Chapter 39. Lamotrigine

Print: Chapter 39. Lamotrigine

http://www.psychiatryonline.com/popup.aspx?aID=432147&print=yes…

1 of 14

10/05/2009 16:19

Print Close Window

David E. Kemp, David J. Muzina, Keming Gao, Joseph R. Calabrese: Chapter 39. Lamotrigine, in The American Psychiatric Publishing Textbook of

Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc.

DOI: 10.1176/appi.books.9781585623860.432143. Printed 5/10/2009 from www.psychiatryonline.com

Textbook of Psychopharmacology >

Chapter 39. Lamotrigine

HISTORY AND DISCOVERY

The initial premise in evaluating lamotrigine as an anticonvulsant was that it might possess sufficient dihydrofolate

reductase inhibition to decrease folate activity, a mechanism known to reduce epileptic effects. Although its

antifolate properties were only modest, anticonvulsant effects were significant. During the clinical development of

lamotrigine as a treatment for intractable seizures, improved mood in lamotrigine-treated patients was anecdotally

reported (Jawad et al. 1989; Smith et al. 1993). Indeed, antiepileptic drugs (AEDs) have been described as a

heterogeneous class of medications with a diverse range of utility in psychiatry with variable effects on mood

(Muzina et al. 2005).

In 1993, Smith et al. evaluated mood state and quality of life among patients taking AEDs. Using a crossover design,

the investigators administered add-on lamotrigine to 81 epileptic patients who were already receiving either

enzyme-inducing AEDs (n = 56) or both enzyme inducers and valproate ( n = 25). The principal variable of interest

was seizure frequency; among the secondary response variables were subjective reports of anxiety, depression,

self-esteem, mastery, and happiness. Although no difference was found in the levels of depression reported by

patients receiving lamotrigine and those receiving placebo, lamotrigine-treated patients reported significantly

higher levels of happiness on the Affect Balance Scale (Bradburn 1969) and an improvement in perceived internal

locus of control according to a self-reported mastery scale (Pearlin and Schooler 1978). There was no correlation

between perceived happiness and changes in seizure frequency or severity. Thus, the investigators concluded that

lamotrigine has an effect on mood independent of its antiepileptic effect (Smith et al. 1993).

STRUCTURE–ACTIVITY RELATIONS

Lamotrigine (3,5-diamino-6-[2,3-dichlorophenyl]-1,2,4-triazine, C 9H7Cl2N5) is an AED of the phenyltriazine class

that is chemically unrelated to hepatic enzyme inducers (e.g., carbamazepine) and enzyme inhibitors (e.g., valproic

acid) (Figure 39–1). The reduction of dihydrofolate to tetrahydrofolate via inhibition of dihydrofolate reductase may

result in the inhibition of nucleic acid and protein synthesis, secondary disruption of neural structure and function,

and tertiary disruption of mood. However, as noted above, the correlation between inhibition of folic acid production

and antiepileptic activity was found to be low, so the structure–activity relationship of lamotrigine with respect to

antiseizure activity is unknown. Similarly, there are no published data clearly linking the structure of lamotrigine to

its empirical mood-stabilizing properties.

FIGURE 39–1. Chemical structure of lamotrigine, with chemical structures of valproic acid and carbamazepine for

comparison.

PHARMACOLOGICAL PROFILE

Lamotrigine has not been shown to inhibit the reuptake of norepinephrine, dopamine, or serotonin. Although it

exerts inhibitory effects at the serotonin3 (5-HT3) receptor, this activity is weak and unlikely to contribute to its

therapeutic profile. Lamotrigine does not exhibit high binding affinity to adrenergic ( 1, 2, ), dopamine (D1, D2),

-aminobutyric acid (GABA), histamine (H 1), opioid ( or ), or muscarinic (M1, M2) acetylcholine receptors. LikePrint: Chapter 39. Lamotrigine

http://www.psychiatryonline.com/popup.aspx?aID=432147&print=yes…

2 of 14

10/05/2009 16:19

phenytoin, lamotrigine inhibits use-dependent Na + channels, allowing continued normal depolarizations but

suppressing paroxysmal burst firing encountered in seizures and hypoxic insult. It exhibits neuroprotective effects

through inhibiting glutamate release secondary to ischemia, but it does not inhibit N-methyl-D-aspartate

(NMDA)–induced depolarizations.

