Recurrence Of Mood Episodes Research Articles

P03-359 Randomized, double-blind, placebo-controlled study of risperidone long-acting injectable in relapse prevention in patients with bipolar I disorder

ObjectivesTo evaluate risperidone long-acting injectable (RLAI) versus placebo in prevention of mood episodes in adults with bipolar I disorder.MethodsA 12-week open-label period with RLAI (N=585) was followed by an 18-month randomized, double-blind period with RLAI (25, 37.5 or 50 mg/2 weeks; N=137) or placebo (N=140); a third group (N=138) was randomized to olanzapine for reference and exploratory comparisons. Primary efficacy endpoint: time to relapse of any mood episode for risperidone LAI vs. placebo in the double-blind period (Kaplan-Meier analysis). Relapse was defined by criteria including DSM diagnosis, further treatment, hospitalisation, or Clinical Global Impression score ≥4 combined with YMRS or MADRS >12.ResultsDosing was fixed during the double-blind period at patients’ final open-label dose (25 mg, 66%; 37.5 mg, 31%; 50 mg, 4%). Time to recurrence (any mood episode) was longer with RLAI versus placebo (log-rank test stratified by region and patient type, p=0.062; stratified by region only, p=0.032); the difference was significant for time to recurrence of elevated mood episodes (p=0.005) but not depressive episodes (p=0.587). Discontinuations due to adverse events (AEs) occurred in 2% of patients in the open-label period, and 4% and 1% in the RLAI and placebo groups, respectively, in the double-blind period. The most frequently reported AE in the open-label period was insomnia (15%). During double-blind treatment, the most frequently reported AEs with RLAI were weight increased (24%; placebo, 9%) and insomnia (16%; placebo, 17%).Table 1.Type of recurrenceType of episode, n (%)Risperidone LAI (N=135)Placebo (N=138)All mood episodes52 (38.5)77 (55.8)Elevated mood episode27 (20.0)54(39.1)Hypomanic2(1.5)4 (2.9)Manic17(12.6)43(31.2)Mixed8 (5.9)7(5.1)Depressive25(18.5)23(16.7)ConclusionRLAI significantly delayed time to relapse of elevated mood episodes and was well tolerated.

Olanzapine in the long-term treatment of bipolar disorder: A systematic review and meta-analysis

Olanzapine was licensed in the USA by the Food and Drug Administration in 2003 for the prevention of relapse in patients with bipolar disorder when the acute manic episode had responded to treatment with olanzapine. However, olanzapine is commonly used in clinical practice for preventing relapse in patients with bipolar disorder even when acute response has not been demonstrated. The aim of this systematic review and meta-analysis is to determine the effectiveness and acceptability of olanzapine in preventing recurrent mood episodes in bipolar disorder. MEDLINE, EMBASE, the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register and the Cochrane Central Register of Controlled up to July 2008 were accessed. Only randomised controlled trials comparing olanzapine with placebo or other active drugs for long-term treatment were included. Two reviewers independently extracted data. Authors were contacted to provide additional data. Of the five trials included in this review, four were conducted by Eli Lilly, the manufacturer of olanzapine. Olanzapine was more effective than placebo at preventing manic relapse, but there was no difference between olanzapine (alone or in combination with lithium or valproate) and placebo (alone or in combination with lithium or valproate) in terms of relapse into any mood episode, as defined as primary outcome by authors in each of the primary studies. We conclude that olanzapine may prevent further manic episodes only in patients who have responded to olanzapine in an acute manic or mixed episode and who have not previously had a satisfactory response to lithium or valproate.

Retrospective age at onset of bipolar disorder and outcome during two‐year follow‐up: results from the STEP‐BD study

Symptoms of bipolar disorder are increasingly recognized among children and adolescents, but little is known about the course of bipolar disorder among adults who experience childhood onset of symptoms. We examined prospective outcomes during up to two years of naturalistic treatment among 3,658 adult bipolar I and II outpatients participating in a multicenter clinical effectiveness study, the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Age at illness onset was identified retrospectively by clinician assessment at study entry. Compared to patients with onset of mood symptoms after age 18 years (n = 1,187), those with onset before age 13 years (n = 1,068) experienced earlier recurrence of mood episodes after initial remission, fewer days of euthymia, and greater impairment in functioning and quality of life over the two-year follow-up. Outcomes for those with onset between age 13 and 18 years (n = 1,403) were generally intermediate between these two groups. Consistent with previous reports in smaller cohorts, adults with retrospectively obtained early-onset bipolar disorder appear to be at greater risk for recurrence, chronicity of mood symptoms, and functional impairment during prospective observation.

