scholarly journals 145 Incidence and Characteristics of Akathisia and Restlessness During Cariprazine Treatment for Bipolar I Disorder

CNS Spectrums ◽  
2020 ◽  
Vol 25 (2) ◽  
pp. 292-292
Author(s):  
Leslie Citrome ◽  
Lakshmi N. Yatham ◽  
Mehul Patel ◽  
Willie R. Earley
Keyword(s):  
Adverse Events ◽  
Bipolar Depression ◽  
Partial Agonist ◽  
Fixed Dose ◽  
Double Blind ◽  
Study Objective ◽  
Bipolar I Disorder ◽  
Bipolar Mania ◽  
Post Hoc ◽  
Depressive Episodes

Abstract:Study Objective:Akathisia and restlessness are common adverse events associated with atypical antipsychotic use; in severe cases, symptoms may lead to treatment discontinuation. Cariprazine, a dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors, is approved for the treatment of schizophrenia (1.5–6 mg/d), and manic or mixed (3–6 mg/d) and depressive episodes (1.5–3 mg/d) associated with bipolar I disorder. Pooled post hoc analyses were conducted to characterize the incidence and severity of cariprazine-related akathisia and restlessness in patients who participated in bipolar disorder studies.Method:All studies were Phase II/III multicenter, randomized, double-blind, placebo-controlled, parallel-group studies in patients with bipolar I disorder who were currently experiencing a manic/mixed (NCT00488618, NCT01058096, NCT01058668) or depressive (NCT01396447, NCT02670538, NCT02670551) mood episode. Patients received flexibly dosed cariprazine 3-12 mg/d (day 1: 1.5 mg; day 2: 3 mg; subsequent up-titration in 3-mg increments if needed) or placebo in the bipolar mania studies and fixed-dose cariprazine 1.5 mg/d, 3 mg/d (slow titration to 1.5 mg [day 8] and 3 mg [day 15] or initiation at 1.5 mg with escalation to 3 mg on day 15), or placebo in the bipolar depression studies. The incidence, severity, and timing of treatment-emergent adverse events (TEAEs) of akathisia and restlessness were evaluated in this analysis.Results:In the bipolar mania studies (N=1065), TEAEs of akathisia occurred in 20.2% of cariprazine-treated patients and 4.8% of placebo-treated patients; 2.4% of cariprazine-treated patients discontinued due to akathisia. TEAEs of restlessness occurred in 6.7% and 2.3% of cariprazine- and placebo-treated patients, respectively, and caused discontinuation of 0.3% of cariprazine-treated patients. In the bipolar depression studies (N=1407), akathisia occurred in 2.1%, 5.5%, and 9.6% of patients in the placebo, cariprazine 1.5 mg/d, and cariprazine 3 mg/d groups, respectively; <2% of patients in each group discontinued due to akathisia. Restlessness occurred in 3.2% of placebo-treated patients and 2.1% and 6.6% of patients in the 1.5 and 3 mg/d groups, respectively; discontinuations due to restlessness occurred in 0.2% and 1.1% of patients in the 1.5 and 3 mg/d groups. Akathisia and restlessness in cariprazine-treated patients was generally mild or moderate in severity (>92% in both populations). Most akathisia events in the bipolar mania studies were reported for the first time within the first 2-3 weeks of treatment.Conclusions:In these post hoc analyses, the incidence of akathisia and restlessness were generally higher with cariprazine than with placebo. However, most incidences were mild or moderate in severity, and infrequently led to discontinuation. Akathisia appears to be dose related in both mania and depression, suggesting lower doses and slower titration may reduce occurrence.Funding Acknowledgements:Allergan plc.

scholarly journals 156 The Broad Efficacy of Cariprazine Across Symptoms in Patients with Bipolar I Disorder: Post Hoc Analysis of Randomized, Placebo-Controlled Trials