PHARMACOKINETICS AND DISPOSITION

Oral lamotrigine is rapidly absorbed with negligible first-pass metabolism. Peak plasma concentrations are reached

in approximately 2–4 hours, and its half-life is approximately 25 hours (GlaxoSmithKline 2007). Bioavailability is not

altered by food, and the chewable tablets are equivalent in the rate and extent of absorption as compared to the

compressed tablets. Lamotrigine is approximately 55% bound to plasma proteins and is unlikely to significantly

interact with drugs that are highly protein bound. Metabolism is primarily achieved by competitive glucuronic acid

conjugation. The principal product is an inactive lamotrigine-2- N-glucuronide conjugate, found predominantly in

urine and to a lesser extent in feces. Ten percent of lamotrigine is excreted unchanged. At steady-state

concentrations, the pharmacokinetics of lamotrigine are linear within a dosage range of 100–700 mg/day (Leach et

1. 1995). The clearance of lamotrigine is reduced in the setting of renal insufficiency and hepatic disease. Race also

appears to affect the clearance of lamotrigine, with rates 25% lower in nonwhites than in whites.

There is growing awareness that perturbations in lamotrigine levels occur during pregnancy. Ohman et al. (2000)

first reported data from nine pregnant epileptic women, revealing marked elevations in maternal plasma lamotrigine

levels during the first 2 weeks postpartum. Lamotrigine levels increased by as much as 170% from levels taken at

the time of delivery. Pennell et al. (2004) extended upon this finding in a sample of 14 women treated with

lamotrigine monotherapy throughout pregnancy and during the postpartum period. The authors observed an

increasing magnitude of lamotrigine clearance during each trimester, reaching a peak of 330% of baseline clearance

by week 32 gestational age. Plasma levels were noted to rapidly return to normal during the first few postpartum

weeks. The increase in clearance during pregnancy presumably reflects an increase in gonadal steroid production

(Pennell 2003) and primary metabolism through hepatic glucuronidation.

In newborns of mothers receiving lamotrigine, extensive placental transfer of drug has been found to occur, with

umbilical cord concentrations approaching those of maternal serum (Ohman et al. 2000). Nursing infants

demonstrate plasma lamotrigine concentrations approximately 23%–50% of maternal levels. Any adverse effects to

neonates that may result from lamotrigine exposure through breast-feeding are not well characterized.

MECHANISM OF ACTION

The mechanism by which lamotrigine exerts its therapeutic psychotropic effects is not clear but is presumed to be

associated with its antiepileptic activity. Given this presumption, it is the use- and voltage-dependent inhibition of

voltage-activated sodium channels (Xie and Hagan 1998) that best characterize lamotrigine’s mechanism of action.

In addition to sodium channel inhibition, lamotrigine demonstrates inhibition of glutamine-induced repetitive burst

firing in cultured rat cortical neurons (Miller et al. 1986) and cultured spinal cord neurons (Cheung et al. 1992).

Initial, but not subsequent, stimuli of burst-firing wavetrains are comparatively unimpeded by high-concentration

lamotrigine (Cheung et al. 1992; Miller et al. 1986). This effect is attenuated by hyperpolarization. Subsequent

stimuli in the wavetrains show attenuation, as evidenced by frequency-dependent inhibition of Na + receptor flux

(Cheung et al. 1992; Lang and Wang 1991; Lang et al. 1993; Miller et al. 1986). Together, these data support the

concept of lamotrigine-induced inhibition of Na + flux at presynaptic use- and voltage-sensitive sodium channels. The

inhibition appears to be greatest in paroxysmally depolarized (rapidly firing) neurons. This is significant, because

paroxysmal discharge produced by neuronally, physically, or chemically induced kindling has been generally

accepted as a model of the induction and propagation of cortical seizure activity (Ayala et al. 1970). In a

complementary manner, kindling has also been proposed as a potential contributor to mood cycling in bipolar

disorder (Post et al. 1984). According to the kindling theory, the progression of bipolar episodes evolves from being

reactive and triggered by environmental life stressors to occurring spontaneously. More worrisome, this process

may contribute to a treatment-refractory course of illness (Post et al. 2001). Mechanistically, preferential

attenuation of paroxysmal wavetrains could permit normal neuronal activity to continue unimpeded but still

suppress seizure activity and affective instability. However, this hypothesis is limited in its ability to explain the

more enduring mood-stabilizing effects that occur apart from bursts of paroxysmal electrical discharges.

