randomized controlled trials of lamotrigine (Lamictal) for bipolar disorder

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(Updated 6/14/05)

Goodwin GM, Bowden CL, Calabrese JR, Grunze H, Kasper S, White R, Greene P, Leadbetter R.
Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, England, UK.
A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder.
J Clin Psychiatry. 2004 Mar;65(3):432-41.
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.
[Abstract]

Ichim L, Berk M, Brook S.
Department of Psychiatry, University of the Witwatersrand Medical School, Parktown, South Africa.
Lamotrigine compared with lithium in mania: a double-blind randomized controlled trial.
Ann Clin Psychiatry. 2000 Mar;12(1):5-10.
"BACKGROUND: Preliminary data from case reports and small open trials suggest a role for lamotrigine in the treatment of bipolar disorder, although controlled data for the manic phase are lacking. METHOD: Thirty inpatients with a DSM-IV diagnosis of bipolar I disorder, currently manic, were randomly allocated to receive either lamotrigine (25 mg once daily for 1 week, 50 mg once daily for the second week, and 100 mg once daily for the last 2 weeks) or lithium (400 mg twice daily) in a 4-week randomized, double-blind, clinical trial. RESULTS: Both treatments improved symptoms of mania, as assessed by the Mania Rating Scale, Brief Psychiatric Rating Scale, Clinical Global Impression severity and improvement scales, and the Global Assessment of Functioning scale. There were no significant differences between groups at any time point, suggesting that the dose escalation required for lamotrigine did not adversely affect its onset of action. Secondary outcome measures, including the use of lorazepam as rescue medication, did not differ between the groups. No significant adverse events were noted in either group. CONCLUSION: In this pilot study, lamotrigine was as effective as lithium in the treatment of patients with bipolar disorder hospitalised for acute mania." [Abstract]

Bowden CL, Calabrese JR, Sachs G, Yatham LN, Asghar SA, Hompland M, Montgomery P, Earl N, Smoot TM, DeVeaugh-Geiss J; Lamictal 606 Study Group.
Department of Psychiatry, University of Texas Health Science Center at San Antonio, 78229, USA. bowdenc@uthscsa.edu
A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder.
Arch Gen Psychiatry. 2003 Apr;60(4):392-400.
"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." [Abstract]

Calabrese JR, Suppes T, Bowden CL, Sachs GS, Swann AC, McElroy SL, Kusumakar V, Ascher JA, Earl NL, Greene PL, Monaghan ET.
University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Ohio, USA.
A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 Study Group.
J Clin Psychiatry. 2000 Nov;61(11):841-50.
"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." [Abstract]

Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD.
Case Western Reserve University, Cleveland, Ohio, USA.
A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group.
J Clin Psychiatry. 1999 Feb;60(2):79-88.
"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." [Abstract]

Bowden CL, Mitchell P, Suppes T.
Department of Psychiatry, University of Texas, Health Science Center at San Antonio, 78284-7792, USA.
Lamotrigine in the treatment of bipolar depression.
Eur Neuropsychopharmacol. 1999 Aug;9 Suppl 4:S113-7.
"Several case reports and open studies have reported the efficacy of lamotrigine in bipolar depression. A randomised placebo-controlled 7-week study comparing two doses of lamotrigine with placebo in 195 patients with moderate to severe bipolar depression has now been completed. Lamotrigine was superior to placebo after 3 weeks as assessed by changes in the Montgomery-Asberg Depression Rating Scale (MADRS). A response, defined as more than 50% improvement on the MADRS occurred in 56 and 48% of the lamotrigine 200 and 50 mg/day groups, respectively, compared with 29% for placebo (P<0.05). There was no evidence that lamotrigine destabilised mood or precipitated mania. Tolerability was good and there were no cases of serious rashes. Preliminary results from an ongoing study also indicate that lamotrigine is more effective than gabapentin in bipolar depression. In conclusion, lamotrigine is effective in alleviating bipolar depression, without causing mood destabilisation. Slow dosage escalation yields good tolerability." [Abstract]

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Recent Lamotrigine RCT Results

