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Lamictal: Mood Stabilizer and Antidepressant














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Lamictal is as close as we have come to a "magic bullet" for bipolar depression, especially treatment-resistant bipolar II depression: it is a mood stabilizer with antidepressant properties.

This page has a lot of research, much of it technical. If you want to read the "bottom line" about each study, read the "CONCLUSION", usually on the bottom line. It's a lot to read, but well worth the time invested.
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Eur Neuropsychopharmacol. 2004 May;14 Suppl 2:S89-93.

 
Lamotrigine: a depression mood stabiliser.

Herman E.

Psychiatric Clinic, Psychiatric Office, Charles University, Na Markvartce 8, 160 00 Praha, Prague 6, Czech Republic. aapsych@mbox.vol.cz

Depression mood stabilisers, which stabilise mood from below the mood baseline (euthymia) without inducing switch into mania or episode acceleration, are urgently needed for the effective treatment of bipolar depression. The anticonvulsant lamotrigine, recently approved as maintenance therapy for bipolar depression, has undergone evaluation as acute and maintenance therapy for bipolar disorder in several controlled clinical trials. Data from these trials suggest that lamotrigine is effective in the treatment and prevention of bipolar depression without destabilising mood. Although the majority of evidence comes from studies in patients with bipolar I disorder, a recent naturalistic study suggests that these observations may also extend to patients with bipolar II disorder. Lamotrigine may therefore fulfil the unmet need for an effective depression mood stabiliser.

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J Clin Psychiatry. 2002 Aug
 
Lamotrigine as an augmentation agent in treatment-resistant depression.

Barbee JG, Jamhour NJ.

Department of Psychiatry, Louisiana State University Health Sciences Center, 1542 Tulane Ave., Box T4-6, New Orleans, LA 70122, USA. jbarbe@lsuhsc.edu

BACKGROUND: The anticonvulsant lamotrigine has been reported to be efficacious and well tolerated as monotherapy in the treatment of bipolar patients as well as in treatment-refractory bipolar disorder. However, there is a paucity of research on the use of lamotrigine as an augmentation agent in treatment-refractory unipolar major depressive disorder. METHOD: This study was a retrospective chart review on the efficacy of lamotrigine augmentation in 37 individuals diagnosed with chronic or recurrent major depressive disorder (DSM-IV) who had failed to respond adequately to at least 2 previous trials of antidepressants. Thirty-one patients who were on lamotrigine treatment for at least 6 weeks (6 discontinued prematurely due to adverse events) took a mean dose of 112.90 mg/day for a mean of 41.80 weeks. The primary efficacy parameter for this study was the Clinical Global Impressions scale, which was retrospectively applied. In addition, these data were supplemented by an analysis of prospectively rated Global Assessment of Functioning scores. RESULTS: On the basis of intent-to-treat analysis, response rates were as follows: 40.5% (15/37) much improved or very much improved, 21.6% (8/37) mildly improved, and 37.8% (14/37) unchanged. The percentage of patients who were rated much or very much improved and completed 6 weeks on the drug was 48.4% (15/31). No differences were found in the doses of lamotrigine given to responders and nonresponders. CONCLUSION: Analyses revealed that lamotrigine treatment was most effective for patients who had been depressed for shorter periods of time and had failed fewer previous trials of antidepressants. Data also suggested a trend toward increased response for patients with comorbid anxiety disorders and/or chronic pain syndromes.

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J Clin Psychiatry. 2004;65 Suppl 10:28-35.

 
Newer anticonvulsants in the treatment of bipolar disorder.

Yatham LN.

Division of Mood Disorders, University of British Columbia, Vancouver, British Columbia, Canada.

The anticonvulsants valproate and carbamazepine have efficacy in treating acute mania, but their efficacy in treating acute bipolar depression and preventing mood episodes remains uncertain. Despite this, and given their utility and widespread use, both are widely accepted as standard treatments for bipolar disorder. All the newer anticonvulsants that have become available during the last decade have been or are being assessed to determine their efficacy in the treatment of various phases of bipolar disorder. Among the newer anticonvulsants, some appear to have efficacy in treating core bipolar symptoms, while others have efficacy in treating psychiatric comorbidity such as substance abuse or an anxiety disorder. Lamotrigine is the most widely studied and is effective in treating and preventing bipolar depression, and it is the only anticonvulsant approved by the U.S. Food and Drug Administration as a maintenance treatment for bipolar disorder. Other newer anticonvulsants, levetiracetam, oxcarbazepine, phenytoin, and zonisamide offer promise, but further studies are required before they can be recommended for routine use to treat bipolar disorder. Gabapentin and topiramate do not appear to have efficacy in treating acute mania, but their utility in bipolar depression and prevention of mood episodes has not been studied in double-blind trials. Pregabalin has utility in treating generalized anxiety disorder, but it has not been studied in bipolar disorder. Given the success of lamotrigine in treating bipolar disorder, further double-blind controlled trials of the newer anticonvulsants in treating bipolar disorder are warranted. This article summarizes current evidence from trials of anticonvulsants in bipolar disorder and makes recommendations for their clinical use.

