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The availability of long-acting injectable (LAI) antipsychotics for the treatment of schizophrenia provides clinicians with options that deliver continuous drug exposure and may improve adherence compared with daily oral antipsychotics. However, all LAI antipsychotics have unique formulations and pharmacokinetic characteristics that have implications for medication selection, administration interval, and injection site. This review outlines key differences in drug formulations and pharmacokinetics among LAI antipsychotics. A systematic search of the PubMed database was conducted to identify physical and formulation properties and pharmacokinetic data of commercially available LAI antipsychotics, including flupentixol decanoate, fluphenazine decanoate, haloperidol decanoate, zuclopenthixol decanoate, aripiprazole monohydrate, aripiprazole lauroxil, olanzapine pamoate, paliperidone palmitate, risperidone microspheres, and risperidone polymeric microspheres. Additional information was obtained from package inserts and product monographs. Relevant data on drug properties, administration details, pharmacokinetic parameters, and oral dose equivalencies of LAI antipsychotics are summarized. Based on our analysis, formulation characteristics (e.g., vehicle medium) and administration characteristics (e.g., injection site) can affect rate of absorption and adverse effects and may factor into whether oral supplementation or an additional injection is needed. Dose adjustments may be necessary based on potential drug–drug interactions, and approximate dose equivalence with oral formulations can help inform titration when switching from oral to LAI formulations. Clinicians administering LAI antipsychotics should consider these formulation and pharmacokinetic factors to maximize clinical impact and to adjust to an individual patient’s needs and treatment goals. Supplementary Information The online version contains supplementary material available at 10.1007/s40263-020-00779-5.

In a recent study, an indirect treatment comparison was performed to examine the relative efficacy and tolerability of aripiprazole once monthly and paliperidone palmitate once monthly. The authors concluded that the results may suggest relative advantages for aripiprazole once monthly over paliperi

DISCLOSURES: The writing of this letter was supported by Janssen Scientific Affairs. The authors are employees of Janssen Scientific Affairs or Janssen Global Services (Johnson & Johnson).

With more long-acting injectable (LAI) antipsychotics available for treating schizophrenia, each with variable durations of action (2 weeks to 3 months), it is important to have clear management strategies for patients developing breakthrough psychotic symptoms or experiencing symptomatic worsening on LAIs. However, no treatment guidelines or clinical practice pathways exist; health-care providers must rely on their own clinical judgment to manage these patients. This article provides practical recommendations—based on a framework of clinical, pharmacokinetic, and dosing considerations—to guide clinicians’ decisions regarding management of breakthrough psychotic symptoms. Management options include ruling out/addressing medical illness or substance abuse/misuse as a contributing factor, addressing stressors, optimizing nonpharmacologic treatments, treating medical/psychiatric comorbidities, ensuring proper LAI administration technique, addressing missed LAI doses or lack of steady-state attainment, and increasing LAI dose directly or indirectly by shortening the injection interval (off-label). If these strategies do not work sufficiently with frequent monitoring, the LAI could be supplemented with a low dose of the corresponding oral formulation for fast symptom control (off-label). However, caution should be exercised with this strategy, because data on the safety of concomitant use of LAI and oral antipsychotics (OAPs) are limited, especially over extended periods. If symptoms abate, therapy optimization could be continued and slow discontinuation of the OAP could be considered. For persistent/worsening symptoms, the OAP should be increased to optimum effective dose while intensifying the initial steps used before it was added. If this fails, switching the OAP or LAI could be considered. We believe that these strategies will help clinicians manage breakthrough psychotic symptoms during LAI treatment and improve overall outcomes among those who can benefit from LAIs.

Summary Aim We assessed the dosage strengths of paliperidone palmitate 1‐month (PP1M) long‐acting injectable resulting in similar steady‐state (SS) exposures to the dosage strengths of oral risperidone using pharmacokinetic (PK) simulations. Methods Population PK simulations of SS PK were performed using the PK models of oral risperidone and PP1M. The concentrations of active moiety (risperidone + paliperidone) from risperidone were compared to paliperidone concentrations resulting from PP1M administration. Similarity was assessed via graphical evaluation of median and 90% prediction intervals of SS PK profiles over 28 days. Results Oral risperidone doses of 1, 2, 3, 4, and 6 mg/d are expected to result in similar SS PK as PP1M doses of 25, 50, 75, 100, and 150 mg eq. (which correspond to 39, 78, 117, 156, and 234 mg of paliperidone palmitate) respectively (ie 25‐fold dose conversion factor from oral risperidone to PP1M). Conclusions This study provides clinicians with a practical guidance to establish suitable maintenance dose levels of PP1M and oral risperidone when transitioning patients from one formulation to another.

