E X P E RT O P I N I O N
`
`The role of lamotrigine in the management
`of bipolar disorder
`
`Felicity Ng1
`Karen Hallam2
`Nellie Lucas3
`Michael Berk1
`1Department of Clinical and
`Biomedical Sciences: Barwon Health,
`University of Melbourne, Geelong,
`Victoria, Australia; 2Department
`of Psychiatry, The University of
`Melbourne, Melbourne, Victoria,
`Australia; 3ORYGEN Research Centre,
`Melbourne, Victoria, Australia
`
`Correspondence: Felicity Ng
`Department of Clinical and Biomedical
`Sciences: Barwon Health, University of
`Melbourne, PO Box 281, Geelong, Victoria
`3220, Australia
`Tel +61 3 5260 3154
`Fax +61 3 5246 5165
`Email felicitn@barwonhealth.org.au
`
`Abstract: Lamotrigine has emerged with a distinct place in the pharmacological treatment of
`bipolar disorder, with the potential to treat and prevent bipolar depression, which is the dominant
`and arguably most disabling and under-treated phase of the illness. This review examines the
`published clinical trials of lamotrigine in bipolar treatment. While the data supports its toler-
`ability and safety, the strongest evidence for its effi cacy lies in the prevention of bipolar depres-
`sion, with weaker evidence for the treatment of acute bipolar depression, refractory unipolar
`and bipolar depression, and rapid cycling bipolar disorder. The total number of published well
`designed trials is small, even the maintenance evidence is derived from two studies. However,
`this relative inadequacy compares favorably with the alternative treatment options for bipolar
`depression, which are marked by poor effi cacy or risk of polarity switch. The designation of
`lamotrigine as fi rst-line treatment for bipolar depression prophylaxis should be done in cogni-
`zance of this context, and it would seem prudent to await greater evidence of effi cacy before
`designating lamotrigine as fi rst-line treatment for other bipolar indications. Further randomized
`controlled trials are required to consolidate the available fi ndings and to explore the boundaries
`of lamotrigine’s effi cacy, which may encompass the soft spectral disorders.
`Keywords: Lamotrigine, bipolar disorder, bipolar depression, clinical trials, effi cacy
`
`Introduction
`Bipolar disorder has been estimated to have a population lifetime prevalence of be-
`tween 0.3%–1.5% (Weissman et al 1996), but this fi gure based on DSM-III criteria
`may belie the extent of the full spectrum. The highly recurrent course of bipolar
`disorder (Angst and Sellaro 2000), its poor functional outcomes (Mitchell et al 2004)
`and over-representation in the completed suicide population (Rihmer and Kiss 2002)
`have been well-documented in the literature. In particular, more recent understanding
`of the natural course of bipolar disorder has highlighted its disease burden and chal-
`lenged its historical conceptualization as an episodic illness with full inter-episode
`recovery (Kraepelin 2002). Judd and colleagues (Judd et al 2002) have demonstrated
`that over the course of 12.8 years, their cohort of 146 patients with bipolar I disorder
`were symptomatic 47.3% of the time. Signifi cantly, depressive symptoms (present
`over 31.9% of the total follow-up period) predominated over symptoms of any other
`phases. Frequent changes in symptom levels and polarity, and the predominance
`of subsyndromal and minor symptoms were also demonstrated. Paykel et al (2006)
`reported comparable trends in 204 patients with bipolar I disorder, studied over 18
`months. In bipolar II disorder, symptomatic illness has been estimated to be present
`over 53.9% of the 13.4-year follow-up, with depression evident for 50.3% of total
`follow-up time, during which subsyndromal and minor symptoms dominated over
`major depression (Judd et al 2003). These fi ndings indicate a need for treatments
`directed towards the alleviation and prevention of depression, and milder albeit still
`disabling subthreshold depressive symptoms in bipolar disorder.
`
`ARGENTUM Exhibit 1116
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` Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
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`Ng et al
`
`The pharmacological management of bipolar disorder
`is rising in complexity, with the continual refi ning of the
`illness spectrum and an expanding pharmacopeia of medi-
`cation options that, in monotherapy or in combination, may
`provide more sophisticated means of targeting phasic symp-
`toms, polarity changes, and subclinical or minor symptoms.
