Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials

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.     

Quetiapine in the treatment of anxiety in patients with bipolar I or II depression: a secondary analysis from a randomized, double-blind, placebo-controlled study

OBJECTIVE: Quetiapine monotherapy shows efficacy in bipolar depression. The analyses in this multicenter, double-blind, randomized, fixed-dose, placebo-controlled study evaluated effects of quetiapine monotherapy on anxiety symptoms in bipolar depression. METHOD: Of 542 outpatients randomly assigned to treatment, 539 with bipolar I (N = 358) or bipolar II (N = 181) disorder experiencing a major depressive episode (DSM-IV) received 8 weeks of quetiapine monotherapy (600 or 300 mg/day) or placebo between September 2002 and October 2003. Anxiety assessments included the Hamilton Rating Scale for Anxiety (HAM-A) and relevant items from the Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Rating Scale for Depression (HAM-D). Analyses evaluated the pooled dose groups versus placebo. RESULTS: At week 8, quetiapine 600 and 300 mg/day each demonstrated significant improvements in HAM-A total score versus placebo (-10.8 and -9.9 vs. -6.7, p < .001). Quetiapine (pooled doses) significantly improved HAM-A total score from week 1. In bipolar I depression, quetiapine showed significant improvement in HAM-A total score versus placebo (-10.4 vs. -5.1, p < .001). In bipolar I depression, quetiapine also showed significant improvements versus placebo on the HAM-A anxious mood and tension items, HAM-A psychic and somatic subscales, MADRS inner tension item, and HAM-D psychic anxiety item (all p < .001), but not the HAM-D somatic anxiety item. In bipolar II depression, quetiapine reduced the HAM-A total score more than placebo, but the difference was not statistically significant (-9.8 vs. -9.0, p = .473). In bipolar II depression, quetiapine showed significant improvement versus placebo on the HAM-A anxious mood, MADRS inner tension, and HAM-D psychic anxiety items (all p < .01). CONCLUSION: Quetiapine monotherapy shows efficacy in treating anxiety symptoms in bipolar I depression; however, the anxiolytic effects in bipolar II disorder require further investigation.     

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.     

Lamotrigine as adjunct to paroxetine in acute depression: a placebo-controlled,double-blind study

BACKGROUND: Mood stabilizers appear to be more potent in treating mania than depression. The anticonvulsant lamotrigine has been shown to be effective for bipolar depression. This study examines putative antidepressive properties of lamotrigine in a mainly unipolar routine clinical patient population. METHOD: Forty patients with a depressive episode (DSM-IV criteria) requiring psychiatric intervention received lamotrigine or placebo using a fixed dose escalation scheme with a target dose of 200 mg/day for 9 weeks. Additionally, all patients were treated with paroxetine. Hamilton Rating Scale for Depression (HAM-D) and Clinical Global Impressions scale (CGI) ratings were used to monitor therapeutic efficacy. RESULTS: Adjunctive treatment with lamotrigine did not result in a significant difference in HAM-D total score at the endpoint of the study when compared with paroxetine alone. However, lamotrigine demonstrated significant efficacy on core depressive symptoms as reflected by HAM-D items 1 (depressed mood; p = .0019), 2 (guilt feelings; p = .0011), and 7 (work and interest; p = .049) and the CGI-Severity of Illness scale (p < .0001). Patients receiving lamotrigine had fewer days on treatment with benzodiazepines and fewer withdrawals for treatment failure. Lamotrigine appeared to accelerate the onset of action of the antidepressant. Two patients on lamotrigine treatment developed neutropenia, and 1 developed a benign rash. There was no detectable pharmacokinetic interaction between lamotrigine and paroxetine. CONCLUSION: Lamotrigine might have antidepressive properties in unipolar patients and may accelerate onset of action when given in combination with typical antidepressants.     

A double-blind, placebo-controlled study of venlafaxine and fluoxetine in geriatric outpatients with major depression.

