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Joseph R Calabrese - One of the best experts on this subject based on the ideXlab platform.
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Lamotrigine for treatment of bipolar depression independent meta analysis and meta regression of individual patient data from five randomised trials
British Journal of Psychiatry, 2009Co-Authors: John R Geddes, Joseph R Calabrese, Guy M GoodwinAbstract:Background There is uncertainty about the efficacy of Lamotrigine in bipolar depressive episodes. Aims To synthesise the evidence for the efficacy of Lamotrigine in bipolar depressive episodes. Method Systematic review and meta-analysis of individual patient data from randomised controlled trials comparing Lamotrigine with placebo. Results Individual data from 1072 participants from five randomised controlled trials were obtained. More individuals treated with Lamotrigine than placebo responded to treatment on both the Hamilton Rating Scale for Depression (HRSD) (relative risk (RR)=1.27, 95% CI 1.09–1.47, P =0.002) and Montgomery–Asberg Depression Rating Scale (MADRS) (RR=1.22, 95% CI 1.06–1.41, P =0.005). There was an interaction ( P =0.04) by baseline severity of depression: Lamotrigine was superior to placebo in people with HRSD score >24 (RR=1.47, 95% CI 1.16–1.87, P =0.001) but not in people with HRSD score ≤24 (RR=1.07, 95% CI 0.90–1.27, P =0.445). Conclusions There is consistent evidence that Lamotrigine has a beneficial effect on depressive symptoms in the depressed phase of bipolar disorder. The overall pool effect was modest, although the advantage over placebo was larger in more severely depressed participants.
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Lamotrigine in the acute treatment of bipolar depression results of five double blind placebo controlled clinical trials
Bipolar Disorders, 2008Co-Authors: Joseph R Calabrese, Russell F Huffman, Robin White, Suzanne Edwards, Thomas R Thompson, John Ascher, Eileen T Monaghan, Robert LeadbetterAbstract:Objectives: The efficacy of Lamotrigine as maintenance treatment for bipolar disorder (BD), particularly for delaying depressive episodes, is well established, but its efficacy in the acute treatment of bipolar depression is less clear. This paper reports the results of five randomized, double-blind, placebo-controlled trials of Lamotrigine monotherapy for the acute treatment of bipolar depression. Methods: Adult subjects with bipolar I or II disorder experiencing a depressive episode were randomized to placebo or Lamotrigine monotherapy (after titration, at a fixed dose of 50 mg or 200 mg daily in Study 1; a flexible dose of 100–400 mg daily in Study 2; or a fixed dose of 200 mg daily in Studies 3, 4 and 5) for 7–10 weeks. Results: Lamotrigine did not differ significantly from placebo on primary efficacy endpoints [17-item Hamilton Depression Rating Scale in Studies 1 and 2; Montgomery–Asberg Depression Rating Scale (MADRS) in Studies 3, 4 and 5]. In Study 1, Lamotrigine significantly separated from placebo on some secondary measures of efficacy, including the MADRS, the Clinical Global Impressions-Severity (CGI-S) and the CGI-Improvement (CGI-I), but seldom differed on secondary efficacy endpoints for the other studies. Conclusions: Lamotrigine monotherapy did not demonstrate efficacy in the acute treatment of bipolar depression in four out of five placebo-controlled clinical studies. Lamotrigine was well tolerated in the acute treatment of bipolar depression.
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a pooled analysis of 2 placebo controlled 18 month trials of Lamotrigine and lithium maintenance in bipolar i disorder
The Journal of Clinical Psychiatry, 2004Co-Authors: Guy M Goodwin, Charles L Bowden, Joseph R Calabrese, Robin White, Heinz Grunze, Siegfried Kasper, Paul Greene, Robert LeadbetterAbstract:Background: Two clinical trials, prospectively designed for combined analysis, compared placebo, lithium, and Lamotrigine for treatment of bipolar I disorder in recently depressed or manic patients. Method: 1315 bipolar I patients (DSM-IV) enrolled in the initial open-label phase, and 638 were stabilized and randomly assigned to 18 months of double-blind monotherapy with Lamotrigine (N = 280; 50-400 mg/day fixed dose or 100-400 mg/day flexible dose), lithium (N = 167; serum level of 0.8-1.1 mEq/L), or placebo (N = 191). The primary endpoint was time from randomization to intervention for a mood episode. Data were gathered from August 1997 to August 2001. Results: Lamotrigine and lithium were superior to placebo for time to intervention for any mood episode (median survival: placebo, 86 days [95% CI = 58 to 121]; lithium, 184 days [95% CI = 119 to not calculable]; Lamotrigine, 197 days [95% CI = 144 to 388]). Lamotrigine was superior to placebo for time to intervention for depression (median survival: placebo, 270 days [95% CI = 138 to not calculable]; lithium, median not calculable; Lamotrigine, median not calculable). Lithium and Lamotrigine were superior to placebo for time to intervention for mania (median survival not calculable for any group). Results of additional analyses adjusted for index mood were similar; however, only lithium was superior to placebo for intervention for mania. There was no evidence that either active treatment caused affective switch. Adverse event analysis indicated more diarrhea (19% vs. 7%, p <.05) and tremor (15% vs. 4%, p <.05) in lithium-treated patients compared with Lamotrigine-treated patients. Conclusions: Lamotrigine and lithium stabilized mood by delaying the time to treatment for a mood episode. Lamotrigine was effective against depression and mania, with more robust activity against depression. Lithium was effective against mania.