`Lithium undoubtedly retains the broadest evidence base,
`with substantiated effi cacy in treating manic and depressive
`phases, prophylaxis (Tondo et al 1998; Maj 2003) and the
`reduction of suicide risk (Baldessarini et al 2003). However,
`its side effect profi le and lesser effi cacy in certain subgroups
`(Calabrese and Woyshville 1995) have led to investigations
`of second generation anticonvulsants and atypical antipsy-
`chotics as alternative treatments. Valproate and carbamaze-
`pine are options in the treatment of mania, mixed states and
`those with rapid cycling illness and comorbid substance
`abuse (Greil 1998; Bowden and Singh 2005), but lack full
`support in prophylaxis and the treatment of bipolar depres-
`sion. Atypical antipsychotics, such as risperidone, olanzap-
`ine, quetiapine and aripiprazole, all have some evidence of
`effi cacy in the treatment of mania (Segal et al 1998; Berk
`et al 1999; Keck et al 2003; Ketter 2004), but they may fi nd
`a further strength in the growing body of evidence for their
`use in bipolar depression (Tohen et al 2003; Calabrese et al
`2005). Newer anticonvulsants, including gabapentin, topira-
`mate and levetiracetam, have had limited investigation that
`have not yielded promising fi ndings in relation to bipolar
`disorder management (Bowden and Karren 2006).
`It remains that few medications have an adequate
`evidence base for the treatment and prevention of bipolar
`depression, despite its phenotypic dominance in bipolar
`disorder. The use of antidepressants remains controversial,
`in view of concerns for the risk of antidepressant-induced
`mania and cycle acceleration (Goldberg and Truman 2003).
`In this regard, lamotrigine, with its apparent effi cacy in the
`treatment and prevention of bipolar depression, may have
`a unique place in the bipolar pharmacological armamen-
`tarium. Ketter (Ketter and Calabrese 2002) has classifi ed
`maintenance therapies into those that stabilize mood from
`above (mania or hypomania) and those that do so from below
`(depression), with lamotrigine the sole member of the latter
`category. This paper aims to review the evidence for the
`effi cacy of lamotrigine in bipolar disorder, and to provide
`some practical recommendations in the clinical setting.
`
`Methods
`A literature search for publications up until August 2006
`was performed, based on the MEDLINE database and
`
`supplemented by identifying relevant references from
`individual articles. Key search terms used included
`lamotrigine, bipolar disorder, bipolar depression, mania,
`mixed state, major depression, maintenance, pharmacology,
`pharmacokinetics, pharmacodynamics, and clinical trial.
`Original research and review articles were studied.
`
`The pharmacology of lamotrigine
`Anticonvulsants are not equivalent to mood stabilizers,
`although several drugs straddle both categories, a fact that
`may have generated often-unfulfi lled expectations of effec-
`tiveness of anticonvulsants when applied to bipolar disorder.
`The established cross-effi cacy of agents such as valproate,
`carbamazepine and lamotrigine has nevertheless contributed
`to the still imprecise understanding of the pathophysiology
`of bipolar disorder and the development of its treatments,
`although the lack of class effects within the anticonvulsants is
`noteworthy, and complicates extrapolation of mechanism of
`action to pathophysiology. Some agents, such as topiramate,
`do not show effi cacy in the disorder, while others, such as
`valproate, show preferential effi cacy in the manic phase.
`Lamotrigine, a phenyltriazine derivative, has been
`demonstrated to possess multiple mechanisms of action, a
`summary of which has been detailed elsewhere (Ketter et al
`2003; Hahn et al 2004). Briefl y, these include the selective
`blockade of the N- and P-type calcium channels in focal
`brain regions, and the voltage-dependent blockade of sodium
`channels via its action on the slow inactivation state that
`occurs when sodium channels are over-activated. Lamotrig-
`ine has also been shown to inhibit the release of excitatory
`amino acids such as glutamate and aspartate, and may have
`some agonistic effects on γ-aminobutyric acid (GABA)
`(Ketter et al 2003; Hahn et al 2004). It selectively suppresses
`supranormal neuronal activities without affecting the basal
`neurophysiological state, which has clear implications in
`neuronal stabilization in seizure disorders, but may also be
`a plausible explanation of its action in bipolar disorder, even
`though the pathophysiology of this condition is less clear
`(Hahn et al 2004). Lamotrigine is also believed to act on
`serotonin reuptake, which may contribute to its antidepres-
`sant effects (Hahn et al 2004; Bourin et al 2005). There is
`evidence of perhipheral glutamate dysregulation in bipolar
`disorder (Berk et al 2000), and the glutamatergic activity of
`lamotrigine may also be implicated in its therapeutic and
`neuroprotective effects.