In addition to inhibitory activity on sodium channels, there is also evidence for antagonistic action by lamotrigine on

N-type Ca++ channels in rat cortical neurons and CA1/CA3 regions of guinea pig hippocampal slices (Stefani et al.

1996; von Wegerer et al. 1997). Given prior reports ascribing modest antimanic effects to calcium channel blockers,

the mechanism of calcium channel blockade may also contribute to lamotrigine’s thymoleptic properties (Dubovsky

1993).

Antiglutamatergic action is another means by which lamotrigine may function as a mood stabilizer. The presynaptic

inhibitory effects of lamotrigine on voltage- and use-sensitive sodium channels, calcium channels, and potassium

channels (Grunze et al. 1998) are believed to result in decreased release of the excitatory amino acid glutamate. In

humans, support for lamotrigine’s antiglutamatergic action includes an ability to reduce perceptual abnormalities

induced by the NMDA receptor antagonist ketamine (Anand et al. 2000). Yet blockade of glutamate release is

independent of any NMDA affinity, as lamotrigine-associated antagonism of NMDA-induced depolarizations or otherPrint: Chapter 39. Lamotrigine

http://www.psychiatryonline.com/popup.aspx?aID=432147&print=yes…

3 of 14

10/05/2009 16:19

NMDA-linked stimuli has not been reported in animal models (Harrison and Simmonds 1985). Lamotrigine’s ability

to inhibit veratrine-induced glutamate and aspartate release (Leach et al. 1986) may translate clinically into greater

activation and alertness, accounting for its observed ability to stabilize mood from below baseline.

Mechanisms unlikely to account for lamotrigine’s clinical efficacy in bipolar depression and ability to provide

prophylaxis against recurring mood episodes include activity at GABAergic, serotonergic, and other monoaminergic

receptors. Lamotrigine does not have robust monoamine oxidase inhibitor activity for either the A or B isoforms

(Southam et al. 2005), nor does lamotrigine have high affinity for GABA A or GABAB receptors. At the 5-HT3 receptor,

only weak inhibitory effects have been reported. Although there were no alterations in 5-HT 1A receptor function

after 1 week of lamotrigine administration to healthy male volunteers (Shiah et al. 1998), there is preliminary

evidence in animals to show that postsynaptic 5-HT 1A receptors may be affected by lamotrigine (Bourin et al. 2005).

In this regard, lamotrigine appears to function more similarly to valproate and carbamazepine than to lithium.

Although the mechanisms are not completely understood, support for potential neuroprotective effects of

lamotrigine come from studies of rat hippocampal CA1 cells, where the agent reduced cell damage resulting from

global cerebral ischemia (Crumrine et al. 1997) and decreased hippocampal neuronal loss after pretreatment with

lamotrigine (Maj et al. 1998).

INDICATIONS AND EFFICACY

Lamotrigine is indicated for adjunctive antiepileptic therapy in adults with partial seizures and in patients with

generalized seizures secondary to Lennox-Gastaut syndrome. The most recently approved indication is for

adjunctive use in primary and generalized tonic-clonic seizures in adults and pediatric patients ( 2 years of age).

In 2003, lamotrigine became the first medication since lithium to be granted U.S. Food and Drug Administration

(FDA) approval for use in the maintenance treatment of bipolar I disorder to delay the time to occurrence of new

mood episodes. Olanzapine, aripiprazole, and quetiapine have subsequently received this indication for bipolar

disorder.

Maintenance Therapy in Bipolar I Disorder

Two large randomized, double-blind, parallel-group, placebo-controlled multicenter studies led to the approval of

lamotrigine as a maintenance therapy in bipolar I disorder (Bowden et al. 2003; Calabrese et al. 2003). Both of

these paired studies included a screening phase of up to 2 weeks; an 8- to 16-week open-label phase during which

lamotrigine was initiated as adjunctive or monotherapy and other psychotropic drugs were discontinued; and an

18-month double-blind phase during which patients received lamotrigine, lithium, or placebo as maintenance

therapy. The primary efficacy variable in both studies was time to intervention for any mood episode.

