Efficacy and safety of zuranolone in Japanese adults with major depressive disorder: A double-blind,randomized, placebo-controlled,phase 2 clinical trial

Aim

To evaluate the efficacy and safety of an oral, once-daily, 14-day treatment course of zuranolone in Japanese patients with major depressive disorder (MDD).

Methods

This multicenter, randomized, double-blind, placebo-controlled study randomized eligible patients (1:1:1) to receive oral zuranolone 20 mg, zuranolone 30 mg, or placebo once daily for 14 days (treatment-period), followed by two 6-week follow-up periods. The primary endpoint was change from baseline in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score on Day 15.

Results

Overall, 250 patients (enrolled: 07/07/2020–05/26/2021) were randomized to receive placebo (n = 83), zuranolone 20 mg (n = 85), or zuranolone 30 mg (n = 82). The demographic and baseline characteristics were balanced between groups. The adjusted mean (standard error) change from baseline in the HAMD-17 total score on Day 15 was −6.22 (0.62), −8.14 (0.62), and − 8.31 (0.63) in the placebo, zuranolone 20-mg, and zuranolone 30-mg groups, respectively. Significant differences in the adjusted mean (95% confidence interval [CI]) for zuranolone 20 mg versus placebo (−1.92; [−3.65, −0.19]; P = 0.0296) and zuranolone 30 mg versus placebo (−2.09; [−3.83, −0.35]; P = 0.0190) groups were observed on Day 15, and also as early as Day 3. A nonsignificant yet distinct drug-placebo separation was observed during follow-up. Somnolence (placebo [3.7%], zuranolone 20 mg [10.6%], and zuranolone 30 mg [20.7%]) and dizziness (3.7%, 9.4%, and 9.8%, respectively) were more common with zuranolone.

Conclusion

Oral zuranolone was safe and demonstrated significant improvements in depressive symptoms, as assessed by HAMD-17 total score change from baseline over 14 days in Japanese patients with MDD.     

A Post-hoc Comparison of Paliperidone Palmitate to Oral Risperidone During Initiation of Long-acting Risperidone Injection in Patients with Acute Schizophrenia

Objective: First-month data of a 13-week acute schizophrenia study were used to compare paliperidone palmitate to oral risperidone during initiation of long-acting injectable risperidone.Design: Double-blind, randomized study.Setting: Outpatient or inpatient.Participants: Adults with established (≥1 year) schizophrenia. Those assigned to risperidone long-acting injectable (n=460) received 25mg on Days 8 and 22 with oral risperidone (l-6mg) supplementation for the first 28 days. The paliperidone palmitate group (n=453) received 150mg eq. on Day 1, l00mg eq. on Day 8, and oral placebo supplementation for the first 28 days.Measurements: Positive and Negative Syndrome Scale, Personal and Social Performance Scale, Clinical Global Impression-Severity score, and responder rate (percentage of patients with ≥30% reduction in PANSS total score). An analysis of covariance model estimated least-square mean differences between treatment groups. A post-hoc analysis of efficacy data for the period of interest, i.e., at the time points before and after the first 28 days, was conducted.Results: Positive and Negative Syndrome Scale, Personal and Social Performance Scale, Clinical global Impression-Severity scores showed similar efficacy between the treatment groups during the first weeks of treatment, corresponding to the risperidone long-acting injection initiation period. Mean Positive and Negative Syndrome Scale total score at baseline was 84.7 for paliperidone palmitate and 84.4 for oral risperidone, on Day 22 was 73.6 and 74.1, respectively, and on Day 36 was 71.8 and 72.8, respectively. Overall incidence of adverse events in the first 28 days was generally similar (45% for paliperidone palmitate vs. 35% for oral risperidone), except for injection site pain (4.6% vs. 0.7%). Similar active moiety plasma concentrations were obtained during this period.Conclusion: During the first month, paliperidone palmitate without oral supplementation has similar efficacy and safety to oral risperidone (during initiation of risperidone long-acting injectable) in acutely exacerbated schizophrenia.     

