A Long-Term Safety and Tolerability Study of TV-46000 for Subcutaneous Use in Patients with Schizophrenia: A Phase 3, Randomized, Double-Blinded Clinical Trial.

BACKGROUND: TV-46000 is a long-acting subcutaneous antipsychotic (LASCA) formulation of risperidone that is approved by the United States Food and Drug Administration for the treatment of schizophrenia in adults. In the phase 3, randomized, double-blind RIsperidone Subcutaneous Extended-release (RISE) study, TV-46000 once monthly (q1m) and once every 2 months (q2m) significantly prolonged time to impending relapse compared with placebo [5.0-fold (q1m) and 2.7-fold (q2m)]. This phase 3, randomized, double-blind Safety in Humans of TV-46000 subcutaneous INjection Evaluation (SHINE) study was designed to evaluate the long-term safety, tolerability, and exposure of TV-46000 in schizophrenia. METHODS: Patients who completed RISE without relapse (rollover) or who were newly recruited (de novo) were eligible for the SHINE study. Patients were initially stabilized on oral risperidone for 12 weeks (completed in RISE for rollover, or in SHINE for de novo). Patients in the de novo cohort and patients who received placebo in RISE were randomized 1:1 in SHINE to receive TV-46000 q1m or q2m for up to 56 weeks. Primary endpoint for SHINE was frequency of reported adverse events (AEs); event rates [ER; events per 100 patient-years (PYs)] were calculated for each AE by patients upon general questioning. RESULTS: Overall, 336 patients were randomized in SHINE [TV-46000 q1m, n = 174; TV-46000 q2m, n = 162; of these, de novo, n = 109 and rollover, n = 227 (n = 172 patients were treated and n = 55 received placebo)]. A total of 334 patients were evaluated for safety [q1m, n = 172 (PY = 97.8); q2m, n = 162 (PY = 104.5)]. Proportions of patients (ER) with ≥ 1 AE and ≥ 1 treatment-related AE were 37% (180.0) and 21% (84.9) for TV-46000 q1m and 46% (157.9) and 20% (70.8) for TV-46000 q2m, respectively. Frequent treatment-related AEs [≥ 3% of patients in either group; proportion of patients (ER)] were injection site pain [q1m, 5% (24.5); q2m, 4% (22.0)] and injection site nodule [q1m, 2% (9.2); q2m, 6% (12.4)]. The proportions of patients with serious AEs was 5% for TV-46000 q1m and 7% for TV-46000 q2m; serious AEs reported for ≥ 2 patients overall were worsening schizophrenia [q1m, n = 1 (< 1%; ER, 1.02); q2m, n = 2 (1%; ER, 1.91)] and hyperglycemia [q1m, n = 1 (< 1%; ER, 1.02); q2m, n = 1 (< 1%; ER, 0.96)]. Of three reported deaths, none were related to treatment. Overall, eight patients discontinued treatment because of AEs. Similar or somewhat lower rates of AEs were reported for patients who rolled over from TV-46000 treatment compared with those who had no prior TV-46000 treatment (de novo and placebo rollover). Most AEs related to injection site reactions were mild; no patient had a severe reaction. CONCLUSION: Results from this long-term safety study add to the favorable safety profiles of TV-46000 q1m and q2m, consistent with other formulations of risperidone and previous studies with TV-46000. REGISTRATION: ClinicalTrials.gov, NCT03893825; 27 March 2019.

