Clinical outcomes with paliperidone palmitate 3-monthly injection as monotherapy: observational 3-year follow-up of patients with schizophrenia.

BACKGROUND: Paliperidone palmitate 3-monthly (PP3M) has been tested in 1-year controlled studies. The aim of this study was to examine the relapse outcomes with PP3M monotherapy at 3 years in patients with schizophrenia. METHODS: This was an observational, non-interventional study of patients started on PP3M according to their clinical need. All patients had a diagnosis of schizophrenia (ICD-10 F20) and were between 18 and 65 years of age. The study took place in a mental health facility in South East London, UK. RESULTS: Among the 166 patients who started PP3M, 97 (58%) met inclusion criteria and were observed for 36 months. In total, five patients (5%) experienced a relapse (defined as step-up in clinical care) while on PP3M. There were no relapses between months 18 and 36. Of the original 97 patients, 56 (58%) remained on PP3M monotherapy at 3 years, and 71 (73%) remained on either PP3M or paliperidone palmitate one-monthly. Reasons for discontinuation of PP3M included patient refusal (n = 11, 33% of discontinuations) and adverse effects in (n = 8, 24%). CONCLUSION: PP3M is a highly effective monotherapy treatment for reducing relapse in people with schizophrenia.

Evaluating the 6-month formulation of paliperidone palmitate: a twice-yearly injectable treatment for schizophrenia in adults.

INTRODUCTION: Paliperidone Palmitate is the only antipsychotic that has been developed in three different intramuscular long-acting injectable (LAI) dosing regimen: monthly (PP1M), quarterly (PP3M), and from 2020 also twice-yearly (PP6M). The latter was approved for the maintenance treatment of adults with schizophrenia and clinically stabilized with PP1M or PP3M. AREAS COVERED: Data from studies evaluating efficacy in the maintenance treatment of schizophrenia with PP6M are reviewed. Since no post-marketing safety studies are currently available, data from spontaneous reporting system databases, FAERS and Eudravigilance, are analyzed and the reported treatment-emergent adverse events of PP6M are discussed. EXPERT OPINION: The efficacy of PP6M is comparable to that of PP3M in terms of relapses prevention in patients with schizophrenia previously stabilized on PP3M or PP1M. Also, the maintenance of clinical efficacy in the long term has been demonstrated. Data from pharmacovigilance analyses, as well as from phase 3 studies, show that PP6M is generally well tolerated, consistently with PP3M safety data. PP6M allows a longer dosing interval than any other LAI antipsychotics, potentially reducing nonadherence and disease relapses. In future, an increase in the prescription rates of PP6M is expected and real-world efficacy and tolerability studies will be conducted.

Influence of CYP2D6 Metabolizer Status on Risperidone and Paliperidone Tolerability in Children and Adolescents.

Background: Risperidone and, to a lesser extent, paliperidone are metabolized by CYP2D6; however, there are limited data related to variation in CYP2D6 phenotypes and the tolerability of these medications in children and adolescents. Furthermore, the impact of CYP2D6 on the association of risperidone and paliperidone with hyperprolactinemia in youth is not well understood. Methods: A retrospective chart review was performed in psychiatrically hospitalized children and adolescents prescribed risperidone (n = 263, age = 3-18 years, mean age = 13 ± 3 years, 49% female) or paliperidone (n = 124, age = 5-18 years, mean age = 15 ± 2 years, 44% female) who had CYP2D6 genotyping performed as part of routine care. CYP2D6 phenotypes were determined based on Clinical Pharmacogenetics Implementation Consortium guidelines and CYP2D6 inhibitors causing phenoconversion. Adverse effects were obtained from a review of the electronic health record, and patients were selected, in part, to enrich non-normal metabolizers. Results: Among risperidone-treated patients, 45% experienced an adverse effect, whereas 36% of paliperidone-treated patients experienced adverse effects. Discontinuation of risperidone due to lack of efficacy was more frequent in the CYP2D6 normal metabolizers and ultrarapid metabolizers compared with intermediate metabolizers (IMs) and phenoconverted poor metabolizers (pPMs) (54.5% vs. 32.7%, p < 0.001). Discontinuation due to weight gain was more common among risperidone- than paliperidone-treated patients (17% vs. 7%, p = 0.011). Among those taking paliperidone, CYP2D6 was associated with discontinuation due to side effects (p = 0.008), and youth with slower CYP2D6 metabolism (i.e., pPMs and IMs) were more likely to discontinue. Hyperprolactinemia was found in 10% of paliperidone-treated patients and 5% of risperidone-treated patients, and slower CYP2D6 metabolizers required higher risperidone doses to cause hyperprolactinemia (p = 0.011). Conclusions: CYP2D6 phenotype is associated with discontinuation of risperidone due to lack of efficacy and the dose of risperidone that induced hyperprolactinemia, as well as discontinuation of paliperidone due to adverse effects. Future studies should evaluate exposure-response and toxicity relationships in risperidone- and paliperidone-treated youth.