Health-related quality of life in patients with schizophrenia during treatment with long-acting, injectable risperidone

BACKGROUND: We investigated the impact of treatment with long-acting, injectable risperidone versus placebo on health-related quality of life (HRQoL) in patients with schizophrenia. Results are discussed in the context of HRQoL in the general U.S. population. METHOD: Patients with DSM-IV schizophrenia entered a randomized, double-blind, placebo-controlled trial. After screening, previous antipsychotics were discontinued, and oral risperidone was titrated up to a dose of 4 mg/day over 1 week. Patients were then randomly assigned to receive placebo [N = 92] or long-acting risperidone (25 [N = 93], 50 [N = 97], or 75 mg [N = 87] every 2 weeks) for 12 weeks. HRQoL was measured using the Medical Outcomes Study Short-Form 36-item questionnaire (SF-36). RESULTS: At week 12, patients receiving long-acting risperidone had improved significantly (p <.05) in 5 domains of the SF-36 (bodily pain, general health, social functioning, role-emotional, and mental health) compared with patients receiving placebo. The effect was greatest for the 25-mg group, with significant improvement versus placebo in 6 domains (p <.05). At baseline, all SF-36 domain scores except bodily pain were significantly lower (p <.05) than normal values in all groups. With placebo, scores in all 8 domains remained below normal values after 12 weeks, while patients receiving long-acting risperidone showed improvement in HRQoL toward normal levels, with clinically meaningful improvements in all mental-health domains. In the 25-mg group, scores in 7 domains were not statistically different from normal values after 12 weeks. CONCLUSIONS: Long-acting, injectable risperidone improved HRQoL toward normal levels. After 12 weeks, HRQoL of patients receiving 25 mg was not significantly different from normal.     

Switching to aripiprazole in subjects with Pervasive Developmental Disorders showing tolerability issues with risperidone

Background

Subjects with Pervasive Developmental Disorders (PDD) often exhibit behavioral symptoms such as aggressiveness and irritability, which are targets of psychopharmacologic intervention. This retrospective study was designed to examine children and adolescents with PDD experiencing tolerability issues with risperidone treatment, and thereby assess the efficacy and tolerability of switching to aripiprazole.

Methods

This naturalistic study included 23 subjects with PDD (16 males, 7 females, age range 9–24 years, mean age 15.1 ± 3.9 years) diagnosed according to DSM-IV criteria and followed up for 14.9 ± 8.4 weeks after switching to aripiprazole from risperidone. Outcome measures were the Clinical Global Impression-Severity (CGI-S) and CGI Improvement (CGI-I) scales.

Results

The mean CGI-S scores of pre-aripiprazole treatment and post-aripiprazole treatment were, respectively 4.7 ± 1.4 and 4.6 ± 1.3. Mean maintenance dosages of risperidone and aripiprazole were, respectively, 0.7 ± 0.5 mg/day and 2.8 ± 1.3 mg/day. The mean CGI-I score, which shows the difference induced by switching from risperidone to aripiprazole, was 3.4 ± 0.8 for the whole sample, suggesting that the efficacy of risperidone for treating behavioral problems of PDD was maintained by aripiprazole. Some improvement of safety/tolerability issues such as increased appetite, somnolence, hyperprolactinemia, and amenorrhea occurred after switching to aripiprazole.

Conclusion

Results show that switching to aripiprazole might be generally well tolerated and might constitute an alternative treatment for subjects with PDD who experience tolerability issues with risperidone treatment. Additional long-term controlled studies of PDD subjects should be undertaken to evaluate the efficacy and safety of switching to aripiprazole from other antipsychotics.     

A double-blind, placebo-controlled study of traditional Chinese medicine sarsasapogenin added to risperidone in patients with negative symptoms dominated schizophrenia

Objective

To identify whether sarsasapogenin, a sapogenin from the Chinese medicinal herb Anemarrhena Asphodeloides Bunge, would augment the efficacy of risperidone and significantly improve cognitive functions in patients with negative symptoms dominated schizophrenia.

Methods

The trial was a double-blind, placebo-controlled, parallel-group design. The eligible patients were randomized into 2 treatment groups: sarsasapogenin group (sarsasapogenin plus risperidone for 8 weeks, n = 41) and placebo group (risperidone only for 8 weeks, n = 39). At the baseline, as well as at weeks 2, 4 and 8 of treatment, the therapeutic response was measured by using scales including Positive and Negative Symptoms Scale (PANSS), Wechsler Memory Scale (WMS), modified Chinese Wechsler Adult Intelligence Scale (mWAIS), Clinical Global Impression (CGI) and Brief Psychiatry Rating Scale (BPRS). The study period for each subject was 8 weeks and duration of overall trial was 2 years.

