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Antony Loebel - One of the best experts on this subject based on the ideXlab platform.
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lurasidone in children and adolescents with Bipolar Depression presenting with mixed subsyndromal hypomanic features post hoc analysis of a randomized placebo controlled trial
Journal of Child and Adolescent Psychopharmacology, 2020Co-Authors: Manpreet K Singh, Andrei Pikalov, Michael Tocco, C Siu, Antony LoebelAbstract:Objectives: To evaluate the efficacy and safety of lurasidone in the treatment of children and adolescents with Bipolar Depression presenting with mixed (subsyndromal hypomanic) features. Methods: ...
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lurasidone compared to other atypical antipsychotic monotherapies for Bipolar Depression a systematic review and network meta analysis
World Journal of Biological Psychiatry, 2018Co-Authors: Michael J Ostacher, Daisy Ngmak, Pankaj A Patel, Dionysios Ntais, Max Schlueter, Antony LoebelAbstract:Objectives: To assess the efficacy and tolerability of lurasidone versus other atypical antipsychotic monotherapy agents in patients with Bipolar Depression, using a Bayesian network meta-analysis....
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recovery in Bipolar Depression post hoc analysis of a placebo controlled lurasidone trial followed by a long term continuation study
Journal of Affective Disorders, 2015Co-Authors: Antony Loebel, Andrei Pikalov, Josephine Cucchiaro, C Siu, Krithika Rajagopalan, Terence A KetterAbstract:Abstract Background In this post-hoc analysis, rates of remission and recovery were evaluated in patients with Bipolar Depression treated with lurasidone. Methods Outpatients meeting DSM-IV-TR criteria for Bipolar I Depression, were randomized to 6 weeks of once-daily, double-blind treatment with lurasidone 20–60 mg, lurasidone 80–120 mg or placebo, followed by a 6-month, open-label, flexible-dose, lurasidone continuation study. Recovery was defined as meeting criteria for combined symptomatic remission (Montgomery–Asberg Depression Rating Scale total score ≤12) and functional remission (all Sheehan Disability Scale domain scores ≤3) sustained for at least 3 months in the 6-month continuation study. Results A significantly higher proportion of lurasidone-treated patients met criteria for combined symptomatic remission and functional remission (33.3%, 91/273) compared to the placebo group (21.0%, 30/143, p Limitations The definition of recovery used has not been previously validated and the analysis was post hoc. Lack of a control group in the continuation study limits data interpretation. Conclusions Recovery in patients with Bipolar Depression was assessed based on rates of combined symptomatic and functional remission sustained over time. A majority of patients initially treated with lurasidone in the acute phase achieved recovery status in the continuation study. Treatment with lurasidone (vs. placebo) earlier in the course of the Bipolar depressive episode increased the likelihood of subsequent recovery.
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lurasidone in the treatment of Bipolar Depression with mixed subsyndromal hypomanic features post hoc analysis of a randomized placebo controlled trial
The Journal of Clinical Psychiatry, 2015Co-Authors: Roger S. Mcintyre, Andrei Pikalov, Josephine Cucchiaro, H Kroger, Antony LoebelAbstract:Objective Mixed (subsyndromal hypomanic) features are prevalent in patients with Bipolar Depression and are associated with more severe and complex illness, including increased risk for suicide attempts, higher switch to mania during antidepressant therapy, and a higher rate of recurrence. The aim of this post hoc analysis was to evaluate the efficacy and safety of lurasidone in the treatment of patients with Bipolar Depression presenting with mixed features. Method Patients with a DSM-IV-TR diagnosis of major depressive episode associated with Bipolar I disorder, with or without rapid cycling, and with a Montgomery-Asberg Depression Rating Scale (MADRS) score ≥ 20 and a Young Mania Rating Scale (YMRS) score ≤ 12 were randomly assigned to 6 weeks of double-blind, once-daily treatment with lurasidone 20-60 mg, lurasidone 80-120 mg, or placebo. The presence of mixed features was defined as a YMRS score ≥ 4 at study baseline. Efficacy analyses included change in MADRS total score from baseline to week 6 (the primary outcome in the original study, conducted between April 2009 and February 2012). Results At baseline, mixed features were present in 56% of patients (lurasidone, n = 182/323; placebo, n = 90/162). Treatment with lurasidone (vs placebo) was associated with significantly greater reductions in MADRS scores in the mixed features group (-15.7 vs -10.9; P = .001; week 6; mixed model for repeated measures [MMRM]; effect size, 0.48) and in the group without mixed features (-15.2 vs -10.8; P = .002; week 6; MMRM; effect size, 0.48). Rates of protocol-defined treatment-emergent hypomania or mania were similar for patients with mixed features (lurasidone, 2.2%; placebo, 3.2%) and without mixed features (lurasidone, 3.4%; placebo, 0.0%). Conclusions Lurasidone was found in this post hoc analysis to be efficacious in the treatment of patients with Bipolar Depression who present with mixed features (assessed cross-sectionally at study baseline). No increased risk of treatment-emergent mania was observed in either group. Trial registration ClinicalTrials.gov identifier: NCT00868699.