A randomized, prospective, active-controlled study comparing intramuscular long-acting paliperidone palmitate versus oral antipsychotics in patients with schizophrenia at risk of violent behavior.

OBJECTIVE: Paliperidone palmitate (PP) is an effective long-acting antipsychotic injection, but its impact on the behavior of schizophrenia patients with dangerous tendencies requires further investigation. This study aims to explore the effects of long-term antipsychotic treatment on this population in the community. METHODS: This 49-week, randomized controlled trial was conducted across 21 communities in Wuhan and enrolled 134 schizophrenia patients at risk for violent behavior. With a fixed block size of 10, participants were randomly assigned to receive either intramuscular PP 1-month formulation (PP1M) or oral antipsychotic medication (OAP) at a 1:1 ratio. Changes in patients' risk for violent/aggressive behavior, family burden, social, and cognitive functioning were measured using VRAPP, MOAS, PANSS, FBS, PSP, and RBANS scales from baseline to endpoint. Longitudinal data from multiple repeated measures were analyzed using linear mixed-effects models. RESULTS: The study protocol was completed by 77.6% of the patients overall. Significant improvements were observed in the risk assessment scores, MOAS total score, PANSS total score, PSP total score, and FBS total score of patients in the PP1M group from baseline to the end of treatment (all P < 0.05). Importantly, compared to patients in the OAP group, the improvements in these measures were also significantly greater in the PP1M group. Commonly observed AEs, such as hyperprolactinemia (70.3% vs. 62.65%) and muscle tension (45.3% vs. 57.8%), were considered to be the PP-related AEs. Nonetheless, the differences between the two groups did not reach statistical significance, and no new safety concerns emerged. CONCLUSIONS: Our study suggests that PP long-acting injection (LAI) is a safe and effective treatment option for community-dwelling schizophrenia patients with impulsive violence and risky behaviors.

Factors influencing concentrations of risperidone and 9-hydroxyrisperidone in psychiatric outpatients taking immediate-release formulations of risperidone.

OBJECTIVES: To analyze the factors affecting the concentrations of the active moiety of risperidone (RIS) and its active metabolite 9-hydroxyrisperidone (9-OH-RIS) in psychiatric outpatients taking immediate-release formulations. METHODS: This is a retrospective study on the therapeutic drug monitoring (TDM) data regarding RIS and 9-OH-RIS in adult psychiatric outpatients. TDM data with simultaneous RIS and 9-OH-RIS monitoring from March 2018 to February 2020 and relevant medical records (including dosage, dosage form, sex, age, diagnosis, combined medication, and comorbid disease) from 399 adult psychiatric outpatients (223 males and 176 females) were included in this study. RESULTS: The daily dose of RIS was 5.56 ± 2.05 mg, the concentration of total active moiety was 42.35 ± 25.46 ng/mL, and the dose-adjusted plasma concentration (C/D) of active moiety was 7.83 ± 3.87 (ng/ml)/(mg/day). Dose, sex, and age were identified as important factors influencing concentrations of RIS and 9-OH-RIS in adult psychiatric outpatients. CONCLUSIONS: Individualized medication adjustments should be made according to the specific conditions of psychiatric outpatients. The findings strongly support the use of TDM to guide dosing decisions in psychiatric outpatients taking RIS.

Long-Acting Injectable Second-Generation Antipsychotics vs Placebo and Their Oral Formulations in Acute Schizophrenia: A Systematic Review and Meta-Analysis of Randomized-Controlled-Trials.