Results

Patients treated with sarsasapogenin plus risperidone demonstrated no statistically significant differences in changes in PANSS, WMS or mWAIS score at the end-point of the trial compared with patients treated with placebo plus risperidone. The incidence of treatment-emergent adverse events in patients treated with sarsasapogenin was not different from that observed in placebo group.

Conclusion

Sarsasapogenin did not augment the efficacy of risperidone in treating negative symptoms dominated schizophrenia. Sarsasapogenin at a dosage of 200 mg per day added to a flexible dosage of risperidone at 2–4 mg per day is safe and well tolerated by patients with negative symptoms dominated schizophrenia.     

Adjunctive lumateperone (ITI-007) in the treatment of bipolar depression: Results from a randomized placebo-controlled clinical trial

Objective

This phase 3, randomized, double-blind, placebo-controlled study (NCT02600507) evaluated the efficacy and safety of lumateperone adjunctive therapy to lithium or valproate in patients with bipolar depression.

Methods

Patients (18–75 years) with bipolar I or bipolar II disorder experiencing a major depressive episode (MDE), with inadequate therapeutic response to lithium or valproate, were randomized 1:1:1 to 6 weeks adjunctive therapy with lumateperone 28 mg (n = 176), lumateperone 42 mg (n = 177), or placebo (n = 176). The primary and key secondary efficacy endpoints were change from baseline to Day 43 in Montgomery-Åsberg Depression Rating Scale (MADRS) Total score and the Clinical Global Impression Scale-Bipolar Version-Severity Scale (CGI-BP-S) depression subscore. Safety assessments included adverse events, laboratory evaluations, vital signs, extrapyramidal symptoms (EPS), and suicidality.

Results

Patients treated with adjunctive lumateperone 42 mg showed significantly greater improvement compared with adjunctive placebo in MADRS Total score (LS mean difference vs placebo [LSMD], −2.4; p = 0.02) and CGI-BP-S depression subscore (LSMD, −0.3; p = 0.01), while adjunctive lumateperone 28 mg showed numerical improvement in MADRS Total score (LSMD, −1.7; p = 0.10) and improvement in the CGI-BP-S depression subscore (LSMD, −0.3; p = 0.04). Adjunctive lumateperone treatment was well tolerated; treatment-emergent adverse events reported at rates >5% and twice placebo for lumateperone 42 mg were somnolence (11.3%), dizziness (10.7%), and nausea (8.5%), with minimal risk of EPS, metabolic abnormalities, or increased prolactin.

Conclusions

Lumateperone 42-mg treatment adjunctive to lithium or valproate significantly improved depression symptoms and was generally well tolerated in patients with MDEs associated with either bipolar I or bipolar II disorder.     

Paliperidone for treatment of schizophrenia

In short-term studies, oral paliperidone is an antipsychotic that is more efficacious than placebo. We found its adverse effects to be similar to those of its parent compound, risperidone, with movement disorders, weight gain, and tachycardia all more common with paliperidone than placebo. In addition, paliperidone is associated with substantial increases in serum prolactin that may be associated with sexual dysfunction, although sexual functioning outcomes were not reported. At doses greater than 3 mg per day, oral paliperidone appears comparable in efficacy to oral olanzapine 10 mg per day. Regarding the critical comparison of oral paliperidone to risperidone, we have no information and are thus unable to determine if paliperidone has any advantages or disadvantages compared to its well-known parent compound.     

Attention behavior and hyperactivity and concurrent neurocognitive and social competence functioning in 4-year-olds from two population-based birth cohorts

Objective

We studied the associations between Attention Deficit Hyperactivity Disorder (ADHD) symptoms and the neurobehavioral status in two population-based birth cohorts.

Methods

Children (n = 467) were assessed by psychologists and teachers for neuropsychological functioning (McCarthy Scales, MCSA), inattention-hyperactivity symptoms (ADHD-DSM-IV form list) and social behavior (California Preschool Social Competence Scale, CPSCS). Regression models were used with covariate adjustment.

Results

Sixteen percent of children had ADHD-DSM-IV symptoms. MCSA scores were linearly associated with ADHD symptom scores (general cognitive Beta = −0.6 [−1.0; −0.3] per symptom), specifically inattention scores (general cognitive Beta = −1.8 [−2.3; −1.2]). CPSCS scores were associated with ADHD symptoms (Beta = −2.19 [−2.5; −1.9]). MCSA scores of executive function, perceptive-performance and quantitative sub-areas had stronger associations with ADHD symptoms.