BACKGROUND: Despite the high prevalence of depression in elderly patients, few well-designed, placebo-controlled studies of antidepressants have been conducted in this population. This masked, placebo-controlled trial assessed the efficacy and safety of venlafaxine and fluoxetine in depressed patients older than 65 years. METHOD: Three hundred patients were randomly assigned to treatment with venlafaxine immediate release ([IR]; N = 104), fluoxetine (N = 100), or placebo (N = 96) in an eight-week trial. Venlafaxine doses were titrated from 37.5 to 225 mg per day and fluoxetine doses were titrated from 20 to 60 mg per day, as necessary, over 29 days. Efficacy variables included the 21-item Hamilton Depression Rating Scale (HAM-D21) total score, HAM-D21 depressed mood item score, scores on the Montgomery Asberg Depression Rating Scale (MADRS), Clinical Global Impression-Severity of Illness (CGI-S) and Improvement (CGI-I) scales, and rates of response (based on change from baseline HAM-D or MADRS score or CGI-I score) and remission (HAM-D17 < or =7). For the purposes of this report, efficacy analyses are focused on the HAM-D21 total score. Safety assessments included monitoring of adverse events (AEs), physical examinations, vital signs assessments, laboratory determinations, and electrocardiograms. RESULTS: In all three of the treatment groups, there was a significant reduction at week 8 compared with the baseline HAM-D21 total score. However, there were no significant differences among the three treatment groups on the change in HAM-D21, MADRS, or CGI scores from baseline to week 8. There was no statistically significant difference in the proportion of remitters at the last on-therapy visit. The incidence of individual AEs was higher in the venlafaxine group (27%) compared with patients taking fluoxetine (19%) or placebo (9%). CONCLUSION: In this study, there was no significant difference in efficacy among placebo, venlafaxine, and fluoxetine for the treatment of depression.     

Adjunctive herbal medicine with carbamazepine for bipolar disorders: A double-blind, randomized, placebo-controlled study

Chinese herbal medicines possess the therapeutic potential for mood disorders. This double-blind, randomized, placebo-controlled study was designed to evaluate the efficacy and side effects of the herbal medicine called Free and Easy Wanderer Plus (FEWP) as an adjunct to carbamazepine (CBZ) in patients with bipolar disorders. One hundred and twenty-four bipolar depressed and 111 manic patients were randomized to treatment with CBZ alone, CBZ plus FEWP, or equivalent placebo for 12 weeks. CBZ was initiated at 300mg/day and FEWP was given at a fixed dose of 36g/day. Efficacy measures included the Hamilton Rating Scale for Depression, Montgomery-Asberg Depression Rating Scale , Young Mania Rating Scale, Bech-Rafaelsen Mania Scale, and Clinical Global Impression-Severity (CGI-S). CBZ monotherapy produced significantly greater improvement on manic measures at week 2 through endpoint and CGI-S of depression at endpoint compared to placebo. CBZ monotherapy also yielded significantly higher clinical response rates than placebo on bipolar depression (63.8% vs. 34.8%, p=0.044) and mania (87.8% vs. 57.1%, p=0.012). Compared to CBZ monotherapy, adjunctive FEWP with CBZ resulted in significantly better outcomes on the three measures of depression at week 4 and week 8 and significantly greater clinical response rate in depressed subjects (84.8% vs. 63.8%, p=0.032), but failed to produce significantly greater improvement on manic measures and the response rate in manic subjects. There was a lesser incidence of dizziness and fatigue in the combination therapy compared to CBZ monotherapy. These results suggest that adjunctive FEWP has additive beneficial effects in bipolar patients, particularly for those in depressive phase.     

Comparative efficacy between venlafaxine and SSRIs: a pooled analysis of patients with depression.

BACKGROUND: Serotonergic and adrenergic enhancement may be synergistic and more effective than serotonergic enhancement alone in treating depression. The dual serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine is a dual reuptake inhibitor that may therefore offer greater efficacy than selective serotonin reuptake inhibitors (SSRIs). METHODS: Data from eight randomized, double-blind, controlled studies were pooled to compare efficacy in depressed patients receiving venlafaxine/venlafaxine extended release (XR), SSRIs, or placebo for 相似文献   

