Mortality risk and mood stabilizers in bipolar disorder: a propensity-score-weighted population-based cohort study in 2002-2018.

AIMS: Accumulating studies have assessed mortality risk associated with mood-stabilizers, the mainstay treatment for bipolar disorder (BD). However, existing data were mostly restricted to suicide risk, focused on lithium and valproate and rarely adequately adjusted for potential confounders. This study aimed to assess comparative mortality risk with all, natural and unnatural causes between lithium, valproate and three frequently prescribed second-generation antipsychotics (SGA), with adjustment for important confounders. METHODS: This population-based cohort study identified 8137 patients with first-diagnosed BD, who had exposed to lithium (n = 1028), valproate (n = 3580), olanzapine (n = 797), quetiapine (n = 1975) or risperidone (n = 757) between 2002 and 2018. Data were retrieved from territory-wide medical-record database of public healthcare services in Hong Kong. Propensity-score (PS)-weighting method was applied to optimize control for potential confounders including pre-existing chronic physical diseases, substance/alcohol use disorders and other psychotropic medications. PS-weighted Cox proportional-hazards regression was conducted to assess risk of all-, natural- and unnatural-cause mortality related to each mood-stabilizer, compared to lithium. Three sets of sensitivity analyses were conducted by restricting to patients with (i) length of cumulative exposure to specified mood-stabilizer ≥90 days and its medication possession ratio (MPR) ≥90%, (ii) MPR of specified mood-stabilizer ≥80% and MPR of other studied mood-stabilizers <20% and (iii) monotherapy. RESULTS: Incidence rates of all-cause mortality per 1000 person-years were 5.9 (95% confidence interval [CI]: 4.5-7.6), 8.4 (7.4-9.5), 11.1 (8.3-14.9), 7.4 (6.0-9.2) and 12.0 (9.3-15.6) for lithium-, valproate-, olanzapine-, quetiapine- and risperidone-treated groups, respectively. BD patients treated with olanzapine (PS-weighted hazard ratio = 2.07 [95% CI: 1.33-3.22]) and risperidone (1.66 [1.08-2.55]) had significantly higher all-cause mortality rate than lithium-treated group. Olanzapine was associated with increased risk of natural-cause mortality (3.04 [1.54-6.00]) and risperidone was related to elevated risk of unnatural-cause mortality (3.33 [1.62-6.86]), relative to lithium. The association between olanzapine and increased natural-cause mortality rate was consistently affirmed in sensitivity analyses. Relationship between risperidone and elevated unnatural-cause mortality became non-significant in sensitivity analyses restricted to low MPR in other mood-stabilizers and monotherapy. Valproate- and lithium-treated groups did not show significant differences in all-, natural- or unnatural-cause mortality risk. CONCLUSION: Our data showed that olanzapine and risperidone were associated with higher mortality risk than lithium, and further supported the clinical guidelines recommending lithium as the first-line mood-stabilizer for BD. Future research is required to further clarify comparative mortality risk associated with individual SGA agents to facilitate risk-benefit evaluation of alternative mood-stabilizers to minimize avoidable premature mortality in BD.

Neuroleptic Malignant Syndrome Concurrent with COVID-19 Infection: A Case Report. / COVID-19 Hastasinda Nöroleptik Malin Sendrom: Bir Olgu Sunumu.

Neuroleptic malignant syndrome (NMS), which most often occurs after the use of antipsychotics, is a rare but life-threatening condition. In this article, a 56-year-old male patient with a diagnosis of bipolar affective disorder (BPD) who developed NMS after a COVID-19 infection will be presented. The patient had been brought to the emergency room with high fever, fatigue, and slowness of movements that had been going on for two days. The examination revealed tachycardia, tachypnea, lethargy and rigidity. Upon further investigation the COVID-19 test came out positive and the serum levels of creatine kinase were considerably high. He was admitted to the psychiatric ward with diagnoses of COVID-19 infection and NMS. COVID-19 infection might have been a risk factor for NMS in this patient. Especially in patients who are taking antipsychotic drugs, if COVID-19 is present, the risk of NMS should be taken into consideration. Keyword: COVID-19, Neuroleptic Malignant Syndrome, Risperidone, Antipsikotik, Enfeksiyon.