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Am J Psychiatry. 1999 Jul

 
Spectrum of activity of lamotrigine in treatment-refractory bipolar disorder.

Calabrese JR, Bowden CL, McElroy SL, Cookson J, Andersen J, Keck PE Jr, Rhodes L, Bolden-Watson C, Zhou J, Ascher JA.

Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106, USA.

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.

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Epilepsia. 2002 Jan;43(1):19-26.

 
Randomized double-blind parallel-group study comparing cognitive effects of a low-dose lamotrigine with valproate and placebo in healthy volunteers.

Aldenkamp AP, Arends J, Bootsma HP, Diepman L, Hulsman J, Lambrechts D, Leenen L, Majoie M, Schellekens A, de Vocht J.

Department of Neurology of the Epilepsy Centre Kempenhaeghe, Heeze, The Netherlands. aldenkampB@kempehaeghe.nl

PURPOSE: This study aimed at investigating the cognitive and mood effects of lamotrigine (LTG) versus valproate (VPA) and placebo (PBO). METHODS: By studying the effects in healthy volunteers, it is possible to separate the genuine effects of LTG from the cognitive improvements, caused by better seizure control. The study used a pretest-posttest comparison of 50 mg LTG, 900 mg VPA, or PBO in a double-blind single-dummy parallel-group design with 30 healthy volunteers. Study duration was 12 days (with a last control on day 13). Outcome measures included cognitive tests (FePsy neuropsychological test battery), mood scales (ASL; mood-rating scale), and a scale for subjective complaints (ABNAS Neurotoxicity scale). Total sleep time was controlled with actigraphic recordings. The results were analyzed by comparing the change over time (pretest with posttest) for the three treatments with Student's t tests. RESULTS: COGNITIVE TESTS: significant differences between the treatments were found for measurements of cognitive activation (i.e., three of the four simple reaction-time measurements showed statistically significant differences in change between PBO and LTG in favor of LTG (p=0.03; 0.03; 0.04); two of four tests showed statistically significant differences in change between LTG and VPA, both in favor of LTG (p=0.03; 0.05). SUBJECTIVE COMPLAINTS: the ABNAS-neurotoxicity scale reveals a significant reduction of drug-related cognitive complaints for the subjects taking LTG, relative to VPA (p=0.02). MOOD RATING: significant changes were found on the scale assessing "tiredness," showing increased tiredness/sedation for VPA relative to PBO (p=0.02) and on the "timid scale" for LTG reporting "being more at ease" compared with both PBO and VPA (p=0.02; 0.02). The general direction of change for the mood scales was toward "activation" for LTG (five of six scales improved), whereas for VPA, the reverse effect was found (four of six scales showed a change in the direction of "tiredness/sedation"). CONCLUSIONS: Short-term treatment in normal volunteers with a low dose of LTG resulted in improved cognitive activation on simple reaction-time measurements, a more positive subjective report about the impact of drug treatment relative to VPA, and mood changes concurring with the activating effect demonstrated by the cognitive tests.

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J Clin Psychopharmacol. 2003 Oct;23(5):484-95.

 
Potential mechanisms of action of lamotrigine in the treatment of bipolar disorders.

Ketter TA, Manji HK, Post RM.

Bipolar Disorders Clinic, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA. tketter@stanford.edu

Based on the mood-stabilizing properties of carbamazepine and valproate, new anticonvulsants have been explored for use in bipolar disorders. One such agent, lamotrigine, has a novel clinical profile in that it may "stabilize mood from below," as it appears to maximally impact depressive symptoms in bipolar disorders. In this paper, we review the mechanisms of action of lamotrigine in an effort to understand the basis of its distinctive clinical use in the management of bipolar disorders as well as its diverse antiseizure effects. We consider lamotrigine mechanisms, emphasizing commonalities and dissociations among actions of lamotrigine, older mood stabilizers, and other anticonvulsants. Although ion channel effects, especially sodium channel blockade, may importantly contribute to antiseizure effects, such actions may be less central to lamotrigine thymoleptic effects. Antiglutamatergic and neuroprotective actions are important candidate mechanisms for lamotrigine psychotropic effects. Lamotrigine has a variable profile in kindling and contingent tolerance experiments and does not appear to have robust gamma-aminobutyric acid or monoaminergic actions. Lamotrigine intracellular signaling effects warrant investigation. Although lamotrigine mechanisms overlap those of other mood-stabilizing anticonvulsants, important dissociations suggest candidate mechanisms, which could contribute to lamotrigine's distinctive psychotropic profile.


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CNS Spectr. 2003 Dec.


New anticonvulsant medication uses in bipolar disorder.

Wang PW, Ketter TA, Becker OV, Nowakowska C.

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, California, USA. wangp0@stanford.edu

Therapy of bipolar disorders is a rapidly evolving field. Lithium has efficacy in classic bipolar disorders whereas divalproex sodium and carbamazepine may have broader spectrum efficacy that includes non-classic bipolar disorder. In the last 10 years, a series of anticonvulsants have been approved for marketing in the United States. Gabapentin has indirect g-aminobuytric acid-ergic actions, is generally well tolerated, and appears to have anxiolytic, analgesic, and hypnotic effects. Lamotrigine has antiglutamatergic actions and is generally well tolerated (aside from rash in 1 in 10, and serious rash in 1 in 1,000 patients). Lamotrigine is indicated for maintenance treatment in bipolar disorder. Emerging evidence suggests lamotrigine may have utility in bipolar disorder patients with depression and treatment-refractory rapid cycling, as well as analgesic effects

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J Clin Psychiatry. 2002 Apr


Third generation anticonvulsants in bipolar disorder: a review of efficacy and summary of clinical recommendations.