Conclusions

Preschooler ADHD symptoms are associated with concurrent decrements in neurocognitive and social competence functioning. The association patterns are similar to those found in older children with ADHD symptomology (Marks et al., 2005 [36], Seidman, 2006 [46], Sonuga-Barke et al., 2003 [48], Yochman et al., 2006 [53]).     

Plecanatide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation: Post hoc analyses of placebo-controlled trials in adults with severe constipation

Background

Patients with chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C) often experience severe symptoms. The current aim was to evaluate plecanatide in adults with CIC or IBS-C with severe constipation.

Methods

Data were analyzed post hoc from randomized, placebo-controlled trials (CIC [n = 2], IBS-C [n = 2]) of plecanatide 3 mg, 6 mg, or placebo administered for 12 weeks. Severe constipation was defined as no complete spontaneous bowel movements (CSBMs) and an average straining score ≥3.0 (CIC; 5-point scale) or ≥8.0 (IBS-C; 11-point scale) during a 2-week screening. Primary efficacy endpoints were durable overall CSBM responders (CIC: ≥3 CSBMs/week, plus increase from baseline of ≥1 CSBM/week, for ≥9 of 12 weeks, including ≥3 of the last 4 weeks) and overall responders (IBS-C: ≥30% reduction from baseline in abdominal pain and ≥1 CSBM/week increase for ≥6 of 12 weeks).

Key Results

Severe constipation was observed in 24.5% (646/2639) and 24.2% (527/2176) of CIC and IBS-C populations, respectively. The CIC durable overall CSBM response rate (plecanatide 3 mg, 20.9%; plecanatide 6 mg, 20.2%; placebo, 11.3%) and IBS-C overall response rate (plecanatide 3 mg, 33.0%; plecanatide 6 mg, 31.0%; placebo, 19.0%) were significantly greater with plecanatide versus placebo (p ≤ 0.01 for all). Median time to first CSBM in CIC and IBS-C populations were significantly shorter with plecanatide 3 mg versus placebo (p = 0.01 for both).

Conclusions and Inferences

Plecanatide was effective in the treatment of severe constipation in adults with CIC or IBS-C.     

Hyaluronidase-facilitated subcutaneous immunoglobulin 10% as maintenance therapy for chronic inflammatory demyelinating polyradiculoneuropathy: The ADVANCE-CIDP 1 randomized controlled trial

Background and Aims

ADVANCE-CIDP 1 evaluated facilitated subcutaneous immunoglobulin (fSCIG; human immunoglobulin G 10% with recombinant human hyaluronidase) efficacy and safety in preventing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) relapse.

Methods

ADVANCE-CIDP 1 was a phase 3, double-blind, placebo-controlled trial conducted at 54 sites in 21 countries. Eligible adults had definite or probable CIDP and adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores of 0–7 (inclusive), and received stable intravenous immunoglobulin (IVIG) for ≥12 weeks before screening. After stopping IVIG, patients were randomized 1:1 to fSCIG 10% or placebo for 6 months or until relapse/discontinuation. fSCIG 10% was administered at the same dose (or matching placebo volume) and interval as pre-randomization IVIG. The primary outcome was patient proportion experiencing CIDP relapse (≥1-point increase in adjusted INCAT score from pre-subcutaneous treatment baseline) in the modified intention-to-treat population. Secondary outcomes included time to relapse and safety endpoints.

Results

Overall, 132 patients (mean age 54.4 years, 56.1% male) received fSCIG 10% (n = 62) or placebo (n = 70). CIDP relapse was reduced with fSCIG 10% versus placebo (n = 6 [9.7%; 95% confidence interval 4.5%, 19.6%] vs n = 22 [31.4%; 21.8%, 43.0%], respectively; absolute difference: −21.8% [−34.5%, −7.9%], p = .0045). Relapse probability was higher with placebo versus fSCIG 10% over time (p = .002). Adverse events (AEs) were more frequent with fSCIG 10% (79.0% of patients) than placebo (57.1%), but severe (1.6% vs 8.6%) and serious AEs (3.2% vs 7.1%) were less common.