BACKGROUND AND HYPOTHESIS: Long-acting injectable antipsychotic drugs (LAIs) are mainly used for relapse prevention but could also be advantageous for acutely ill patients with schizophrenia. STUDY DESIGN: We conducted a systematic review and meta-analysis of randomized-controlled-trials (RCTs) comparing the second-generation long-acting injectable antipsychotics (SGA-LAIs) olanzapine, risperidone, paliperidone, and aripiprazole with placebo or their oral counterparts in acutely ill patients with schizophrenia. We analyzed 23 efficacy and tolerability outcomes, with the primary outcome being overall symptoms of schizophrenia. The results were obtained through random effects, pairwise meta-analyses, and subgroup tests. The study quality was assessed using the Cochrane-Risk-of-Bias-Tool version-1. STUDY RESULTS: Sixty-six studies with 16 457 participants were included in the analysis. Eleven studies compared second-generation long-acting injectable antipsychotics (SGA-LAIs) with a placebo, 54 compared second-generation oral antipsychotics (SGA-orals) with a placebo, and one compared an SGA-LAI (aripiprazole) with its oral formulation. All 4 SGA-LAIs reduced overall symptoms more than placebo, with mean standardized differences of -0.66 (95% CI: -0.90; -0.43) for olanzapine, -0.64 (-0.80; -0.48) for aripiprazole, -0.62 (-0.76; -0.48) for risperidone and -0.42 (-0.53; -0.31) for paliperidone. The side-effect profiles of the LAIs corresponded to the patterns known from the oral formulations. In subgroup tests compared to placebo, some side effects were less pronounced under LAIs than under their oral formulations. CONCLUSIONS: SGA-LAIs effectively treat acute schizophrenia. Some side effects may be less frequent than under oral drugs, but due to the indirect nature of the comparisons, this finding must be confirmed by RCTs comparing LAIs and orals head-to-head.

Effectiveness and Safety of Switching from Oral Antipsychotics to Once-Monthly Paliperidone Palmitate (PP1M) in the Management of Schizophrenia: A Systematic Review and Meta-Analysis.

BACKGROUND: Considering the improvement in adherence and convenience, once-monthly paliperidone palmitate (PP1M) has been increasingly used in the treatment of schizophrenia. However, the outcomes for patients who switch from oral antipsychotics (OAPs) to PP1M have not been reliably assessed. The objective of this systematic review and meta-analysis was to investigate the efficacy and safety of PP1M in the management of patients with schizophrenia with a prior history of OAP use. METHODS: We conducted a systematic search in PubMed, EMBASE, and the Cochrane Library on 19 July 2022 to identify eligible studies. All studies that examined the effectiveness and safety of switching from OAPs to PP1M in patients with schizophrenia were included. The primary outcomes were relapse rate, hospitalisation rate, and the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score. The secondary outcomes included the changed number of inpatient visits, changed length of stay hospitalisation, change from baseline in the Clinical Global Impressions-Severity (CGI-S) score and the personal and social performance (PSP) total score, response rate, proportion of treatment discontinuation, and adverse events. We included randomised-controlled trials (RCTs), single-arm studies, and observational studies. Case reports, case series, and reviews were excluded. The quality assessment of included studies was performed using the Revised Cochrane risk-of-bias tool for randomised trials (RoB2), the 9-point Newcastle-Ottawa Scale (NOS) instrument for non-randomised studies and cohort studies, and the 12-item National Institutes of Health (NIH) quality assessment tool for before-after (Pre-Post) study without control group. Follow-up times were reported as short- (≤ 13 weeks), medium- (14-26 weeks), and long term (≥ 27 weeks). Data were pooled using meta-analysis. RESULTS: Fifteen studies with a total of 4740 patients were included. The long-term relapse rates and hospitalisation rates were 12% (95% CI 0.07-0.18) and 18% (95% CI 0.15-0.20), respectively. The short-, medium-, and long-term change in PANSS total score was - 21.69 (95% CI - 30.02 to -13.36), - 14.98 (95% CI - 21.45 to - 8.51) and - 17.88 (95% CI - 31.94 to -3.82), respectively. Approximately 50% of patients reported at least a 30% reduction in the PANSS score at the short-term follow-up. Improvements in CGI-S and PSP score were observed during various periods. There was a reduction in the length of stay hospitalisation and the number of inpatient visits at the medium- and long-term follow-ups. Low discontinuation and adverse event rates were reported. CONCLUSION: Based on our findings, this study may support the efficacy and safety of switching from OAPs to PP1M for the treatment of patients with schizophrenia. Future large-scale studies are warranted to confirm our findings.