`The absorption of lamotrigine after oral administration is
`rapid, complete and unaffected by food ingestion. It under-
`goes minimal fi rst-pass metabolism, and has a bioavailability
`
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`of 98% (Peck 1991; Keck and McElroy 2002; Hahn et al
`2004). Peak plasma concentrations are reached in 1.4 to 4.8
`hours, and plasma protein binding is approximately 55%,
`which makes interaction with high plasma protein-binding
`drugs unlikely (Keck and McElroy 2002; Hahn et al 2004).
`Lamotrigine primarily undergoes hepatic metabolization
`through glucuronidation, producing inactive metabolites that
`mainly consist of lamotrigine 2N-glucuronide, and to a lesser
`extent the 5N-glucuronide, N-oxide and N-methyl metabolites,
`all of which are renally excreted (Sinz and Remmel 1991;
`Hachad et al 2002). The kinetics of lamotrigine is linear within
`the daily dose range of 100 to 700 mg. Its mean elimination
`half-life is approximately one day in healthy volunteers (Peck
`1991). Clearance is substantially decreased in the presence of
`hepatic or renal impairment, although age, gender and smoking
`do not appear to have signifi cant impact on kinetics. Clearance
`is also estimated to be about 25% lower in non-Caucasians
`(Keck and McElroy 2002; Hahn et al 2004).
`Drug interactions are generally less pronounced with
`newer anticonvulsants compared with older ones, but signifi -
`cant interactions may occur between lamotrigine and other
`drugs, primarily via interference with the UDP-glucuronos-
`yltransferase enzymes (UGT), which are responsible for the
`hepatic microsomal glucuronidation of lamotrigine and other
`drugs. Interactions can occur when enzyme-inducing drugs
`such as phenytoin, carbamazepine, oxcarbazepine, pheno-
`barbital and primidone are co-administered with lamotrigine,
`which may increase its clearance (Hachad et al 2002; Perucca
`2006). Conversely, valproate is an inhibitor of UGT and may
`produce a two-fold increase in lamotrigine serum concentra-
`tions (Hachad et al 2002). Dose adjustments are required in
`both of these situations. Potential reduction of lamotrigine
`levels with rifampicin (Ebert et al 2000) and oral contracep-
`tives (Sabers et al 2001), and risk of toxicity with sertraline
`(Kaufman and Gerner 1998), have also been documented.
`There has also been evidence for a modest reduction in oral
`contraceptive hormone levels due to lamotrigine, although
`the impact on contraceptive effi cacy may not be affected
`(Sidhu et al 2006). Nevertheless, women on concurrent oral
`contraceptive pills and lamotrigine may benefi t from caution-
`ary advice on contraceptive dose adjustments or alternative
`contraceptive methods (Perucca 2006).
`
`Studies of lamotrigine in bipolar
`disorder
`Building on anecdotal reports of lamotrigine’s psychotropic
`properties in epileptic and bipolar patients, Calabrese et al
`(Calabrese, Bowden, McElroy, et al 1999) conducted the
`
`Lamotrigine in bipolar disorder
`
`fi rst study to investigate its spectrum of therapeutic activity
`in bipolar disorder. This 48-week, open-label, prospective
`trial used lamotrigine as monotherapy or adjunctive phar-
`macotherapy in 75 patients with refractory bipolar I or II
`disorder, who variously presented in depressed, hypomanic,
`manic or mixed phases of the illness. Their results suggested
`that lamotrigine was effective as both monotherapy and
`adjunctive therapy, and for all phases of the illness with
`large magnitudes of improvements. Specifi cally, in the 40
`subjects presenting with depression, 48% showed “marked
`improvement”, defi ned as a 50% or greater reduction in
`the 17-item Hamilton Depression Scale (HAMD); 20%
`showed “moderate improvement”, defi ned as a 26%–49%
`reduction in HAMD; and a mean HAMD reduction of 42%.