1) Maina G, Albert U, Rosso G, Bogetto F
Olanzapine or lamotrigine addition to lithium in remitted bipolar disorder patients with anxiety disorder comorbidity: a randomized, single-blind, pilot study.
J Clin Psychiatry. 2008 Apr;69(4):609-16.
OBJECTIVE: The aim of the present randomized, single-blind, pilot study was to assess the efficacy of the addition of a second mood stabilizer, either olanzapine or lamotrigine, to lithium in patients with remitted bipolar disorder and comorbid anxiety disorder. METHOD: Adult DSM-IV bipolar disorder patients with a current anxiety disorder and a Hamilton Rating Scale for Anxiety (HAM-A) score of 12 or higher, in remission from an affective episode for at least 2 months while on lithium maintenance treatment, were randomly assigned to receive 12 weeks of single-blind olanzapine 5 to 10 mg/day (N = 24) or lamotrigine 50 to 200 mg/day (N = 23) addition to lithium. The primary outcome measure was the HAM-A; secondary outcome measures were the Clinical Global Impressions-Severity of Illness scale and the Global Assessment of Functioning (GAF) scale. Data were collected from July 2005 to February 2007. RESULTS: Twenty-two patients in the olanzapine and 18 in the lamotrigine group completed the trial. Mean +/- SD final doses of olanzapine and lamotrigine were, respectively, 7.7 +/- 4.2 mg/day and 96.7 +/- 46.7 mg/day in the intent-to-treat sample (N = 47). Both olanzapine and lamotrigine were effective in reducing HAM-A scores from baseline to endpoint (paired t test for completers: t = 11.361, df = 21, p < .001 for olanzapine and t = 6.301, df = 17, p < .001 for lamotrigine). Both drugs were also effective on the secondary outcome measures. Olanzapine was more effective than lamotrigine at weeks 6 and 12 with a last-observation-carried-forward analysis on all 3 outcome measures, while such differences disappeared on the HAM-A and GAF at week 12 with the visit-wise analysis. CONCLUSIONS: The addition of a second mood stabilizer (olanzapine or lamotrigine) to lithium is effective in reducing anxiety symptoms in bipolar disorder patients with a co-occurring anxiety disorder. [PubMed Citation] [Order full text from Infotrieve]

2) Calabrese JR, Huffman RF, White RL, Edwards S, Thompson TR, Ascher JA, Monaghan ET, Leadbetter RA
Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials.
Bipolar Disord. 2008 Mar;10(2):323-33.
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. [PubMed Citation] [Order full text from Infotrieve]

3) Bowden CL, Edwards S, Evoniuk G
Open-label, concomitant use of lamotrigine and other medications for bipolar disorder.
CNS Spectr. 2008 Jan;13(1):75-83.
OBJECTIVE: A post-hoc, descriptive analysis was undertaken to assess the tolerability of and changes in psychiatric rating scales with lamotrigine (LTG) administered concomitantly with commonly prescribed bipolar medications. METHODS: During the 8- to 16-week, open-label, preliminary phase of two large clinical trials of patients (N=1,305) with bipolar I disorder, LTG was added to each patient's existing psychotropic regimen. Medications for acute symptoms could have been added and later discontinued to achieve LTG monotherapy. Data were compared for patients taking LTG with or without concomitant valproate, lithium, any atypical antipsychotic, or any selective serotonin reuptake inhibitor. RESULTS: The percentages of patients with any reported adverse event and reported adverse events of mood symptoms or rash were comparable between those taking LTG with or without other concomitant bipolar medications. Adverse events in >10% of patients in at least one subgroup were headache, infection, nausea, rash, influenza, diarrhea, dizziness, and somnolence. Baseline scores on psychiatric rating scales improved similarly with LTG co-administered with other bipolar medications, and the pattern of results did not differ by baseline polarity of mood symptoms. CONCLUSION: LTG co-administered with valproate, lithium, an atypical antipsychotic, or a selective serotonin reuptake inhibitor in the treatment of bipolar disorder seemed to be well tolerated and was associated with clinical improvement. [PubMed Citation] [Order full text from Infotrieve]

