Risperidone Long-acting Injection Research Articles

Real-World Data Show Patients With Schizophrenia Adhere Better to Clozapine and LAIs

Back to table of contents Previous article Next article Clinical & ResearchFull AccessReal-World Data Show Patients With Schizophrenia Adhere Better to Clozapine and LAIsNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:8 Oct 2021https://doi.org/10.1176/appi.pn.2021.9.32AbstractAn analysis of national VA health databases shows clozapine along with long-acting formulas of aripiprazole and paliperidone have lower discontinuation rates than oral olanzapine, while oral quetiapine and ziprasidone have higher discontinuation rates.Patients with schizophrenia may be less likely to discontinue treatment if prescribed clozapine or long-acting injectable (LAI) formulations of second-generation antipsychotics, according to a report in AJP in Advance. The findings, which also revealed that patients who were taking multiple antipsychotics (polypharmacy) had lower discontinuation rates, were based on data from the U.S. Department of Veterans Affairs (VA).Though the data was limited to veterans, lead author Marc Weiser, M.D., head of the Division of Psychiatry at Sheba Medical Center in Ramat Gan, Israel, noted the findings mirrored those of a 2017 study that used Swedish medical data. “Replicating research findings is difficult,” Weiser noted. “When you have nearly identical outcomes from two studies done by different investigators in different countries using different patient populations, it points to the results being broadly applicable.”Weiser and colleagues compiled VA clinical and pharmacy data from all patients who received a schizophrenia diagnosis and at least one antipsychotic prescription lasting 60 days or more between October 2010 and September 2015. To keep the data robust, the investigators focused on antipsychotics with at least 150 prescriptions during the analysis period. The final sample included 37,368 patients with 62,056 antipsychotic prescriptions among 15 categories: nine oral medications (aripiprazole, clozapine, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, and all first-generation antipsychotics), five LAI formulations (first-generation drugs fluphenazine and haloperidol and second-generation aripiprazole, paliperidone, and risperidone), and patients receiving polypharmacy.The investigators compared the treatment discontinuation rates and hospital admission rates associated with all the medications relative to olanzapine. Weiser noted olanzapine was chosen as the reference since it is considered the most well-tolerated oral antipsychotic and it was used as the reference drug in the 2017 Swedish study.After adjusting for patient sociodemographic factors, Weiser and colleagues found that five groups had a lower risk of treatment discontinuation than olanzapine. These included patients taking clozapine (with nearly 60% less discontinuation risk than olanzapine), a trio of second-generation LAIs (aripiprazole, paliperidone, and risperidone), and patients on polypharmacy. Patients taking oral quetiapine, oral ziprasidone, oral aripiprazole, oral risperidone, and oral first-generation antipsychotics all had higher risks of discontinuation than those taking olanzapine. In a secondary analysis, the investigators found that all three second-generation LAIs were associated with lower risks of discontinuation with the oral formulations of the medications.Weiser told Psychiatric News that he was not surprised by the findings that clozapine was associated with a lower risk of treatment discontinuation than the other antipsychotics. “Since clozapine requires patients to check in regularly, physicians tend to prescribe it to patients who they believe will be compliant; there is a pre-screening process built in.”The polypharmacy findings were a bit more surprising, he noted. “Giving patients multiple antipsychotics is considered a no-no in clinical settings, but this finding supports that giving the right combination of drugs can boost their effectiveness,” he said. Future studies should look at which combinations may offer the most symptom improvement along with lowest risks of side effects.In contrast to the discontinuation findings, none of the medications were found to reduce the risk of psychiatric hospitalization compared with olanzapine. Weiser noted this was the one of the few divergences from the Swedish study, which found clozapine to be superior to olanzapine.While no antipsychotics were superior to olanzapine in terms of hospitalizations, several were associated with increased hospitalization risk: these included oral and LAI first-generation antipsychotics, as well as oral lurasidone, quetiapine, and ziprasidone.Weiser noted that he was particularly concerned about the quetiapine finding, being that this was the second most-prescribed medication in the sample (behind oral risperidone) and this medication was associated with a 36% increased risk of hospitalization. “It is interesting since in the general population, quetiapine is not used that extensively for schizophrenia,” he said. Rather, quetiapine is more commonly prescribed off-label for conditions like anxiety or insomnia.This study was supported by the Stanley Medical Research Institute. Weiser also serves on the staff of the Stanley Institute. ■“Differences in Antipsychotic Treatment Discontinuation Among Veterans With Schizophrenia in the U.S. Department of Veterans Affairs” is posted here.The 2017 analysis, “Real-World Effectiveness of Antipsychotic Treatments in a Nationwide Cohort of 29 823 Patients With Schizophrenia” is posted here. ISSUES NewArchived

PANSS Individual Item and Marder Dimension Analyses From a Pivotal Trial of RBP-7000 (Monthly Extended-Release Risperidone) in Schizophrenia Patients.