Interpretation

fSCIG 10% more effectively prevented CIDP relapse than placebo, supporting its potential use as maintenance CIDP treatment.     

Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled trial

Objective:

Because cholinergic deficits are prominent in dementia with Lewy bodies (DLB), we investigated the effects of a cholinesterase inhibitor, donepezil, in such patients in a randomized, double‐blind, placebo‐controlled exploratory phase 2 trial.

Methods:

One‐hundred forty patients with DLB, recruited from 48 specialty centers in Japan, were randomly assigned to receive placebo or 3, 5, or 10mg of donepezil hydrochloride daily for 12 weeks (n = 35, 35, 33, and 37, respectively). Effects on cognitive function were assessed using the Mini‐Mental State Examination (MMSE) and several domain‐specific neuropsychological tests. Changes in behavior were evaluated using the Neuropsychiatric Inventory, caregiver burden using the Zarit Caregiver Burden Interview, and global function using the Clinician's Interview‐Based Impression of Change‐plus Caregiver Input (CIBIC‐plus). Safety measures included the Unified Parkinson's Disease Rating Scale part III.

Results:

Donepezil at 5 and 10mg/day was significantly superior to placebo on both the MMSE (5mg: mean difference, 3.8; 95% confidence interval [CI], 2.3–5.3; p < 0.001; 10 mg: mean difference, 2.4; 95% CI, 0.9–3.9; p = 0.001) and CIBIC‐plus (p < 0.001 for each); 3mg/day was significantly superior to placebo on CIBIC‐plus (p < 0.001), but not on the MMSE (p = 0.017). Significant improvements were found also in behavioral measures (p < 0.001) at 5 and 10mg/day and caregiver burden (p = 0.004) at 10 mg/day. The safety results were consistent with the known profile of donepezil and similar among groups.

Interpretation:

Donepezil at 5 and 10mg/day produces significant cognitive, behavioral, and global improvements that last at least 12 weeks in DLB patients, reducing caregiver burden at the highest dose. Donepezil is safe and well tolerated. ANN NEUROL 2012;72:41–52     

The influence of switching from risperidone to paliperidone on the extrapyramidal symptoms and cognitive function in elderly patients with schizophrenia: A preliminary open-label trial

Objective. This study was to evaluate the effects on clinical symptoms and cognitive function of switching the treatment of elderly patients with schizophrenia from risperidone to paliperidone (PAL). Methods. This study was a 12-weeks, preliminary open-label trial. The subjects were 17 inpatients. Their extrapyramidal symptoms (EPS) were assessed using the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS), Abnormal Involuntary Movement Scale (AIMS), and Barnes Akathisia Scale (BAS), and their cognitive function was assessed using the Brief Assessment Cognition in Schizophrenia: Japanese language version (BACS-J), and their clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity of illness scale (CGI-S) at the 0 and 12 weeks. Results. The DIEPSS and BAS significantly improved after switching from risperidone to PAL. Furthermore, improvement was found on AIMS. The mean change from baseline in z-score of the digit sequencing task was significantly increased. All items on the PANSS and CGI-S were not significant; however, changes in some cognitive function were correlated with changes in EPS. Conclusions. The results of this study suggest the possibility that switching elderly patients from risperidone to PAL may have improved pre-existing EPS, and may also have helped improve working memory.     

Treatment of schizophrenia with paliperidone extended-release tablets: a 6-week placebo-controlled trial

BACKGROUND: Paliperidone extended-release tablet (paliperidone ER) is an investigational oral psychotropic developed for schizophrenia treatment. It utilizes OROS technology to provide a unique pharmacokinetic profile, eliminating the need for titration and potentially leading to improved tolerability. Furthermore, paliperidone undergoes limited hepatic metabolism. METHODS: The efficacy and safety of once-daily paliperidone ER (6 mg, 9 mg and 12 mg) were assessed versus placebo in 628 patients with acute schizophrenia in a 6-week, multicenter, double-blind, randomized, parallel-group study. RESULTS: All doses of paliperidone ER demonstrated significant improvement in PANSS score, all PANSS Marder factor scores (p<0.001) and personal and social functioning versus placebo (p<0.001). The PANSS total score also improved significantly in the olanzapine treatment arm. Significantly higher percentages of paliperidone ER patients demonstrated a > or =30% reduction in PANSS total score versus placebo (p<0.001). The incidence of movement disorder-related AEs and rating scales measurements were similar to placebo for the paliperidone ER 6 mg group and higher in the 9 mg and 12 mg groups. In the paliperidone ER groups there were no reports of glucose-related AEs or clinically relevant changes in plasma lipid levels and changes in mean bodyweight<1 kg. CONCLUSION: In this study, all doses of paliperidone ER were effective in significantly improving the symptoms of schizophrenia and personal and social functioning and were generally well tolerated. Paliperidone ER offers a distinctive treatment profile and may provide a valuable new treatment option for patients with schizophrenia.     

