Lurasidone Adjunctive to Lithium or Valproate for Prevention of Recurrence in Patients with Bipolar I Disorder

IntroductionInformation is not available on the maintenance efficacy of lurasidone in bipolar disorder.Objectives/aimsTo evaluate the recurrence prevention efficacy of lurasidone plus lithium (Li) or valproate (VPA) for the maintenance treatment of bipolar disorder.MethodsPatients with bipolar I disorder received up to 20 weeks of open-label lurasidone (20–80 mg/d) plus Li or VPA. Patients who achieved consistent clinical stability were randomized to 28 weeks of double-blind treatment with lurasidone (20–80 mg/d) or placebo, plus Li or VPA.ResultsA total of 496 patients met stabilization criteria and were randomized to adjunctive lurasidone vs. placebo. Fewer patients in the lurasidone group had recurrence of any mood episode compared with the placebo group, with a hazard ratio of 0.71 (P = 0.078). In pre-planned secondary analyses, recurrence rates were significantly lower for the lurasidone group treated with a modal open-label dose of 80 mg/d (hazard ratio [HR], 0.35; P = 0.020); when patients presented with an index episode of depression (HR = 0.57; P = 0.039); and when outcome was time-to-all-cause discontinuation (HR = 0.72; P = 0.034), or time-to-recurrence based on symptom severity criteria (HR = 0.53; P = 0.025).ConclusionsIn patients stabilized on lurasidone plus Li or VPA, continued treatment was associated with non-significant reduction in risk of recurrence of any mood disorder (primary). Consistent with dose-response effects observed during acute treatment of bipolar depression, risk of recurrence on lurasidone was significantly reduced after open-label treatment with the 80 mg/d dose, and in the 20–80 mg/d dose in patients presenting with an index episode of depression.Clinicaltrials.gov: NCT01358357.Sponsored by Sunovion Pharmaceuticals Inc.Disclosure of interestDrs. Pikalov, Cucchiaro, Mao, and Loebel are employees of Sunovion Pharmaceuticals IncDr. Calabrese has received research support from Abbott, AstraZeneca, Bristol-Myers Squibb, Cephalon, Cleveland Foundation, Eli Lilly, GlaxoSmithKline, Janssen, Lundbeck, NARSAD, Repligen, Stanley Medical Research Institute, Takeda, and Wyeth. Dr. Calabrese consulted to or served on advisory boards of Abbott, AstraZeneca, Bristol-Myers Squibb, Cephalon, Dainippon Sumitomo, Elan, EPI-Q, Inc., Forest, France Foundation, GlaxoSmithKline, Hoffman LaRoche, Janssen, Johnson and Johnson, Lundbeck, Merck, Neurosearch, OrthoMcNeil, Otsuka, Pfizer, Repligen, Servier, Solvay, Sunovion, Supernus, Synosia, Takeda, Teva, and Wyeth. Dr. Calabrese has provided CME lectures supported by AstraZeneca, Bristol-Myers Squibb, France Foundation, GlaxoSmithKline, Janssen, Johnson and Johnson, Merck, Sanofi-Aventis, Schering-Plough, Pfizer, Solvay, Sunovion, and Wyeth.

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Quetiapine or Lithium Versus Placebo for Maintenance Treatment of Bipolar I Disorder After Stabilization on Quetiapine

European Psychiatry ◽

10.1016/s0924-9338(09)70828-4 ◽

2009 ◽

Vol 24 (S1) ◽

pp. 1-1 ◽

Cited By ~ 5

Author(s):

W.A. Nolen ◽

R.H. Weisler ◽

A. Neijber ◽

Å. Hellqvist ◽

B. Paulsson

Keyword(s):