Maintenance treatment of adolescent bipolar disorder: open study of the effectiveness and tolerability of quetiapine

BackgroundThe purpose of the study was to determine the effectiveness and tolerability of quetiapine as a maintenance treatment preventing against relapse or recurrence of acute mood episodes in adolescent patients diagnosed with bipolar disorder.MethodsConsenting patients meeting DSM-IV lifetime criteria for a bipolar disorder and clinically appropriate for maintenance treatment were enrolled in a 48-week open prospective study. After being acutely stabilized (CGI-S ≤ 3 for 4 consecutive weeks), patients were started or continued on quetiapine and other medications were weaned off over an 8-week period. Quetiapine monotherapy was continued for 40-weeks and other mood stabilizers or antidepressants were added if clinically indicated. A neurocognitive test battery assessing the most reliable findings in adult patients was administered at fixed time points throughout the study to patients and matched controls.ResultsOf the 21 enrolled patients, 18 completed the 48-week study. Thirteen patients were able to be maintained without relapse or recurrence in good quality remission on quetiapine monotherapy, while 5 patients required additional medication to treat impairing residual depressive and/or anxiety symptoms. According to symptom ratings and global functioning scores, the quality of remission for all patients was very good.Neurocognitive test performance over treatment was equivalent to that of a matched control group of never ill adolescents. Quetiapine was generally well tolerated with no serious adverse effects.ConclusionThis study suggests that a proportion of adolescent patients diagnosed with bipolar disorder can be successfully maintained on quetiapine monotherapy. The good quality of clinical remission and preserved neurocognitive functioning underscores the importance of early diagnosis and effective stabilization.Clinical Trials RegistryD1441L00024

Course and Outcome after the First Manic Episode in Patients with Bipolar Disorder: Prospective 12-Month Data from the Systematic Treatment Optimization Program for Early Mania Project

To describe clinical characteristics, course, and outcome during a 1-year period after the first manic episode in patients with bipolar disorder (BD). This paper describes the project design, demographics, clinical outcomes, and predictors at 6 months to 1 year of follow-up of the first 53 recruited subjects with first-episode mania from the Systematic Treatment Optimization Program for Early Mania. Survival analysis for recurrence of mood episodes showed that 46.7% of patients survived without a mood episode during 1-year of follow-up, and the mean time-to-mood event was 7.9 months. Earlier age of onset was the only variable that significantly predicted recurrence of mood episodes. When examined separately, the survival rates were 76% for a manic episode and 58.7% for a depressive episode. These results suggest that recurrences are common after the first manic episode with more than one-half of the patients experiencing a mood event within 12 months. Aggressive treatment strategies aimed at preventing depressive episodes are needed in the management of early course BD.

Lithium: Updated Human Knowledge Using an Evidence-Based Approach

Although there has been a decrease in lithium use over several years, it is still recommended as a first-line mood stabilizer in all recent guidelines. It has been argued that many studies of lithium were conducted at a time when study design, assessment standards and the diagnostic criteria for patient selection were not as established as they presently are. However, recent placebo-controlled data from three-arm trials have demonstrated a definite efficacy of lithium in bipolar disorder. Regarding mania, recent trials of novel antimanic treatments (such as second-generation antipsychotics) that have included both placebo and lithium control groups have confirmed that lithium is effective in the treatment of moderate to severe manic episodes. The efficacy of lithium as monotherapy for acute bipolar depression is still controversial, but this therapy is recognized as a therapeutic option. For maintenance therapy, lithium is superior to placebo for the prevention of relapse or recurrence of mood episodes in bipolar I disorder patients with recent manic or hypomanic episodes. Lithium is more effective in preventing episodes of the manic/hypomanic type, including mixed episodes, than preventing depressive episodes. In rapid cycling patients, lithium improves clinical symptoms as efficiently as in nonrapid cycling persons, but is not likely to prevent recurrences. Finally, data from a number of studies suggest that lithium reduces the high suicide rates associated with mood disorders. A well designed cohort study and two independent meta-analyses are in agreement with this finding. In conclusion, most experts, and the most recent guidelines, continue to consider lithium as a keystone therapy of bipolar disorders.