`For the 31 subjects presenting with hypomania, mania or
`mixed state, 81% showed “marked improvement” and 3%
`“moderate improvement”, as correspondingly defi ned using
`the mania rating scale (MRS), and a mean score reduction
`of 74% was achieved. These results must be interpreted
`with caution, given the many methodological limitations of
`this preliminary study, such as its treatment-refractory and
`heterogeneous population with regards to both bipolar type
`and phase, open-label non-randomized design, and lack of
`control for concurrent psychotropic use. Furthermore, the
`drop-out rate was high (51%), and largely refl ected adverse
`events and ineffectiveness which jointly accounted for two-
`thirds of this fi gure.
`Findings of such broad spectrum activity and therapeutic
`magnitude have more recently been reported by a retro-
`spective chart review of 587 bipolar disorder outpatients,
`comprising all subtypes and in various illness phases, in a
`private practice setting (Ginsberg 2006). Despite obvious
`methodological limitations, this study had the benefi t of a
`large sample size. Using the Clinical Global Impression-
`Improvement (CGI-I) scale as outcome measure, 59.5%
`of patients were rated as either “very much improved” or
`“much improved” on lamotrigine, and a further 20.4% were
`deemed to have “minimally improved”. Response rates were
`comparable across bipolar disorder subtypes (ie, bipolar
`I, II and not otherwise specifi ed) and index mood episode
`(ie, depressed, manic and mixed) for the bipolar I subset. The
`median time from lamotrigine initiation to observed response
`was 95 days, with a mean of 205 days.
`There have been a number of published studies of higher-
`order design for lamotrigine in bipolar disorder. These have
`specifi cally examined the effects of lamotrigine on mania,
`bipolar depression, rapid cycling illness and bipolar disorder
`maintenance. These are sequentially discussed below.
`
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`Ng et al
`
`Studies in acute mania
`In the fi rst double-blind, randomized controlled trial of
`lamotrigine in mania, Ichim and colleagues (Ichim et al 2000)
`allocated 30 hospital inpatients meeting the DSM-IV criteria
`for bipolar I disorder, manic phase, to treatment with either
`lamotrigine or lithium over 4 weeks. Other psychotropic
`agents were discontinued for at least a day prior to com-
`mencing the trial. Both treatment arms produced comparable
`response rates and extent of improvement, as measured by
`the MRS, brief psychiatric rating scale (BPRS), CGI sever-
`ity (CGI-S) and improvement (CGI-I) scales, and the Global
`assessment of functioning (GAF) scale. Additionally, there
`were no signifi cant differences between the treatment arms
`over the course of the study period, notable given the slow
`dose titration for lamotrigine. This study had several limi-
`tations, the strongest of which being its insuffi cient power
`arising from the small sample size. The use of a relatively
`low dose of lamotrigine (100 mg/day) and a fi xed lithium
`dose (800 mg/day) may also have confounded the results.
`Such encouraging fi ndings have not been replicated by other
`double-blind trials, although these have been few in number
`and their comparability compromised by differing method-
`ologies that were likewise imperfect.
`Three such studies were described in a review by Yatham
`(2004). One was an 8-week study of 16 lithium-refractory manic
`and hypomanic patients, which found lamotrigine to be no more
`useful than placebo. Conclusions of effi cacy are diffi cult to make
`considering the small sample size and refractory population.
`In the other two cited studies, neither found lamotrigine to be
`superior to placebo in the treatment of acute mania. In the
`3-week monotherapy study, lamotrigine at 50 mg/day (N = 84)
`
`was compared against lithium, given to reach serum levels of
`0.8 to 1.3 (N = 36), and placebo (N = 95). The second study
`compared lamotrigine at 200 mg/day (N = 74) with lithium
`(N = 78) and placebo (N = 77) as adjunctive therapy to anti-
`psychotics over 6 weeks. The low lamotrigine dose used in
`the fi rst study, and the adjunctive design of the second, are
`confounding factors that preclude direct comparisons.
