A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder

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for currently or recently depressed DSM-IV-defined bipolar I outpatients (N = 966) and concomitant drugs were gradually withdrawn.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.     

A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder

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.     

Maintenance treatment outcomes in older patients with bipolar I disorder.

OBJECTIVE: The efficacy and tolerability of mood stabilizers in older adults with bipolar disorder remains understudied. Authors retrospectively examined response to lamotrigine, lithium, and placebo in older (>or=age 55) adults with Bipolar I disorder (DSM-IV) who participated in two mixed-age, maintenance studies examining time to intervention for an emerging mood episode (manic/hypomanic/mixed or depressed) and drug tolerability. METHODS: In all, 588 patients received double-blind lamotrigine (LTG, 100 mg-400 mg/day), lithium (Li, 0.8 mEq/L-1.1 mEq/L), or placebo (PBO); data from 98 older adults (LTG: 33, Li: 34, PBO: 31) were examined. Mean modal total daily doses were LTG 240 mg and Li 750 mg. RESULTS: LTG significantly delayed time to intervention for any mood episode and for a depressive episode, compared with placebo. Li significantly delayed time to intervention for mania/hypomania/mixed compared with placebo. Back pain and headache were the most common adverse events during LTG treatment; rash: LTG, 3%; Li, 6%; and PBO, 0; no serious rash was reported. The most common adverse events (>10%) during lithium treatment were dyspraxia, tremor, xerostomia, headache, infection, amnesia, dizziness, diarrhea, nausea, and fatigue. CONCLUSION: Lamotrigine and lithium may be effective and well-tolerated maintenance therapies for older adults with Bipolar I depression.     

拉莫三嗪治疗双相心境障碍对照研究

目的：探讨拉莫三嗪治疗双相情感障碍的疗效与安全性。方法：双相心境障碍患者135例，其中双相抑郁78例，躁狂57例。将患者随机分为3组，每组抑郁相26例，躁狂相19例。疗程32周。前8周为急性期治疗阶段，对照组抑郁相只服选择性5-羟色胺回收抑制剂（SSRI）类抗抑郁剂，躁狂相只服利培酮；拉莫三嗪组在对照组用药的基础上加服拉莫三嗪；碳酸锂组在对照组用药的基础上加服碳酸锂。后24周为巩固治疗阶段，所有患者随机分为两组，只服拉莫三嗪或碳酸锂。采用汉密尔顿抑郁量表（HAMD）、Young躁狂评定量表（YMRS）、治疗中出现的症状量表（TESS）评定疗效及安全性。结果：急性期治疗结束后，无论躁狂相还是抑郁相，拉莫三嗪组和碳酸锂组的临床疗效显著高于对照组（P〈0．01或〈0．05）。巩固治疗阶段两组相比，拉莫三嗪的抗抑郁作用较好，碳酸锂的抗躁狂作用较强。不良反应发生率，碳酸锂组40％，拉莫三嗪组22％。巩固治疗阶段病情复发率，拉莫三嗪组8％，碳酸锂组11％，两组差异无显著性（P〉0．05）。结论：拉莫三嗪作为心境稳定剂治疗双相情感障碍疗效可靠，不良反应小，与碳酸锂相比，抗抑郁作用更强。     

A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group

BACKGROUND: Long-term outcomes are often poor in patients with bipolar disorder despite treatment; more effective treatments are needed to reduce recurrences and morbidity. This study compared the efficacy of divalproex, lithium, and placebo as prophylactic therapy. METHODS: A randomized, double-blind, parallel-group multicenter study of treatment outcomes was conducted over a 52-week maintenance period. Patients who met the recovery criteria within 3 months of the onset of an index manic episode (n = 372) were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2:1:1 ratio. Psychotropic medications were discontinued before randomization, except for open-label divalproex or lithium, which were gradually tapered over the first 2 weeks of maintenance treatment. The primary outcome measure was time to recurrence of any mood episode. Secondary measures were time to a manic episode, time to a depressive episode, average change from baseline in Schedule for Affective Disorders and Schizophrenia-Change Version subscale scores for depression and mania, and Global Assessment of Function scores. RESULTS: The divalproex group did not differ significantly from the placebo group in time to any mood episode. Divalproex was superior to placebo in terms of lower rates of discontinuation for either a recurrent mood episode or depressive episode. Divalproex was superior to lithium in longer duration of successful prophylaxis in the study and less deterioration in depressive symptoms and Global Assessment Scale scores. CONCLUSIONS: The treatments did not differ significantly on time to recurrence of any mood episode during maintenance therapy. Patients treated with divalproex had better outcomes than those treated with placebo or lithium on several secondary outcome measures.     

