Risperidone long-acting in-situ microimplant in the acute management of manic episodes with psychotic symptoms in non-adherent patients with schizoaffective disorder: a retrospective real-world study

Risperidone long-acting in-situ microimplant in the acute management of manic episodes with psychotic symptoms in non-adherent patients with schizoaffective disorder: a retrospective real-world study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Risperidone long-acting in-situ microimplant in the acute management of manic episodes with psychotic symptoms in non-adherent patients with schizoaffective disorder: a retrospective real-world study Giovanni Barillà, Andrea Fagiolini, Debora Bussolotti, Cristina Venco, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8503226/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 14 You are reading this latest preprint version Abstract Background : Nonadherence is a major cause of relapse in patients with schizophrenia, schizoaffective disorder, or bipolar disorder who have achieved remission. However, it is also a significant challenge during manic episodes. Risperidone in-situ microimplant (ISM) releases the drug early and in a sustained manner once a month, eliminating the need for daily administration, which can be difficult during a manic episode. In this study, we examined the short-term efficacy and tolerability of risperidone ISM in real-world nonadherent inpatients with schizoaffective disorder experiencing a manic episode with psychotic symptoms. Methods : This retrospective, observational, single-centre study included 50 consecutive adults admitted after discontinuation/marked non-adherence and with prior response to risperidone received ≥6 days of oral risperidone to confirm tolerability, then risperidone ISM (75 or 100 mg) and were followed for 6 weeks. Mania severity was assessed with the Young Mania Rating Scale (YMRS). Results : Fifty patients were included; most received concomitant mood stabilisers and benzodiazepines. Median YMRS decreased from 32 at admission to 26 at first injection (after the oral lead-in), 8 by day 8, and remained low at day 28 (5) and day 42 (6). Activation/behavioural items improved earlier, whereas psychotic thought content improved more gradually, predominantly between days 8 and 28. Side-effect burden at weeks 4 and 6 was minimal, and no discontinuations due to adverse events occurred. Conclusions : In this exploratory uncontrolled cohort, oral risperidone lead-in plus monthly risperidone ISM within multimodal inpatient care was associated with rapid and sustained improvement and favourable short-term tolerability. These findings should be interpreted as resulting from a combination of ISM treatment and a structured inpatient strategy, rather than as evidence of the effect of ISM alone. Prospective, controlled studies are warranted. risperidone ISM in situ microparticles acute mania schizoaffective disorder bipolar disorder long-acting injectable antipsychotic Figures Figure 1 Figure 2 Figure 3 Figure 4 1. Introduction Schizoaffective disorder, bipolar type, is a severe mood–psychotic condition in which manic, depressive and schizophrenia-spectrum symptoms coexist over time [1]. Longitudinal studies suggest that schizoaffective disorder occupies an intermediate position between prototypical schizophrenia and bipolar I disorder, showing a chronic or recurrent course with persistent symptoms, functional impairment and frequent need for ongoing antipsychotic treatment [2,3]. Real-world analyses highlight a substantial burden of illness in schizophrenia and schizoaffective disorder, with high healthcare resource utilization, frequent hospitalizations and substantial direct and indirect costs [4,5]. Across psychotic and bipolar disorders, non-adherence to antipsychotic medication is common, with many patients taking treatment on fewer than half of prescribed days and average adherence rates in the 40–60% range [6]. Even relatively brief periods of non-adherence in recent-onset schizophrenia have been associated with markedly increased risks of relapse and rehospitalization [7]. In schizoaffective disorde treatment interruptions may precipitate acute episodes with psychotic features, leading to emergency admission and further longitudinal destabilization [2–4]. Long-acting injectable (LAI) antipsychotics were developed to address some challenges of daily oral treatment by providing sustained drug delivery and reducing reliance on daily pill-taking. International guidelines recommend considering LAIs for patients with schizophrenia-spectrum disorders and bipolar disorder, particularly in those with partial adherence, frequent relapse or difficulty engaging with treatment [8]. While randomized trials in relatively adherent and stable patients have sometimes shown limited differences between LAIs and oral antipsychotics, mirror-image, cohort and registry studies in routine practice more consistently report reductions in relapse and rehospitalization after LAI initiation [9,10]. Network meta-analytic evidence also supports the role of both oral and long-acting antipsychotics for relapse prevention across schizophrenia-spectrum disorders [11]. Risperidone, a second-generation antipsychotic, is widely used across the schizophrenia–bipolar–schizoaffective spectrum. Randomized and open-label studies have demonstrated antimanic efficacy of risperidone, including long-acting formulations, in bipolar I disorder and have suggested benefits in schizoaffective disorder- particularly as maintenance therapy in patients with frequent relapses or poor adherence [12–16]. These data support the broader concept that risperidone-based LAIs can provide both antipsychotic and mood-stabilizing effects in mood–psychotic disorders. Risperidone in situ microparticles (risperidone ISM) is a once-monthly LAI formulation that employs an in situ microimplant technology to achieve a biphasic pattern of drug release. After intramuscular injection, a fraction of the dose is rapidly released, while the remainder forms a biodegradable depot that provides controlled risperidone delivery over the 4-week dosing interval [17,18]. Phase II–III trials and extension studies in schizophrenia have shown that risperidone ISM produces rapid improvements in psychotic symptoms, maintains therapeutic exposure over the dosing interval and has a tolerability profile broadly comparable to oral risperidone [17,18]. However, current evidence for risperidone ISM is largely confined to schizophrenia, and— to our knowledge—no published clinical studies have specifically evaluated this formulation in bipolar I disorder or in schizoaffective disorder, bipolar type, particularly in the context of acute manic episodes with psychotic symptoms and recent antipsychotic non-adherence. Given (i) the established antimanic efficacy of oral and long-acting risperidone in bipolar and schizoaffective populations [12–15], (ii) the central role of LAIs in the management of non-adherent patients [8,10], and (iii) the pharmacokinetic profile of risperidone ISM—combining early release with once-monthly dosing [17,18]—a systematic real-world evaluation of risperidone ISM in schizoaffective mania appears clinically warranted. This retrospective study was therefore undertaken to characterize the short-term clinical course and tolerability of a pragmatic “oral risperidone lead-in plus monthly risperidone ISM” strategy in a consecutive series of non-adherent inpatients with schizoaffective disorder, bipolar type, hospitalized for an acute manic episode with psychotic features and a documented previous clinical response to risperidone. 2. Methods 2.1. Ethical approval and informed consent statement The study protocol (acronym “REALSAD” ) was approved by the Territorial Ethics Committee CET Lombardia 4 (promoter: ASST Mantova; protocol code CET 140/24). All procedures were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. At the time of hospitalisation, all patients (or their legal representatives) provided written informed consent for the collection and use of anonymised clinical data for research purposes, as required by the local Ethics Committee. 2.2. Study design and setting This was a retrospective, observational, single-centre study conducted in the Psychiatry Unit Mantova 1 (S.C. Psichiatria, ASST Mantova, Mantova, Italy). Electronic medical records of consecutive in-patients with schizoaffective disorder (SAD) were reviewed. Patients were selected according to the formal diagnosis and documentation available in the clinical charts, adhering to DSM-5-TR criteria for schizoaffective disorder, bipolar type, currently manic episode with psychotic symptoms [1]. The study included admissions between January 2024 and November 2025. The study followed the STROBE recommendations for observational studies [19]. Clinical management (choice of antipsychotic, adjunctive mood stabilisers or benzodiazepines) was entirely naturalistic and based on the treating psychiatrist’s judgement. 2.2.1. Participants – inclusion criteria Patients were eligible for inclusion if they: Were aged ≥ 18 years and admitted to the adult psychiatric inpatient unit. Had a primary diagnosis of schizoaffective disorder, bipolar type, in a current manic episode with psychotic features according to DSM-5-TR [1]. Had clinical relapse temporally associated with discontinuation or marked non-adherence to ongoing antipsychotic treatment, defined as taking <50% of prescribed doses during the month preceding admission, as documented in the medical record. Received risperidone ISM (in-situ microimplant) during the index hospitalisation as part of routine clinical care, with at least one injection recorded. Had a documented history of previous clinical response to risperidone (oral or depot formulation), reported in previous treatment episodes. Had Young Mania Rating Scale (YMRS) and Clinical Global Impression (CGI) scores available at admission (Tx) and at least one subsequent post-injection time point. 2.2.2. Exclusion criteria Patients were excluded if they: Had an alternative primary diagnosis (e.g. bipolar disorder without psychosis, schizophrenia, schizophreniform disorder) or if the current manic/psychotic presentation was judged to be primarily substance-induced (i.e. attributable to acute intoxication or withdrawal from alcohol or illicit substances). Had incomplete or inconsistent clinical documentation, precluding reliable reconstruction of treatment timing or rating-scale trajectories. Were pregnant or breastfeeding at the time of hospitalisation, or had a documented contraindication to risperidone according to the summary of product characteristics (e.g. severe, unstable cardiovascular disease, known hypersensitivity to risperidone or excipients). Included patients were diagnosed in routine clinical practice by board-certified psychiatrists using DSM-5-TR criteria and confirmed by the Mini International Neuropsychiatric Interview [20]. In the following text we refer to “SAD mania” to indicate manic episodes occurring within schizoaffective disorder, bipolar type. 2.2.2.1. Data sources and measurements Data were extracted from electronic charts and structured case-report forms and included: Demographic and clinical variables: age, sex, body mass index (BMI), duration of diagnosed illness, number of previous mood episodes, history of substance abuse (none, alcohol, cannabis), cluster-B personality disorder, Axis III medical comorbidities, and concomitant psychotropic medications (lithium, valproate, haloperidol, other antipsychotics, benzodiazepines). Risperidone ISM exposure: dose of the first injection at T0 (75 or 100 mg), dose at T4 (100 mg, 75 mg, stopped depot, or switched to another long-acting antipsychotic), and timing of each injection. Assessment time points Rating scales were collected as part of routine care at the following time points: Tx (admission) – baseline, before risperidone ISM; demographic and clinical data; YMRS and CGI-BP. T0 (injection 1) – day of first risperidone ISM injection; YMRS and CGI-BP. T1 (24 h) – approximately 24 hours after T0; YMRS and CGI-BP. T2 (48 h) – approximately 48 hours after T0; YMRS and CGI-BP.. T3 (day 8 ± 1 day) – early post-acute phase; YMRS and CGI-BP. T4 (day 28 ± 2 days; injection 2) – consolidation phase and second risperidone ISM injection; YMRS, CGI-BP and Glasgow Antipsychotic Side-Effect Scale (GASS). T5 (day 42 ± 2 days) – follow-up visit; YMRS, CGI-BP and GASS. Symptom rating scales Young Mania Rating Scale (YMRS) Mania severity was assessed with the 11-item Young Mania Rating Scale (YMRS; total score 0–60) [21]. In addition, we planned a priori to describe the temporal course of individual YMRS items across all time points. Analyses of single-item trajectories were considered exploratory and primarily descriptive. Clinical Global Impression for Bipolar Disorder (CGI-BP) Global illness severity was rated at each time point using the Clinical Global Impression for Bipolar Disorder–Severity scale (CGI-BP-S; 1 = normal, not at all ill; 7 = among the most extremely ill patients), anchored to overall bipolar illness [22]. Tolerability and adverse events Glasgow Antipsychotic Side-Effect Scale (GASS) Tolerability was evaluated at T4 and T5 using the Glasgow Antipsychotic Side-Effect Scale (GASS; 21 items, total score 0–63), capturing nine domains: sedation/CNS, cardiovascular, extrapyramidal, anticholinergic, gastrointestinal, genitourinary, prolactinaemic/sexual, diabetes-screening items, and weight gain [23].Domain scores and total scores were recorded. Adverse events (AEs) All adverse events documented in the charts during hospitalisation and follow-up (e.g. extrapyramidal symptoms, sedation, metabolic changes, prolactin-related AEs) were extracted and qualitatively summarised. 2.3. Risperidone ISM treatment protocol Risperidone ISM (in-situ microimplant) was prescribed according to the approved summary of product characteristics and local clinical practice. In brief, oral risperidone was initiated or optimised during the first days of admission and maintained for at least 6 consecutive days to confirm both clinical stabilisation and tolerability, in line with the prescribing information. The first intramuscular risperidone ISM injection at T0 (75 mg or 100 mg) was then administered on the first available day after completion of this ≥6-day tolerability period. In keeping with dose-conversion recommendations, 100 mg ISM was generally used in patients who had been receiving ≥4 mg/day of oral risperidone, whereas 75 mg ISM was selected in those stabilised on 3 mg/day, with adjustments left to the discretion of the treating psychiatrist based on overall clinical status and comorbidities. The choice of 75 vs 100 mg at T0 was at the discretion of the treating clinician, based on prior exposure, severity of the manic episode, comorbidities and concomitant medications. As per the label, risperidone ISM provides an early release of risperidone without requiring oral supplementation; no systematic oral overlap was maintained beyond the acute titration period. At T4 (day 28 ± 2 days) patients were re-evaluated. In those who continued risperidone ISM, a second injection was administered at either 100 mg or 75 mg. In a minority of cases the depot was stopped or switched to another long-acting antipsychotic, again according to clinical judgement. Concomitant mood stabilisers (lithium, valproate) and benzodiazepines were allowed and recorded. 2.3.1. Variables and outcomes The primary efficacy outcome was the change in YMRS total score across subsequent time points, with particular focus on the short-term antimanic effect (Tx to T2 and T3) and the maintenance of improvement at T4 and T5. Secondary endpoints included: Change in CGI-BP score across the same time points. Trajectories of individual YMRS items, and, specifically, core YMRS items (items 5, 8, 9), describing the temporal profile of irritability, aggressive behaviour and psychotic thought content. The proportion of patients achieving clinical response (defined as ≥50% reduction in YMRS total score from admission) and complete symptomatic remission (YMRS total score <8) Tolerability outcomes, including: GASS total score and domain scores at T4 and T5, the proportion of patients with any symptom in each GASS domain, the distribution of GASS total scores across predefined categories: absent/mild (0–21), moderate (22–42), and severe (43–63), the frequency and nature of clinically recorded adverse events. 