`
`Studies in acute bipolar depression
`Monotherapy trials
`Several studies have investigated the effi cacy of lamotrigine
`monotherapy with fi ndings relevant to bipolar depression
`(Table 1). Calabrese and colleagues (Calabrese, Bowden,
`Sachs, et al 1999) reported the fi rst double-blind placebo-
`controlled trial of lamotrigine monotherapy in the treatment
`of bipolar I depression. They recruited 195 subjects meeting
`the DSM-IV diagnostic criteria for bipolar I disorder who
`were in a major depressive episode. These patients were
`randomized into 3 monotherapy treatment arms of equal size
`(N = 66), consisting of 50 mg/day lamotrigine, 200 mg/day
`lamotrigine and placebo, given over 7 weeks. All psychoactive
`agents except sedatives had been ceased prior to randomiza-
`tion, at durations equivalent to 5 half-lives of the drugs. Both
`lamotrigine groups showed moderately larger margins of im-
`provement than placebo as measured by HAMD, montgomery-
`åsberg depression rating scale (MADRS), CGI-S and CGI-I,
`although only differences on MADRS, CGI-S and CGI-I for
`the lamotrigine 200 mg/day group reached statistical signifi -
`cance at the p < 0.05 level. The 200 mg/day group showed
`an earlier response compared with the 50 mg/day group,
`with signifi cant differentiation of the trajectories between the
`
`Table 1 Randomized, controlled trials of lamotrigine monotherapy in acute bipolar depression
`Trial
`Study arms
`N
`Sample
`Trial length
`in weeks
`7
`
`Calabrese,
`Bowden, Sachs
`et al 1999
`
`Brown EB
`et al 2006
`
`LTG
`50 mg/day
`LTG
`200 mg/day
`Placebo
`
`LTG
`OFC
`
`66
`
`66
`
`66
`
`205
`205
`
`Bipolar I
`major
`depressive
`episode,
`outpatients
`
`Bipolar I
`major
`depressive episode
`
`7
`
`Response rate in percentagea
`
`HAMD
`45
`
`MADRS
`48b
`
`54b
`
`29
`
`51
`
`37
`
`MADRS
`59.7
`68.8
`
`CGI-I
`41
`
`51b
`
`26
`
`CGI-S
`64.4
`71.8
`
`Abbreviation: N, sample size; HAMD, 17-item hamilton rating scale for depression; MADRS, montgomery-åsberg depression rating scale; CGI-I, clinical global impressions
`scale for improvement; CGI-S, clinical global impressions scale for severity; LTG, lamotrigine; OFC, olanzapine/fl uoxetine combination
`aNote that defi nitions of response vary with different studies: HAMD and MADRS defi nitions of response are ⱖ50% reduction from baseline scores for the respective
`scales; CGI-I defi nition of response is a rating of much improved or very much improved; CGI-S defi nition of response is a rating of ⱕ3
`bp < 0.05 vs placebo
`
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`

`
`lamotrigine and placebo groups after Week 3. No signifi cant
`treatment-emergent polarity switch was found.
`In the second monotherapy study (Frye et al 2000)
`(Table 2), lamotrigine was compared with gabapentin and
`placebo in a double-blind, randomized, crossover trial on 31
`patients with refractory unipolar and bipolar affective illness
`requiring hospitalization. The diagnostic distribution of these
`patients was 6 unipolar illness, 11 bipolar I and 14 bipolar
`II disorder, the majority of the bipolar group (23 out of 25)
`had a rapid cycling course. Patients were randomized, with
`stratifi cation by diagnostic classifi cation, to receive sequen-
`tial 6-week trials of each of the 3 treatment arms. Maximum
`tolerated doses of lamotrigine and gabapentin were used with
`mean daily doses being 274 mg and 3987 mg, respectively.
`Using the CGI for bipolar illness as primary outcome mea-
`sure, 52% of the lamotrigine group had a rating of “much
`improved” or “very much improved”, compared with 26% of
`the gabapentin and 23% of the placebo groups (p = 0.031).