P01-210 Quetiapine: Mood stabilization across all phases of bipolar disorder

Background:Following resolution of acute symptoms (manic and depressed), most patients with bipolar disorder experience affective recurrences and residual functional impairment. This indicates a need for a treatment that not only manages the acute phase of illness but also maintains the stabilized patient.Methods:Data are presented to support the effectiveness of quetiapine in: managing the acutely ill patient; maintaining the euthymic patient by preventing mood event recurrence; and improving patient-perceived functioning.Results:Quetiapine monotherapy demonstrates efficacy against mania symptoms as early as Day 4 (Trials 104 and 105 [pooled datasets]; P< 0.05 vs placebo) and Week 1 in bipolar depression (BOLDER and EMBOLDEN [pooled datasets]; P< 0.001 vs placebo). The acute antidepressive effect was significant for both bipolar I and II populations. As continuation therapy in bipolar depression, quetiapine is associated with a significant reduction in the risk of depressive mood event recurrence (EMBOLDEN I and II; P< 0.001 vs placebo). Moreover, quetiapine significantly reduces the risk of recurrence of mania or depression events as an adjunct to lithium or divalproex (Trials 126 and 127; P< 0.0001), and as monotherapy (Trial 144; P< 0.001). Quetiapine is generally well tolerated in all phases.Conclusions:Quetiapine fulfills mood stabilization criteria by demonstrating efficacy in all phases of bipolar disorder. To date, quetiapine is the only treatment to show robust efficacy against both poles of bipolar disorder, without causing an excess shift to the opposite pole, and to prevent mood episode recurrence irrespective of the index episode.Supported by funding from AstraZeneca Pharmaceuticals LP.

A 6-Month, Double-Blind, Maintenance Trial of Lithium Monotherapy Versus the Combination of Lithium and Divalproex for Rapid-Cycling Bipolar Disorder and Co-Occurring Substance Abuse or Dependence

To assess whether combination treatment with lithium and divalproex is more effective than lithium monotherapy in prolonging the time to mood episode recurrence in patients with rapid-cycling bipolar disorder and comorbid substance abuse and/or dependence. A 6-month, double-blind, parallel-group comparison was carried out in patients who met DSM-IV criteria for (1) bipolar I or II disorder; (2) alcohol, cannabis, or cocaine abuse within the last 3 months or dependence within the last 6 months; (3) rapid cycling during the 12 months preceding study entry; and (4) a history of at least 1 manic, hypomanic, or mixed episode within 3 months of study entry and who had demonstrated a persistent bimodal response to combined treatment with lithium and divalproex. Subjects were randomly assigned to remain on combination treatment or to discontinue divalproex and remain on lithium monotherapy. The study was conducted at an outpatient mood disorders program between October 1997 and October 2006. Of 149 patients enrolled into the open-label acute stabilization phase, 79% discontinued prematurely (poor adherence: 42%, nonresponse: 25%, intolerable side effects: 10%). Of 31 patients (21%) randomly assigned to double-blind maintenance treatment, 55% (N = 17) relapsed (24% [N = 4] into depression and 76% [N = 13] into a manic/hypomanic/mixed episode), 26% (N = 8) completed the study, and 19% (N = 6) were poorly adherent or exited prematurely. The median time to recurrence of a new mood episode was 15.9 weeks for patients receiving lithium monotherapy and 17.8 weeks for patients receiving the combination of lithium and divalproex (not significant). The rate of relapse into a mood episode for those receiving lithium monotherapy or the combination of lithium and divalproex was 56% (N = 9) and 53% (N = 8), respectively. The rate of depressive relapse in both arms was 13% (N = 2), while the rate of relapse into a manic, hypomanic, or mixed episode was 44% (N = 7) for lithium monotherapy and 40% (N = 6) for the combination of lithium and divalproex. A small subgroup of patients in this study stabilized after 6 months of treatment with lithium plus divalproex. Of those who did, the addition of divalproex to lithium conferred no additional prophylactic benefit over lithium alone. Although depression is regarded as the hallmark of rapid-cycling bipolar disorder in general, these data suggest that recurrent episodes of mania tend to be more common in presentations accompanied by comorbid substance use. clinical trials.gov Identifier: NCT00194129.

Lamotrigine for agitation in older patients with dementia

Although not approved by the Food and Drug Administration (FDA) for behavioral disturbances, the largest number of antipsychotic prescriptions in older adults is for this indication associated with dementia (Sultzer et al., 2008). In 2005, the FDA determined that atypical antipsychotic medications were associated with a 1.6 to 1.7 greater risk of mortality compared with placebo when administered to older patients with dementia (De-Deyn et al., 2005). Psychosis and agitation symptoms in patients with dementia are common, disruptive, and costly but there are no well-established, evidenced-based effective treatment alternatives (Jeste et al., (2008). A limited amount of mostly anecdotal scientific data suggests that anticonvulsant medications, including some of the newer agents like lamotrigine, may be helpful for agitation and psychosis in older patients with dementia (DeLeon, 2004). Lamotrigine is an anti-epileptic drug whose mechanism of action is thought to be linked to voltage-sensitive sodium channel blockade in the neuronal membrane and inhibition of presynaptic glutamate and aspartate release (Baumann et al., 2007). Lamotrigine has a safe profile and has documented efficacy in delaying recurrence of mood episodes in patients with bipolar disorder in trials conducted for up to 18 months.