Bipolar Disorder ◽

Interim Analysis ◽

Maintenance Treatment ◽

Additional Benefit ◽

Study Medication ◽

Open Label ◽

Double Blind ◽

Bipolar I Disorder ◽

Time To Recurrence ◽

Positive Results

Purpose:Quetiapine combined with lithium or divalproex is an effective maintenance treatment for bipolar I disorder.1,2 This double-blind, randomized trial (D1447C00144) investigated quetiapine monotherapy as maintenance treatment.Methods:Adults experiencing manic, depressed, or mixed episodes of bipolar disorder received open-label quetiapine. Patients achieving stabilization (YMRS ≤12 and MADRS ≤12, 4 consecutive weeks) were randomized to continue quetiapine (300-800 mg/d) or to switch to placebo or lithium (target serum 0.6-1.2 mEq/L) for up to 104 weeks or recurrent mood event. The primary endpoint was time to recurrence of any mood event. The study was terminated when interim analysis provided positive results.Results:Of 2438 patients starting open-label quetiapine, 1226 (50.3%) were randomized to study medication with 1172 in the ITT population. Mean median quetiapine dose was 546 mg/d; mean median lithium serum level was 0.63 mEq/L. Time to recurrence of any mood event was longer for continued quetiapine versus switching to placebo (HR, 0.29; 95% CI, 0.23-0.38; P< 0.0001), for switching to lithium versus switching to placebo (HR, 0.46; 95% CI, 0.36-0.59; P< 0.0001), and for continued quetiapine versus switching to lithium (HR, 0.66; 95% CI, 0.49-0.88; P=0.005). Safety findings were consistent with known profiles.Conclusions:In patients stabilized on quetiapine, continued quetiapine significantly decreased time to recurrence of any mood event versus switching to placebo. Switching to lithium was also more effective than switching to placebo and conferred no additional benefit versus continuing quetiapine.Supported by funding from AstraZeneca Pharmaceuticals LP.

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

International Journal of Bipolar Disorders ◽

10.1186/s40345-019-0155-y ◽

2019 ◽

Vol 7 (1) ◽

Author(s):

Maximilian Pilhatsch ◽

Thomas J Stamm ◽

Petra Stahl ◽

Ute Lewitzka ◽

Anne Berghöfer ◽

...

Keyword(s):

Bipolar Disorder ◽

Rating Scale ◽

Bipolar Depression ◽

Phenotypic Expression ◽

Anxiety Symptoms ◽

Controlled Study ◽

Double Blind ◽

Comorbid Anxiety ◽

Depressed Patients ◽

Depressive Episodes

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

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

CNS Spectrums ◽

10.1017/s1092852920000619 ◽

2020 ◽

Vol 25 (2) ◽

pp. 292-292

Author(s):

Leslie Citrome ◽

Lakshmi N. Yatham ◽

Mehul Patel ◽

Willie R. Earley

Keyword(s):

Adverse Events ◽

Bipolar Depression ◽

Partial Agonist ◽

Fixed Dose ◽

Double Blind ◽

Study Objective ◽

Bipolar I Disorder ◽

Bipolar Mania ◽

Post Hoc ◽

Depressive Episodes

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

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The efficacy of valproate, lamotrigine and gabapentin in bipolar disorder; review of double-blind controlled studies

Acta Neuropsychiatrica ◽

10.1017/s0924270800035572 ◽

2000 ◽

Vol 12 (3) ◽

pp. 122-127 ◽

Cited By ~ 6

Author(s):

W.A. Nolen ◽

R.W. Kupka

Keyword(s):

Bipolar Disorder ◽

Bipolar Depression ◽

Good Alternative ◽

Effective Drug ◽

Acute Mania ◽

Sources Of Information ◽

Double Blind ◽

Proven Efficacy ◽

Continuation Treatment

AbstractAims: The efficacy of the anticonvulsants valproate, lamotrigine and gabapentin in bipolar disorder is reviewed.Method: Using Medline ® and other sources of information, 12 double-blind controlled studies with either of these compounds were identified.Results: None of the compounds has been proven effective in the prophylaxis of bipolar disorder. Valproate has been found an effective drug in acute mania, while in continuation treatment after acute mania it proved to be save, i.e. not causing switches into depression. Lamotrigine is the only anticonvulsant with proven efficacy in acute bipolar depression. So far gabapentin has not been found effective.Conclusion: For the prophylaxis of bipolar disorder, lithium is still the treatment of choice. Carbamazepine and valproate are good alternatives, especially for patients not responding to lithium or not tolerating it. Lamotrigine may be a good alternative in bipolar depression.