Influence of CYP2C19 and CYP2D6 on side effects of aripiprazole and risperidone: A systematic review.

Variability in hepatic cytochrome P450 (CYP) enzymes such as 2C19 and 2D6 may influence side-effect and efficacy outcomes for antipsychotics. Aripiprazole and risperidone are two commonly prescribed antipsychotics, metabolized primarily through CYP2D6. Here, we aimed to provide an overview of the effect of CYP2C19 and CYP2D6 on side-effects of aripiprazole and risperidone, and expand on existing literature by critically examining methodological issues associated with pharmacogenetic studies. A PRISMA compliant search of six electronic databases (Pubmed, PsychInfo, Embase, Central, Web of Science, and Google Scholar) identified pharmacogenetic studies on aripiprazole and risperidone. 2007 publications were first identified, of which 34 were included. Quality of literature was estimated using Newcastle-Ottowa Quality Assessment Scale (NOS) and revised Cochrane Risk of Bias tool. The average NOS score was 5.8 (range: 3-8) for risperidone literature and 5 for aripiprazole (range: 4-6). All RCTs on aripiprazole were rated as high risk of bias, and four out of six for risperidone literature. Study populations ranged from healthy volunteers to inpatient individuals in psychiatric units and included adult and pediatric samples. All n = 34 studies examined CYP2D6. Only one study genotyped for CYP2C19 and found a positive association with neurological side-effects of risperidone. Most studies did not report any relationship between CYP2D6 and any side-effect outcome. Heterogeneity between and within studies limited the ability to synthesize data and draw definitive conclusions. Studies lacked statistical power due to small sample size, selective genotyping methods, and study design. Large-scale randomized trials with multiple measurements, providing robust evidence on this topic, are suggested.

Risperidone-Induced Leukoneutropenia: Evidence from a Positive Rechallenge and Review of the Literature.

Antipsychotics can cause hematologic disorders, and they can have life-threatening consequences. Risperidone, less commonly associated with hematologic adverse effects, is an atypical antipsychotic medication used to treat conditions such as schizophrenia, bipolar disorder and irritability associated with autism. While risperidone primarily affects the central nervous system, it can have some hematologic adverse effects, although these are relatively rare. It is crucial to note that these side effects are not common, and most people taking risperidone do not experience hematologic disorders. The reporting of such disorders may be more frequent with clozapine compared to other atypical antipsychotics because clozapine treatment necessitates regular hematological monitoring 1.

Pregabalin Adjuventia Helped Risperidone-Induced Extrapyramidal Syndrome and Augmented Antipsychotic Response in an Adolescent with Schizophrenia.

Here, authors report on an interesting case of early-onset of schizophrenia where adjunctive pregabalin alleviated risperidone-induced pseudoparkinsonism, helped with insomnia and agitation and boosted antipsychotic response with great tolerability. We wager that gabapentenoids can be a viable option in the niche of psychopharmacotherapy of schizophrenia in CAP population.

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

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

Emerging drugs for the treatment of irritability associated with autism spectrum disorder.

INTRODUCTION: Autism spectrum disorder (ASD) is an early-onset disorder with a prevalence of 1% among children and reported disability-adjusted life years of 4.31 million. Irritability is a challenging behavior associated with ASD, for which medication development has lagged. More specifically, pharmacotherapy effectiveness may be limited against high adverse effects (considering side effect profiles and patient medication sensitivity); thus, the possible benefits of pharmacological interventions must be balanced against potential adverse events in each patient. AREAS COVERED: After reviewing the neuropathophysiology of ASD-associated irritability, the benefits and tolerability of emerging medications in its treatment based on randomized controlled trials were detailed in light of mechanisms and targets of action. EXPERT OPINION: Succeeding risperidone and aripiprazole, monotherapy with memantine may be beneficial. In addition, N-acetylcysteine, galantamine, sulforaphane, celecoxib, palmitoylethanolamide, pentoxifylline, simvastatin, minocycline, amantadine, pregnenolone, prednisolone, riluzole, propentofylline, pioglitazone, and topiramate, all adjunct to risperidone, and clonidine and methylphenidate outperformed placebo. These effects were through glutamatergic, γ-aminobutyric acidergic, inflammatory, oxidative, cholinergic, dopaminergic, and serotonergic systems. All medications were reported to be safe and tolerable. Considering sample size, follow-up, and effect size, further studies are necessary. Along with drug development, repositioning and combining existing drugs supported by the mechanism of action is recommended.