Background: Positive and Negative Syndrome Scale (PANSS) data from a pivotal phase 3 study in participants with schizophrenia of RBP-7000, a recently marketed long-acting subcutaneous injectable risperidone formulation, were examined to determine if dose-response relationships existed for different items of the PANSS.Methods: Changes in the 30 PANSS items were analyzed individually and using the 5 factor-analysis-derived dimensions defined by Marder and colleagues. Subgroups of patients who could benefit from the RBP-7000 120 mg dose were investigated.Results: 337 participants were randomized and received study medication (RBP-7000 90 mg n = 111, RBP-7000 120 mg n = 114, placebo n = 112). Dose-dependent responses were observed in items from the study-specified PANSS positive and general psychopathology exploratory subscales. Dose-dependent responses were observed across all 5 Marder dimensions, with the largest effect sizes observed with the 120 mg dose in the uncontrolled hostility/excitement (UHE) and anxiety/depression dimensions. Participants with baseline UHE dimension scores ≥ 9 demonstrated greater improvement in PANSS total score at the 120 mg dose compared to the 90 mg dose.Conclusions: RBP-7000 demonstrated efficacy across both the primary and exploratory PANSS study endpoints and the post hoc Marder dimensions. Schizophrenia patients with higher baseline Marder UHE scores may benefit from initiation of treatment at the 120 mg dose.Trial Registration: ClinicalTrials.gov identifier: NCT02109562.

Differences in Antipsychotic Treatment Discontinuation Among Veterans With Schizophrenia in the U.S. Department of Veterans Affairs.

Effectiveness of antipsychotic drugs is inferred from relatively small randomized clinical trials conducted with carefully selected and monitored participants. This evidence is not necessarily generalizable to individuals treated in daily clinical practice. The authors compared the clinical effectiveness between all oral and long-acting injectable (LAI) antipsychotic medications used in the treatment of schizophrenia in the U.S. Department of Veterans Affairs (VA) health care system. This was an observational study utilizing VA pharmacy data from 37,368 outpatient veterans with schizophrenia. Outcome measures were all-cause antipsychotic discontinuation and psychiatric hospitalizations. Oral olanzapine was used as the reference group. In multivariable analysis, clozapine (hazard ratio=0.43), aripiprazole long-acting injectable (LAI) (hazard ratio=0.71), paliperidone LAI (hazard ratio=0.76), antipsychotic polypharmacy (hazard ratio=0.77), and risperidone LAI (hazard ratio=0.91) were associated with reduced hazard of discontinuation compared with oral olanzapine. Oral first-generation antipsychotics (hazard ratio=1.16), oral risperidone (hazard ratio=1.15), oral aripiprazole (hazard ratio=1.14), oral ziprasidone (hazard ratio=1.13), and oral quetiapine (hazard ratio=1.11) were significantly associated with an increased risk of discontinuation compared with oral olanzapine. No treatment showed reduced risk of psychiatric hospitalization compared with oral olanzapine; quetiapine was associated with a 36% worse outcome in terms of hospitalizations compared with olanzapine. In a national sample of veterans with schizophrenia, those treated with clozapine, two of the LAI second-generation antipsychotics, and antipsychotic polypharmacy continued the same antipsychotic therapy for a longer period of time compared with the reference drug. This may reflect greater overall acceptability of these medications in clinical practice.

Review of Pharmacokinetics and Pharmacogenetics in Atypical Long-Acting Injectable Antipsychotics.

Over the last two decades, pharmacogenetics and pharmacokinetics have been increasingly used in clinical practice in Psychiatry due to the high variability regarding response and side effects of antipsychotic drugs. Specifically, long-acting injectable (LAI) antipsychotics have different pharmacokinetic profile than oral formulations due to their sustained release characteristics. In addition, most of these drugs are metabolized by CYP2D6, whose interindividual genetic variability results in different metabolizer status and, consequently, into different plasma concentrations of the drugs. In this context, there is consistent evidence which supports the use of therapeutic drug monitoring (TDM) along with pharmacogenetic tests to improve safety and efficacy of antipsychotic pharmacotherapy. This comprehensive review aims to compile all the available pharmacokinetic and pharmacogenetic data regarding the three major LAI atypical antipsychotics: risperidone, paliperidone and aripiprazole. On the one hand, CYP2D6 metabolizer status influences the pharmacokinetics of LAI aripiprazole, but this relation remains a matter of debate for LAI risperidone and LAI paliperidone. On the other hand, developed population pharmacokinetic (popPK) models showed the influence of body weight or administration site on the pharmacokinetics of these LAI antipsychotics. The combination of pharmacogenetics and pharmacokinetics (including popPK models) leads to a personalized antipsychotic therapy. In this sense, the optimization of these treatments improves the benefit–risk balance and, consequently, patients’ quality of life.