4) Zarzar MN, Graham J, Roberts J, Thompson T, Nanry K
Effectiveness and weight effects of open-label lamotrigine with and without concomitant psychotropic medications in patients with bipolar I disorder.
MedGenMed. 2007;9(2):41.
BACKGROUND: Approximately half of all patients with diagnosed bipolar disorder are prescribed 2 or more psychotropic medications. Lamotrigine was approved in 2003 for the maintenance treatment of bipolar I disorder. This study examined comparative effects of lamotrigine with and without concomitant medications. METHODS: A post hoc analysis of data from a prospective, open-label study of lamotrigine in 1175 patients with bipolar I disorder evaluated the clinical response to and quality-of-life and weight effects of lamotrigine as monotherapy and in patients receiving concomitant valproate, lithium, antipsychotics, or antidepressants. The study was originally designed to assess the rate of rash among patients instructed to use specific dermatologic precautions compared with those receiving usual care. Lamotrigine was administered for 12 weeks, including a 5-week titration, with target dose of 200 mg/d, adjusted as necessary for concomitant medication(s). Evaluations at baseline and week 12 included the severity component of the Clinical Global Impression-Bipolar Version scale, the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form, and weight and body mass index (BMI). RESULTS: Efficacy data were available for 1139 patients. Symptoms and quality-of-life mean scores improved following treatment in all patient groups. Quality-of-life scores improved significantly more in patients not receiving than in those receiving concomitant antipsychotics. There were no changes in weight or BMI after lamotrigine monotherapy or adjuvant therapy. Most patients were satisfied with lamotrigine treatment. CONCLUSION: Lamotrigine was effective and well tolerated and appeared to have no effect on body weight when given as monotherapy or as adjunctive therapy with valproate, antipsychotics, lithium, or antidepressants to outpatients with bipolar I disorder in a 12-week open-label study. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]

5) Sajatovic M, Elhaj O, Youngstrom EA, Bilali SR, Rapport DJ, Ganocy SJ, Calabrese JR
Treatment adherence in individuals with rapid cycling bipolar disorder: results from a clinical-trial setting.
J Clin Psychopharmacol. 2007 Aug;27(4):412-4.
[PubMed Citation] [Order full text from Infotrieve]

6) Goldberg JF, Bowden CL, Calabrese JR, Ketter TA, Dann RS, Frye MA, Suppes T, Post RM
Six-month prospective life charting of mood symptoms with lamotrigine monotherapy versus placebo in rapid cycling bipolar disorder.
Biol Psychiatry. 2008 Jan 1;63(1):125-30.
BACKGROUND: Fluctuations in mood are quintessential features of bipolar disorder; however, previous studies have seldom examined the extent to which pharmacotherapies for bipolar disorder may reduce or ameliorate daily or weekly mood variability. The anticonvulsant lamotrigine has demonstrated efficacy for relapse prevention in bipolar disorder, but its possible mood-stabilizing properties on a day-to-day or week-to-week basis have not previously been investigated. METHODS: Weekly mood shifts were examined over 26 weeks using patients' self-reported prospective Life Chart Method (LCM) data obtained as part of a previously reported randomized relapse prevention comparison of lamotrigine monotherapy or placebo in 182 bipolar patients with DSM-IV rapid cycling. Generalized estimating equation (GEE) analyses were used to compare treatment arms for subjects who achieved euthymia across weeks. RESULTS: After adjusting for potential confounding factors, a final GEE model revealed that subjects taking lamotrigine were 1.8 times more likely than those taking placebo to achieve euthymia, as measured by LCM, at least once per week over 6 months (95% confidence interval [CI] = 1.03-3.13). Subjects taking lamotrigine had an increase of .69 more days per week euthymic as compared with those taking placebo (p = .014). CONCLUSIONS: Achievement of euthymia across weeks represents a novel paradigm shift in gauging the mood-stabilizing properties of a psychotropic agent. The present findings demonstrate the utility of the prospective Life Chart Method for assessing longitudinal mood stability during randomized clinical trials for bipolar disorder. The results lend support to the potential mood-stabilizing properties of lamotrigine monotherapy for bipolar disorder. [PubMed Citation] [Order full text from Infotrieve]

7) Amann B, Grunze H, Vieta E, Trimble M
Antiepileptic drugs and mood stability.
Clin EEG Neurosci. 2007 Apr;38(2):116-23.
This paper will discuss different definitions of the term "mood stabilizer" and highlight in detail the antiepileptic drugs carbamazepine, valproate and lamotrigine with respect to their relative strengths in stabilizing mood in bipolar patients. These drugs are heterogeneous in their mechanisms of action and in their efficacy to stabilize patients with epilepsy and the various mood states in bipolar disorder. Lamotrigine has obtained approval in several countries for the indication of preventing bipolar depressive episodes, which raises the question of differential efficacy of other antiepileptic drugs as mood stabilizers in the prevention of either depressive or hypo-/manic episodes. A Medline Search to 2006 was conducted for controlled acute and maintenance studies of the three scientifically and clinically most established antiepileptic drugs carbamazepine, valproate and lamotrigine. The medications discussed in this review only partly fulfill definitions of a mood stabilizer, and we suggest that future research should focus on combined treatment strategies. [PubMed Citation] [Order full text from Infotrieve]