Long-Term Efficacy and Safety of Paliperidone 6-Month Formulation: An Open-Label 2-Year Extension of a 1-Year Double-Blind Study in Adult Participants With Schizophrenia.

BACKGROUND: Paliperidone palmitate 6-month (PP6M) demonstrated noninferiority to paliperidone palmitate 3-month in preventing relapse in patients with schizophrenia in a phase 3 double-blind (DB) study (NCT03345342). Here, we report long-term efficacy and safety results from a 2-year single-arm, open-label extension (OLE; NCT04072575) of this DB study. METHODS: Participants who completed the DB study without relapse were enrolled and followed-up every 3 months up to 2 years. Participants received 4 PP6M gluteal injections (700/1000 mg eq.) at baseline, 6-month, 12-month, and 18-month visits. Efficacy endpoints included assessment of relapse, Positive and Negative Syndrome Scale total score, Personal and Social Performance score, and Clinical Global Impression-Severity scale change from baseline. Safety was assessed by treatment-emergent adverse events (TEAEs), physical examinations, and laboratory tests. RESULTS: Of 178 participants enrolled, 154 (86.5%) completed the OLE (mean age: 40.4 years, men: 70.8%; mean duration of PP6M exposure during OLE: 682.1 days). Overall, 7/178 (3.9%) participants relapsed between 20 and 703 days after enrolment. Mean (SD) changes from baseline to endpoint were as follows: Positive and Negative Syndrome Scale total score, 0.7 (8.22); Clinical Global Impression-Severity, 0.0 (0.51); and Personal and Social Performance Scale, 0.5 (7.47). Overall, 111/178 participants (62.4%) reported ≥1 TEAE; most common (>5%) TEAEs were headache (13.5%) and increased blood prolactin/hyperprolactinemia (18.0%); 8/178 (4.5%) participants experienced serious TEAEs, and 6/178 (3.4%) participants withdrew due to TEAEs. No deaths were reported. CONCLUSIONS: The relapse rate observed with PP6M during the 2-year OLE was low (3.9%). Clinical and functional improvements demonstrated in the DB study were maintained during OLE, and no new safety concerns were identified. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04072575; EudraCT number: 2018-004532-30.

Predicting psychotic relapse following randomised discontinuation of paliperidone in individuals with schizophrenia or schizoaffective disorder: an individual participant data analysis.

BACKGROUND: Predicting relapse for individuals with psychotic disorders is not well established, especially after discontinuation of antipsychotic treatment. We aimed to identify general prognostic factors of relapse for all participants (irrespective of treatment continuation or discontinuation) and specific predictors of relapse for treatment discontinuation, using machine learning. METHODS: For this individual participant data analysis, we searched the Yale University Open Data Access Project's database for placebo-controlled, randomised antipsychotic discontinuation trials with participants with schizophrenia or schizoaffective disorder (aged ≥18 years). We included studies in which participants were treated with any antipsychotic study drug and randomly assigned to continue the same antipsychotic drug or to discontinue it and receive placebo. We assessed 36 prespecified baseline variables at randomisation to predict time to relapse, using univariate and multivariate proportional hazard regression models (including multivariate treatment group by variable interactions) with machine learning to categorise the variables as general prognostic factors of relapse, specific predictors of relapse, or both. FINDINGS: We identified 414 trials, of which five trials with 700 participants (304 [43%] women and 396 [57%] men) were eligible for the continuation group and 692 participants (292 [42%] women and 400 [58%] men) were eligible for the discontinuation group (median age 37 [IQR 28-47] years for continuation group and 38 [28-47] years for discontinuation group). Out of the 36 baseline variables, general prognostic factors of increased risk of relapse for all participants were drug-positive urine; paranoid, disorganised, and undifferentiated types of schizophrenia (lower risk for schizoaffective disorder); psychiatric and neurological adverse events; higher severity of akathisia (ie, difficulty or inability to sit still); antipsychotic discontinuation; lower social performance; younger age; lower glomerular filtration rate; benzodiazepine comedication (lower risk for anti-epileptic comedication). Out of the 36 baseline variables, predictors of increased risk specifically after antipsychotic discontinuation were increased prolactin concentration, higher number of hospitalisations, and smoking. Both prognostic factors and predictors with increased risk after discontinuation were oral antipsychotic treatment (lower risk for long-acting injectables), higher last dosage of the antipsychotic study drug, shorter duration of antipsychotic treatment, and higher score on the Clinical Global Impression (CGI) severity scale The predictive performance (concordance index) for participants who were not used to train the model was 0·707 (chance level is 0·5). INTERPRETATION: Routinely available general prognostic factors of psychotic relapse and predictors specific for treatment discontinuation could be used to support personalised treatment. Abrupt discontinuation of higher dosages of oral antipsychotics, especially for individuals with recurring hospitalisations, higher scores on the CGI severity scale, and increased prolactin concentrations, should be avoided to reduce the risk of relapse. FUNDING: German Research Foundation and Berlin Institute of Health.