Yatham LN, Kusumakar V, Calabrese JR, Rao R, Scarrow G, Kroeker G.

Department of Psychiatry, University of British Columbia, Vancouver, Canada. yatham@interchange.ubc.ca

BACKGROUND: To review the literature on efficacy of third generation anticonvulsants for treatment of bipolar disorder and provide clinical recommendations. METHOD: Open and controlled studies, case reports, and case series on the efficacy of lamotrigine, gabapentin, topiramate, tiagabine, and zonisamide were located through electronic searches of several databases, by manual search of proceedings of international meetings, and through contacting authors of recent reports. RESULTS: Lamotrigine is the best studied anticonvulsant and has efficacy in acute bipolar depression and in longer term treatment of bipolar depression as well as rapid-cycling bipolar II disorder but not in acute mania. Open reports suggest usefulness of gabapentin as an adjunct in bipolar disorder, but double-blind trials failed to confirm efficacy in acute mania and treatment-resistant rapid-cycling bipolar disorder. Topiramate is reported to be effective in acute mania and rapid-cycling bipolar disorder in several open studies, but methodological problems in a double-blind study led to a failed study in acute mania. However, topiramate may lead to weight loss in some patients. Zonisamide deserves further investigation, but tiagabine does not appear to be useful in acute mania. CONCLUSION: Lamotrigine clearly fills an unmet need in treating bipolar depression and rapid-cycling bipolar disorder. Other third generation anticonvulsants with the exception of tiagabine offer promise but require confirmation of their efficacy from double-blind studies.

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Ann Pharmacother. 2002 May;36(5):860-73.

 
Lamotrigine update and its use in mood disorders.

Hurley SC.

College of Pharmacy, Idaho State University, Pocatello, ID, USA. hurley@otc.isu.edu

OBJECTIVE: To provide a qualitative, systematic update and review of the pharmacology, pharmacokinetics, efficacy in mood disorders, adverse effects, and costs of lamotrigine. DATA SOURCES: Citations obtained from MEDLINE searches (1985-September 2001) using lamotrigine as a text word, articles identified in reference lists of pertinent articles, abstracts presented at conferences, and research data from GlaxoSmithKline. DATA EXTRACTION: English-language articles were considered for possible inclusion. Each title and abstract was examined to determine whether the publication contained up-to-date information relevant to the objective. Twenty clinical trials that provided data on response rates in mood disorders were tabulated. DATA SYNTHESIS: Lamotrigine's primary action is to modulate voltage-gated sodium channels. Evidence suggests that it decreases glutamate transmission, directly reduces calcium influx, mildly blocks transmitter reuptake, and alters intracellular mechanisms of resting transmitter release. The average half-life of lamotrigine is approximately 24 hours, but decreases to approximately 7.4 hours when used concurrently with phenytoin, and increases to approximately 59 hours with valproic acid. Seven of the 20 clinical trials were randomized, double-blind, and controlled. Existing data are inadequate to evaluate lamotrigine use in major depression. The pooled response rates for patients with depressed, manic, mixed, and rapid cycling bipolar disorder were similar, ranging from 52% to 63%. Adverse effects are infrequent when the drug is used alone, but become more frequent when lamotrigine is combined with other anticonvulsants. While most rashes are mild, approximately 1 in 500 patients develops exfoliative dermatitis. A slow upward dose titration is recommended to reduce the incidence of serious rash, but this may delay the attainment of adequate dosage for 6 weeks. Lamotrigine has positive effects on cognitive function, but occasionally produces insomnia. Lamotrigine costs 2-4 times more than lithium, carbamazepine, and generic valproic acid. CONCLUSIONS: When efficacy, adverse effects, and cost are considered, lamotrigine should probably be reserved as a second-line agent for bipolar depression.

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Biol Psychiatry. 2002 Feb 1;51(3):253-60.

 
Clinical predictors of response to lamotrigine and gabapentin monotherapy in refractory affective disorders.

Obrocea GV, Dunn RM, Frye MA, Ketter TA, Luckenbaugh DA, Leverich GS, Speer AM, Osuch EA, Jajodia K, Post RM.

National Institute of Mental Health, Biological Psychiatry Branch, Bethesda, Maryland 20892, USA.