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a placebo controlled 18 month trial of Lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar i disorder
The Journal of Clinical Psychiatry, 2003Co-Authors: Joseph R Calabrese, Charles L Bowden, Gary S Sachs, Lakshmi N Yatham, Paul Montgomery, Kirsten Behnke, Olli Pekka Mehtonen, John A Ascher, Walter Paska, N EarlAbstract:Background The anticonvulsant Lamotrigine was previously shown to be effective for bipolar depression. This study assessed the efficacy and tolerability of Lamotrigine and lithium compared with placebo for the prevention of mood episodes in bipolar disorder. Method During an 8- to 16-week open-label phase, Lamotrigine (titrated to 200 mg/day) was added to current therapy for currently or recently depressed DSM-IV-defined bipolar I outpatients (N = 966) and concomitant drugs were gradually withdrawn. Patients stabilized on open-label treatment (N = 463) were then randomly assigned to Lamotrigine (50, 200, or 400 mg/day; N = 221), lithium (0.8-1.1 mEq/L; N = 121), or placebo (N = 121) monotherapy for up to 18 months. The primary outcome measure was time from randomization to intervention (addition of pharmacotherapy) for any mood episode (depressive, manic, hypomanic, or mixed). Data were gathered from September 1997 to August 2001. Results Time to intervention for any mood episode was statistically superior (p = .029) for both Lamotrigine and lithium compared with placebo-median survival times were 200, 170, and 93 days, respectively. Intervention for depression was more frequent than for mania by a factor of nearly 3:1. Lamotrigine was statistically superior to placebo at prolonging the time to intervention for a depressive episode (p = .047). The proportions of patients who were intervention-free for depression at 1 year were Lamotrigine 57%, lithium 46%, and placebo 45%. Lithium was statistically superior to placebo at prolonging the time to intervention for a manic or hypomanic episode (p = .026). The proportions of patients who were intervention-free for mania at 1 year were Lamotrigine 77%, lithium 86%, and placebo 72%. Headache was the most frequent adverse event for all 3 treatment groups. Conclusion Lamotrigine and lithium were superior to placebo for the prevention of mood episodes in bipolar I patients, with Lamotrigine predominantly effective against depression and lithium predominantly effective against mania.
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a placebo controlled 18 month trial of Lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar i disorder
Archives of General Psychiatry, 2003Co-Authors: Charles L Bowden, Joseph R Calabrese, Gary S Sachs, Lakshmi N Yatham, Shaheen Asghar, Magne Hompland, Paul Montgomery, N Earl, Tonya M Smoot, Joseph DeveaughgeissAbstract:Background Lamotrigine has been shown to be an effective treatment for bipolar depression and rapid cycling in placebo-controlled clinical trials. This double-blind, placebo-controlled study was conducted to assess the efficacy and tolerability of Lamotrigine and lithium compared with placebo for the prevention of relapse or recurrence of mood episodes in recently manic or hypomanic patients with bipolar I disorder. Methods After an 8- to 16-week open-label phase during which treatment with Lamotrigine was initiated and other psychotropic drug regimens were discontinued, patients were randomized to Lamotrigine (100-400 mg daily), lithium (0.8-1.1 mEq/L), or placebo as double-blind maintenance treatment for as long as 18 months. Results Of 349 patients who met screening criteria and entered the open-label phase, 175 met stabilization criteria and were randomized to double-blind maintenance treatment (Lamotrigine, 59 patients; lithium, 46 patients; and placebo, 70 patients). Both Lamotrigine and lithium were superior to placebo at prolonging the time to intervention for any mood episode (Lamotrigine vs placebo, P = .02; lithium vs placebo, P = .006). Lamotrigine was superior to placebo at prolonging the time to a depressive episode ( P = .02). Lithium was superior to placebo at prolonging the time to a manic, hypomanic, or mixed episode( P =.006). The most common adverse event reported for Lamotrigine was headache. Conclusions Both Lamotrigine and lithium were superior to placebo for the prevention of relapse or recurrence of mood episodes in patients with bipolar I disorder who had recently experienced a manic or hypomanic episode. The results indicate that Lamotrigine is an effective, well-tolerated maintenance treatment for bipolar disorder, particularly for prophylaxis of depression.