The United States Food and Drug Administration approved TV-46000 in April 2023 for the treatment of schizophrenia in adults. TV-46000 is a long-acting subcutaneous antipsychotic (LASCA) that uses technology that allows for the slow release of risperidone. TV-46000 is injected under the skin once monthly or once every 2 months. When people start taking TV-46000, they do not need an additional injection or oral risperidone. The Safety in Humans of TV-46000 subcutaneous INjection Evaluation (SHINE) was a clinical study in which patients with schizophrenia received TV-46000. SHINE was conducted in patients who completed the RIsperidone Subcutaneous Extended-release (RISE) study and new patients. All patients (TV-46000 once monthly, n = 162; TV-46000 once every 2 months, n = 172) received TV-46000 in SHINE to see whether safety results were the same long term compared with RISE. The proportions with more than one adverse event were 37% for TV-46000 once monthly and 46% for TV-46000 once every 2 months. The proportions with more than one adverse event related to treatment were 21% for TV-46000 once monthly and 20% for TV-46000 once every 2 months. Common adverse events related to treatment were injection site pain and small swelling. Serious adverse events were rare. None of the three reported deaths were related to treatment. Similar or lower rates of adverse events were reported for those who received TV-46000 in RISE compared with those with no prior TV-46000 treatment. The long-term safety results in SHINE were consistent with other forms of risperidone and previous studies with TV-46000.

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.

Safety and Efficacy of Long-Term Deutetrabenazine Use in Children and Adolescents with Tics Associated with Tourette Syndrome: An Open-Label Extension Study.

Background: Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and phonic tics. Objective: To assess the safety and efficacy of deutetrabenazine (Teva Neuroscience, Inc, Parsippany, NJ), a vesicular monoamine transporter 2 inhibitor, in children and adolescents with TS. Methods: Alternatives for Reducing Tics in TS (ARTISTS) open-label extension (OLE) (NCT03567291) was a 54-week, global, phase 3, open-label extension study of deutetrabenazine (6-48 mg daily) conducted May 28, 2018 to April 3, 2020 with a 2-week randomized withdrawal period. Participants (6-16 years of age) had TS and active tics causing distress or impairment. Safety (primary outcome) was assessed by treatment-emergent adverse events (TEAEs) and clinical laboratory testing. Efficacy was measured by the Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS). Results: The intent-to-treat population (228 participants; mean age, 12.0 years; 79.8% male; 86.4% white) had a median (range) duration of exposure of 28.4 (0.3-52.9) weeks. Of 227 participants in the safety analysis, 161 (70.9%) reported ≥1 TEAE (exposure-adjusted incidence rate, 2.77/patient-year), of which 95 (41.9%) were treatment related. The most frequently reported TEAEs were headaches, somnolence, nasopharyngitis, weight increases, and anxiety. No additional safety signals were observed. Worsening of YGTSS-TTS after the 2-week randomized withdrawal was not statistically significant (least squares mean difference, -0.4; P = 0.78). Several exploratory measures showed sustained improvement throughout the treatment periods. Conclusions: In this long-term, open-label trial, deutetrabenazine was well tolerated with low frequency of TEAEs. There was no significant difference in tics between treatment arms during the 2-week randomized withdrawal period, however, descriptive statistics and comparison with baseline showed a numeric improvement in tics, quality of life, and other measures.

Population Pharmacokinetic Modeling and Simulation of TV-46000: A Long-Acting Injectable Formulation of Risperidone.

TV-46000 is a long-acting subcutaneous antipsychotic that uses a novel copolymer drug delivery technology in combination with a well-characterized molecule, risperidone, that is in clinical development as a treatment for schizophrenia. A population pharmacokinetic (PPK) modeling and simulation approach was implemented to identify TV-46000 doses and dosing schedules for clinical development that would provide the best balance between clinical efficacy and safety. The PPK model was created by applying pharmacokinetic data from a phase 1 study of 97 patients with a diagnosis of schizophrenia or schizoaffective disorder who received either single or repeated doses of TV-46000. The PPK model was used to characterize the complex release profile of the total active moiety (TAM; the sum of the risperidone and 9-OH risperidone concentrations) concentration following subcutaneous injections of TV-46000. The PK profile was best described by a double Weibull function of the in vivo release rate and by a 2-compartment disposition and elimination model. Simulations were performed to determine TV-46000 doses and dosing schedules that maintained a median profile of TAM concentrations similar to published TAM exposure following oral risperidone doses that have been correlated to a 40% to 80% dopamine-D2 receptor occupancy therapeutic window. The simulations showed that therapeutic dose ranges for TV-46000 are 50 to 125 mg for once-monthly and 100 to 250 mg for the once every 2 months regimens. This PPK model provided a basis for prediction of patient-specific exposure and dopamine-D2 receptor occupancy estimates to support further clinical development and dose selection for the phase 3 studies.

