Rapid-cycling bipolar disorder in children.
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Adolescent↗
Biomedical subjects
J R Calabrese
Publications and source records attributed to J R Calabrese.
A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 Study Group.
BACKGROUND: Patients with rapid-cycling bipolar disorder are often treatment refractory. This study examined lamotrigine as maintenance monotherapy for rapid-cycling bipolar disorder. METHOD: Lamotrigine was added to patients' current psychotropic regimens and titrated to clinical effect during an open-label treatment phase. Stabilized patients were tapered off other psychotropics and randomly assigned to lamotrigine or placebo monotherapy for 6 months. Time to additional pharmacotherapy for emerging symptoms was the primary outcome measure. Secondary efficacy measures included survival in study (time to any premature discontinuation), percentage of patients stable without relapse for 6 months, and changes in the Global Assessment Scale and Clinical Global Impressions-Severity scale. Safety was assessed from adverse event, physical examination, and laboratory data. RESULTS: 324 patients with rapid-cycling bipolar disorder (DSM-IV criteria) received open-label lamotrigine, and 182 patients were randomly assigned to the double-blind maintenance phase. The difference between the treatment groups in time to additional pharmacotherapy did not achieve statistical significance in the overall efficacy population. However, survival in study was statistically different between the treatment groups (p = .036). Analyses also indicated a 6-week difference in median survival time favoring lamotrigine. Forty-one percent of lamotrigine patients versus 26% of placebo patients (p = .03) were stable without relapse for 6 months of monotherapy. Lamotrigine was well tolerated; there were no treatment-related changes in laboratory parameters, vital signs, or body weight. No serious rashes occurred. CONCLUSION: This was the largest and only prospective placebo-controlled study of rapid-cycling bipolar disorder patients to date; results indicate lamotrigine monotherapy is a useful treatment for some patients with rapid-cycling bipolar disorder.
Adolescent↗
Mania: gender, transmitter function, and response to treatment.
Noradrenergic and GABA systems may be involved in mania, but there is little information about relationships between the function of these systems and response to specific antimanic treatments. We investigated relationships between indices of catecholamine or GABA system function, pretreatment mania severity and antimanic response to divalproex, lithium, or placebo. Plasma GABA and urinary excretion of catecholamine metabolites were measured before randomization to lithium, divalproex or placebo in patients hospitalized for manic episodes. Severity of mania was evaluated using the Manic Syndrome, Behavior and Ideation and Mania Rating Scale scores from the SADS-C. Multiple regression analysis showed that pretreatment plasma GABA was related to severity of manic symptoms. This relationship seemed stronger in women. Multiple regression analysis showed that pretreatment levels of urinary MHPG correlated with improvement in manic syndrome scores. These data suggest that GABA and norepinephrine may be related to different aspects of the manic state and to its pharmacologic sensitivity.
Adult↗
The efficacy of lamotrigine in rapid cycling and non-rapid cycling patients with bipolar disorder.
BACKGROUND: Patients with bipolar disorder (BD) who have rapid cycling features are often treatment refractory. Clear and conclusive evidence regarding effective treatments for this group is not available. METHODS: Patients with diagnoses of refractory bipolar disorder who were currently experiencing manic, mixed, depressive, or hypomanic episodes were treated with lamotrigine as add-on therapy (60 patients) or monotherapy (15 patients). We compared the efficacy of lamotrigine in the 41 rapid cycling and 34 non-rapid cycling patients with BD. RESULTS: Improvement from baseline to last visit was significant among both rapid cycling and non-rapid cycling patients for both depressive and manic symptomatology. For patients entering the study in a depressive episode, improvement in depressive symptomatology was equivalent in the two groups. Among patients entering the study in a manic, mixed, or hypomanic episode, those with rapid cycling improved less in manic symptomatology than did non-rapid cycling patients. Among rapid cycling patients with initial mild-to-moderate manic symptom severity, improvement was comparable to that in non-rapid cycling subjects; however, the subset of rapid cycling patients with severe initial manic symptomatology had little improvement in mania. Rapid cycling patients had earlier onset and more lifetime episodes of mania, depression, and mixed mania. CONCLUSIONS: Lamotrigine was generally effective and well tolerated in this group of previously non-responsive, rapid cycling bipolar patients.
Activity Cycles↗
Fish oils and bipolar disorder: a promising but untested treatment.
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Bipolar Disorder↗
Lamotrigine and the treatment of bipolar disorder. Introduction.
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Antidepressive Agents↗
Controlled trials in bipolar I depression: focus on switch rates and efficacy.