8) Nolen WA, Kupka RW, Hellemann G, Frye MA, Altshuler LL, Leverich GS, Suppes T, Keck PE, McElroy S, Grunze H, Mintz J, Post RM
Tranylcypromine vs. lamotrigine in the treatment of refractory bipolar depression: a failed but clinically useful study.
Acta Psychiatr Scand. 2007 May;115(5):360-5.
OBJECTIVE: To compare the efficacy and tolerability of tranylcypromine vs. lamotrigine in bipolar depression not responding to conventional antidepressants. METHOD: Bipolar depressed patients received open randomized treatment with tranylcypromine or lamotrigine as add-on to a mood stabilizer during 10 weeks. In a second treatment phase, non-responding patients could receive the opposite drug. Outcome criteria were response (measured with CGI-BP and IDS-C), switch into mania, and completion of the study. RESULTS: Only 20 of 70 planned patients were randomized, due to problems with recruitment, and 19 patients received any medication. During the first treatment phase 5/8 patients (62.5%) responded to tranylcypromine without switch into mania, compared with 4/11 patients (36.4%) on lamotrigine with two switches (statistically not significant). Over both treatment phases, 8/10 patients (80%) receiving tranylcypromine completed the study vs. 5/13 (38.5%) on lamotrigine (likelihood 0.02). CONCLUSION: There still appears to be a role for tranylcypromine in the treatment of refractory bipolar depression. Larger controlled studies are demanded. [PubMed Citation] [Order full text from Infotrieve]

9) Cousins DA, Young AH
The armamentarium of treatments for bipolar disorder: a review of the literature.
Int J Neuropsychopharmacol. 2007 Jun;10(3):411-31.
To assess current pharmacotherapeutic options for bipolar disorder, with particular emphasis on the use of antipsychotic agents, Medline and EMBASE were searched between January 1980 and December 2005 using the keywords "schizoaffective disorder" and "bipolar disorder", combined with various antidepressants, antipsychotics, lithium or other mood stabilizers. English-language articles, review articles and original research articles were reviewed. Most data are available for the "mood stabilizers" lithium and valproate. However, these agents have important limitations regarding their tolerability and efficacy in certain groups. Newer anticonvulsants, especially lamotrigine, have demonstrated efficacy across mood-symptom domains. Antidepressants are not generally favoured as monotherapy in patients with bipolar depression or schizoaffective disorder, due to their potential to induce switching to manic states. However, data are emerging for the efficacy of selective serotonin reuptake inhibitors for bipolar depression in combination with atypical antipsychotics. Atypical antipsychotics may also be used as monotherapy or in conjunction with mood stabilizers for the treatment of acute mania and for continuing maintenance therapy. The choice of antipsychotic may be influenced by the therapeutic situation; formulations that facilitate administration in the acute scenario can provide rapid tranquillization, whereas those that enhance compliance may have a place in maintenance therapy. Our results suggest a growing role for atypical antipsychotics in the treatment of bipolar disorder and further data are anticipated. [PubMed Citation] [Order full text from Infotrieve]