Mortality and Lithium-Protective Effects after First-Episode Mania Diagnosis in Bipolar Disorder: A Nationwide Retrospective Cohort Study in Taiwan.

INTRODUCTION: This study aimed to estimate all-cause mortality in patients after a first-episode mania (FEM) and examine whether six guideline-recommended medications can reduce mortality. METHODS: The cohort included population-based FEM samples and matched controls from Taiwan, spanning 2007 to 2018. The primary outcomes assessed were all-cause/suicide-related mortality, while the secondary outcome focused on mortality associated with pharmacological treatments. We compared mortality in post-FEM patients and age-/sex-matched controls without any diagnosed bipolar disorders and patients with and without psychopharmacological treatment using Cox regression analysis, respectively. Statistics were presented with time-to-event adjusted hazard ratios (AHRs) and 95% confidence intervals (CIs). RESULTS: The study included 54,092 post-FEM patients and 270,460 controls, totaling 2,467,417 person-years of follow-up. Post-FEM patients had higher risks of all-cause mortality (AHR 2.38, 95% CI: 2.31-2.45) and suicide death (10.80, 5.88-19.84) than controls. Lithium (0.62, 0.55-0.70), divalproex (0.89, 0.83-0.95), and aripiprazole (0.81, 0.66-1.00) were associated with reduced all-cause mortality compared to non-users. There were no significant all-cause mortality differences for quetiapine (0.95, 0.89-1.01), risperidone (0.92, 0.82-1.02), and paliperidone (1.24, 0.88-1.76) users. When accounting for drug action onset times in sensitivity analyses, only lithium significantly reduced all-cause mortality (AHR range 0.65-0.72). There were 35 and 16 suicide deaths in post-FEM patients and controls, respectively. No drug had a significant effect on suicide deaths (lithium: 6; divalproex: 7; aripiprazole: 0; quetiapine: 10; risperidone: 4; paliperidone: 1). CONCLUSION: Post-FEM patients had a higher risk of all-cause/suicide-related mortality, and lithium treatment might reduce all-cause mortality.

Risperidone plasma level, and its correlation with CYP2D6 gene polymorphism, clinical response and side effects in chronic schizophrenia patients.

BACKGROUND: To explore the influence of CYP2D6 genetic polymorphism on risperidone metabolism, thereby affecting risperidone's effects and safeties in patients with chronic schizophrenia. METHODS: Sixty-nine subjects with chronic schizophrenia treated with risperidone were recruited. CYP2D6 genotypes was determined using targeted sequencing and translated into phenotype using activity system. Risperidone plasma concentrations were measured using HPLC. Positive and Negative Symptom Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) were used to evaluate the existence and severity of psychiatric symptoms, Barnes Akathisia Scale (BAS) and Extrapyramidal Symptom Rating Scale (ESRS) for neurological side effects. Metabolic and endocrine status assess were also included. RESULTS: The plasma drug concentrations varied hugely among individuals. Intermediate metabolizer (IM) group had higher plasma levels of RIP and dose corrected RIP concentration, RIP/9-OH-RIP ratio and C/D ratio than normal metabolizer (NM) group (p < 0.01). There was no statistic difference between responders and non-responders in dose-adjusted plasma concentrations and ratios of RIP/9-OH-RIP and C/D. The occurrence of EPS was related to active moiety levels in 4th week (p < 0.05). The prolactin (PRL) levels in two follow-ups were both significantly higher than baseline (p < 0.01). PRL change from baseline to week 4 and week 8 were both positively associated with active moiety concentration detected in week 4 (p < 0.05). CONCLUSIONS: The risperidone plasma levels have great inter- and intraindividual variations, and are associated with the CYP2D6 phenotypes, as well as the changes in serum prolactin in patients diagnosed with chronic schizophrenia.

Relationship between C-reactive protein and antipsychotics levels in schizophrenic patients infected with COVID-19.