Charles L Bowden - One of the best experts on this subject based on the ideXlab platform.
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Lamotrigine lamictal ir for the treatment of bipolar disorder
Expert Opinion on Pharmacotherapy, 2012Co-Authors: Charles L Bowden, Vivek SinghAbstract:Introduction: Over the past decade the use of Lamotrigine in bipolar disorder has increased. However, the evidence base suggests a more limited role for Lamotrigine as part of an overall treatment regimen in bipolar disorder. Areas covered: We reviewed publications of randomized clinical trials of Lamotrigine, emphasizing studies in bipolar disorder. The low burden of adverse effects with Lamotrigine has been confirmed in these studies. Its lack of benefit in acute mania is established. Despite modest benefits for a subset of depressive episodes in bipolar disorder, it was not superior to placebo in well-designed studies. As monotherapy, in randomized, blinded trials in rapid cycling bipolar disorder it was not superior to placebo. Its role in maintenance treatment is relatively well established as one component of combination therapy, with evidence for benefits when combined with lithium or valproate. Combination regimens including Lamotrigine appear to be superior to monotherapy. Monotherapy utilization...
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a pooled analysis of 2 placebo controlled 18 month trials of Lamotrigine and lithium maintenance in bipolar i disorder
The Journal of Clinical Psychiatry, 2004Co-Authors: Guy M Goodwin, Charles L Bowden, Joseph R Calabrese, Robin White, Heinz Grunze, Siegfried Kasper, Paul Greene, Robert LeadbetterAbstract:Background: Two clinical trials, prospectively designed for combined analysis, compared placebo, lithium, and Lamotrigine for treatment of bipolar I disorder in recently depressed or manic patients. Method: 1315 bipolar I patients (DSM-IV) enrolled in the initial open-label phase, and 638 were stabilized and randomly assigned to 18 months of double-blind monotherapy with Lamotrigine (N = 280; 50-400 mg/day fixed dose or 100-400 mg/day flexible dose), lithium (N = 167; serum level of 0.8-1.1 mEq/L), or placebo (N = 191). The primary endpoint was time from randomization to intervention for a mood episode. Data were gathered from August 1997 to August 2001. Results: Lamotrigine and lithium were superior to placebo for time to intervention for any mood episode (median survival: placebo, 86 days [95% CI = 58 to 121]; lithium, 184 days [95% CI = 119 to not calculable]; Lamotrigine, 197 days [95% CI = 144 to 388]). Lamotrigine was superior to placebo for time to intervention for depression (median survival: placebo, 270 days [95% CI = 138 to not calculable]; lithium, median not calculable; Lamotrigine, median not calculable). Lithium and Lamotrigine were superior to placebo for time to intervention for mania (median survival not calculable for any group). Results of additional analyses adjusted for index mood were similar; however, only lithium was superior to placebo for intervention for mania. There was no evidence that either active treatment caused affective switch. Adverse event analysis indicated more diarrhea (19% vs. 7%, p <.05) and tremor (15% vs. 4%, p <.05) in lithium-treated patients compared with Lamotrigine-treated patients. Conclusions: Lamotrigine and lithium stabilized mood by delaying the time to treatment for a mood episode. Lamotrigine was effective against depression and mania, with more robust activity against depression. Lithium was effective against mania.
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a placebo controlled 18 month trial of Lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar i disorder
The Journal of Clinical Psychiatry, 2003Co-Authors: Joseph R Calabrese, Charles L Bowden, Gary S Sachs, Lakshmi N Yatham, Paul Montgomery, Kirsten Behnke, Olli Pekka Mehtonen, John A Ascher, Walter Paska, N EarlAbstract:Background The anticonvulsant Lamotrigine was previously shown to be effective for bipolar depression. This study assessed the efficacy and tolerability of Lamotrigine and lithium compared with placebo for the prevention of mood episodes in bipolar disorder. Method During an 8- to 16-week open-label phase, Lamotrigine (titrated to 200 mg/day) was added to current therapy for currently or recently depressed DSM-IV-defined bipolar I outpatients (N = 966) and concomitant drugs were gradually withdrawn. Patients stabilized on open-label treatment (N = 463) were then randomly assigned to Lamotrigine (50, 200, or 400 mg/day; N = 221), lithium (0.8-1.1 mEq/L; N = 121), or placebo (N = 121) monotherapy for up to 18 months. The primary outcome measure was time from randomization to intervention (addition of pharmacotherapy) for any mood episode (depressive, manic, hypomanic, or mixed). Data were gathered from September 1997 to August 2001. Results Time to intervention for any mood episode was statistically superior (p = .029) for both Lamotrigine and lithium compared with placebo-median survival times were 200, 170, and 93 days, respectively. Intervention for depression was more frequent than for mania by a factor of nearly 3:1. Lamotrigine was statistically superior to placebo at prolonging the time to intervention for a depressive episode (p = .047). The proportions of patients who were intervention-free for depression at 1 year were Lamotrigine 57%, lithium 46%, and placebo 45%. Lithium was statistically superior to placebo at prolonging the time to intervention for a manic or hypomanic episode (p = .026). The proportions of patients who were intervention-free for mania at 1 year were Lamotrigine 77%, lithium 86%, and placebo 72%. Headache was the most frequent adverse event for all 3 treatment groups. Conclusion Lamotrigine and lithium were superior to placebo for the prevention of mood episodes in bipolar I patients, with Lamotrigine predominantly effective against depression and lithium predominantly effective against mania.