Long-acting injectable antipsychotics during pregnancy: An update

IntroductionLong-acting injectable (LAI) antipsychotics are related to proven compliance to treatment and more constant medication levels (hence the apparent lower side-effect burden).ObjectivesTo highlight the experience with LAI antipsychotic treatment during pregnancy.MethodsLiterature review.ResultsSeven cases are reported. A 35year old with schizophrenia received zuclopenthixole LAI (mostly 200mg/monthly) during both her pregnancies (of healthy girls born at weeks 39 and 40). A 35year old with schizophrenia was under risperidone LAI (25mg/2 weeks) and gave birth to a healthy girl at week 37. Another 35year old (probably with schizophrenia) was on olanzapine LAI (300mg/month during the last quarter of her pregnancy) that led to the birth of a healthy girl at week 40. A 37year old with schizophrenia received paliperidone LAI (100mg/monthly, last injection at week 28) and gave birth to a healthy boy at week 39. Paliperidone LAI (50mg/monthly) was the treatment of another 34year old with schizoaffective disorder that gave birth to a healthy boy at week 40, as well as of a 26year old (263mg/3-monthly), mother of a healthy boy as well (born at an unspecified week of pregnancy). Finally, a 43year old with bipolar disorder was on aripiprazole LAI (300mg/monthly) during her pregnancy that led to the birth of a healthy girl at week 40.ConclusionsAll pregnant women on LAI antipsychotic treatment gave birth to (apparently) healthy babies. LAI doses were mostly low. Long-term follow-up could clarify eventual delayed aftereffects. Based on the literature, LAI antipsychotic treatment could be considered as an option for selected pregnant patients.DisclosureNo significant relationships.

Pharmacokinetics, pharmacodynamics and safety of a single-dose long-acting Risperidone injection in Chinese patients with schizophrenia

Pharmacokinetics, pharmacodynamics and safety of a single-dose long-acting Risperidone injection in Chinese patients with schizophrenia

Neuroleptic malignant syndrome associated with long-acting injectable versus oral second-generation antipsychotics: Analyses based on a spontaneous reporting system database in Japan

Long-acting injectable antipsychotics (LAI-APs) remain underutilized. One reason is the concern that LAI-APs might cause serious adverse events such as neuroleptic malignant syndrome (NMS) and lead to prolonged symptoms compared with oral treatment. Because the risk of NMS associated with LAI second-generation antipsychotics (LAI-SGAs) remains unclear, we compared reporting frequency, time to onset, and mortality of NMS between LAI- and oral SGAs using data from a Japanese spontaneous adverse event reporting database between April 2004 and September 2019. Of 5791 patients reporting adverse events due to LAI-SGAs or the equivalent oral SGAs, 768 (13%) developed NMS. LAI aripiprazole and LAI paliperidone were associated with a significantly lower reporting frequency of NMS than the equivalent oral SGAs (adjusted reporting odds ratio [95% confidence interval]: 0.35 [0.19–0.63] and 0.40 [0.27–0.59], respectively). Between 42% and 62% of the NMS associated with LAI- and oral SGAs other than LAI risperidone occurred within 30 days after initiation. The proportion of mortality due to NMS associated with oral aripiprazole was 13.1% and no deaths occurred in patients with NMS associated with LAI aripiprazole. The proportions of mortality due to NMS associated with oral risperidone/paliperidone, LAI risperidone, and LAI paliperidone were 8.8%, 4.2%, and 3.4%, respectively. Our findings showed that LAI-SGAs were not associated with a higher reporting frequency and mortality of NMS compared with oral SGAs, although clinicians need to closely monitor the occurrence of NMS not only during oral SGA treatment, but also, and in particular, in the early stage of LAI-SGA treatment.

Effects of CYP2D6, CYP3A5, and ABCB1 gene polymorphisms on the pharmacokinetics of two risperidone long-acting injection microsphere formulations

BackgroundLY03004, a novel investigational risperidone long-acting injection (LAI) microsphere formulation, can release risperidone more quickly after injection than Risperdal Consta®. This study aimed to investigate the effects of genetic polymorphisms on the pharmacokinetics of LY03004 compared with those on Risperdal Consta®. MethodsA total of 100 Chinese patients with stable schizophrenia were randomly assigned to the LY03004 or Risperdal Consta® treatment group. Each patient received five biweekly intramuscular injections of 25 mg risperidone long-acting injection microspheres. A total of 34 blood samples before and after injections from Day 1 to Day 113 were collected from each patient, and polymorphic alleles of cytochrome P450 enzymes CYP2D6 (*4, *10, *14), CYP3A5 (*3), and ABCB1 (C1236 > T, G2677T/A, and C3435T) were analyzed using Sanger sequencing and polymerase chain reaction-restriction fragment length polymorphism. ResultsThe risperidone Cmax,ss, Cmin,ss, AUC0-tau,ss, and the ratio of risperidone to 9-hydroxyrisperidone (9-OH-R) in CYP2D6 intermediate metabolizers (IMs) were significantly different compared with those in normal metabolizers (NMs) in both the LY03004 and Risperdal Consta® groups (P < 0.05). However, 9-OH-R was not significantly different between IMs and NMs (P > 0.05). The AUC0-tau,ss of the active moiety (risperidone plus 9-OH-R) was 6.51 ± 3.34 in NMs and 7.00 ± 1.81 in IMs (P = 0.071) in the LY03004 group and 6.07 ± 2.31 and 7.95 ± 3.42 (P = 0.053) in NMs and IMs, respectively, in the Risperdal Consta® group. In the LY03004 group, the Cmax,ss of risperidone in carriers of the ABCB1-C3435T TT variant was significantly lower than that in CC and CT carriers (TT 7.76 ± 4.23 ng/mL, CT 11.6 ± 8.27 ng/mL, CC 14.3 ± 7.66 ng/ml; P = 0.045), but no significant differences were found in the active moiety. In the Risperdal Consta® group, C3435T TT carriers had significantly lower Cmin,ss of the active moiety (TT 5.09 ± 4.38 ng/mL, CT 11.4 ± 8.42 ng/mL, CC 14.3 ± 6.43 ng/mL; P = 0.007). Furthermore, Cmin,ss of the active moiety was significantly different among all ABCB1-G2677T/A genotypes (P < 0.05). ConclusionThe pharmacokinetics of risperidone and the ratio of risperidone to 9-OH-R were highly dependent on CYP2D6 activity. However, there was no significant effect in 9-OH-R. A future study involving a larger sample is required to verify whether CYP2D6 IMs have lower risperidone active moiety clearance than CYP2D6 NMs for LAI formulations. In addition, the risperidone active moiety was eliminated faster in ABCB1-G2677T/A and C3435T TT carriers receiving Risperdal Consta®.