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Double-Blind, Randomized, Placebo-Controlled Trials of Ethyl-Eicosapentanoate in the Treatment of Bipolar Depression and Rapid Cycling Bipolar Disorder

Biological Psychiatry ◽

10.1016/j.biopsych.2006.03.056 ◽

2006 ◽

Vol 60 (9) ◽

pp. 1020-1022 ◽

Cited By ~ 152

Author(s):

Paul E. Keck ◽

Jim Mintz ◽

Susan L. McElroy ◽

Marlene P. Freeman ◽

Trisha Suppes ◽

...

Keyword(s):

Bipolar Disorder ◽

Bipolar Depression ◽

Controlled Trials ◽

Rapid Cycling ◽

Double Blind

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Recurrence rates in stable bipolar disorder patients after drug discontinuation v. drug maintenance: a systematic review and meta-analysis

Psychological Medicine ◽

10.1017/s0033291720003505 ◽

2020 ◽

pp. 1-9

Author(s):

Taro Kishi ◽

Yuki Matsuda ◽

Kenji Sakuma ◽

Makoto Okuya ◽

Kazuo Mishima ◽

...

Keyword(s):

Bipolar Disorder ◽

Recurrence Rate ◽

Meta Analysis ◽

Mood Stabilizer ◽

Recurrence Risk ◽

Drug Discontinuation ◽

Recurrence Rates ◽

Double Blind ◽

Mood Episode ◽

Depressive Episodes

Abstract Background This random-effects model meta-analysis of double-blind, randomized placebo-controlled trials compared recurrence rates in bipolar disorder (BD) patients between antipsychotic/mood stabilizer discontinuation and maintenance groups. Methods We conducted systematic literature search of Embase, PubMed, and CENTRAL databases without language restriction from inception until 22 May 2020. Independent investigators assessed studies and extracted data. We calculated risk ratios (RRs) and numbers needed to benefit or harm (NNTB/NNTH). Primary outcome was the recurrence rate of any mood episode at 6 months. Secondary outcomes were recurrence rates of depressive episodes and manic/hypomanic/mixed episodes and all-cause discontinuation at 6 months. We also investigated these outcomes at 1, 3, 9, 12, 18, and 24 months. Results We identified 22 studies (n = 5462) receiving aripiprazole, asenapine, divalproex, long-acting injectable (LAI)-aripiprazole, LAI-risperidone, lamotrigine, lithium, olanzapine, paliperidone, or quetiapine. Mean study duration was 64.50 ± 69.35 weeks. The maintenance group demonstrated lower recurrence rates of any mood episode, depressive episodes, and manic/hypomanic/mixed episodes as well as reduced all-cause discontinuation at every observational point. The RRs (95% confidence interval, NNTB/NNTH) of recurrence rate at 6 months were 0.61 (0.54–0.70, 5) for any mood episode, 0.72 (0.60–0.87, 13) for depressive episodes, and 0.45 (0.36–0.57, 6) for manic/hypomanic/mixed episodes. The RR for all-cause discontinuation at 6 months was 0.71 (0.61–0.82, 6). Conclusions Maintaining drug treatment during clinically stable BD prevented recurrence for up to 24 months. Discontinuation of medications for ⩾1 month significantly increased recurrence risk. However, 47.3% of patients who discontinued drugs for 6 months did not experience recurrence.