One of the studies (Bowden et al. 2003) evaluated subjects who were or had recently been in a manic, hypomanic,

or mixed state. The other study (Calabrese et al. 2003) examined subjects who were or had recently been

depressed.

Both lamotrigine and lithium were significantly superior to placebo on time to intervention for any mood episode ( P

= 0.018 for previously manic; P = 0.029 for previously depressed). Lamotrigine-treated patients showed longer

survival-in-study times than did control subjects ( P = 0.03 for formerly manic; P = 0.003 for formerly depressed).

Lithium-treated formerly depressed patients also showed longer survival-in-study times relative to control subjects

(P = 0.022), and there was a nonsignificant trend for lithium-treated formerly manic patients to show longer

in-study survival as well (P = 0.07). Lamotrigine, but not lithium, was superior to placebo at prolonging the time to

a depressive episode (P = 0.015 for previously manic; P = 0.047 for previously depressed). Lithium, but not

lamotrigine, was superior to placebo at prolonging the time to a manic, hypomanic, or mixed episode ( P = 0.006 for

previously manic; P = 0.026 for previously depressed). There was no evidence in these studies of worsening manic

or depressive symptoms or of accelerated cycling frequency during lamotrigine treatment.

In contrast to both individual maintenance studies, a pooled analysis of these two clinical trials conducted by

Goodwin et al. (2004) found lithium and lamotrigine to be statistically superior to placebo at prolonging the time to

intervention for a manic, hypomanic, or mixed episode ( P = 0.034 for lamotrigine vs. placebo; P 0.001 for lithium

1. placebo). However, lamotrigine, but not lithium, remained the only compound that was statistically superior to

placebo at prolonging the time to intervention for a depressive episode ( P = 0.009 for lamotrigine vs. placebo; P =

0.120 for lithium vs. placebo).

In the interpretation of maintenance-phase data, it is important to distinguish between efficacy in relapse

prevention and pure prophylactic efficacy (Ghaemi et al. 2004). Mood episodes of the same polarity as the index

episode that occur during the initial 2 months following recovery are generally regarded as relapses. As such, this

period is termed the acute recovery phase. Alternatively, mood episodes that occur beyond this phase during the

period of remission are regarded as recurrences. To test the pure maintenance efficacy of lamotrigine, Calabrese et

1. (2006) conducted a post hoc analysis of the two double-blind 18-month maintenance trials that compared

lamotrigine and lithium against placebo. In their analysis, all subjects were excluded who experienced a relapse to a

mood episode of the same polarity as the index episode within 90 or 180 days of randomization. After subjects who

relapsed to a mood episode within 90 days of randomization were excluded, data were available from 167

lamotrigine-treated patients, 131 lithium-treated patients, and 133 placebo-treated patients. Lamotrigine andPrint: Chapter 39. Lamotrigine

http://www.psychiatryonline.com/popup.aspx?aID=432147&print=yes…

4 of 14

10/05/2009 16:19

lithium were both more effective than placebo at delaying the time to intervention for a mood episode ( P = 0.02 for

lamotrigine; P = 0.010 for lithium). Similar results were found when patients who relapsed to a mood episode of the

same polarity as their index episode within 180 days of randomization were excluded. When overall survival in the

study until dropout for any reason was examined, only lamotrigine was significantly more effective than placebo ( P

= 0.002 for lamotrigine; P = 0.098 for lithium). Because these results are consistent with the primary analyses of

the independent studies that included patients who potentially relapsed into their index episode, the findings

indicate that lamotrigine and lithium possess true maintenance efficacy.

Acute Treatment of Bipolar Depression

Evaluation of lamotrigine’s spectrum of activity was prompted by early reports of putative psychotropic efficacy in

patients with epilepsy as summarized above. To replicate and extend preliminary open-label prospective findings

suggesting moderate to marked efficacy in depression, hypomania, and mixed states (Calabrese et al. 1999a), a

series of multicenter double-blind, placebo-controlled studies was completed. The first study in this series was

conducted to evaluate the efficacy and safety of two doses of lamotrigine compared with placebo in the acute

treatment of a major depressive episode in 195 patients with bipolar I disorder (Calabrese et al. 1999b).

Outpatients 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-Åsberg Depression

Rating Scale (MADRS), the Mania Rating Scale (MRS), and the Severity of Illness and Improvement subscales of the

Clinical Global Impression Scale (CGI-S and CGI-I, respectively), were completed at 4 days and then weekly.