Until recently, the rate at which patients switch from bipolar depression to the manic or hypomanic phase of the disorder during treatment with antidepressant medications was poorly defined. The completion of three large-scale, double-blind controlled trials in bipolar I depression has improved understanding of this phenomenon. The low switching rates observed in these studies of lamotrigine, paroxetine and moclobemide may indicate a special application of these drugs in the management of patients prone to antidepressant-induced switching. These studies also confirm prior suggestions that tricyclic antidepressants present the highest risk of switching. At present there is no consensus over the optimal definition of switching. Standardising the definition may lead to improvements in the clinical management of bipolar disorder.
Antidepressive Agents↗
Spectrum of activity of lamotrigine in treatment-refractory bipolar disorder.
OBJECTIVE: New mood stabilizers are needed that possess efficacy for all phases of bipolar disorder. This study was designed to provide preliminary evidence for the safety and efficacy of a new anticonvulsant, lamotrigine, in adult patients with bipolar disorder who had been inadequately responsive to or intolerant of prior pharmacotherapy. METHOD: A 48-week, open-label, prospective trial was conducted in 75 patients with bipolar I or bipolar II disorder. Lamotrigine was used as adjunctive therapy (N = 60) or monotherapy (N = 15) in patients presenting in depressed, hypomanic, manic, or mixed states. RESULTS: Of the 40 depressed patients included in the efficacy analysis, 48% exhibited a marked response and 20% a moderate response as measured by reductions in 17-item Hamilton Depression Rating Scale scores. Of the 31 with a hypomanic, manic, or mixed state, 81% displayed a marked response and 3% a moderate response on the Mania Rating Scale. From baseline to endpoint, the depressed patients exhibited a 42% decrease in Hamilton depression scale scores, and the patients presenting with hypomania, mania, or a mixed state exhibited a 74% decrease in Mania Rating Scale scores. The most common drug-related adverse events were dizziness, tremor, somnolence, headache, nausea, and rash. Rash was the most common adverse event resulting in drug discontinuation (9% of patients); one patient developed a serious rash and required hospitalization. CONCLUSIONS: These open-label data provide preliminary evidence that lamotrigine may be an effective treatment option for patients with refractory bipolar disorder; however, potential benefits must be weighed against potential side effects, including rash.
Adult↗
Differential effect of number of previous episodes of affective disorder on response to lithium or divalproex in acute mania.
OBJECTIVE: The authors investigated the relationship between number of lifetime episodes of affective disorder and the antimanic response to lithium, divalproex, or placebo. METHOD: The subjects were 154 of the 179 inpatients with acute mania who entered a 3-week parallel group, double-blind study. The primary efficacy measure was the manic syndrome score from the Schedule for Affective Disorders and Schizophrenia. The relationship between improvement and number of previous episodes was investigated by using nonlinear regression analysis. RESULTS: An apparent transition in the relationship between number of previous episodes and response to antimanic medication occurred at about 10 previous episodes. For patients who had experienced more episodes, response to lithium resembled the response to placebo but was worse than response to divalproex. For patients who had experienced fewer episodes, however, the responses to lithium and divalproex did not differ and were better than the response to placebo. This differential response pattern was not related to rapid cycling or mixed states. CONCLUSIONS: A history of many previous episodes was associated with poor response to lithium or placebo but not to divalproex.
Acute Disease↗
A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group.
BACKGROUND: More treatment options for bipolar depression are needed. Currently available antidepressants may increase the risk of mania and rapid cycling, and mood stabilizers appear to be less effective in treating depression than mania. Preliminary data suggest that lamotrigine, an established antiepileptic drug, may be effective for both the depression and mania associated with bipolar disorder. This is the first controlled multicenter study evaluating lamotrigine monotherapy in the treatment of bipolar I depression. METHODS: Outpatients with bipolar I disorder experiencing a major depressive episode (DSM-IV, N = 195) received lamotrigine (50 or 200 mg/day) or placebo as monotherapy for 7 weeks. Psychiatric evaluations, including the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), Mania Rating Scale, and the Clinical Global Impressions scale for Severity (CGI-S) and Improvement (CGI-I) were completed at each weekly visit. RESULTS: Lamotrigine 200 mg/day demonstrated significant antidepressant efficacy on the 17-item HAM-D, HAM-D Item 1, MADRS, CGI-S, and CGI-I compared with placebo. Improvements were seen as early as week 3. Lamotrigine 50 mg/day also demonstrated efficacy compared with placebo on several measures. The proportions of patients exhibiting a response on CGI-I were 51%, 41%, and 26% for lamotrigine 200 mg/day, lamotrigine 50 mg/day, and placebo groups, respectively. Adverse events and other safety results were similar across treatment groups, except for a higher rate of headache in the lamotrigine groups. CONCLUSION: Lamotrigine monotherapy is an effective and well-tolerated treatment for bipolar depression.