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a placebo controlled 18 month trial of Lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar i disorder
Archives of General Psychiatry, 2003Co-Authors: Charles L Bowden, Joseph R Calabrese, Gary S Sachs, Lakshmi N Yatham, Shaheen Asghar, Magne Hompland, Paul Montgomery, N Earl, Tonya M Smoot, Joseph DeveaughgeissAbstract:Background Lamotrigine has been shown to be an effective treatment for bipolar depression and rapid cycling in placebo-controlled clinical trials. This double-blind, placebo-controlled study was conducted to assess the efficacy and tolerability of Lamotrigine and lithium compared with placebo for the prevention of relapse or recurrence of mood episodes in recently manic or hypomanic patients with bipolar I disorder. Methods After an 8- to 16-week open-label phase during which treatment with Lamotrigine was initiated and other psychotropic drug regimens were discontinued, patients were randomized to Lamotrigine (100-400 mg daily), lithium (0.8-1.1 mEq/L), or placebo as double-blind maintenance treatment for as long as 18 months. Results Of 349 patients who met screening criteria and entered the open-label phase, 175 met stabilization criteria and were randomized to double-blind maintenance treatment (Lamotrigine, 59 patients; lithium, 46 patients; and placebo, 70 patients). Both Lamotrigine and lithium were superior to placebo at prolonging the time to intervention for any mood episode (Lamotrigine vs placebo, P = .02; lithium vs placebo, P = .006). Lamotrigine was superior to placebo at prolonging the time to a depressive episode ( P = .02). Lithium was superior to placebo at prolonging the time to a manic, hypomanic, or mixed episode( P =.006). The most common adverse event reported for Lamotrigine was headache. Conclusions Both Lamotrigine and lithium were superior to placebo for the prevention of relapse or recurrence of mood episodes in patients with bipolar I disorder who had recently experienced a manic or hypomanic episode. The results indicate that Lamotrigine is an effective, well-tolerated maintenance treatment for bipolar disorder, particularly for prophylaxis of depression.
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rash in multicenter trials of Lamotrigine in mood disorders clinical relevance and management
The Journal of Clinical Psychiatry, 2002Co-Authors: Joseph R Calabrese, Charles L Bowden, John R Sullivan, Trisha Suppes, Joseph F Goldberg, Gary S Sachs, Melvin D Shelton, Frederick K Goodwin, Mark A Frye, Vivek KusumakarAbstract:Background The rate of Lamotrigine-associated rash in patients with mood disorders has not been well characterized. The objective of this report was to determine rash rates in clinical trials of Lamotrigine in DSM-IV unipolar depression or bipolar disorder. Method A retrospective analysis was conducted of rates of Lamotrigine-related rash in 12 multicenter studies, including 1 open study, 7 randomized controlled acute trials, and 4 randomized controlled maintenance trials from 1996 to 2001. Results A total of 1955 patients were treated with Lamotrigine in open-label settings (open-label phases preceding or following randomization and 1 stand-alone open-label study); 1198 patients received Lamotrigine in controlled settings, and 1056 patients received placebo. In controlled settings, rates of benign rash were 8.3% and 6.4% in Lamotrigine- and placebo-treated patients, respectively. Rates of serious rash were 0% with Lamotrigine, 0.1% (N = 1) with placebo, and 0% with comparators. In the open-label setting, the overall rate of rash for Lamotrigine was 13.1% (N = 257) and of serious rash, 0.1% (N = 2). One mild case of Stevens-Johnson syndrome not requiring hospitalization occurred in a patient treated with Lamotrigine. There were no cases of toxic epidermal necrolysis in any setting. Conclusion Serious drug eruptions associated with Lamotrigine were rare. Although rash is a potentially life-threatening reaction, the risk of serious rash due to Lamotrigine should be weighed against more common risks associated with untreated or undertreated bipolar depression.
Lynette E Mullens - One of the best experts on this subject based on the ideXlab platform.