Lamotrigine at a dosage of 200 mg/day demonstrated significant antidepressant efficacy on the MADRS, Ham-D

Item 1, CGI-S, and CGI-I compared with placebo. Improvements were seen as early as week 3. Lamotrigine at a

dosage of 50 mg/day approached significance compared with placebo on several efficacy measures. The proportion

of patients exhibiting a marked response on the CGI I was 51%, 41%, and 26% for the lamotrigine 200 mg/day,

lamotrigine 50 mg/day, and placebo groups, respectively. The rate of switching was not significantly different

between lamotrigine (4.6%–5.4%) and placebo (5%) without concurrent psychotropic medication. Of 65 subjects

randomly assigned to placebo, 3% cycled into hypomania, 0% into mania, and less than 1% into mixed states. Of

129 patients randomly assigned to lamotrigine, less than 1% cycled into hypomania, 3% into mania, and less than

1% into mixed states. These data suggest that lamotrigine monotherapy is an efficacious and well-tolerated

treatment for bipolar depression and that the switch rate associated with the use of lamotrigine does not exceed

that typically seen in the natural course of the illness.

Although there is expert consensus that lamotrigine is effective for acute bipolar depression and confirmation with

one adequately powered placebo-controlled trial (Calabrese et al. 1999b), there have been four randomized,

parallel-group, placebo-controlled monotherapy trials of lamotrigine that have failed to separate from placebo

(Calabrese et al. 2008). These include a 10-week flexible-dose (100–400 mg) study of patients with bipolar I or II

disorder, an 8-week fixed-dose (200 mg) study of patients with bipolar II disorder, and two 8-week fixed-dose (200

1. mg) studies of patients with bipolar I disorder. In none of the four studies were significant improvements over

placebo observed on the 17- and 31-item Ham-D, MADRS, CGI-S, or CGI-I. The effect sizes of the primary and

secondary endpoints for these four studies were small, suggesting that insufficient numbers of subjects may have

been randomized to detect a significant treatment effect. In contrast to the study demonstrating superiority of

lamotrigine over placebo in treating acute bipolar depression, the placebo response rates in these four studies were

variably high.

To clarify the effects of lamotrigine in acute bipolar depression, Geddes et al. (2009) conducted a systematic

meta-analysis of individual patient data from 1,072 participants in all five randomized, controlled trials comparing

lamotrigine with placebo. The pooled analysis showed that more patients treated with lamotrigine than with placebo

responded on both the Ham-D and the MADRS ( P = 0.002). However, the advantage over placebo was larger in more

severely depressed patients.

Rapid-Cycling Bipolar Disorder

Calabrese et al. (2000) conducted a large study in rapid-cycling bipolar disorder consisting of two phases: an 8- to

12-week open-label preliminary phase and a 26-week randomized phase. Subjects who met criteria for mood

stabilization at the end of the preliminary phase were stratified for type I and II bipolar disorder and then randomly

assigned to flexible-dose lamotrigine (100–500 mg/day) or placebo to compare the efficacy of lamotrigine

monotherapy with that of placebo in preventing mood episodes and to evaluate the safety of lamotrigine in this

population. Three hundred twenty-six subjects were enrolled into the preliminary phase, and 182 subjects were

randomly assigned to receive placebo ( n = 89) or lamotrigine (n = 93). The difference between the treatment

groups in time to additional pharmacotherapy for a developing or fully developed mood episode did not achieve

statistical significance. However, overall survival time in the study (i.e., time to dropout for any reason) was

significantly different between the treatment groups in favor of lamotrigine ( P = 0.036). When patients with bipolar

I and II subtypes were compared, lamotrigine-treated bipolar II disorder patients demonstrated a significantly

longer median survival of 17 weeks compared with a median of 7 weeks for placebo-treated patients ( P = 0.015).

This study was the first long-term prospective placebo-controlled evaluation of a maintenance treatment in a large

population of patients diagnosed with rapid-cycling bipolar disorder. The results suggest that lamotrigine isPrint: Chapter 39. Lamotrigine

http://www.psychiatryonline.com/popup.aspx?aID=432147&print=yes…

5 of 14

10/05/2009 16:19

particularly useful for the prevention of mood episodes in bipolar II disorder. This is likely due to the predominance

of depressive symptoms in bipolar II patients.