Can multisite clinical trial results change clinical practice? Use of long-acting injectable risperidone nationally in the Veterans Health Administration.

BACKGROUND: Multisite practical clinical trials evaluate treatments in real-world practice. A multisite randomized Veterans Health Administration (VHA) cooperative study (CSP#555) published in 2011 compared the first long-acting injectable (LAI) second-generation antipsychotic (SGA), Risperidone Consta®, in veterans with a diagnosis of schizophrenia or schizoaffective disorder, to oral antipsychotics, with unexpected null results for effectiveness and cost-effectiveness. Whether null results of this type could change VHA practice has not been studied. METHODS: A longitudinal observational analysis was used to evaluate the impact of the trial findings on VHA clinical practices. National administrative data compared new starts on LAI risperidone during the 4 years before the publication of CSP#555 in 2011 to new starts on LAI risperidone during the 4 years after. RESULTS: Among 119,565 Veterans with the indicated diagnoses treated with antipsychotics from 2007 to 2015, the number and proportion of new starts on LAI risperidone declined significantly following the study publication, as did the total number of annual users and drug expenditures. However, data from 2007 to 2010 showed the decline in new starts actually preceded the publication of CSP#555. This change was likely explained by the increase in new starts, total use, and expenditures on a newer medicine, LAI paliperidone, a 4-week LAI treatment, in the 2 years prior to the publication of CSP#555. CONCLUSIONS: The declining use of LAI risperidone likely primarily reflects the substitution of a longer-acting LAI SGA, paliperidone, that came to market 2 years before the study publication, a substitution that may have been reinforced by null CSP#555 study results for LAI risperidone.

What Role for Long-Acting Injectable Antipsychotics in Managing Schizophrenia Spectrum Disorders in Children and Adolescents? A Systematic Review.

BACKGROUND: Long-acting injectable antipsychotics (LAIAs) are an efficacious and well-tolerated treatment in adults with schizophrenia spectrum disorders (SSD). However, there is less evidence for their use in children and adolescents. OBJECTIVES: The aim of this systematic review was to summarize findings regarding the effectiveness and side effects of LAIA in children and adolescents with SSD. METHODS: Four databases (Web of Science, PubMed, MEDES, and Dialnet) were systematically searched for articles published between inception and 12 March, 2022, with the following inclusion criteria: (1) original articles or case reports; (2) providing data on efficacy/effectiveness or safety/tolerability of LAIA treatment in children and adolescents diagnosed with SSD (schizophrenia, schizoaffective disorder, schizophreniform disorder, non-affective psychotic disorder); (3) mean age of samples ≤ 18 years; and (4) written in English or Spanish. Exclusion criteria were review articles, clinical guides, expert consensus as well as posters or oral communication in conferences. The risk of bias was assessed using the ROBIS tool. RESULTS: From 847 articles found, 13 met the inclusion criteria. These included seven single case reports or case series, four retrospective chart reviews, a 24-week open-label trial, and one observational prospective study, covering a total of 119 adolescents (aged 12-17 years) with SSD. Almost all the articles described data on second-generation LAIA (53 patients on risperidone [once every other week], 33 on paliperidone palmitate [once monthly], 10 on aripiprazole [once monthly], and two on olanzapine pamoate [once monthly]). Twenty-one patients were reported to be only on first-generation LAIAs. Non-adherence was the main reason for starting an LAIA. In all of the studies, the use of LAIAs was associated with improvement in the patients' symptoms. CONCLUSIONS: There are few studies assessing the use of LAIAs in adolescents with SSD. Overall, these treatments have suggested good effectiveness and acceptable safety and tolerability. However, we found no studies examining their use in children aged < 12 years. The problems and benefits linked to this type of antipsychotic formulation in the child and adolescent population require further study, ideally with prospective, controlled designs.

