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Robert Litman,1,2 Dieter Naber,3 Lourdes Anta,4 Javier Martínez,4 Yuriy Filts,5 Christoph U Correll6– 8 1CBH Health LLC, Gaithersburg, MD, USA; 2Department of Psychiatry, Georgetown University Medical School, Washington, DC, USA; 3Department of Psychiatry and Psychotherapy, Hamburg-Eppendorf University, Hamburg, Germany; 4Medical Department, Laboratorios Farmacéuticos ROVI, S.A., Madrid, Spain; 5Communal Noncommercial Enterprise of Lviv Regional Council, Lviv Regional Clinical Psychiatric Hospital, Lviv, Ukraine; 6Department of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY, USA; 7Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA; 8Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin Berlin, Berlin, GermanyCorrespondence: Javier Martínez, Laboratorios Farmacéuticos ROVI, S.A., Calle Alfonso Gómez, 45A, Madrid, 28037, Spain, Tel +34 91 375 63 36, Fax +34 91 304 78 81, Email jmartinez@rovi.esObjective: To analyze the effect of Risperidone ISM on social functioning and health-related quality of life (HR-QoL) in both short- and long-term treatment of patients with schizophrenia.Patients and Methods: This analysis was based on data from both phases of the PRISMA-3 study, including 433 relapsed patients from the double-blind (DB) phase of the PRISMA-3 trial who were treated for 12-weeks with once-monthly (every 28 days) intramuscular Risperidone ISM 75 mg or 100 mg (n = 288), or placebo (n = 145), as well as 174 patients transitioning from the DB to an open-label 52-week extension (OLE) phase, plus 41 de novo patients treated on a stable maintenance dose of oral risperidone. The clinician-administered Personal and Social Performance (PSP) scale and the patient-reported 20-item Subjective Well-being under Neuroleptics scale (SWN-20) were used to measure social functioning and HR-QoL outcomes, respectively.Results: Risperidone ISM significantly improved PSP total score from baseline to endpoint (Day 85) versus placebo in the DB phase with mean change total score (95% CI) of 10.7 (9; 12) compared to 4.8 (3; 7) for placebo (p < 0.0001). The statistically significant improvement was present from the first measurement time point (Day 29). SWN-20-measured HR-QoL increased on average in patients treated with Risperidone ISM in the DB phase. A significant improvement was also observed for PSP and SWN-20 scores from the OLE baseline to week 52 for patients transitioning from the DB phase. Stable de novo patients maintained similar PSP and SWN-20 scores during the whole OLE phase.Conclusion: Risperidone ISM provided a rapid and sustained improvement in personal and social functioning, and HR-QOL without need of oral risperidone supplementation or loading doses. These findings, along with a fast onset of efficacy, could contribute to reinforcing the therapeutic alliance and possibly an earlier discharge. Moreover, patient functioning continued improving or was maintained with long-term treatment.Keywords: risperidone, long-acting injectable, antipsychotics, schizophrenia, social functioning, quality of life

David P Walling,1 Howard A Hassman,2 Lourdes Anta,3 Lourdes Ochoa,4 Ignacio Ayani,3 Javier Martínez,3 Ibon Gutierro4 1Collaborative Neuroscience Network, LLC Garden Grove, Garden Grove, CA, USA; 2Hassman Research Institute, Berlin, NJ, USA; 3Medical Department, Laboratorios Farmacéuticos ROVI, S.A., Madrid, Spain; 4R&D Department, Laboratorios Farmacéuticos ROVI, S.A., Madrid, SpainCorrespondence: Javier MartínezLaboratorios Farmacéuticos ROVI, S.A., Calle Alfonso Gómez, 45A, Madrid, 28037, SpainTel + 34 91 375 63 36Fax + 34 91 304 78 81Email jmartinez@rovi.esIntroduction: This open-label, one-sequence study evaluated the steady-state comparative bioavailability of risperidone in situ microimplants (ISM®) and oral risperidone in patients stabilized on oral risperidone treatment.Methods: Repeat oral administration of once daily 4 mg risperidone for 7 days was followed by 4 monthly (once every four weeks) intramuscular (IM) doses of risperidone ISM 100 mg. Mean steady-state concentration versus time profiles for risperidone, 9-OH risperidone, and risperidone active moiety was characterized.Results: A total of 104 subjects were enrolled, 81 were included in the safety population and 58 completed the study. Intersubject variability for the steady-state concentrations versus time profiles for risperidone active moiety presented a greater variability range for oral risperidone versus risperidone ISM (% coefficient of variation [CV] range: 40– 65% and 38– 52%, respectively). Minimum plasma concentration at steady-state (Cmin, ss) and fluctuation in plasma concentrations (Fluc) of risperidone active moiety after risperidone ISM administration met bioequivalence criteria compared to the reference oral risperidone (geometric mean ratio [GMR] = 1.09 and 0.96, respectively; both 90% CIs were within 0.80– 1.25). Area under the curve during the dosing interval (AUCtau), maximum plasma concentration at steady-state (Cmax, ss) and average plasma concentration (Cave) were only slightly higher (GMR [90% CI] = 1.25 [1.16– 1.34], 1.17 [1.08– 1.27], and 1.25 [1.16– 1.34], respectively). Overall, once daily oral risperidone 4 mg and once monthly IM risperidone ISM 100 mg were generally safe and well tolerated in the participating subjects with schizophrenia previously stabilized with oral risperidone.Conclusion: The rapid release of risperidone ISM allows the achievement of the desired levels similar to those observed at the steady-state after oral risperidone treatment. Therefore, direct switch after 24 hours from the last oral risperidone dose to risperidone ISM treatment can be done in schizophrenia patients with no time lag, maintaining steady-state levels of the active moiety throughout treatment and without the need for oral risperidone supplementation or loading doses.Keywords: bioequivalence, comparative bioavailability, long-acting injectables, LAIs, pharmacokinetic, risperidone, schizophrenia