A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness

BACKGROUND: Up to one half of depressed patients have partial or no response to antidepressant monotherapy. This multicenter, placebo-controlled study evaluated the efficacy of modafinil augmentation in major depressive disorder (MDD) patients with fatigue and excessive sleepiness despite selective serotonin reuptake inhibitor (SSRI) monotherapy. METHOD: Patients (18-65 years) with a DSM-IV diagnosis of MDD and partial response to SSRI monotherapy (> or = 8 weeks) at a stable dose for > or = 4 weeks were eligible. Patients had screening/baseline 31-item Hamilton Rating Scale for Depression (HAM-D) scores of 14 to 26, Epworth Sleepiness Scale (ESS) scores > or = 10, and Fatigue Severity Scale (FSS) scores > or = 4. Patients were randomly assigned to augmentation therapy with modafinil 200 mg/day or placebo for 8 weeks. Assessments included the ESS, Clinical Global Impressions-Improvement scale (CGI-I), 31- and 17-item HAM-D, FSS, Brief Fatigue Inventory (BFI), and Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Of 311 enrolled patients who received > or = 1 dose of study drug, 158 were randomly assigned to modafinil (70% women) and 153 to placebo (72% women); 85% of each treatment group completed the study. At final visit, modafinil significantly improved patients' overall clinical condition compared with placebo on the basis of CGI-I scores (p = .02), and there were trends toward greater mean reductions in ESS, 31- and 17-item HAM-D, and MADRS scores versus placebo. Modafinil significantly reduced BFI scores for worst fatigue at final visit (p < .05 vs. placebo). There were no significant differences between modafinil and placebo at final visit in FSS or BFI total scores. Adverse events significantly more common during modafinil compared with placebo treatment were nausea (9% vs. 2%; p = .01) and feeling jittery (4% vs. 1%; p = .03). CONCLUSION: These findings suggest that modafinil is a well-tolerated and potentially effective augmenting agent for SSRI partial responders with fatigue and sleepiness.     

Quetiapine monotherapy in the treatment of patients with bipolar I or II depression and a rapid-cycling disease course: a randomized, double-blind, placebo-controlled study

OBJECTIVES: To investigate the efficacy and tolerability of quetiapine monotherapy in patients with bipolar I or II disorder with a rapid-cycling disease course. METHODS: Adult patients with a DSM-IV diagnosis of bipolar disorder, most recent episode depressed, with a rapid-cycling disease course from a previously completed multicenter trial randomized to 8 weeks of treatment with quetiapine 600 mg/day (n = 31), quetiapine 300 mg/day (n = 42), or placebo (n = 35) were included in this sub-analysis. The primary efficacy variable was change from baseline to week 8 in Montgomery-Asberg Depression Rating Scale (MADRS) total score. RESULTS: Quetiapine (600 and 300 mg/day) provided significantly greater mean reductions from baseline to week 8 in the MADRS total score than placebo (-21.1, -20.7 versus -11.6, both p < 0.001) in this patient population. Effect sizes in patients with a rapid-cycling disease course were 1.2 (600 mg/day) and 1.1 (300 mg/day) and were similar for bipolar I (0.98 and 1.22) and bipolar II (1.45 and 0.97) sub-groups. Significant improvements were also noted on the Clinical Global Impression, Hamilton Rating Scale for Depression, Hamilton Rating Scale for Anxiety, Pittsburgh Sleep Quality Index, and Quality of Life Enjoyment and Satisfaction Questionnaire scales. Quetiapine was generally well tolerated with moderate increases in weight and extrapyramidal side effects compared to placebo. The incidence of treatment-emergent mania was similar to placebo. CONCLUSIONS: Quetiapine monotherapy (600 or 300 mg/day) is clinically effective and well tolerated in the short-term treatment of depressive episodes in patients with bipolar I or II disorder who have a rapid-cycling disease course.     

Lamotrigine in patients with bipolar disorder and cocaine dependence

BACKGROUND: Bipolar disorder is associated with the highest substance abuse rates of any psychiatric illness. Therefore, treatments that stabilize mood and decrease drug use or cravings are of great interest. Open-label lamotrigine was examined in 30 outpatients with DSM-IV bipolar disorder and cocaine dependence. Lamotrigine was either added to existing medication regimens or used as monotherapy. METHOD: Lamotrigine was started at a dose of 25 mg/day (12.5 mg/day in those taking valproic acid) and titrated to a maximum dose of 300 mg/day. Subjects received a baseline evaluation including a structured clinical interview and weekly assessments for 12 weeks with the Hamilton Rating Scale for Depression (HAM-D), Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale (BPRS), and Cocaine Craving Questionnaire (CCQ). At each appointment, a urine sample was obtained, and participants reported drug use during the previous week. The subjects consisted of 13 men and 17 women with cocaine dependence and bipolar I disorder (N = 22), bipolar II disorder (N = 7), or bipolar disorder not otherwise specified (N = 1), with a mean +/- SD age of 35.4 +/- 7.2 years. Data were analyzed using the last observation carried forward on all subjects who completed the baseline evaluation and at least 1 postbaseline assessment. RESULTS: Significant improvement was observed in HAM-D, YMRS, and BPRS scores (p < or =.02). Cravings also significantly decreased as measured by the CCQ (p <.001). Dollar amount spent on drugs decreased nonsignificantly. Lamotrigine was well tolerated, with no subjects discontinuing due to side effects. CONCLUSION: Lamotrigine treatment was well tolerated in this sample and associated with statistically significant improvement in mood and drug cravings but not drug use. The findings suggest that larger controlled trials of lamotrigine are needed in this population.     