2.4. Statistical analysis Continuous variables are presented as mean ± standard deviation (SD) or median and interquartile range [IQR], according to their distribution. Categorical variables are reported as absolute and relative frequencies (n, %). Normality of continuous variables was assessed visually (histograms, Q–Q plots) and with the Shapiro–Wilk test. Because YMRS and CGI-BP scores did not consistently meet normality assumptions, overall changes across time (Tx, T0, T1, T2, T3, T4, T5) were first evaluated using the Friedman test for repeated measures. When overall tests were significant, pairwise comparisons between baseline (Tx) and each post-baseline time point were performed using the Wilcoxon signed-rank test. To control for multiple testing, Holm–Bonferroni correction was applied to the family of comparisons. For YMRS single items, analogous Friedman and Wilcoxon procedures were used to assess changes over time. In exploratory post-hoc analyses, additional Wilcoxon signed-rank tests were used to compare all pairs of post-baseline time points within each measure. In addition, linear mixed-effects models for repeated measures were fitted for YMRS total and CGI-BP severity scores, with time (Tx, T0, T1, T2, T3, T4, T5) entered as a categorical fixed effect and a random intercept for patient. Least-squares means (estimated marginal means) were derived for each timepoint, and prespecified pairwise contrasts were tested for selected time comparisons (YMRS: Tx vs T0, T0 vs T1, T0 vs T2, T2 vs T3, T3 vs T4, T4 vs T5; CGI-BP: Tx vs T0, T0 vs T2, T2 vs T3, T3 vs T4) using Wald statistics and 95% confidence intervals. For YMRS and CGI-BP contrasts, p-values were adjusted for multiplicity using the Holm–Bonferroni method. In sensitivity analyses, the YMRS and CGI-BP mixed models were additionally adjusted for potential confounders, including age, sex, body mass index and concurrent psychotropic medications (e.g. lithium, valproate). GASS total scores at T4 and T5 were summarised descriptively and categorised into absent/mild, moderate and severe burden; GASS domains were described as the percentage of patients with ≥1 point symptom (score > 0). All tests were two-sided. Statistical significance was set at p < 0.05, with Bonferroni-type corrections applied where indicated. Statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA). 3. Results 3.1. Cohort description During the study period, 66 hospitalised patients with a diagnosis of schizoaffective disorder, bipolar type, manic episode with psychotic features were screened. Of these, 9 patients were excluded because clinical documentation was incomplete or inconsistent, preventing a reliable reconstruction of treatment timing or rating-scale trajectories, and 7 patients were excluded because the acute presentation was considered predominantly substance-induced, with manic and psychotic symptoms occurring in the context of marked alcohol or illicit-substance intoxication or withdrawal, rather than a primary schizoaffective manic episode. The final cohort therefore consisted of 50 in-patients who fulfilled all inclusion and exclusion criteria. All 50 patients completed all seven planned clinical assessments (Tx to T5), and GASS forms were available for all patients at both T4 and T5. Sociodemographic and clinical characteristics are summarised in Table 1. Table 1. Sociodemographic and clinical characteristics; concomitant medications at baseline Sociodemographic and clinical characteristics Characteristic Value Sample size N = 50 Age, years 37.5 [28.2–48.0] (mean 39.8 ± 14.0) BMI, kg/m² 24.0 [21.0–31.0] (mean 26.2 ± 6.9) Duration of diagnosed illness, years 7.5 [4.0–15.0] (mean 11.3 ± 10.5) Number of mood episodes 3.0 [2.0–4.0] (mean 3.6 ± 2.6) Sex, male 35 (70.0%) Sex, female 15 (30.0%) Substance abuse: none 32 (64.0%) Substance abuse: alcohol 10 (20.0%) Substance abuse: cannabis 8 (16.0%) Personality disorder, cluster B 7 (14.0%) Medical comorbidity (Axis III) 17 (34.0%) Risperidone ISM first injection (T0) 75 mg: 9 (18.0%); 100 mg: 41 (82.0%) Risperidone ISM second injection (T4) – dose 75 mg: 7 (14.0%); 100 mg: 39 (78.0%) Risperidone ISM second injection (T4) – change Stopped depot: 2 (4.0%); Switched depot: 2 (4.0%) Concomitant medications at baseline Psychotropic drugs Patients, n (%) Lithium 14 (28.0%) Valproate 33 (66.0%) Haloperidol 2 (4.0%) Other antipsychotics 9 (18.0%) Benzodiazepines 36 (72.0%) The median age was 37.5 years [IQR 28.2–48.0], and 35 patients (70.0%) were male. At baseline, lithium was prescribed in 14 patients (28.0%), valproate in 33 (66.0%), haloperidol in 2 (4.0%), other antipsychotics in 9 (18.0%), and benzodiazepines in 36 (72.0%) (Table 1). With regard to risperidone ISM exposure, the first injection at T0 was 75 mg in 9 patients (18.0%) and 100 mg in 41 (82.0%), consistent with the preceding oral dose (75 mg in patients on 3 mg/day oral risperidone and 100 mg in those on ≥4 mg/day). At T4 (day 28 ± 2 days), a second injection was administered in the majority of cases (100 mg in 39/50, 78.0%; 75 mg in 7/50, 14.0%), whereas the depot was stopped in 2 patients (4.0%) and switched to another long-acting antipsychotic in 2 (4.0%). At admission (Tx), the cohort presented with moderate-to-severe mania and marked psychotic symptoms. The median YMRS total score was 32 [29–36], and the CGI-BP score was 6 [5–6], indicating patients who were severely ill (Table 2). Table 2. CGI-BP, YMRS total and YMRS single items across time points: Values are median [IQR]. ⁎p < 0.05 vs Tx; ᵃp < 0.05 vs T0; ᵇp < 0.05 vs T1; ᶜp < 0.05 vs T2; ᵈp < 0.05 vs T3; ᵉp < 0.05 vs T4 (Wilcoxon signed-rank tests with Holm–Bonferroni correction for multiple pairwise comparisons). Measure Tx T0 T1 T2 T3 T4 T5 p (Friedman) CGI-BP score 6 [5–6] 5 [4–6]⁎ 4 [4–5]⁎ᵃ 4 [4–5]⁎ᵃ,ᵇ 4 [3–4]⁎ᵃ,ᵇ,ᶜ 3 [2–4]⁎ᵃ,ᵇ,ᶜ,ᵈ 3 [2–3]⁎ᵃ,ᵇ,ᶜ,ᵈ,ᵉ < 0.0001 YMRS total score 32 [29–36] 26 [21–30]⁎ 20 [15–30]⁎ᵃ 17 [10–27]⁎ᵃ,ᵇ 8 [6–11]⁎ᵃ,ᵇ,ᶜ 5 [4–8]⁎ᵃ,ᵇ,ᶜ,ᵈ 6 [4–8]⁎ᵃ,ᵇ,ᶜ,ᵈ,ᵉ < 0.0001 YMRS item 1 – Elevated mood 2 [2–2] 2 [1–2]⁎ 2 [1–2]⁎ᵃ 1 [0–2]⁎ᵃ,ᵇ 0 [0–1]⁎ᵃ,ᵇ,ᶜ 0 [0–1]⁎ᵃ,ᵇ,ᶜ 0 [0–1]⁎ᵃ,ᵇ,ᶜ < 0.0001 YMRS item 2 – Increased activity/energy 2 [2–3] 2 [2–2]⁎ 2 [1–2]⁎ᵃ 1 [0–2]⁎ᵃ 0 [0–1]⁎ᵃ,ᵇ,ᶜ 0 [0–1]⁎ᵃ,ᵇ,ᶜ,ᵈ 0 [0–1]⁎ᵃ,ᵇ,ᶜ < 0.0001 YMRS item 3 – Increased sexual interest 2 [1–2] 1 [0–2]⁎ 1 [0–2]⁎ 1 [0–2]⁎ 0 [0–1]⁎ᵃ,ᵇ,ᶜ 0 [0–1]⁎ᵃ,ᵇ,ᶜ 0 [0–1]⁎ᵃ,ᵇ,ᶜ < 0.0001 YMRS item 4 – Reduced sleep 2 [2–3] 2 [1–2]⁎ 2 [1–2]⁎ᵃ 1 [0–2]⁎ᵃ,ᵇ 0 [0–1]⁎ᵃ,ᵇ,ᶜ 0 [0–1]⁎ᵃ,ᵇ,ᶜ,ᵈ 0 [0–1]⁎ᵃ,ᵇ,ᶜ < 0.0001 YMRS item 5 – Irritability 5 [4–5] 4 [3–5]⁎ 2 [2–3]⁎ᵃ 2 [2–3]⁎ᵃ 1 [1–2]⁎ᵃ,ᵇ,ᶜ 1 [0–1]⁎ᵃ,ᵇ,ᶜ,ᵈ 1 [0–1]⁎ᵃ,ᵇ,ᶜ,ᵈ < 0.0001 YMRS item 6 – Speech (rate and amount) 5 [3–5] 3 [3–5]⁎ 2 [2–4]⁎ᵃ 2 [1–4]⁎ᵃ,ᵇ 1 [1–2]⁎ᵃ,ᵇ,ᶜ 1 [0–1]⁎ᵃ,ᵇ,ᶜ,ᵈ 1 [0–1]⁎ᵃ,ᵇ,ᶜ,ᵈ < 0.0001 YMRS item 7 – Language/thought disorder 3 [3–5] 3 [2–5] 3 [2–5]⁎ᵃ 3 [2–4]⁎ᵃ 1 [1–2]⁎ᵃ,ᵇ,ᶜ 1 [1–1]⁎ᵃ,ᵇ,ᶜ,ᵈ 1 [0–2]⁎ᵃ,ᵇ,ᶜ,ᵈ < 0.0001 YMRS item 8 – Thought content 5 [5–5] 5 [4–5] 5 [4–5]⁎ 4 [3–5]⁎ᵃ,ᵇ 2 [1–3]⁎ᵃ,ᵇ,ᶜ 2 [1–2]⁎ᵃ,ᵇ,ᶜ,ᵈ 2 [1–2]⁎ᵃ,ᵇ,ᶜ,ᵈ < 0.0001 YMRS item 9 – Disruptive/aggressive behaviour 2 [2–5] 2 [1–2]⁎ 2 [1–2]⁎ᵃ 1 [0–2]⁎ᵃ 0 [0–1]⁎ᵃ,ᵇ,ᶜ 0 [0–0]⁎ᵃ,ᵇ,ᶜ 0 [0–0]⁎ᵃ,ᵇ,ᶜ < 0.0001 YMRS item 10 – Appearance 2 [2–2] 2 [1–2]⁎ 2 [1–2]⁎ 2 [1–2]⁎ᵃ 1 [0–1]⁎ᵃ,ᵇ,ᶜ 0 [0–1]⁎ᵃ,ᵇ,ᶜ,ᵈ 0 [0-1]⁎ᵃ,ᵇ,ᶜ,ᵈ < 0.0001 YMRS item 11 – Insight 3 [2–3] 2 [2–3]⁎ 2 [2–3]⁎ 2 [2–2]⁎ᵃ 1 [1–2]⁎ᵃ,ᵇ,ᶜ 1 [1–1]⁎ᵃ,ᵇ,ᶜ,ᵈ 1 [1–2]⁎ᵃ,ᵇ,ᶜ < 0.0001 3.2 YMRS total score A marked and progressive improvement in YMRS total score was observed over the 6-week observation period (Friedman p < 0.0001; Table 2, Fig. 1). The median score decreased from 32 [29–36] at Tx to 26 [21–30] at T0, 20 [15–30] at T1 (24 h), and 17 [10–27] at T2 (48 h). The initial reduction between Tx and T0 occurred during the ≥6-day oral risperidone lead-in and standard inpatient management, before administration of the first risperidone ISM injection at T0. This corresponded to a median 6-point reduction from Tx to T0 and an additional 9-point decrease from T0 (day of the first Risperidone ISM injection) to T2. Improvement continued into the early post-acute phase: at T3 (day 8 ± 1), the median YMRS score further declined to 8 [6–11], and reached 5 [4–8] at T4 (day 28 ± 2) and 6 [4–8] at T5 (day 42 ± 2) (Table 2). Compared with Tx, YMRS total scores were significantly lower at all subsequent time points (T0–T5; all Wilcoxon p < 0.05 after Holm–Bonferroni correction). Mixed-effects models confirmed rapid and clinically relevant LS-mean reductions in YMRS from admission through day 8, with all prespecified contrasts from Tx to T3 reaching statistical significance, followed by more modest improvement between day 8 and day 28 and stabilisation thereafter ( see Additional file 1: Supplementary Table S1). Exploratory pairwise analyses further showed that YMRS total scores not only improved significantly from Tx to each post-baseline time point, but also declined stepwise from T0 to subsequent visits up to day 8, with most comparisons between T0 and T1–T3 reaching statistical significance (Table 2). Using the predefined YMRS-based criteria, all patients met the ≥50% response threshold from day 8 (T3) onwards. Symptomatic remission (YMRS <8) was achieved by 24/50 patients (48.0%) at T3 and by 37/50 (74.0%) at both T4 and T5. These trajectories are graphically illustrated in Fig. 1, where both medians and dispersion clearly show a rapid early antimanic effect followed by stabilisation and maintenance of low YMRS scores through week 6. 3.2.1. CGI-BP score Global clinical severity, as measured by the CGI-BP, improved in parallel with YMRS (Friedman p < 0.0001; Table 2, Fig. 2). The median CGI-BP at Tx was 6 [5–6], consistent with “markedly” to “severely” ill patients. Scores decreased to 5 [4–6] at T0 (initiation of once monthly Risperidone ISM), followed by 4 [4–5] at T1 and T2, and 4 [3–4] at T3. By T4, the median CGI-BP further improved to 3 [2–4], and remained 3 [2–3] at T5, indicating a shift towards “mildly” to “moderately” ill. All post-baseline CGI-BP scores were significantly lower than Tx after Holm–Bonferroni correction, confirming a robust clinical impression of improvement (Fig. 2). Consistent with YMRS, mixed-effects models estimated a progressive reduction in LS-mean CGI-BP severity scores from 5.7 at admission to 2.8 at day 42. All prespecified pairwise contrasts (Tx–T0, T0–T2, T2–T3, T3–T4) were statistically significant (all Holm-adjusted p < 0.001), supporting a steady improvement in global illness severity over the observation period ( see Additional file 1: Supplementary Table S2). Consistent with the YMRS findings, pairwise comparisons also indicated significant decreases in CGI-BP scores from T0 to subsequent early post-injection visits, particularly up to day 8 (Table 2). 3.2.2 Sensitivity analyses Covariate-adjusted mixed models that included baseline age, sex, BMI, and concomitant lithium and valproate treatment yielded LS-mean trajectories for YMRS and CGI-BP that were virtually identical to those from the unadjusted models. For YMRS, all prespecified contrasts from admission to day 28 remained highly significant after Holm–Bonferroni correction, whereas the contrast between day 28 and day 42 remained non-significant, confirming rapid early improvement followed by stabilisation. Likewise, adjustment did not materially alter the magnitude or significance of the CGI-BP contrasts, which continued to show a consistent, progressive reduction in global illness severity ( see Additional file 1: Supplementary Tables S1C and S2C). 3.3. YMRS single-item trajectories Changes in YMRS single items across all time points are summarised and depicted in Fig. 3. Friedman tests were significant for each item (all p < 0.0001). All YMRS single-items showed significant improvements over time (all Friedman p < 0.0001; Table 2), with most of the decline occurring between Tx/T0 and T3. As regard core YMRS single items (see Table 2, Fig. 3), “Irritability” showed one of the steepest early improvements, with medians falling from 5 [4–5] at Tx to 4 [3–5] at T0, 2 [2–3] at T1–T2, 1 [1–2] at T3, and 1 [0–1] at T4–T5. “Aggressive behaviour” decreased from 2 [2–5] at Tx to 2 [1–2] at T0, 2 [1–2] at T1, and 1 [0–2] at T2. By T3, the median score was 0 [0–1], and 0 [0–0] at T4 and T5, indicating near-complete reduction of overt aggressive behaviours in most patients. Psychotic “thought content” (Item 8) showed a more gradual trajectory. Median scores decreased from 5 [5–5] at Tx to 5 [4–5] at T0–T1, 4 [3–5] at T2, and only then to 2 [1–3] at T3, stabilising at 2 [1–2] at T4–T5. This pattern suggests that psychotic ideation tended to normalise more slowly, following the early antimanic and behavioural changes. 3.4. Tolerability and side effects GASS total scores at week 4 (T4) and week 6 (T5) were very low, with median values of 0 (IQR 0–0; range 0–7 at T4 and 0–4 at T5). All patients remained within the absent/mild category (0–21), and none met the thresholds for moderate (22–42) or severe (43–63) side-effect burden. Analysis of GASS domains confirmed a low prevalence of adverse effects (Fig. 4). At T4, at least one symptom (domain score >0) was reported by 3/50 patients (6.0%) in the sedation/CNS domain, 1/50 (2.0%) in the cardiovascular domain, 6/50 (12.0%) for extrapyramidal symptoms, 1/50 (2.0%) in the genitourinary domain, 1/50 (2.0%) in the diabetes-screening items and 4/50 (8.0%) for prolactinaemic/sexual symptoms; no patient reported anticholinergic/gastrointestinal side effects or weight gain. At T5, domain prevalences were similar or slightly reduced: sedation/CNS symptoms in 1/50 (2.0%) patients, cardiovascular in 1/50 (2.0%), extrapyramidal in 5/50 (10.0%), genitourinary in 1/50 (2.0%), diabetes-screening items in 1/50 (2.0%), prolactinaemic/sexual in 3/50 (6.0%) and weight gain in 1/50 (2.0%), with anticholinergic/gastrointestinal symptoms remaining absent. Across domains, maximum scores remained in the mildrange (e.g. extrapyramidal domain up to 6 points, prolactinaemic up to 3, weight gain up to 3), and no severe or unexpected adverse events related to risperidone ISM emerged from chart review. Importantly, no patient discontinued risperidone ISM because of tolerability issues during the observation period, and the safety profile was consistent with expectations for risperidone and long-acting antipsychotic formulations. 