Comparative efficacy study of haloperidol, olanzapine and risperidone in delirium

Objective

The objective of the study was to assess the efficacy and safety of second-generation antipsychotics olanzapine and risperidone vs. haloperidol in patients of delirium admitted to medical and surgical wards.

Methods

Prospective follow-up single-blind randomized controlled trials were performed. Consecutive patients with delirium referred to the consultation–liaison psychiatry team were eligible for the study. The study sample comprised 64 patients, with 20 subjects in the haloperidol group, 21 subjects in the risperidone group and 23 subjects in the olanzapine group. A flexible dose regimen (haloperidol −0.25 to 10 mg; risperidone −0.25 to 4 mg; olanzapine −1.25 to 20 mg) was used. Delirium Rating Scale-Revised-98 (DRS-R98) was used as the primary efficacy measure, and mini mental status examination (MMSE) was used as a secondary efficacy measure.

Results

There was no significant difference in mean baseline DRS-R98 severity scores and MMSE scores between the three groups. However, there were a significant reduction in DRS-R98 severity scores and a significant improvement in MMSE scores over the period of 6 days, but there was no difference between the three groups. Four patients in the haloperidol group, six subjects in the risperidone group and two subjects in the olanzapine group experienced some side effects.

Conclusions

Risperidone and olanzapine are as efficacious as haloperidol in the treatment of delirium.     

Short-term effects of estrogen, tamoxifen and raloxifene on hemostasis: a randomized-controlled study and review of the literature

Introduction

Estrogen therapy (ET), tamoxifen and raloxifene are associated with a two- to three-fold increased risk of venous thrombosis (VT); however, the mechanisms by which each drug increases venous thrombosis propensity are not fully understood. The objectives of this investigation were to compare the effects of these three treatments on hemostasis in a head to head randomized placebo-controlled trial.

Patients/methods

Ninety-four postmenopausal women were assigned to receive oral estrogen (conjugated equine estrogen [CEE] 0.625 mg, n=23), tamoxifen 20 mg (n=24), raloxifene 60 mg (n=24) or placebo (n=23) daily for 6 months. Blood samples were analyzed for procoagulant factors (prothrombin, factors VII [fVII], VIII [fVIII], IX [fIX] and XI [fXI], D-dimer and von Willebrand factor [vWf]), anticoagulant factors (antithrombin [AT], total and free protein S, protein C and activated protein C [APC] resistance) and fibrinolytic factors (thrombin activatable fibrinolysis inhibitor [TAFI] and plasminogen activator inhibitor-1 [PAI-1]), at baseline and at 6 months of treatment.

Results

Estrogen increased factor VII and D-dimer, and decreased antithrombin, total and free protein S and PAI-1. Changes with tamoxifen were distinct from estrogen with increases in factors VIII, IX, vWf and free protein S, and decreases in AT, total protein S, protein C and plasminogen activator inhibitor-1. Raloxifene produced similar effects as tamoxifen, but did not increase factor IX or decrease protein C.

Conclusions

Estrogen, tamoxifen and raloxifene affected hemostasis favoring procoagulation and impairing anticoagulation. The biochemical effects of the selective estrogen receptor modulators (SERMs) were distinct from those of estrogen and differed only subtly from each other.     