BACKGROUND: The objective of the current study was to examine possible clinical predictors of positive response to lamotrigine or gabapentin monotherapy in treatment-refractory affectively ill patients. METHODS: Forty-five patients with treatment refractory bipolar (n = 35) or unipolar (n = 10) affective disorder participated in a clinical study evaluating six weeks of treatment with lamotrigine, gabapentin, or placebo monotherapy given in a double-blind, randomized fashion with two subsequent cross-overs to the other agents. Patients received daily mood ratings and weekly cross-sectional scales. Much or very much improved on the Clinical Global Impression scale modified for bipolar illness was considered a positive response. Degree of response was correlated with a number of baseline demographic and course of illness variables in a univariate analysis and then by linear regression. RESULTS: Response rates to lamotrigine (51%) exceeded those to gabapentin (28%) and placebo (21%). A positive response to lamotrigine monotherapy was associated with a bipolar diagnosis; fewer hospitalizations; fewer prior medication trials; and male gender (of which the latter two variables survived logistic regression). For gabapentin, degree of response correlated with shorter duration of illness; younger age; and lower baseline weight (with the latter two surviving linear regression). CONCLUSIONS: In this highly treatment-refractory population, lamotrigine appeared most effective for male patients with fewer prior medication trials. Gabapentin monotherapy, although not better than placebo, appeared most effective in those with younger age and lower baseline weight. These preliminary data in a treatment refractory subgroup may help in the further definition of the range of clinical utility of these widely used anticonvulsants.
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J Clin Psychopharmacol. 2000 Dec;20(6):607-14.


A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders.

Frye MA, Ketter TA, Kimbrell TA, Dunn RT, Speer AM, Osuch EA, Luckenbaugh DA, Cora-Ocatelli G, Leverich GS, Post RM.

Biological Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1272, USA.

There is a pressing need for additional treatment options for refractory mood disorders. This controlled comparative study evaluated the efficacy of lamotrigine (LTG) and gabapentin (GBP) monotherapy versus placebo (PLC). Thirty-one patients with refractory bipolar and unipolar mood disorders participated in a double-blind, randomized, crossover series of three 6-week monotherapy evaluations including LTG, GBP, and PLC. There was a standardized blinded titration to assess clinical efficacy or to determine the maximum tolerated daily dose (LTG 500 mg or GBP 4,800 mg). The primary outcome measure was the Clinical Global Impressions Scale (CGI) for Bipolar Illness as supplemented by other standard rating instruments. The mean doses at week 6 were 274 +/- 128 mg for LTG and 3,987 +/- 856 mg for GBP. Response rates (CGI ratings of much or very much improved) were the following: LTG, 52% (16/31); GBP, 26% (8/31); and PLC, 23% (7/31) (Cochran's Q = 6.952, df = 2, N = 31, p = 0.031). Post hoc Q differences (df = 1, N = 31) were the following: LTG versus GBP (Qdiff = 5.33, p = 0.011); LTG versus PLC (Qdiff = 4.76, p = 0.022); and GBP versus PLC (Qdiff = 0.08, p = 0.70). With respect to anticonvulsant dose and gender, there was no difference between the responders and the nonresponders. The agents were generally well tolerated. This controlled investigation preliminarily suggests the efficacy of LTG in treatment-refractory affectively ill patients. Further definition of responsive subtypes and the role of these medications in the treatment of mood disorders requires additional study.

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J Psychopharmacol. 2003 Jun;17(2):174-8.

 
GABA-ergic drugs: exit stage left, enter stage right.

Ashton H, Young AH.

Department of Psychiatry, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne, UK.

Drugs that enhance gamma-aminobutyric acid (GABA) activity by interacting at post-synaptic GABA(A) receptors have long been used as hypnotics, sedatives, tranquillizers and anticonvulsants. In this category, benzodiazepines rapidly gained pride of place, replacing barbiturates and becoming the most commonly prescribed of all drugs in the Western world in the 1970s. However, problems such as dependence and withdrawal reactions became apparent in the 1980s, and it seemed that the usefulness of drugs with this mode of action was limited. Recently, focus has shifted to a new group of drugs with GABA-ergic actions mediated through various mechanisms not directly involving the GABA(A) receptor. These drugs include gabapentin, vigabatrin, tiagabine, lamotrigine, pregabalin and others. Although originally developed as anticonvulsants for epilepsy, they appear to have wider applications for use in affective disorders, especially bipolar depression, anxiety disorders and pain conditions. The current information on the properties and therapeutic potential of this new generation of GABA-ergic drugs is reviewed. It remains to be seen whether long-term use leads to tolerance, dependence and withdrawal or discontinuation reactions.

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Eur Neuropsychopharmacol. 2003 Aug;
 
Latest maintenance data on lamotrigine in bipolar disorder.

Calabrese JR, Vieta E, Shelton MD.

Case Western Reserve University School of Medicine, University Hospitals of Cleveland, Cleveland, OH, USA. Joseph.Calabrese@uhhs.com

Two 18-month, randomised, double-blind trials have compared lamotrigine, lithium, and placebo as maintenance treatment in a total of 1315 recently manic or depressed patients with bipolar I disorder. Individual and combined analyses of these studies showed that both lamotrigine and lithium significantly prolonged the time to intervention for any mood episode compared with placebo. Lamotrigine was primarily effective against depression and lithium was primarily effective against mania. There was no evidence that lamotrigine induced mania/hypomania/mixed states, caused episode acceleration, or destabilised the overall course of illness. Lamotrigine was well tolerated, with a placebo-like adverse-event profile. In summary, lamotrigine is an effective and well-tolerated maintenance treatment for bipolar I disorder, providing a spectrum of efficacy complementary to that of lithium.
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J Clin Psychiatry. 2002

Long-term treatment of bipolar disorder with lamotrigine.