Sex-Specific Associations Between Bipolar Disorder Pharmacological Maintenance Therapies and Inpatient Rehospitalizations: A 9-Year Swedish National Registry Study.

Background: Long-term pharmacological maintenance therapy is often essential among people with bipolar disorder to reduce the need for inpatient care. Sex-specific responses to maintenance therapies are expected but remain largely unknown. Here, we examined for sex-specific associations between common maintenance therapies for bipolar disorder with inpatient rehospitalizations following patients' index discharges during 2006–2014.Methods: Population-based data on maintenance therapies and rehospitalizations were extracted from Swedish national registries. We adopted the within-individual design to compare the time on- vs. off- maintenance therapy for males and females, respectively. Extended stratified Cox proportional hazards regression models were employed to quantify the rate of rehospitalization as a function of common maintenance drugs and other important time-varying control variables.Results: Our primary analysis included 22,681 bipolar disorder rehospitalizations by 6,400 males and 9,588 (60.0%) females over an observation time of 62,813 person-years. The time spent on- vs. off- maintenance lithium, lamotrigine, quetiapine, or olanzapine was statistically significant upon adjustment among either sex for reducing the rate of bipolar rehospitalizations. Adjusted sex-specific statistically significant associations were also observed. Among females, the time on- (vs. off-) long-acting injectable risperidone reduced the rate of bipolar rehospitalizations by 73% (56–84%), carbamazepine by 44% (18–62%), aripiprazole by 29% (13–42%), and valproate by 23% (11–33%); whereas among males, ziprasidone by 65% (41–79%).Conclusion: The effectiveness of most maintenance therapies is generally comparable and uniform among both males and females. Despite some statistically significant sex-specific associations, estimates for each drug were fairly consistent between sexes.

Mood stabilizers and/or antipsychotics for bipolar disorder in the maintenance phase: a systematic review and network meta-analysis of randomized controlled trials

We searched Embase, PubMed, and CENTRAL from inception until 22 May 2020 to investigate which antipsychotics and/or mood stabilizers are better for patients with bipolar disorder in the maintenance phase. We performed two categorical network meta-analyses. The first included monotherapy studies and studies in which the two drugs used were specified (i.e., aripiprazole, aripiprazole once monthly, aripiprazole+lamotrigine, aripiprazole+valproate, asenapine, carbamazepine, lamotrigine, lamotrigine+valproate, lithium, lithium+oxcarbazepine, lithium+valproate, olanzapine, paliperidone, quetiapine, risperidone long-acting injection, valproate, and placebo). The second included studies on second-generation antipsychotic combination therapies (SGAs) (i.e., aripiprazole, lurasidone, olanzapine, quetiapine, and ziprasidone) with lithium or valproate (LIT/VAL) compared with placebo with LIT/VAL. Outcomes were recurrence/relapse rate of any mood episode (RR-any, primary), depressive episode (RR-dep) and manic/hypomanic/mixed episode (RR-mania), discontinuation, mortality, and individual adverse events. Risk ratios and 95% credible interval were calculated. Forty-one randomized controlled trials were identified (n = 9821; mean study duration, 70.5 ± 36.6 weeks; percent female, 54.1%; mean age, 40.7 years). All active treatments other than carbamazepine, lamotrigine+valproate (no data) and paliperidone outperformed the placebo for RR-any. Aripiprazole+valproate, lamotrigine, lamotrigine+valproate, lithium, olanzapine, and quetiapine outperformed placebo for RR-dep. All active treatments, other than aripiprazole+valproate, carbamazepine, lamotrigine, and lamotrigine+valproate, outperformed placebo for RR-mania. Asenapine, lithium, olanzapine, quetiapine, and valproate outperformed placebo for all-cause discontinuation. All SGAs+LIT/VALs other than olanzapine+LIT/VAL outperformed placebo+LIT/VAL for RR-any. Lurasidone+LIT/VAL and quetiapine+LIT/VAL outperformed placebo+LIT/VAL for RR-dep. Aripiprazole+LIT/VAL and quetiapine+LIT/VAL outperformed placebo+LIT/VAL for RR-mania. Lurasidone+LIT/VAL and quetiapine+LIT/VAL outperformed placebo+LIT/VAL for all-cause discontinuation. Treatment efficacy, tolerability, and safety profiles differed among treatments.