Purpose To evaluate injection site reactions and pain following paliperidone palmitate 1-month (PP1M) and 3-month (PP3M) administration using safety data of double-blind (DB), noninferiority study. Methods Patients (n = 1,429) with schizophrenia, treated with PP1M (50-150 mg-eq, 17-week open-label [OL] phase) were randomized to PP1M or PP3M in 48-week DB phase. Findings PP1M and PP3M injections were well tolerated. Incidence of induration, redness, and swelling were low in both phases (OL: 9-12%; DB: 7-13%), and were mostly mild in both groups. Mean (SD) visual analog scale scores decreased from OL-baseline (22.0 [21.6]) to DB-baseline (19.5 [20.6] vs. 18.4 [20.4]) and DB-endpoint (15.6 [17.9] vs. 15.5 [18.3]). Practice implications Injection site reactions and pain were low and similar between both treatments, regardless of administration site and dose.

Background: The metabolic/biotransformation pathways of atypical antipsychotics (aripiprazole, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone) have been characterized and reviewed. However, comparisons of excretory pathways remain unexplored. Objective: To analyze the excretion profile of atypical antipsychotic agents and compare the overall magnitude of metabolism (changed vs. unchanged drug) and route of excretion (feces vs. urine). Secondary objectives include providing: 1) dosing information in hepatic and renal impairment, and 2) context of the specific enzymes and pathways involved in each agents biotransformation. Methods: Published literature and each manufacturers radiolabeled drug absorption, distribution, metabolism and excretion data and U.S. prescribing information were reviewed. Results: With the exception of paliperidone, atypical antipsychotics undergo extensive metabolism (i.e.,≤50% of dose recovered unchanged). Quetiapine undergoes the greatest overall metabolism ( < 1% of the dose recovered unchanged) and paliperidone the least (59% recovered unchanged in the urine). Between-agent differences exist in the extent of cytochrome P450 (CYP450) metabolism and the specific isozymes involved. After administration of a radioactive dose, fecal elimination of unchanged drug plus metabolites ranged from 11% (paliperidone) to 71% (ziprasidone) and renal elimination ranged from 21% (ziprasidone) to 80% (paliperidone). Conclusions: Understanding the differences in the elimination profiles of atypical antipsychotics agents may permit better-informed drug and dose selection in special populations such as those with comorbid conditions (e.g. hepatitis, diabetes, end-stage renal disease) or pharmacogenetic variability; or at risk for drug-drug interactions. The use of patient tailored drug and dose-selection may result in greater treatment efficacy and a reduction in adverse events.

Early in the course of illness, patients with schizophrenia may be particularly susceptible to adverse events (AEs). In this post-hoc, subgroup analysis of a 13-week, double-blind, double-dummy, multicenter study, patients recently diagnosed with schizophrenia (≤ 5 years) were administered once-monthly flexible-dose paliperidone palmitate (PP) (n=161; initiation doses, 150 mg eq day 1 and 100 mg eq day 8) [PP doses can be expressed as milligram equivalents (mg eq) of paliperidone or as milligrams (mg) of PP. 150 mg eq paliperidone=234 mg PP; 100 mg eq paliperidone=156 mg PP. In the USA, dosing tends to be expressed in mg] or oral risperidone [during initiation of risperidone long-acting injection (RLAI) days 1-28] and biweekly flexible-dose RLAI (n=173; initial injection day 8). Assessments were performed at baseline and days 4, 15, 22, 36, 64, and 92. Because of RLAI's release profile, data through day 22 correspond to oral risperidone in the RLAI arm. During this period, the AE profile and onset of efficacy of PP and oral risperidone were similar. The overall AE rates at week 13 for PP and RLAI were 54.7 and 50.3%, respectively, for any AE; 11.2 and 8.1% for extrapyramidal symptom-related AEs; and 2.5 and 2.3% for prolactin-related AEs. No significant differences in the mean weight change, most metabolic parameters, or mean efficacy measures were observed at end point. In patients with recently diagnosed schizophrenia, the tolerability and efficacy of PP and RLAI were generally similar over 13 weeks.