Risperidone is not only a prodrug: psychosis induced by medication switch from risperidone to paliperidone - a case report.

Once administered, risperidone is converted into its pharmacologically active form, paliperidone. Thus, their pharmacological effects are expected to be equivalent. We encountered a psychosis induced by the switch from risperidone to paliperidone.This is the case of a schizoaffective patient stabilised on risperidone long-acting injection (LAI) who consented to switch to paliperidone LAI. On day 0, he received his first dose of paliperidone. On day 86, he presented to the emergency department with an acute psychotic episode. On day 92, he committed a violent act. The patient was restarted on risperidone LAI and stabilised.Risperidone is extensively metabolised to paliperidone via CYP450 2D6. Interindividual and ethnic genetic polymorphism cause variability in CYP450 2D6 phenotypes. In this possible case of low-functioning alleles, the patient had a higher risperidone to paliperidone ratio at steady state. Although risperidone is paliperidone's prodrug, this case highlights the interindividual pharmacotherapeutic response to these two antipsychotics.

Long-acting injectable paliperidone palmitate induced severe cutaneous allergic reaction in a patient with first episode delusional disorder tolerating oral paliperidone regimen: a case report.

BACKGROUND: Paliperidone is a second-generation antipsychotic agent that is effective in the treatment of schizophrenia and schizoaffective disorder as well as an adjunct to mood stabilizers and antidepressants for bipolar and depressive disorders. Paliperidone is available in both oral and injection forms. Here we report an unexpected case of cutaneous allergic reaction induced by paliperidone long-acting injection (LAI) following oral tolerance. CASE PRESENTATION: A 55-year-old man with first episode delusional disorder was treated with paliperidone tablets with tolerance. On day seven he received the paliperidone LAI and developed an allergic reaction in minutes including flushing of the face, widespread urticaria with mild airway constriction. The allergic symptoms were relived following the administration of antihistamine within several minutes. CONCLUSION: The allergic reaction that occurred post administration of the paliperidone LAI but not the oral tablets suggest it is likely due to the excipients in the formulation of the LAI rather than paliperidone itself. This case highlights the necessity of monitoring allergic reactions in psychiatric patients when converting from oral to LAI format of paliperidone.

A Meta-Analysis of Antipsychotic-Induced Hypo- and Hyperprolactinemia in Children and Adolescents.

Objective: Antipsychotic-related prolactin changes may expose children and adolescents to severe adverse reactions (ARs) related to pubertal development and growth. We therefore aimed to assess the effects of antipsychotics on prolactin levels and associated somatic ARs in children and adolescents. Methods: We systematically searched PubMed and CENTRAL for placebo-controlled randomized trials of antipsychotics in children and adolescents aged ≤18 years, reporting prolactin levels and related ARs. We conducted a random-effect meta-analysis and assessed risk of bias version 2 (ROB2). Results: Thirty-two randomized controlled trials with an average trial duration of 6 weeks, covering 4643 participants with an average age of 13 years and a male majority of 65.3%. Risk of bias across domains was low or unclear. The following antipsychotic compounds: aripiprazole (n = 810), asenapine (n = 506), lurasidone (n = 314), olanzapine (n = 179), paliperidone (n = 149), quetiapine (n = 381), risperidone (n = 609), and ziprasidone (n = 16) were compared with placebo (n = 1658). Compared with placebo, statistically significant higher prolactin increase occurred with risperidone (mean difference [MD] = 28.24 ng/mL), paliperidone (20.98 ng/mL), and olanzapine (11.34 ng/mL). Aripiprazole significantly decreased prolactin (MD = -4.91 ng/mL), whereas quetiapine, lurasidone, and asenapine were not associated with significantly different prolactin levels than placebo. Our results on ziprasidone are based on a single study, making it insufficient to draw strong conclusions. On average, 20.8% of patients treated with antipsychotic developed levels of prolactin that were too high (hyperprolactinemia), whereas only 1.03% of patients reported prolactin-related ARs. Data were highly limited for long-term effects. Conclusions: In children and adolescents, risperidone, paliperidone, and olanzapine are associated with significant prolactin increase, whereas aripiprazole is associated with significant decrease. Despite the significant changes in prolactin level, few ARs were reported. Study protocol on PROSPERO: CRD42018116451.