Walling DP, Hassman HA, Anta L, et al. Drug Des Devel Ther. 2021;15:4371–4382. Page 4378, Table 2, PK Parameter column, the text “Cave (ng/nL)” should read “Cave (ng/mL)”. Page 4379, Table 3, PK Parameter column, the text “Cave (ng/nL)” should read “Cave (ng/mL)”. The authors apologize for the errors. Read the original article

Background. Electroconvulsive therapy (ECT) is an effective and safe medical procedure that mainly indicated for depression, but is also indicated for patients with other conditions. However, ECT is among the most stigmatized and controversial treatments in medicine. Our objective was to examine social media contents on Twitter related to ECT to identify and evaluate public views on the matter. Methods. We collected Twitter posts in English and Spanish mentioning ECT between January 1, 2019 and October 31, 2020. Identified tweets were subject to a mixed method quantitative– qualitative content and sentiment analysis combining manual and semi-supervised natural language processing machine-learning analyses. Such analyses identified the distribution of tweets, their public interest (retweets and likes per tweet), and sentiment for the observed different categories of Twitter users and contents. Results. “Healthcare providers” users produced more tweets (25%) than “people with lived experience” and their“relatives”(including family members and close friends or acquaintances) (10% combined), and were the main publishers of “medical” content (mostly related to ECT’s main indications). However, more than half of the total tweets had “joke or trivializing” contents, and such had a higher like and retweet ratio. Among those tweets manifesting personal opinions on ECT, around 75% of them had a negative sentiment. Conclusions. Mixed method analysis of social media contents on Twitter offers a novel perspective to examine public opinion on ECT, and our results show attitudes more negative than those reflected in studies using surveys and other traditional methods. [ABSTRACT FROM AUTHOR]

Introduction Risperidone-ISM is a new long-acting intramuscular formulation intended to achieve sustained plasma concentrations over 4 weeks without oral supplementation. The clinical efficacy to risperidone has been associated with 65–80% occupancy of dopamine D2 receptor (D2RO) and a mean C max between 7.5 ng/mL and 80 ng/mL. Aim Use a population PK/PD model to predict the PK and the D2RO for Risperidone-ISM in schizophrenic patients and to characterize the relationship among doses, in order to guide dose selection for a future Phase-III trial. Methods A population PK/PD analysis for Risperidone-ISM using Monolix software was conducted based on 6641 plasma samples from two Phase-I studies (17 healthy subjects and 31 schizophrenic subjects, respectively) and 1 Phase-II study (60 schizophrenic subjects). Simulations were subsequently undertaken predicting the steady state PK and D2RO after multiple Risperidone-ISM doses administered every 28 days for 12 weeks. Results Doses of 75 and 100 mg, administered either in gluteal or deltoid muscle, were predicted to result in median C max and C trough that stayed between 7.5 ng/mL and 80 ng/mL. At steady state 75 mg and 100 mg dose (gluteal) achieved a D2RO average [min–max] of 70.8% [61.4–80.4] and 74.3% [66.2–82.1], respectively; a 75-mg and 100-mg dose (deltoid) achieved a D2RO average [min–max] of 69.3% [56.5–80.3] and 73.0% [61.8–82.1], respectively. The model estimated that the 65% D2RO occurs within first 8 h after treatment. Conclusions Simulations were carried out supporting doses of 75 mg and 100 mg Risperidone-ISM to show the greatest efficacy and safety potential to be assessed in the future Phase-III trial. [ABSTRACT FROM AUTHOR]

