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Eduard Vieta - One of the best experts on this subject based on the ideXlab platform.

  • two randomized double blind placebo controlled trials and one open label long term trial of brexpiprazole for the acute treatment of Bipolar Mania
    Journal of Psychopharmacology, 2021
    Co-Authors: Eduard Vieta, Gary S Sachs, Denise Chang, Johan Hellsten, Claudette Brewer, Timothy Petersstrickland, Nanco Hefting
    Abstract:

    Background:Brexpiprazole is a dopamine/serotonin receptor partial agonist (D2, 5-HT1A) and antagonist (5-HT2A) approved for treatment of schizophrenia and major depressive disorder (adjunct to anti...

  • a network meta analysis on comparative efficacy and all cause discontinuation of antimanic treatments in acute Bipolar Mania
    Psychological Medicine, 2015
    Co-Authors: Aysegul Yildiz, Eduard Vieta, Christoph U. Correll, M Nikodem, Ross J Baldessarini
    Abstract:

    Background Evidence synthesis methods enabling direct and indirect comparisons over the entire set of relevant clinical data produce quantitative point estimates for the treatments contrasts between competing interventions, and provide a hierarchical rank ordering between them. We aimed to provide evidence-based guidance on the efficacy and all-cause discontinuation of antimanic treatments. Method We conducted a network meta-analysis within a Bayesian framework. We searched all standard literature databases without language restrictions up to 15 January 2014 to identify reports of short-term, randomized, blinded trials of putative antimanic drugs as monotherapy for adults with Bipolar-I Mania. Results Altogether, 14256 manic patients randomized to one of 18 active treatments or placebo provided 95 direct comparisons on 128 data points. For the primary outcome, standardized mean difference as Hedges’ g (standardized mean difference; SMD), the hierarchies indicated by surface under the cumulative ranking (SUCRA) probabilities were in agreement with the point estimates for all antimanic drugs identified as effective. For the 12 effective antimanic drugs on clinical use, SMDs against placebo ranged from 0.32 to 0.66 without superiority of one over another, except for risperidone v . aripiprazole and valproate. Aripiprazole, olanzapine, quetiapine, risperidone, and valproate had less all-cause discontinuation rates than placebo. Sensitivity analysis by drug class indicated similar efficacy profiles for haloperidol, second-generation antipsychotics, and mood stabilizers. Conclusions Hierarchical rank ordering by comparative efficacy and risk of all-cause discontinuations should help to guide antimanic treatment choices by clinicians, healthcare policy makers, and guideline developers.

  • factors modifying drug and placebo responses in randomized trials for Bipolar Mania
    The International Journal of Neuropsychopharmacology, 2011
    Co-Authors: Aysegul Yildiz, Mauricio Tohen, Eduard Vieta, Ross J Baldessarini
    Abstract:

    Randomized placebo-controlled trials (RCTs) are standard for assessing efficacy and safety of treatments. We pursued preliminary indications that some factors are associated differentially with responses to placebo or drugs in RCTs for Bipolar Mania. We meta-analysed data from RCTs to assess influences of study-site count, subjects' age, sex distribution, diagnostic subgroups, clinical features, trial-completion rates, and publication year on mean difference (MD) in Mania ratings between intake and final assessments. In 38 RCTs involving 3812 placebo-treated and 6988 drug-treated patients, symptomatic improvement was similar in placebo arms of trials of effective (6.77, 95% CI 5.77-7.76) and ineffective (7.61, 95% CI 5.47-8.75) drugs. Lesser placebo responses (MD) and greater drug-placebo differences (Hedges' g) were associated with fewer study sites, younger patients' age, and male sex. More patients with initial psychotic features and more trial completion in drug arms were associated with greater drug-associated improvement (MD) and drug-placebo contrast (Hedges' g), whereas more mixed-state diagnoses decreased both measures. Identifying modifying factors can support more efficient and cost-effective designs of therapeutic trials. In trials for Mania, fewer sites may limit placebo response and enhance drug-placebo contrasts.

  • factors modifying drug and placebo responses in randomized trials for Bipolar Mania
    The International Journal of Neuropsychopharmacology, 2011
    Co-Authors: Aysegul Yildiz, Mauricio Tohen, Eduard Vieta, Ross J Baldessarini
    Abstract:

    Randomized placebo-controlled trials (RCTs) are standard for assessing efficacy and safety of treatments. We pursued preliminary indications that some factors are associated differentially with responses to placebo or drugs in RCTs for Bipolar Mania. We meta-analysed data from RCTs to assess influences of study-site count, subjects’ age, sex distribution, diagnostic subgroups, clinical features, trial-completion rates, and publication year on mean difference (MD) in Mania ratings between intake and final assessments. In 38 RCTs involving 3812 placebo-treated and 6988 drug-treated patients, symptomatic improvement was similar in placebo arms of trials of effective (6.77, 95 % CI 5.77–7.76) and ineffective (7.61, 95 % CI 5.47–8.75) drugs. Lesser placebo responses (MD) and greater drug–placebo differences (Hedges’ g) were associated with fewer study sites, younger patients ’ age, and male sex. More patients with initial psychotic features and more trial completion in drug arms were associated with greater drugassociated improvement (MD) and drug–placebo contrast (Hedges’ g), whereas more mixed-state diagnoses decreased both measures. Identifying modifying factors can support more efficient and cost-effective designs of therapeutic trials. In trials for Mania, fewer sites may limit placebo response and enhance drug–placebo contrasts. Received 21 October 2010 ; Reviewed 28 November 2010 ; Revised 4 December 2010 ; Accepted 14 December 2010