4. Discussion To our knowledge, this is the first real-world study specifically examining once-monthly risperidone ISM in a cohort of non-adherent inpatients with schizoaffective disorder, bipolar type, admitted for an acute manic episode with psychotic symptoms and a documented previous response to risperidone. In this retrospective cohort, risperidone ISM—introduced after a short oral risperidone lead-in and within a multimodal treatment regimen—was associated with a rapid and marked improvement in manic symptomatology, sustained over a 6-week period. Accordingly, the observed improvement should be interpreted within a structured inpatient treatment strategy, rather than as a causal effect of risperidone ISM per se. YMRS total scores decreased steeply over the early post-injection window and the vast majority of patients maintained improvement through week 6, with high proportions meeting standard response and remission thresholds by day 8 after the LAI injection and beyond. CGI-BP ratings closely mirrored the YMRS trajectory, indicating that symptom-scale change was reflected in global clinical impression. It should be emphasized, however, that all patients received at least 6 consecutive days of oral risperidone before the first ISM injection, in addition to mood stabilizers and benzodiazepines in most cases and, in a minority, other antipsychotics. Thus, early symptomatic improvement likely reflects the combined effect of oral risperidone, risperidone ISM and concomitant treatments, rather than the LAI formulation alone. Nevertheless, tolerability—captured by structured GASS ratings and chart-recorded adverse events—was favorable and broadly consistent with expectations for risperidone and long-acting antipsychotic formulations [17,18]. These findings extend to schizoaffective disorder the evidence supporting risperidone’s antimanic efficacy that has been demonstrated in randomized and open-label studies in bipolar I disorder and related mood–psychotic conditions, including long-acting risperidone formulations [12–15].They also align with pharmacokinetic and clinical trial data in schizophrenia showing rapid attainment of therapeutic exposure and sustained effect with monthly risperidone ISM [17,18,24]. Risperidone ISM employs an in situ microimplant technology in which, after reconstitution and intramuscular injection, a proportion of risperidone is released early while the remainder precipitates into a polymeric matrix that biodegrades over the dosing interval [18]. The temporal pattern observed in our cohort—early antimanic improvement followed by maintenance of low YMRS scores at later visits—may be compatible with this biphasic release profile, although the respective contributions of oral risperidone, risperidone ISM and concomitant pharmacological and environmental interventions cannot be disentangled. A distinctive aspect of this study is the evaluation of YMRS single-item trajectories. Activation-related and behavioral dimensions (e.g., irritability, disruptive/aggressive behavior, etc) showed steep early reductions, reaching very low median values by day 8. In contrast, thought content (reflecting psychotic and cognitive aspects of schizoaffective disorder) improved more gradually. This temporal dissociation is clinically plausible: motor activation, irritability and overt aggression are often the earliest targets of pharmacological and environmental containment on acute wards, whereas psychotic ideation and insight may normalize more slowly. The present data quantify this pattern in a diagnostically homogeneous schizoaffective sample and suggest that a monthly LAI strategy incorporating risperidone ISM may be particularly useful when rapid behavioral stabilization is required in patients with high risk of non-adherence. From a clinical standpoint, these results have several implications. First, in schizoaffective patients with non-adherence and prior response to risperidone, a combined oral lead-in and transition to once-monthly risperidone ISM may represent a pragmatic strategy to re-establish therapeutic antipsychotic exposure and secure continuity of treatment beyond the acute phase—consistent with guideline recommendations and evidence supporting LAIs in patients at high risk of non-adherence and relapse [8,10,11,25,26]. Second, the rapid improvement in behavioral dimensions coupled with the slower but robust change in psychotic thought content supports integration of LAI strategies into multimodal management (including mood stabilizers, benzodiazepines when indicated, and psychosocial interventions) for complex manic presentations with psychosis. Third, the low post-acute YMRS levels observed by day 8 raise the hypothesis that, in selected patients, earlier discharge with continued LAI treatment and structured community follow-up might be feasible—an hypothesis that warrants prospective evaluation. Strengths and limitations This study has several strengths. The sample is diagnostically homogeneous, focusing specifically on DSM-5-TR schizoaffective disorder, bipolar type, in a manic episode with psychotic features [1]. The design is naturalistic and reflects routine practice in an acute psychiatric unit, where comorbidity and polypharmacy are common and non-adherence is a frequent precipitant of admission [4–6]. Multiple time points were available, including very early assessments and follow-up to six weeks, allowing granular description of both global and item-level trajectories. The use of the GASS provided a structured, patient-centered assessment of antipsychotic side effects at two clinically relevant follow-up visits [23]. Important limitations must also be acknowledged. First, the retrospective, uncontrolled design precludes firm causal inference about the specific contribution of risperidone ISM; outcomes reflect a combined inpatient strategy rather than the effect of the LAI formulation in isolation. Symptom improvement may be partly attributable to the natural course of manic episodes, intensive inpatient care and concomitant treatments. Second, all patients underwent at least 6 days of oral risperidone before the first ISM injection; the separate impact of the oral lead-in versus the LAI component was not formally modeled. Third, the sample size is modest and recruitment was from a single center, limiting generalizability. Fourth, all patients had a documented previous response to risperidone, which may overestimate benefits in risperidone-naïve or risperidone-non-responsive individuals. Fifth, ratings were performed in routine practice without formal inter-rater reliability assessment, and documentation bias cannot be excluded. Sixth, tolerability was evaluated only over six weeks; metabolic, endocrine and cardiovascular effects beyond this window were not systematically captured and may be under-detected early after acute hospitalization. Finally, use of risperidone ISM in acute schizoaffective mania is off-label, underscoring the exploratory nature of these findings and the need for prospective controlled studies. 5. Conclusions In a real-world cohort of non-adherent inpatients with schizoaffective disorder, bipolar type, hospitalized for acute mania with psychotic symptoms and prior response to risperidone, a pragmatic strategy consisting of a brief oral risperidone lead-in followed by initiation of once-monthly risperidone ISM within a multimodal regimen was associated with rapid and marked reductions in manic symptom severity, progressive improvement in psychotic thought content, and a favorable short-term tolerability profile. Activation-related and behavioral symptoms improved particularly quickly, whereas psychotic thought content normalized more gradually but substantially over the 6-week observation period. The overall temporal pattern is compatible with the formulation characteristics of risperidone ISM, which combines early release with sustained delivery across the monthly dosing interval [17]. However, these findings should be interpreted as reflecting the combined effect of oral risperidone, the long-acting formulation and concomitant treatments under acute inpatient conditions, rather than the action of risperidone ISM in isolation. Future prospective, randomized and ideally pragmatic trials—comparing risperidone ISM with oral antipsychotics and other LAIs and incorporating longer-term safety, functional and quality-of-life outcomes—are warranted to confirm these preliminary observations and to better define the role of ISM formulations in severe mood–psychotic disorders [10,11,25]. Declarations Ethics approval and consent to participate The study protocol (acronym “REALSAD”) was approved by the Territorial Ethics Committee CET Lombardia 4 (promoter: ASST Mantova; protocol code CET 140/24). All procedures were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. At the time of hospitalisation, all patients (or their legal representatives) provided written informed consent for the collection and use of anonymised clinical data for research purposes, as required by the local Ethics Committee. Declaration of generative AI and AI-assisted technologies in the manuscript preparation process During the preparation of this work, the authors used ChatGPT (OpenAI) to assist in language refinement and formatting. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article. Consent for publication Not applicable. No identifiable individual data are included in this manuscript. Competing interests Conflict of Interest Statement Andrea Fagiolini has served as a consultant and/or speaker and/or has received research grants from the following pharmaceutical and healthcare companies: Allergan, Angelini, Apsend, Generici DOC, Boehringer Ingelheim, Idorsia, Italfarmaco, Lundbeck, Janssen, Medicamenta, Mylan, Otsuka, Pfizer, Recordati, Rovi, Roche, Sanofi Aventis, Sunovion, Teva, and Viatris. These relationships include research funding, consultancy fees, and/or honoraria for speaking engagements related to academic research activities, advisory roles, and participation in scientific meetings within the field of psychiatry and psychopharmacology. None of these relationships had any influence on the conception, design, conduct, interpretation, or reporting of the present study, and none are directly related to the content of this manuscript. Alessandro Cuomo has served as a consultant and/or speaker and/or has received research grants from the following pharmaceutical and healthcare companies: Allergan, Angelini, Apsend, Boehringer Ingelheim, Idorsia, Italfarmaco, Lundbeck, Janssen, Medicamenta, Mylan, Otsuka, Pfizer, Recordati, Roche, Sanofi Aventis, and Viatris. These relationships include research funding, consultancy fees, and/or honoraria for speaking engagements related to academic research activities, advisory roles, and participation in scientific meetings within the field of psychiatry and psychopharmacology. None of these relationships had any influence on the conception, design, conduct, interpretation, or reporting of the present study, and none are directly related to the content of this manuscript. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Authors’ contributions (CRediT taxonomy) Giovanni Barillà: Conceptualization, Methodology, Investigation, Data curation, Formal analysis, Writing – original draft, Writing – review & editing. Alessandro Cuomo: Validation, Writing – review & editing, Supervision. Debora Bussolotti: Project administration, Supervision, Validation, Writing – review & editing. Cristina Venco: Investigation, Data curation, Validation. Andrea Fagiolini: Conceptualization, Methodology, Validation, Supervision, Writing – review & editing. All authors approved the final manuscript. Availability of data and materials The data generated and/or analysed during the current study are not publicly available due to ethical and legal restrictions related to patient confidentiality, but de-identified data may be made available from the corresponding author upon reasonable request and subject to Ethics Committee approval. Acknowledgements Figures 1–4 were created with BioRender.com (publication licence, personal account). References American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5-TR. 5th ed, text revision. Washington (DC): American Psychiatric Association; 2022. Benabarre A, Vieta E, Martínez-Arán A, et al. Bipolar disorder, schizoaffective disorder and schizophrenia: epidemiologic, clinical and prognostic differences. Eur Psychiatry. 2001;16:167–172. doi:10.1016/S0924-9338(01)00559-4. Pinna F, Sanna L, Perra V, et al. Long-term outcome of schizoaffective disorder: are there relevant differences with schizophrenia? 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Guidelines for the use and management of long-acting injectable antipsychotics in serious mental illness. BMC Psychiatry. 2013;13:340. doi:10.1186/1471-244X-13-340. Kishimoto T, Robenzadeh A, Leucht C, et al. Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: a meta-analysis of randomized trials. Schizophr Bull. 2014;40:192–213. doi:10.1093/schbul/sbs150. Kishimoto T, Hagi K, Nitta M, et al. Long-acting injectable versus oral antipsychotics for the maintenance treatment of schizophrenia: a systematic review and comparative meta-analysis of randomised, cohort, and pre-post studies. Lancet Psychiatry. 2021;8(5):387–404. doi:10.1016/S2215-0366(21)00039-0. Ostuzzi G, Bertolini F, Tedeschi F, et al. Oral and long-acting antipsychotics for relapse prevention in schizophrenia-spectrum disorders: a network meta-analysis of 92 randomized trials including 22,645 participants. World Psychiatry. 2022;21:56–69. doi:10.1002/wps.20972. Macfadden W, Alphs L, Haskins JT, et al. A randomized, double-blind, placebo-controlled study of maintenance treatment with adjunctive risperidone long-acting therapy in patients with bipolar I disorder who relapse frequently. Bipolar Disord. 2009;11(8):827–839. doi:10.1111/j.1399-5618.2009.00761.x. Quiroz JA, Yatham LN, Palumbo JM, et al. Risperidone long-acting injectable monotherapy in the maintenance treatment of bipolar I disorder. Biol Psychiatry. 2010;68:156–162. doi:10.1016/j.biopsych.2010.01.015. Vieta E, Goikolea JM, Corbella B, et al. Risperidone safety and efficacy in the treatment of bipolar and schizoaffective disorders: results from a 6-month, multicenter, open study. J Clin Psychiatry. 2001;62:818–825. PMID:11816872. Vieta E, Montgomery S, et al. A randomized, double-blind, placebo-controlled trial to assess prevention of mood episodes with risperidone long-acting injectable in patients with bipolar I disorder. Eur Neuropsychopharmacol. 2012;22:825–835. doi:10.1016/j.euroneuro.2012.03.004. Bartoli F, Cavaleri D, Riboldi I, et al. Clinical utility of long-acting injectable risperidone in schizophrenia and bipolar I disorder: a review of clinical studies. Psychol Res Behav Manag. 2025;18:1455–1469. doi:10.2147/PRBM.S474513. Correll CU, Litman RE, Filts Y, et al. Efficacy and safety of once-monthly risperidone ISM in schizophrenic patients with an acute exacerbation: a randomized, double-blind, placebo-controlled trial. NPJ Schizophr. 2020;6:37. doi:10.1038/s41537-020-00127-y. Syed YY. Risperidone in situ microparticles: a review in schizophrenia. Drugs. 2025;85:425–435. doi:10.1007/s40265-024-02140-2. von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. PLoS Med. 2007;4:e296. doi:10.1371/journal.pmed.0040296. Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric Interview (MINI): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(Suppl 20):22–33. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429–435. doi:10.1192/bjp.133.5.429. Spearing MK, Post RM, Leverich GS, Brandt D, Nolen W. Modification of the Clinical Global Impressions (CGI) Scale for use in bipolar illness (CGI-BP). Psychiatry Res. 1997;73:159–171. doi:10.1016/S0165-1781(97)00123-6. Waddell L, Taylor M. A new self-rating scale for detecting atypical or second-generation antipsychotic side effects. J Psychopharmacol. 2008;22(3):238–243. doi:10.1177/0269881107087976. Toja-Camba FJ, Peñas-Lledó E, Anta L, et al. Evaluating the real-world pharmacokinetics of risperidone ISM® in routine clinical practice. Biomedicines. 2025;13(2):384. doi:10.3390/biomedicines13020384. Vieta E, Tohen M, McIntosh D, et al. Early use of long-acting injectable antipsychotics in bipolar disorder type I: an expert consensus. Bipolar Disord. 2025;27:7–16. doi:10.1111/bdi.13498. Fu DJ, Turkoz I, Simonson RB, et al. Paliperidone palmitate once-monthly reduces risk of relapse of psychotic, depressive, and manic symptoms and maintains functioning in a double-blind, randomized study of schizoaffective disorder. J Clin Psychiatry. 