case for the trials of long-acting injectable risperidone. However, in general, the small number of studies limited the ability to analyze for such a trend. Furthermore, it was also not possible to control for factors such as the number of trials for each SGA, patient demographics, study design (randomized versus open-label), medication dose (flexible versus fixed), and the option to switch medications. Thus, our findings should be interpreted with caution in light of study heterogeneity. Despite these inherent limitations, even this "crude" estimate provides useful information, and it is reassuring that our result is consistent with the prevalence reported in our previous review (40.8%)5)
as well as in the EUFEST study (42%),3)
which was a longer trial (52 weeks) than the mean duration in this report (35.1 weeks).
Furthermore, for the studies of long-acting injectable risperidone, subjects were treated with oral SGAs for one to twelve weeks prior to study entry. For example, in the study by Kim et al.,17)
participants were stable on oral SGAs for 4 weeks prior to the baseline visit. Similarly, in the PREvent First Episode Relapse (PREFER) trial by Weiden et al.,18)
subjects were treated for up to twelve weeks prior to randomization. Subjects randomized to long-acting injectable risperidone in this trial were given this recommendation in the context of a two-session psychoeducational intervention tailored to patients with FEP and their families. Thus, the potential for selection bias-towards patients who were both early responders to SGAs and better engaged in treatment-may have contributed to the lower all-causes discontinuation rate for this agent.
Although aripiprazole had the lowest all-causes discontinuation rate of all agents studied, we note the limitation that this finding was based on one small trial of relatively short duration.15)
Thus, future studies are needed to replicate this observation.
The all-causes discontinuation rates for oral risperidone (24.5%) and olanzapine (20.5%) were similar to each other, and these two SGAs also had similar discontinuation rates in our previous study.5)
All-causes discontinuation rates for oral risperidone and olanzapine were lower than those for amisulpiride (30.8%) and ziprasidone (37.8) from the EUFEST trial.3)
The TMAP notes that dosing for ziprasidone has not been systematically studied in FEP. The mean dose of ziprasidone in the EUFEST study was 107.2 mg/day. One possible explanation for the relatively higher discontinuation rate for ziprasidone is that higher dosing is required in FEP.
Quetiapine had the highest all-causes discontinuation rate in both studies. Of note, both TMAP and PORT recommended higher doses of quetiapine (up to 500-600 mg/day) relative to doses of other SGAs. However, the mean dose of quetiapine in the four trials reviewed here was 400 mg/day. For example, Berger et al.11)
compared quetiapine 200 versus 400 mg/day in a fixed dose trial. Patients randomized to the lower (200 mg/day) dose were more likely to discontinue study medication due to both lack of efficacy and medication nonadherence (for which lack of efficacy may have also been a contributing factor). Thus, under-dosing of quetiapine may have contributed to the higher all-causes discontinuation rate for this agent.