Introduction Risperidone-ISM is a new long acting intramuscular formulation of risperidone, for monthly administration without oral supplementation. Objective To characterize the pharmacokinetic of risperidone over multiple intramuscular injections in patients with schizophrenia. Method A multicenter, open label, two-arm, parallel design clinical trial was performed. Each patient received 4 intramuscular injections of 75 mg of risperidone-ISM in either, gluteal or deltoid muscle at 28-day intervals. Results A total of 70 patients were randomized, 67 received at least one dose of study medication. Preliminary data show that mean C max of the active moiety was achieved 24-48 hours (T max ) after each administration and ranged over four consecutive doses from 39.6-53.2 ng/mL and 54.1-61 ng/mL, when given in gluteal or deltoid, respectively. All subjects achieved therapeutic levels (> 7.5 ng/mL for the active moiety) between 2-8 hours after drug administration. The mean concentrations were maintained above therapeutic levels throughout the 4-week dosing period. No significance changes across the study were observed, either on Positive and Negative Syndrome Scale or Extrapyramidal Symptoms Scale. Overall, 63 subjects (94%) experienced at least 1 Treatment Emergent Adverse Event (TEAE) during the study. One serious TEAE (dystonia) was related to study treatment. One death not related to study medication was informed. The most frequently reported TEAEs were hyperprolactinaemia (57.7%) and injection site pain (32.8%). Conclusions Risperidone-ISM achieved therapeutic levels from the first hours after drug administration and provided a sustained release throughout the 4-weeks dosing period over multiple intramuscular injections independently of the injection site. Risperidone-ISM was found to be safe and well tolerated. [ABSTRACT FROM AUTHOR]

Abstract Background Thymidine analogue resistance mutations (TAMs) selected under treatment with nucleoside analogues generate two distinct genotypic profiles in the HIV-1 reverse transcriptase (RT): (i) TAM1: M41L, L210W and T215Y, and (ii) TAM2: D67N, K70R and K219E/Q, and sometimes T215F. Secondary mutations, including thumb subdomain polymorphisms (e.g. R284K) have been identified in association with TAMs. We have identified mutational clusters associated with virological failure during salvage therapy with tenofovir/emtricitabine-based regimens. In this context, we have studied the role of R284K as a secondary mutation associated with mutations of the TAM1 complex. Results The cross-sectional study carried out with >200 HIV-1 genotypes showed that virological failure to tenofovir/emtricitabine was strongly associated with the presence of M184V (P < 10-10) and TAMs (P < 10-3), while K65R was relatively uncommon in previously-treated patients failing antiretroviral therapy. Clusters of mutations were identified, and among them, the TAM1 complex showed the highest correlation coefficients. Covariation of TAM1 mutations and V118I, V179I, M184V and R284K was observed. Virological studies showed that the combination of R284K with TAM1 mutations confers a fitness advantage in the presence of zidovudine or tenofovir. Studies with recombinant HIV-1 RTs showed that when associated with TAM1 mutations, R284K had a minimal impact on zidovudine or tenofovir inhibition, and in their ability to excise the inhibitors from blocked DNA primers. However, the mutant RT M41L/L210W/T215Y/R284K showed an increased catalytic rate for nucleotide incorporation and a higher RNase H activity in comparison with WT and mutant M41L/L210W/T215Y RTs. These effects were consistent with its enhanced chain-terminated primer rescue on DNA/DNA template-primers, but not on RNA/DNA complexes, and can explain the higher fitness of HIV-1 having TAM1/R284K mutations. Conclusions Our study shows the association of R284K and TAM1 mutations in individuals failing therapy with tenofovir/emtricitabine, and unveils a novel mechanism by which secondary mutations are selected in the context of drug-resistance mutations.

We characterized transmitted drug resistance to rilpivirine and the predicted efficacy of first-line rilpivirine-containing regimens in antiretroviral-naive Spanish patients. International Antiviral Society-USA mutations were detected in 138 of 2781 patients (4.9%), E138A (3.4%) being the most prevalent. Using the Stanford Algorithm, 121 patients (4.4%) showed low-level or intermediate resistance. No differences in the predicted efficacy of first-line non-nucleoside reverse transcriptase inhibitor-based regimens were observed. As rilpivirine becomes more widely used in clinical practice, the evolution of its transmitted drug resistance will need to be monitored. In addition, the exact role of E138A singletons on rilpivirine activity as part of first-line regimens merits further evaluation. [ABSTRACT FROM AUTHOR]