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efficacy and tolerability of lurasidone in older adults with Bipolar Depression analysis of two 6 week double blind placebo controlled studies
European Psychiatry, 2015Co-Authors: Martha Sajatovic, Joyce Tsai, Andrei Pikalov, Josephine Cucchiaro, Brent P Forester, H Kroger, Antony LoebelAbstract:Introduction The acute treatment of Bipolar Depression in the elderly has not been well-studied. Objectives/Aims To evaluate the acute efficacy and tolerability of lurasidone in older adults (age ≥55 years) with Bipolar I Depression (BPD). Methods The older adult sample was analyzed from two, randomized, double-blind, 6-week studies of BPD patients with a Montgomery-Asberg Depression Rating Scale (MADRS) score ≥20: a monotherapy trial (lurasidone 18.5-56 mg/d vs 74-111 mg/d vs placebo); and an adjunctive trial (with lithium or valproate; lurasidone 18.5-111 mg/d vs placebo). Results The older adult sample consisted of 83 patients (17.1%) on monotherapy, and 53 patients (15.6%) on adjunctive therapy. At Week 6, mean change in MADRS was significantly greater for lurasidone 18.5-56 mg (-15.4; P P Conclusions Results of these analyses suggest that lurasidone, in doses of 18.5-111 mg, was an efficacious and well-tolerated acute treatment for Bipolar Depression in older adults. Significance vs placebo was achieved with lurasidone monotherapy, however, adjunctive therapy with lurasidone did not reach statistical significance. NCT00868699, NCT00868452. Sponsored by Sunovion Pharmaceuticals Inc.
Joseph R Calabrese - One of the best experts on this subject based on the ideXlab platform.
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response and remission rates during 24 weeks of mood stabilizing treatment for Bipolar Depression depending on early non response
Psychiatry Research-neuroimaging, 2021Co-Authors: Ole Kohlerforsberg, Charles L Bowden, Joseph R Calabrese, Louisa G Sylvia, Mauricio Tohen, Michael E Thase, Kirstine H Sloth, Melvin G Mcinnis, James H Kocsis, Edward S FriedmanAbstract:Abstract Background We aimed to study the probability of Bipolar Depression response at 24 weeks given initial non-response. Methods We combined two multi-site, 24-week trials including similar populations following the same evidence-based guidelines randomizing patients to lithium or quetiapine. Additional mood-stabilizing treatment was possible if clinically indicated. We report using cumulative proportions of response (>50% improvement in MADRS) and remission (MADRS Results We included 592 participants with Bipolar Depression (mean 39 years, 59% female, mean MADRS 25). Among 393 (66%) participants without response after 2 weeks, 46% responded by 24 weeks; for 291 (49%) without response at 4 weeks, 40% responded and 33% remitted by 24 weeks; for 222 (38%) without a response at 6 weeks, 36% responded and 29% remitted by 24 weeks; for 185 (31%) without a response at 8 weeks, 29% responded and 24% remitted by 24 weeks. Rates were similar for participants who had started an additional mood-stabilizing drug during the first 6 or 8 weeks. Conclusions Among patients with Bipolar Depression and non-response after 6 weeks treatment, representing an adequate Bipolar Depression trial, only one-third responded by 24 weeks. These results highlight the need for better treatment alternatives for non-responders to evidence-based treatments for Bipolar Depression.
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evaluation of madrs severity thresholds in patients with Bipolar Depression
Journal of Affective Disorders, 2021Co-Authors: Michael E Thase, Joseph R Calabrese, Amanda Harrington, S A Montgomery, Xiaomeng Niu, M PatelAbstract:Abstract Background The Montgomery-Asberg Depression Rating Scale (MADRS) is commonly used to assess Depression symptom changes in clinical trials; however, the score itself can be difficult to interpret without clinical context. Categories of Depression severity corresponding to MADRS total score have not been established for Bipolar Depression, which was the objective of this study. Methods Data were pooled from 3 randomized, double-blind, placebo-controlled trials of cariprazine in patients with Bipolar I Depression; placebo and cariprazine arms were pooled. An anchor-based approach was used to map MADRS total score to the clinician-rated, 7-category Clinical Global Impression of Severity scale (CGI-S). Spearman's correlation coefficient was used to assess associations between MADRS total and CGI-S scores. Optimal MADRS severity thresholds for each CGI-S category was determined via Youden index using receiver operating characteristic (ROC) analyses. Results Using data from 1523 patients with Bipolar Depression, mean MADRS total scores were positively correlated with mean CGI-S scores at week 6 (r = 0.87; P Conclusions Utilizing data from 3 clinical trials of patients with Bipolar Depression, MADRS severity thresholds were identified. These empirical findings may help clinicians contextualize MADRS results from Bipolar clinical research and apply to their practice. Trial Registration clinicaltrials.gov NCT01396447, NCT02670538, NCT02670551.
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evaluation of madrs severity thresholds in patients with Bipolar Depression
Cns Spectrums, 2021Co-Authors: Michael E Thase, Joseph R Calabrese, Amanda Harrington, S A Montgomery, Xiaomeng Niu, M PatelAbstract:Introduction The Montgomery-Asberg Depression Rating Scale (MADRS) is commonly used for the assessment of depressive symptom changes in patients with major depressive disorder (MDD) or Bipolar Depression. Categories of Depression severity that correspond to ranges of MADRS total score have been previously reported in patients with MDD, but it appears that MADRS severity ranges have not been reported for patients with Bipolar I disorder. The objective of this study was to evaluate MADRS total score ranges that correspond with different grades of Depression severity in patients with Bipolar I Depression. Methods Data were pooled from 3 randomized, double-blind, placebo-controlled, 6- or 8-week trials of cariprazine in patients with Bipolar I Depression. MADRS severity ranges were evaluated using an anchor-based approach with the clinician-rated, 7-category Clinical Global Impression-Severity (CGI-S) scale. CGI-S has previously been used to determine severity thresholds in MDD. Correlations between MADRS total score and CGI-S score were assessed in the pooled dataset at week 6; placebo and active treatment arms were pooled together. Youden index from receiver operating characteristic (ROC) curves was used to determine the optimal threshold for MADRS total score corresponding to each CGI-S severity level. Results The pooled dataset included 1523 patients with Bipolar Depression. Mean CGI-S scores were highly correlated with mean MADRS total scores at week 6 (r=.87; P<.0001), with MADRS total scores increasing with CGI-S severity. Using the ROC curves, MADRS total score ranges corresponding to each CGI-S severity category were estimated as follows: score of 0-6 for “normal, not at all ill”, 7-12 for “borderline mentally ill”, 13-18 for “mildly ill”, 19-23 for “moderately ill”, 24-36 for “markedly ill”, 37-39 for “severely ill”, and 40 or greater for “extremely ill”. Area under the curve (AUC) values for these cutoffs ranged from 0.930 to 0.997, representing outstanding sensitivity and specificity. Conclusions Utilizing data from 3 recent clinical trials of subjects with Bipolar Depression, we were able to identify MADRS severity thresholds. These empirical findings may help clinicians to understand and contextualize MADRS results from Bipolar clinical research and apply to their patients in practice. Funding AbbVie Inc.