10) Spaulding T, Westlund R, Thomason C, White R, Dann R, Thompson T
Adjunctive treatment for mood stabilization of patients with bipolar I disorder treated with lamotrigine.
CNS Spectr. 2006 Sep;11(9):711-6; quiz 719.
OBJECTIVE: To describe the effect of supplemental psychotropic medications, specifically anxiolytics with sedative/hypnotics (ASH) combined with lamotrigine (LTG) on stabilization of symptoms in patients with bipolar I disorder. METHOD: Symptomatic patients participating in two LTG maintenance trials were classified post-hoc as those initiating LTG as monotherapy (n=313) or as adjunctive therapy (n=814) and further characterized by supplemental add-on therapies received during an open-label treatment phase. Patients were considered stabilized if they reached a stable dose of LTG monotherapy (100-200 mg/day) and had a Clinical Global Impressions-Severity scale score <3 for at least 4 weeks. Stabilization rates were compared across initial- and supplemental-treatment groups. RESULTS: Patients who initiated and were maintained on LTG monotherapy were stabilized at a slightly higher rate compared with those taking LTG adjunctive therapy (55% vs 48%; P=.080). Stabilization rates were numerically higher for LTG monotherapy patients who later received only ASH as supplemental medication compared with LTG monotherapy throughout, but this difference was not significant (66% vs 55%; P=.271). Stabilization rates were significantly higher for monotherapy patients who later received ASH alone versus other psychotropic medications (66% vs 28%; P=.001). For patients initiating LTG as adjunctive therapy, adding ASH alone resulted in significantly higher stabilization rates than adding another psychotropic medication (62% vs 33%; P<.001). CONCLUSION: LTG and adjunctive treatment with ASH may be useful in the treatment of acute mood symptoms in patients with bipolar I disorder. [PubMed Citation] [Order full text from Infotrieve]

11) Brown EB, McElroy SL, Keck PE, Deldar A, Adams DH, Tohen M, Williamson DJ
A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression.
J Clin Psychiatry. 2006 Jul;67(7):1025-33.
OBJECTIVE: Determine the efficacy and tolerability of olanzapine/fluoxetine combination (OFC) for treatment of acute bipolar I depression compared with lamotrigine. METHOD: The 7-week, acute phase of a randomized, double-blind study compared OFC (6/25, 6/50, 12/25, or 12/50 mg/day; N = 205) with lamotrigine ([LMG] titrated to 200 mg/day; N = 205) in patients with DSM-IV-diagnosed bipolar I disorder, depressed. The study was conducted from November 2003 to August 2004. RESULTS: Completion rates were similar between treatments (OFC, 66.8% vs. LMG, 65.4%; p = .835). OFC-treated patients had significantly greater improvement than lamotrigine-treated patients in change from baseline across the 7-week treatment period on the Clinical Global Impressions-Severity of Illness scale (primary outcome) (p = .002, effect size = 0.26), Montgomery-Asberg Depression Rating Scale (MADRS) (p = .002, effect size = 0.24), and Young Mania Rating Scale total scores (p = .001, effect size = 0.24). Response rates did not significantly differ between groups when defined as > or = 50% reduction in MADRS score (OFC, 68.8% vs. LMG, 59.7%; p = .073). Time to response was significantly shorter for OFC-treated patients (median days [95% CI] = OFC, 17 [14 to 22] vs. LMG, 23 [21 to 34]; p = .010). There was a significant difference in incidence of "suicidal and self-injurious behavior" adverse events (OFC, 0.5% vs. LMG, 3.4%; p = .037). Somnolence, increased appetite, dry mouth, sedation, weight gain, and tremor occurred more frequently (p < .05) in OFC-treated patients than lamotrigine-treated patients. Weight, total cholesterol, and triglyceride levels were significantly elevated in OFC-treated patients compared with lamotrigine-treated patients (all p < or = .001). CONCLUSIONS: Patients with acute bipolar I depression had statistically significantly greater improvement in depressive and manic symptoms, more treatment-emergent adverse events, greater weight gain, and some elevated metabolic factors with OFC than lamotrigine. Treatment differences were of modest size. [PubMed Citation] [Order full text from Infotrieve]

12) Schaffer A, Zuker P, Levitt A
Randomized, double-blind pilot trial comparing lamotrigine versus citalopram for the treatment of bipolar depression.
J Affect Disord. 2006 Nov;96(1-2):95-9.
BACKGROUND: Uncertainty exists regarding the best approach for treating bipolar depression among patients already receiving a first-line mood stabilizer. The aim of this pilot study was to compare adding a second mood stabilizer or an antidepressant at this treatment decision point. METHODS: Twelve-week, randomized, double-blind pilot trial comparing the addition of lamotrigine or citalopram for bipolar depressed patients on mood stabilizer medication. Change in depressive symptoms and risk of switch were examined. RESULTS: Twenty subjects were randomized. Each treatment group experienced a significant mean reduction in total MADRS scores (citalopram Delta - 14.2, p=0.002; lamotrigine Delta - 13.3, p= 0.001), and there was no significant difference between treatment groups (p=0.78). Total response rates increased from 31.6% at week 6 to 52.6% at week 12. One out of ten patients in each group experienced a switch to hypomania. LIMITATIONS: Small sample size. Lack of a placebo arm. CONCLUSIONS: Results of this small trial suggest that both lamotrigine and citalopram appear to be reasonable choices as add-on acute treatment for bipolar depression, with response rates continuing to rise considerably past 6 weeks of treatment. [PubMed Citation] [Order full text from Infotrieve]