Efficacy and Safety of Fixed-Dose Deutetrabenazine in Children and Adolescents for Tics Associated With Tourette Syndrome: A Randomized Clinical Trial.

Importance: Tourette syndrome is a neurodevelopmental disorder characterized by childhood onset of motor and phonic tics, often accompanied by behavioral and psychiatric comorbidities. Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor approved in the US for the treatment of chorea associated with Huntington disease and tardive dyskinesia. Objective: To report results of the ARTISTS 2 (Alternatives for Reducing Tics in Tourette Syndrome 2) study examining deutetrabenazine for treatment of Tourette syndrome. Design, Setting, and Participants: This phase 3, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study was conducted over 8 weeks with a 1-week follow-up (June 21, 2018, to December 9, 2019). Children and adolescents aged 6 to 16 years with a diagnosis of Tourette syndrome and active tics causing distress or impairment were enrolled in the study. Children were recruited from 52 sites in 10 countries. Data were analyzed from February 4 to April 22, 2020. Interventions: Participants were randomized (1:1:1) to low-dose deutetrabenazine (up to 36 mg/d), high-dose deutetrabenazine (up to 48 mg/d), or a matching placebo, which were titrated over 4 weeks to the target dose followed by a 4-week maintenance period. Main Outcomes and Measures: The primary efficacy end point was change from baseline to week 8 in the Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS) for high-dose deutetrabenazine. Key secondary end points included changes in YGTSS-TTS for low-dose deutetrabenazine, Tourette Syndrome Clinical Global Impression score, Tourette Syndrome Patient Global Impression of Impact score, and Child and Adolescent Gilles de la Tourette Syndrome-Quality of Life Activities of Daily Living subscale score. Safety assessments included incidence of treatment-emergent adverse events, laboratory parameters, vital signs, and questionnaires. Results: The study included 158 children and adolescents (mean [SD] age, 11.7 [2.6] years). A total of 119 participants (75%) were boys; 7 (4%), Asian; 1 (1%), Black; 32 (20%), Hispanic; 4 (3%), Native American; 135 (85%), White; 2 (1%), multiracial; 9 (6%), other race; and 1 (0.6%), of unknown ethnic origin. Fifty-two participants were randomized to the high-dose deutetrabenazine group, 54 to the low-dose deutetrabenazine group, and 52 to the placebo group. Baseline characteristics for participants were similar between groups. Of the total 158 participants, 64 (41%) were aged 6 to 11 years, and 94 (59%) were aged 12 to 16 years at baseline. Mean time since Tourette syndrome diagnosis was 3.3 (2.8) years, and mean baseline YGTSS-TTS was 33.8 (6.6) points. At week 8, the difference in YGTSS-TTS was not significant between the high-dose deutetrabenazine and placebo groups (least-squares mean difference, -0.8 points; 95% CI, -3.9 to 2.3 points; P = .60; Cohen d, -0.11). There were no nominally significant differences between groups for key secondary end points. Treatment-emergent adverse events were reported for 34 participants (65%) treated with high-dose deutetrabenazine, 24 (44%) treated with low-dose deutetrabenazine, and 25 (49%) treated with placebo and were generally mild or moderate. Conclusions and Relevance: In this fixed-dose randomized clinical trial of deutetrabenazine in children and adolescents with Tourette syndrome, the primary efficacy end point was not met. No new safety signals were identified. Trial Registration: ClinicalTrials.gov Identifier: NCT03571256.