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decreased activation and subsyndromal manic symptoms predict lower remission rates in Bipolar Depression
Australian and New Zealand Journal of Psychiatry, 2018Co-Authors: Marco Antonio Knob Caldieraro, Terence A Ketter, Thilo Deckersbach, Keming Gao, Mauricio Tohen, Samantha Walsh, William V Bobo, Richard C Shelton, Noreen A Reillyharrington, Joseph R CalabreseAbstract:Objective:Activation encompasses energy and activity and is a central feature of Bipolar disorder. However, the impact of activation on treatment response of Bipolar Depression requires further exp...
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Bipolar Depression overview and commentary
Harvard Review of Psychiatry, 2010Co-Authors: Ross J Baldessarini, Eduard Vieta, Joseph R Calabrese, Mauricio Tohen, Charles L BowdenAbstract:Depressive phases are the most prevalent component of Bipolar disorders, even with modern treatment. Bipolar depressive morbidity is often misdiagnosed and is limited in response to available treatments. These conditions are especially debilitating and are associated with psychiatric comorbidity, substance abuse, functional disability, and increased mortality owing to early suicide and accidents, and later medical illnesses. There is growing awareness that Bipolar Depression is one of the greatest challenges in modern psychiatry. It is essential to differentiate various forms of Depression, dysthymia, and dysphoric mixed states of Bipolar disorders from the clinical features of more common, unipolar major depressive disorders. In Bipolar Depression, antidepressant responses often are unsatisfactory, and these agents probably are overused. Emerging treatments, including several anticonvulsant and modern antipsychotic drugs, as well as lithium-alone or in selected combinations-are partially effective for Bipolar Depression. Interest in recognizing Bipolar Depression and seeking more effective, specific, and safer treatments for it are growing.
Andrei Pikalov - One of the best experts on this subject based on the ideXlab platform.
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long term effectiveness of lurasidone in pediatric Bipolar Depression response remission and recovery
Cns Spectrums, 2021Co-Authors: Manpreet K Singh, Edward Schweizer, Michael Tocco, Andrei PikalovAbstract:Background Bipolar disorder frequently has an early onset, with an estimated 1.8% prevalence of Bipolar I disorder in children and adolescents. Childhood onset of Bipolar disorder is typically associated with a chronic, severe, and disabling course of illness. Relatively few prospective studies are available that evaluate the long-term efficacy of atypical antipsychotics in achieving and sustaining response or remission in pediatric patients with Bipolar Depression. Lurasidone has been approved by the FDA as monotherapy for Bipolar Depression in pediatric patients ages 10-17 years. The aim of the current post-hoc analysis was to evaluate the long-term efficacy of lurasidone in achieving response or remission in children and adolescents with Bipolar Depression followed over a two-year period. Method Patients 10-17 years with Bipolar I Depression who completed a 6-week double-blind (DB) study of lurasidone vs. placebo were eligible to enroll in a two-year, open-label (OL) extension study in which patients were continued on flexibly-dosed lurasidone (20-80 mg/d) or switched from placebo to lurasidone. Efficacy measures included the Children's Depression Rating Scale, Revised (CDRS-R) and the Clinical Global Impression, Bipolar Depression Severity scale (CGI-BP-S). Functioning was evaluated utilizing the Clinician-rated Children's Global Assessment Scale (CGAS) score, with a score >70 indicating no clinically meaningful functional impairment. Responder criteria were met if a patient achieved criteria = 50% reduction from DB baseline in the CDRS-R total score: remission criteria were met if a patient achieved a CDRS-R Total Score =28 and a YMRS total score =8 and CGI-BP-S Depression score =3, and a patient was considered to have met recovery criteria if they achieved remission with a CGAS score >70. In addition, a more stringent outcome, sustained remission, was also analyzed, which required a patient to meet remission criteria for =24 consecutive weeks. Results A total of 306 patients completed the 6-week DB study and entered the extension study; 195 (63.7%) patients completed one year of treatment and 168 (54.9%) patients completed two years of treatment. Responder rates at OL baseline, one year, and two years were: 51.0%, 88.4% and 91.1%, respectively; remission rates were 24.3%, 61.3%, and 75.6%, respectively; and recovery rates were 17.7%, 53.8%, and 73.8%. On a Pearson correlation analysis, there was a strong inverse relationship (r = -0.71) between CDRS-R total score, and global functioning as measured by the CGAS. Sustained remission was achieved by 37.2% of patients at one year and 57% of patients after two years. Conclusions In children and adolescents with Bipolar Depression, up to 2 years of treatment with lurasidone was associated with continued improvement in depressive symptoms, resulting in progressively higher rates of response, remission, recovery, and the more rigorously calculated outcome of sustained remission. Funding Sunovion Pharmaceuticals Inc.