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.     

An open-label study of lamotrigine adjunct or monotherapy for the treatment of adolescents with bipolar depression

OBJECTIVE: The treatment of pediatric bipolar depression has not been well studied. The authors wished to prospectively study the efficacy of lamotrigine as adjunctive or monotherapy in adolescents with bipolar disorder who were experiencing a depressive episode. METHOD: This was an 8-week open-label trial of lamotrigine with 20 adolescents ages 12-17 years (mean age 15.8; 7 boys, 13 girls) with diagnoses of bipolar disorder I, II, or not otherwise specified, who were experiencing a depressive episode. Lamotrigine was begun at 12.5 to 25 mg/day. Primary response criteria was a 1 or a 2 on the Clinical Global Impression-Improvement at week 8. A secondary criterion was at least a 50% decrease in Children's Depression Rating Scale-Revised scores. RESULTS: Nineteen subjects completed the trial. The mean final dose was 131.6 mg/day. Seven subjects were taking other psychotropic medications. Sixteen subjects (84%) responded by primary criteria, and 12 (63%) responded to our secondary criteria. Eleven subjects (58%) were considered in remission at week 8. Young Mania Rating Scale and Overt Aggression Scale-Modified scores also decreased significantly during the trial. There was no significant weight change, rash, or other adverse effects during the trial. CONCLUSIONS: Adolescents with bipolar depression appeared to respond to lamotrigine treatment, whether as adjunctive therapy or monotherapy, with decreases in depression, mania, and aggression. Larger, placebo-controlled studies of lamotrigine are needed in this population.     

Bipolar depression: a new role for atypical antipsychotics?

Bipolar depression, the most common phase of bipolar disorder, causes significant morbidity and mortality. Traditional drugs such as lithium, lamotrigine or antidepressants each offer some clinical efficacy; however, efficacy can be limited and side effects are sometimes problematic. Thus there is a major unmet need for effective, well-tolerated agents for the treatment of bipolar depression. The atypical antipsychotics, with their proven efficacy against manic symptoms, are emerging as candidates for use against the depressive phase of bipolar disorder. Several studies have shown that some atypicals improve depressive symptoms in mixed episodes in patients with bipolar disorder; however, few studies have been performed in patients specifically with bipolar depressive episodes. In a randomized, placebo-controlled trial in patients with acute bipolar I depression, olanzapine monotherapy and an olanzapine-fluoxetine combination significantly improved Montgomery-Asberg Depression Rating Scale (MADRS) total scores compared with placebo (p < 0.001) with corresponding effect sizes (improvement of active treatment over placebo divided by pooled standard deviation) of 0.32 and 0.68, respectively. Importantly, there were no significant differences in rates of switch into mania among the three groups. Recent results from an 8-week, randomized placebo-controlled trial in patients with bipolar I and II disorder who were experiencing a bipolar depressive episode showed that quetiapine (300 and 600 mg/day) had significantly greater efficacy compared with placebo in improving the core symptoms of depression, including suicidal thoughts. Quetiapine significantly improved MADRS total scores compared with placebo (p < 0.001); effect sizes (improvement of quetiapine over placebo divided by pooled standard deviation) of 0.66 and 0.80 for 300 and 600 mg/day quetiapine, respectively, were observed. Both doses of quetiapine significantly improved symptoms of anxiety, sleep quality and global quality of life (all, p < 0.001 versus placebo). These initial findings suggest that atypical antipsychotics may prove to be important future treatments for patients with bipolar depression.     