A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder

OBJECTIVE: The authors tested the hypothesis that divalproex would be more effective than lithium in the long-term management of patients with recently stabilized rapid-cycling bipolar disorder. METHOD: A 20-month, double-blind, parallel-group comparison was carried out in recently hypomanic/manic patients who had experienced a persistent bimodal response to combined treatment with lithium and divalproex. Sixty patients were randomly assigned to lithium or divalproex monotherapy in a balanced design after stratification for illness type (bipolar I versus bipolar II disorder). RESULTS: Of the 254 patients enrolled in the open-label acute stabilization phase, 76% discontinued the study prematurely (poor adherence: 28%; nonresponse: 26% [of whom 74% remained depressed and 26% remained in a hypomanic/manic/mixed episode], intolerable side effects: 19%). Of the 60 patients (24%) randomly assigned to double-blind maintenance monotherapy, 53% relapsed (59% into depression and 41% into a hypomanic/manic/mixed episode), 22% completed the study, 10% had intolerable side effects, and 10% were poorly adherent. The rates of relapse into any mood episode for those given lithium versus divalproex were 56% and 50%, respectively; the rates were 34% and 29% for a depressive relapse and 19% and 22% for a hypomania/mania relapse. There were no significant differences in time to relapse. The proportion discontinuing prematurely because of side effects was 16% for lithium and 4% for divalproex. CONCLUSIONS: The hypothesis that divalproex is more effective than lithium in the long-term management of rapid-cycling bipolar disorder is not supported by these data. Preliminary data suggest highly recurrent refractory depression may be the hallmark of rapid-cycling bipolar disorder.     

Recurrence in bipolar I disorder: a post hoc analysis excluding relapses in two double-blind maintenance studies.

OBJECTIVE: To assess the efficacy of lamotrigine or lithium in preventing mood recurrence (i.e., a new mood episode) in bipolar disorder. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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

OBJECTIVE: 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. METHOD: The authors reviewed key literature using Medline searches using key words: bipolar disorder, controlled trials, mood stabilizer, lithium, lomotrigine, divalproex, olanzapine, carbamazepine. RESULTS: 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. CONCLUSIONS: 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.     

Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine

OBJECTIVE: In a placebo-controlled, double-blind study, the authors investigated the efficacy and safety of olanzapine as monotherapy in relapse prevention in bipolar I disorder. METHOD: Patients achieving symptomatic remission from a manic or mixed episode of bipolar I disorder (Young Mania Rating Scale [YMRS] total score < or =12 and 21-item Hamilton Depression Rating Scale [HAM-D] score or =15, HAM-D score > or =15, or hospitalization). RESULTS: Time to symptomatic relapse into any mood episode was significantly longer among patients receiving olanzapine (a median of 174 days, compared with a median of 22 days in patients receiving placebo). Times to symptomatic relapse into manic, depressive, and mixed episodes were all significantly longer among patients receiving olanzapine than among patients receiving placebo. The relapse rate was significantly lower in the olanzapine group (46.7%) than in the placebo group (80.1%). During olanzapine treatment, the most common emergent event was weight gain; during the open-label phase, patients who received olanzapine gained a mean of 3.1 kg (SD=3.4). In double-blind treatment, placebo patients lost a mean of 2.0 kg (SD=4.4) and patients who continued to take olanzapine gained an additional 1.0 kg (SD=5.2). CONCLUSIONS: Compared to placebo, olanzapine delays relapse into subsequent mood episodes in bipolar I disorder patients who responded to open-label acute treatment with olanzapine for a manic or mixed episode.     