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lurasidone in children and adolescents with Bipolar Depression presenting with mixed subsyndromal hypomanic features post hoc analysis of a randomized placebo controlled trial
Journal of Child and Adolescent Psychopharmacology, 2020Co-Authors: Manpreet K Singh, Andrei Pikalov, Michael Tocco, C Siu, Antony LoebelAbstract:Objectives: To evaluate the efficacy and safety of lurasidone in the treatment of children and adolescents with Bipolar Depression presenting with mixed (subsyndromal hypomanic) features. Methods: ...
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recovery in Bipolar Depression post hoc analysis of a placebo controlled lurasidone trial followed by a long term continuation study
Journal of Affective Disorders, 2015Co-Authors: Antony Loebel, Andrei Pikalov, Josephine Cucchiaro, C Siu, Krithika Rajagopalan, Terence A KetterAbstract:Abstract Background In this post-hoc analysis, rates of remission and recovery were evaluated in patients with Bipolar Depression treated with lurasidone. Methods Outpatients meeting DSM-IV-TR criteria for Bipolar I Depression, were randomized to 6 weeks of once-daily, double-blind treatment with lurasidone 20–60 mg, lurasidone 80–120 mg or placebo, followed by a 6-month, open-label, flexible-dose, lurasidone continuation study. Recovery was defined as meeting criteria for combined symptomatic remission (Montgomery–Asberg Depression Rating Scale total score ≤12) and functional remission (all Sheehan Disability Scale domain scores ≤3) sustained for at least 3 months in the 6-month continuation study. Results A significantly higher proportion of lurasidone-treated patients met criteria for combined symptomatic remission and functional remission (33.3%, 91/273) compared to the placebo group (21.0%, 30/143, p Limitations The definition of recovery used has not been previously validated and the analysis was post hoc. Lack of a control group in the continuation study limits data interpretation. Conclusions Recovery in patients with Bipolar Depression was assessed based on rates of combined symptomatic and functional remission sustained over time. A majority of patients initially treated with lurasidone in the acute phase achieved recovery status in the continuation study. Treatment with lurasidone (vs. placebo) earlier in the course of the Bipolar depressive episode increased the likelihood of subsequent recovery.
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lurasidone in the treatment of Bipolar Depression with mixed subsyndromal hypomanic features post hoc analysis of a randomized placebo controlled trial
The Journal of Clinical Psychiatry, 2015Co-Authors: Roger S. Mcintyre, Andrei Pikalov, Josephine Cucchiaro, H Kroger, Antony LoebelAbstract:Objective Mixed (subsyndromal hypomanic) features are prevalent in patients with Bipolar Depression and are associated with more severe and complex illness, including increased risk for suicide attempts, higher switch to mania during antidepressant therapy, and a higher rate of recurrence. The aim of this post hoc analysis was to evaluate the efficacy and safety of lurasidone in the treatment of patients with Bipolar Depression presenting with mixed features. Method Patients with a DSM-IV-TR diagnosis of major depressive episode associated with Bipolar I disorder, with or without rapid cycling, and with a Montgomery-Asberg Depression Rating Scale (MADRS) score ≥ 20 and a Young Mania Rating Scale (YMRS) score ≤ 12 were randomly assigned to 6 weeks of double-blind, once-daily treatment with lurasidone 20-60 mg, lurasidone 80-120 mg, or placebo. The presence of mixed features was defined as a YMRS score ≥ 4 at study baseline. Efficacy analyses included change in MADRS total score from baseline to week 6 (the primary outcome in the original study, conducted between April 2009 and February 2012). Results At baseline, mixed features were present in 56% of patients (lurasidone, n = 182/323; placebo, n = 90/162). Treatment with lurasidone (vs placebo) was associated with significantly greater reductions in MADRS scores in the mixed features group (-15.7 vs -10.9; P = .001; week 6; mixed model for repeated measures [MMRM]; effect size, 0.48) and in the group without mixed features (-15.2 vs -10.8; P = .002; week 6; MMRM; effect size, 0.48). Rates of protocol-defined treatment-emergent hypomania or mania were similar for patients with mixed features (lurasidone, 2.2%; placebo, 3.2%) and without mixed features (lurasidone, 3.4%; placebo, 0.0%). Conclusions Lurasidone was found in this post hoc analysis to be efficacious in the treatment of patients with Bipolar Depression who present with mixed features (assessed cross-sectionally at study baseline). No increased risk of treatment-emergent mania was observed in either group. Trial registration ClinicalTrials.gov identifier: NCT00868699.