Calabrese JR, Shelton MD, Rapport DJ, Kimmel SE, Elhaj O.

jrc8@po.cwru.edu

Bipolar depression is as debilitating as mania in bipolar disorder, but the treatment of bipolar depression has historically received less attention. To date, there is no mood stabilizer (liberally defined as a medication that decreases episode severity, duration, or frequency in one phase of bipolar illness without producing a negative effect in other phases) that demonstrates similar efficacy in both the depressive and the manic phases of bipolar disorder. However, bipolar depression--which is prevalent, sometimes chronic, and associated with a low quality of life and a high risk of suicide--must be addressed as energetically as mania. Recent research into the long-term treatment of bipolar disorder has raised several questions about the generalizability of early lithium studies, as a result of these studies' designs. Researchers conducting more recent studies of mood stabilizers in the long-term treatment of bipolar disorder have attempted to clarify their results by, for example, performing survival analyses of the data. Until pharmacotherapy has been found that is equally efficacious in the treatment of both manic and depressive episodes in bipolar disorder, the use of combination therapy to manage bipolar disorder is advised. Lithium and divalproex sodium remain the first-line treatments for mania. Lamotrigine has been found to have acute efficacy in treating episodes of bipolar depression without increasing cycling or provoking a switch into mania, as well as a long-term role in delaying relapse and recurrence of depressive episodes.

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Drugs. 2003

Lamotrigine: a review of its use in bipolar disorder.

Goldsmith DR, Wagstaff AJ, Ibbotson T, Perry CM.

Adis International Limited, Mairangi Bay, Auckland, New Zealand. demail@adis.co.nz

Lamotrigine (Lamictal), a phenyltriazine derivative, is a well established anticonvulsant agent that has shown efficacy in the prevention of mood episodes in adult patients with bipolar I disorder. The mechanism of action of the drug in patients with bipolar disorder may be related to the inhibition of sodium and calcium channels in presynaptic neurons and subsequent stabilisation of the neuronal membrane. Lamotrigine monotherapy significantly delayed time to intervention with additional pharmacotherapy or electroconvulsive therapy for any new mood episode (mania, hypomania, depression and mixed episodes), compared with placebo, in two large, randomised, double-blind trials of 18 months' duration. Additionally, lamotrigine was significantly superior to placebo at prolonging time to intervention for depression. These effects of lamotrigine were demonstrated in both recently manic/hypomanic and recently depressed patients. Lamotrigine showed efficacy in delaying manic/hypomanic episodes in pooled data only, although lithium was superior to lamotrigine on this measure. Two of four double-blind, short-term studies have shown lamotrigine to be more effective than placebo in the treatment of patients with treatment-refractory bipolar disorder or those with bipolar depression. Lamotrigine has not demonstrated efficacy in the treatment of acute mania.Lamotrigine was generally well tolerated in maintenance studies with the most common adverse events being headache, nausea, infection and insomnia. Incidences of diarrhoea and tremor were significantly lower in lamotrigine- than in lithium-treated patients. The incidence of serious rash with lamotrigine treatment was 0.1% in all studies of bipolar disorder and included one case of mild Stevens-Johnson syndrome. Lamotrigine did not appear to cause bodyweight gain. The dosage of lamotrigine is titrated over a 6-week period to 200 mg/day to minimise the incidence of serious rash. Adjustments to the initial and target dosages are required if coadministered with valproate semisodium or carbamazepine. CONCLUSION: Lamotrigine has been shown to be an effective maintenance therapy for patients with bipolar I disorder, significantly delaying time to intervention for any mood episode. Additionally, lamotrigine significantly delayed time to intervention for a depressive episode and showed limited efficacy in delaying time to intervention for a manic/hypomanic episode, compared with placebo. Although not approved for the short-term treatment of mood episodes, lamotrigine has shown efficacy in the acute treatment of patients with bipolar depression but has not demonstrated efficacy in the treatment of acute mania. Lamotrigine is generally well tolerated, does not appear to cause bodyweight gain and, unlike lithium, generally does not require monitoring of serum levels.

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Neuropsychopharmacology: The Fifth Generation of Progress
Psychopharmacology - The Fourth Generation of Progress

VI. LAMOTRIGINE

Lamotrigine is an antiepileptic drug of the phenyltriazine class which has been shown to be effective as add-on treatment and monotherapy treatment of partial seizures (Schachter et al 1995). In 14 clinical reports involving 207 patients with bipolar disorder (66 with rapid cycling), lamotrigine was observed to possess moderate to marked efficacy in depression, hypomania, and mixed states; efficacy in hospitalized mania was unclear (see Calabrese et al 1998 for a review).