  • assessment of safety tolerability and effectiveness of adjunctive aripiprazole to lithium valproate in Bipolar Mania a 46 week open label extension following a 6 week double blind study
    Current Medical Research and Opinion, 2010
    Co-Authors: Eduard Vieta, Robert D Mcquade, Raymond Sanchez, Randall Owen, Christine Baudelet, Ronald N Marcus
    Abstract:

    AbstractObjective:This study evaluated the long-term tolerability and effectiveness of aripiprazole adjunctive to lithium or valproate in partial responders with Bipolar Mania.Methods:Completers of a 6-week double-blind comparison of adjunctive aripiprazole versus placebo in Bipolar Mania partially responsive to lithium or valproate monotherapy could enter a 46-week extension treatment with open-label adjunctive aripiprazole plus lithium (ARI + LI) or valproate (ARI + VAL). Safety, efficacy and functioning were assessed.Clinical trial registration:CN138-134LT: Study of Aripiprazole in Patients With Bipolar I Disorder; ID number: NCT00257972; registry: www.clinicaltrials.govResults:In total, 283 (ARI + LI n = 108; ARI + VAL n = 175) patients entered and 146 (ARI + LI n = 55; ARI + VAL n = 91) completed the 46-week, open-label extension. Frequently reported adverse events (AEs) that occurred with ARI + LI vs. ARI + VAL were: tremor (17.0% vs. 12.1%), akathisia (6.6% vs. 8.6%), headache (6.6% vs. 4.0%), inso...

Mauricio Tohen - One of the best experts on this subject based on the ideXlab platform.

  • Increased Activity or Energy as a Primary Criterion for the Diagnosis of Bipolar Mania in DSM-5: Findings From the STEP-BD Study.
    The American journal of psychiatry, 2016
    Co-Authors: Rodrigo Machado-vieira, David A. Luckenbaugh, Elizabeth D. Ballard, Ioline D. Henter, Mauricio Tohen, Trisha Suppes, Carlos A. Zarate
    Abstract:

    Objective:DSM-5 describes “a distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity or energy” as a primary criterion for Mania. Thus, increased energy or activity is now considered a core symptom of manic and hypomanic episodes. Using data from the Systematic Treatment Enhancement Program for Bipolar Disorder study, the authors analyzed point prevalence data obtained at the initial visit to assess the diagnostic validity of this new DSM-5 criterion. The study hypothesis was that the DSM-5 criterion would alter the prevalence of Mania and/or hypoMania.Method:The authors compared prevalence, clinical characteristics, validators, and outcome in patients meeting the DSM-5 criteria (i.e., DSM-IV criteria plus the DSM-5 criterion of increased activity or energy) and those who did not meet the new DSM-5 criterion (i.e., who only met DSM-IV criteria).Results:All 4,360 participants met DSM-IV criteria for Bipolar disorder, and 310 m...

  • safety and efficacy of olanzapine monotherapy and olanzapine with a mood stabilizer in 18 week treatment of manic mixed episodes for japanese patients with Bipolar i disorder
    Current Medical Research and Opinion, 2012
    Co-Authors: Hideaki Katagiri, Mauricio Tohen, Yasushi Takita, Teruhiko Higuchi, Shigenobu Kanba, Michihiro Takahashi
    Abstract:

    AbstractObjective:To assess the safety and efficacy of 18-week olanzapine monotherapy in Japanese patients with Bipolar Mania, following a 6-week, placebo- and haloperidol-controlled double-blind study (acute study). For those who discontinued the acute study due to lack of efficacy, safety and efficacy was assessed with a combination therapy of olanzapine and a mood stabilizer.Research design and methods:In this open-label, multicenter extension study, patients who completed the acute study received olanzapine (5–20 mg/day) as monotherapy, and patients who discontinued the acute study due to lack of efficacy with greater Young Mania Rating Scale (YMRS) total score than the acute study baseline, received olanzapine in combination with one of three mood stabilizers: lithium, carbamazepine, or valproate. Safety was assessed by treatment-emergent adverse events (TEAEs), vital signs, weight, and extrapyramidal symptoms (EPSs). Efficacy measures included YMRS total score, and response and remission rates of ma...