13) Bowden CL, Calabrese JR, Ketter TA, Sachs GS, White RL, Thompson TR
Impact of lamotrigine and lithium on weight in obese and nonobese patients with bipolar I disorder.
Am J Psychiatry. 2006 Jul;163(7):1199-201.
OBJECTIVE: This study assessed weight changes in a large cohort of patients with bipolar disorder who were treated with randomly assigned maintenance monotherapies. METHOD: A post hoc analysis was conducted to assess the effects of lamotrigine, lithium, and placebo administration on body weight in obese and nonobese patients with bipolar disorder from two double-blind, placebo-controlled, 18-month studies. RESULTS: Mean changes in weight among obese patients (N=155) at week 52 were -4.2, +6.1, and -0.6 kg with lamotrigine, lithium, and placebo, respectively (lamotrigine versus lithium and lithium versus placebo). Among nonobese patients (N=399), mean changes in weight (kg) at week 52 were -0.5, +1.1, and +0.7 with lamotrigine, lithium, and placebo, respectively, with no significant differences among groups. CONCLUSIONS: Obese patients with bipolar I disorder lost weight while taking lamotrigine and gained weight while taking lithium. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]

14) Calabrese JR, Goldberg JF, Ketter TA, Suppes T, Frye M, White R, DeVeaugh-Geiss A, Thompson TR
Recurrence in bipolar I disorder: a post hoc analysis excluding relapses in two double-blind maintenance studies.
Biol Psychiatry. 2006 Jun 1;59(11):1061-4.
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. [PubMed Citation] [Order full text from Infotrieve]

15) Ketter TA, Greist JH, Graham JA, Roberts JN, Thompson TR, Nanry KP
The effect of dermatologic precautions on the incidence of rash with addition of lamotrigine in the treatment of bipolar I disorder: a randomized trial.
J Clin Psychiatry. 2006 Mar;67(3):400-6.
OBJECTIVE: Prescribing recommendations specify that lamotrigine should ordinarily be discontinued at the first sign of rash, regardless of its type and severity, unless the rash is clearly not drug related. This practice helps to ensure that lamotrigine is discontinued in instances of serious rash (an event occurring in up to 0.13% of cases in bipolar clinical trials) but may lead to unnecessary discontinuation of lamotrigine for cases of nonserious rash arising from nondrug causes. Measures aimed at reducing overall occurrence of dermatologic reactions might reduce the incidence of nonserious rash leading to premature lamotrigine discontinuation. This study assessed the impact of specific instructions designed to decrease risk of dermatologic reactions, including nonserious rash, during initiation of and early treatment with lamotrigine in patients with bipolar I disorder. METHOD: Outpatients with DSM-IV-diagnosed bipolar I disorder >/= 13 years of age at 188 sites were randomly assigned to receive Usual Care Precautions (UCP; precautions from the patient instructions in the prescribing information for reducing risk of rash including nonserious rash) or Dermatologic Precautions (DP; precautions as above [UCP] plus additional precautions intended to decrease risk of any dermatologic reaction including nonserious rash) during 12 weeks of adding open-label lamotrigine to concomitant medications. Patients with comorbid medical and psychiatric problems were not excluded unless, in the opinion of the investigators, these problems were sufficiently severe to preclude participation. Investigators and patients were blinded to which precaution group patients were randomly assigned. The primary outcome measure was the rate of rash during the treatment period. Secondary outcome measures included clinical response to lamotrigine, assessed with the investigator- and self-rated Clinical Global Impressions-Bipolar version (CGI-BP) and the Clinical Global Impressions-Efficacy Index (CGI-EI). Data were collected from August 2003 to August 2004. RESULTS: 867 (74%) of 1175 patients completed the study. Only 182 (15%) of 1175 patients had an adverse event leading to discontinuation of study medication or withdrawal, including 62 (5.3%) of 1175 due to non-serious rash. No serious rashes were reported during the study in either group. The incidence of nonserious rash was similarly low in patients with UCP and DP (8.8% and 8.6%, respectively). CGI-BP-Severity and -Improvement scores indicated mood improvement when lamotrigine was added to existing therapy, and CGI-EI scores at weeks 5 and 12 reflected a favorable balance between control of mood symptoms and tolerability. At both weeks 5 and 12, investigators reported that therapeutic effects of additional lamotrigine outweighed side effects in 74% of subjects. CONCLUSION: UCP and DP yielded low, similar non-serious rash rates, which were marginally lower than nonserious rash rates in prior clinical trials that did not utilize DP but marginally higher than that in a prior open case series using DP. Nevertheless, the results are encouraging: in this large study reflecting real-world use, lamotrigine was well tolerated with no serious rash and low incidences of nonserious rash and discontinuation due to rash, and lamotrigine therapy was associated with clinical improvement in a heterogeneous cohort of patients with bipolar I disorder. [PubMed Citation] [Order full text from Infotrieve]