拉莫三嗪维持治疗双相障碍躁狂发作的疗效评价

目的评价拉莫三嗪维持治疗双相障碍躁狂发作的疗效。方法将73例维持期双相障碍躁狂发作患者随机分为两组，研究组用拉莫三嗪系统治疗，对照组用碳酸锂系统治疗，共治疗12周，并在入组时和治疗后第4、12、24周末评定蹂狂量表（BRMS）和社会功能缺陷筛查量表（SDSS），分别评估躁狂症状严重程度和社会功能受损情况，副反应量表（TESS）评定不良反应。结果在治疗第4周末及第12周末，研究组BRMS和SDSS评分均较治疗前有显著性降低（P〈0.05），而对照组无显著性变化。治疗第4周末、第12周末及第24周末，研究组的BRMS和SDSS评分均显著低于对照组（P〈0.05）。结论拉莫三嗪对双相障碍躁狂发作的维持期治疗有显著疗效，且可有效改善患者的社会功能。     

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.     

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.     

Antipsychotics in bipolar disorders

This article is a review of the various treatments that are currently available, in particular in France, for the treatment of bipolar disorders. This article specifically addresses the use of novel antipsychotic agents as alternative therapy to a lithium therapy and/or the use of conventional antipsychotics. The prevalence of bipolar disorder over a lifetime is around 1% of the general population. Bipolar disorder consists of alternating depressive and manic episodes. It mainly affects younger subjects, and is often associated with alcohol and drug addictions. There are two main subtypes of bipolar disorder. According to the DSM IV-R, type 1 of bipolar disorder is characterised when at least one manic episode (or a mixed episode) has been diagnosed. Type 2 of bipolar disorder is related to patients enduring recurrent depressive episodes but no manic episode. Type 2 affects women more frequently as opposed to type 1 affecting individuals of both sexes. Manic-depressive disorder (or cyclo-thymic disorder) appears in relation to patients who has never suffered manic episode, mixed episode or severe depressive episode but have undergone numerous periods with some symptoms of depression and hypomanic symptoms over a two-year period during which any asymptomatic periods last no longer than two months. The average age of the person going through a first episode (often a depressive one) is 20 years-old. Untreated bipolar patients may endure more than ten manic or depressive episodes. Finally, in relation to 10 to 20% of patients, the bipolar disorder will turn into a fast cycle form, either spontaneously or as a result of certain medical treatments. Psychiatrists are now able to initiate various treating strategies which are most likely to be effective as a result of the identification of clinical subtypes of the bipolar disorder. Lithium therapy has been effectively and acutely used for patients with pure or elated mania and its prophylaxis. However, lithium medication may worsen depressive symptoms when used for a long term maintenance therapy. Additionally, mixed mania, rapid cycling type patients and bipolar disorder associated with substance abuse do not respond well to lithium therapy. In addition to the lithium therapy or in place of a lithium therapy, one can report the frequent use of antipsychotic agents in respect of patients with bipolar disorder during both the acute and maintenance phases of treatment. Antipsychotic agents have been used for almost forty years and may be used in combination with a lithium therapy. Conventional antipsychotics are effective but they may induce late dyskinesia, weight gain, sedation, sexual dysfunction and depression. These adverse side effects often lead to non compliance in particular in circumstances where antipsychotic agents are combined with a lithium therapy. A number of alternative somatic treatment approaches have been reported for patients who do not respond well or who are intolerant to lithium therapy. As such, valproate has received regulatory approval for the acute treatment of mania and carbamazepine has been indicated for this condition in a number of countries. Divalproex (Depakote) has recently obtained the authorization to market in France and may be prescribed for manic states or hypomanic states that do not tolerate lithium therapy or for which lithium therapy is contraindicated. A number of other anticonvulsants (lamotrigine, gabapentin and topiramate) are currently being tested. Because of the side effects of the conventional antipsychotic agents, atypical antipsychotic agents are currently on trial and appear to be of interest in the treatment of bipolar disorders. Currently, a number of prospective studies are available with clozapine, risperidone and olanzapine in the treatment of bipolar disorder. Most are short-term studies. Recent randomised, double-blind, placebo-controlled studies have shown clozapine, risperidone and olanzapine to be effective with antimanic and antidepressive effects, both as monotherapy and as add-on maintenance therapy with lithium or valproate. They also have a favorable side effect profile and a positive effect on overall functioning. Similarly, valproate combined with antipsychotics provides greater improvement in mania