Updating the Comparative Evidence on Second-Generation Antipsychotic Use With Schizophrenia.

ObjectiveThe objective of this study was to conduct a systematic review of literature comparing second‐generation antipsychotics (SGAs) with each other and with first‐generation antipsychotics (FGAs) in treating schizophrenia.MethodsMEDLINE, the Cochrane Library, and PsycINFO databases were searched through January 2020. Following standard methods, recent high‐quality systematic reviews of each drug comparison and subsequently published primary studies were included to update the meta‐analyses with any new data. Two reviewers independently conducted study selection, abstraction, and quality assessment.ResultsTwo systematic reviews and 29 newer trials (total of 162 trials of SGAs, N=53,861; 116 trials of SGAs versus FGAs, N=119,558) were included. Most trials were of fair quality, industry‐funded, and included older SGAs and a few recently approved SGAs (asenapine, lurasidone, iloperidone, cariprazine, brexpiprazole and long‐acting injection [LAI] formulations of aripiprazole and paliperidone). Older SGAs had similar effects on function, quality of life, mortality, and adverse event incidence, although clozapine improved symptoms more than most other drugs and olanzapine and risperidone were superior to some other drugs. Olanzapine, risperidone, ziprasidone, and aripiprazole performed similarly on outcomes of benefit compared with haloperidol. Risperidone LAI and olanzapine resulted in fewer withdrawals due to adverse events, but risk of diabetes increased with olanzapine. Haloperidol had greater incidence of adverse events than did olanzapine and risperidone, but similar effects on other outcomes.ConclusionsMost comparative evidence favored older SGAs, with clozapine, olanzapine, and risperidone superior on more outcomes than other SGAs. Older SGAs had similar benefits as haloperidol but with fewer adverse events.

A randomized controlled trial of cognitive remediation and long-acting injectable risperidone after a first episode of schizophrenia: improving cognition and work/school functioning.

Cognitive deficits at the first episode of schizophrenia are predictive of functional outcome. Interventions that improve cognitive functioning early in schizophrenia are critical if we hope to prevent or limit long-term disability in this disorder. We completed a 12-month randomized controlled trial of cognitive remediation and of long-acting injectable (LAI) risperidone with 60 patients with a recent first episode of schizophrenia. Cognitive remediation involved programs focused on basic cognitive processes as well as more complex, life-like situations. Healthy behavior training of equal treatment time was the comparison group for cognitive remediation, while oral risperidone was the comparator for LAI risperidone in a 2 × 2 design. All patients were provided supported employment/education to encourage return to work or school. Both antipsychotic medication adherence and cognitive remediation contributed to cognitive improvement. Cognitive remediation was superior to healthy behavior training in the LAI medication condition but not the oral medication condition. Cognitive remediation was also superior when medication adherence and protocol completion were covaried. Both LAI antipsychotic medication and cognitive remediation led to significantly greater improvement in work/school functioning. Effect sizes were larger than in most prior studies of first-episode patients. In addition, cognitive improvement was significantly correlated with work/school functional improvement. These results indicate that consistent antipsychotic medication adherence and cognitive remediation can significantly improve core cognitive deficits in the initial period of schizophrenia. When combined with supported employment/education, cognitive remediation and LAI antipsychotic medication show separate significant impact on improving work/school functioning.

Dissociation in Pharmacokinetic Attenuation Between Central Dopamine D2 Receptor Occupancy and Peripheral Blood Concentration of Antipsychotics: A Systematic Review.

The objective of this study was to examine the extent of possible dissociation in pharmacokinetic decay between central dopamine D₂ receptor occupancy with antipsychotics and their peripheral blood concentrations. MEDLINE and Embase were searched using the following keywords: (positron emission tomography OR PET OR single-photon emission computed tomography OR SPECT) AND (dopamine OR D2) AND (receptor* OR occupanc*) AND antipsychotic*, with a limitation of English language (last search: December 14, 2019). The search identified 18 studies that met the following criteria: (1) including patients with schizophrenia spectrum disorders and/or healthy subjects, (2) using positron emission tomography or single-photon emission computed tomography, and (3) examining the time courses of D₂ occupancy with antipsychotics and their blood concentrations. The ratios of D₂ occupancy reduction rate (%) from peak to blood concentration reduction rate (%) from peak (relative attenuation ratio) were calculated. Among the studies, oral risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, perospirone, haloperidol, sulpiride, and clozapine and long-acting injectable risperidone and haloperidol were included. Relative attenuation ratios were less than 1, indicating a slower central versus peripheral attenuation, across the time points for all antipsychotic types and doses with only a few exceptions. The ratio decreased in a dose-dependent as well as a peak D₂ occupancy-dependent fashion. It contrarily increased in a time-dependent manner. The findings indicate pharmacokinetic attenuation of antipsychotics was generally slower at the central versus the peripheral level and pose a critical challenge to the current dosing strategy that primarily relies on peripheral pharmacokinetics of antipsychotics.