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safety review of adult clinical trial experience with Lamotrigine
Drug Safety, 1998Co-Authors: John Messenheimer, Lynette E Mullens, Luigi Giorgi, Frances YoungAbstract:To date approximately 4000 adults >12 years of age have been treated with Lamotrigine in Glaxo Wellcome sponsored clinical trials. Review of the data from these trials shows Lamotrigine to be effective and well tolerated in both add-on and monotherapy treatment. Safety of Lamotrigine was comparable to that of other anticonvulsants in add-on controlled clinical trials. In addition, fewer than half the number of patients in monotherapy studies who were taking Lamotrigine discontinued treatment because of adverse events compared to those taking carbamazepine and phenytoin. Most of the reported adverse events seen in Lamotrigine treated patients in all studies were judged by the investigator to be mild or moderate in severity; few of the adverse events resulted in the withdrawal of patients from studies. Analysis of vital signs and clinical laboratory data have revealed no undesirable effect of Lamotrigine on major systems of the body. The most concerning adverse event has been rash. In clinical trials, this has most often been limited to a simple morbilliform rash which is not associated with evidence of systemic involvement. The incidence of Stevens-Johnson syndrome (SJS) in clinical trials is approximately 1 in 1000. Rash associated with Lamotrigine has typically occurred within the first 8 weeks of treatment. Data from clinical trials clearly point to exceeding currently recommended dosage guidelines of Lamotrigine and co-administration of valproic acid (valproate sodium) as risk factors for rash. Early in 1997, Glaxo Wellcome strengthened existing warnings in the product label regarding the risk of rash and reinforced the importance of adherence to administration guidelines in an effort to reduce the incidence of rash.
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Lamotrigine lamictal in refractory trigeminal neuralgia results from a double blind placebo controlled crossover trial
Pain, 1997Co-Authors: Joanna M. Zakrzewska, Zareena Chaudhry, Turo Nurmikko, D W Patton, Lynette E MullensAbstract:Abstract Lamotrigine is a chemically novel antiepileptic drug which has not been adequately assessed for its antineuralgic properties. It was used in a double-blind placebo controlled crossover trial in 14 patients with refractory trigeminal neuralgia. Patients continued to take a steady dose of carbamazepine or phenytoin throughout the trial over a 31-day period. Each arm of the trial lasted 2 weeks with an intervening 3-day washout period. The maintenance dose of Lamotrigine was 400 mg. Lamotrigine was superior to placebo (P=0.011) based on analysis of a composite efficacy index which compared the numbers of patients assigned greater efficacy on Lamotrigine with those assigned greater efficacy on placebo. Efficacy for one treatment over another was determined according to a hierarchy of: (i) use of escape medication; (ii) total pain scores; or (iii) global evaluations. Eleven of the 13 patients eligible for inclusion in the composite efficacy index showed better efficacy on Lamotrigine compared with placebo. Global evaluations further suggested that patients did better on Lamotrigine than placebo (P=0.025). The adverse reactions with both Lamotrigine and placebo were predominantly dose-dependent effects on the central nervous system. A 14th patient withdrew from the study due to severe pain during the placebo arm of the trial. It would appear that Lamotrigine has antineuralgic properties.
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Lamotrigine lamictal in refractory trigeminal neuralgia results from a double blind placebo controlled crossover trial
Pain, 1997Co-Authors: Joanna M. Zakrzewska, Zareena Chaudhry, Turo Nurmikko, D W Patton, Lynette E MullensAbstract:Abstract Lamotrigine is a chemically novel antiepileptic drug which has not been adequately assessed for its antineuralgic properties. It was used in a double-blind placebo controlled crossover trial in 14 patients with refractory trigeminal neuralgia. Patients continued to take a steady dose of carbamazepine or phenytoin throughout the trial over a 31-day period. Each arm of the trial lasted 2 weeks with an intervening 3-day washout period. The maintenance dose of Lamotrigine was 400 mg. Lamotrigine was superior to placebo (P=0.011) based on analysis of a composite efficacy index which compared the numbers of patients assigned greater efficacy on Lamotrigine with those assigned greater efficacy on placebo. Efficacy for one treatment over another was determined according to a hierarchy of: (i) use of escape medication; (ii) total pain scores; or (iii) global evaluations. Eleven of the 13 patients eligible for inclusion in the composite efficacy index showed better efficacy on Lamotrigine compared with placebo. Global evaluations further suggested that patients did better on Lamotrigine than placebo (P=0.025). The adverse reactions with both Lamotrigine and placebo were predominantly dose-dependent effects on the central nervous system. A 14th patient withdrew from the study due to severe pain during the placebo arm of the trial. It would appear that Lamotrigine has antineuralgic properties.
Guy M Goodwin - One of the best experts on this subject based on the ideXlab platform.