  • factors modifying drug and placebo responses in randomized trials for Bipolar Mania
    The International Journal of Neuropsychopharmacology, 2011
    Co-Authors: Aysegul Yildiz, Mauricio Tohen, Eduard Vieta, Ross J Baldessarini
    Abstract:

    Randomized placebo-controlled trials (RCTs) are standard for assessing efficacy and safety of treatments. We pursued preliminary indications that some factors are associated differentially with responses to placebo or drugs in RCTs for Bipolar Mania. We meta-analysed data from RCTs to assess influences of study-site count, subjects' age, sex distribution, diagnostic subgroups, clinical features, trial-completion rates, and publication year on mean difference (MD) in Mania ratings between intake and final assessments. In 38 RCTs involving 3812 placebo-treated and 6988 drug-treated patients, symptomatic improvement was similar in placebo arms of trials of effective (6.77, 95% CI 5.77-7.76) and ineffective (7.61, 95% CI 5.47-8.75) drugs. Lesser placebo responses (MD) and greater drug-placebo differences (Hedges' g) were associated with fewer study sites, younger patients' age, and male sex. More patients with initial psychotic features and more trial completion in drug arms were associated with greater drug-associated improvement (MD) and drug-placebo contrast (Hedges' g), whereas more mixed-state diagnoses decreased both measures. Identifying modifying factors can support more efficient and cost-effective designs of therapeutic trials. In trials for Mania, fewer sites may limit placebo response and enhance drug-placebo contrasts.

  • factors modifying drug and placebo responses in randomized trials for Bipolar Mania
    The International Journal of Neuropsychopharmacology, 2011
    Co-Authors: Aysegul Yildiz, Mauricio Tohen, Eduard Vieta, Ross J Baldessarini
    Abstract:

    Randomized placebo-controlled trials (RCTs) are standard for assessing efficacy and safety of treatments. We pursued preliminary indications that some factors are associated differentially with responses to placebo or drugs in RCTs for Bipolar Mania. We meta-analysed data from RCTs to assess influences of study-site count, subjects’ age, sex distribution, diagnostic subgroups, clinical features, trial-completion rates, and publication year on mean difference (MD) in Mania ratings between intake and final assessments. In 38 RCTs involving 3812 placebo-treated and 6988 drug-treated patients, symptomatic improvement was similar in placebo arms of trials of effective (6.77, 95 % CI 5.77–7.76) and ineffective (7.61, 95 % CI 5.47–8.75) drugs. Lesser placebo responses (MD) and greater drug–placebo differences (Hedges’ g) were associated with fewer study sites, younger patients ’ age, and male sex. More patients with initial psychotic features and more trial completion in drug arms were associated with greater drugassociated improvement (MD) and drug–placebo contrast (Hedges’ g), whereas more mixed-state diagnoses decreased both measures. Identifying modifying factors can support more efficient and cost-effective designs of therapeutic trials. In trials for Mania, fewer sites may limit placebo response and enhance drug–placebo contrasts. Received 21 October 2010 ; Reviewed 28 November 2010 ; Revised 4 December 2010 ; Accepted 14 December 2010

  • olanzapine monotherapy and olanzapine combination therapy in the treatment of Mania 12 week results from the european Mania in Bipolar longitudinal evaluation of medication emblem observational study
    Journal of Affective Disorders, 2008
    Co-Authors: Mauricio Tohen, Eduard Vieta, Francesco Panicali, Iris Goetz, Catherine Reed, Merce Comes
    Abstract:

    Background To evaluate the 12-week outcomes (effectiveness, tolerability, and patterns of medication use) of olanzapine (either in antimanic monotherapy or in combination with other antipsychotics, anticonvulsants, and/or lithium) in patients with Bipolar Mania or mixed Mania. Method EMBLEM (European Mania in Bipolar Longitudinal Evaluation of Medication) is a 24-month prospective observational study of in- and outpatients with acute Mania/mixed Mania conducted in 14 European countries. Primary outcome measures included Clinical Global Impressions–Bipolar Disorder scale (overall, Mania, and depression); 5-item Hamilton Depression Rating Scale; and Young Mania Rating Scale. Tolerability measures included a questionnaire to assess patients’ symptomatic complaints. Results Overall, 2004 patients received olanzapine (olanzapine monotherapy, n = 673; olanzapine combination, n = 1331). Concomitant therapy with antidepressants and/or anxiolytics was possible in both groups. The countries significantly differed in the use of olanzapine monotherapy versus olanzapine combination (p < .0001). Baseline-to-endpoint changes on the CGI-BP subscales, YMRS, and HAMD-5 were significant within both treatment groups (p < .0001). Olanzapine monotherapy was generally better tolerated than olanzapine combination, particularly with regard to sedation (12% vs 17%; p < .001), tremor (2% vs 5%; p < .001), and akathisia (3% vs 6%; p < .001). Discussion The acute-phase EMBLEM results suggest that in naturalistic settings, olanzapine (both as monotherapy and combination) may be effective in treating patients with Bipolar Mania. The use of olanzapine monotherapy or combination varies significantly across countries, but combination is generally the rule, rather than the exception.

Paul E Keck - One of the best experts on this subject based on the ideXlab platform.