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efficacy and tolerability of lurasidone in older adults with Bipolar Depression analysis of two 6 week double blind placebo controlled studies
European Psychiatry, 2015Co-Authors: Martha Sajatovic, Joyce Tsai, Andrei Pikalov, Josephine Cucchiaro, Brent P Forester, H Kroger, Antony LoebelAbstract:Introduction The acute treatment of Bipolar Depression in the elderly has not been well-studied. Objectives/Aims To evaluate the acute efficacy and tolerability of lurasidone in older adults (age ≥55 years) with Bipolar I Depression (BPD). Methods The older adult sample was analyzed from two, randomized, double-blind, 6-week studies of BPD patients with a Montgomery-Asberg Depression Rating Scale (MADRS) score ≥20: a monotherapy trial (lurasidone 18.5-56 mg/d vs 74-111 mg/d vs placebo); and an adjunctive trial (with lithium or valproate; lurasidone 18.5-111 mg/d vs placebo). Results The older adult sample consisted of 83 patients (17.1%) on monotherapy, and 53 patients (15.6%) on adjunctive therapy. At Week 6, mean change in MADRS was significantly greater for lurasidone 18.5-56 mg (-15.4; P P Conclusions Results of these analyses suggest that lurasidone, in doses of 18.5-111 mg, was an efficacious and well-tolerated acute treatment for Bipolar Depression in older adults. Significance vs placebo was achieved with lurasidone monotherapy, however, adjunctive therapy with lurasidone did not reach statistical significance. NCT00868699, NCT00868452. Sponsored by Sunovion Pharmaceuticals Inc.
Michael Berk - One of the best experts on this subject based on the ideXlab platform.
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efficacy of adjunctive garcinia mangostana linn mangosteen pericarp for Bipolar Depression study protocol for a proof of concept trial
Revista Brasileira de Psiquiatria, 2019Co-Authors: Michael Berk, Melanie M Ashton, Malcolm Hopwood, Seetal Dodd, Alyna Turner, Ellie BrownAbstract:Objective: Bipolar Depression is characterized by neurobiological features including perturbed oxidative biology, reduction in antioxidant levels, and a concomitant rise in oxidative stress markers. Bipolar Depression manifests systemic inflammation, mitochondrial dysfunction, and changes in brain growth factors. The depressive phase of the disorder is the most common and responds the least to conventional treatments. Garcinia mangostana Linn, commonly known as mangosteen, is a tropical fruit. The pericarp's properties may reduce oxidative stress and inflammation and improve neurogenesis, making mangosteen pericarp a promising add-on therapy for Bipolar Depression.Methods: Participants will receive 24 weeks of either 1,000 mg mangosteen pericarp or placebo per day, in addition to their usual treatment. The primary outcome is change in severity of mood symptoms, measured using the Montgomery-Asberg Depression Rating Scale (MADRS), over the treatment phase. Secondary outcomes include global psychopathology, quality of life, functioning, substance use, cognition, safety, biological data, and cost-effectiveness. A follow-up interview will be conducted 4 weeks post-treatment.Conclusion: The findings of this study may have implications for improving treatment outcomes for those with Bipolar disorder and may contribute to our understanding of the pathophysiology of Bipolar Depression.
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treatment resistant and multi therapy resistant criteria for Bipolar Depression consensus definition
British Journal of Psychiatry, 2019Co-Authors: Diego Hidalgomazzei, Heinz Grunze, Michael Berk, Andrea Cipriani, Anthony J Cleare, Arianna Di Florio, Daniel Dietch, John R Geddes, Guy M Goodwin, Joseph F HayesAbstract:Background Most people with Bipolar disorder spend a significant percentage of their lifetime experiencing either subsyndromal depressive symptoms or major depressive episodes, which contribute greatly to the high levels of disability and mortality associated with the disorder. Despite the importance of Bipolar Depression, there are only a small number of recognised treatment options available. Consecutive treatment failures can quickly exhaust these options leading to treatment-resistant Bipolar Depression (TRBD). Remarkably few studies have evaluated TRBD and those available lack a comprehensive definition of multi-therapy-resistant Bipolar Depression (MTRBD). Aims To reach consensus regarding threshold definitions criteria for TRBD and MTRBD. Method Based on the evidence of standard treatments available in the latest Bipolar disorder treatment guidelines, TRBD and MTRBD criteria were agreed by a representative panel of Bipolar disorder experts using a modified Delphi method. Results TRBD criteria in Bipolar Depression was defined as failure to reach sustained symptomatic remission for 8 consecutive weeks after two different treatment trials, at adequate therapeutic doses, with at least two recommended monotherapy treatments or at least one monotherapy treatment and another combination treatment. MTRBD included the same initial definition as TRBD, with the addition of failure of at least one trial with an antidepressant, a psychological treatment and a course of electroconvulsive therapy. Conclusions The proposed TRBD and MTRBD criteria may provide an important signpost to help clinicians, researchers and stakeholders in judging how and when to consider new non-standard treatments. However, some challenging diagnostic and therapeutic issues were identified in the consensus process that need further evaluation and research.