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comparative economic evaluation of quetiapine plus Lamotrigine combination vs quetiapine monotherapy and folic acid vs placebo in patients with bipolar depression cequel
Bipolar Disorders, 2018Co-Authors: John R Geddes, Guy M Goodwin, Judit Simon, A Gardiner, Jennifer M Rendell, Susanne MayerAbstract:OBJECTIVES Although not licensed for acute bipolar depression, Lamotrigine has evidence for efficacy in trials and its use is recommended in guidelines. So far there had been no prospective health economic evaluation of its use. METHODS Cost-utility analysis of the CEQUEL trial comparing quetiapine plus Lamotrigine vs quetiapine monotherapy (and folic acid vs placebo in an add-on factorial design) for patients with bipolar depression (n = 201) from the health and social care perspective. Differences in costs together with quality-adjusted life years (QALYs) between the groups were assessed over 52 weeks using a regression-based approach. RESULTS Health-related quality of life improved substantially for all randomization groups during follow-up with no significant difference in QALYs between any of the comparisons (mean adjusted QALY difference: Lamotrigine vs placebo -0.001 (95% CI: -0.05 to 0.05), folic acid vs placebo 0.002 (95% CI: -0.05 to 0.05)). While medication costs in the Lamotrigine group were higher than in the placebo group (£647, P < 0.001), mental health community/outpatient costs were significantly lower (-£670, P < 0.001). Mean total costs were similar in the groups (-£180, P = 0.913). CONCLUSIONS Lamotrigine improved clinical ratings in bipolar depression compared with placebo. This differential effect was not detected using the EQ-5D-3L. The additional cost of Lamotrigine was balanced by significant savings in some other medical costs which made its use cost neutral to the health service. Compared to placebo, folic acid produced neither clinical nor significant health economic benefits. The study supports the use of Lamotrigine in combination with other drugs to treat bipolar depression.
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comparative evaluation of quetiapine plus Lamotrigine combination versus quetiapine monotherapy and folic acid versus placebo in bipolar depression cequel a 2 2 factorial randomised trial
The Lancet Psychiatry, 2016Co-Authors: John R Geddes, Judit Simon, A Gardiner, Jennifer M Rendell, Merryn Voysey, Elizabeth M Tunbridge, Chris Hinds, Jane Hainsworth, Mary Jane Attenburrow, Guy M GoodwinAbstract:Summary Background Depressive symptoms are a major cause of disability in bipolar disorder and there are few safe and effective treatments. The combination of Lamotrigine plus quetiapine potentially offers improved outcomes for people with bipolar depression. We aimed to determine if combination therapy with quetiapine plus Lamotrigine leads to greater improvement in depressive symptoms over 12 weeks than quetiapine monotherapy plus Lamotrigine placebo. Methods In this double-blind, randomised, placebo-controlled, parallel group, 2 × 2 factorial trial (CEQUEL), patients with DSM-IV bipolar disorder I or II, who were aged 16 years or older, and required new treatment for a depressive episode, were enrolled from 27 sites in the UK. Patients were randomly assigned (1:1) by an adaptive minimisation algorithm to Lamotrigine or placebo and to folic acid or placebo. Participants and investigators were masked to the treatment groups. The primary outcome was improvement in depressive symptoms at 12 weeks with the Quick Inventory of Depressive Symptomatology—self report version 16 (QIDS-SR16). Analysis was by modified intention-to-treat. This trial is registered with EUdraCT, number 2007-004513-33. Findings Between Oct 21, 2008, and April 27, 2012, 202 participants were randomly assigned; 101 to Lamotrigine and 101 to placebo. The mean difference in QIDS-SR16 total score between the group receiving Lamotrigine versus the placebo group at 12 weeks was −1·73 ([95% CI −3·57 to 0·11]; p=0·066) and at 52 weeks was −2·69 ([–4·89 to −0·49]; p=0·017). Folic acid was not superior to placebo. There was a significant interaction (p=0·028), with folic acid reducing the effectiveness of Lamotrigine at 12 weeks. The mean difference on QIDS-SR16 was −4·14 ([95% CI −6·90 to −1·37]; p=0·004) for patients receiving Lamotrigine without folic acid compared with 0·12 ([–2·58 to 2·82]; p=0·931) for those receiving Lamotrigine and folic acid. Interpretation Addition of Lamotrigine to quetiapine treatment improved outcomes. Folic acid seems to nullify the effect of Lamotrigine. CEQUEL should encourage clinicians and patients to consider Lamotrigine for bipolar depression, but also to be aware that concurrent folic acid might reduce its effectiveness. Funding Medical Research Council.