  • aripiprazole monotherapy in the treatment of acute Bipolar i Mania a randomized double blind placebo and lithium controlled study
    Journal of Affective Disorders, 2009
    Co-Authors: Paul E Keck, Robert D Mcquade, Raymond Sanchez, Paul J Orsulak, Andrew J Cutler, Anne Torbeyns, R Marcus, William H Carson
    Abstract:

    Abstract Objectives To evaluate the efficacy and safety of aripiprazole as acute and maintenance of effect monotherapy for acute Bipolar Mania. Methods Patients with acute Bipolar I Mania (DSM-IV-TR: YMRS ≥ 20), manic or mixed (with or without psychotic features) were randomized to double-blind aripiprazole (15–30 mg/day; n  = 155), placebo ( n  = 165) or lithium (900–1500 mg/day; n  = 160) (1:1:1) for 3 weeks. Aripiprazole- and lithium-treated patients remained on blinded treatment for 9 additional weeks. The primary outcome was the mean change from baseline in YMRS Total score (LOCF) to Week 3. Secondary outcomes included the mean change from baseline in YMRS Total score (LOCF) at all other timepoints up to Week 12. Results Aripiprazole demonstrated significantly greater improvement than placebo in mean YMRS Total score from baseline to Day 2 (− 4.3 vs.− 2.8; p  = 0.003), and up to Week 3 (− 12.6 vs. − 9.0; p p  = 0.005). Improvements in YMRS Total score were maintained to Week 12 for aripiprazole (− 14.5) and lithium (− 12.7). Response rates at Week 3 were significantly higher with aripiprazole (46.8%) and lithium (45.8%) than placebo (34.4%; both p Conclusions Aripiprazole provided statistically significant improvement of acute Mania within 2 days, continuing over 3 weeks and sustained over 12 weeks. The magnitude of improvement to Week 12 was similar with aripiprazole and lithium.

  • aripiprazole monotherapy in the treatment of acute Bipolar i Mania a randomized double blind placebo and lithium controlled study
    Journal of Affective Disorders, 2009
    Co-Authors: Paul E Keck, Robert D Mcquade, Raymond Sanchez, Paul J Orsulak, Andrew J Cutler, Anne Torbeyns, R Marcus, William H Carson
    Abstract:

    Abstract Objectives To evaluate the efficacy and safety of aripiprazole as acute and maintenance of effect monotherapy for acute Bipolar Mania. Methods Patients with acute Bipolar I Mania (DSM-IV-TR: YMRS ≥ 20), manic or mixed (with or without psychotic features) were randomized to double-blind aripiprazole (15–30 mg/day; n = 155), placebo (n = 165) or lithium (900–1500 mg/day; n = 160) (1:1:1) for 3 weeks. Aripiprazole- and lithium-treated patients remained on blinded treatment for 9 additional weeks. The primary outcome was the mean change from baseline in YMRS Total score (LOCF) to Week 3. Secondary outcomes included the mean change from baseline in YMRS Total score (LOCF) at all other timepoints up to Week 12. Results Aripiprazole demonstrated significantly greater improvement than placebo in mean YMRS Total score from baseline to Day 2 (− 4.3 vs.− 2.8; p = 0.003), and up to Week 3 (− 12.6 vs. − 9.0; p  Conclusions Aripiprazole provided statistically significant improvement of acute Mania within 2 days, continuing over 3 weeks and sustained over 12 weeks. The magnitude of improvement to Week 12 was similar with aripiprazole and lithium.

  • atypical antipsychotics in the treatment of Mania a meta analysis of randomized placebo controlled trials
    The Journal of Clinical Psychiatry, 2006
    Co-Authors: Roy H Perlis, Jeffrey A Welge, Lana A Vornik, Robert M A Hirschfeld, Paul E Keck
    Abstract:

    Background Randomized, controlled trials have demonstrated efficacy for atypical antipsychotics in the treatment of Mania in Bipolar disorder, either as monotherapy or adjunctive treatment. However, there are no published comparisons of individual atypical antipsychotics for Mania. Data sources and study selection We conducted a systematic review and meta-analysis of randomized, placebo-controlled monotherapy and adjunctive therapy trials of atypical antipsychotics for acute Bipolar Mania. Studies published through 2004 were identified using searches of PubMed/MEDLINE with the search terms Mania, placebo, and each of the atypical antipsychotics, limited to randomized, controlled clinical trials; review of abstracts from the 2003 meetings of the American College of Neuropsychiatry, American Psychiatric Association, and International Conference on Bipolar Disorder; and consultations with study investigators and representatives of pharmaceutical companies that market atypical antipsychotics. Data extraction Analyses were performed on the changes in Young Mania Rating Scale or Mania Rating Scale total scores from baseline to endpoint, using last observation carried forward and computing the difference in change scores between each drug and its corresponding placebo arm. A random-effects model with fixed drug effects was used to combine the studies and make comparisons of the antipsychotics to each other and to placebo. Data synthesis Data from 12 placebo-controlled monotherapy and 6 placebo-controlled adjunctive therapy trials involving a total of 4304 subjects (including 1750 placebo-treated subjects) with Bipolar Mania were obtained. Aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone all demonstrated significant efficacy in monotherapy (i.e., all confidence intervals exclude zero). However, after adjusting for multiple comparisons, pairwise comparisons of individual effects identified no significant differences in efficacy among antipsychotics. Magnitude of improvement was similar whether the antipsychotic was utilized as monotherapy or adjunctive therapy. Conclusions The 5 newer atypical antipsychotics were all superior to placebo in the treatment of Bipolar Mania. For monotherapy and add-on therapy, cross-trial comparisons suggest that differences in acute efficacy between the drugs, if any, are likely to be small.