A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression

OBJECTIVE: There is a major unmet need for effective options in the treatment of bipolar depression. METHOD: Five hundred forty-two outpatients with bipolar I (N=360) or II (N=182) disorder experiencing a major depressive episode (DSM-IV) were randomly assigned to 8 weeks of quetiapine (600 or 300 mg/day) or placebo. The primary efficacy measure was mean change from baseline to week 8 in the Montgomery-Asberg Depression Rating Scale total score. Additional efficacy assessments included the Hamilton Depression Rating Scale, Clinical Global Impression of severity and improvement, Hamilton Anxiety Rating Scale, Pittsburgh Sleep Quality Index, and Quality of Life Enjoyment and Satisfaction Questionnaire. RESULTS: Quetiapine at either dose demonstrated statistically significant improvement in Montgomery-Asberg Depression Rating Scale total scores compared with placebo from week 1 onward. The proportions of patients meeting response criteria (> or =50% Montgomery-Asberg Depression Rating Scale score improvement) at the final assessment in the groups taking 600 and 300 mg/day of quetiapine were 58.2% and 57.6%, respectively, versus 36.1% for placebo. The proportions of patients meeting remission criteria (Montgomery-Asberg Depression Rating Scale < or =12) were 52.9% in the groups taking 600 and 300 mg/day of quetiapine versus 28.4% for placebo. Quetiapine at 600 and 300 mg/day significantly improved 9 of 10 and 8 of 10 Montgomery-Asberg Depression Rating Scale items, respectively, compared to placebo, including the core symptoms of depression. Treatment-emergent mania rates were low and similar for the quetiapine and placebo groups (3.2% and 3.9%, respectively). CONCLUSIONS: Quetiapine monotherapy is efficacious and well tolerated for the treatment of bipolar depression.     

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.     

A double-blind,randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes

BACKGROUND: Evidence of the antidepressant efficacy of lamotrigine is increasing, although there are no placebo-controlled trials of lamotrigine augmentation in depression. The aim of this study was to assess if augmentation with lamotrigine was superior to placebo in patients who were receiving fluoxetine for resistant major depressive episodes. METHOD: Twenty-three patients who had experienced at least 1 major depressive episode that was resistant to at least 1 prior trial of antidepressant therapy were selected. These patients were treated with fluoxetine, 20 mg/day, and concomitantly randomly assigned to receive either lamotrigine (N = 13) or placebo (N = 10) for 6 weeks. The dose of lamotrigine was titrated upward from 25 mg/day to 100 mg/day. Patients suffering from bipolar II disorder (N = 8) or from major depressive disorder (N = 15) (DSM-IV criteria) were enrolled, resulting in heterogeneity of the sample. The primary outcome measure was Hamilton Rating Scale for Depression score. Data were collected from 2000-2001. RESULTS: Lamotrigine was statistically superior to placebo on the Clinical Global Impressions scale at endpoint, both in absolute terms (mean +/- SD Clinical Global Impressions-Severity of Illness scores: lamotrigine, 2.15 +/- 1.28; placebo, 3.40 +/- 1.17; p =.0308) and using a responder analysis, with response defined as a Clinical Global Impressions-Improvement score of 2 or less (lamotrigine, 84.62% [N = 11]; placebo, 30.00% [N = 3]; p =.013). The effect of lamotrigine on Clinical Global Impressions scale scores was seen in both major depressive disorder and bipolar II disorder. Lamotrigine, however, failed to separate statistically from placebo on the Hamilton Rating Scale for Depression and Montgomery-Asberg Depression Rating Scale. This failure to differentiate on a primary outcome measure is essentially a negative study result. This result is most likely an artifact of the small sample size used and the resultant limited power of the study. CONCLUSION: The results of this trial add to the literature suggesting potential efficacy of the antidepressant profile of lamotrigine. In addition, this study points to a possible role of lamotrigine as an augmentation agent in depression.     