Objective: To examine the tolerability of the recommended initiation doses for once-monthly injectable paliperidone palmitate in patients who have recently been diagnosed with schizophrenia and for whom high doses may pose tolerability concerns. Methods: A post hoc analysis from a 13-week double-blind study of patients with schizophrenia randomized 1:1:1:1 to placebo or paliperidone palmitate at 25, 100, or 150 mg equivalents (mg eq) of paliperidone (corresponding to 39, 156, or 234 mg respectively). This analysis focused on the recently diagnosed subgroup (≤5 years; N = 146) who received the recommended initiation dosage of paliperidone palmitate [150 mg eq on day 1 ( n = 109) followed by 100 mg eq on day 8 ( n = 39)] or placebo ( n = 37). Adverse events (AEs), reported in ≥2% of patients receiving paliperidone palmitate during days 1–7 or ≥5% during days 8–36, and in a higher percentage of patients receiving paliperidone palmitate than placebo, were identified. AE relative risks (RRs) and 95% confidence intervals (CIs) were determined. A RR was considered potentially significant when its 95% CI did not include 1. Results: Overall, day 1–7 AE rates were 37.6% (41 of 109) and 29.7% (11 of 37) with paliperidone palmitate and placebo respectively; injection site pain (5.5% versus 2.7%, RR 2.0; 95% CI 0.25 to 16.37), agitation (4.6% versus 2.7%; RR 1.7; 95% CI 0.21 to 14.06), and headache (3.7% versus 0.0%; RR 3.1; 95% CI 0.17 to 56.41) met the ≥2% criteria. Day 8–36 AE rates were 41.0% (16 of 39) and 37.8% (14 of 37) with paliperidone palmitate and placebo respectively; anxiety (5.1% versus 0.0%; RR 4.8; 95% CI 0.24 to 95.76) met the ≥5% criteria. Key limitations were that some patients may have been ill for a significant time before formal diagnosis and that the number of patients is low in this subgroup, limiting the ability to detect statistical significance for AE RRs. Conclusions: Paliperidone palmitate initiation doses (150 mg eq day 1, 100 mg eq day 8) were tolerated in this subgroup of patients who were recently diagnosed with schizophrenia, with no unexpected findings. Although the same size was small, these data identified AEs that may be encountered during the week and month after initiation dosing. These findings may assist clinicians when paliperidone palmitate is considered an appropriate treatment choice for these patients.

Video abstract Video, Background This post hoc subgroup analysis of a randomized, double-blind trial evaluated the response to treatment with two long-acting injectable atypical antipsychotics, ie, paliperidone palmitate and risperidone long-acting injectable (RLAI), in subjects with schizophrenia experiencing clinically significant symptoms despite recent treatment with oral risperidone only or other oral antipsychotics. Methods Adult subjects were eligible for the 13-week, double-blind, double-dummy trial (NCT00589914) if they had an established diagnosis of schizophrenia for at least one year and a Positive and Negative Syndrome Scale (PANSS) total score of 60–120 inclusive at screening. Subjects received either paliperidone palmitate (234 mg, day 1; 156 mg, day 8; then once-monthly flexible dosing) or RLAI (25–50 mg biweekly, with oral risperidone supplementation on days 1–28), plus matched placebo injections/tablets. Results This post hoc analysis reports data on 747 subjects who, within 2 weeks of starting double-blind study medication, had reportedly received oral risperidone only (paliperidone palmitate group, n = 126; RLAI group, n = 107), other oral antipsychotics (paliperidone palmitate group, n = 199; RLAI group, n = 203), or no antipsychotic (paliperidone palmitate group, n = 56; RLAI group, n = 56). Mean PANSS total scores improved significantly at end point across all subgroups (mean change from baseline ranged from −17.5 to −19.5, all P < 0.0001). Clinical Global Impression-Severity and Personal and Social Performance scale measures also significantly improved from baseline (all P < 0.0001). Conclusion Treatment with paliperidone palmitate or RLAI resulted in a significant reduction in the symptoms of schizophrenia irrespective of previous recent treatment with oral risperidone only or other oral antipsychotics. For subjects who had previously received oral risperidone only, the difference in formulation was the main change in the intervention because the molecule delivered remained the same or similar. These data support the contribution of a long-acting formulation to improving the treatment response and suggest that nonadherence may be a significant contributor to inadequate efficacy of oral formulations in subjects with schizophrenia.