Lamotrigine Comparator Trials

To date, only two compounds are FDA approved for the treatment of acute bipolar depression: an

olanzapine–fluoxetine combination (OFC) and quetiapine. To compare efficacy with an established agent for

managing bipolar depression, a head-to-head randomized, double-blind, parallel-group study of lamotrigine and OFC

was conducted over 7 weeks in patients with bipolar I disorder in an acute depressive phase (E. B. Brown et al.

2006). The study randomly assigned 410 subjects to either lamotrigine (titrated to 200 mg/day; n = 205) or OFC

(6/25, 6/50, 12/25, or 12/50 mg/day; n = 205). Rates of response, defined as a 50% reduction in MADRS total

score, did not differ significantly between lamotrigine (59.7%) and OFC (68.8%; P = 0.073). When a MADRS score

of 12 was used to define remission, no significant differences were observed in the remission rate between

lamotrigine (49.2%) and OFC (56.4%; P = 0.181), nor were there differences in the time to remission ( P = 0.072).

However, when improvement on the individual rating scales was compared, OFC-treated subjects showed greater

decreases in the MADRS total score (P = 0.002) and Young Mania Rating Scale total score ( P = 0.001) compared

with lamotrigine-treated subjects. Although overall response and remission rates were comparable between the

active agents, interesting differences did emerge in regard to tolerability profiles. Adverse-event rates of suicidal

and self-injurious behavior were more common among patients treated with lamotrigine (3.4%) compared with OFC

(0.5%; P = 0.037). However, significant differences in mean change from baseline to endpoint for clinically relevant

laboratory results favored treatment with lamotrigine on measures such as hemoglobin A1c, prolactin, total

cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride levels.

Importantly, the incidence of potentially clinically relevant weight gain, defined as a 7% increase in body weight, in

OFC-treated patients was 23.4%, compared with 0% with lamotrigine ( P <0.001). As anticipated for a treatment

trial comparing two active treatments, the effect size was modest between treatment arms (0.26).

Although lamotrigine is not indicated for the treatment of acute bipolar I depression, the similarity of its response

and remission rates to those seen with OFC, an agent granted FDA approval, provide a rationale for lamotrigine’s use

in the acutely depressed phase of bipolar disorder, especially for patients at risk for weight gain or adverse

metabolic effects. One explanation for the greater improvement on MADRS scores, but not overall response or

remission rates, among OFC-treated patients may pertain to the tolerability profile of olanzapine. Side effects such

as sedation or weight gain may be driving improvement on standardized rating scale measurements of insomnia or

appetite loss, rather than a true antidepressant mechanism. This may place agents with a clean tolerability profile,

such as lamotrigine, at a disadvantage.

An add-on trial comparing lamotrigine with placebo has also been conducted in the treatment of bipolar I and II

depression (van der Loos et al. 2006). All patients were required to be taking lithium maintained at a therapeutic

blood level (0.6–1.2 mmol/L) prior to randomization to lamotrigine ( n = 64) or placebo (n = 60). Subjects were

treated for 8 weeks and assessed for response using the MADRS (primary outcome measure) and the Clinical Global

Impression Scale–Bipolar Version (CGI-BP; Spearing et al. 1997). The change from baseline to endpoint on the

MADRS was significantly greater in lamotrigine-treated subjects (15.38) compared with those receiving placebo

(11.03; P = 0.024). A higher percentage of patients responded to add-on lamotrigine (51.6%) compared with

placebo (31.7%; P = 0.030), although no difference was observed in the rate of response based on the CGI-BP

(64.1% for lamotrigine vs. 48.3% for placebo; P = 0.103). A randomized, double-blind pilot trial has also compared

lamotrigine (n = 10) and citalopram (n = 10) as an add-on to lithium, divalproex, or carbamazepine for bipolar I or

II depression (Schaffer et al. 2006). MADRS scores decreased to a similar degree for patients taking citalopram

(–10.6, SD = 8.6) as for patients taking lamotrigine (–5.0, SD = 10; P = 0.21). There was one case of adverse switch

into hypomania in each treatment arm.

A summary of the 16 randomized, controlled multicenter trials involving lamotrigine in the treatment of mood

disorders is represented in Table 39–1.