`When response rates were analysed by affective episode
`types, both mania (lamotrigine 44%, gabapentin 20%, pla-
`cebo 32%) and depression (lamotrigine 45%, gabapentin
`26%, placebo 19%) showed similar non-signifi cant trends. In
`an extension to this study with a bigger sample size (N = 45),
`of which there were 35 bipolar and 10 unipolar treatment-
`refractory patients, response rates of 53% for lamotrigine,
`28% for gabapentin and 22% for placebo (p = 0.01), were
`reported (Obrocea et al 2002). Response to lamotrigine
`monotherapy was signifi cantly correlated with a diagnosis
`of bipolar disorder, the male gender, exposure to fewer prior
`medication trials and a history of fewer prior hospitalizations
`
`Lamotrigine in bipolar disorder
`
`for depression, although only the last two survived logistic
`regression. These studies lend further support for the effi cacy
`of lamotrigine in bipolar depression, but their generalizability
`is restricted by their highly-refractory and diagnostically
`heterogeneous populations.
`Brown and colleagues conducted a double-blind, random-
`ized trial comparing the effi cacy of olanzapine/fl uoxetine
`combination (OFC) (N = 205) to lamotrigine (N = 205)
`as acute treatments in bipolar depression (Brown EB et al
`2006) (Table 1). They found that OFC showed signifi cantly
`greater improvement than lamotrigine across the 7-week
`study period, as measured by CGI-S, MADRS and the Young
`Mania Rating Scale (YMRS), as well as a signifi cantly shorter
`time to response. However, the prolonged dose titration of
`lamotrigine (over 5 weeks) relative to the study period could
`have infl uenced the results. Lamotrigine, however, was
`associated with less adverse effects and showed comparable
`response and remission rates as OFC.
`
`Adjunctive trials
`Data also exists for the adjunctive use of lamotrigine in
`treatment-resistant bipolar depression. One such report
`stemmed from the Systematic Treatment Enhancement
`Program for Bipolar Disorder (STEP-BD) (Nierenberg et al
`2006). Patients (N = 66) in a major depressive episode who
`had not responded to combination mood stabilizer and anti-
`depressant, were randomized, with equipoise stratifi cation,
`to up to 16 weeks of open-label adjunctive treatment with
`lamotrigine, inositol or risperidone. No signifi cant inter-group
`differences were found on primary outcome measure, which
`
`Table 2 Controlled trials of lamotrigine monotherapy in refractory bipolar disorder
`Trial
`Study arms
`N
`Sample
`Trial length
`in weeks
`6
`(sequential
`crossover
`design)
`
`Frye
`et al 2000
`
`31
`
`LTG
`Gabapentin
`Placebo
`
`Obrocea
`et al 2002
`
`LTG
`Gabapentin
`Placebo
`
`
`45
`
`
`
`Response rate in percentagea
`
`CGI-I
`overallb
`52
`26
`23
`
`CGI-I
`mania
`44
`20
`32
`
`CGI-Ic
`53
`28
`22
`
`CGI-I
`depression
`45
`26
`19
`
`6
`(sequential
`crossover
`design)
`
`Refractory
`disorder: 6
`unipolar;
`11 bipolar
`I; 14
`bipolar II
`Refractory
`disorder:
`10
`unipolar;
`15 bipolar
`I; 20
`bipolar II
`
`Abbreviation: N, sample size; CGI-I, clinical global impressions scale for improvement; LTG, lamotrigine
`aCGI-I defi nition of response is a rating of much improved or very much improved
`bp = 0.031
`cp = 0.01
`
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`

`
`Ng et al
`
`was defi ned using the DSM-IV criteria for full remission.
`However, remission rate was highest for lamotrigine (23.8%
`compared with 17.4% for inositol and 4.6% for risperidone),
`suggesting some superiority of adjunctive lamotrigine
`although the differences did not reach statistical signifi cance.
`These results encourage further exploration of the adjunctive
`role of lamotrigine in treatment-resistant bipolar depression,
`but this trial on its own was hindered by low statistical power,
`equipoise randomization and open-label design.