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Lamotrigine for treatment of bipolar depression independent meta analysis and meta regression of individual patient data from five randomised trials
British Journal of Psychiatry, 2009Co-Authors: John R Geddes, Joseph R Calabrese, Guy M GoodwinAbstract:Background There is uncertainty about the efficacy of Lamotrigine in bipolar depressive episodes. Aims To synthesise the evidence for the efficacy of Lamotrigine in bipolar depressive episodes. Method Systematic review and meta-analysis of individual patient data from randomised controlled trials comparing Lamotrigine with placebo. Results Individual data from 1072 participants from five randomised controlled trials were obtained. More individuals treated with Lamotrigine than placebo responded to treatment on both the Hamilton Rating Scale for Depression (HRSD) (relative risk (RR)=1.27, 95% CI 1.09–1.47, P =0.002) and Montgomery–Asberg Depression Rating Scale (MADRS) (RR=1.22, 95% CI 1.06–1.41, P =0.005). There was an interaction ( P =0.04) by baseline severity of depression: Lamotrigine was superior to placebo in people with HRSD score >24 (RR=1.47, 95% CI 1.16–1.87, P =0.001) but not in people with HRSD score ≤24 (RR=1.07, 95% CI 0.90–1.27, P =0.445). Conclusions There is consistent evidence that Lamotrigine has a beneficial effect on depressive symptoms in the depressed phase of bipolar disorder. The overall pool effect was modest, although the advantage over placebo was larger in more severely depressed participants.
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a pooled analysis of 2 placebo controlled 18 month trials of Lamotrigine and lithium maintenance in bipolar i disorder
The Journal of Clinical Psychiatry, 2004Co-Authors: Guy M Goodwin, Charles L Bowden, Joseph R Calabrese, Robin White, Heinz Grunze, Siegfried Kasper, Paul Greene, Robert LeadbetterAbstract:Background: Two clinical trials, prospectively designed for combined analysis, compared placebo, lithium, and Lamotrigine for treatment of bipolar I disorder in recently depressed or manic patients. Method: 1315 bipolar I patients (DSM-IV) enrolled in the initial open-label phase, and 638 were stabilized and randomly assigned to 18 months of double-blind monotherapy with Lamotrigine (N = 280; 50-400 mg/day fixed dose or 100-400 mg/day flexible dose), lithium (N = 167; serum level of 0.8-1.1 mEq/L), or placebo (N = 191). The primary endpoint was time from randomization to intervention for a mood episode. Data were gathered from August 1997 to August 2001. Results: Lamotrigine and lithium were superior to placebo for time to intervention for any mood episode (median survival: placebo, 86 days [95% CI = 58 to 121]; lithium, 184 days [95% CI = 119 to not calculable]; Lamotrigine, 197 days [95% CI = 144 to 388]). Lamotrigine was superior to placebo for time to intervention for depression (median survival: placebo, 270 days [95% CI = 138 to not calculable]; lithium, median not calculable; Lamotrigine, median not calculable). Lithium and Lamotrigine were superior to placebo for time to intervention for mania (median survival not calculable for any group). Results of additional analyses adjusted for index mood were similar; however, only lithium was superior to placebo for intervention for mania. There was no evidence that either active treatment caused affective switch. Adverse event analysis indicated more diarrhea (19% vs. 7%, p <.05) and tremor (15% vs. 4%, p <.05) in lithium-treated patients compared with Lamotrigine-treated patients. Conclusions: Lamotrigine and lithium stabilized mood by delaying the time to treatment for a mood episode. Lamotrigine was effective against depression and mania, with more robust activity against depression. Lithium was effective against mania.
Gary S Sachs - One of the best experts on this subject based on the ideXlab platform.
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a placebo controlled 18 month trial of Lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar i disorder
The Journal of Clinical Psychiatry, 2003Co-Authors: Joseph R Calabrese, Charles L Bowden, Gary S Sachs, Lakshmi N Yatham, Paul Montgomery, Kirsten Behnke, Olli Pekka Mehtonen, John A Ascher, Walter Paska, N EarlAbstract:Background The anticonvulsant Lamotrigine was previously shown to be effective for bipolar depression. This study assessed the efficacy and tolerability of Lamotrigine and lithium compared with placebo for the prevention of mood episodes in bipolar disorder. Method During an 8- to 16-week open-label phase, Lamotrigine (titrated to 200 mg/day) was added to current therapy for currently or recently depressed DSM-IV-defined bipolar I outpatients (N = 966) and concomitant drugs were gradually withdrawn. Patients stabilized on open-label treatment (N = 463) were then randomly assigned to Lamotrigine (50, 200, or 400 mg/day; N = 221), lithium (0.8-1.1 mEq/L; N = 121), or placebo (N = 121) monotherapy for up to 18 months. The primary outcome measure was time from randomization to intervention (addition of pharmacotherapy) for any mood episode (depressive, manic, hypomanic, or mixed). Data were gathered from September 1997 to August 2001. Results Time to intervention for any mood episode was statistically superior (p = .029) for both Lamotrigine and lithium compared with placebo-median survival times were 200, 170, and 93 days, respectively. Intervention for depression was more frequent than for mania by a factor of nearly 3:1. Lamotrigine was statistically superior to placebo at prolonging the time to intervention for a depressive episode (p = .047). The proportions of patients who were intervention-free for depression at 1 year were Lamotrigine 57%, lithium 46%, and placebo 45%. Lithium was statistically superior to placebo at prolonging the time to intervention for a manic or hypomanic episode (p = .026). The proportions of patients who were intervention-free for mania at 1 year were Lamotrigine 77%, lithium 86%, and placebo 72%. Headache was the most frequent adverse event for all 3 treatment groups. Conclusion Lamotrigine and lithium were superior to placebo for the prevention of mood episodes in bipolar I patients, with Lamotrigine predominantly effective against depression and lithium predominantly effective against mania.