Risk of Recurrence in Women With Bipolar Disorder During Pregnancy: Prospective Study of Mood Stabilizer Discontinuation

This study estimated the risk of recurrence of mood episodes among women with a history of bipolar disorder who continued or discontinued treatment with mood stabilizers during pregnancy. In a prospective observational clinical cohort study, the authors determined recurrence risk and survival-analysis-based time to recurrence of a new episode in 89 pregnant women with DSM-IV bipolar disorder. Eligible subjects were euthymic at conception and continued mood stabilizer treatment or discontinued treatment proximate to conception. The overall risk of at least one recurrence in pregnancy was 71%. Among women who discontinued versus continued mood stabilizer treatment, recurrence risk was twofold greater, median time to first recurrence was more than fourfold shorter, and the proportion of weeks ill during pregnancy was five times greater. Median recurrence latency was 11 times shorter after abrupt/rapid versus gradual discontinuation of mood stabilizer. Most recurrences were depressive or mixed (74%), and 47% occurred during the first trimester. Predictors of recurrence included bipolar II disorder diagnosis, earlier onset, more recurrences/year, recent illness, use of antidepressants, and use of anticonvulsants versus lithium. Discontinuation of mood stabilizer, particularly abruptly, during pregnancy carries a high risk for new morbidity in women with bipolar disorder, especially for early depressive and dysphoric states. However, this risk is reduced markedly by continued mood stabilizer treatment. Treatment planning for pregnant women with bipolar disorder should consider not only the relative risks of fetal exposure to mood stabilizers but also the high risk of recurrence and morbidity associated with stopping maintenance mood stabilizer treatment.

Olanzapine as Maintenance Therapy in Patients with Bipolar I Disorder

ABSTRACTEffective treatments for the prevention of relapse and recurrence of mood episodes in patients with bipolar disorder are essential to reduce the high mortality associated with this condition, and to improve long-term outcomes. While lithium is considered to be effective as a first line maintenance treatment, additional treatment options would provide clinicians with tools to address the needs of individual patients. The efficacy of olanzapine, an atypical antipsychotic, for the prevention of relapse in bipolar disorder has been demonstrated in several randomized controlled double-blind clinical trials, both as monotherapy and in combination with other agents. The data reviewed herein suggest a more robust efficacy of treatment with olanzapine in the prevention of relapse into manic episodes than into depressive episodes. The adverse events observed most frequently in patients treated with olanzapine relative to comparators were related to somnolence (somnolence, fatigue, or hypersomnia) and weight gain (weight gain, or increased appetite). Moreover, a larger proportion of olanzapine-treated patients than comparator-treated patients experienced clinically important weight gain.

Electroconvulsive Therapy as an Alternative Treatment for Obese Patients With Mood Disorders

With the increased use of atypical antipsychotic medication in the treatment of mood disorders, patients are increasingly experiencing side effects, such as obesity, insulin resistance, and the metabolic syndrome, which, in turn, increases the risk of developing cardiovascular disease, type 2 diabetes, and hypertension. Maintenance electroconvulsive therapy (MECT) can be used as a prophylaxis for the recurrence of mood episodes for treatment-resistant patients. There are no reports of metabolic syndromes associated with ECT. We reviewed the charts of 10 patients who have received MECT at our institution over the last 10-year period. Five of 10 patients were obese pre-ECT, all of whom had a significant weight loss after ECT. Patients whose weights were normal pre-ECT, did not experience weight loss. Our finding suggests that ECT is a viable alternative for overweight patients with mood disorders who do not respond to mood stabilizers or cannot tolerate side effects.