`Another trial studied the adjunctive use of lamotrigine
`in treatment-resistant depression, including a subset with
`bipolar II depression (N = 8) although the majority had uni-
`polar depression (N = 15) (Barbosa et al 2003) (Table 3).
`The 23 patients were in a major depressive episode that had
`not responded to at least one antidepressant trial, which did
`not include fl uoxetine. They were randomized to receive
`100 mg/day lamotrigine (N = 13) or placebo (N = 10), in
`addition to 20 mg/day of fl uoxetine, for a period of 6 weeks.
`All other psychotropic medications were ceased. The groups
`did not signifi cantly differ on HAMD, but the lamotrigine
`group was signifi cantly superior to placebo in terms of
`improvement in CGI-S scores and response rate as measured
`by the CGI-I. There was no difference between the unipolar
`and bipolar II groups.
`A few negative unpublished randomized, placebo-
`controlled trials of lamotrigine in bipolar depression have
`been conducted (Data on fi le 1999, 2002, 2006). A pooled
`meta-analysis of these trials has shown an effi cacy signal for
`lamotrigine (Geddes, unpublished data). There are also small
`studies comparing lamotrigine to venlafaxine (McIntyre
`et al 2004) and to citalopram (Schaffer et al 2006) for bipolar
`depression, neither showing any advantage with lamotrigine.
`
`Studies in rapid cycling
`There is only a single reported double-blind, placebo-
`controlled study of lamotrigine in rapid cycling bipolar
`
`disorder (Calabrese et al 2000) (Table 4). This trial recruited
`324 patients in various mood states (euthymia or active
`mood episode), but all meeting the DSM-IV criteria for rapid
`cycling bipolar disorder, into the preliminary stabilization
`phase. In this phase, lamotrigine was introduced and when
`the patient became affectively well, existing psychotropic
`agents were withdrawn. At the end of this phase, 182 patients
`emerged eligible to participate in the randomization phase,
`during which they were allocated to lamotrigine or placebo
`monotherapy for 6 months, using fl exible lamotrigine dos-
`ing from 100 to 500 mg per day. Time to additional phar-
`macotherapy to treat emergent mood symptoms was the
`primary outcome measure, and this did not differ between the
`lamotrigine and placebo groups. Neither did the groups differ
`on secondary outcome measures such as changes in CGI-S
`and the global assessment scale (GAS). However, the two
`groups statistically diverged in their survival in study fi gures
`in favor of lamotrigine, a difference that retained statistical
`signifi cance in the bipolar II population when the subtypes
`were analyzed. 41% of the lamotrigine group completed
`the 6-month randomization phase without illness relapse,
`compared with 26% of the placebo group. This signifi cant
`difference was again only observed for bipolar II disorder
`on subtype analysis.
`A small (N = 14), open-label study also reported on
`the prophylactic efficacy of lamotrigine monotherapy in
`rapid cycling bipolar disorder (Walden et al 2000). This
`cohort of bipolar I disorder patients was treated with
`either lithium or lamotrigine monotherapy for one year,
`and found that 43% of the lithium group no longer met the
`criteria for rapid cycling (ie, more than four mood episodes
`in a year) compared with 86% of the lamotrigine group,
`with 43% of the latter having no episodes. Despite many
`methodological weaknesses, this study demonstrated
`positive findings in a literature-poor area, and observed
`that possibly greater benefits could be associated with
`
`Table 3 Randomized, controlled trials of adjunctive lamotrigine in bipolar disorder
`Trial
`Study arms
`N
`Sample
`Trial length
`in weeks
`6
`
`Barbosa
`et al 2003
`
`LTG +
`fl uoxetine
`Placebo +
`fl uoxetine
`
`13
`
`10
`
`Treatment-
`resistant major
`depression: 15
`unipolar; 8
`bipolar II
`
`Response rate in percentagea
`
`HAMD
`76.9
`
`MADRS
`76.9
`
`50.0
`
`40.0
`
`CGI-I
`84.6b
`
`30.0
`
`Abbreviation: N, sample size; CGI-I, clinical global impressions scale for improvement; LTG, lamotrigine
`aNote that defi nitions of response vary with different studies: HAMD and MADRS defi nitions of response are ⱖ50% reduction from baseline scores for the respective
`scales; CGI-I defi nition of response is a rating of much improved or very much improved.