CNS Spectrums ◽  
2020 ◽  
Vol 25 (2) ◽  
pp. 300-300
Author(s):  
Lakshmi N. Yatham ◽  
Eduard Vieta ◽  
Roger S. McIntyre ◽  
Rakesh Jain ◽  
Willie R. Earley ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Depressive Symptoms ◽  
Rating Scale ◽  
Bipolar Depression ◽  
Partial Agonist ◽  
Controlled Trials ◽  
Bipolar I Disorder ◽  
Manic Symptoms ◽  
Bipolar Mania ◽  
Post Hoc

Abstract:Study Objective:Patients with bipolar disorder experience a wide range of depressive and manic symptoms. Only 2 drugs are FDA-approved to treat episodes of both mania and depression in patients with bipolar disorder, highlighting the need for treatments with proven efficacy at opposite poles of the bipolar spectrum. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, is approved in the US for the treatment of both bipolar depression and manic and mixed episodes associated with bipolar I disorder. Cariprazine has previously demonstrated broad efficacy in patients with bipolar mania, with significantly greater improvement in favor of cariprazine vs placebo (PBO) across all individual symptom domains (P<.001) measured by the Young Mania Rating Scale (YMRS). Additionally, cariprazine has demonstrated efficacy vs PBO in 3 phase II/III clinical studies in patients with depressive episodes associated with bipolar I disorder (NCT01396447, NCT02670538, NCT02670551). To further assess the broad efficacy of cariprazine in patients with bipolar I disorder, we performed post hoc analyses to evaluate the range of depressive symptoms comprising the individual items of the Montgomery-Åsberg Depression Rating Scale (MADRS) in patients from the bipolar depression studies.Methods:Data from the 3 randomized, double-blind, PBO-controlled trials in patients with bipolar depression were pooled. Least squares (LS) mean change from baseline to week 6 in MADRS individual items was assessed in the pooled cariprazine 1.5 and 3 mg/d groups vs PBO using a mixed-effects model for repeated measures in the intent-to-treat (ITT) population.Results:There were 1383 patients in the ITT population (placebo=460; cariprazine 1.5-3 mg/d=923). At week 6, LS mean change from baseline was significantly greater for cariprazine 1.5-3 mg/d vs PBO on 9 of 10 individual MADRS items: Apparent Sadness (-2.0 vs -1.6, P<.0001); Reported Sadness (-2.0 vs -1.6, P<.0001); Reduced Sleep (-1.6 vs -1.4, P=.0357); Reduced Appetite (-1.2 vs -1.0, P=.0001); Concentration Difficulties (-1.5 vs -1.2, P=.0002); Lassitude (-1.7 vs -1.4, P=.0003); Inability To Feel (-1.7 vs -1.5, P=.0009); Pessimistic Thoughts (-1.4 vs -1.2, P=.0054) and Suicidal Thoughts (-0.3 vs -0.2, P=.0383); differences between cariprazine and PBO on the Inner Tension item were not significant.Conclusions:Significant improvement in most MADRS single items suggests broad efficacy in depressive symptoms for cariprazine 1.5-3 mg/d vs PBO in patients with bipolar depression. Coupled with broad efficacy in manic symptoms as demonstrated by significant improvement in all YMRS individual items in patients with bipolar mania or mixed episodes, cariprazine appears be effective across the range of symptoms that affect patients with bipolar disorder.Funding Acknowledgements:Supported by Allergan plc.

scholarly journals Cariprazine in the Treatment of Bipolar Disorder: Within and Beyond Clinical Trials

2021 ◽  
Vol 12 ◽  
Author(s):  
André Do ◽  
Kamyar Keramatian ◽  
Ayal Schaffer ◽  
Lakshmi Yatham
Keyword(s):  
Bipolar Disorder ◽  
Clinical Trials ◽  
Psychosocial Functioning ◽  
Bipolar Depression ◽  
Partial Agonist ◽  
Current Evidence ◽  
Tolerability Profile ◽  
Significant Impairment ◽  
Post Hoc ◽  
Depressive Episodes