S56. SWITCHING FROM RISPERIDONE TO PALIPERIDONE PALMITATE IN SCHIZOPHRENIA: CHANGES IN COGNITIVE FUNCTION

BackgroundPrevious studies assessing the neurotoxicity of haloperidol, risperidone and paliperidone in cell culture suggest that paliperidone shows the strongest neuroprotective effect and a reduced apoptosis level. Other studies including patients with schizophrenia suggest that switching from risperidone long-acting injection (RLAI) to paliperidone palmitate (PP) may improve cognitive function in processing speed and attention. We aimed to study whether switching from risperidone to PP is associated with improved cognitive abilities at 3 or 6 months after the switch.MethodsOur initial sample included 32 patients with schizophrenia attending to the Department of Mental Health from Parc Taulí Hospital (Sabadell, Barcelona). All patients were treated with oral risperidone or RLAI (at least two months of stable treatment in monotherapy) and had the indication to be switched to PP by their psychiatrists. Of all 32 patients, 24 (75%) had at least a follow-up visit at 3 months. Therefore, statistical analyses were conducted in a final sample of 24 patients (88% men; 35.6 ± 12.3 years; 63% were receiving RLAI at baseline visit). Ethical approval was obtained from the local Ethics Committee and all participants provided written informed consent. Clinical diagnoses for schizophrenia were generated with the OPCRIT checklist v.4.0. Three assessments were completed: 1) baseline (pre-switch), 2) 3 months post-switch, 3) 6 months post-switch. Cognitive assessment was conducted at each visit with the MATRICS Consensus Cognitive Battery, which includes 10 cognitive tests for assessing 7 cognitive domains. Statistical analyses were performed with SPSS v 23.0 (IBM, USA). A non-parametric paired test (Wilcoxon test) was used for comparing changes in cognitive function over time (baseline vs 3 months; baseline vs 6 months). Significance was set at p<0.05.ResultsSignificant improvements in cognitive function were found for two cognitive tasks dealing with processing speed (BACS-SC and TMT-A) and one task dealing with attention and vigilance (CPT-IP) at both 3 and 6 months. Although reasoning and problem solving (NAB Mazes) or spatial working memory (WMS-III-Spatial Span) did not improve at 3 months, significant improvements in these two cognitive tasks were found at 6 months. Verbal memory, visual memory and social cognition did not improve over time.DiscussionIn patients with schizophrenia, switching from risperidone to PP is associated with cognitive improvement in tasks dealing with processing speed, attention, working memory and reasoning and problem solving. Our findings are in accordance with previous studies that suggest a potential neuroprotective effect of paliperidone. Some limitations of our study include the lack of randomization (no control group) and the small sample size. The small number of female patients does not allow to explore potential sex differences in the improved cognitive outcome.

What Antipsychotic Dose Is Most Effective?