  • ziprasidone in acute Bipolar Mania a 21 day randomized double blind placebo controlled replication trial
    Journal of Clinical Psychopharmacology, 2005
    Co-Authors: Steven G Potkin, Paul E Keck, Kathleen Ice, Scott Segal, Patricia English
    Abstract:

    BACKGROUND In an earlier 21-day, placebo-controlled trial, ziprasidone was efficacious in improving symptoms of Mania and was well tolerated. To confirm these results, a similarly designed 21-day trial was conducted. METHODS Inpatients with Bipolar I disorder, manic or mixed, were randomized to ziprasidone (40 to 80 mg BID) or placebo. Efficacy rating scales were derived from the Schedule for Affective Disorders and Schizophrenia-Change Bipolar Scale (SADS-CB). SADS-CB-derived Mania Rating Scale (MRS) total score was the primary efficacy parameter. Secondary SADS-CB-derived efficacy parameters included Manic Syndrome and Behavior and Ideation Subscales, Hamilton Depression Rating Scale (HAM-D), and the Montgomery Asberg Depression Rating Scale (MADRS). The Clinical Global Impression-Severity Scale (CGI-S), the Global Assessment of Functioning (GAF), and the Positive and Negative Syndrome Scale (PANSS) were also assessed. RESULTS Sixty-five placebo and 137 ziprasidone patients were evaluable for efficacy. Baseline-to-endpoint mean changes in MRS scores were -11.1 for ziprasidone and -5.6 for placebo (all patients, last observation carried forward [LOCF]; P < 0.01). Ziprasidone produced significantly greater improvements in Manic Syndrome (P < or = 0.01) and Behavior and Ideation Subscales (P < or = 0.001), CGI-S score, (P < or = 0.001), PANSS Total (P < or = 0.01) and Positive Subscale (P < or = 0.001) scores, and GAF (P < or = 0.001). With ziprasidone, significant improvements were observed from Day 2 onward for MRS and CGI-S at all time points except Day 4 for MRS. Treatment-related discontinuations due to adverse events were 5.8% for ziprasidone and 1.5% for placebo (P = 0.20). CONCLUSIONS Ziprasidone was well tolerated, rapidly efficacious, and superior to placebo in improving symptoms and global illness severity in these inpatients with acute Bipolar Mania, both manic and mixed episodes.

  • a placebo controlled double blind study of the efficacy and safety of aripiprazole in patients with acute Bipolar Mania
    American Journal of Psychiatry, 2003
    Co-Authors: Paul E Keck, Ronald N Marcus, Stavros Tourkodimitris, Mirza Ali, Amy Liebeskind, A Saha, Gary Ingenito
    Abstract:

    Objective: The authors compared the efficacy and safety of aripiprazole, a novel antipsychotic, to placebo for treatment of patients in an acute manic or mixed episode of Bipolar disorder. Method: This 3-week, multicenter, double-blind study randomly assigned 262 Bipolar disorder patients in an acute manic or mixed episode to aripiprazole, 30 mg/ day (reduced to 15 mg/day if needed for tolerability), or placebo. Patients remained hospitalized for at least 2 of the weeks. The primary efficacy measure was mean change from baseline in total score on the Young Mania Rating Scale; response was defined as a decrease in score of ≥50%. Results: Aripiprazole produced statistically significant mean improvements in total score on the Young Mania Rating Scale compared with placebo (–8.2 versus –3.4, respectively) and produced a significantly higher response rate (40% versus 19%). For key efficacy variables (response per Young Mania Rating Scale; Clinical Global Impression—Bipolar Version scores for severity of illness [Mania] and change from preceding phase [Mania]), aripiprazole separated from placebo by day 4. The completion rate was significantly higher with aripiprazole than with placebo (42% versus 21%). Discontinuations due to adverse events did not differ significantly between the aripiprazole and placebo groups. There were no significant changes in body weight versus placebo, and aripiprazole was not associated with elevated serum prolactin or QTc prolongation. Conclusions: Aripiprazole had significantly greater efficacy than placebo for the treatment of Bipolar disorder patients in acute manic or mixed episodes and was safe and well tolerated in this randomized controlled trial.

Roger S. Mcintyre - One of the best experts on this subject based on the ideXlab platform.

