Two common clinical questions regarding the initiation dosing of paliperidone palmitate, specifically the time to onset of efficacy and the associated tolerability, were addressed in these post-hoc analyses of a large, double-blind, placebo-controlled trial. The question of when clinicians and patients can anticipate an improvement in symptoms is integral to clinical decision-making, particularly when managing a symptomatic patient with schizophrenia and planning a treatment strategy. While some clinicians may prefer to initiate paliperidone palmitate at a lower than the recommended initiation regimen due to tolerability concerns, previously published data suggest this may result in sub-therapeutic plasma levels and poor longer-term clinical response in some patients [9
]. Thus, data were presented in this report for the early days and weeks following the initiation regimen to examine the efficacy and tolerability of the recommended initiation doses for paliperidone palmitate.
Findings showed significantly greater symptom improvement by Day 8 with paliperidone palmitate (234 mg on Day 1) compared to placebo, without oral antipsychotic supplementation, with this effect maintained after the 156 mg injections through Day 64, as well as at study endpoint [14
]. When looking across the treatment arms, a trend towards a dose-dependent response was observed during the first 36 days of this study, again consistent with the data reported through study endpoint [14
]. Also of note, the effect size vs. placebo for PANSS data illustrate an increasing improvement over time with the 156 mg dose (0.30, 0.43, 0.42, and 0.49 at Days 22, 36, 64, and endpoint, respectively), and the 234 mg dose (0.41, 0.40, 0.48, and 0.55, respectively). The 39 mg arm had lower and relatively constant effect sizes from Day 22 through endpoint (0.27, 0.28, 0.26, and 0.28, respectively). The early reduction in mean PANSS score shown here is supported by that from a non-inferiority trial [15
], where PANSS improvement was similar at the Day 4 timepoint for subjects receiving an initial injection of paliperidone palmitate at 234 mg compared to oral risperidone given at 1 to 6 mg per day.
The clinical improvement observed with the initiation doses of paliperidone palmitate in this study is supported by the attainment of therapeutic serum concentrations of paliperidone reported in clinical and pharmacokinetic modeling analyses [7
]. Following a single intramuscular dose, the release of paliperidone into the systemic circulation occurs as early as Day 1, with a gradual rise to reach maximum plasma concentrations at a median of 13 days [6
]. The two initial doses of paliperidone palmitate (234 mg Day 1/156 mg Day 8) into the deltoid help attain therapeutic concentrations rapidly, with the AUC profiles being dose proportional over the 39 to 234 mg dose range [6
]. In studies that used lower doses of paliperidone palmitate and initiation dose administration into the gluteal muscle, an onset of efficacy by Day 8 was not consistently observed [9
With respect to tolerability concerns with the recommended paliperidone palmitate initiation dosing, this study did not reveal unexpected adverse events or high rates of specific adverse events in the first week or subsequent month after the initiation injections. In addition, overall treatment discontinuations and discontinuations due to adverse events were generally low during this time. However, these are data from a single clinical study. Further, the relative risk analysis requires comment. This analysis was undertaken with the intent of providing a useful way identifying adverse events that may be more likely to occur with active treatment as compared with placebo. Findings were that events such as agitation, anxiety, dizziness, headache, injection site pain, and psychotic disorder had a relative risk ranging from approximately 1.1 to 2.5 during the first month of treatment. Although these relative risks were not statistically significant, as determined by the 95% CIs, they may be clinically relevant providing useful information for clinicians to consider when initiating treatment with paliperidone palmitate. Additionally, it must be noted that the analysis of this relatively small database is not sufficient to identify rare treatment-related events.
Extrapyramidal symptoms such as parkinsonism, akathisia, dyskinesia, and dystonia are also an area of concern with respect to the tolerability of an antipsychotic regimen. Substantial literature supports that the incidence of these events as well as the time of onset differ substantially [16
]. In terms of onset, dystonic reactions and akathisia generally occur within the first few hours to days of treatment while parkinsonism occurs within the first few weeks and tardive dyskinesia or dystonia generally appearing after months or years of treatment [16
]. Broadly speaking the risk for extrapyramidal symptoms is generally considered to be lower with atypical compared with typical antipsychotics--however, the risk for these events varies among the agents in each class. Within the atypical class of agents the risk for extrapyramidal events is often dose-related [16
]. In this analysis, the incidence of extrapyramidal symptoms was less than 2%, with akathisia being the only extrapyramidal symptom having an incidence of > 2% (2.5%) during Days 8 to 36 at the highest dose of paliperidone palmitate (234 mg).
One must also consider that this study was not designed to assess onset of efficacy or the tolerability associated with the initiation regimen. Therefore, these findings are somewhat limited by the timepoints that were assessed (i.e., Days 4, 8, 22, 36) and data collected at these visits. For example, more timepoints would be valuable to assess onset. It should also be noted that while commonly used criteria were applied to define onset as well as response, other criteria could result in different outcomes. Further, these criteria were applied to a population of subjects enrolled in a large double-blind clinical trial and these findings may not generalize to patient populations with different characteristics. Also, the results presented here are population-based data that do not fully address the heterogeneity that is associated with individual treatment response. That is, mean responses from a population address probabilities of clinical response but do not predict the response for a particular patient. Finally, it should be pointed out that there was a substantial placebo response observed in this trial. This is not uncommon in studies of patients with schizophrenia and, nevertheless, the effect size data for paliperidone palmitate compared to placebo suggests a clinically meaningful dose- and time-dependent treatment effect in this population.