Back to table of contents Previous article Next article Clinical & ResearchFull AccessWhat Antipsychotic Dose Is Most Effective?Nick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:10 Jan 2020https://doi.org/10.1176/appi.pn.2020.1b3AbstractA large meta-analysis calculated optimal doses for 19 different antipsychotics and found that for several medications, doses above the maximum licensed dose might be most effective. Combining clinical data from 68 separate studies, a research team has estimated the most effective dose for 19 different antipsychotic medications, including both oral and long-acting injectable (LAI) formulations. The researchers also calculated the dose equivalents of these 19 medications to guide physicians who may be considering switching patients from one antipsychotic to another. This meta-analysis was published in December 2019 in AJP in Advance.The minimum and maximum effective doses of antipsychotic drugs are not well understood, wrote Stefan Leucht, M.D., of the Technical University of Munich and colleagues. Though approved medications are licensed within a specific range of doses, these amounts are usually calculated early in the drug development process and may not reflect the optimal range for patients.Leucht and colleagues identified clinical trials that compared multiple doses of the same antipsychotics relative to placebo in people with acute schizophrenia symptoms. They then calculated how well symptoms improved in those taking different doses of the following medications: amisulpride, aripiprazole (oral and LAI), asenapine, brexpiprazole, cariprazine, clozapine, haloperidol, iloperidone, lurasidone, olanzapine (oral and LAI), paliperidone (oral and LAI), quetiapine, risperidone (oral and LAI), sertindole, and ziprasidone.he dose-response profiles for these 19 medications fell into two major classes. The first were antipsychotics whose effects plateaued or started dropping at higher tested doses, suggesting the optimal dose is within the currently licensed range. These medications included the following: amisulpride, oral and LAI aripiprazole, asenapine, brexpiprazole, cariprazine, haloperidol, oral olanzapine (when given to patients with predominantly negative symptoms), quetiapine, and oral and LAI risperidone.In some instances, the most effective dose was well below the upper prescribing limits. For example, the most effective dose of oral risperidone—which is approved up to 16 mg/day—is 6.3 mg/day, according to the analysis.“Clinicians often use relatively high doses of antipsychotics in practice,” Leucht told Psychiatric News. “Our analysis shows that for many antipsychotics such doses are not generally recommendable.”For the other medications—including clozapine, iloperidone, lurasidone, oral olanzapine (in patients with predominantly positive symptoms), LAI olanzapine, oral and LAI paliperidone, sertindole, and ziprasidone—there was no indication that the dose-response was plateauing. The authors said that this finding suggests that doses above the licensed limit might be more effective.Leucht cautioned that the dosing analysis considered only symptom improvements and that patients prescribed higher doses of these medications might experience worse side effects. Further controlled studies on dosing are needed to assess the risk-benefit profile of these antipsychotics at elevated doses, he said.“Clinicians need to be aware that if they go beyond the officially licensed doses, they are applying the drug ‘off label’ and should be careful in this regard.”Leucht also noted that the dose estimates for clozapine, haloperidol, LAI aripipazole, LAI olanzapine, and LAI risperidone were each based on a single dosing study, so the data should be interpreted with caution.The researchers also calculated the dose equivalencies of the antipsychotics, using haloperidol, olanzapine, and risperidone as reference drugs (for example, 1 mg of risperidone = x amount of the other medications). These equivalencies can help physicians considering prescribing a different medication, but the researchers cautioned that physicians should look at the full profiles of each medication and not just rely on the conversion calculator. For example, 20 mg/day olanzapine corresponds to 8.25 mg/day risperidone, but an 8.25 mg/day dose of risperidone may be less effective than the optimal level of 6.3 mg/day.“We stress that our results provide some guidance based on ‘average’ patients with chronic illness,” Leucht and colleagues wrote in the article. “The dose-response relationships in specific populations, such as first-episode patients, elderly patients (who need lower doses), and patients with treatment-resistant illness, are likely to be different.” Physicians should use these data as a starting point and then base individual dosing decisions on the properties of each medication, patient characteristics, and any other treatments that might influence antipsychotic response, they concluded.The authors reported no funding information in the article. ■ “Dose-Response Meta-Analysis of Antipsychotic Drugs for Acute Schizophrenia” is posted here. ISSUES NewArchived

PMH28 ASSESSING THE LIFE-CYCLE VALUE ADDED OF SECOND-GENERATION ANTIPSYCHOTICS IN SWEDEN AND THE UK: THE CASE OF RISPERIDONE

To estimate the life-cycle value of risperidone – representative of Second-Generation Antipsychotics– relative to First Generation Antipsychotics to balance the view that cost per Quality-Adjusted Life Year (QALY) at launch are enough to guide access decisions. Study aims to drive the discussion on access and price, through recognition of the dynamic nature of value added by pharmaceutical innovation over the long-run. We estimated the number of patients with schizophrenia treated with risperidone in Sweden and the UK (1994-2017). We collected cost-effectiveness data from the literature of risperidone and haloperidol – representative of First-Generation Antipsychotics. We modelled the life-cycle uptake of risperidone to estimate the life-cycle incremental cost, incremental QALYs and Net monetary Benefit (NMB). We also assessed the life-cycle distribution of the consumer (the payer) and the producer (innovator) surpluses. For the UK, the producer surplus represents around 28% of the total surplus before patent expiration and around 5% after patent expiration. Life-cycle NMB for the health system is estimated at €1,116m. During the life-cycle, the NMB significantly increased in response to two events: (i) the launch of Risperidone Long-Acting Injectable (RLAI); and (ii) generic entry. The ICER was negative (dominant) for the whole period. For Sweden, the producer surplus represents around 6% of the total surplus before patent expiration and around 1% after generic competition. Life-cycle NMB is estimated at €803m, and both NMB and ICER follow the same pattern as in the UK. Analysis shows that health systems appropriated most of the life-cycle value (surplus) generated. This suggests that, considering the entire life-cycle, the value added by SGAs to the system is higher than the value estimated using cost-effectiveness analysis at launch. Pricing and reimbursement decisions should take into account the dynamic nature of pharmaceutical markets and the value added by innovative medicines over the long-run.