2015;76(3):253–262. doi:10.4088/JCP.14m09416. Additional Declarations Competing interest reported. Andrea Fagiolini has served as a consultant and/or speaker and/or has received research grants from the following pharmaceutical and healthcare companies: Allergan, Angelini, Apsend, Generici DOC, Boehringer Ingelheim, Idorsia, Italfarmaco, Lundbeck, Janssen, Medicamenta, Mylan, Otsuka, Pfizer, Recordati, Rovi, Roche, Sanofi Aventis, Sunovion, Teva, and Viatris. These relationships include re-search funding, consultancy fees, and/or honoraria for speaking engagements related to academic re-search activities, advisory roles, and participation in scientific meetings within the field of psychiatry and psychopharmacology. None of these relationships had any influence on the conception, design, conduct, interpretation, or reporting of the present study, and none are directly related to the content of this manuscript. Alessandro Cuomo has served as a consultant and/or speaker and/or has received research grants from the following pharmaceutical and healthcare companies: Allergan, Angelini, Apsend, Boehringer Ingelheim, Idorsia, Italfarmaco, Lundbeck, Janssen, Medicamenta, Mylan, Otsuka, Pfizer, Recordati, Roche, Sanofi Aventis, and Viatris. These relationships include research funding, consultancy fees, and/or honoraria for speaking engagements related to academic research activities, advisory roles, and participation in scientific meetings within the field of psychiatry and psychopharmacology. None of these relationships had any influence on the conception, design, conduct, interpretation, or reporting of the present study, and none are directly related to the content of this manuscript. All other authors declare that they have no known competing financial interests or personal relation-ships that could have appeared to influence the work reported in this paper. 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05:28:29","extension":"xml","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":149600,"visible":true,"origin":"","legend":"","description":"","filename":"c689fa6f21ed44ff9c0d0a42e79f23651structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8503226/v1/0ae42980e91962fa703eaeae.xml"},{"id":100004769,"identity":"7b3d578a-d2ae-499b-9f32-834a265c01e2","added_by":"auto","created_at":"2026-01-12 05:28:29","extension":"html","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":165146,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8503226/v1/055160a1cef510cb7f50288e.html"},{"id":100004753,"identity":"76434da6-9010-439c-84a8-30657b23364c","added_by":"auto","created_at":"2026-01-12 05:28:28","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":118831,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eYMRS total score over time.\u003c/strong\u003e\u003cbr\u003e\n \u003cem\u003eViolin plots (with embedded boxplots) summarising the distribution of Young Mania Rating Scale (YMRS; total score range 0–60) scores across assessment time points: admission/baseline (Tx), day of first risperidone ISM injection (T0), 24 h (T1), 48 h (T2), day 8 ± 1 (T3), day 28 ± 2 (T4; second injection), and day 42 ± 2 (T5). Embedded boxplots depict the median and interquartile range, with whiskers indicating dispersion. Asterisks (***) indicate statistically significant reductions versus baseline (Tx) using Wilcoxon signed-rank tests with Holm–Bonferroni correction (p\u0026lt;0.05)\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure1.YMRStotalscore.png","url":"https://assets-eu.researchsquare.com/files/rs-8503226/v1/7dd851cc736875063e6832e9.png"},{"id":100004750,"identity":"fb1f67fe-a547-44cc-939c-ac8430277a30","added_by":"auto","created_at":"2026-01-12 05:28:28","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":53680,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCGI-BP severity over time.\u003c/strong\u003e\u003cbr\u003e\n \u003cem\u003eBoxplots showing Clinical Global Impression for Bipolar Disorder—Severity (CGI-BP-S; 1 = normal, not at all ill; 7 = among the most extremely ill patients) at Tx, T0, T1, T2, T3, T4, and T5. Boxes represent the interquartile range with the median line; whiskers indicate dispersion. Asterisks denote statistically significant reductions versus baseline (Tx) using Wilcoxon signed-rank tests with Holm–Bonferroni correction (p\u0026lt;0.05).\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure2.CGIBP.png","url":"https://assets-eu.researchsquare.com/files/rs-8503226/v1/ef50624d136b3379ecd6947f.png"},{"id":100360665,"identity":"08871071-121f-423b-a1e9-dc84ed168f7f","added_by":"auto","created_at":"2026-01-16 07:40:42","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":128170,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTrajectories of selected YMRS single items.\u003c/strong\u003e\u003cbr\u003e\n \u003cem\u003eBar chart depicting median scores over time for three predefined YMRS items reflecting key symptom domains: irritability (item 5), thought content/psychotic ideation (item 8), and disruptive/aggressive behaviour (item 9). Time points are Tx, T0, T1, T2, T3, T4 and T5 as defined in the Methods. Asterisks indicate statistically significant differences versus baseline (Tx) in Wilcoxon signed-rank tests with Holm–Bonferroni correction (p\u0026lt;0.05).\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure3.TrajectoriesofselectedYMRSsingleitems.png","url":"https://assets-eu.researchsquare.com/files/rs-8503226/v1/5d6441414185b4150a787e88.png"},{"id":100360563,"identity":"a4ad2836-20a0-46cb-a994-15a7e1ca2d08","added_by":"auto","created_at":"2026-01-16 07:39:31","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":114983,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePrevalence of GASS domain symptoms at weeks 4 and 6.\u003c/strong\u003e\u003cbr\u003e\n \u003cem\u003eGrouped bar chart showing the proportion of patients reporting at least one symptom (domain score \u0026gt;0) in each Glasgow Antipsychotic Side-Effect Scale (GASS) domain at day 28 ± 2 (T4) and day 42 ± 2 (T5). Domains include sedation/CNS, cardiovascular, extrapyramidal, anticholinergic, gastrointestinal, genitourinary, prolactinaemic/sexual, diabetes-screening items, and weight gain. Percentages are calculated using N=50 at each time point.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure4.GASS.png","url":"https://assets-eu.researchsquare.com/files/rs-8503226/v1/981b7cceaa8e6237dc4b1c80.png"},{"id":100406341,"identity":"1d8839e0-440d-45e0-b024-075ed09f6462","added_by":"auto","created_at":"2026-01-16 13:00:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1307366,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8503226/v1/996a6de2-1f9f-4322-acd0-1ed252bdcdec.pdf"},{"id":100360315,"identity":"ad2df621-2797-4a00-9b18-ea2473a8894e","added_by":"auto","created_at":"2026-01-16 07:38:22","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":34781,"visible":true,"origin":"","legend":"","description":"","filename":"Additionalfile1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8503226/v1/3dd8488788df890b7ef48ea0.docx"}],"financialInterests":"Competing interest reported. Andrea Fagiolini has served as a consultant and/or speaker and/or has received research grants from the following pharmaceutical and healthcare companies: Allergan, Angelini, Apsend, Generici DOC, Boehringer Ingelheim, Idorsia, Italfarmaco, Lundbeck, Janssen, Medicamenta, Mylan, Otsuka, Pfizer, Recordati, Rovi, Roche, Sanofi Aventis, Sunovion, Teva, and Viatris. These relationships include re-search funding, consultancy fees, and/or honoraria for speaking engagements related to academic re-search activities, advisory roles, and participation in scientific meetings within the field of psychiatry and psychopharmacology. None of these relationships had any influence on the conception, design, conduct, interpretation, or reporting of the present study, and none are directly related to the content of this manuscript.\nAlessandro Cuomo has served as a consultant and/or speaker and/or has received research grants from the following pharmaceutical and healthcare companies: Allergan, Angelini, Apsend, Boehringer Ingelheim, Idorsia, Italfarmaco, Lundbeck, Janssen, Medicamenta, Mylan, Otsuka, Pfizer, Recordati, Roche, Sanofi Aventis, and Viatris. These relationships include research funding, consultancy fees, and/or honoraria for speaking engagements related to academic research activities, advisory roles, and participation in scientific meetings within the field of psychiatry and psychopharmacology. None of these relationships had any influence on the conception, design, conduct, interpretation, or reporting of the present study, and none are directly related to the content of this manuscript.\nAll other authors declare that they have no known competing financial interests or personal relation-ships that could have appeared to influence the work reported in this paper.","formattedTitle":"Risperidone long-acting in-situ microimplant in the acute management of manic episodes with psychotic symptoms in non-adherent patients with schizoaffective disorder: a retrospective real-world study","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eSchizoaffective disorder, bipolar type, is a severe mood\u0026ndash;psychotic condition in which manic, depressive and schizophrenia-spectrum symptoms coexist over time [1]. Longitudinal studies suggest that schizoaffective disorder occupies an intermediate position between prototypical schizophrenia and bipolar I disorder, showing a chronic or recurrent course with persistent symptoms, functional impairment and frequent need for ongoing antipsychotic treatment [2,3].\u003c/p\u003e\n\u003cp\u003eReal-world analyses highlight a substantial burden of illness in schizophrenia and schizoaffective disorder, with high healthcare resource utilization, frequent hospitalizations and substantial direct and indirect costs [4,5]. Across psychotic and bipolar disorders, non-adherence to antipsychotic medication is common, with many patients taking treatment on fewer than half of prescribed days and average adherence rates in the 40\u0026ndash;60% range [6]. Even relatively brief periods of non-adherence in recent-onset schizophrenia have been associated with markedly increased risks of relapse and rehospitalization [7]. In schizoaffective disorde treatment interruptions may precipitate acute episodes with psychotic features, leading to emergency admission and further longitudinal destabilization [2\u0026ndash;4].\u003c/p\u003e\n\u003cp\u003eLong-acting injectable (LAI) antipsychotics were developed to address some challenges of daily oral treatment by providing sustained drug delivery and reducing reliance on daily pill-taking. International guidelines recommend considering LAIs for patients with schizophrenia-spectrum disorders and bipolar disorder, particularly in those with partial adherence, frequent relapse or difficulty engaging with treatment [8]. While randomized trials in relatively adherent and stable patients have sometimes shown limited differences between LAIs and oral antipsychotics, mirror-image, cohort and registry studies in routine practice more consistently report reductions in relapse and rehospitalization after LAI initiation [9,10]. Network meta-analytic evidence also supports the role of both oral and long-acting antipsychotics for relapse prevention across schizophrenia-spectrum disorders [11].\u003c/p\u003e\n\u003cp\u003eRisperidone, a second-generation antipsychotic, is widely used across the schizophrenia\u0026ndash;bipolar\u0026ndash;schizoaffective spectrum. Randomized and open-label studies have demonstrated antimanic efficacy of risperidone, including long-acting formulations, in bipolar I disorder and have suggested benefits in schizoaffective disorder- particularly as maintenance therapy in patients with frequent relapses or poor adherence [12\u0026ndash;16]. These data support the broader concept that risperidone-based LAIs can provide both antipsychotic and mood-stabilizing effects in mood\u0026ndash;psychotic disorders.\u003c/p\u003e\n\u003cp\u003eRisperidone in situ microparticles (risperidone ISM) is a once-monthly LAI formulation that employs an in situ microimplant technology to achieve a biphasic pattern of drug release. After intramuscular injection, a fraction of the dose is rapidly released, while the remainder forms a biodegradable depot that provides controlled risperidone delivery over the 4-week dosing interval [17,18]. Phase II\u0026ndash;III trials and extension studies in schizophrenia have shown that risperidone ISM produces rapid improvements in psychotic symptoms, maintains therapeutic exposure over the dosing interval and has a tolerability profile broadly comparable to oral risperidone [17,18]. However, current evidence for risperidone ISM is largely confined to schizophrenia, and\u0026mdash; to our knowledge\u0026mdash;no published clinical studies have specifically evaluated this formulation in bipolar I disorder or in schizoaffective disorder, bipolar type, particularly in the context of acute manic episodes with psychotic symptoms and recent antipsychotic non-adherence.\u003c/p\u003e\n\u003cp\u003eGiven (i) the established antimanic efficacy of oral and long-acting risperidone in bipolar and schizoaffective populations [12\u0026ndash;15], (ii) the central role of LAIs in the management of non-adherent patients [8,10], and (iii) the pharmacokinetic profile of risperidone ISM\u0026mdash;combining early release with once-monthly dosing [17,18]\u0026mdash;a systematic real-world evaluation of risperidone ISM in schizoaffective mania appears clinically warranted. This retrospective study was therefore undertaken to characterize the short-term clinical course and tolerability of a pragmatic \u0026ldquo;oral risperidone lead-in plus monthly risperidone ISM\u0026rdquo; strategy in a consecutive series of non-adherent inpatients with schizoaffective disorder, bipolar type, hospitalized for an acute manic episode with psychotic features and a documented previous clinical response to risperidone.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003ch3\u003e2.1. Ethical approval and informed consent statement\u003c/h3\u003e\n\u003cp\u003eThe study protocol (acronym \u0026ldquo;REALSAD\u0026rdquo; ) was approved by the Territorial Ethics Committee CET Lombardia 4 (promoter: ASST Mantova; protocol code CET 140/24). All procedures were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. At the time of hospitalisation, all patients (or their legal representatives) provided written informed consent for the collection and use of anonymised clinical data for research purposes, as required by the local Ethics Committee.\u003c/p\u003e\n\u003ch3\u003e2.2. Study design and setting\u003c/h3\u003e\n\u003cp\u003eThis was a retrospective, observational, single-centre study conducted in the Psychiatry Unit Mantova 1 (S.C. Psichiatria, ASST Mantova, Mantova, Italy). Electronic medical records of consecutive in-patients with schizoaffective disorder (SAD) were reviewed. Patients were selected according to the formal diagnosis and documentation available in the clinical charts, adhering to DSM-5-TR criteria for schizoaffective disorder, bipolar type, currently manic episode with psychotic symptoms [1]. The study included admissions between January 2024 and November 2025.\u003c/p\u003e\n\u003cp\u003eThe study followed the STROBE recommendations for observational studies [19]. Clinical management (choice of antipsychotic, adjunctive mood stabilisers or benzodiazepines) was entirely naturalistic and based on the treating psychiatrist\u0026rsquo;s judgement.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003e\u0026nbsp;\u003c/h3\u003e\n\u003ch3\u003e2.2.1. Participants \u0026ndash; inclusion criteria\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003ePatients were eligible for inclusion if they:\u003c/p\u003e\n\u003col class=\"decimal_type\"\u003e\n \u003cli\u003eWere aged \u0026ge; 18 years and admitted to the adult psychiatric inpatient unit.\u003c/li\u003e\n \u003cli\u003eHad a primary diagnosis of schizoaffective disorder, bipolar type, in a current manic episode with psychotic features according to DSM-5-TR [1].\u003c/li\u003e\n \u003cli\u003eHad clinical relapse temporally associated with discontinuation or marked non-adherence to ongoing antipsychotic treatment, defined as taking \u0026lt;50% of prescribed doses during the month preceding admission, as documented in the medical record.\u003c/li\u003e\n \u003cli\u003eReceived risperidone ISM (in-situ microimplant) during the index hospitalisation as part of routine clinical care, with at least one injection recorded.\u003c/li\u003e\n \u003cli\u003eHad a documented history of previous clinical response to risperidone (oral or depot formulation), reported in previous treatment episodes.\u003c/li\u003e\n \u003cli\u003eHad Young Mania Rating Scale (YMRS) and Clinical Global Impression (CGI) scores available at admission (Tx) and at least one subsequent post-injection time point.