than antipsychotic medication alone and results in lower dosage of the antipsychotic medication. There is currently no double-blind study regarding the use of clozapine for bipolar disorders. However, based on the results of a number of open-label studies, clozapine appears to be effective in relation to schizo-affective and bipolar patients including those with rapid cycling or those who respond inadequately to mood stabilizers, carbamazepine, valproate or conventional antipsychotics. Clozapine seems to be more appropriate for bipolar and schizo-affective patients than schizophrenics. In particular, studies show that patients with manic and mixed-psychotic state of illness are better responders than patients with major depressive syndromes. Four open studies suggest the efficacy of clozapine in the maintenance treatment of bipolar disorder and three prospective, open-label studies show the efficacy of clozapine in the manic state of the illness. However, the number of patients in the studies was not important and these studies are not controlled. Clozapine has also adverse side affects, one of which consisting of a major risk of agranulocytosis and, potentially, death. In addition, clozapine has been shown to produce significant weight gain and sialorrhea as well as significant anticholinergic effects. As a result, clozapine should not be prescribed in the first place. As opposed to clozapine, there are open-label reports and controlled studies in respect of risperidone and olanzapine. Two recent double-blind studies of acute mania found olanzapine to be more effective than placebo. Based on these two studies, olanzapine has recently been approved for the indication of mania. The effects of olanzapine and divalproex in the treatment of mania have also been compared in a large randomized clinical trial. The olanzapine treatment group had significantly greater mean improvement of mania ratings and a significantly greater proportion of patients achieving protocol-defined remission. Significantly more weight gain and cases of dry mouth, increased appetite and somnolence were reported with olanzapine while more cases of nausea were reported with divalproex. The comparison of olanzapine with lithium for the treatment of mania has also been the subject of a double-blind randomized controlled trial. That study shows no differences between the two drugs. While these studies support the idea that olanzapine has direct acute anti-manic effects, a number of authors are of the opinion that olanzapine may have specific prophylactic mood-stabilizing properties. Olanzapine would appear to be effective in the maintenance treatment, as it exhibited both antimanic and antidepressant effects. Systematic trials have shown that risperidone may be effective and safe in the treatment of acute mania, as an add-on therapy with lithium or valproate (open studies and two controlled double-blind studies) and as monotherapy (open studies). In an open, multi-center, 6-month study, risperidone seems to be effective and safe as long-term adjunctive therapy in treatment-resistant bipolar and schizo-affective disorders, with no exacerbation of manic symptoms. Risperidone had few adverse side effects (and where there were any, they were mostly mild), mostly consisting of APS and weight gain. A naturalistic comparison of clozapine, risperidone and olanzapine in the treatment of bipolar disorder suggests that the efficacy and tolerability of the three treatments are similar. One major differentiation factor of these drugs appears to be weight gain, particularly between olanzapine and risperidone. However, this may partially be caused by the use of mood-stabilizing agents. Bipolar and schizo-affective patients now require combination therapy approach because of the cyclic nature of these disorders. Many studies report the combination of mood-stabilizing agents with conventional antipsychotics and atypical antipsychotics. Combination therapies produce a number of adverse side effects. Atypical antipsychotics (other than clozapine) are now rated as first-line agents for adjunctive treatment of mania because they produce less adverse side effects. Atypical antipsychotics are also rated as first-line agents for combined treatment of psychotic depression and they are strongly preferred when an antipsychotic is required for long-term maintenance.     

氟西汀与碳酸锂预防双相II型障碍重性抑郁发作复燃和转躁对照研究

目的:观察双相II型重性抑郁发作临床症状控制后较长期的单用氟西汀与单用碳酸锂治疗的复燃或转躁情况。方法:对75例双相II型障碍重性抑郁发作临床症状控制的患者随机分成两组,分别单用氟西汀与碳酸锂进行26周的治疗并随访,并进行汉密尔顿抑郁量表(HAMD)、杨氏躁狂量表(YMRS)评定。结果:治疗前1周、治疗2周、10周、18周、26周两组HAMD、YMRS评分两组同期比较差异均无显著性(P>0.05)。氟西汀组亚综合征抑郁和抑郁症复燃率低,碳酸锂组亚综合征轻躁狂和轻躁狂发作率低,两组比较差异均有显著性(P<0.05)。结论:双相II型障碍重性抑郁发作后氟西汀单一治疗比锂盐单一治疗可较好预防复燃,但能增加轻躁狂心境转换的发作。     

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.     