16) Sachs G, Bowden C, Calabrese JR, Ketter T, Thompson T, White R, Bentley B
Effects of lamotrigine and lithium on body weight during maintenance treatment of bipolar I disorder.
Bipolar Disord. 2006 Apr;8(2):175-81.
OBJECTIVE: The effect of lamotrigine maintenance therapy on body weight was assessed retrospectively in analyses of data from two double-blind, placebo- and lithium-controlled, 18-month studies in patients with bipolar I disorder (n = 227 for lamotrigine, 190 for placebo, 166 for lithium). METHODS: Endpoints included mean change in weight, the percentage of patients with > or = 7% change (increase, decrease, fluctuation) in weight, and the percentage of patients with weight-related adverse events during double-blind treatment. RESULTS: Mean weight remained stable during maintenance therapy with lamotrigine. In a mixed-model repeated-measures analysis, mean changes in weight (kg) at week 52 were -1.2 with lamotrigine, +0.2 with placebo, and +2.2 with lithium [estimated difference (95% CI) lamotrigine minus placebo = -1.3 (-3.6, 0.9), p = 0.237; lithium minus placebo = +2.0 (-0.3, 4.4), p = 0.094; lithium minus lamotrigine = +3.4 (1.4, 5.4), p < 0.001]. Analyses were truncated at week 52 because of the high incidence of missing data at later time points. The percentages of patients with a >/=7% weight gain, during randomized treatment, were 10.9%, 7.6% and 11.8% for the lamotrigine, placebo, and lithium groups, respectively. The percentages of patients with a > or = 7% weight loss, during randomized treatment, were 12.1%, 11.5%, and 5.1% for the lamotrigine, placebo, and lithium groups, respectively. The percentage of patients with a > or = 7% weight loss did not significantly differ between lamotrigine and placebo but was significantly higher with lamotrigine than lithium. The incidences of > or = 7% weight changes and of weight changes reported as adverse events were comparable between active treatments and placebo. CONCLUSION: Lamotrigine was associated with stable body weight during 1 year of treatment and was comparable to placebo in mean weight change, incidence of clinically significant weight change, and incidence of weight changes reported as adverse events in patients with bipolar disorder. Lithium was associated with weight gain, but the magnitude of lithium-associated weight gain was lower in the current analysis than in previous studies. [PubMed Citation] [Order full text from Infotrieve]

17) Nierenberg AA, Ostacher MJ, Calabrese JR, Ketter TA, Marangell LB, Miklowitz DJ, Miyahara S, Bauer MS, Thase ME, Wisniewski SR, Sachs GS
Treatment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol, or risperidone.
Am J Psychiatry. 2006 Feb;163(2):210-6.
OBJECTIVE: Clinicians have few evidence-based options for the management of treatment-resistant bipolar depression. This study represents the first randomized trial of competing options for treatment-resistant bipolar depression and assesses the effectiveness and safety of antidepressant augmentation with lamotrigine, inositol, and risperidone. METHOD: Participants (N=66) were patients with bipolar I or bipolar II disorder enrolled in the NIMH Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). All patients were in a current major depressive episode that was nonresponsive to a combination of adequate doses of established mood stabilizers plus at least one antidepressant. Patients were randomly assigned to open-label adjunctive treatment with lamotrigine, inositol, or risperidone for up to 16 weeks. The primary outcome measure was the rate of recovery, defined as no more than two symptoms meeting DSM-IV threshold criteria for a mood episode and no significant symptoms present for 8 weeks. RESULTS: No significant between-group differences were seen when any pair of treatments were compared on the primary outcome measure. However, the recovery rate with lamotrigine was 23.8%, whereas the recovery rates with inositol and risperidone were 17.4% and 4.6%, respectively. Patients receiving lamotrigine had lower depression ratings and Clinical Global Impression severity scores as well as greater Global Assessment of Functioning scores compared with those receiving inositol and risperidone. CONCLUSIONS: No differences were found in primary pairwise comparison analyses of open-label augmentation with lamotrigine, inositol, or risperidone. Post hoc secondary analyses suggest that lamotrigine may be superior to inositol and risperidone in improving treatment-resistant bipolar depression. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]