In the context of the COVID-19, inflammation emerges as a prominent characteristic. C-reactive protein (CRP) serves as a commonly employed marker for the evaluation of inflammation. This study aimed to examine the correlation between CRP levels and antipsychotic drug concentrations in patients diagnosed with SCZ during the COVID-19 pandemic. A total of 186 SCZ patients were included in this study, which utilized electronic medical records. The collected data encompassed SCZ diagnoses based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, respiratory symptoms, and treatments. Laboratory assessments involved the measurement of CRP levels and monitoring of blood drug concentrations. The most prevalent symptoms observed in the patient cohort were fever (59.14%), cough (52.15%), fatigue (45.7%), sore throat (46.24%), runny nose (28.49%), and stuffy nose (25.27%). The levels of CRP during the infection period were significantly higher compared to both the prophase and anaphase of infection (all p < 0.001). The serum levels of clozapine, olanzapine, aripiprazole, quetiapine, and risperidone were elevated during the infection period (all p < 0.001). During the anaphase of infection, patients exhibited higher serum levels of clozapine, olanzapine, and risperidone (all p < 0.001) compared to the infection period, but there was no significant change in serum levels of aripiprazole and quetiapine. Multiple regression analysis revealed a statistically significant positive correlation (P < 0.0001) between CRP and clozapine concentration. In light of the COVID-19 pandemic, it is crucial to adjust the dosage based on drug serum concentration to prevent intoxication or adverse drug reactions.

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

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

Efficacy and Safety of Risperidone in Patients With Delirium: The RIDDLE Pilot Study.

BACKGROUND: The cornerstone treatment of delirium is to assess and treat its underlying causes and prevent further complications. Drug therapy may be necessary to control agitation and behavioral symptoms associated with delirium. The aim of this pilot study was to evaluate the feasibility of a randomized placebo controlled trial to evaluate the efficacy and safety of risperidone in the treatment of delirium. METHODS: This was a randomized double-blinded placebo-controlled trial. Patients were enrolled in the study if they were hospitalized and 65 years or older and had a diagnosis of delirium. Delirium Rating Scale revised 98 was used to determine delirium and motor agitation. RESULTS: A total of 14 participants with 57% being men and having a mean age of 86 years were included. There were no statistically significant differences between the risperidone and placebo group for the Delirium Rating Scale revised 98 score. There were no severe adverse reactions reported in the study, and no patients discontinued the study for adverse reactions. CONCLUSIONS: Risperidone at low doses (1 mg daily or less) was well tolerated for the treatment of delirium. Future large-scale trials are needed to evaluate the safety and efficacy of risperidone in the treatment of delirium. This pilot study taught us that the phase 2 RIsperDone DELirium trial will need a multicenter design with more research personnel to increase the number of participants enrolled.

Effectiveness and safety of second-generation antipsychotics for psychiatric disorders apart from schizophrenia: A systematic review and meta-analysis.

Second-generation antipsychotics (SGAs) are widely used in treating schizophrenia and related disorders, also other mental disorders. However, the efficacy and safety of SGAs for treating other mental disorders is unclear. A systematic literature search for randomized, placebo-controlled trials of 11 SGAs for treating 18 mental disorders apart from schizophrenia were carried out from database inception to April 3, 2022. The primary outcome was the mean change in the total score for different mental disorders. The secondary outcome was the odds ratio (OR) of response, remission rates and risk ratio (RR) of adverse events (AEs). A total of 181 studies (N = 65,480) were included. All SGAs showed significant effects in treating other mental disorders compared with placebo, except autistic disorder and dementia. Aripiprazole is the most effective treatment for bipolar mania [effect size = -0.90, 95% CI: -1.59, -0.21] and Tourette's disorder [effect size = -0.80, 95% CI: -1.14, -0.45], olanzapine for bipolar depression [effect size = -0.86, 95% CI: -1.32, -0.39] and post-traumatic stress disorder [effect size = -0.98, 95% CI: -1.55, -0.41], lurasidone for depression [effect size = -0.66, 95% CI: -0.82, -0.50], quetiapine for anxiety [effect size = -1.20, 95% CI: -1.96, -0.43], sleep disorders [effect size = -1.2, 95% CI: -1.97, -0.58], and delirium [effect size = -0.36, 95% CI: -0.70, -0.03], and risperidone for obsessive-compulsive disorder [effect size = -2.37, 95% CI: -3.25, -1.49], respectively. For safety, AE items for each SGAs was different. Interestingly, we found that some AEs of OLZ, QTP, RIS and PALI have significant palliative effects on some symptoms. Significant differences in the efficacy and safety of different SGAs for treatment of other mental disorders should be considered for choosing the drug and for the balance between efficacy and tolerability for the specific patient.