Video abstract Video, Background A post hoc analysis from a multiphase trial with open-label transition and maintenance phases, a double-blind relapse prevention phase, and an optional open-label extension examined the long-term tolerability with continuous once-monthly injectable paliperidone palmitate 39, 78, 117, or 156 mg (25, 50, 75, or 100 mg equivalents [mg eq] of paliperidone) in subjects with recently diagnosed (≤5 years; n = 216) versus chronic illness (>5 years; n = 429) schizophrenia. Methods Adverse events reported at a ≥2% margin between subgroups were identified. Relative risks (in the recently diagnosed compared with the chronically ill) and 95% confidence intervals (CI) were determined, and CI not including 1 were considered potentially significant. Results In both subgroups, the mean monthly dose was 109 mg (69.9 mg eq). Continuous mean exposures were 333.9 ± 271.9 and 308.7 ± 278.3 days in the recently diagnosed and chronic illness subgroups, respectively. Using the criteria outlined in the methods, nasopharyngitis was a potentially significant event reported in more chronically ill than recently diagnosed subjects at months 6, 9, 12, and endpoint (7.2% versus 2.8%; relative risk 0.384; 95% CI 0.163–0.907). Influenza (2.8% versus 0.7%; relative risk 3.9; 95% CI 1.003–15.730) and amenorrhea (3.2% versus 0.9%; relative risk 3.476; 95% CI 1.029–11.744) at endpoint were potentially significant events in more recently diagnosed than chronically ill subjects. Mean weight changes, sedation/somnolence, any extrapyramidal symptom-related or glucose-related events were generally similar between the groups. The mean prolactin level increased in both sexes in both subgroups (changes from baseline of +41.8 ng/mL and +26.5 ng/mL in recently diagnosed and chronic illness females and +12.3 ng/mL and +15.1 ng/mL in recently diagnosed and chronic illness males, respectively), and were higher in females with recently diagnosed illness than in females who were chronically ill (P = 0.0002 at endpoint). Prolactin-related events were reported by 7.9% of recently diagnosed subjects with schizophrenia and 3.5% of those who were chronically ill. Conclusion The long-term tolerability of paliperidone palmitate was generally similar in recently diagnosed schizophrenia subjects and those with more chronic illness, with the exception of some prolactin-related measures.

Objective To examine efficacy and safety of acute treatment with paliperidone palmitate in subjects with schizophrenia whose disease remained symptomatic despite recent treatment with oral risperidone. Methods Post hoc analysis of a 13-week, double-blind, placebo-controlled study of subjects with symptomatic schizophrenia randomized to paliperidone palmitate 39, 156, or 234 mg (25, 100, or 150 mg equivalents of paliperidone) or placebo. Paliperidone palmitate subjects received a 234-mg day 1 dose, followed by their assigned dose on day 8 and monthly thereafter. Subjects treated with oral risperidone within 2 weeks before randomization regardless of duration were included. Assessments: PANSS, CGI-S, PSP scores; AEs. ANCOVA models with LOCF methodology evaluated treatment group differences. Results 216 subjects received prior oral risperidone (paliperidone palmitate 39 mg, n = 53; 156 mg, n = 58; 234 mg, n = 48; placebo, n = 57). Median prior risperidone use was 22 days. Significant improvement was observed with paliperidone palmitate 156-mg or 234-mg versus placebo in least-squares mean (SE) score change at end point in PANSS total (156 mg, −15.8 [3.0], p = 0.0001; 234 mg, −17.6 [3.2], p = 0.0001), CGI-S (156 mg, −0.9 [0.2], p = 0.0068; 234 mg, −1.1 [0.2], p = 0.0003), and PSP (156 mg, 10.7 [2.3], p = 0.0061; 234 mg, 12.9 [2.4], p = 0.0009). Most common AEs (≥ 10%) in any paliperidone palmitate group were insomnia, anxiety, and headache. Conclusions In subjects with schizophrenia who recently received oral risperidone but who remained symptomatic, acute treatment with monthly doses of 156-mg and 234-mg paliperidone palmitate significantly improved clinical symptoms, global illness ratings, and functioning compared with placebo, with no unexpected safety findings.