Adult↗
Mood stabilizers and the evolution of maintenance study designs in bipolar I disorder.
The designs employed in bipolar maintenance studies have evolved greatly over the last 28 years. Consequently, there has been minimal consensus set for methods used to demonstrate the ability of any new putative mood stabilizers to prevent relapse and recurrence in bipolar disorder. The methods that have evolved the most include enrollment procedures, randomization schemes, use of outcome measures, statistical analyses, and country-specific commercial and regulatory issues. This article contrasts the various methods employed in first- and second-generation placebo-controlled bipolar I maintenance studies. This article also explores the advantages and disadvantages associated with various designs.
Anticonvulsants↗
Clinical studies on the use of lamotrigine in bipolar disorder.
New mood stabilizers that possess efficacy in the depressed phase of bipolar disorder are needed. The use of marketed antidepressants puts bipolar patients at some increased risk for drug-induced hypomania/mania and rapid cycling. During the development of the antiepileptic, lamotrigine, the drug was observed to improve mood, alertness, and social interactions in some patients with epilepsy. These early observations provided the rationale for investigations into lamotrigine's potential efficacy in bipolar disorder. There are now 14 open clinical reports involving a total of 207 lamotrigine-treated patients with bipolar disorder that suggest this drug possesses a broad spectrum of efficacy in the management of the depressed, hypomanic, manic, and mixed phases of bipolar disorder. In an attempt to replicate and extend these preliminary open-label prospective findings, a series of multicenter, double-blind, placebo-controlled studies evaluating the efficacy and dose-response relationships of lamotrigine in the various phases of the illness, including both acute and maintenance designs in both bipolar I and II disorder, is ongoing.
Anticonvulsants↗
Depression during mania. Treatment response to lithium or divalproex.
BACKGROUND: Little information exists from controlled studies about clinical characteristics that predict treatment response in mania. The presence of depressive symptoms during manic episodes may be associated with poor response to psychopharmacological treatments. This is an investigation of the relation between depressive symptoms and treatment response in acute manic episodes. METHODS AND DESIGN: In a parallel-group, double-blind study, 179 patients hospitalized for acute manic episodes were randomized to receive divalproex sodium, lithium carbonate, or placebo (ratio, 2:1:2). The study was carried out at 9 academic medical centers. Patients had comprehensive evaluations of behavior and symptoms before and during 3 weeks of treatment. The primary outcome measure, change in mania factor scores derived from the Schedule for Affective Disorders and Schizophrenia: Change Version, was compared in patients with and without depressive symptoms at baseline according to nurse- or physician-rated scales. RESULTS: Depressive symptoms were associated with poor antimanic response to lithium and with better response to divalproex. This was not due to differences in overall severity of illness, substance abuse, gender, age, or history. CONCLUSIONS: These data suggest that even a modest level of pretreatment depression-related symptoms is a robust predictor of lithium nonresponse, and is associated with better response to divalproex. Although their overall efficacy in acute mania is similar, lithium and divalproex may be most effective in clinically and biologically distinct groups of patients.
Adult↗
Lamotrigine in rapid-cycling bipolar disorder.
BACKGROUND: We evaluated the antidepressant and mood-stabilizing effects of lamotrigine, a novel anticonvulsant, in a group of rapid-cycling bipolar patients. Most were already nonresponders or poor partial responders to other conventional mood-stabilizing agents. METHODS: This open, naturalistic, and prospective study was conducted with five rapid-cycling bipolar patients (DSM-IV). Each received lamotrigine titrated to a minimum dose of 150 mg/day as monotherapy or in combination with other psychotropic agents. Patients were assessed with the Global Assessment Scale (GAS), Beck Depression Inventory (BDI), and Young Mania Rating Scale (YMRS) for evidence of cycling mood. RESULTS: Lamotrigine was used at a mean +/- SD dose of 185.0 +/- 33.5 mg/day for 225.8 +/- 28.0 days. Random regression modeling of data showed significant dose- and time-dependent improvements in depressive symptoms and social function of patients taking lamotrigine (Dose: z = 2.17, p < .03 for BDI, z = 4.44, p < .001 for GAS; Time: z = -3.79, p < .001 for BDI, z = 2.16, p < .03 for GAS). Further random regression modeling analysis of change over time in symptoms prior to lamotrigine compared with symptoms during lamotrigine treatment showed a significant treatment by time effect for GAS (z = 2.40, p < .016) and a trend for BDI scores (z = -1.79, p < .073). No significant time or dosage effect or time by treatment effect was observed for YMRS. Finally, t statistics showed a significant reduction in mean BDI scores following treatment with lamotrigine (t = -5.26, p < .006). Lamotrigine was well tolerated by all patients; only one patient experienced several side effects, which were probably due to interaction between several psychotropic medications. CONCLUSION: Lamotrigine augmentation therapy and monotherapy appeared to have mood-stabilizing and antidepressant efficacy in the treatment of five rapid-cycling bipolar patients. The effect persisted for an average of 7.5 months.