18) Severus WE, Grunze H, Kleindienst N, Frangou S, Moeller HJ
Is the prophylactic antidepressant efficacy of lithium in bipolar I disorder dependent on study design and lithium level?
J Clin Psychopharmacol. 2005 Oct;25(5):457-62.
In the 1970s, several randomized controlled trials demonstrated significant antimanic and antidepressant properties of lithium in the prophylactic treatment of bipolar disorder. However, a recent meta-analysis of randomized, placebo-controlled trials of lithium in bipolar disorder found that its protective effect against depressive relapse/recurrence was equivocal. By examining potentially relevant parameters of recent randomized controlled trials with regard to lithium's prophylactic antidepressant efficacy, we try to identify factors which might help to explain these discrepant results across the different trials. Lithium's efficacy against manic relapse/recurrence appears rather robust at plasma levels between 0.8 and 1.2 mmol/L, whereas lithium's efficacy against depressive relapse/recurrence may be more modest and dependent on whether a response during the preceding acute episode was achieved by lithium treatment. Furthermore, it might be advisable to continue lithium without interruption at the same dose/plasma level, which yielded the initial response. A lithium level between 0.5 and 0.8 mmol/L may be equally efficacious against overall relapse and associated with equal or even superior efficacy regarding depressive relapse/recurrence. To provide evidence-based guidelines on this issue, large prospective, randomized, double-blind, placebo-controlled trials are needed comparing the efficacy of lithium at different plasma levels against manic and depressive relapse/recurrence. In these trials, factors previously associated with predicting response to lithium should also be assessed. [PubMed Citation] [Order full text from Infotrieve]

19) Deshauer D, Fergusson D, Duffy A, Albuquerque J, Grof P
Re-evaluation of randomized control trials of lithium monotherapy: a cohort effect.
Bipolar Disord. 2005 Aug;7(4):382-7.
OBJECTIVE: The reported reduction of lithium's efficacy in the prophylaxis of bipolar illness has been attributed to various factors, including diagnostic changes and heterogeneous study designs. We attempted to quantify the impact of pre-randomization enrichment designs and diagnostic drift on randomized controlled trials (RCTs) of lithium maintenance therapy. METHODS: Using the Cochrane RCT search filter, MEDLINE, EMBASE, and PSYCHINFO were searched (1966 to June 2004) for all available randomized studies using the text word 'lithium'. Studies of 1 year minimum duration in bipolar disorder involving lithium and placebo arms were identified. Superiority trials without a placebo arm, discontinuation and mirror image studies were excluded. Standardized scales were used to assess randomization and allocation concealment. RESULTS: Nine RCTs enrolling 1432 bipolar I and II patients, randomizing 341 to lithium and 386 to placebo were identified, with 705 reported pre-randomization dropouts. The pooled odds of remaining recurrence free in two non-enriched RCTS using Research Diagnostic Criteria (RDC) or Feighner criteria were 3.2:1 (95% CI 0.65--15.46) trending in favor of lithium over placebo, and 22.0:1 (95% CI 7.0--68.7) for three trials using lithium enrichment and excluding atypical bipolar disorder. The odds of remaining recurrence free using DSM-IV criteria and lamotrigine enrichment were 1.9:1 (95% CI 1.2-2.8). Conclusion: Lithium maintenance RCTs differ in patient selection, design, and outcome. A cohort effect can be associated with the use of pre-randomization enrichment phases and, to a lesser extent, with diagnostic drift, compromising straightforward comparisons across three decades of lithium monotherapy in bipolar illness. [PubMed Citation] [Order full text from Infotrieve]