\u003c/li\u003e\n\u003c/ol\u003e\n\u003ch3\u003e2.2.2. Exclusion criteria\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003ePatients were excluded if they:\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eHad an alternative primary diagnosis (e.g. bipolar disorder without psychosis, schizophrenia, schizophreniform disorder) or if the current manic/psychotic presentation was judged to be primarily substance-induced (i.e. attributable to acute intoxication or withdrawal from alcohol or illicit substances).\u003c/li\u003e\n \u003cli\u003eHad incomplete or inconsistent clinical documentation, precluding reliable reconstruction of treatment timing or rating-scale trajectories.\u003c/li\u003e\n \u003cli\u003eWere pregnant or breastfeeding at the time of hospitalisation, or had a documented contraindication to risperidone according to the summary of product characteristics (e.g. severe, unstable cardiovascular disease, known hypersensitivity to risperidone or excipients).\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eIncluded patients were diagnosed in routine clinical practice by board-certified psychiatrists using DSM-5-TR criteria and confirmed by the Mini International Neuropsychiatric Interview [20]. In the following text we refer to \u0026ldquo;SAD mania\u0026rdquo; to indicate manic episodes occurring within schizoaffective disorder, bipolar type.\u003c/p\u003e\n\u003ch3\u003e2.2.2.1. Data sources and measurements\u003c/h3\u003e\n\u003cp\u003eData were extracted from electronic charts and structured case-report forms and included:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eDemographic and clinical variables: age, sex, body mass index (BMI), duration of diagnosed illness, number of previous mood episodes, history of substance abuse (none, alcohol, cannabis), cluster-B personality disorder, Axis III medical comorbidities, and concomitant psychotropic medications (lithium, valproate, haloperidol, other antipsychotics, benzodiazepines).\u003c/li\u003e\n \u003cli\u003eRisperidone ISM exposure: dose of the first injection at T0 (75 or 100 mg), dose at T4 (100 mg, 75 mg, stopped depot, or switched to another long-acting antipsychotic), and timing of each injection.\u003c/li\u003e\n\u003c/ul\u003e\n\u003ch4\u003eAssessment time points\u003c/h4\u003e\n\u003cp\u003eRating scales were collected as part of routine care at the following time points:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eTx (admission) \u0026ndash; baseline, before risperidone ISM; demographic and clinical data; YMRS and CGI-BP.\u003c/li\u003e\n \u003cli\u003eT0 (injection 1) \u0026ndash; day of first risperidone ISM injection; YMRS and CGI-BP.\u003c/li\u003e\n \u003cli\u003eT1 (24 h) \u0026ndash; approximately 24 hours after T0; YMRS and CGI-BP.\u003c/li\u003e\n \u003cli\u003eT2 (48 h) \u0026ndash; approximately 48 hours after T0; YMRS and CGI-BP..\u003c/li\u003e\n \u003cli\u003eT3 (day 8 \u0026plusmn; 1 day) \u0026ndash; early post-acute phase; YMRS and CGI-BP.\u003c/li\u003e\n \u003cli\u003eT4 (day 28 \u0026plusmn; 2 days; injection 2) \u0026ndash; consolidation phase and second risperidone ISM injection; YMRS, CGI-BP and Glasgow Antipsychotic Side-Effect Scale (GASS).\u003c/li\u003e\n \u003cli\u003eT5 (day 42 \u0026plusmn; 2 days) \u0026ndash; follow-up visit; YMRS, CGI-BP and GASS.\u003c/li\u003e\n\u003c/ul\u003e\n\u003ch4\u003eSymptom rating scales\u003c/h4\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eYoung Mania Rating Scale (YMRS)\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Mania severity was assessed with the 11-item Young Mania Rating Scale (YMRS; total score 0\u0026ndash;60) [21]. In addition, we planned a priori to describe the temporal course of individual YMRS items across all time points. Analyses of single-item trajectories were considered exploratory and primarily descriptive.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eClinical Global Impression for Bipolar Disorder (CGI-BP)\u003cbr\u003e\u003c/strong\u003eGlobal illness severity was rated at each time point using the Clinical Global Impression for Bipolar Disorder\u0026ndash;Severity scale (CGI-BP-S; 1 = normal, not at all ill; 7 = among the most extremely ill patients), anchored to overall bipolar illness [22].\u003c/li\u003e\n\u003c/ul\u003e\n\u003ch4\u003eTolerability and adverse events\u003c/h4\u003e\n\u003cul class=\"decimal_type\"\u003e\n \u003cli\u003e\u003cstrong\u003eGlasgow Antipsychotic Side-Effect Scale (GASS)\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Tolerability was evaluated at T4 and T5 using the Glasgow Antipsychotic Side-Effect Scale (GASS; 21 items, total score 0\u0026ndash;63), capturing nine domains: sedation/CNS, cardiovascular, extrapyramidal, anticholinergic, gastrointestinal, genitourinary, prolactinaemic/sexual, diabetes-screening items, and weight gain [23].Domain scores and total scores were recorded.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAdverse events (AEs)\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;All adverse events documented in the charts during hospitalisation and follow-up (e.g. extrapyramidal symptoms, sedation, metabolic changes, prolactin-related AEs) were extracted and qualitatively summarised.\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e\n\u003ch3\u003e2.3. Risperidone ISM treatment protocol\u003c/h3\u003e\n\u003cp\u003eRisperidone ISM (in-situ microimplant) was prescribed according to the approved summary of product characteristics and local clinical practice. In brief, oral risperidone was initiated or optimised during the first days of admission and maintained for at least 6 consecutive days to confirm both clinical stabilisation and tolerability, in line with the prescribing information. The first intramuscular risperidone ISM injection at T0 (75 mg or 100 mg) was then administered on the first available day after completion of this \u0026ge;6-day tolerability period. In keeping with dose-conversion recommendations, 100 mg ISM was generally used in patients who had been receiving \u0026ge;4 mg/day of oral risperidone, whereas 75 mg ISM was selected in those stabilised on 3 mg/day, with adjustments left to the discretion of the treating psychiatrist based on overall clinical status and comorbidities.\u003c/p\u003e\n\u003cp\u003eThe choice of 75 vs 100 mg at T0 was at the discretion of the treating clinician, based on prior exposure, severity of the manic episode, comorbidities and concomitant medications. As per the label, risperidone ISM provides an early release of risperidone without requiring oral supplementation; no systematic oral overlap was maintained beyond the acute titration period.\u003c/p\u003e\n\u003cp\u003eAt T4 (day 28 \u0026plusmn; 2 days) patients were re-evaluated. In those who continued risperidone ISM, a second injection was administered at either 100 mg or 75 mg. In a minority of cases the depot was stopped or switched to another long-acting antipsychotic, again according to clinical judgement. Concomitant mood stabilisers (lithium, valproate) and benzodiazepines were allowed and recorded.\u003c/p\u003e\n\u003ch3\u003e2.3.1. Variables and outcomes\u003c/h3\u003e\n\u003cp\u003eThe primary efficacy outcome was the change in YMRS total score across subsequent time points, with particular focus on the short-term antimanic effect (Tx to T2 and T3) and the maintenance of improvement at T4 and T5.\u003c/p\u003e\n\u003cp\u003eSecondary endpoints included:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eChange in CGI-BP score across the same time points.\u003c/li\u003e\n \u003cli\u003eTrajectories of individual YMRS items, and, specifically, core YMRS items (items 5, 8, 9), describing the temporal profile of irritability, aggressive behaviour and psychotic thought content.\u003c/li\u003e\n \u003cli\u003eThe proportion of patients achieving clinical response (defined as \u0026ge;50% reduction in YMRS total score from admission) and complete symptomatic remission (YMRS total score \u0026lt;8)\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eTolerability outcomes, including:\u003c/p\u003e\n\u003cp\u003eGASS total score and domain scores at T4 and T5,\u003c/p\u003e\n\u003cul class=\"decimal_type\"\u003e\n \u003cli\u003ethe proportion of patients with any symptom in each GASS domain,\u003c/li\u003e\n \u003cli\u003ethe distribution of GASS total scores across predefined categories: absent/mild (0\u0026ndash;21), moderate (22\u0026ndash;42), and severe (43\u0026ndash;63),\u003c/li\u003e\n \u003cli\u003ethe frequency and nature of clinically recorded adverse events.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e2.4. Statistical analysis\u003c/p\u003e\n\u003cp\u003eContinuous variables are presented as mean \u0026plusmn; standard deviation (SD) or median and interquartile range [IQR], according to their distribution. Categorical variables are reported as absolute and relative frequencies (n, %). Normality of continuous variables was assessed visually (histograms, Q\u0026ndash;Q plots) and with the Shapiro\u0026ndash;Wilk test.\u003c/p\u003e\n\u003cp\u003eBecause YMRS and CGI-BP scores did not consistently meet normality assumptions, overall changes across time (Tx, T0, T1, T2, T3, T4, T5) were first evaluated using the Friedman test for repeated measures. When overall tests were significant, pairwise comparisons between baseline (Tx) and each post-baseline time point were performed using the Wilcoxon signed-rank test. To control for multiple testing, Holm\u0026ndash;Bonferroni correction was applied to the family of comparisons.\u003c/p\u003e\n\u003cp\u003eFor YMRS single items, analogous Friedman and Wilcoxon procedures were used to assess changes over time.\u0026nbsp;\u003cbr\u003e\u0026nbsp;In exploratory post-hoc analyses, additional Wilcoxon signed-rank tests were used to compare all pairs of post-baseline time points within each measure.\u003c/p\u003e\n\u003cp\u003eIn addition, linear mixed-effects models for repeated measures were fitted for YMRS total and CGI-BP severity scores, with time (Tx, T0, T1, T2, T3, T4, T5) entered as a categorical fixed effect and a random intercept for patient. Least-squares means (estimated marginal means) were derived for each timepoint, and prespecified pairwise contrasts were tested for selected time comparisons (YMRS: Tx vs T0, T0 vs T1, T0 vs T2, T2 vs T3, T3 vs T4, T4 vs T5; CGI-BP: Tx vs T0, T0 vs T2, T2 vs T3, T3 vs T4) using Wald statistics and 95% confidence intervals. For YMRS and CGI-BP contrasts, p-values were adjusted for multiplicity using the Holm\u0026ndash;Bonferroni method. In sensitivity analyses, the YMRS and CGI-BP mixed models were additionally adjusted for potential confounders, including age, sex, body mass index and concurrent psychotropic medications (e.g. lithium, valproate).\u003c/p\u003e\n\u003cp\u003eGASS total scores at T4 and T5 were summarised descriptively and categorised into absent/mild, moderate and severe burden; GASS domains were described as the percentage of patients with \u0026ge;1 point symptom (score \u0026gt; 0).\u003c/p\u003e\n\u003cp\u003eAll tests were two-sided. Statistical significance was set at p \u0026lt; 0.05, with Bonferroni-type corrections applied where indicated. Statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA).\u003c/p\u003e"},{"header":"3. Results","content":"\u003ch3\u003e3.1. Cohort description\u003c/h3\u003e\n\u003cp\u003eDuring the study period, 66 hospitalised patients with a diagnosis of schizoaffective disorder, bipolar type, manic episode with psychotic features were screened. Of these, 9 patients were excluded because clinical documentation was incomplete or inconsistent, preventing a reliable reconstruction of treatment timing or rating-scale trajectories, and 7 patients were excluded because the acute presentation was considered predominantly substance-induced, with manic and psychotic symptoms occurring in the context of marked alcohol or illicit-substance intoxication or withdrawal, rather than a primary schizoaffective manic episode.\u003c/p\u003e\n\u003cp\u003eThe final cohort therefore consisted of 50 in-patients who fulfilled all inclusion and exclusion criteria. All 50 patients completed all seven planned clinical assessments (Tx to T5), and GASS forms were available for all patients at both T4 and T5. Sociodemographic and clinical characteristics are summarised in Table 1.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003e\u003cem\u003eSociodemographic and clinical characteristics; concomitant medications at baseline\u003c/em\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003e\u003cem\u003eSociodemographic and clinical characteristics\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eValue\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eSample size\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eN = 50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e37.5 [28.2\u0026ndash;48.0] (mean 39.8 \u0026plusmn; 14.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eBMI, kg/m\u0026sup2;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e24.0 [21.0\u0026ndash;31.0] (mean 26.2 \u0026plusmn; 6.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eDuration of diagnosed illness, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e7.5 [4.0\u0026ndash;15.0] (mean 11.3 \u0026plusmn; 10.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eNumber of mood episodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e3.0 [2.0\u0026ndash;4.0] (mean 3.6 \u0026plusmn; 2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eSex, male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e35 (70.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eSex, female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e15 (30.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eSubstance abuse: none\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e32 (64.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eSubstance abuse: alcohol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e10 (20.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eSubstance abuse: cannabis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e8 (16.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003ePersonality disorder, cluster B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e7 (14.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eMedical comorbidity (Axis III)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e17 (34.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eRisperidone ISM first injection (T0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e75 mg: 9 (18.0%); 100 mg: 41 (82.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eRisperidone ISM second injection (T4) \u0026ndash; dose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e75 mg: 7 (14.0%); 100 mg: 39 (78.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eRisperidone ISM second injection (T4) \u0026ndash; change\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eStopped depot: 2 (4.0%); Switched depot: 2 (4.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003e\u003cem\u003eConcomitant medications at baseline\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cem\u003ePsychotropic drugs\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cem\u003ePatients, n (%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eLithium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e14 (28.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eValproate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e33 (66.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eHaloperidol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e2 (4.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eOther antipsychotics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e9 (18.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003eBenzodiazepines\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e36 (72.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eThe median age was 37.5 years [IQR 28.2\u0026ndash;48.0], and 35 patients (70.0%) were male.