In the largest of these clinical reports, the spectrum of activity of lamotrigine was examined in a 48-week, open-label, prospective trial of lamotrigine in 75 patients with either bipolar I or II disorder (Calabrese et al In Press a). Lamotrigine was used as add-on therapy (n = 60) or monotherapy (n = 15) in patients presenting in depressed, hypomanic, manic, or mixed states. Of the 40 depressed patients included in the analysis, 48% exhibited a marked response and 20% a moderate response as measured by reductions in the 17-item Hamilton Depression Scale (HAM-D) scores. Of the 31 presenting hypomanic, manic, or mixed, 81% displayed a marked response and 3% a moderate response on the Mania Rating Scale (MRS). The magnitude of overall observed improvement was substantial with the depressed patients exhibiting a 42% decrease in HAM-D scores from baseline to endpoint, and the patients presenting hypomanic/manic/mixed exhibiting a 74% decrease in MRS scores from baseline to endpoint. The most common drug-related adverse events included 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 which required hospitalization. Lamotrigine appeared to exhibit a broad spectrum of efficacy in the management of the depressed, hypomanic, manic, and mixed phases of bipolar disorder.

Acute Bipolar Depression: The findings of these clinical reports have been replicated by two recent controlled studies. A study was conducted to evaluate the efficacy and safety of two doses of lamotrigine compared with placebo in the treatment of a major depressive episode in patients with bipolar I disorder (Calabrese et al, In Press b). Outpatients with bipolar I disorder experiencing a major depressive episode ((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 (HAMD), the Montgomery-Asberg Depression Rating Scale (MADRS), the Mania Rating Scale (MRS), and the Clinical Global Impressions Scale for Severity (CGI-S) and Improvement (CGI-I), were completed weekly. Lamotrigine 200 mg/day demonstrated significant antidepressant efficacy on HAMD-17, HAMD 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 proportion of patients exhibiting a marked response on CGI-I was 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 (including switch rates), except for the higher rate of headaches in the lamotrigine groups. The conclusion was that lamotrigine monotherapy was an effective and well-tolerated treatment for bipolar depression.

In a preliminary NIMH communication which compared the efficacy of gabapentin, lamotrigine, and placebo in a double-blind cross-over design, Frye and colleagues (Frye et al 1998) reported that lamotrigine, but not gabapentin, was superior to placebo in mixed cohort of patients with bipolar I and II disorder, as well as recurrent major depression.

Pharmacokinetics and Adverse Effects of Lamotrigine: Lamotrigine has no significant effect on the hepatic cyclo-oxygenase system or on the metabolism of other antiepileptic drugs. It is moderately bound to plasma proteins (55%), has no active metabolites, and has no effect on the pharmacokinetics of oral contraceptives (see Table 1). Routine monitoring of chemistries, complete blood counts, blood pressure, and heart rate is not necessary. Body weight remains relatively stable with chronic lamotrigine use. In the management of epilepsy, there does not appear to be a correlation between blood level and efficacy. Valproate inhibits the metabolism of lamotrigine by immediately and significantly competing for metabolism through glucuronidation. As a result of this, the mean half-life of lamotrigine is immediately increased to about 70 hours and steady state lamotrigine plasma concentrations are increased. Therefore, when lamotrigine is added to ongoing treatment with valproate, the initial dose of lamotrigine should be much lower than the monotherapy dose. When valproate is added to ongoing treatment with lamotrigine, the daily dose of lamotrigine should be immediately decreased by approximately one-half. Carbamazepine induces the metabolism of lamotrigine by gradually decreasing the mean half-life of lamotrigine's half-life to about 12 hours and reducing steady state lamotrigine plasma concentrations. Therefore, when lamotrigine is added to ongoing treatment with carbamazepine, the initial dose of lamotrigine is higher than the monotherapy dose of lamotrigine. When carbamazepine is added to ongoing treatment with lamotrigine, the dose of lamotrigine must be gradually increased by 100%.

The most common side effects associated with the use of lamotrigine in bipolar disorder include dizziness, tremor, somnolence, headache, nausea, and rash (Calabrese et al In Press a). Rash is the most common adverse event resulting in drug discontinuation. The nature of the reported adverse events in bipolar disorder are consistent with those observed in patients with epilepsy. In open-label and placebo-controlled epilepsy clinical trials involving 3,501 patients, rash has been observed to occur in 10% of lamotrigine and 5% of placebo patients. Rash led to drug discontinuation in 3.8% of lamotrigine patients and hospitalization in 0.3% (Physician's Desk Reference). The spectrum of lamotrigine-associated cutaneous reactions include simple morbilliform (measle-like) rash, hives, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reaction syndrome. The rash typically occurs within 2-8 weeks of initiation of treatment. The incidence of rash is higher in patients taking concomitant valproate, and higher if the recommended initial lamotrigine dose and titration schedules are exceeded. The prevalence of serious rash resulting in hospitalization is significantly higher (approximately 1 in 100) in children (< 16 years of age) than in adults. The consensus of clinical opinion is that, unless an alternative etiology can be clearly identified, the drug should be discontinued when patients present with rash of any kind regardless of severity, since the clinician is unable to predict which cutaneous reactions will become serious. Strict adherence to the recommended dose escalation schedule may diminish the likelihood of rash (Physicians Desk Reference, 1997). Lamotrigine is a Category C teratogen which indicates that studies in women and animals are not available.