Effect of catecholamine depletion on lithium-induced long-term remission of bipolar disorder.

BACKGROUND: This study investigated the effects of catecholamine depletion with alpha-methylparatyrosine (AMPT) on mood indices in patients with bipolar disorder who were in long-term remission with lithium therapy. METHODS: Eight subjects with DSM-IV bipolar disorder currently in remission for > 3 months on lithium were included in the study. Subjects were given either AMPT or placebo, in a randomized double-blind manner, in two test sessions of 4 days each. RESULTS: Subjects did not have any significant changes in mood during AMPT or placebo administration; however, 24-48 hours after the last active AMPT dose subjects had a transient relapse of hypomanic symptoms. Relapse of hypomanic symptoms did not correlate with increases in serum levels of homovanillic acid or 3-methoxy-4-hydroxyphenylglycol. CONCLUSIONS: These findings suggest that the mechanism of prevention of manic relapse by long-term lithium therapy may be dependent on stability of the catecholamine system.     

Prophylactic efficacy of lithium versus carbamazepine in treatment-naive bipolar patients

BACKGROUND: Alternatives to lithium for prophylactic treatment of patients with bipolar affective disorders are increasingly being advocated. However, trials comparing lithium with alternatives are scarce and often biased. METHOD: We studied 94 patients with at least 2 episodes of bipolar disorder (DSM-III-R) during the previous 3 years who were in remission at entry into the study. Treatment with lithium or carbamazepine had not exceeded a total of 6 months during their lifetime. Patients were randomly assigned to carbamazepine or lithium at entry into the 2-year double-blind study or during the acute index episode previous to entry into the study. No concurrent antipsychotics or antidepressants were allowed. RESULTS: On lithium treatment, 12/44 patients developed an episode, compared with 21/50 on carbamazepine treatment. Episodes on lithium treatment occurred almost exclusively during the first 3 months of the trial. Carbamazepine carried a constant risk of an episode of about 40% per year. Efficacy of lithium was superior to that of carbamazepine in patients with a (hypo)manic index episode that had not been treated with study drug during the index episode (p <.01) and also in patients with prior hypomanic but no manic episodes (p <.05). The proportion of patients who dropped out was slightly higher among those taking lithium (16/44) compared with those taking carbamazepine (13/50), resulting in 16/44 patients (36%) on lithium treatment completing the 2 years with no episode, compared with 16/50 (32%) on carbamazepine treatment. CONCLUSION: Lithium appears to be superior in prophylactic efficacy to carbamazepine in bipolar patients not previously treated with mood stabilizers. Our results should reinforce efforts to put and maintain such patients on treatment with lithium.     

Clinical features of antidepressant associated manic and hypomanic switches in bipolar disorder

The present study investigated possible clinical differences between bipolar patients with and without manic or hypomanic switch during antidepressant (AD) treatment. The authors undertook a retrospective assessment of 169 individuals affected by bipolar disorder type I (BP I: n=96) and II (BP II: n=73) who experienced at least one manic or hypomanic episode following depression without any interposed normothymic period ("manic switch") during AD therapy. They were compared with a sex, age (+/-5 years), and ethnicity-matched group of 247 subjects, randomly selected from our pool of bipolar subjects who have never had manic switches. Only 2 of the 169 patients had had spontaneous switches before the AD-related one. Switched subjects were marginally older (t=-2.65, df=414, P=.008) compared to not switched and less frequently delusional (chi2=13.86, P=.0002). Polarity of the onset episode was more frequently depressive in switched patients (chi2=21.93, P=.00002), which had also less previous manic episodes than not switched (t=3.44, df=332, P=.0006). Those differences were more pronounced in the BP I subsample. Switched patients were more frequently BP I (chi2=29.66; P<.00001). Maintenance with mood stabilizers appears to be a strong protective factor; in fact, of the 124 individuals undertaking a mood stabilizer therapy, 21 had a switch and 103 had no switches (chi2=41.10, P<.000001). In conclusion, some clinical variables, such as the number of manic episodes, the presence of delusions, the polarity of onset episode, and the mood-stabilizing treatment, may be involved in AD-related switches. Further studies are required to investigate the causal relationships between those factors.     