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt baseline, lithium was prescribed in 14 patients (28.0%), valproate in 33 (66.0%), haloperidol in 2 (4.0%), other antipsychotics in 9 (18.0%), and benzodiazepines in 36 (72.0%) (Table 1).\u003c/p\u003e\n\u003cp\u003eWith regard to risperidone ISM exposure, the first injection at T0 was 75 mg in 9 patients (18.0%) and 100 mg in 41 (82.0%), consistent with the preceding oral dose (75 mg in patients on 3 mg/day oral risperidone and 100 mg in those on \u0026ge;4 mg/day). At T4 (day 28 \u0026plusmn; 2 days), a second injection was administered in the majority of cases (100 mg in 39/50, 78.0%; 75 mg in 7/50, 14.0%), whereas the depot was stopped in 2 patients (4.0%) and switched to another long-acting antipsychotic in 2 (4.0%).\u003c/p\u003e\n\u003cp\u003eAt admission (Tx), the cohort presented with moderate-to-severe mania and marked psychotic symptoms. The median YMRS total score was 32 [29\u0026ndash;36], and the CGI-BP score was 6 [5\u0026ndash;6], indicating patients who were severely ill (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eTable 2.\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cem\u003eCGI-BP, YMRS total and YMRS single items across time points: Values are median [IQR]. ⁎p \u0026lt; 0.05 vs Tx; ᵃp \u0026lt; 0.05 vs T0; ᵇp \u0026lt; 0.05 vs T1; ᶜp \u0026lt; 0.05 vs T2; ᵈp \u0026lt; 0.05 vs T3; ᵉp \u0026lt; 0.05 vs T4 (Wilcoxon signed-rank tests with Holm\u0026ndash;Bonferroni correction for multiple pairwise comparisons).\u003c/em\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"709\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22.8491%;\"\u003e\n \u003cp\u003eMeasure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.44993%;\"\u003e\n \u003cp\u003eTx\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7066%;\"\u003e\n \u003cp\u003eT0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7193%;\"\u003e\n \u003cp\u003eT1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.59097%;\"\u003e\n \u003cp\u003eT2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.88575%;\"\u003e\n \u003cp\u003eT3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.0268%;\"\u003e\n \u003cp\u003eT4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.19323%;\"\u003e\n \u003cp\u003eT5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5783%;\"\u003e\n \u003cp\u003ep (Friedman)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22.8491%;\"\u003e\n \u003cp\u003eCGI-BP score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.44993%;\"\u003e\n \u003cp\u003e6 [5\u0026ndash;6]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7066%;\"\u003e\n \u003cp\u003e5 [4\u0026ndash;6]⁎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7193%;\"\u003e\n \u003cp\u003e4 [4\u0026ndash;5]⁎ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.59097%;\"\u003e\n \u003cp\u003e4 [4\u0026ndash;5]⁎ᵃ,ᵇ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.88575%;\"\u003e\n \u003cp\u003e4 [3\u0026ndash;4]⁎ᵃ,ᵇ,ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.0268%;\"\u003e\n \u003cp\u003e3 [2\u0026ndash;4]⁎ᵃ,ᵇ,ᶜ,ᵈ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.19323%;\"\u003e\n \u003cp\u003e3 [2\u0026ndash;3]⁎ᵃ,ᵇ,ᶜ,ᵈ,ᵉ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5783%;\"\u003e\n \u003cp\u003e\u0026lt; 0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22.8491%;\"\u003e\n \u003cp\u003eYMRS total score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.44993%;\"\u003e\n \u003cp\u003e32 [29\u0026ndash;36]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7066%;\"\u003e\n \u003cp\u003e26 [21\u0026ndash;30]⁎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7193%;\"\u003e\n \u003cp\u003e20 [15\u0026ndash;30]⁎ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.59097%;\"\u003e\n \u003cp\u003e17 [10\u0026ndash;27]⁎ᵃ,ᵇ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.88575%;\"\u003e\n \u003cp\u003e8 [6\u0026ndash;11]⁎ᵃ,ᵇ,ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.0268%;\"\u003e\n \u003cp\u003e5 [4\u0026ndash;8]⁎ᵃ,ᵇ,ᶜ,ᵈ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.19323%;\"\u003e\n \u003cp\u003e6 [4\u0026ndash;8]⁎ᵃ,ᵇ,ᶜ,ᵈ,ᵉ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5783%;\"\u003e\n \u003cp\u003e\u0026lt; 0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22.8491%;\"\u003e\n \u003cp\u003eYMRS item 1 \u0026ndash; Elevated mood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.44993%;\"\u003e\n \u003cp\u003e2 [2\u0026ndash;2]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7066%;\"\u003e\n \u003cp\u003e2 [1\u0026ndash;2]⁎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7193%;\"\u003e\n \u003cp\u003e2 [1\u0026ndash;2]⁎ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.59097%;\"\u003e\n \u003cp\u003e1 [0\u0026ndash;2]⁎ᵃ,ᵇ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.88575%;\"\u003e\n \u003cp\u003e0 [0\u0026ndash;1]⁎ᵃ,ᵇ,ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.0268%;\"\u003e\n \u003cp\u003e0 [0\u0026ndash;1]⁎ᵃ,ᵇ,ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.19323%;\"\u003e\n \u003cp\u003e0 [0\u0026ndash;1]⁎ᵃ,ᵇ,ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5783%;\"\u003e\n \u003cp\u003e\u0026lt; 0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22.8491%;\"\u003e\n \u003cp\u003eYMRS item 2 \u0026ndash; Increased activity/energy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.44993%;\"\u003e\n \u003cp\u003e2 [2\u0026ndash;3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7066%;\"\u003e\n \u003cp\u003e2 [2\u0026ndash;2]⁎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7193%;\"\u003e\n \u003cp\u003e2 [1\u0026ndash;2]⁎ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.59097%;\"\u003e\n \u003cp\u003e1 [0\u0026ndash;2]⁎ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.88575%;\"\u003e\n \u003cp\u003e0 [0\u0026ndash;1]⁎ᵃ,ᵇ,ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.0268%;\"\u003e\n \u003cp\u003e0 [0\u0026ndash;1]⁎ᵃ,ᵇ,ᶜ,ᵈ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.19323%;\"\u003e\n \u003cp\u003e0 [0\u0026ndash;1]⁎ᵃ,ᵇ,ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5783%;\"\u003e\n \u003cp\u003e\u0026lt; 0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22.8491%;\"\u003e\n \u003cp\u003eYMRS item 3 \u0026ndash; Increased sexual interest\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.44993%;\"\u003e\n \u003cp\u003e2 [1\u0026ndash;2]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7066%;\"\u003e\n \u003cp\u003e1 [0\u0026ndash;2]⁎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7193%;\"\u003e\n \u003cp\u003e1 [0\u0026ndash;2]⁎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.59097%;\"\u003e\n \u003cp\u003e1 [0\u0026ndash;2]⁎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.88575%;\"\u003e\n \u003cp\u003e0 [0\u0026ndash;1]⁎ᵃ,ᵇ,ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.0268%;\"\u003e\n \u003cp\u003e0 [0\u0026ndash;1]⁎ᵃ,ᵇ,ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.19323%;\"\u003e\n \u003cp\u003e0 [0\u0026ndash;1]⁎ᵃ,ᵇ,ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5783%;\"\u003e\n \u003cp\u003e\u0026lt; 0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22.8491%;\"\u003e\n \u003cp\u003eYMRS item 4 \u0026ndash; Reduced sleep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.44993%;\"\u003e\n \u003cp\u003e2 [2\u0026ndash;3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7066%;\"\u003e\n \u003cp\u003e2 [1\u0026ndash;2]⁎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7193%;\"\u003e\n \u003cp\u003e2 [1\u0026ndash;2]⁎ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.59097%;\"\u003e\n \u003cp\u003e1 [0\u0026ndash;2]⁎ᵃ,ᵇ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.88575%;\"\u003e\n \u003cp\u003e0 [0\u0026ndash;1]⁎ᵃ,ᵇ,ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.0268%;\"\u003e\n \u003cp\u003e0 [0\u0026ndash;1]⁎ᵃ,ᵇ,ᶜ,ᵈ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.19323%;\"\u003e\n \u003cp\u003e0 [0\u0026ndash;1]⁎ᵃ,ᵇ,ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5783%;\"\u003e\n \u003cp\u003e\u0026lt; 0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22.8491%;\"\u003e\n \u003cp\u003eYMRS item 5 \u0026ndash; Irritability\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.44993%;\"\u003e\n \u003cp\u003e5 [4\u0026ndash;5]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7066%;\"\u003e\n \u003cp\u003e4 [3\u0026ndash;5]⁎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7193%;\"\u003e\n \u003cp\u003e2 [2\u0026ndash;3]⁎ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.59097%;\"\u003e\n \u003cp\u003e2 [2\u0026ndash;3]⁎ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.88575%;\"\u003e\n \u003cp\u003e1 [1\u0026ndash;2]⁎ᵃ,ᵇ,ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.0268%;\"\u003e\n \u003cp\u003e1 [0\u0026ndash;1]⁎ᵃ,ᵇ,ᶜ,ᵈ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.19323%;\"\u003e\n \u003cp\u003e1 [0\u0026ndash;1]⁎ᵃ,ᵇ,ᶜ,ᵈ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5783%;\"\u003e\n \u003cp\u003e\u0026lt; 0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22.8491%;\"\u003e\n \u003cp\u003eYMRS item 6 \u0026ndash; Speech (rate and amount)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.44993%;\"\u003e\n \u003cp\u003e5 [3\u0026ndash;5]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7066%;\"\u003e\n \u003cp\u003e3 [3\u0026ndash;5]⁎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7193%;\"\u003e\n \u003cp\u003e2 [2\u0026ndash;4]⁎ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.59097%;\"\u003e\n \u003cp\u003e2 [1\u0026ndash;4]⁎ᵃ,ᵇ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.88575%;\"\u003e\n \u003cp\u003e1 [1\u0026ndash;2]⁎ᵃ,ᵇ,ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.0268%;\"\u003e\n \u003cp\u003e1 [0\u0026ndash;1]⁎ᵃ,ᵇ,ᶜ,ᵈ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.19323%;\"\u003e\n \u003cp\u003e1 [0\u0026ndash;1]⁎ᵃ,ᵇ,ᶜ,ᵈ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5783%;\"\u003e\n \u003cp\u003e\u0026lt; 0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22.8491%;\"\u003e\n \u003cp\u003eYMRS item 7 \u0026ndash; Language/thought disorder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.44993%;\"\u003e\n \u003cp\u003e3 [3\u0026ndash;5]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7066%;\"\u003e\n \u003cp\u003e3 [2\u0026ndash;5]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7193%;\"\u003e\n \u003cp\u003e3 [2\u0026ndash;5]⁎ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.59097%;\"\u003e\n \u003cp\u003e3 [2\u0026ndash;4]⁎ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.88575%;\"\u003e\n \u003cp\u003e1 [1\u0026ndash;2]⁎ᵃ,ᵇ,ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.0268%;\"\u003e\n \u003cp\u003e1 [1\u0026ndash;1]⁎ᵃ,ᵇ,ᶜ,ᵈ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.19323%;\"\u003e\n \u003cp\u003e1 [0\u0026ndash;2]⁎ᵃ,ᵇ,ᶜ,ᵈ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5783%;\"\u003e\n \u003cp\u003e\u0026lt; 0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22.8491%;\"\u003e\n \u003cp\u003eYMRS item 8 \u0026ndash; Thought content\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.44993%;\"\u003e\n \u003cp\u003e5 [5\u0026ndash;5]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7066%;\"\u003e\n \u003cp\u003e5 [4\u0026ndash;5]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7193%;\"\u003e\n \u003cp\u003e5 [4\u0026ndash;5]⁎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.59097%;\"\u003e\n \u003cp\u003e4 [3\u0026ndash;5]⁎ᵃ,ᵇ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.88575%;\"\u003e\n \u003cp\u003e2 [1\u0026ndash;3]⁎ᵃ,ᵇ,ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.0268%;\"\u003e\n \u003cp\u003e2 [1\u0026ndash;2]⁎ᵃ,ᵇ,ᶜ,ᵈ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.19323%;\"\u003e\n \u003cp\u003e2 [1\u0026ndash;2]⁎ᵃ,ᵇ,ᶜ,ᵈ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5783%;\"\u003e\n \u003cp\u003e\u0026lt; 0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22.8491%;\"\u003e\n \u003cp\u003eYMRS item 9 \u0026ndash; Disruptive/aggressive behaviour\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.44993%;\"\u003e\n \u003cp\u003e2 [2\u0026ndash;5]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7066%;\"\u003e\n \u003cp\u003e2 [1\u0026ndash;2]⁎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7193%;\"\u003e\n \u003cp\u003e2 [1\u0026ndash;2]⁎ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.59097%;\"\u003e\n \u003cp\u003e1 [0\u0026ndash;2]⁎ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.88575%;\"\u003e\n \u003cp\u003e0 [0\u0026ndash;1]⁎ᵃ,ᵇ,ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.0268%;\"\u003e\n \u003cp\u003e0 [0\u0026ndash;0]⁎ᵃ,ᵇ,ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.19323%;\"\u003e\n \u003cp\u003e0 [0\u0026ndash;0]⁎ᵃ,ᵇ,ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5783%;\"\u003e\n \u003cp\u003e\u0026lt; 0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22.8491%;\"\u003e\n \u003cp\u003eYMRS item 10 \u0026ndash; Appearance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.44993%;\"\u003e\n \u003cp\u003e2 [2\u0026ndash;2]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7066%;\"\u003e\n \u003cp\u003e2 [1\u0026ndash;2]⁎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7193%;\"\u003e\n \u003cp\u003e2 [1\u0026ndash;2]⁎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.59097%;\"\u003e\n \u003cp\u003e2 [1\u0026ndash;2]⁎ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.88575%;\"\u003e\n \u003cp\u003e1 [0\u0026ndash;1]⁎ᵃ,ᵇ,ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.0268%;\"\u003e\n \u003cp\u003e0 [0\u0026ndash;1]⁎ᵃ,ᵇ,ᶜ,ᵈ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.19323%;\"\u003e\n \u003cp\u003e0 [0-1]⁎ᵃ,ᵇ,ᶜ,ᵈ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5783%;\"\u003e\n \u003cp\u003e\u0026lt; 0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22.8491%;\"\u003e\n \u003cp\u003eYMRS item 11 \u0026ndash; Insight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.44993%;\"\u003e\n \u003cp\u003e3 [2\u0026ndash;3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7066%;\"\u003e\n \u003cp\u003e2 [2\u0026ndash;3]⁎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.7193%;\"\u003e\n \u003cp\u003e2 [2\u0026ndash;3]⁎\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.59097%;\"\u003e\n \u003cp\u003e2 [2\u0026ndash;2]⁎ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.88575%;\"\u003e\n \u003cp\u003e1 [1\u0026ndash;2]⁎ᵃ,ᵇ,ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.0268%;\"\u003e\n \u003cp\u003e1 [1\u0026ndash;1]⁎ᵃ,ᵇ,ᶜ,ᵈ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.19323%;\"\u003e\n \u003cp\u003e1 [1\u0026ndash;2]⁎ᵃ,ᵇ,ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5783%;\"\u003e\n \u003cp\u003e\u0026lt; 0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003ch2\u003e3.2 YMRS total score\u003c/h2\u003e\n\u003cp\u003eA marked and progressive improvement in YMRS total score was observed over the 6-week observation period (Friedman p \u0026lt; 0.0001; Table 2, Fig. 1). The median score decreased from 32 [29\u0026ndash;36] at Tx to 26 [21\u0026ndash;30] at T0, 20 [15\u0026ndash;30] at T1 (24 h), and 17 [10\u0026ndash;27] at T2 (48 h).\u003c/p\u003e\n\u003cp\u003eThe initial reduction between Tx and T0 occurred during the \u0026ge;6-day oral risperidone lead-in and standard inpatient management, before administration of the first risperidone ISM injection at T0. This corresponded to a median 6-point reduction from Tx to T0 and an additional 9-point decrease from T0 (day of the first Risperidone ISM injection) to T2.\u003c/p\u003e\n\u003cp\u003eImprovement continued into the early post-acute phase: at T3 (day 8 \u0026plusmn; 1), the median YMRS score further declined to 8 [6\u0026ndash;11], and reached 5 [4\u0026ndash;8] at T4 (day 28 \u0026plusmn; 2) and 6 [4\u0026ndash;8] at T5 (day 42 \u0026plusmn; 2) (Table 2). Compared with Tx, YMRS total scores were significantly lower at all subsequent time points (T0\u0026ndash;T5; all Wilcoxon p \u0026lt; 0.05 after Holm\u0026ndash;Bonferroni correction).