Bipolar disorder (BD) is chronic psychiatric disorder associated with significant impairment in psychosocial functioning and quality of life. Although current pharmacological treatments for BD have improved its clinical management, many patients do not achieve remission, particularly those suffering from bipolar depression. In addition, available treatments are associated with a myriad of potential adverse effects, which highlights the need for novel therapeutic agents that can be effective for both phases of the illness with a reduced side effect burden. Cariprazine is a novel antipsychotic that is a dopamine D2/D3 partial agonist with a preference for D3 receptors. In this review, we examine the pharmacological properties, clinical efficacy and tolerability profile of cariprazine in patients with BD, taking into account the latest clinical trials data. We also review post hoc analyses addressing clinically relevant subgroups and symptom domains in BD. Current evidence suggests efficacy for cariprazine 3–12 mg/day in the treatment of acute manic and mixed episodes; for bipolar depression, the efficacy of cariprazine appears to be dose-related, with doses of 1.5–3 mg/day beneficial as monotherapy. Cariprazine is overall well-tolerated by patients in both manic and depressive episodes. Its most common side effects relative to placebo include akathisia, extrapyramidal symptoms and nausea. There are no metabolic concerns reported with cariprazine use. In summary, the latest evidence suggests that cariprazine is an effective and safe treatment option for BD.

scholarly journals Aripiprazole monotherapy in acute mania: 12-week randomised placebo- and haloperidol-controlled study

2009 ◽  
Vol 194 (1) ◽  
pp. 40-48 ◽  
Author(s):  
Allan H. Young ◽  
Dan A. Oren ◽  
Adam Lowy ◽  
Robert D. McQuade ◽  
Ronald N. Marcus ◽  
...  
Keyword(s):  
Adverse Events ◽  
Rating Scale ◽  
Trial Registration ◽  
Acute Mania ◽  
Controlled Study ◽  
Young Mania ◽  
Double Blind ◽  
Bipolar I Disorder ◽  
Scale Total Score ◽  
Bipolar Mania

BackgroundWell-tolerated and effective therapies for bipolar mania are required.AimsTo evaluate the efficacy and tolerability of aripiprazole as acute and maintenance of effect therapy in patients with bipolar I disorder experiencing manic or mixed episodes.MethodPatients were randomised to double-blind aripiprazole (15 or 30 mg/day; n=167) placebo (n=153) or haloperidol (5–15 mg/day, n=165) for 3 weeks (trial registration NCT00097266). Aripiprazole- and haloperidol-treated patients remained on masked treatment for 9 additional weeks.ResultsMean change in Young Mania Rating Scale Total score (primary end-point) at week 3 was significantly greater with aripiprazole (–12.0; P<0.05) and haloperidol (–12.8; P<0.01) than with placebo (–9.7). Improvements were maintained to week 12 for aripiprazole (–17.2) and haloperidol (–17.8). Aripiprazole was well tolerated. Extrapyramidal adverse events were more frequent with haloperidol than aripiprazole (53.3% v. 23.5%).ConclusionsClinical improvements with aripiprazole were sustained to week 12. Aripiprazole was generally well tolerated.

scholarly journals Treatment of bipolar depression with supraphysiologic doses of levothyroxine: a randomized, placebo-controlled study of comorbid anxiety symptoms

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Maximilian Pilhatsch ◽  
Thomas J Stamm ◽  
Petra Stahl ◽  
Ute Lewitzka ◽  
Anne Berghöfer ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Rating Scale ◽  
Bipolar Depression ◽  
Phenotypic Expression ◽  
Anxiety Symptoms ◽  
Controlled Study ◽  
Double Blind ◽  
Comorbid Anxiety ◽  
Depressed Patients ◽  
Depressive Episodes