Long-acting injectable (LAI) formulations of antipsychotics are valuable treatment alternatives for patients with psychotic disorders, and understanding their safe use is critical. Post-injection delirium/sedation syndrome (PDSS) has been reported following treatment with one atypical antipsychotic LAI. Clinical databases of risperidone LAI and paliperidone palmitate were explored to identify if cases of PDSS had been observed. No cases of PDSS were identified in 15 completed trials of 3,164 subjects (approximately 115,000 injections) or the postmarketing safety database of risperidone LAI. Only one case of PDSS was identified among 10 completed trials (3,817 subjects, 33,906 injections) of paliperidone palmitate-that case having been reported in a patient randomized to treatment with placebo. Examination of these prospective databases finds no evidence that risperidone LAI and paliperidone palmitate are associated with PDSS and suggest that findings seen with another antipsychotic LAI are not generalizable.

Objective: To examine onset of efficacy of two long-acting injectable atypical antipsychotics in markedly-to-severely ill schizophrenia subjects. Methods: This subgroup analysis included 292 subjects with baseline Clinical Global Im pressions-Severity scores of markedly ill or worse from a 13-week, randomized, double-dummy noninferiority study (NCT00589914). Subjects received either: 1) paliperidone palmitate (PP; 234 mg day 1 and 156 mg day 8 [corresponding to 150 and 100 milligram equivalents of paliperidone, respectively], both administered in deltoid muscle, followed by once-monthly flexible dosing in deltoid or gluteal muscle) and risperidone long-acting injection (RLAI)–matched placebo injections; or, 2) RLAI (25 mg, days 8 and 22; followed by biweekly flexible dosing) and PP-matched placebo injections. RLAI subjects received oral risperidone days 1–28; PP subjects received oral placebo. Because of RLAI’s release profile, data through day 22 correspond to oral risperidone. Assessments included Positive and Negative Syn drome Scale (PANSS) and adverse event (AE) reports. Paired t-tests assessed within-group changes. Results: LS mean (SE) PANSS total scores improved significantly (both p

There is a strong association between weight gain and metabolic events in patients with schizophrenia receiving many of the second-generation antipsychotic agents. We explored the relationship between body mass index (BMI) and metabolic events in patients with schizophrenia receiving long-acting injectable paliperidone palmitate (PP) in a long-term trial. We conducted a post hoc analysis of data from a PP study that included a 33-week open-label transition (TR) and maintenance phase; a variable duration, randomized, double-blind (DB), placebo-controlled phase and a 52-week open-label extension (OLE) phase. Overall, 644 patients received PP continuously from study entry through discontinuation or study completion and were grouped by baseline BMI (kg/m2): underweight (BMI

Video abstract Video, Background Paliperidone palmitate (PP) is a long-acting injectable formulation of an atypical antipsychotic, paliperidone. Its dose can be expressed in milligram or milligram equivalents (mg eq) of active paliperidone (39, 78, 117, 156, and 234 mg of PP correspond to 25, 50, 75, 100, and 150 mg eq of paliperidone). The recommended initiation dosing regimen for PP is 150 [day 1]/100[day 8] mg eq. Labeling guidance allowed a ± 2 day window for the day 8 injection that provides more flexibility with patient scheduling and avoids missing the day 8 initiation dose. Recently, expansion of the day 8 dosing window from ±2 to ±4 days has been approved in the United States based on results obtained from the model-based simulations and review of safety data presented here. Methods The predicted exposure for the recommended initiation regimen of PP was compared with day 1/day 4, and day 1/day 12 dosing scenarios; each scenario was compared with the highest clinically evaluated initiation regimen (150[day 1]/150[day 8] mg eq) and to the recommended 6 mg/day oral dose of extended-release paliperidone. Results Simulated exposures with PP 150 mg eq on day 1 and 100 mg eq on days 4, 8, or 12 overlap considerably, with ±3 ng/mL variation in median maximum plasma concentrations. Based upon pharmacokinetic bridging/bracketing, the peak concentration with PP 150/100 mg eq [days 1/4] was lower than that with the highest initiation regimen. Exposures for PP 150 mg eq on day 1 and 100 mg eq on days 4, 8, or 12 were maintained close to those of 6 mg of paliperidone extended-release. Conclusion These simulations indicate that using the expanded dosing window of ±4 days has little effect on paliperidone exposure. A review of the overall pattern of treatment-emergent adverse events did not identify any new safety risks associated with the expanded dosing window.