Safety outcomes of antipsychotics classes in drug-naïve patients with first-episode schizophrenia: A nationwide cohort study in South Korea.

INTRODUCTION: Given the similar efficacies across antipsychotic medications for schizophrenia, understanding their safety profiles, particularly concerning receptor-binding differences, is crucial for optimal drug selection, especially for patients with first episode schizophrenia. We aimed to compare the safety outcomes of second-generation antipsychotics. METHODS: We conducted a retrospective cohort study with new user active comparator design using a nationwide claims database in South Korea. Participants were drug-naïve adult patients with first-episode schizophrenia. Three representative drugs with different pharmacologic profiles were compared: risperidone, olanzapine, and aripiprazole. Propensity scores were used to match the study groups, and the Cox proportional hazard model was used to calculate hazard ratios. Sensitivity analyses were performed in various epidemiological settings. Seventeen safety outcomes, including neuropsychiatric, cardiometabolic and gastrointestinal events, were assessed, with upper-respiratory-tract infection as a negative control outcome. RESULTS: A total of 1044, 2078, and 3634 participants were matched for olanzapine vs. risperidone, olanzapine vs. aripiprazole, and risperidone vs. aripiprazole comparisons, respectively. For parkinsonism, there was a significant difference in outcomes between the risperidone and aripiprazole groups (HR 1.80 [95% CI 1.13-2.91]), with consistent sensitivity analysis results. There were no significant differences in other neuropsychiatry outcomes or in the risk of cardiometabolic and gastrointestinal outcomes between any of the comparative group pairs. CONCLUSIONS: The risk of drug-induced parkinsonism was significantly higher with risperidone than with aripiprazole. Although olanzapine is known for its metabolic risk, there were no significant differences in risk between the other pairs.

When the fever will not stop, stop the pills! A case report.

BACKGROUND: Neuroleptic malignant syndrome (NMS) is a neurologic emergency potentially fatal. This rare side effect is most commonly associated with first-generation antipsychotics and less frequently with atypical or second-generation antipsychotics. The diagnosis relies on both clinical and laboratory criteria, with other organic and psychiatric conditions being ruled out. CASE REPORT: A 39-year-old female patient, who is institutionalized and completely dependent, has a medical history of recurrent urinary infections and colonization by carbapenem-resistant Klebsiella pneumoniae. Her regular medication regimen included sertraline, valproic acid, quetiapine, risperidone, lorazepam, diazepam, haloperidol, baclofen, and fentanyl. The patient began experiencing dyspnea. Upon physical examination, she exhibited hypotension and a diminished vesicular murmur at the right base during pulmonary auscultation. Initially, after hospitalization, she developed high febrile peaks associated with hemodynamic instability, prompting the initiation of antibiotic treatment. Despite this, her fever persisted without an increase in blood inflammatory parameters, and she developed purulent sputum, necessitating antibiotherapy escalation. The seventh day of hospitalization showed no improvement in symptoms, suggesting NNMS as a differential diagnosis. All antipsychotic and sedative drugs, as well as antibiotherapy, were discontinued, after which the patient showed significant clinical improvement. CONCLUSION: Antipsychotic agents are commonly employed to manage behavioral changes linked to various disorders. However, their severe side effects necessitate a high degree of vigilance, the cessation of all medications, and the implementation of supportive care measures. A prompt and accurate diagnosis of NMS is crucial to alleviating the severe, prolonged morbidity and potential mortality associated with this syndrome.

Oculogyric crisis symptoms related to risperidone treatment: a case report.