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Bipolar Disorder in Children and Adolescents

CNS Spectrums ◽

10.1017/s1092852900028728 ◽

2003 ◽

Vol 8 (12) ◽

pp. 954-959 ◽

Cited By ~ 8

Author(s):

Dwight V. Wolf ◽

Karen Dineen Wagner

Keyword(s):

Bipolar Disorder ◽

Children And Adolescents ◽

Psychosocial Development ◽

Age Of Onset ◽

Mood Stabilizers ◽

Diagnostic Challenge ◽

Open Label ◽

Double Blind ◽

Hyperactivity Disorder ◽

Combination Treatments

AbstractThere is increased recognition that bipolar disorder has an early age of onset. The prevalence of bipolar disorder in prepubertal children has not been determined, however the prevalence in adolescence is ˜1%. Bipolar disorder in children poses a diagnostic challenge since the symptoms may differ from those in late adolescence and adulthood. Comorbid disorders, such as attention-deficit/hyperactivity disorder, further complicate both the diagnosis and course of the disorder. There is increasing evidence of the chronicity and severity of this disorder in youths. Bipolar disorder significantly disrupts a child's psychosocial development including impairments in academic functioning, family functioning, and relationship with peers. Although this disorder has significant morbidity in children and adolescents, there is a paucity of controlled studies to assess the efficacy and safety of mood stabilizers in the treatment of this disorder in youths. The treatment literature consists largely of case studies, retrospective chart reviews, and open-label studies. There is a compelling need for double-blind, placebo-controlled trials to determine whether commonly used medications to treat this disorder are significantly superior to placebo. Since many children in clinical practice require more than one psychotropic medication to adequately manage this disorder, studies of combination treatments are warranted. This review will provide an overview of the literature of bipolar disorder in children and adolescents, including discussion of the prevalence, diagnosis, epidemiology, course of the illness, and treatment issues.

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An Open-Label Trial of Aripiprazole Monotherapy in Children and Adolescents with Bipolar Disorder

CNS Spectrums ◽

10.1017/s1092852900021519 ◽

2007 ◽

Vol 12 (9) ◽

pp. 683-689 ◽

Cited By ~ 43

Author(s):

Joseph Biederman ◽

Eric Mick ◽

Thomas Spencer ◽

Robert Doyle ◽

Gagan Joshi ◽

...

Keyword(s):

Bipolar Disorder ◽

Rating Scale ◽

Vital Signs ◽

Pediatric Bipolar Disorder ◽

Open Label ◽

Young Mania ◽

Double Blind ◽

Scale Scores ◽

Psychiatric Rating ◽

Psychiatric Rating Scale

ABSTRACTIntroduction: Aripiprazole is a novel second-generation antipsychotic approved for the treatment of bipolar disorder in adults but there is no systematic data available in pediatric bipolar disorder.Methods: This was an 8-week, open-label, prospective study of aripiprazole 9.4±4.2 mg/day monotherapy to assess the efficacy and tolerability of this compound in treating pediatric bipolar disorder. Assessments included the Young Mania Rating Scale, Clinical Global Impressions-Improvement scale, and Brief Psychiatric Rating Scale. Adverse events were assessed through spontaneous self-reports, vital signs weight monitoring, and laboratory analysis.Results: Fifteen of the 19 bipolar youth (79%) completed the study. Aripiprazole treatment was associated with clinically and statistically significant improvement in mean Young Mania Rating Scale scores (−18.0±6.9, P<.0001). With the important exception of two cases of extrapyramidal symptoms that precipitated dropout, aripiprazole was well tolerated with no statistically significant increase in body weight (1.8±1.7 kg, P=.2).Conclusion: Open-label aripiprazole treatment was beneficial in the treatment of mania in youth with bipolar disorder. Future placebo-controlled, double blind studies are warranted.

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Relationship of Brain Glutamate Response to D-Cycloserine and Lurasidone to Antidepressant Response in Bipolar Depression: A Pilot Study

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.653026 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhengchao Dong ◽

Michael F. Grunebaum ◽

Martin J. Lan ◽

Vashti Wagner ◽

Tse-Hwei Choo ◽

...