Abstract Background Symptoms of anxiety co-occur in a variety of disorders including in depressive episodes of bipolar disorder and in patients with thyrotoxicosis. Treatment of refractory bipolar disorder with supraphysiologic doses of levothyroxine (L-T4) has been shown to improve the phenotypic expression of the disorder and is associated with an increase of circulating thyroid hormones. However, it might be associated with somatic and mental adverse effects. Here we report the investigation of the influence of treatment with supraphysiologic doses of L-T4 on symptoms of anxiety in patients with refractory bipolar depression. Methods Post-hoc analysis from a 6-week, multi-center, randomized, double-blind, placebo-controlled study of the effects of supraphysiologic L-T4 treatment on anxiety symptoms in bipolar depression. Anxiety symptoms were measured weekly with the Hamilton anxiety/somatization factor (HASF) score of the Hamilton Depression Rating Scale (HAMD) and the State- and Trait Anxiety Inventory (STAI). Results Treatment of both groups was associated with a significant reduction in anxiety symptoms (p < 0.001) with no statistical difference between groups (LT-4: from 5.9 (SD = 2.0) at baseline to 3.7 (SD = 2.4) at study end; placebo: from 6.1 (SD = 2.4) at baseline to 4.4 (SD = 2.8) at study end; p = 0.717). Severity of anxiety at baseline did not show a statistically significant correlation to the antidepressive effect of treatment with supraphysiologic doses of L-T4 (p = 0.811). Gender did not show an influence on the reduction of anxiety symptoms (females: from 5.6 (SD = 1.7) at baseline to 3.5 (SD = 2.4) at study end; males: from 6.1 (SD = 2.3) at baseline to 4.0 (SD = 2.4) at study end; p = 0.877). Conclusions This study failed to detect a difference in change of anxiety between bipolar depressed patients treated with supraphysiologic doses of L-T4 or placebo. Comorbid anxiety symptoms should not be considered a limitation for the administration of supraphysiologic doses of L-T4 refractory bipolar depressed patients. Trial registration ClinicalTrials, ClinicalTrials.gov identifier: NCT01528839. Registered 2 June 2012—Retrospectively registered, https://clinicaltrials.gov/ct2/show/study/NCT01528839

Pharmacological Treatment of Osteoporosis in Elderly People: A Systematic Review and Meta-Analysis

Gerontology ◽  
2021 ◽  
pp. 1-11
Author(s):  
Qin-Yi Wang ◽  
Na Ding ◽  
Yi-He Dong ◽  
Zhang-Xin Wen ◽  
Rong Chen ◽  
...  
Keyword(s):  
Adverse Events ◽  
Elderly Patients ◽  
Meta Analysis ◽  
Controlled Trials ◽  
Cochrane Central Register ◽  
Anabolic Agents ◽  
Double Blind ◽  
Antiresorptive Agents ◽  
Statistical Heterogeneity ◽  
Post Hoc

<b><i>Background:</i></b> The evidence supporting the use of antiresorptive and anabolic agents for fracture prevention in elderly patients is still inconclusive. Whether it is too late to alter the course of the disease in this age-group has remained uncertain. <b><i>Objectives:</i></b> The objective of this study was to determine the efficacy and safety of antiresorptive and anabolic agents in elderly patients. <b><i>Methods:</i></b> PubMed, Web of Science, MEDLINE, and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) and post hoc analyses of RCTs reporting efficacy outcomes or adverse events of antiresorptive and anabolic agents in elderly patients. Statistical heterogeneity was assessed with the Cochran <i>Q</i> χ<sup>2</sup> test and <i>I</i><sup>2</sup> statistic. All results were expressed as relative risk (RR) with 95% confidence intervals (CIs). <b><i>Results:</i></b> The meta-analysis included 1 RCT and 11 post hoc analyses of data from 10 double-blind placebo-controlled RCTs. Antiresorptive therapy significantly reduced the pooled incidence of vertebral fractures (RR = 0.43; 95% CI = 0.35–0.53; and <i>p</i> &#x3c; 0.001). It was also associated with lower risk of nonvertebral and hip fractures (RR = 0.84; 95% CI = 0.74–0.96; and <i>p</i> = 0.009 and RR = 0.75; 95% CI = 0.58–0.97; and <i>p</i> = 0.028, respectively). For any adverse events, no difference was observed between antiresorptive agents and placebo groups (RR = 1.01; 95% CI = 1.00–1.02; and <i>p</i> = 0.23). <b><i>Conclusions:</i></b> Both antiresorptive and anabolic agents represented potentially important osteoporosis treatments, showing significant effects on reducing vertebral, nonvertebral, or hip fracture risk, and were well-tolerated by elderly patients. Even in the elderly, maybe it is not too late to alter the course of the disease.