Mahesh N Samtani,1 John J Sheehan,2 Dong-Jing Fu,2 Bart Remmerie,3 Jennifer Kern Sliwa,2 Larry Alphs21Janssen Research and Development, Raritan, NJ, USA; 2Janssen Scientific Affairs, Titusville, NJ, USA; 3Janssen Research and Development, Division of Janssen Pharmaceutica, Beerse, BelgiumBackground: Medication nonadherence is a well described and prevalent clinical occurrence in schizophrenia. These pharmacokinetic model-based simulations analyze predicted antipsychotic plasma concentrations in nonadherence and treatment interruption scenarios and with treatment reinitiation.Methods: Starting from steady state, pharmacokinetic model-based simulations of active moiety plasma concentrations of oral, immediate-release risperidone 3 mg/day, risperidone long-acting injection 37.5 mg/14 days, oral paliperidone extended-release 6 mg/day, and paliperidone palmitate 117 mg (75 mg equivalents)/28 days were assessed under three treatment discontinuation/interruption scenarios, ie, complete discontinuation, one week of interruption, and four weeks of interruption. In the treatment interruption scenarios, pharmacokinetic simulations were performed using medication-specific reinitiation strategies.Results: Following complete treatment discontinuation, plasma concentrations persisted longest with paliperidone palmitate, followed by risperidone long-acting injection, while oral formulations exhibited the most rapid decrease. One week of oral paliperidone or risperidone interruption resulted in near complete elimination from the systemic circulation within that timeframe, reflecting the rapid elimination rate of the active moiety. After 1 and 4 weeks of interruption, minimum plasma concentrations were higher with paliperidone palmitate than risperidone long-acting injection over the simulated period. Four weeks of treatment interruption followed by reinitiation resulted in plasma levels returning to predicted therapeutic levels within 1 week.Conclusion: Due to the long half-life of paliperidone palmitate (25–49 days), putative therapeutic plasma concentrations persisted longest in simulated cases of complete discontinuation or treatment interruption. These simulations may help clinicians better conceptualize the impact of antipsychotic nonadherence on plasma concentrations, and the impact of medication-specific reinitiation strategies after intermittent nonadherence.Keywords: paliperidone palmitate, risperidone, long-acting injection, pharmacokinetics, nonadherence, plasma concentrationsErratum for this paper has been published

Background This post hoc analysis (trial registration: ClinicalTrials.gov NCT00590577) assessed onset of efficacy and tolerability of acute treatment with once-monthly paliperidone palmitate (PP), a long-acting atypical antipsychotic initiated by day 1 and day 8 injections, in a markedly to severely ill schizophrenia population. Methods Subjects entering the 13-week, double-blind trial were randomized to PP (39, 156, or 234 mg [25, 100, and 150 mg eq of paliperidone, respectively]) or placebo. This subgroup analysis included those with a baseline Clinical Global Impressions-Severity (CGI-S) score indicating marked to severe illness. PP subjects received a 234-mg day 1 injection (deltoid), followed by their assigned dose on day 8 and monthly thereafter (deltoid or gluteal). Thus, data for PP groups were pooled for days 4 and 8. Measures included Positive and Negative Syndrome Scale (PANSS), CGI-S, Personal and Social Performance (PSP), and adverse events (AEs). Analysis of covariance (ANCOVA) and last-observation-carried-forward (LOCF) methodologies, without multiplicity adjustments, were used to assess changes in continuous measures. Onset of efficacy was defined as the first time point a treatment group showed significant PANSS improvement (assessed days 4, 8, 22, 36, 64, and 92) versus placebo, which was maintained through end point. Results A total of 312 subjects met inclusion criterion for this subgroup analysis. After the day 1 injection, mean PANSS total scores improved significantly with PP (all received 234 mg) versus placebo at day 4 (P = 0.012) and day 8 (P = 0.007). After the day 8 injection, a significant PANSS improvement persisted at all subsequent time points in the 234-mg group versus placebo (P < 0.05). PANSS improvements were greater from day 36 through end point in the 156-mg group (P < 0.05) and only at end point in the 39-mg group (P < 0.05). CGI-S and PSP scores improved significantly in the 234-mg and 156-mg PP groups versus placebo at end point (P < 0.05 for both, respectively); improvement in the 39-mg group was not significant. The most common AEs for PP-treated subjects (≥10%, any treatment group) were headache, insomnia, schizophrenia exacerbation, injection site pain, and agitation. Conclusions In this markedly to severely ill population, acute treatment with 234 mg PP improved psychotic symptoms compared with placebo by day 4. After subsequent injections, observed improvements are suggestive of a dose-dependent effect. No unexpected tolerability findings were noted.