\u003c/p\u003e\n\u003cp\u003eMixed-effects models confirmed rapid and clinically relevant LS-mean reductions in YMRS from admission through day 8, with all prespecified contrasts from Tx to T3 reaching statistical significance, followed by more modest improvement between day 8 and day 28 and stabilisation thereafter (\u003cem\u003esee Additional file 1: Supplementary Table S1).\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eExploratory pairwise analyses further showed that YMRS total scores not only improved significantly from Tx to each post-baseline time point, but also declined stepwise from T0 to subsequent visits up to day 8, with most comparisons between T0 and T1\u0026ndash;T3 reaching statistical significance (Table 2).\u003c/p\u003e\n\u003cp\u003eUsing the predefined YMRS-based criteria, all patients met the \u0026ge;50% response threshold from day 8 (T3) onwards. Symptomatic remission (YMRS \u0026lt;8) was achieved by 24/50 patients (48.0%) at T3 and by 37/50 (74.0%) at both T4 and T5.\u003c/p\u003e\n\u003cp\u003eThese trajectories are graphically illustrated in Fig. 1, where both medians and dispersion clearly show a rapid early antimanic effect followed by stabilisation and maintenance of low YMRS scores through week 6.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003e3.2.1. CGI-BP score\u003c/h3\u003e\n\u003cp\u003eGlobal clinical severity, as measured by the CGI-BP, improved in parallel with YMRS (Friedman p \u0026lt; 0.0001; Table 2, Fig. 2). The median CGI-BP at Tx was 6 [5\u0026ndash;6], consistent with \u0026ldquo;markedly\u0026rdquo; to \u0026ldquo;severely\u0026rdquo; ill patients. Scores decreased to 5 [4\u0026ndash;6] at T0 (initiation of once monthly Risperidone ISM), followed by 4 [4\u0026ndash;5] at T1 and T2, and 4 [3\u0026ndash;4] at T3. By T4, the median CGI-BP further improved to 3 [2\u0026ndash;4], and remained 3 [2\u0026ndash;3] at T5, indicating a shift towards \u0026ldquo;mildly\u0026rdquo; to \u0026ldquo;moderately\u0026rdquo; ill.\u003c/p\u003e\n\u003cp\u003eAll post-baseline CGI-BP scores were significantly lower than Tx after Holm\u0026ndash;Bonferroni correction, confirming a robust clinical impression of improvement (Fig. 2).\u003c/p\u003e\n\u003cp\u003eConsistent with YMRS, mixed-effects models estimated a progressive reduction in LS-mean CGI-BP severity scores from 5.7 at admission to 2.8 at day 42. All prespecified pairwise contrasts (Tx\u0026ndash;T0, T0\u0026ndash;T2, T2\u0026ndash;T3, T3\u0026ndash;T4) were statistically significant (all Holm-adjusted p \u0026lt; 0.001), supporting a steady improvement in global illness severity over the observation period (\u003cem\u003esee Additional file 1: Supplementary Table S2).\u0026nbsp;\u003cbr\u003e\u0026nbsp;\u003c/em\u003eConsistent with the YMRS findings, pairwise comparisons also indicated significant decreases in CGI-BP scores from T0 to subsequent early post-injection visits, particularly up to day 8 (Table 2).\u003c/p\u003e\n\u003ch2\u003e3.2.2 Sensitivity analyses\u003c/h2\u003e\n\u003cp\u003eCovariate-adjusted mixed models that included baseline age, sex, BMI, and concomitant lithium and valproate treatment yielded LS-mean trajectories for YMRS and CGI-BP that were virtually identical to those from the unadjusted models. For YMRS, all prespecified contrasts from admission to day 28 remained highly significant after Holm\u0026ndash;Bonferroni correction, whereas the contrast between day 28 and day 42 remained non-significant, confirming rapid early improvement followed by stabilisation. Likewise, adjustment did not materially alter the magnitude or significance of the CGI-BP contrasts, which continued to show a consistent, progressive reduction in global illness severity (\u003cem\u003esee Additional file 1: Supplementary Tables S1C and S2C).\u003c/em\u003e\u003c/p\u003e\n\u003ch3\u003e3.3. YMRS single-item trajectories\u003c/h3\u003e\n\u003cp\u003eChanges in YMRS single items across all time points are summarised and depicted in Fig. 3. Friedman tests were significant for each item (all p \u0026lt; 0.0001).\u003c/p\u003e\n\u003cp\u003eAll YMRS single-items showed significant improvements over time (all Friedman p \u0026lt; 0.0001; Table 2), with most of the decline occurring between Tx/T0 and T3.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs regard core YMRS single items (see Table 2, Fig. 3), \u0026ldquo;Irritability\u0026rdquo; showed one of the steepest early improvements, with medians falling from 5 [4\u0026ndash;5] at Tx to 4 [3\u0026ndash;5] at T0, 2 [2\u0026ndash;3] at T1\u0026ndash;T2, 1 [1\u0026ndash;2] at T3, and 1 [0\u0026ndash;1] at T4\u0026ndash;T5.\u003cbr\u003e\u0026nbsp;\u0026ldquo;Aggressive behaviour\u0026rdquo; decreased from 2 [2\u0026ndash;5] at Tx to 2 [1\u0026ndash;2] at T0, 2 [1\u0026ndash;2] at T1, and 1 [0\u0026ndash;2] at T2. By T3, the median score was 0 [0\u0026ndash;1], and 0 [0\u0026ndash;0] at T4 and T5, indicating near-complete reduction of overt aggressive behaviours in most patients.\u003cbr\u003e\u0026nbsp;Psychotic \u0026ldquo;thought content\u0026rdquo; (Item 8) showed a more gradual trajectory. Median scores decreased from 5 [5\u0026ndash;5] at Tx to 5 [4\u0026ndash;5] at T0\u0026ndash;T1, 4 [3\u0026ndash;5] at T2, and only then to 2 [1\u0026ndash;3] at T3, stabilising at 2 [1\u0026ndash;2] at T4\u0026ndash;T5. This pattern suggests that psychotic ideation tended to normalise more slowly, following the early antimanic and behavioural changes.\u003cbr\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003e3.4. Tolerability and side effects\u003c/h3\u003e\n\u003cp\u003eGASS total scores at week 4 (T4) and week 6 (T5) were very low, with median values of 0 (IQR 0\u0026ndash;0; range 0\u0026ndash;7 at T4 and 0\u0026ndash;4 at T5). All patients remained within the absent/mild category (0\u0026ndash;21), and none met the thresholds for moderate (22\u0026ndash;42) or severe (43\u0026ndash;63) side-effect burden.\u003c/p\u003e\n\u003cp\u003eAnalysis of GASS domains confirmed a low prevalence of adverse effects (Fig. 4). At T4, at least one symptom (domain score \u0026gt;0) was reported by 3/50 patients (6.0%) in the sedation/CNS domain, 1/50 (2.0%) in the cardiovascular domain, 6/50 (12.0%) for extrapyramidal symptoms, 1/50 (2.0%) in the genitourinary domain, 1/50 (2.0%) in the diabetes-screening items and 4/50 (8.0%) for prolactinaemic/sexual symptoms; no patient reported anticholinergic/gastrointestinal side effects or weight gain. At T5, domain prevalences were similar or slightly reduced: sedation/CNS symptoms in 1/50 (2.0%) patients, cardiovascular in 1/50 (2.0%), extrapyramidal in 5/50 (10.0%), genitourinary in 1/50 (2.0%), diabetes-screening items in 1/50 (2.0%), prolactinaemic/sexual in 3/50 (6.0%) and weight gain in 1/50 (2.0%), with anticholinergic/gastrointestinal symptoms remaining absent. Across domains, \u003cstrong\u003emaximum scores remained in the mildrange\u003c/strong\u003e (e.g. extrapyramidal domain up to 6 points, prolactinaemic up to 3, weight gain up to 3), and no severe or unexpected adverse events related to risperidone ISM emerged from chart review. Importantly, \u003cstrong\u003eno patient discontinued risperidone ISM because of tolerability issues\u003c/strong\u003e during the observation period, and the safety profile was consistent with expectations for risperidone and long-acting antipsychotic formulations.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eTo our knowledge, this is the first real-world study specifically examining once-monthly risperidone ISM in a cohort of non-adherent inpatients with schizoaffective disorder, bipolar type, admitted for an acute manic episode with psychotic symptoms and a documented previous response to risperidone. In this retrospective cohort, risperidone ISM\u0026mdash;introduced after a short oral risperidone lead-in and within a multimodal treatment regimen\u0026mdash;was associated with a rapid and marked improvement in manic symptomatology, sustained over a 6-week period. Accordingly, the observed improvement should be interpreted within a structured inpatient treatment strategy, rather than as a causal effect of risperidone ISM per se.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eYMRS total scores decreased steeply over the early post-injection window and the vast majority of patients maintained improvement through week 6, with high proportions meeting standard response and remission thresholds by day 8 after the LAI injection and beyond. CGI-BP ratings closely mirrored the YMRS trajectory, indicating that symptom-scale change was reflected in global clinical impression. It should be emphasized, however, that all patients received at least 6 consecutive days of oral risperidone before the first ISM injection, in addition to mood stabilizers and benzodiazepines in most cases and, in a minority, other antipsychotics. Thus, early symptomatic improvement likely reflects the combined effect of oral risperidone, risperidone ISM and concomitant treatments, rather than the LAI formulation alone. Nevertheless, tolerability\u0026mdash;captured by structured GASS ratings and chart-recorded adverse events\u0026mdash;was favorable and broadly consistent with expectations for risperidone and long-acting antipsychotic formulations [17,18].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThese findings extend to schizoaffective disorder the evidence supporting risperidone\u0026rsquo;s antimanic efficacy that has been demonstrated in randomized and open-label studies in bipolar I disorder and related mood\u0026ndash;psychotic conditions, including long-acting risperidone formulations [12\u0026ndash;15].They also align with pharmacokinetic and clinical trial data in schizophrenia showing rapid attainment of therapeutic exposure and sustained effect with monthly risperidone ISM [17,18,24]. Risperidone ISM employs an in situ microimplant technology in which, after reconstitution and intramuscular injection, a proportion of risperidone is released early while the remainder precipitates into a polymeric matrix that biodegrades over the dosing interval [18]. The temporal pattern observed in our cohort\u0026mdash;early antimanic improvement followed by maintenance of low YMRS scores at later visits\u0026mdash;may be compatible with this biphasic release profile, although the respective contributions of oral risperidone, risperidone ISM and concomitant pharmacological and environmental interventions cannot be disentangled.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA distinctive aspect of this study is the evaluation of YMRS single-item trajectories. Activation-related and behavioral dimensions (e.g., irritability, disruptive/aggressive behavior, etc) showed steep early reductions, reaching very low median values by day 8. In contrast, thought content (reflecting psychotic and cognitive aspects of schizoaffective disorder) improved more gradually. This temporal dissociation is clinically plausible: motor activation, irritability and overt aggression are often the earliest targets of pharmacological and environmental containment on acute wards, whereas psychotic ideation and insight may normalize more slowly. The present data quantify this pattern in a diagnostically homogeneous schizoaffective sample and suggest that a monthly LAI strategy incorporating risperidone ISM may be particularly useful when rapid behavioral stabilization is required in patients with high risk of non-adherence.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFrom a clinical standpoint, these results have several implications. First, in schizoaffective patients with non-adherence and prior response to risperidone, a combined oral lead-in and transition to once-monthly risperidone ISM may represent a pragmatic strategy to re-establish therapeutic antipsychotic exposure and secure continuity of treatment beyond the acute phase\u0026mdash;consistent with guideline recommendations and evidence supporting LAIs in patients at high risk of non-adherence and relapse [8,10,11,25,26]. Second, the rapid improvement in behavioral dimensions coupled with the slower but robust change in psychotic thought content supports integration of LAI strategies into multimodal management (including mood stabilizers, benzodiazepines when indicated, and psychosocial interventions) for complex manic presentations with psychosis. Third, the low post-acute YMRS levels observed by day 8 raise the hypothesis that, in selected patients, earlier discharge with continued LAI treatment and structured community follow-up might be feasible\u0026mdash;an hypothesis that warrants prospective evaluation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStrengths and limitations\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis study has several strengths. The sample is diagnostically homogeneous, focusing specifically on DSM-5-TR schizoaffective disorder, bipolar type, in a manic episode with psychotic features [1]. The design is naturalistic and reflects routine practice in an acute psychiatric unit, where comorbidity and polypharmacy are common and non-adherence is a frequent precipitant of admission [4\u0026ndash;6]. Multiple time points were available, including very early assessments and follow-up to six weeks, allowing granular description of both global and item-level trajectories. The use of the GASS provided a structured, patient-centered assessment of antipsychotic side effects at two clinically relevant follow-up visits [23].\u003c/p\u003e\n\u003cp\u003eImportant limitations must also be acknowledged. First, the retrospective, uncontrolled design precludes firm causal inference about the specific contribution of risperidone ISM; outcomes reflect a combined inpatient strategy rather than the effect of the LAI formulation in isolation. Symptom improvement may be partly attributable to the natural course of manic episodes, intensive inpatient care and concomitant treatments. Second, all patients underwent at least 6 days of oral risperidone before the first ISM injection; the separate impact of the oral lead-in versus the LAI component was not formally modeled. Third, the sample size is modest and recruitment was from a single center, limiting generalizability. Fourth, all patients had a documented previous response to risperidone, which may overestimate benefits in risperidone-na\u0026iuml;ve or risperidone-non-responsive individuals. Fifth, ratings were performed in routine practice without formal inter-rater reliability assessment, and documentation bias cannot be excluded. Sixth, tolerability was evaluated only over six weeks; metabolic, endocrine and cardiovascular effects beyond this window were not systematically captured and may be under-detected early after acute hospitalization. Finally, use of risperidone ISM in acute schizoaffective mania is off-label, underscoring the exploratory nature of these findings and the need for prospective controlled studies.\u003c/p\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eIn a real-world cohort of non-adherent inpatients with schizoaffective disorder, bipolar type, hospitalized for acute mania with psychotic symptoms and prior response to risperidone, a pragmatic strategy consisting of a brief oral risperidone lead-in followed by initiation of once-monthly risperidone ISM within a multimodal regimen was associated with rapid and marked reductions in manic symptom severity, progressive improvement in psychotic thought content, and a favorable short-term tolerability profile.\u003c/p\u003e\n\u003cp\u003eActivation-related and behavioral symptoms improved particularly quickly, whereas psychotic thought content normalized more gradually but substantially over the 6-week observation period. The overall temporal pattern is compatible with the formulation characteristics of risperidone ISM, which combines early release with sustained delivery across the monthly dosing interval [17]. However, these findings should be interpreted as reflecting the combined effect of oral risperidone, the long-acting formulation and concomitant treatments under acute inpatient conditions, rather than the action of risperidone ISM in isolation.