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treatment resistant and multi therapy resistant criteria for Bipolar Depression consensus definition
British Journal of Psychiatry, 2019Co-Authors: Diego Hidalgomazzei, Heinz Grunze, Michael Berk, Andrea Cipriani, Anthony J Cleare, Arianna Di Florio, Daniel Dietch, John R Geddes, Guy M Goodwin, Joseph F HayesAbstract:Background Most people with Bipolar disorder spend a significant percentage of their lifetime experiencing either subsyndromal depressive symptoms or major depressive episodes, which contribute greatly to the high levels of disability and mortality associated with the disorder. Despite the importance of Bipolar Depression, there are only a small number of recognised treatment options available. Consecutive treatment failures can quickly exhaust these options leading to treatment-resistant Bipolar Depression (TRBD). Remarkably few studies have evaluated TRBD and those available lack a comprehensive definition of multi-therapy-resistant Bipolar Depression (MTRBD).AimsTo reach consensus regarding threshold definitions criteria for TRBD and MTRBD. Method Based on the evidence of standard treatments available in the latest Bipolar disorder treatment guidelines, TRBD and MTRBD criteria were agreed by a representative panel of Bipolar disorder experts using a modified Delphi method. Results TRBD criteria in Bipolar Depression was defined as failure to reach sustained symptomatic remission for 8 consecutive weeks after two different treatment trials, at adequate therapeutic doses, with at least two recommended monotherapy treatments or at least one monotherapy treatment and another combination treatment. MTRBD included the same initial definition as TRBD, with the addition of failure of at least one trial with an antidepressant, a psychological treatment and a course of electroconvulsive therapy. Conclusions The proposed TRBD and MTRBD criteria may provide an important signpost to help clinicians, researchers and stakeholders in judging how and when to consider new non-standard treatments. However, some challenging diagnostic and therapeutic issues were identified in the consensus process that need further evaluation and research.Declaration of interestIn the past 3 years, M.B. has received grant/research support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Rotary Health, Geelong Medical Research Foundation, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Meat and Livestock Board, Organon, Novartis, Mayne Pharma, Servier, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvay and Wyeth and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Eli Lilly, Grunbiotics, Glaxo SmithKline, Janssen Cilag, LivaNova, Lundbeck, Merck, Mylan, Otsuka, Pfizer and Servier. A.C. has received fees for lecturing from pharmaceutical companies namely Lundbeck and Sunovion. A.J.C. has in the past 3 years received honoraria for speaking from Astra Zeneca and Lundbeck, honoraria for consulting from Allergan, Janssen, Lundbeck and LivaNova and research grant support from Lundbeck. G.M.G. holds shares in P1Vital and has served as consultant, advisor or CME speaker for Allergan, Angelini, Compass pathways, MSD, Lundbeck, Otsuka, Takeda, Medscape, Minervra, P1Vital, Pfizer, Servier, Shire and Sun Pharma. J.G. has received research funding from National Institute for Health Research, Medical Research Council, Stanley Medical Research Institute and Wellcome. H.G. received grants/research support, consulting fees or honoraria from Gedeon Richter, Genericon, Janssen Cilag, Lundbeck, Otsuka, Pfizer and Servier. R.H.M.-W. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from various pharmaceutical companies including Astra Zeneca, Cyberonics, Eli Lilly, Janssen, Liva Nova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier, SPIMACO and Sunovion. R.M. has received research support from Big White Wall, Electromedical Products, Johnson and Johnson, Magstim and P1Vital. S.N. received honoraria from Lundbeck, Jensen and Otsuka. J.C.S. has received funds for research from Alkermes, Pfizer, Allergan, JaJ, BMS and been a speaker or consultant for Astellas, Abbott, Sunovion, Sanofi. S.W has, within the past 3 years, attended advisory boards for Sunovion and LivaNova and has undertaken paid lectures for Lundbeck. D.J.S. has received honoraria from Lundbeck. T.S. has reported grants from Pathway Genomics, Stanley Medical Research Institute and Palo Alto Health Sciences; consulting fees from Sunovion Pharamaceuticals Inc.; honoraria from Medscape Education, Global Medical Education and CMEology; and royalties from Jones and Bartlett, UpToDate and Hogrefe Publishing. S.P. has served as a consultant or speaker for Janssen, and Sunovion. P.T. has received consultancy fees as an advisory board member from the following companies: Galen Limited, Sunovion Pharmaceuticals Europe Ltd, myTomorrows and LivaNova. E.V. received grants/ research support, consulting fees or honoraria from Abbott, AB-Biotics, Allergan, Angelini, Dainippon Sumitomo, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka and Sunovion. L.N.Y. has received grants/research support, consulting fees or honoraria from Allergan, Alkermes, Dainippon Sumitomo, Janssen, Lundbeck, Otsuka, Sanofi, Servier, Sunovion, Teva and Valeant. A.H.Y. has undertaken paid lectures and advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders and LivaNova. He has also previously received funding for investigator-initiated studies from AstraZeneca, Eli Lilly, Lundbeck and Wyeth. P.R.A.S. has received research funding support from Corcept Therapeutics Inc. Corcept Therapeutics Inc fully funded attendance at their internal conference in California USA and all related expenses. He has received grant funding from the Medical Research Council UK for a collaborative study with Janssen Research and Development LLC. Janssen Research and Development LLC are providing non-financial contributions to support this study. P.R.A.S. has received a presentation fee from Indivior and an advisory board fee from LivaNova.
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affective instability and the course of Bipolar Depression results from the step bd randomised controlled trial of psychosocial treatment
British Journal of Psychiatry, 2016Co-Authors: Jonathan P Stange, Michael Berk, Michael W Otto, Louisa G Sylvia, Pedro Vieira Da Silva Magalhaes, David J Miklowitz, Ellen Frank, Christine Yim, Darin D Dougherty, Andrew A NierenbergAbstract:Background Little is known about predictors of recovery from Bipolar Depression. Aims We investigated affective instability (a pattern of frequent and large mood shifts over time) as a predictor of recovery from episodes of Bipolar Depression and as a moderator of response to psychosocial treatment for acute Depression. Method A total of 252 out-patients with DSM-IV Bipolar I or II disorder and who were depressed enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) and were randomised to one of three types of intensive psychotherapy for Depression ( n = 141) or a brief psychoeducational intervention ( n = 111). All analyses were by intention-to-treat. Results Degree of instability of symptoms of Depression and mania predicted a lower likelihood of recovery and longer time until recovery, independent of the concurrent effects of symptom severity. Affective instability did not moderate the effects of psychosocial treatment on recovery from Depression. Conclusions Affective instability may be a clinically relevant characteristic that influences the course of Bipolar Depression.
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Anti-inflammatory agents in the treatment of Bipolar Depression: a systematic review and meta-analysis.