IX. METHODOLOGIC ISSUES

Although one can work towards treatment with bimodal monotherapy, it is clear that many patients require combination therapy during acute episodes of mania or depression. In fact, during the course of the illness most patients will eventually require adjunctive or augmentation pharmacotherapy with either other bimodal mood stabilizers or benzodiazepines, antidepressants, and/or antipsychotic agents. Informed combination therapy (polypharmacy) is routine and the "state of the art" in longitudinal management of this illness. Despite the above and the pre-existing literature, the Food and Drug Administration requires that studies be designed to evaluate monotherapies against PBO so as to gauge study reliability. Accordingly, the design and completion of studies comparing different acute combination therapy paradigms is normally preceded by acute monotherapy designs with PBO arms. This practice has slowed the development of pharmacotherapy for bipolar disorder.

In addition to the above, it has become increasingly clear that major mood disorders should be viewed longitudinally rather than solely in terms of the acute episode. Unfortunately, the rigor of the scientific literature evaluating the prophylactic pharmacotherapy of bipolar disorder is seriously encumbered by the 3 mood states that accompany this illness and multiple patterns of presentation. Due to the illness's inherent complexity, the methods are not available that allow controlled acute and prophylaxis studies to simultaneously focus on both antidepressant, antimanic, and antimixed prophylactic efficacy with similar degrees of rigor. Naturalistic longitudinal studies more adequately address this need. Optimally, these prospective naturalistic studies, such as the one recently published by Lambert and Venaud, might openly randomize patients to different treatment groups and then allow for either crossovers or augmentation for nonresponders. If these designs are not employed, the remaining patient population at the end of maintenance studies will be so small and atypical, as to not have general relevance to the pool of patients normally treated in the general population. Studies involving rapid cycling and mixed states (dysphoric mania/hypomania, mixed mania) are particularly challenging because these phenomena appears to migrate unpredictably throughout the natural course of the illness.

Study designs employing PBO arms are feasible for research subjects who are hospitalized for acute studies, but not always practical for evaluations of maintenance therapies. Placebo response rates in recent acute hospitalized mania studies have now been noted to range from 10.5% to 45%. The lowest placebo-response rate (10.5%) was observed in a study that skewed enrollment towards lithium non-responders (Pope et al 1991), whereas intermediate response rates of 21% (Bowden et al 1994) and 24% (Tohen et al 1998) have been observed in studies enrolling unselected populations of patients, and more recently, 45% for a study which employed an augmentation design (Muller-Oerlinghausen et al 1998). A survey of response rates in early double-blind PBO controlled LI maintenance studies in classic bipolar patients has been conducted. Whereas 55-100% of patients given PBO relapse over 5 months to 2 years, 0 to 49% of those given LI relapse (Davis 1976). The data of Schou suggest the "half-life" of the untreated patient in remission is approximately 4 1/2 months. More recently, and consistent with this finding, a metanalysis of 14 maintenance studies involving 257 patients with bipolar type I illness reported a 50% mania relapse rate after five months when LI was rapidly discontinued (Suppes et al 1991). Given the remarkably high relapse rate for classic bipolar patients given PBO during these early maintenance studies and the human cost in suicide attempts documented in these studies, it was not clear that the additional methodologic rigor obtained from a PBO arm merited the additional risk. However, a recent multicenter maintenance study (Bowden et al 1997) in bipolar I disorder reported a high PBO response rate which highlighted the importance of PBO arms in studies which use recent nomenclatures and employ random assignment to double blind parallel treatment groups.

The designs employed in bipolar maintenance studies have evolved greatly over the last 28 years. Consequently, there has been minimal or no consensus set for methods used to demonstrate the ability of a new putative mood stabilizer to prevent relapse and recurrence in bipolar disorder. The methods that have evolved the most include enrollment procedures, randomization schemes, use of outcome measures, statistical analyses, and country-specific commercial/regulatory issues. Until recently, controlled trials of patients with bipolar disorder has been viewed as labor-intensive, expensive, not practical, and generally not funded by the National Institute of Mental Health or the pharmaceutical industry. With the recent completion of the first placebo-controlled bipolar maintenance trial in over a quarter of a century (Bowden et al 1997), this impression has begun to change.

published 2000





Effect of acute and chronic lamotrigine on basal and stimulated extracellular 5-hydroxytryptamine and dopamine in the hippocampus of the freely moving rat.

Ahmad S, Fowler LJ, Whitton PS.

Department of Pharmacology, The School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX.

1. We have studied the effects of acute and chronic treatment with the anticonvulsant lamotrigine (LTG) on basal and stimulated extracellular 5-hydroxytryptamine (5-HT), dopamine (DA) and their metabolites in the hippocampus of freely moving rats using in vivo microdialysis. 2. Acute LTG (10 and 20 mg kg(-1)) decreased extracellular 5-HT, but had no effect on its metabolite 5-hydroxyindoleacetic acid (5-HIAA). Dialysate DA was also decreased by LTG as were its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). When transmitter release was stimulated by either 50 microm veratridine or 100 mm K(+), marked increases in the release of both transmitters occurred, but LTG was entirely without effect on this. 3. In chronic experiments, rats were dialysed after 2, 4, 7, 14 and 21 days of LTG treatment (5 mg kg(-1), twice daily). During this period a progressively different response to the drug was seen. After 2 days, basal extracellular 5-HT was significantly greater in treated rats than control rats. This effect persisted up to 14 days, but by 21 days 5-HT levels had returned to control values. 5-HIAA levels were unaltered and there was no effect of LTG on veratridine or K(+) stimulated 5-HT release. 4. Similarly, DA concentrations significantly increased after 2-7 days of LTG treatment, but returned and remained at basal values thereafter. During the treatment period LTG had no effect on extracellular DOPAC, but HVA followed a similar pattern to its parent transmitter. As with 5-HT, at no time point did LTG have any effect on stimulated DA release. 5. These neurochemical findings observed in these experiments are considered in relation to the use of LTG in bipolar disorder.