\u003c/p\u003e\n\u003cp\u003eFuture prospective, randomized and ideally pragmatic trials\u0026mdash;comparing risperidone ISM with oral antipsychotics and other LAIs and incorporating longer-term safety, functional and quality-of-life outcomes\u0026mdash;are warranted to confirm these preliminary observations and to better define the role of ISM formulations in severe mood\u0026ndash;psychotic disorders [10,11,25].\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThe study protocol (acronym \u0026ldquo;REALSAD\u0026rdquo;) was approved by the Territorial Ethics Committee CET Lombardia 4 (promoter: ASST Mantova; protocol code CET 140/24). All procedures were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. At the time of hospitalisation, all patients (or their legal representatives) provided written informed consent for the collection and use of anonymised clinical data for research purposes, as required by the local Ethics Committee.\u003c/p\u003e\n\u003cp\u003eDeclaration of generative AI and AI-assisted technologies in the manuscript preparation process\u003c/p\u003e\n\u003cp\u003eDuring the preparation of this work, the authors used ChatGPT (OpenAI) to assist in language refinement and formatting. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot applicable. No identifiable individual data are included in this manuscript.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eConflict of Interest Statement\u003c/p\u003e\n\u003cp\u003eAndrea Fagiolini has served as a consultant and/or speaker and/or has received research grants from the following pharmaceutical and healthcare companies: Allergan, Angelini, Apsend, Generici DOC, Boehringer Ingelheim, Idorsia, Italfarmaco, Lundbeck, Janssen, Medicamenta, Mylan, Otsuka, Pfizer, Recordati, Rovi, Roche, Sanofi Aventis, Sunovion, Teva, and Viatris. These relationships include research funding, consultancy fees, and/or honoraria for speaking engagements related to academic research activities, advisory roles, and participation in scientific meetings within the field of psychiatry and psychopharmacology. None of these relationships had any influence on the conception, design, conduct, interpretation, or reporting of the present study, and none are directly related to the content of this manuscript.\u003c/p\u003e\n\u003cp\u003eAlessandro Cuomo has served as a consultant and/or speaker and/or has received research grants from the following pharmaceutical and healthcare companies: Allergan, Angelini, Apsend, Boehringer Ingelheim, Idorsia, Italfarmaco, Lundbeck, Janssen, Medicamenta, Mylan, Otsuka, Pfizer, Recordati, Roche, Sanofi Aventis, and Viatris. These relationships include research funding, consultancy fees, and/or honoraria for speaking engagements related to academic research activities, advisory roles, and participation in scientific meetings within the field of psychiatry and psychopharmacology. None of these relationships had any influence on the conception, design, conduct, interpretation, or reporting of the present study, and none are directly related to the content of this manuscript.\u003c/p\u003e\n\u003cp\u003eAll other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026rsquo; contributions (CRediT taxonomy)\u003c/p\u003e\n\u003cp\u003eGiovanni Barill\u0026agrave;: Conceptualization, Methodology, Investigation, Data curation, Formal analysis, Writing \u0026ndash; original draft, Writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003eAlessandro Cuomo: Validation, Writing \u0026ndash; review \u0026amp; editing, Supervision.\u003c/p\u003e\n\u003cp\u003eDebora Bussolotti: Project administration, Supervision, Validation, Writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003eCristina Venco: Investigation, Data curation, Validation.\u003c/p\u003e\n\u003cp\u003eAndrea Fagiolini: Conceptualization, Methodology, Validation, Supervision, Writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003eAll authors approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\u003cp\u003eThe data generated and/or analysed during the current study are not publicly available due to ethical and legal restrictions related to patient confidentiality, but de-identified data may be made available from the corresponding author upon reasonable request and subject to Ethics Committee approval.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eFigures 1\u0026ndash;4 were created with BioRender.com (publication licence, personal account).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eAmerican Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5-TR. 5th ed, text revision. Washington (DC): American Psychiatric Association; 2022.\u003c/li\u003e\n \u003cli\u003eBenabarre A, Vieta E, Mart\u0026iacute;nez-Ar\u0026aacute;n A, et al. Bipolar disorder, schizoaffective disorder and schizophrenia: epidemiologic, clinical and prognostic differences. Eur Psychiatry. 2001;16:167\u0026ndash;172. doi:10.1016/S0924-9338(01)00559-4.\u003c/li\u003e\n \u003cli\u003ePinna F, Sanna L, Perra V, et al. Long-term outcome of schizoaffective disorder: are there relevant differences with schizophrenia? Riv Psichiatr. 2014;49:85\u0026ndash;94. doi:10.1708/1407.15624.\u003c/li\u003e\n \u003cli\u003eCrowe CL, Xiang P, Smith JL, et al. Real-world healthcare resource utilization, costs, and predictors of relapse among US patients with incident schizophrenia or schizoaffective disorder. Schizophrenia. 2024;10:86. doi:10.1038/s41537-024-00509-6.\u003c/li\u003e\n \u003cli\u003eRivelli A, Fitzpatrick V, Nelson M, et al. Real-world predictors of relapse in patients with schizophrenia and schizoaffective disorder in a large health system. Schizophrenia. 2024;10:28. doi:10.1038/s41537-024-00448-2.\u003c/li\u003e\n \u003cli\u003eGarc\u0026iacute;a S, Martinez-Cengotitabengoa M, L\u0026oacute;pez-Zurbano S, et al. Adherence to antipsychotic medication in bipolar disorder and schizophrenic patients: a systematic review. J Clin Psychopharmacol. 2016;36:355\u0026ndash;371. doi:10.1097/JCP.0000000000000523.\u003c/li\u003e\n \u003cli\u003eMorken G, Widen JH, Grawe RW. Non-adherence to antipsychotic medication, relapse and rehospitalisation in recent-onset schizophrenia. BMC Psychiatry. 2008;8:32. doi:10.1186/1471-244X-8-32.\u003c/li\u003e\n \u003cli\u003eLlorca PM, Abbar M, Courtet P, et al. Guidelines for the use and management of long-acting injectable antipsychotics in serious mental illness. BMC Psychiatry. 2013;13:340. doi:10.1186/1471-244X-13-340.\u003c/li\u003e\n \u003cli\u003eKishimoto T, Robenzadeh A, Leucht C, et al. Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: a meta-analysis of randomized trials. Schizophr Bull. 2014;40:192\u0026ndash;213. doi:10.1093/schbul/sbs150.\u003c/li\u003e\n \u003cli\u003eKishimoto T, Hagi K, Nitta M, et al. Long-acting injectable versus oral antipsychotics for the maintenance treatment of schizophrenia: a systematic review and comparative meta-analysis of randomised, cohort, and pre-post studies. Lancet Psychiatry. 2021;8(5):387\u0026ndash;404. doi:10.1016/S2215-0366(21)00039-0.\u003c/li\u003e\n \u003cli\u003eOstuzzi G, Bertolini F, Tedeschi F, et al. Oral and long-acting antipsychotics for relapse prevention in schizophrenia-spectrum disorders: a network meta-analysis of 92 randomized trials including 22,645 participants. World Psychiatry. 2022;21:56\u0026ndash;69. doi:10.1002/wps.20972.\u003c/li\u003e\n \u003cli\u003eMacfadden W, Alphs L, Haskins JT, et al. A randomized, double-blind, placebo-controlled study of maintenance treatment with adjunctive risperidone long-acting therapy in patients with bipolar I disorder who relapse frequently. Bipolar Disord. 2009;11(8):827\u0026ndash;839. doi:10.1111/j.1399-5618.2009.00761.x.\u003c/li\u003e\n \u003cli\u003eQuiroz JA, Yatham LN, Palumbo JM, et al. Risperidone long-acting injectable monotherapy in the maintenance treatment of bipolar I disorder. Biol Psychiatry. 2010;68:156\u0026ndash;162. doi:10.1016/j.biopsych.2010.01.015.\u003c/li\u003e\n \u003cli\u003eVieta E, Goikolea JM, Corbella B, et al. Risperidone safety and efficacy in the treatment of bipolar and schizoaffective disorders: results from a 6-month, multicenter, open study. J Clin Psychiatry. 2001;62:818\u0026ndash;825. PMID:11816872.\u003c/li\u003e\n \u003cli\u003eVieta E, Montgomery S, et al. A randomized, double-blind, placebo-controlled trial to assess prevention of mood episodes with risperidone long-acting injectable in patients with bipolar I disorder. Eur Neuropsychopharmacol. 2012;22:825\u0026ndash;835. doi:10.1016/j.euroneuro.2012.03.004.\u003c/li\u003e\n \u003cli\u003eBartoli F, Cavaleri D, Riboldi I, et al. Clinical utility of long-acting injectable risperidone in schizophrenia and bipolar I disorder: a review of clinical studies. Psychol Res Behav Manag. 2025;18:1455\u0026ndash;1469. doi:10.2147/PRBM.S474513.\u003c/li\u003e\n \u003cli\u003eCorrell CU, Litman RE, Filts Y, et al. Efficacy and safety of once-monthly risperidone ISM in schizophrenic patients with an acute exacerbation: a randomized, double-blind, placebo-controlled trial. NPJ Schizophr. 2020;6:37. doi:10.1038/s41537-020-00127-y.\u003c/li\u003e\n \u003cli\u003eSyed YY. Risperidone in situ microparticles: a review in schizophrenia. Drugs. 2025;85:425\u0026ndash;435. doi:10.1007/s40265-024-02140-2.\u003c/li\u003e\n \u003cli\u003evon Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. PLoS Med. 2007;4:e296. doi:10.1371/journal.pmed.0040296.\u003c/li\u003e\n \u003cli\u003eSheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric Interview (MINI): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(Suppl 20):22\u0026ndash;33.\u003c/li\u003e\n \u003cli\u003eYoung RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429\u0026ndash;435. doi:10.1192/bjp.133.5.429.\u003c/li\u003e\n \u003cli\u003eSpearing MK, Post RM, Leverich GS, Brandt D, Nolen W. Modification of the Clinical Global Impressions (CGI) Scale for use in bipolar illness (CGI-BP). Psychiatry Res. 1997;73:159\u0026ndash;171. doi:10.1016/S0165-1781(97)00123-6.\u003c/li\u003e\n \u003cli\u003eWaddell L, Taylor M. A new self-rating scale for detecting atypical or second-generation antipsychotic side effects. J Psychopharmacol. 2008;22(3):238\u0026ndash;243. doi:10.1177/0269881107087976.\u003c/li\u003e\n \u003cli\u003eToja-Camba FJ, Pe\u0026ntilde;as-Lled\u0026oacute; E, Anta L, et al. Evaluating the real-world pharmacokinetics of risperidone ISM\u0026reg; in routine clinical practice. Biomedicines. 2025;13(2):384. doi:10.3390/biomedicines13020384.\u003c/li\u003e\n \u003cli\u003eVieta E, Tohen M, McIntosh D, et al. Early use of long-acting injectable antipsychotics in bipolar disorder type I: an expert consensus. Bipolar Disord. 2025;27:7\u0026ndash;16. doi:10.1111/bdi.13498.\u003c/li\u003e\n \u003cli\u003eFu DJ, Turkoz I, Simonson RB, et al. Paliperidone palmitate once-monthly reduces risk of relapse of psychotic, depressive, and manic symptoms and maintains functioning in a double-blind, randomized study of schizoaffective disorder. J Clin Psychiatry. 2015;76(3):253\u0026ndash;262. doi:10.4088/JCP.14m09416.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-general-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"agps","sideBox":"Learn more about [Annals of General Psychiatry](http://annals-general-psychiatry.biomedcentral.com/)","snPcode":"12991","submissionUrl":"https://submission.nature.com/new-submission/12991/3","title":"Annals of General Psychiatry","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"risperidone ISM, in situ microparticles, acute mania, schizoaffective disorder, bipolar disorder, long-acting injectable antipsychotic","lastPublishedDoi":"10.21203/rs.3.rs-8503226/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8503226/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Nonadherence is a major cause of relapse in patients with schizophrenia, schizoaffective disorder, or bipolar disorder who have achieved remission. However, it is also a significant challenge during manic episodes. Risperidone in-situ microimplant (ISM) releases the drug early and in a sustained manner once a month, eliminating the need for daily administration, which can be difficult during a manic episode. In this study, we examined the short-term efficacy and tolerability of risperidone ISM in real-world nonadherent inpatients with schizoaffective disorder experiencing a manic episode with psychotic symptoms.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: This retrospective, observational, single-centre study included 50 consecutive adults admitted after discontinuation/marked non-adherence and with prior response to risperidone received ≥6 days of oral risperidone to confirm tolerability, then risperidone ISM (75 or 100 mg) and were followed for 6 weeks. Mania severity was assessed with the Young Mania Rating Scale (YMRS).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: Fifty patients were included; most received concomitant mood stabilisers and benzodiazepines. Median YMRS decreased from 32 at admission to 26 at first injection (after the oral lead-in), 8 by day 8, and remained low at day 28 (5) and day 42 (6). Activation/behavioural items improved earlier, whereas psychotic thought content improved more gradually, predominantly between days 8 and 28. Side-effect burden at weeks 4 and 6 was minimal, and no discontinuations due to adverse events occurred.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: In this exploratory uncontrolled cohort, oral risperidone lead-in plus monthly risperidone ISM within multimodal inpatient care was associated with rapid and sustained improvement and favourable short-term tolerability. These findings should be interpreted as resulting from a combination of ISM treatment and a structured inpatient strategy, rather than as evidence of the effect of ISM alone. Prospective, controlled studies are warranted.\u003c/p\u003e","manuscriptTitle":"Risperidone long-acting in-situ microimplant in the acute management of manic episodes with psychotic symptoms in non-adherent patients with schizoaffective disorder: a retrospective real-world study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-12 05:28:23","doi":"10.21203/rs.3.rs-8503226/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-20T18:26:20+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-20T18:12:58+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-19T13:26:39+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-14T22:18:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"265734789813036290566878844514630104616","date":"2026-01-13T09:20:27+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-12T10:46:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"218567691730376139006038849150438100205","date":"2026-01-10T15:17:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"130381966275312048382121037712825469102","date":"2026-01-08T14:58:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"133660644881492526966170376369412493501","date":"2026-01-07T19:37:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"178243034318251078156290670029749844225","date":"2026-01-07T07:26:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-06T14:19:46+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-05T03:50:28+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-05T03:48:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of General Psychiatry","date":"2026-01-02T20:31:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-general-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"agps","sideBox":"Learn more about [Annals of General Psychiatry](http://annals-general-psychiatry.biomedcentral.com/)","snPcode":"12991","submissionUrl":"https://submission.nature.com/new-submission/12991/3","title":"Annals of General Psychiatry","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c133681f-fd5e-4cc0-941e-1f35d55fa8f0","owner":[],"postedDate":"January 12th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-06T08:55:42+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-12 05:28:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8503226","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8503226","identity":"rs-8503226","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}