BACKGROUND: Oculogyric crisis (OGC) is a rare focal dystonia of the ocular muscles that not only interferes with patients' medication adherence but also negatively affects the course and prognosis of the primary disease. Early detection and treatment of OGC can improve patients' medication adherence and quality of life. CASE PRESENTATION: This paper reports a case of a 19-year-old Asian female with a diagnosis of schizophrenia who was treated intermittently with atypical antipsychotics aripiprazole or risperidone for 2 years, with improvement of psychotic symptoms during the course of medication, and then developed double eye rolling and staring with irritability when treated with risperidone 4 mg/d or 6 mg/d. Then, we changed the medication to clozapine, and the patient's psychotic symptoms were controlled and stable. The symptoms of double eye rolling and gaze disappeared. CONCLUSION: Oculogyric crisis (OGC) is a rare focal dystonia of the oculogyric muscle. This case provides clinicians with a basis for the early recognition and management of oculogyric crisis during the use of atypical antipsychotics (risperidone).

Efficacy and safety of TV-46000, a long-acting, subcutaneous, injectable formulation of risperidone, for schizophrenia: a randomised clinical trial in the USA and Bulgaria.

BACKGROUND: TV-46000 is a long-acting, subcutaneous, antipsychotic agent that combines risperidone and an innovative, copolymer-based drug delivery technology in a suspension that was approved in April, 2023 for subcutaneous use. The aim of the phase 3 Risperidone Subcutaneous Extended-release (RISE) study was to evaluate the efficacy of TV­46000 in schizophrenia. METHODS: The RISE study consisted of two treatment stages: a 12-week, open-label stabilisation phase with oral risperidone (stage 1), and an open-ended, randomised, double-blind, placebo-controlled, relapse-prevention phase with subcutaneous TV-46000 (stage 2) done at 69 clinical sites across the USA and Bulgaria. Patients diagnosed with schizophrenia more than 1 year before screening by DSM-5 criteria and confirmed at screening by the Structured Clinical Interview for DSM-5 and who had at least one relapse within 24 months before screening were eligible for enrolment. Patients who were outpatients and stabilised in stage 1 continued to stage 2 and were randomly assigned 1:1:1 by a computer-generated randomisation list to receive either subcutaneous TV-46000 once monthly, TV-46000 once every 2 months, or placebo until relapse, early discontinuation, or the study was stopped because the prespecified stopping criterion of at least 90 relapse events was met. The primary endpoint was time to impending relapse of the intention-to-treat patient population in stage 2. This study is registered with ClinicalTrials.gov, number NCT03503318, and is complete. FINDINGS: The study enrolled the first patient on June 1, 2018, and the last patient completed on Dec 3, 2020. 1267 patients were screened, 863 enrolled, and 544 (male, n=332 [61%], female, n=212 [39%]; mean [SD] age, 49·3 [10·98] years; Black or African American, n=322 [59%]; White, n=206 [38%]; Asian, n=7 [1%]; Native Hawaiian or other Pacific Islander, n=2 [<1%]; race not reported, n=3 [<1%]; other race, n=4 [<1%]; Hispanic or Latinx, n=117 [22%]) randomly assigned to subcutaneous TV-46000 once monthly (n=183), TV-46000 once every 2 months (n=180), or placebo (n=181). Time to impending relapse was significantly prolonged by 5·0 times with TV-46000 once monthly (hazard ratio, 0·200 [95% CI 0·109-0·367]; p<0·0001) and by 2·7 times with TV-46000 once every 2 months (0·375 [0·227-0·618]; p<0·0001) versus placebo. Most frequently reported treatment-related adverse events (ie, ≥5% of patients in either TV-46000 group) that occurred more often in patients receiving TV-46000 (once monthly or once every 2 months) versus placebo were injection site nodules (7% for TV-46000 once monthly, 7% for TV-46000 once every 2 months, 3% for placebo), weight increased (4%, 6%, 2%, respectively), and extrapyramidal disorder (5%, 3%, 0% respectively). Serious adverse events were reported for eight (4%) patients in the TV-46000 once-monthly group, ten (6%) patients in the TV-46000 once-every-2-months group, and 14 (8%) patients in the placebo group. The safety profile of TV-46000 was consistent with other approved formulations of risperidone. No new safety signals were identified. INTERPRETATION: In patients with schizophrenia, subcutaneous TV-46000 once monthly and once every 2 months significantly delayed impending relapse versus placebo. TV-46000 is an effective long-acting, subcutaneous, antipsychotic agent treatment option in adult patients with schizophrenia, with a favourable benefit-risk profile. FUNDING: Teva Branded Pharmaceutical Products R&D.