Tardive Dyskinesia and Long-Acting Injectable Antipsychotics: Analyses Based on a Spontaneous Reporting System Database in Japan.

Objective: This study compared the reporting frequency of tardive dyskinesia (TD) between long-acting injectable antipsychotics (LAI-APs) and the equivalent oral antipsychotics (O-APs), LAI first-generation antipsychotics (LAI-FGAs) and LAI second-generation antipsychotics (LAI-SGAs), and individual LAI-APs.Methods: The Japanese Adverse Drug Event Report was used in this study, and data were obtained from April 2004 to February 2021. Patients who received LAI-APs available in Japan (LAI haloperidol, LAI fluphenazine, LAI aripiprazole, LAI risperidone, and LAI paliperidone) or the equivalent O-APs were included in this study. We calculated the adjusted reporting odds ratios (aRORs) to compare the reporting frequency of TD.Results: A total of 8,425 patients were included in the study. TD was reported significantly less frequently with LAI paliperidone than with oral paliperidone (aROR [95% confidence interval (CI)] = 0.13 [0.05-0.36]). Other LAI-APs were associated with a numerically lower reporting frequency of TD than the equivalent oral SGAs. The reporting frequency of TD associated with LAI-SGAs was significantly lower than that of LAI-FGAs (aROR [95% CI] = 0.18 [0.08-0.43]). All LAI-SGAs were significantly associated with a lower reporting frequency of TD than that of LAI fluphenazine (aROR [95% CI]: LAI aripiprazole, 0.11 [0.04-0.35]; LAI risperidone, 0.09 [0.03-0.32]; LAI paliperidone, 0.02 [0.005-0.09]). and LAI haloperidol, 8.58 [1.85-39.72]). LAI fluphenazine was significantly associated with a higher reporting frequency of TD than LAI haloperidol (aROR [95% CI] = 8.58 [1.85-39.72]). The reporting frequency of TD associated with LAI paliperidone was significantly lower than that with LAI aripiprazole (aROR [95% CI] = 0.18 [0.05-0.73]).Conclusions: Compared to O-APs, LAI-APs, particularly LAI-SGAs, may be associated with a lower risk of TD.

Paliperidone-Associated Sialorrhea: A Case Report With Review of Current Literature.

PURPOSE/BACKGROUND: Antipsychotic-associated sialorrhea is a problematic adverse effect with potentially negative consequences on quality of life and medication adherence. While clozapine is the antipsychotic that is most associated with sialorrhea, there have been published reports of other second-generation antipsychotics associated with sialorrhea, including aripiprazole, olanzapine, quetiapine, and risperidone. Although drooling is mentioned within the package insert for paliperidone, to date there have been minimal published reports in which paliperidone is implicated as the offending agent. METHODS/PROCEDURES: Here, we present a case of sialorrhea in a 56-year-old man with schizoaffective disorder who had a supratherapeutic paliperidone level after both oral and intramuscular paliperidone use. FINDINGS/RESULTS: Paliperidone was ultimately cross tapered to aripiprazole, and the patient was given atropine drops and benztropine with resolution of the sialorrhea. We provide a review of the literature regarding the other available reports of paliperidone-associated sialorrhea, possible mechanisms behind pathophysiology, as well as reports from the World Health Organization and Food and Drug Administration adverse event reporting systems. IMPLICATIONS/CONCLUSIONS: Clinicians should be aware of the potential for paliperidone and other nonclozapine second-generation antipsychotics to be associated with sialorrhea, especially given the increased frequency of their use for a variety of psychiatric disorders.