Bipolar disorders, 2016Co-Authors: Joshua D. Rosenblat, Ron Kakar, Michael Berk, Lars Vedel Kessing, Vinberg, Bernhard T. Baune, Rodrigo B. Mansur, Elisa Brietzke, Benjamin I. Goldstein, Roger S. McintyreAbstract:Objective Inflammation has been implicated in the risk, pathophysiology, and progression of mood disorders and, as such, has become a target of interest in the treatment of Bipolar disorder (BD). Therefore, the objective of the current qualitative and quantitative review was to determine the overall antidepressant effect of adjunctive anti-inflammatory agents in the treatment of Bipolar Depression. Methods Completed and ongoing clinical trials of anti-inflammatory agents for BD published prior to 15 May 15 2015 were identified through searching the PubMed, Embase, PsychINFO, and Clinicaltrials.gov databases. Data from randomized controlled trials (RCTs) assessing the antidepressant effect of adjunctive mechanistically diverse anti-inflammatory agents were pooled to determine standard mean differences (SMDs) compared with standard therapy alone. Results Ten RCTs were identified for qualitative review. Eight RCTs (n = 312) assessing adjunctive nonsteroidal anti-inflammatory drugs (n = 53), omega-3 polyunsaturated fatty acids (n = 140), N-acetylcysteine (n = 76), and pioglitazone (n = 44) in the treatment of BD met the inclusion criteria for quantitative analysis. The overall effect size of adjunctive anti-inflammatory agents on depressive symptoms was −0.40 (95% confidence interval −0.14 to −0.65, p = 0.002), indicative of a moderate and statistically significant antidepressant effect. The heterogeneity of the pooled sample was low (I² = 14%, p = 0.32). No manic/hypomanic induction or significant treatment-emergent adverse events were reported. Conclusions Overall, a moderate antidepressant effect was observed for adjunctive anti-inflammatory agents compared with conventional therapy alone in the treatment of Bipolar Depression. The small number of studies, diversity of agents, and small sample sizes limited interpretation of the current analysis.
Carlos A Zarate - One of the best experts on this subject based on the ideXlab platform.
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a double blind placebo controlled pilot study of riluzole monotherapy for acute Bipolar Depression
Journal of Clinical Psychopharmacology, 2017Co-Authors: Lawrence T Park, Marc S Lener, Matthew Hopkins, Nicolas Iadorola, Rodrigo Machadovieira, Elizabeth D Ballard, Allison C Nugent, Carlos A ZarateAbstract:AbstractBackgroundGlutamatergic system abnormalities are implicated in the pathophysiology and treatment of both major depressive disorder and Bipolar Depression (BDep). Subsequent to studies demonstrating the rapid and robust antidepressant effects of ketamine, an N-methyl-D-aspartate receptor anta
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lithium and valproate levels do not correlate with ketamine s antidepressant efficacy in treatment resistant Bipolar Depression
Neural Plasticity, 2015Co-Authors: Mark J Niciu, Rodrigo Machadovieira, Elizabeth D Ballard, Nancy E Brutsche, David A Luckenbaugh, Nancy B Lundin, Dawn F Ionescu, Erica M Richards, Jennifer Vande L Voort, Carlos A ZarateAbstract:Ketamine and lithium both inhibit glycogen synthase kinase 3. In addition, lithium and ketamine have synergistic antidepressant-like effects at individually subeffective doses in rodents. We hypothesized that ketamine's antidepressant effects would be improved by therapeutic doses of lithium versus valproate and that serum lithium levels would positively correlate with ketamine's antidepressant efficacy. Thirty-six patients with treatment-resistant Bipolar Depression maintained on therapeutic-dose lithium (n = 23, 0.79 ± 0.15 mEq/L) or valproate (n = 13, 79.6 ± 12.4 mg/mL) received 0.5 mg/kg ketamine infusion in a randomized, double-blind, placebo-controlled, crossover trial. The primary Depression outcome measure-the Montgomery-Asberg Depression Rating Scale (MADRS)-was assessed before infusion and at numerous postinfusion time points. Both lithium (F 1,118 = 152.08, p < 0.001, and d = 2.27) and valproate (F 1,128 = 20.12, p < 0.001, and d = 0.79) significantly improved depressive symptoms, but no statistically significant difference was observed between mood stabilizer groups (F 1,28 = 2.51, p = 0.12, and d = 0.60). Serum lithium and valproate levels did not correlate with ketamine's antidepressant efficacy. Although the study was potentially underpowered, our results suggest that lithium may not potentiate ketamine's antidepressant efficacy in treatment-resistant Bipolar Depression.
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anti anhedonic effect of ketamine and its neural correlates in treatment resistant Bipolar Depression
Translational Psychiatry, 2014Co-Authors: Niall Lally, Allison C Nugent, David A Luckenbaugh, Rezvan Ameli, Jonathan P Roiser, Carlos A ZarateAbstract:Anhedonia--which is defined as diminished pleasure from, or interest in, previously rewarding activities-is one of two cardinal symptoms of a major depressive episode. However, evidence suggests that standard treatments for Depression do little to alleviate the symptoms of anhedonia and may cause reward blunting. Indeed, no therapeutics are currently approved for the treatment of anhedonia. Notably, over half of patients diagnosed with Bipolar disorder experience significant levels of anhedonia during a depressive episode. Recent research into novel and rapid-acting therapeutics for Depression, particularly the noncompetitive N-Methyl-D-aspartate receptor antagonist ketamine, has highlighted the role of the glutamatergic system in the treatment of Depression; however, it is unknown whether ketamine specifically improves anhedonic symptoms. The present study used a randomized, placebo-controlled, double-blind crossover design to examine whether a single ketamine infusion could reduce anhedonia levels in 36 patients with treatment-resistant Bipolar Depression. The study also used positron emission tomography imaging in a subset of patients to explore the neurobiological mechanisms underpinning ketamine's anti-anhedonic effects. We found that ketamine rapidly reduced the levels of anhedonia. Furthermore, this reduction occurred independently from reductions in general depressive symptoms. Anti-anhedonic effects were specifically related to increased glucose metabolism in the dorsal anterior cingulate cortex and putamen. Our study emphasizes the importance of the glutamatergic system in treatment-refractory Bipolar Depression, particularly in the treatment of symptoms such as anhedonia.