Predicting relapse with residual symptoms in schizophrenia: A secondary analysis of the PROACTIVE trial

IntroductionLittle attention has been paid to the contribution of individual residual symptom to predict relapse in patients with schizophrenia receiving oral or long-acting injectable (LAI) antipsychotics. MethodWe used the data from the Preventing Relapse on Oral Antipsychotics Compared to Injectables - Evaluating Efficacy (PROACTIVE) study, in which 305 outpatients with schizophrenia were randomly allocated to either biweekly LAI-risperidone (LAI-R) or daily oral second-generation antipsychotics (SGA) and assessed for up to 30 months. Baseline individual symptoms that could predict subsequent relapse were identified, using a Cox proportional hazards model. Moreover, among those who relapsed during the study (n = 73), individual symptoms were compared between baseline and biweekly ratings 8 to 2 weeks before relapse, using the linear mixed model. ResultsA greater score in grandiosity at baseline was significantly associated with subsequent relapse (adjusted HR = 1.24, p = 0.006). When the two treatment groups were separately analyzed, more severe grandiosity (adjusted HR = 1.43, p = 0.003) and less severe hallucinatory behavior (adjusted HR = 0.70, p = 0.013) at baseline were significantly associated with relapse in the oral SGA group, but none was identified in the LAI-R group. Emotional withdrawal was significantly worse 8 and 2 weeks before relapse compared to the baseline (p = 0.032 and p = 0.043, respectively). DiscussionMore severe grandiosity and less hallucination may have led to more frequent relapses in patients with schizophrenia receiving oral antipsychotics, which was not a case in those receiving LAI-R. The exploratory analysis indicates an increase in emotional withdrawal before relapse may be a useful marker for earlier interventions to possibly avert relapse.

Real-life persistence of long-acting injectable antipsychotics in schizophrenic patients: Aretrospective observational study in France .

Antipsychotics exhibit different profiles of efficacy and safety in patients with schizophrenia. It has recently been reported that the risk of rehospitalization was the lowest with paliperidone palmitate (PP), a long-acting injectable (LAI), when compared with other LAIs (of zuclopenthixol, perphenazine, and olanzapine). We aimed to investigate whether treating patients with PP was also associated with improved real-life treatment persistence. We conducted a retrospective observational study of the LAI antipsychotics (LAIAs) dispensed in French retail pharmacies. Treatment persistence was defined as the non-discontinuation of LAIAs for ≥5 months after LAIA initiation (and was also analyzed by Kaplan-Meier persistence curves). A total of 4,492 patients were included in the study. The persistence rate was significantly greater for LAI-PP (64.5%) than for either LAI haloperidol decanoate (HD) or LAI risperidone microspheres (R) (46.4% and 35.4%, respectively). Multivariate Cox analyses illustrated that LAIA initiation with HD or R significantly increased the risk of discontinuation when compared with PP. PP demonstrated a significantly higher persistence rate than HD or R. Moreover, LAIA initiation with HD or R significantly increased the risk of treatment discontinuation relative to PP. Further comparative studies are required to comprehensively determine whether PP has a better efficacy and/or safety profile than other LAIs.

Modeling the Choice Between Risperidone Long-Acting Injectable and Generic Risperidone from the Perspective of a Japanese Hospital.

IntroductionThe Japanese government’s current policy is to encourage hospitals to discharge hospital patients with schizophrenia earlier and provide them with community care. This study aims to analyze clinical and economic outcomes of different discharge strategies in psychiatric hospitals in Japan.MethodsA simulation was conducted to compare patient relapse and hospital revenues for different discharge plans. We constructed a decision tree where each tree consists of a different Markov chain that models hospital revenue for four different discharge plans: discharge of the patient after 1, 2, or 3 months, or 4 months or more. The simulation also included variations in the medical treatment regimen in an outpatient setting as part of the discharge strategy. In particular, we looked at the choice between risperidone long-acting injectable (RLAI) and generic risperidone (RIS GE).ResultsThe use of RLAI in an outpatient setting reduced the number of rehospitalizations compared to generic risperidone use under all discharge plans. Different discharge plans were associated with differences in economic outcomes as well. One of the key revenue drivers for the hospital was the continuation of treatment in the outpatient setting after discharge.ConclusionThe use of RLAI in an outpatient setting could help to prevent rehospitalization, thereby contributing to better community care.FundingThe Rapid Service Fee was funded by Janssen KK.

Continuation of schizophrenia treatment with three long-acting injectable antipsychotics in South Korea: A nationwide population-based study

Long-acting injectable (LAI) antipsychotics have been developed to prevent symptom relapse in patients with schizophrenia; relapse has a detrimental clinical impact and high social burden. However, data on treatment continuation rates of LAI antipsychotics are inconsistent, primarily because of study design; limited data exist for patients taking oral psychotropic medications taken along with LAI antipsychotics, and factors related to LAI antipsychotics treatment discontinuation. Patients with schizophrenia in the South Korea Health Insurance Review Agency database from 2007 to 2016 who had received LAI haloperidol, LAI paliperidone, or LAI risperidone were included. Treatment continuation rates and proportions of patients using concurrent oral psychotropic medications were calculated. Cox proportional hazard ratios were used for analysis related to discontinuation. There was a significant difference in treatment continuation rates at 6 months after initiation (36.8% LAI haloperidol, 57.5% LAI paliperidone, and 34.5% LAI risperidone). A substantial proportion of patients in all three groups were prescribed oral antipsychotics during LAI antipsychotics treatment. In the LAI paliperidone group, type of hospital was significantly associated with a higher risk of treatment discontinuation, with a hazard ratio of 1.195–1.598. Early discontinuation of LAI antipsychotic treatment occurs in a large number of patients with schizophrenia. Intervention strategies for improving the LAI antipsychotics treatment adherence are needed.