`bp = 0.013.
`
`468
`
`Neuropsychiatric Disease and Treatment 2007:3(4)
`
`Page 00006
`
`

`
`Table 4 Randomized, controlled trials of lamotrigine monotherapy in prophylaxis of bipolar disorder
`Trial
`Study arms
`N
`Sample
`Trial length
`in months
`6
`
`Calabrese
`et al 2000
`
`Calabrese
`et al 2003
`
`Bowden
`et al 2003
`
`LTG
`Placebo
`
`LTG
`Lithium
`Placebo
`
`LTG
`Lithium
`Placebo
`
`93
`89
`
`221
`121
`121
`
`59
`46
`70
`
`Stabilized,
`rapid-cycling
`bipolar I or II
`patients
`Stabilized
`bipolar I
`patients with
`index
`depressive
`episode
`Stabilized
`bipolar I
`patients with
`index mania
`or hypomania
`
`18
`
`18
`
`Lamotrigine in bipolar disorder
`
`Effi cacya
`
`No
`intervention
`50
`44
`No
`intervention
`18
`17
`10
`
`No
`intervention
`53
`61
`30
`
`Survival time
`
`18 weeks
`12 weeks
`Survival time
`
`200 daysa
`170 daysa
`93 days
`
`Survival time
`
`141 daysb
`292 daysb
`85 days
`
`Abbreviation: N, sample size; LTG, lamotrigine
`aEffi cacy outcome defi nitions: No intervention refers to the proportion (in percentage) of patients who did not required treatment for an emergent mood episode; Survival
`time refers to the median time until treatment was required for an emergent mood episode
`ap = 0.029 for LTG vs placebo, p = 0.029 for lithium vs placebo, with no signifi cant difference between LTG and lithium
`bp = 0.02 for LTG vs placebo, p = 0.003 for lithium vs placebo
`
`the higher plasma lamotrigine levels (above 5 mg/L) that
`were recommended in epileptology.
`
`Studies in maintenance treatment
`In a continuation study to the afore-mentioned 7-week,
`double-blind, placebo-controlled trial of lamotrigine
`monotherapy in the treatment of bipolar I depression
`(Calabrese, Bowden, Sachs, et al 1999), 92% of those who
`had completed the controlled trial (N = 124) entered the
`1-year open-label lamotrigine continuation phase, although
`only 69 (56%) completed it with a mean duration of expo-
`sure of 10.4 months (McElroy et al 2004). Those who had
`received placebo in the controlled trial showed signifi cant
`reduction in MADRS scores as early as Week 4 (maximum
`mean decrease of 9.7 points), and all participants maintained
`their improved MADRS scores throughout the continuation
`phase. Furthermore, the proportion of patients reporting
`manic, hypomanic or mixed episodes during the one year
`of lamotrigine continuation was half that of the year before
`(31% versus 62%). Study design limitations including the
`allowance of concomitant psychotropic medications, nota-
`bly with a third of the group receiving antidepressants and
`a minority on additional mood stabilizers, should be borne
`in mind. Nevertheless, this study provided support for the
`mood stabilizing in addition to antidepressant properties of
`lamotrigine.
`Two 18-month placebo-controlled trials compared
`lamotrigine and lithium as maintenance monotherapy in
`
`bipolar I disorder, each focusing on a single pole of the illness
`at entry (Table 4). In one study (Calabrese et al 2003), patients
`currently or recently in a major depressive episode were fi rst
`stabilized on lamotrigine in an 8- to 16-week open-label phase,
`before being randomized to receive lamotrigine (N = 221),
`lithium (N = 121) or placebo (N = 121) monotherapy for up
`to 18 months. Using time from randomization to interven-
`tion for any emergent mood episode as outcome measure,
`lamotrigine and lithium did not differ from one another, but
`both were superior to placebo. Depressive episodes outnum-
`bered mania by a ratio of 3:1 as cause for intervention. When
`time to intervention was examined a