A randomized controlled trial of risperidone in the treatment of aggression in hospitalized adolescents with subaverage cognitive abilities

BACKGROUND: Risperidone is an atypical antipsychotic drug that blocks dopamine as well as serotonin receptor systems. The present study was designed to examine the efficacy and safety of risperidone in a 6-week double-blind, randomized, parallel-group design in the treatment of aggression in adolescents with a primary diagnosis of DSM-IV disruptive behavior disorders and with subaverage intelligence. METHOD: We randomly assigned 38 adolescents (33 boys; 10 subjects with slightly subaverage IQ, 14 with borderline IQ, and 14 with mild mental retardation), who were hospitalized for treatment of psychiatric disorders associated with severe aggression, to receive risperidone or placebo. The main efficacy measures were the Clinical Global Impressions-Severity of Illness scale (CGI-S), the modified Overt Aggression Scale (OAS-M), and the Aberrant Behavior Checklist (ABC). Side effects were measured using the Extrapyramidal Symptom Rating Scale (ESRS). RESULTS: The mean daily dose of risperidone at the end of treatment was 2.9 mg (range, 1.5-4 mg). Risperidone, compared with placebo, was associated with significant improvements on the CGI-S (p < .001) and the at-school ABC overall and hyperactivity scales (p < .05). During a 2-week washout following the 6-week trial, a statistically significant worsening was found in the risperidone group on the CGI-S scale, the OAS-M. and the ABC. Extrapyramidal symptoms were absent or very mild during risperidone treatment. Transient tiredness was present in 11 (58%) of 19 drug-treated subjects. Other untoward effects included sialorrhea, nausea, and slight weight gain (mean = 3.5% of body weight in the risperidone group). No clinically relevant changes were found in laboratory parameters, electrocardiogram, heart rate, or blood pressure. CONCLUSION: These results suggest that risperidone may be effective for severe aggression in adolescents with disruptive behavior disorders and subaverage intelligence, and these results are consistent with reports suggesting its effectiveness for treating severe aggression in adolescents in general.     

A double-blind study of paliperidone palmitate and risperidone long-acting injectable in adults with schizophrenia

This 13-week double-blind study was designed to assess noninferiority of the recently approved (in the U.S.) injectable atypical antipsychotic paliperidone palmitate (PP) versus risperidone long-acting injectable (RIS-LAI) in adult patients with schizophrenia. Patients (N = 1220) were randomized (1:1) to either a) PP: deltoid injections on day 1 (150 mg eq.), day 8 (100 mg eq.), and once-monthly flexible dosing as deltoid or gluteal injections on day 36 (50 mg eq. or 100 mg eq.) and day 64 (50 mg eq. or 100 mg eq. or 150 mg eq.) or b) RIS-LAI: gluteal injections days 8 and 22 (25 mg), days 36, 50 (25 or 37.5 mg) and days 64, 78 (25, 37.5 or 50 mg). RIS-LAI-treated patients received oral supplementation with RIS 1-6 mg/day (days 1 to 28), and PP-treated patients received oral placebo. The safety analysis set (n = 1214) included 58% men, 78% white, with mean (SD) baseline PANSS total score: PP, 84.1 (12.09); and RIS-LAI, 83.6 (11.28). Mean (SD) change from baseline to endpoint in PANSS total score decreased similarly in both groups; PP (−18.6 [15.45]) and RIS-LAI (−17.9 [14.24]). PP treatment was noninferior to RIS-LAI (point estimate [95% CI]: 0.4 [−1.62;2.38], per-protocol analysis set [primary analysis]). The tolerability and safety of PP was generally similar to RIS-LAI with no new safety or tolerability findings.     

Effects of risperidone and paliperidone pre-treatment on locomotor response following prenatal immune activation

Aim

Limited data are available regarding pharmacological characteristics of effective interventions for psychosis prevention. Enrollment challenges in psychosis prevention trials impede screening diverse interventions for efficacy. Relevant animal models could help circumvent this barrier. We previously described prevention with risperidone of abnormal behavior following neonatal hippocampal lesion. We aimed to extend those findings evaluating risperidone and paliperidone following prenatal immune activation, a developmental model of a schizophrenia risk factor. We evaluated a later developmental time point to determine persistent effects of drug treatment.

Methods

Pregnant Sprague-Dawley rats were injected with poly I:C or saline on gestational day 14. Offspring of poly I:C and saline-treated dams received risperidone (0.45 mg/kg/d), paliperidone (0.05 mg/kg/d), or vehicle from postnatal days 35-70. Locomotor responses to novelty, saline injection, and amphetamine (1 and 5 mg/kg) were determined at three months, i.e., 21 days following antipsychotic discontinuation.