TABLE 39–1. Summary of multicenter randomized, controlled trials of lamotrigine in mood disorders

Study (protocol

number)

Mood state Bipolar

subtype

Study type Dose Duration Response or overall

efficacy

Calabrese et al.

1999b (602)

Bipolar

depression

I Acute

monotherapy

LTG 200 mg/day (n =

63)LTG 50 mg/day (n =

66)PBO (n = 65)

7 weeks Ham-D: NSMADRS:

LTG>PBOCGI-I:

LTG>PBO

Calabrese et al.

2008 (603)

Bipolar

depression

I and II Acute

monotherapy

LTG 100–400 mg/day (n

= 103)PBO (n = 103)

10 weeks NS

Calabrese et al.

2008 (SCA 40910)

Bipolar

depression

I Acute

monotherapy

LTG 200 mg/day (n =

133)PBO (n = 124)

8 weeks NSPrint: Chapter 39. Lamotrigine

http://www.psychiatryonline.com/popup.aspx?aID=432147&print=yes…

6 of 14

10/05/2009 16:19

Study (protocol

number)

Mood state Bipolar

subtype

Study type Dose Duration Response or overall

efficacy

Calabrese et al.

2008 (SCA

100223)

Bipolar

depression

II Acute

monotherapy

LTG 200 mg/day (n =

111)PBO (n = 124)

8 weeks MADRS: NSHam-D:

NSCGI-I responders:

LTG>PBO

Calabrese et al.

2008 (SCA 30924)

Bipolar

depression

I Acute

monotherapy

LTG 200 mg/day (n =

131)PBO (n = 128)

8 weeks NS

1. B. Brown et al.

2006

Bipolar

depression

I Acute

monotherapy

LTG 200 mg/day (n =

205)OFC up to 12/50

mg/day (n = 205)

7 weeks MADRS:

OFC>LTGCGI-S:

OFC>LTG

van der Loos et al.

2006

Bipolar

depression

I or II Acute, add-on

therapy

LTG 200 mg/day (N =

64)PBO (N = 60)

8 weeks MADRS:

LTG>PBOCGI-I: NS

Calabrese et al.

2003 (605)

Bipolar

depression

(index

episode)

I Maintenance

monotherapy

following open

stabilization

LTG 50, 200, or 400

mg/day(n = 221)Li

0.8–1.1 mEq/L (n =

121)PBO (n = 121)

76 weeks LTG>PBOLi>PBO

Bowden et al. 2000

(609)

Mania I Acute

monotherapy

LTG 50 mg/d (n = 84)Li

0.8–1.3 mEq/L (n =

36)PBO (n = 95)

3 weeks NS

Bowden et al. 2000

(610)

Mania I Acute, add-on

therapy

LTG 200 mg/day (n =

74)Li 0.7–1.3 mEq/L (n =

78)PBO (n = 77)

6 weeks LTG: NSLi>PBO

Bowden et al. 2003

(606)

Mania (index

episode)

I Maintenance

monotherapy

following open

stabilization

LTG 100–400 mg/day (n

= 59)Li 0.8–1.1 mEq/L (n

= 46)PBO (n = 70)

76 weeks LTG>PBOLi>PBO

GlaxoSmithKline

Study* (611)

Rapid cycling I and II Prophylaxis,

add-on therapy

LTG 100–500 mg/day (n

= 68)PBO (n = 69)

32 weeks NS

Calabrese et al.

2000 (614)

Rapid cycling I and II Maintenance

monotherapy

following open

stabilization

LTG 100–500 mg/day (n

= 92)PBO (n = 88)

26 weeks LTG>PBO for BP II

Laurenza et al.