  • Anxiety, irritability, and agitation as indicators of Bipolar Mania with depressive symptoms: a post hoc analysis of two clinical trials
    SpringerOpen, 2017
    Co-Authors: Trisha Suppes, Allan H Young, Jonas Eberhard, Ole Lemming, Roger S. Mcintyre
    Abstract:

    Abstract Background Symptoms of anxiety, irritability, and agitation (AIA) are prevalent among patients with Bipolar I disorder (BD-I) Mania with depressive symptoms, and could potentially be used to aid physicians in the identification of this more severe form of BD-I. Using data from two clinical trials, the aims of this post hoc analysis were to describe the phenomenology of Bipolar Mania in terms of AIA and depressive symptoms, and to evaluate the influence of these symptoms on the likelihood of remission during treatment. Methods Patients with a BD-I manic or mixed episode (Diagnostic and Statistical Manual of Mental Disorders IV criteria) were randomised to 3 weeks of double-blind treatment with asenapine, placebo, or olanzapine (active comparator). Anxiety was defined as a score of ≥3 on the Positive and Negative Syndrome Scale ‘anxiety’ item, irritability as a score of ≥4 on the Young Mania Rating Scale (YMRS) ‘irritability’ item, and agitation as a score of ≥3 on the YMRS ‘increased motor activity–energy’ item. Depressive symptoms were defined as a score of ≥1 on three or more individual Montgomery–Åsberg Depression Rating Scale (MADRS) items, or a MADRS Total score of ≥20. Results A total of 960 patients with BD-I were analysed, 665 with a manic episode and 295 with a mixed episode. At baseline, 61.4% had anxiety, 62.4% had irritability, 76.4% had agitation, and 34.0% had all three AIA symptoms (‘severe AIA’); 47.3% had three or more depressive symptoms, and 13.5% had a MADRS total score of ≥20. Anxiety, irritability, and severe AIA (but not agitation) were statistically significantly more common in patients with depressive symptoms. Patients with anxiety or severe AIA at baseline were statistically significantly less likely to achieve remission (YMRS total

  • mixed specifier for Bipolar Mania and depression highlights of dsm 5 changes and implications for diagnosis and treatment in primary care
    The Primary Care Companion To The Journal of Clinical Psychiatry, 2014
    Co-Authors: Jia Hu, Rodrigo B Mansur, Roger S. Mcintyre
    Abstract:

    Abstract Bipolar disorder, while commonly encountered in the primary care setting, is often misdiagnosed or undiagnosed. In the DSM-IV-TR, patients could be diagnosed as being in a mixed state only if they had concurrent manic and depressive symptoms; while this occurs in some patients, many more experience subsyndromal mixed symptoms that would disqualify a "mixed state" diagnosis. The recently released DSM-5 attempts to capture this large proportion of patients with subsyndromal mixed symptoms with the inclusion of the "mixed specifier." The presence of such subsyndromal mixed symptoms has significant implications for both diagnosis and treatment. For those presenting with major depressive disorder with subsyndromal manic symptoms, clinicians must be vigilant for the development of full-blown Bipolar disease. In treating this group, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors remain first-line therapy, but augmentation with other therapies is often required. If a diagnosis of Bipolar disorder is confirmed and the patient is experiencing a depressive phase, traditional antidepressants should be avoided. For those presenting with Mania and mixed depressive symptoms, treatment with a combination of atypical antipsychotics and mood stabilizers is best.

  • effects of lithium on oxidative stress and behavioral alterations induced by lisdexamfetamine dimesylate relevance as an animal model of Mania
    Progress in Neuro-psychopharmacology & Biological Psychiatry, 2013
    Co-Authors: Danielle Silveira Macedo, David Freitas De Lucena, Ana Isabelle De Gois Queiroz, Rafaela Carneiro Cordeiro, Maira Morais De Araujo, Francisca C F Sousa, Silvânia Maria Mendes Vasconcelos, Thomas Hyphantis, Joao Quevedo, Roger S. Mcintyre
    Abstract:

    Abstract Lisdexamfetamine dimesylate (LDX) is a prodrug that requires conversion to d -amphetamine ( d -AMPH) for bioactivity. Treatment with d -AMPH induces hyperlocomotion and is regarded as a putative animal model of Bipolar Mania. Therefore, we sought to determine the behavioral and oxidative stress alterations induced by sub-chronic LDX administration as well as their reversal and prevention by lithium in rats. A significant increment in locomotor behavior was induced by LDX (10 and 30 mg/kg). To determine Li effects against LDX-induced alterations, in the reversal protocol rats received LDX (10 or 30 mg/kg) or saline for 14 days. Between days 8 and 14 animals received Li (47.5 mg/kg, i.p.) or saline. In the prevention paradigm, rats were pretreated with Li or saline prior to LDX administration. Glutathione (GSH) levels and lipid peroxidation was determined in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) of rats. Lithium prevented LDX-induced hyperlocomotion at the doses of 10 and 30 mg/kg, but only reversed LDX-induced hyperlocomotion at dose of 10 mg/kg. In addition, both doses of LDX decreased GSH content (in ST and PFC), while Li was able to reverse and prevent these alterations mainly in the PFC. LDX (10 and 30 mg/kg) increased lipid peroxidation which was reversed and prevented by Li. In conclusion, LDX-induced hyperlocomotion along with associated increments in oxidative stress show promise as an alternative animal model of Mania.