Safety and Efficacy of Flexible-Dose Deutetrabenazine in Children and Adolescents With Tourette Syndrome: A Randomized Clinical Trial.

Importance: Tourette syndrome is a neurodevelopmental disorder characterized by childhood onset of motor and phonic tics; treatments for tics are associated with safety concerns. Deutetrabenazine is a selective vesicular monoamine transporter 2 inhibitor approved for the treatment of chorea associated with Huntington disease and tardive dyskinesia in adults. Objective: To examine whether deutetrabenazine is effective and safe for the treatment of Tourette syndrome in children and adolescents. Design, Setting, and Participants: This phase 2/3, randomized, double-masked, placebo-controlled, parallel-group, dose-titration study included children and adolescents (aged 6-16 years) with Tourette syndrome with active tics causing distress or impairment (ie, Yale Global Tic Severity Scale-Total Tic Score [YGTSS-TTS] ≥20). The trial was conducted over 12 weeks, with 1 week of follow-up from February 2018 to November 2019 at 36 centers in the United States, Canada, Denmark, Russia, Serbia, and Spain. Data analysis was conducted from January 31 to April 22, 2020. Intervention: Patients were randomized (1:1) to receive deutetrabenazine or placebo, titrated during 7 weeks to an optimal level, followed by a 5-week maintenance period. The maximum total daily deutetrabenazine dose was 48 mg/d. Main Outcomes and Measures: The primary efficacy end point was change from baseline to week 12 in YGTSS-TTS. Key secondary end points included changes in Tourette Syndrome-Clinical Global Impression, Tourette Syndrome-Patient Global Impression of Impact, and Child and Adolescent Gilles de la Tourette Syndrome-Quality of Life Activities of Daily Living subscale score. Safety was assessed based on treatment-emergent adverse events, vital signs, questionnaires, and laboratory parameters. Results: A total of 119 participants were randomized to deutetrabenazine (59 participants; mean [SD] age, 11.5 [2.5] years; 53 [90%] boys; 49 [83%] White; 3 [5%] Black) and placebo (60 participants; mean [SD] age, 11.5 [2.6] years; 51 [85%] boys; 53 [88%] White; 3 [5%] Black). At week 12, the difference in YGTSS-TTS score was not significant between deutetrabenazine and placebo (least squares mean difference, -0.7; 95% CI, -4.1 to 2.8; P = .69; Cohen d, -0.07). There were no nominally significant differences between groups for key secondary end points. Treatment-emergent adverse events were reported for 38 patients (66%) and 33 patients (56%) receiving deutetrabenazine and placebo, respectively, and were generally mild or moderate. Conclusions and Relevance: In this study of deutetrabenazine in children and adolescents with Tourette syndrome, the primary efficacy end point was not met. No new safety signals were identified. These results may be informative for future studies of treatments for tics in Tourette syndrome. Trial Registration: ClinicalTrials.gov Identifier: NCT03452943.

The burden of caring for dementia patients: caregiver reports from a cross-sectional hospital-based study in China.

The impact of dementia care on caregivers' professional, personal, emotional and social well-being was measured in a cohort of 1,387 caregivers in seven regions across mainland China, using a Chinese version of the Zarit Burden Interview (ZBI) and four supplementary questions. Caregivers also estimated costs of care and medical resource utilization. Caregiver burden was generally low to moderate. Dementia care had the greatest impact on caregivers' professional lives, with 25.5% reporting a reduced work schedule in the past month. Lost work time was greater for caregivers of patients with previously diagnosed dementia than for those with newly diagnosed dementia. Average monthly out-of-pocket costs of dementia care exceeded national average monthly incomes of rural and urban residents. These findings highlight the obstacles facing the country with the fastest-growing elderly population in the world.

Clinical Characterization and the Caregiver Burden of Dementia in China.