scholarly journals 170 Efficacy and Safety of Dasotraline in Adults with Binge-Eating Disorder: A Randomized, Double-blind, Fixed-dose Trial

CNS Spectrums ◽  
2020 ◽  
Vol 25 (2) ◽  
pp. 308-309
Author(s):  
Joyce Tsai ◽  
Brad Navia ◽  
Susan L McElroy ◽  
James I Hudson ◽  
Carlos M. Grilo ◽  
...  
Keyword(s):  
Eating Disorder ◽  
Adverse Events ◽  
Binge Eating ◽  
Binge Eating Disorder ◽  
Dry Mouth ◽  
Fixed Dose ◽  
Type I ◽  
Efficacy And Safety ◽  
Double Blind ◽  
Dose Study

Abstract:Background:Dasotraline is a long-acting dopamine/norepinephrine reuptake inhibitor with a PK profile characterized by slow absorption and a t½ of 47-77 hours, permitting once-daily dosing. In a previous flexible dose study, dasotraline demonstrated significant efficacy in the treatment of binge-eating disorder (BED). The aim of this confirmatory fixed-dose study was to evaluate efficacy and safety of dasotraline in the treatment of patients with BED.Methods:Patients meeting DSM-5 criteria for BED were randomized to 12 weeks of double-blind treatment with dasotraline (4 mg/d or 6 mg/d), or placebo. The primary efficacy endpoint was change in number of binge-eating days per week at week 12. Secondary efficacy endpoints included changes at Week 12 on the Binge Eating Clinical Global Impression of Severity Scale (BE-CGI-S), the Yale-Brown Obsessive-Compulsive Scale Modified for Binge Eating (Y-BOCS-BE), and the proportion of patients with 100% cessation of binge-eating episodes during the final 4 weeks of treatment. Efficacy was assessed using an MMRM analysis (and a logistic regression model for cessation) with a pre-specified sequential testing procedure used to control overall type I error rate.Results:A total of 486 were in the ITT population (dasotraline 6 mg/d (N=162), 4 mg/d (N=161), or placebo (N=163). At week 12, treatment with dasotraline was associated with significant reduction in number of binge-eating days per week in the 6 mg/d group vs. placebo (-3.5 vs. -2.9; P=0.0045), but non-significant improvement in the 4 mg/d group vs. placebo (-3.2; P=0.12). Greater improvement was observed vs. placebo for dasotraline 6 mg/d and 4 mg/d, respectively, on the BE-CGI-S (P<0.01 and P<0.03) and the Y-BOC-BE (P<0.001 and P<0.02; all P-values were nominal, not adjusted for multiplicity). The proportion of patients who achieved 4-week cessation of binge-eating episodes was only significant for the dasotraline 6 mg in the completer population (P<0.05; post-hoc analysis) but was not significant for either dose of dasotraline vs. placebo when drop-outs were included in the analysis. The most common adverse events on dasotraline 6 mg/d and 4 mg/d were combined insomnia (early, middle, late), dry mouth, headache, decreased appetite, nausea, and anxiety. Changes in systolic and diastolic blood pressure were minimal. Mean baseline to endpoint changes in supine pulse rate on dasotraline 6 mg/d and 4 mg/d vs. placebo was +6.2 bpm and +4.8 vs. +0.2 bpm.Conclusions:In this 12-week, placebo-controlled, fixed-dose study, treatment with dasotraline 6 mg/d was associated with a significant reduction in frequency of binge-eating days per week; efficacy was not demonstrated for the 4 mg dose. Treatment with both doses of dasotraline resulted in improvement in the Y-BOCS-BE and the BE-CGI-S. Dasotraline was safe and generally well-tolerated at both doses; most common adverse events were insomnia, dry mouth and headache.Clinicaltrials.gov: NCT03107026Funding Acknowledgements:Supported by funding from Sunovion Pharmaceuticals Inc.

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