Background Paliperidone palmitate is a long-acting injectable atypical antipsychotic for the acute and maintenance treatment of adults with schizophrenia. The recommended initiation dosing regimen is 234 mg on Day 1 and 156 mg on Day 8 via intramuscular (deltoid) injection; followed by 39 to 234 mg once-monthly thereafter (deltoid or gluteal). These post-hoc analyses addressed two commonly encountered clinical issues regarding the initiation dosing: the time to onset of efficacy and the associated tolerability. Methods In a 13-week double-blind trial, 652 subjects with schizophrenia were randomized to paliperidone palmitate 39, 156, or 234 mg (corresponding to 25, 100, or 150 mg equivalents of paliperidone, respectively) or placebo (NCT#00590577). Subjects randomized to paliperidone palmitate received 234 mg on Day 1, followed by their randomized fixed dose on Day 8, and monthly thereafter, with no oral antipsychotic supplementation. The onset of efficacy was defined as the first timepoint where the paliperidone palmitate group showed significant improvement in the Positive and Negative Syndrome Scale (PANSS) score compared to placebo (Analysis of Covariance [ANCOVA] models and Last Observation Carried Forward [LOCF] methodology without adjusting for multiplicity) using data from the Days 4, 8, 22, and 36 assessments. Adverse event (AE) rates and relative risks (RR) with 95% confidence intervals (CI) versus placebo were determined. Results Paliperidone palmitate 234 mg on Day 1 was associated with greater improvement than placebo on Least Squares (LS) mean PANSS total score at Day 8 (p = 0.037). After the Day 8 injection of 156 mg, there was continued PANSS improvement at Day 22 (p ≤ 0.007 vs. placebo) and Day 36 (p < 0.001). Taken together with results in the 39 mg and 234 mg Day 8 arms, these findings suggest a trend towards a dose-dependent response. During Days 1 to 7, AEs reported in ≥2% of paliperidone palmitate subjects (234 mg) and a greater proportion of paliperidone palmitate than placebo subjects were: agitation (3.2% vs. 1.3%; RR 2.52 [95% CI 0.583, 10.904]), headache (4.0% vs. 3.8%; RR 1.06 [95% CI 0.433, 2.619]), and injection site pain (6.7% vs. 3.8%; RR 1.79 [95% CI 0.764, 4.208]). Days 8 to 36 AEs meeting the same criteria in the 156 mg Day 8 arm were: anxiety (3.1% vs. 2.5%; RR 1.24 [95% CI 0.340, 4.542]), psychotic disorder (2.5% vs. 1.3%; RR 1.99 [95% CI 0.369, 10.699]), dizziness (2.5% vs. 1.3%; RR 1.99 [95% CI 0.369, 10.699]), and injection site pain (2.5% vs. 1.3%; RR 1.99 [95% CI 0.369, 10.699]). Corresponding Days 8 to 36 AEs in the 39 mg Day 8 group were: agitation (4.5% vs. 4.4%; RR 1.03 [95% CI 0.371, 2.874]), anxiety (3.9% vs. 2.5%; RR 1.55 [95% CI 0.446, 5.381]), and psychotic disorder (2.6% vs. 1.3%; RR 2.07 [95% CI 0.384, 11.110]) while in the 234 mg Day 8 group it was anxiety (3.1% vs. 2.5%, RR 1.25 [95% CI 0.342, 4.570]). Conclusions Significantly greater symptom improvement was observed by Day 8 with paliperidone palmitate (234 mg on Day 1) compared to placebo; this effect was maintained after the 156 mg Day 8 injection, with a trend towards a dose-dependent response. No unexpected tolerability findings were noted in the first week or month after the initiation dosing. Trial registration ClinicalTrials.gov: NCT#00590577