OBJECTIVES: The prevalence of dementia in China is among the highest in the world, but systematic estimates of the rate of dementia subtypes and characterization of associated deficits are lacking. The primary aim of this study was to determine the clinical presentation of dementia and describe the caregiver burden in mainland China. METHODS: A 3-month, open-enrollment, multicenter, cross-sectional study was conducted at 48 tier-3 hospitals. Caregivers who qualified for study entry (provided amount and duration of care information), had intimate knowledge of patient status, and accompanied enrolled patients to study sites were asked to participate in an interview about patient care and caregiver burden. Caregiver burden was assessed via the Chinese version of the validated Zarit Burden Interview. RESULTS: A total of 1425 caregivers completed the survey. Patients had mild to moderate dementia (mean Clinical Dementia Rating score of 1.67±0.79), and the most common dementia subtypes were Alzheimer disease (46.7%) and vascular dementia (28.7%). Among caregivers, 57% were females, 52% were patients' spouses, and 67.3% had been caring for patients for 1 year or more. Most patients required family help and lived at home or with a family member. Caregiver awareness of dementia was limited. The mean total caregiver Zarit Burden Interview score was 26.6. Observations were similar across age, gender, education, dementia type, Clinical Dementia Rating score, and duration of care. CONCLUSIONS: China faces multiple obstacles in preparing to care for its fast-growing dementia population. Better understanding of patients and caregivers may mitigate these challenges by improving awareness and education.

Trazodone for the treatment of sexual dysfunction induced by serotonin reuptake inhibitors: a preliminary open-label study.

INTRODUCTION: Treatment with selective serotonin reuptake inhibitors (SSRIs) may lead to sexual dysfunction in up to 70% of patients. Because the SSRIs are widely used antidepressants, their propensity to cause sexual dysfunction may affect compliance with therapy and ultimately treatment success. To date, the pathophysiological mechanism of sexual dysfunction caused by SSRIs remains incompletely understood, and the management of SSRIs-induced sexual dysfunction remains unsatisfactory. We suggest that medications that antagonize serotonin receptors such as trazodone may improve sexual dysfunction reverting the stimulation of serotonin receptors by SSRIs. OBJECTIVE: The aim of this study was to investigate the efficacy of trazodone administration in the management of SSRI-induced sexual dysfunction. METHODS: Twenty patients (11 men/9 women) with SSRIs-induced sexual dysfunction were recruited for the study. Trazodone was added to the existing SSRI regimen in open-label fashion for 4 weeks (50 mg for the first week increased to 100 mg until the completion of the study). The improvement in the 4 dimensions of sexual function (desire, erection or lubrication problems in women, ejaculation or orgasm in women, and overall satisfaction by both sexes) was the primary outcome measure of the study. RESULTS: Fifteen subjects completed the study. Results indicated improvement in sexual function and overall clinical improvement (depression, anxiety) as well. Specific gender differences indicated improvement in erectile performance in men and lubrication in women. No correlations were noted between clinical improvement of depression or anxiety and improvement in sexual dysfunction. CONCLUSIONS: The 5-HT2 antagonist, trazodone, may be beneficial in the management of SSRI-induced sexual dysfunction. Large-scale, placebo-controlled, double-blind studies with 5-HT2 antagonists are required to substantiate these preliminary observations.

[Prophecy and mental illness].

It is a well known platitude that a mentally ill person may "think that he is God" or "believes that he is the Messiah". Despite the generalization and shallowness of this attitude, sometimes psychotic patients indeed have delusions with contents of divine revelation, messianic assignments or prophetic power. In this current article we examine the different connections between prophecy and mental condition, especially psychotic. We present sources that combine prophecy and insanity, and also possible psychiatric interpretation of these situations. Finally, we present the attitude of the Rambam to prophecy and the personality characteristics of the prophet, limiting the possibility of the mentally ill patient who pretends to be a prophet.