A 52-week, open-label continuation study of lamotrigine in the treatment of bipolar depression

BACKGROUND: Lamotrigine has demonstrated efficacy for the acute treatment of depression in bipolar I patients in a placebo-controlled, monotherapy study. We describe the results of a 52-week, open-label continuation of that trial. METHOD: Patients meeting DSM-IV criteria for bipolar I disorder with a current major depressive episode who completed a 7-week, double-blind study of bipolar depression were offered 1 year of open-label lamotrigine therapy (flexible doses of 100-500 mg/day) in a continuation study. To maintain the acute study blind, the first 3 weeks of the continuation study remained blinded while patients previously randomly assigned to placebo were titrated to a lamotrigine dose of 50 mg/day. Patients who had been randomly assigned to lamotrigine continued at their fixed doses. Beginning at week 4, all patients received open-label lamotrigine for up to 49 additional weeks. Concomitant psychotropic medications were permitted during the open-label phase. Effectiveness (Montgomery-Asberg Depression Rating Scale [MADRS], Clinical Global Impressions-Improvement scale) and safety assessments were administered at weeks 4, 12, 24, 36, and 52. The study was conducted from June 1996 to December 1998. RESULTS: Of 135 patients completing the acute study, 124 (92%) entered the continuation study: 77 had received lamotrigine and 47 had received placebo in the acute study. The mean duration of lamotrigine exposure was 10.4 months, with a mean modal dose of 187 mg/day. Sixty-nine patients (56%) completed 1 year of treatment. Significant and sustained improvement from baseline was seen in mean observed MADRS scores (p <.05). The proportion of patients achieving remission (MADRS score < or = 11) by week 4 of the study was 81.4%, and episodes of mania/hypomania occurred less frequently than in the preceding year. Headache was the most common drug-related adverse event. CONCLUSION: During 1 year of open-label therapy with lamotrigine as adjunctive therapy or monotherapy, bipolar I patients experienced sustained improvement in depressive symptoms without evidence of mood destabilization.     

A randomized, double-blind, placebo-controlled 26-week trial of aripiprazole in recently manic patients with bipolar I disorder

OBJECTIVE: To investigate the safety and efficacy of aripiprazole in preventing relapse of a mood episode in recently manic- or mixed-episode patients with bipolar I disorder stabilized on aripiprazole. METHOD: This randomized, double-blind, parallel-group, placebo-controlled, multicenter study enrolled patients from 76 centers in 3 countries (Argentina, Mexico, United States) from March 2000 to June 2003. Bipolar I disorder (DSM-IV) patients who had recently been hospitalized and treated for a manic or mixed episode entered an open-label stabilization phase (aripiprazole monotherapy: 15 or 30 mg/day, 6-18 weeks). After meeting stabilization criteria (Young Mania Rating Scale score of < or = 10 and Montgomery-Asberg Depression Rating Scale score of < or = 13 for 6 consecutive weeks), 161 patients were randomly assigned to aripiprazole or placebo for the 26-week, double-blind phase. The primary endpoint was time to relapse for a manic, mixed, or depressive episode (defined by discontinuation caused by lack of efficacy). RESULTS: Aripiprazole was superior to placebo in delaying the time to relapse (p = .020). Aripiprazole-treated patients had significantly fewer relapses (25%) than placebo patients (43%; p = .013). Aripiprazole was superior to placebo in delaying the time to manic relapse (p = .01); however, no significant differences were observed in time to depressive relapse (p = .68). Weight gain (> or = 7% increase) occurred in 7 (13%) aripiprazole-treated and 0 placebo-treated patients. Adverse events (> or = 5% incidence and twice that of placebo) reported by aripiprazole-treated patients were akathisia, pain in the extremities, tremor, and vaginitis. CONCLUSIONS: Aripiprazole, 15 or 30 mg/day, was superior to placebo in maintaining efficacy in patients with bipolar I disorder with a recent manic or mixed episode who were stabilized and maintained on aripiprazole treatment for 6 weeks, as shown by a longer time to relapse.