  • a 3 week randomized placebo controlled trial of asenapine in the treatment of acute Mania in Bipolar Mania and mixed states
    Bipolar Disorders, 2009
    Co-Authors: Roger S. Mcintyre, Jun Zhao, M. Cohen, Larry Alphs, Thomas A. Macek, John Panagides
    Abstract:

    Objective:  Asenapine is approved for Bipolar disorder and schizophrenia. This was a 3-week, randomized, double-blind, placebo-controlled trial of asenapine for treating acute Bipolar Mania. Methods:  After a single-blind placebo run-in period, adults (n = 488) experiencing manic or mixed episodes were randomized to flexible-dose sublingual asenapine (10 mg BID on day 1; 5 or 10 mg BID thereafter; n = 194), placebo (n = 104), or oral olanzapine (15 mg BID on day 1; 5–20 mg QD thereafter; n = 191). Primary efficacy, change in Young Mania Rating Scale (YMRS) total score from baseline to day 21, was assessed using analysis of covariance with last observation carried forward [(LOCF); primary analysis]. A mixed model for repeated measures [(MMRM); prespecified secondary analysis] was also used to assess efficacy. Tolerability and safety assessments included adverse events, physical examinations, extrapyramidal symptom ratings, and laboratory values. Results:  Mean daily dosages were asenapine 18.2 mg and olanzapine 15.8 mg. Significantly greater least squares (LS) mean ± SE changes in YMRS scores were observed on day 2 with asenapine (−3.0 ± 0.4) and olanzapine (−3.4 ± 0.4) versus placebo (−1.5 ± 0.5, both p < 0.01) and were maintained until day 21 (−10.8 ± 0.8 with asenapine, −12.6 ± 0.8 with olanzapine; both p ≤ 0.0001 versus placebo, −5.5 ± 1.1) with LOCF. The results of MMRM analyses were consistent with those of LOCF. Asenapine had a modest impact on weight and metabolic measures. Conclusions:  These results indicate that asenapine is rapidly acting, efficacious, and well tolerated for patients with Bipolar I disorder experiencing an acute manic episode.

  • Asenapine versus olanzapine in acute Mania: a double-blind extension study.
    Bipolar disorders, 2009
    Co-Authors: Roger S. Mcintyre, Jun Zhao, M. Cohen, Larry Alphs, Thomas A. Macek, John Panagides
    Abstract:

    Objective:  To assess the efficacy and tolerability of asenapine versus olanzapine in the extended treatment of Bipolar Mania. Methods:  Patients with Bipolar I disorder experiencing acute manic or mixed episodes who completed either of two 3-week, double-blind trials with asenapine 5 or 10 mg twice daily, olanzapine 5 to 20 mg once daily, or placebo were eligible for this 9-week, double-blind extension study. Patients receiving active medication in the 3-week trials continued the same regimen; those who had received placebo were blindly switched to asenapine but were assessed for safety outcomes only. The primary efficacy measure was the change from baseline to day 84 on the Young Mania Rating Scale (YMRS) total score in the per-protocol population. Results on the primary efficacy outcome were used to determine the noninferiority of asenapine versus olanzapine. Results:  A total of 504 patients (placebo/asenapine, n = 94; asenapine, n = 181; olanzapine, n = 229) were enrolled in the extension study. At day 84, the mean (SD) change from baseline in YMRS total score was −24.4 (8.7) for asenapine and −23.9 (7.9) for olanzapine. Prespecified statistical analysis for noninferiority indicated no significant difference between asenapine and olanzapine. The overall incidence of treatment-emergent adverse events was similar across treatment groups (77% placebo/asenapine, 77% asenapine, 78% olanzapine). Clinically significant weight gain occurred in 10%, 19%, and 31% of the placebo/asenapine, asenapine, and olanzapine groups, respectively. Conclusions:  Asenapine was efficacious, showed noninferiority to olanzapine, and was well tolerated in the extended treatment of patients experiencing manic symptoms associated with Bipolar I disorder.

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  • antipsychotic drug induced somnolence incidence mechanisms and management
    CNS Drugs, 2016
    Co-Authors: Fang Fang, Zuowei Wang, Joseph R Calabrese
    Abstract:

    Somnolence is a common side effect of antipsychotics. To assess the incidence of this side effect, we performed a MEDLINE search for randomized, double-blinded, placebo- or active-controlled studies of adult patients treated with antipsychotics for schizophrenia, Mania, Bipolar depression, or Bipolar disorder. We extracted rates of somnolence from original publications and pooled them based on the dose of each antipsychotic in the same psychiatric condition, then estimated the absolute risk increase (ARI) and the number needed to harm (NNH) of an antipsychotic relative to placebo or an active comparator in the same psychiatric condition. According to the ARI in acute schizophrenia, Bipolar Mania, and Bipolar depression, antipsychotics can be classified as high somnolence (clozapine), moderate somnolence (olanzapine, perphenazine, quetiapine, risperidone, ziprasidone), and low somnolence (aripiprazole, asenapine, haloperidol, lurasidone, paliperidone, cariprazine). The risk of somnolence with blonanserin, brexpiprazole, chlorpromazine, iloperidone, sertindole, and zotepine needs further investigation. The rates of somnolence were positively correlated to dose and duration for some antipsychotics, but not for others. Many factors, including antipsychotic per se, the method used to measure somnolence, patient population, study design, and dosing schedule, might affect the incidence of antipsychotic-induced somnolence. The mechanisms of antipsychotic-induced somnolence are likely multifactorial, although the blockade of histamine 1 receptors and α1 receptors may play a major role. The management of antipsychotic-induced somnolence should include sleep hygiene education, choosing an antipsychotic with a lower risk for somnolence, starting at a lower dose with a slower titration based on psychiatric diagnoses, adjusting doses when necessary, and minimizing concurrent somnolence-prone agents. Since most cases of somnolence were mild to moderate, allowing tolerance to develop over at least 4 weeks is reasonable before discontinuing an antipsychotic.

  • pw01 28 asenapine as adjunctive treatment for Bipolar Mania a placebo controlled 12 week study and 40 week extension
    European Psychiatry, 2010
    Co-Authors: Joseph R Calabrese, Armin Szegedi, Jun Zhao, L Stet, H Kotari, A Kouassi, John Panagides
    Abstract:

    Objectives Asenapine is indicated in adults for acute treatment of schizophrenia and Bipolar I disorder. We describe the efficacy and tolerability of adjunctive asenapine in Bipolar patients showing incomplete response to lithium or valproate monotherapy. Methods In a 12-week core study, patients were randomized to flexible-dose asenapine (5 or 10 mg BID) or placebo as an adjunct to continued mood stabilizer therapy. Patients completing the core study without protocol violations could enter a 40-week extension. Changes from core study baseline on the Young Mania Rating Scale (YMRS) and Montgomery-Asberg Depression Rating Scale (MADRS) total scores were assessed at week 3 of the core study and at week 52 in the extension. Efficacy in the core study was assessed using ANCOVA with LOCF to impute missing data. The extension was not powered for statistical comparisons; descriptive statistics were employed. Results The intent-to-treat population comprised 318 patients (asenapine, 155; placebo, 163) in the core study and 71 (38; 33) in the extension. Mean±SD changes at week 3 with asenapine and placebo, respectively, were -9.7±10.1 versus -7.7±9.6 (P=0.0257) on YMRS and -2.8±7.2 versus -2.2±6.8 (P=0.3684) on MADRS. Mean±SD changes at week 52 with asenapine and placebo were -17.2±13.7 versus -19.7±11.8 on YMRS and -3.3±9.8 versus -3.9±7.7 on MADRS. The incidence of treatment-emergent AEs with asenapine and placebo was 73% and 69% in the core study, 78% and 69% in the extension. Conclusions Asenapine was effective as an adjunct to mood stabilizer in Bipolar I disorder and was well tolerated.

  • typical and atypical antipsychotics in Bipolar depression
    The Journal of Clinical Psychiatry, 2005
    Co-Authors: Keming Gao, Prashant Gajwani, Omar Elhaj, Joseph R Calabrese
    Abstract:

    Background: Symptomatic Bipolar patients experience more depressive than manic symptoms, but fewer studies have been designed for Bipolar depression than for Bipolar Mania. Since the antipsychotic agents have been shown to diminish depressive symptoms during the treatment of Mania, atypical agents are now being studied for use in Bipolar depression. Data Sources: English-language articles published from 1980 through July 2004 and cited in MEDLINE were searched using the keywords antipsychotics, typical antipsychotics, atypical antipsychotics, Bipolar depression, Bipolar disorder, manic-depressive illness, placebo, and clinical trial. The generic and brand names of individual antipsychotics were also entered as keywords . Peer-reviewed abstracts of placebo-controlled studies assessing acute or long-term efficacy in Bipolar depression presented at major scientific meetings were also reviewed. Study Selection: Use of a depression rating scale was required for inclusion of studies of the atypical antipsychotic agents in our analysis. Data Synthesis: Twenty-one randomized trials and 13 nonrandomized prospective trials were identified. In the only 2 acute, double-blind, placebo-controlled studies of antipsychotics in Bipolar depression, the effect size of olanzapine was small (0.32) compared with the effect sizes of quetiapine (0.91-1.09, depending on dose). The effect size in acute Mania of olanzapine at week 4 and quetiapine at week 3 was 0.50 and 0.39, respectively. Both olanzapine and quetiapine have been shown to be superior to placebo in the acute treatment of Bipolar I depression. In addition, olanzapine has been shown to be more effective than placebo in delaying relapse into Bipolar depression. With the exception of a 6-month perphenazine study, there are no other randomized studies of typical antipsychotics that support the conclusion that this class of medication worsens Bipolar depression. Conclusion: Emerging data suggest that the atypical antipsychotic agents have a role in the acute and long-term treatment of Bipolar depression. No convincing data support the impression that the typical antipsychotic agents worsen Bipolar depression.