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family history of alcohol dependence and antidepressant response to an n methyl d aspartate antagonist in Bipolar Depression
Bipolar Disorders, 2012Co-Authors: David A Luckenbaugh, Nancy E Brutsche, Lobna Ibrahim, Jose Francochaves, Craig A Marquardt, Daniel C Mathews, Christy Cassarly, Carlos A ZarateAbstract:Substance use disorders, particularly alcohol dependence, are highly prevalent in individuals diagnosed with Bipolar disorder (BD) (1). In addition, the presence of substance abuse or alcoholism significantly affects the course and prognosis of BD (2–6). Recent evidence from diverse studies suggests that glutamatergic dysfunction may be involved in the pathophysiology of both BD (7, 8) and alcoholism (9–11), as well as both disorders concomitantly (12). Furthermore, the glutamatergic system, particularly the N-methyl-D-aspartate (NMDA) receptor complex, has been investigated as a putative target for the development of novel treatments for both disorders (7, 13–18). For mood disorders, much of the recent work in this area has centered on ketamine, an NMDA receptor antagonist with rapid (within hours) antidepressant effects in both major depressive disorder (MDD) and Bipolar Depression. Notably, both ketamine and ethanol are NMDA receptor antagonists and show dose-related similarities with regard to their subjective effects in healthy subjects—an effect that appears to be mediated by positive family history of alcohol dependence (FHP) (19, 20). In healthy subjects undergoing ketamine infusion, individuals with FHP showed an attenuated response in terms of perceptual alterations and dysphoric mood compared to those with a negative family history of alcohol dependence (FHN) (20). Alcohol-dependent patients also appear to have a blunted behavioral affect in response to ketamine, suggesting cross-tolerance between alcohol and ketamine (19). Relative to healthy subjects, ketamine administration in recovering ethanol-dependent patients was associated with reduced psychotomimetic symptoms and dysphoric mood (11). A previous study from our laboratory examined whether FHP would mediate the subjective and behavioral effects of ketamine in individuals with MDD. Indeed, consistent with the extant literature, we found that treatment-resistant MDD patients with FHP had fewer dysphoric and psychotomimetic effects in response to ketamine administration than MDD patients with FHN. In addition, we found that FHP patients had a significantly better initial antidepressant response to ketamine (21). Thus, in patients with MDD, FHP predicted a differential response to the perceptual disturbances, dysphoric effects, and antidepressant effects associated with ketamine. To date, no studies have investigated the link between FHP and ketamine’s antidepressant properties in patients with Bipolar Depression. Nevertheless, identifying predictors of robust treatment response could improve research efforts to develop glutamatergic modulators for the treatment of mood disorders. Thus, this study sought to determine whether the dysphoric, psychotomimetic, and antidepressant effects associated with ketamine are altered in FHP individuals with Bipolar Depression; the study combines samples from two recently published controlled studies investigating the antidepressant properties of ketamine in individuals with Bipolar Depression (7, 8). The relationship between personal history of alcohol dependence and ketamine’s effects was also examined.
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replication of ketamine s antidepressant efficacy in Bipolar Depression a randomized controlled add on trial
Biological Psychiatry, 2012Co-Authors: Carlos A Zarate, Nancy E Brutsche, Lobna Ibrahim, Jose Francochaves, Nancy Diazgranados, Anibal Cravchik, Jessica Selter, Craig A Marquardt, Victoria Liberty, David A LuckenbaughAbstract:Background Currently, no pharmacological treatments for Bipolar Depression exist that exert rapid (within hours) antidepressant or antisuicidal effects. We previously reported that intravenous administration of the N -methyl-D-aspartate antagonist ketamine produced rapid antidepressant effects in patients with treatment-resistant Bipolar Depression. The present study sought to replicate this finding in an independent sample. Methods In this double-blind, randomized, crossover, placebo-controlled study, 15 subjects with DSM-IV Bipolar I or II Depression maintained on therapeutic levels of lithium or valproate received a single intravenous infusion of either ketamine hydrochloride (.5 mg/kg) or placebo on 2 test days 2 weeks apart. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline; at 40, 80, 110, and 230 minutes postinfusion; and on days 1, 2, 3, 7, 10, and 14 postinfusion. Results Within 40 minutes, depressive symptoms, as well as suicidal ideation, significantly improved in subjects receiving ketamine compared with placebo ( d = .89, 95% confidence interval=.61–1.16, and .98, 95% confidence interval=.64–1.33, respectively); this improvement remained significant through day 3. Seventy-nine percent of subjects responded to ketamine and 0% responded to placebo at some point during the trial. The most common side effect was dissociative symptoms, which occurred only at the 40-minute time point. Conclusions This study replicated our previous finding that patients with Bipolar Depression who received a single ketamine infusion experienced a rapid and robust antidepressant response. In addition, we found that ketamine rapidly improved suicidal ideation in these patients.