Neurochemical and behavioral aspects of lamotrigine.

Leach MJ, Baxter MG, Critchley MA.

Department of Pharmacology, Wellcome Research Laboratories, Beckenham, Kent, England.

Lamotrigine (LTG), a new anticonvulsant, chemically unrelated to current antiepileptic drugs (AEDs), resembles phenytoin (PHT) and carbamazepine (CBZ) in ability to block hindlimb extension in both the maximal electroshock test and leptazol-induced seizures. Results indicate that LTG may be of value in both partial and generalized seizures. In in vitro studies, LTG has been shown to inhibit veratrine-evoked release of glutamate when a threshold depolarizing concentration (4 micrograms/ml) is used, and also inhibits aspartate release when a larger stimulus is given (10 micrograms/ml). However, LTG does not block potassium-evoked transmitter release. LTG is a less potent inhibitor of the release of gamma-aminobutyric acid (GABA), acetylcholine, noradrenaline, and dopamine.

The novel anticonvulsant lamotrigine prevents dopamine depletion in C57 black mice in the MPTP animal model of Parkinson's disease.

Jones-Humble SA, Morgan PF, Cooper BR.

Wellcome Research Laboratories, Department of Pharmacology, Research Triangle Park, NC 27709.

The effect of the novel anticonvulsant Lamotrigine (LTG) was studied on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced dopamine depletion in C57BL/6 mouse brain. Whole brain dopamine levels were measured by HPLC-ED 2 days after treatment with MPTP (15 mg/kg s.c.). While LTG alone had no direct effect on dopamine levels at two hours or two days after treatment, MPTP induced dopamine depletion was significantly less in mice pretreated with LTG (approximate ED50: 6 mg/kg). LTG (38 mg/kg) was shown to completely protect against dopamine depletion when given 1 or 2 hours prior to MPTP administration. The effect of LTG (38, 100 mg/kg) on MPTP toxicity was compared to the effects of the anticonvulsants phenytoin (67 mg/kg), carbamazepine (156 mg/kg), and riluzole (33 mg/kg) and the Ca++ channel blocker nicardipine (0.1 mg/kg). Only phenytoin and LTG showed significant protection against MPTP. Results suggest LTG prevents MPTP induced dopamine depletion via a novel mechanism.

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Similar potency of carbamazepine, oxcarbazepine, and lamotrigine in inhibiting the release of glutamate and other neurotransmitters.

Waldmeier PC, Baumann PA, Wicki P, Feldtrauer JJ, Stierlin C, Schmutz M.

Research Department, Pharmaceuticals Division, Ciba-Geigy Ltd., Basel, Switzerland.

We compared the effects of the antiepileptic drugs carbamazepine, oxcarbazepine, and lamotrigine on the release from rat brain slices of endogenous glutamate, [3H]-GABA, and [3H]-dopamine, elicited by the Na+ channel opener, veratrine, and of the same transmitters as well as [3H]-noradrenaline, [3H]-5-hydroxytryptamine, and [3H]-acetylcholine, elicited by electrical stimulation. The three antiepileptic drugs inhibited veratrine-induced release of endogenous glutamate, [3H]-GABA, and [3H]-dopamine, with IC50 values between 23 and 150 microM, in or near the concentration range in which they interact with Na+ channels, and there was little difference between the compounds. They were five to seven times less potent in inhibiting electrically as compared with veratrine-stimulated release of [3H]-GABA and [3H]-dopamine; similarly, carbamazepine and tetrodotoxin were more potent in inhibiting veratrine-induced as compared with electrically induced release of endogenous glutamate. Carbamazepine, oxcarbazepine, and lamotrigine also inhibited electrically stimulated release of [3H]-5-hydroxytryptamine (IC50 values, 150 to 250 microM) and [3H]-acetylcholine (IC50 values, 50 to 150 microM); [3H]-noradrenaline release was affected to a lesser degree. The active concentration ranges of these drugs with respect to inhibition of veratrine-stimulated neurotransmitter release matched the therapeutic plasma and brain concentrations. It is uncertain whether these effects are relevant in vivo at anticonvulsant doses, because the drugs are markedly less potent in inhibiting the more physiologic release elicited by electrical stimulation. Therefore, the hypothesis that inhibition of glutamate release is the mechanism of anticonvulsant action of lamotrigine (or carbamazepine and oxcarbazepine) is doubtful. Other consequences of Na+ channel blockade may have an important role.
















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