Keyword(s):

Rating Scale ◽

Bipolar Depression ◽

Anterior Cingulate ◽

Antidepressant Effect ◽

Resonance Spectroscopy ◽

Open Label ◽

Double Blind ◽

Open Label Phase ◽

Relationship Of ◽

The Impact

N-methyl-D-aspartate glutamate-receptor (NMDAR) antagonists such as ketamine have demonstrated efficacy in both major depressive disorder (MDD) and bipolar disorder depression (BP-D). We have previously reported that reduction in Glx (glutamate + glutamine) in the ventromedial prefrontal cortex/anterior cingulate cortex (vmPFC/ACC), measured by proton magnetic resonance spectroscopy (1H MRS) at 3T during a ketamine infusion, mediates the relationship of ketamine dose and blood level to improvement in depression. In the present study, we assessed the impact of D-cycloserine (DCS), an oral NMDAR antagonist combined with lurasidone in BP-D on both glutamate and Glx. Subjects with DSM-V BP-D-I/II and a Montgomery-Asberg Depression Rating Scale (MADRS) score>17, underwent up to three 1H MRS scans. During Scan 1, subjects were randomized to receive double-blind lurasidone 66 mg or placebo. During Scan 2, all subjects received single-blind DCS 950 mg + lurasidone 66 mg, followed by 4 weeks of open label phase of DCS+lurasidone and an optional Scan 3. Five subjects received lurasidone alone and three subjects received placebo for Scan 1. Six subjects received DCS+lurasidone during Scan 2. There was no significant baseline or between treatment-group differences in acute depression improvement or glutamate response. In Scan 2, after a dose of DCS+lurasidone, peak change in glutamate correlated negatively with improvement from baseline MADRS (r = −0.83, p = 0.04). There were no unexpected adverse events. These preliminary pilot results require replication but provide further support for a link between antidepressant effect and a decrease in glutamate by the NMDAR antagonist class of antidepressants.

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A 6-month, Randomized, Placebo-controlled, Double Blind Trial of Ziprasidone Plus a Mood Stabilizer in Subjects With Bipolar I Disorder

European Psychiatry ◽

10.1016/s0924-9338(09)70827-2 ◽

2009 ◽

Vol 24 (S1) ◽

pp. 1-1 ◽

Cited By ~ 2

Author(s):

E. Vieta ◽

C. Bowden ◽

K. Ice ◽

O. Gurtovaya ◽

J. Schwartz ◽

...

Keyword(s):

Maintenance Treatment ◽

Mood Stabilizer ◽

Adjunctive Treatment ◽

Rank Test ◽

Open Label ◽

Double Blind ◽

Bipolar I Disorder ◽

Mood Episode ◽

Bipolar Mania ◽

Group 5

Background:The objective of this study was to evaluate the efficacy and safety of ziprasidone adjunctive to a mood stabilizer for the maintenance treatment of bipolar mania.Methods:Male and female subjects with bipolar I disorder with MRS 3 14 were enrolled. Subjects achieving ≥ 8 consecutive weeks of stability with open-label ziprasidone (80-160 mg/d) and lithium or divalproex were randomized into the 6-month double-blind maintenance period, to ziprasidone + mood stabilizer or placebo + mood stabilizer. The primary and key secondary end points were the time to intervention for a mood episode, and time to discontinuation for any reason, respectively. Inferential analysis was performed using a Kaplan-Meier product-limit estimator (Log-rank test).Results:127 and 112 subjects were randomized to and treated in the ziprasidone and placebo groups, respectively. The time to intervention for a mood episode was significantly different, favoring ziprasidone (p = 0.0104). 19.7% and 32.4% of ziprasidone and placebo subjects, respectively, required intervention for a mood episode. Time to discontinuation for any reason was significantly different (p = 0.0047), favoring ziprasidone. Among treatment-emergent adverse events occurring in the double-blind period, the only event occurring more frequently in the ziprasidone group than in the placebo group (≥ 5%) was tremor (6.3% vs 3.6%, respectively).Conclusions:These results demonstrate that ziprasidone is an effective, safe, and well-tolerated adjunctive treatment with a mood stabilizer for long-term maintenance treatment of bipolar mania.

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