Recurrence in Bipolar I Disorder: A Post Hoc Analysis Excluding Relapses in Two Double-blind Maintenance Studies

To assess the efficacy of lamotrigine or lithium in preventing mood recurrence (i.e., a new mood episode) in bipolar disorder. Data from bipolar I patients with relapses (i.e., mood episodes having the same polarity as the index episode within 90 or 180 days of randomization) were excluded from post hoc efficacy analyses of two 18-month, placebo-controlled maintenance trials of lamotrigine and lithium. Both lamotrigine and lithium were more effective than placebo in delaying the time to intervention for any mood episode (depression, mania, hypomania, or mixed) when relapses that occurred in the first 90 days were excluded from the analyses (p = .002, lamotrigine vs. placebo; p = .010, lithium vs. placebo). Results were similar when patients with mood episodes within 180 days of randomization were excluded. Both lamotrigine and lithium maintenance therapy protected against mood episode recurrence in bipolar I disorder.

Maintenance Therapies in Bipolar Disorder: Focus on Randomized Controlled Trials

Lithium remains the cornerstone of maintenance therapy for bipolar disorder despite growing use of other agents, including divalproex, lamotrigine, carbamazepine and the atypical antipsychotics. Lithium has the largest body of data to support its continued use as a prophylactic agent; however, most of this data comes from early studies that did not use contemporary analytic methods. Alternatives to lithium are needed because of the relatively high rate of non-response to lithium monotherapy and the drug's frequent side-effects. This article reviews available data with an emphasis on double-blind, placebo-controlled studies that examine the efficacy of lithium and other putative mood stabilizers: carbamazepine, divalproex, lamotrigine and olanzapine. The authors reviewed key literature using Medline searches using key words: bipolar disorder, controlled trials, mood stabilizer, lithium, lomotrigine, divalproex, olanzapine, carbamazepine. Lithium remains the gold standard for overall preventative efficacy in bipolar disorder, especially to decrease manic or hypomanic relapse. Of the mood stabilizers that have marked prophylactic antimanic properties, lithium appears to possess the greatest antidepressant effect. Divalproex may also prevent recurrent bipolar mood episodes but the relative lack of controlled maintenance studies makes this less certain. There now exists an extensive and well-designed research database supporting the use of lamotrigine in the acute and prophylactic management of bipolar I disorder. Lamotrigine offers a spectrum of clinical effectiveness that complements lithium, in that it appears to stabilize mood 'from below baseline' by preventing episodes of depression and has been shown to be effective in rapid-cycling bipolar II disorder. Carbamazepine may be a useful alternative to lithium, divalproex and lamotrigine, particularly for patients with a history of mood-incongruent delusions and other comorbidities, but controlled data is more equivocal and it may lose some of its prophylactic effect over time. Emerging data continue to support the growing use of atypical antipsychotics, particularly olanzapine. Any monotherapy for use as a maintenance therapy of bipolar disorder appears to be inadequate for long-term use in the management of the majority of patients with bipolar disorder. Combination therapy has become the standard of care in the treatment of bipolar disorder and particularly in patients with treatment-refractory variants such as those with rapid-cycling. The emerging consensus is that patients on monotherapy, if followed for sufficiently long periods, will eventually require concomitant treatment to maintain a full remission. There exists a need for controlled trials that use random assignment to parallel arms including combination therapy followed by data analyses that include both relapse rate and survival techniques.

Divalproex did not differ from placebo or lithium in preventing recurrence of new mood episodes in bipolar I disorder, remission phase

Bowden CL, Calabrese JR, McElroy SL, et al, for the Divalproex Maintenance Study Group. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I...

Recovery from major depression. A 10-year prospective follow-up across multiple episodes.

Major depressive disorder is often marked by repeated episodes of depression. We describe recovery from major depression across multiple mood episodes in patients with unipolar major depression at intake and examine the association of sociodemographic and clinical variables with duration of illness. A cohort of 258 subjects treated for unipolar major depressive disorder was followed up prospectively for 10 years as part of the Collaborative Depression Study, a multicenter naturalistic study of the mood disorders. Diagnoses were made according to the Research Diagnostic Criteria, and the course of illness was assessed with the Longitudinal Interval Follow-up Evaluation. Survival analyses were used to calculate the duration of illness for the first 5 recurrent mood episodes after recovery from the index episode. Diagnosis remained unipolar major depressive disorder for 235 subjects (91%). The median duration of illness was 22 weeks for the first recurrent mood episode, 20 weeks for the second, 21 weeks for the third, and 19 weeks for the fourth and fifth recurrent mood episodes; the 95% confidence intervals were highly consistent. From one episode to the next, the proportion of subjects who recovered by any one time point was similar. For subjects with 2 or more recoveries, the consistency of duration of illness from one recovery to the next was low to moderate. None of the sociodemographic or clinical variables consistently predicted duration of illness. In this sample of patients treated at tertiary care centers for major depressive disorder, the duration of recurrent mood episodes was relatively uniform and averaged approximately 20 weeks.