Adult↗
Maintenance clinical trials in bipolar disorder: design implications of the divalproex-lithium-placebo study.
Maintenance studies in bipolar disorder have received increased attention in recent years. The interest is driven by apparent contradictions between results of early placebo-controlled trials of lithium and recent open studies, as well as interest in a new group of drugs with mood-stabilizing properties. The multiple outcome indices that require attention in prophylactic bipolar disorder studies add a dimension not present in acute studies of bipolar disorder. We present the methodology of a recently completed randomized, double-blind, placebo-controlled, parallel-group comparison of divalproex and lithium. We examine the consequences of salient design features, along with their implications for future studies. A fundamental conclusion is that such maintenance studies should be designed and executed to emphasize enrollment of patients with relatively active, severe forms of the illness. This goal is not achieved simply, as inherent features of long-term, placebo-controlled studies drive recruitment and enrollment in the direction of patients with milder forms of bipolar disorder. Attention to the frequency of both manic and depressive episodes and the severity of an index manic episode may aid in the selection of patients most suitable for studies designed to achieve adequate statistical power.
Adult↗
Plasma GABA predicts acute response to divalproex in mania.
Bipolar I, manic phase inpatients were treated with divalproex sodium, lithium, or placebo in a previously reported parallel group multicenter, double-blind, randomized, controlled acute phase treatment trial. Plasma concentrations of gamma aminobutyric acid (GABA) were measured before and after treatment. Higher pretreatment plasma GABA levels were significantly (p = .04) related to a better clinical response to divalproex (n = 19). Pretreatment plasma GABA levels did not correlate with response to either lithium (n = 13) or placebo (n = 31). Following treatment with divalproex sodium, plasma GABA levels decreased significantly (p < .05), compared to placebo. Pretreatment plasma GABA levels were not related to overall severity of manic symptoms. Plasma GABA may predict response to pharmacologic agents acting on the GABA system.
Adult↗
Predictors of response to mood stabilizers.
Although lithium remains the preferred treatment of bipolar disorder, only 60 to 80% of patients with the classic presentation have an adequate response to this drug. When the response rate to lithium is considered across the entire spectrum of bipolar disorders, this rate probably decreases to 50%. Natural history, illness subtype, and comorbidity are all important general predictors of response to treatment. At present, the only predictors that seem to differentially favor divalproex, and possible, carbamazepine over lithium are mixed states and rapid cycling. An overview of clinical presentations that predict general and differential response to mood stabilizers is provided.
Antimanic Agents↗
Clozapine for treatment-refractory mania.
OBJECTIVE: The efficacy of clozapine for treatment-resistant mania was examined in a prospective trial for patients with bipolar or schizoaffective disorder. METHOD: The subjects were 25 acutely manic patients with either bipolar disorder (N = 10) or schizoaffective disorder-bipolar subtype (N = 15) for whom lithium, anticonvulsants, and neuroleptics had been ineffective, had produced intolerable side effects, or both. After a 7-day washout, the patients were treated with clozapine monotherapy. They were evaluated over 13 weeks with the Young Mania Rating Scale and the Brief Psychiatric Rating Scale (BPRS). RESULTS: Of the 25 patients, 18 (72%) exhibited marked improvement on the Young Mania Rating Scale, and eight (32%) exhibited marked improvement on the BPRS. The bipolar patients as compared to schizo-affective patients, and the nonrapid as compared to rapid cyclers, had significantly greater improvement in total BPRS score. CONCLUSIONS: These results suggest that clozapine is an effective therapy for treatment-resistant bipolar and schizoaffective mania.
Adult↗