Effects of lamotrigine in patients with bipolar disorder and alcohol dependence

BACKGROUND: Bipolar disorder is significantly associated with alcohol use disorders. Anticonvulsant drugs are used in the treatment of bipolar disorder and they have also been used to treat alcohol dependence. The purpose of the present study was to evaluate tolerance and safety of lamotrigine in a dual-diagnosis population presenting bipolar disorder and alcohol dependence. Open-label lamotrigine was examined in 28 outpatients with DSM-IV bipolar disorder and alcohol dependence. Lamotrigine was added to existing medication regimens. METHOD: Lamotrigine was started at a dose of 25 mg/day and titrated to a maximum dose of 300 mg/day. Subjects received a baseline evaluation which included a Structured Clinical Interview for DSM-IV (SCID) and weekly assessments for 12 weeks with the Hamilton Rating Scale for Depression (HAM-D), Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale (BPRS), Severity of Alcohol Dependence Scale (SADS), a Visual Analogue Scale for Craving severity (VASC), and alcohol consumption. The concentration of carbohydrate-deficient transferrin (CDT) was used as an indirect measure of alcohol consumption. The sample consisted of 18 men and 10 women diagnosed with alcohol dependence and bipolar disorder I (n = 21) or bipolar disorder II (n = 7), with a mean age of 36.5 +/- 7.7 years. RESULTS: Significant improvement was observed in HAM-D, YMRS, and BPRS scores (p < 0.01). Craving and CDT also significantly decreased (p < 0.001). Lamotrigine was well tolerated with no dropout subjects due to adverse events. CONCLUSION: Lamotrigine is safe and well tolerated in this sample and associated with improvement in mood, alcohol craving and alcohol consumption. A placebo-controlled study would be of interest.     

The effect of lamotrigine on platelet monoamine oxidase type B activity in patients with bipolar depression

Lamotrigine is an anticonvulsant drug effective in the treatment of epilepsy and bipolar depression. Preclinical data showed that lamotrigine inhibited monoamine oxidase (MAO) activity in vitro. The aim of the study was to determine the effects of 6-weeks lamotrigine treatment on platelet MAO type B (MAO-B) activity in patient with bipolar depression. The study included 26 female patients with bipolar I disorder in depressive episode (DSM-IV criteria, Hamilton Depression Rating Scale (HAMD) and Young Mania Rating Scale). Platelet MAO-B activity was determined spectrofluorimetrically before and after 6 weeks of the treatment with a relatively low dose of lamotrigine (100 mg/day). Six weeks of treatment with lamotrigine significantly decreased platelet MAO-B activity in bipolar depressed patients. This inhibitory effect was not related to smoking status and was independent of the treatment combinations (lamotrigine alone or in combination with either lithium or antipsychotics). Lamotrigine treatment induced a decrease in total HAMD scores in bipolar depressed patients, which was not significantly correlated with reduction of platelet MAO-B activity. These findings provide in vivo insight of lamotrigine effect on platelet MAO-B activity in patients with bipolar depression. Its in vivo MAO-B inhibiting effect might have contributed in part to its antidepressant activity.     

Lamotrigine Monotherapy Improves Depressive Symptoms in Epilepsy: A Double-Blind Comparison with Valproate

Depressive symptoms are highly prevalent in patients with epilepsy. The antiepileptic drug lamotrigine has been shown to be an effective treatment for the depressive phase of bipolar disorder and to enhance mood and well-being in epilepsy patients. The effects of lamotrigine monotherapy on depressive symptoms in epilepsy have not been evaluated to date in a controlled clinical trial. A recently completed double-blind epilepsy trial comparing the effects of lamotrigine monotherapy and valproate monotherapy on weight change incorporated a battery of standard mood assessments. Mean screening Beck Depression Inventory scores showed that both lamotrigine and valproate groups suffered from mild depression at baseline. Lamotrigine monotherapy was reliably associated with earlier and larger improvements than valproate in mood assessed with the Beck Depression Inventory, the Cornell Dysthymia Rating Scale, and the Profile of Mood States. Considered in the context of other data showing lamotrigine's antidepressant efficacy in bipolar depression, these results suggest that lamotrigine improves mood in mildly depressed patients with epilepsy. Lamotrigine may be particularly useful in treating epilepsy patients with comorbid depression, the most common psychiatric illness in epilepsy.     

Citalopram treatment of minor depression in elderly men: an open pilot study.

Antidepressant pharmacotherapy in elderly patients is challenging. The authors examined the use of citalopram to treat late-life minor depression. Ten men (mean age: 73+/-2 years) with DSM-IV Minor Depression were administered citalopram 20 mg/day. Efficacy was measured with the Geriatric Depression Scale (GDS), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions of Severity (CGI-S) scales. Citalopram was well tolerated, and GDS, MADRS, and CGI-S scores decreased after 12 weeks. These findings indicate that citalopram is safe and effective in the treatment of late-life minor depression.