Results

Risperidone and paliperidone had persistent effects on behavioral response to amphetamine (1 mg/kg) at 3 months, ameliorating the impact of prenatal immune activation on offspring of poly I:C-treated dams. Risperidone, but not paliperidone, also exerted persistent effects in offspring of saline-treated dams on locomotor response to saline and amphetamine (5 mg/kg) injection.

Conclusions

Risperidone and paliperidone pre-treatment of poly I:C offspring during peri-pubertal development stabilized response to amphetamine exposure persisting into early adulthood. Prenatal immune activation provides a model for evaluating effects of an environmental risk factor for schizophrenia, and has potential utility for identifying pharmacological approaches to early intervention.     

Safety and tolerability of oral paliperidone extended-release tablets in elderly patients with schizophrenia: a double-blind, placebo-controlled study with six-month open-label extension.

OBJECTIVE: The objective of this multicenter, international study was to evaluate safety and tolerability of paliperidone extended-release (ER) tablets in elderly (age > or =65 years) patients with schizophrenia. The authors conducted a 6-week, double-blind, randomized, placebo-controlled, optional 24-week open-label extension study. Interventions consisted of flexible, once-daily doses of paliperidone ER (3-12 mg/day; 6-mg starting dose, adjusted in 3-mg dose increments) or placebo (2:1) during double-blind treatment and paliperidone ER only during open-label treatment. Measurements included adverse events, laboratory tests, physical examinations, 12-lead electrocardiograms, movement disorder rating scales, Positive and Negative Syndrome Scale, and Clinical Global Impression scale. The study was not powered to show statistical differences. RESULTS: Patients (N = 114) were predominantly female (73%); mean age was 70 years (double-blind phase). Concomitant disease presence was consistent with that of an older population. During the double-blind phase, discontinuation rates resulting from adverse events were similar between groups (paliperidone ER: 7%, placebo: 8%) as were incidences of treatment-emergent adverse events (paliperidone ER: 67%, placebo: 71%). Serious adverse events occurred in 3% of the paliperidone ER- and 8% of the placebo-treated patients. Elevated prolactin levels occurred in approximately one half of patients. No prolactin- or glucose treatment-related adverse events or noteworthy mean changes in body weight (0 kg [standard deviation: 2.1] and 0 kg [standard deviation: 2.3] for paliperidone ER and placebo, respectively) were observed. Safety and tolerability results in the extension were consistent with the shorter-term results. Efficacy measures did not show consistent statistical improvement between treatment groups. CONCLUSION: Paliperidone ER (3-12 mg/day) treatment over a 30-week period was generally well-tolerated and may improve symptom severity in elderly patients with schizophrenia.     

Effects of treatment cessation and re-treatment in randomized controlled trials of prucalopride in patients with chronic idiopathic constipation

Background

Prucalopride is a selective, high-affinity serotonin type 4 receptor agonist approved for the treatment of chronic idiopathic constipation (CIC) in adults. We investigated the impact of prucalopride cessation and re-treatment on efficacy and safety.

Methods

Data were from two randomized controlled trials in adults with CIC. In a dose-finding trial, complete spontaneous bowel movements (CSBMs) and treatment-emergent adverse events (TEAEs) were assessed during a 4-week run-out period after a 4-week treatment period (TP; prucalopride 0.5–4 mg once daily or placebo). In a re-treatment trial, CSBMs and TEAEs were assessed during two 4-week TPs (prucalopride 4 mg once daily or placebo) separated by a 2- or 4-week washout period.

Key Results

In the dose-finding trial (N = 234; 43–48 patients/group), mean CSBMs/week and the proportion of responders (≥3 CSBMs/week) were higher with prucalopride than placebo during the TP, but similar in all groups 1–4 weeks after treatment cessation. TEAEs were less frequent following treatment cessation. In the re-treatment trial (efficacy analyses: prucalopride, n = 189; placebo, n = 205), the proportion of responders was similar in both TPs and significantly higher (p ≤ 0.001) with prucalopride (TP1, 38.6%; TP2, 36.0%) than placebo (TP1, 10.7%; TP2, 11.2%). Most patients who responded to prucalopride in TP1 responded again in TP2 (71.2%). TEAEs were less frequent in TP2 than TP1.

Conclusions and Inferences

Prucalopride cessation resulted in a loss of clinical effect to baseline levels within 7 days. Similar efficacy and safety were observed between TP1 and TP2 after prucalopride was re-initiated following a washout period.