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a placebo controlled 18 month trial of Lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar i disorder
Archives of General Psychiatry, 2003Co-Authors: Charles L Bowden, Joseph R Calabrese, Gary S Sachs, Lakshmi N Yatham, Shaheen Asghar, Magne Hompland, Paul Montgomery, N Earl, Tonya M Smoot, Joseph DeveaughgeissAbstract:Background Lamotrigine has been shown to be an effective treatment for bipolar depression and rapid cycling in placebo-controlled clinical trials. This double-blind, placebo-controlled study was conducted to assess the efficacy and tolerability of Lamotrigine and lithium compared with placebo for the prevention of relapse or recurrence of mood episodes in recently manic or hypomanic patients with bipolar I disorder. Methods After an 8- to 16-week open-label phase during which treatment with Lamotrigine was initiated and other psychotropic drug regimens were discontinued, patients were randomized to Lamotrigine (100-400 mg daily), lithium (0.8-1.1 mEq/L), or placebo as double-blind maintenance treatment for as long as 18 months. Results Of 349 patients who met screening criteria and entered the open-label phase, 175 met stabilization criteria and were randomized to double-blind maintenance treatment (Lamotrigine, 59 patients; lithium, 46 patients; and placebo, 70 patients). Both Lamotrigine and lithium were superior to placebo at prolonging the time to intervention for any mood episode (Lamotrigine vs placebo, P = .02; lithium vs placebo, P = .006). Lamotrigine was superior to placebo at prolonging the time to a depressive episode ( P = .02). Lithium was superior to placebo at prolonging the time to a manic, hypomanic, or mixed episode( P =.006). The most common adverse event reported for Lamotrigine was headache. Conclusions Both Lamotrigine and lithium were superior to placebo for the prevention of relapse or recurrence of mood episodes in patients with bipolar I disorder who had recently experienced a manic or hypomanic episode. The results indicate that Lamotrigine is an effective, well-tolerated maintenance treatment for bipolar disorder, particularly for prophylaxis of depression.
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rash in multicenter trials of Lamotrigine in mood disorders clinical relevance and management
The Journal of Clinical Psychiatry, 2002Co-Authors: Joseph R Calabrese, Charles L Bowden, John R Sullivan, Trisha Suppes, Joseph F Goldberg, Gary S Sachs, Melvin D Shelton, Frederick K Goodwin, Mark A Frye, Vivek KusumakarAbstract:Background The rate of Lamotrigine-associated rash in patients with mood disorders has not been well characterized. The objective of this report was to determine rash rates in clinical trials of Lamotrigine in DSM-IV unipolar depression or bipolar disorder. Method A retrospective analysis was conducted of rates of Lamotrigine-related rash in 12 multicenter studies, including 1 open study, 7 randomized controlled acute trials, and 4 randomized controlled maintenance trials from 1996 to 2001. Results A total of 1955 patients were treated with Lamotrigine in open-label settings (open-label phases preceding or following randomization and 1 stand-alone open-label study); 1198 patients received Lamotrigine in controlled settings, and 1056 patients received placebo. In controlled settings, rates of benign rash were 8.3% and 6.4% in Lamotrigine- and placebo-treated patients, respectively. Rates of serious rash were 0% with Lamotrigine, 0.1% (N = 1) with placebo, and 0% with comparators. In the open-label setting, the overall rate of rash for Lamotrigine was 13.1% (N = 257) and of serious rash, 0.1% (N = 2). One mild case of Stevens-Johnson syndrome not requiring hospitalization occurred in a patient treated with Lamotrigine. There were no cases of toxic epidermal necrolysis in any setting. Conclusion Serious drug eruptions associated with Lamotrigine were rare. Although rash is a potentially life-threatening reaction, the risk of serious rash due to Lamotrigine should be weighed against more common risks associated with untreated or undertreated bipolar depression.
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a double blind placebo controlled prophylaxis study of Lamotrigine in rapid cycling bipolar disorder
The Journal of Clinical Psychiatry, 2000Co-Authors: Joseph R Calabrese, Charles L Bowden, Trisha Suppes, Gary S Sachs, Vivek Kusumakar, N Earl, John A Ascher, Alan C Swann, Susan L Mcelroy, Paul GreeneAbstract: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.
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a double blind placebo controlled study of Lamotrigine monotherapy in outpatients with bipolar i depression
The Journal of Clinical Psychiatry, 1999Co-Authors: Joseph R Calabrese, Charles L Bowden, John Ascher, Gary S Sachs, Eileen Monaghan, David G RuddAbstract: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.