1999 (613)

Unipolar

depression

N/A Acute

monotherapy

LTG 200 mg/day (n =

142)Desipramine 200

mg/day (n = 147)PBO (n

= 145)

8 weeks Ham-D: NSMADRS:

NSCGI-S: LTG>PBO

DeVeaugh-Geiss et

1. 2000 (20022)

Unipolar

depression

N/A Acute

monotherapy

LTG 200 mg/day (n =

74)PBO (n = 75)

7 weeks NS

DeVeaugh-Geiss et

1. 2000 (20025)

Unipolar

depression

N/A Acute

monotherapy

LTG 200 mg/day (n =

151)PBO (n = 150)

7 weeks NS

* = data on file, GlaxoSmithKline

BP I = bipolar I disorder; BP II = bipolar II disorder; CGI-I = Clinical Global Impression–Improvement Scale; CGI-S = Clinical

Global Impression–Severity Scale; Ham-D = Hamilton Rating Scale for Depression; Li = lithium; LTG = lamotrigine; MADRS =

Montgomery-Åsberg Depression Rating Scale; N/A = not applicable; NS = not statistically significant (P 0.05); OFC =

olanzapine–fluoxetine combination; PBO = placebo.

Alternative Clinical Applications

Case studies and open-label reports have been published supporting further investigation of lamotrigine for use in

the treatment of myriad disorders and behavioral symptoms, including depersonalization disorder (Sierra et al.

2006), impulsive behavior (Daly and Fatemi 1999); Alzheimer’s disease (Tekin et al. 1998), aggression in dementia

(Devarajan and Dursun 2000), borderline personality disorder (Pinto and Akiskal 1998), posttraumatic stress

disorder (Hertzberg et al. 1999), treatment-resistant unipolar depression (Gabriel 2006), alcohol (Rubio et al. 2006)

and cocaine dependence (E. S. Brown et al. 2006) comorbid with bipolar disorder, schizoaffective disorder (Erfurth

et al. 1998b), Rett syndrome (Stenbom et al. 1998), self-injurious behavior in the profoundly mentally retarded

(Davanzo and King 1996), refractory schizophrenia (coadministered with clozapine [Saba et al. 2002]), and

decreased consciousness with impaired cognition in severe brain injury (Showalter and Kimmel 2000).Print: Chapter 39. Lamotrigine

http://www.psychiatryonline.com/popup.aspx?aID=432147&print=yes…

7 of 14

10/05/2009 16:19

DOSING

The recommended titration schedule for lamotrigine added to valproate in adult patients begins at 25 mg every

other day for 14 days, advances to 25 mg daily for 14 days, and then increases by 50 mg daily beginning each of the

fifth and sixth week of treatment, reaching a target dose of 100 mg daily (Table 39–2). Titration of adjunctive

lamotrigine in the presence of an enzyme inducer begins at 50 mg daily for 14 days, advances to 100 mg daily

(divided doses) for 14 days, to a target dosage of 400 mg daily (Table 39–3). There are no published data

supporting greater efficacy of lamotrigine in the treatment of bipolar disorder at dosages greater than 200 mg/day.

Additionally, there is no clear association between serum levels of lamotrigine and measures of affective response.

TABLE 39–2. Recommended titration schedule for lamotrigine for patients with bipolar disorder taking valproate

Week

Dosage

Weeks 1 and 2

25 mg every other day

Weeks 3 and 4

25 mg daily

Week 5

50 mg daily

Week 6

100 mg daily

Week 7

100 mg daily

The usual maintenance dosage when lamotrigine is added to valproate is 100 mg/day.

Source. Adapted from GlaxoSmithKline 2007.

TABLE 39–3. Recommended titration schedule for lamotrigine when used as monotherapy and when added to an

enzyme-inducing antiepileptic drug regimen* (without valproate)

For patients not taking an enzyme-inducing

antiepileptic drug regimen* and not taking

valproate

For patients taking an enzyme-inducing

antiepileptic drug regimen* and not taking

valproate

Weeks 1 and 2 25 mg daily

50 mg daily

Weeks 3 and 4 50 mg daily

100 mg/day (in two divided doses)

Week 5 100 mg daily

200 mg daily (in two divided doses)

Week 6 200 mg daily

300 mg daily (in two divided doses)

Usual

maintenance

dosage

200 mg daily

400 mg daily (in two divided doses)

*Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of

lamotrigine.

Source. Adapted from GlaxoSmithKline 2007.

SIDE EFFECTS AND TOXICITY

In trials of epileptic patients who received adjunctive or monotherapy lamotrigine, the spectrum of reported side

effects included dizziness, headache, diplopia, nausea, and ataxia (Messenheimer et al. 1998). In controlled

monotherapy trials in mood disorders, lamotrigine has been associated with headache, changes in sleep habits,

nausea, and dizziness (Bowden et al. 2004). Although the prevalence of rash in mood disorder randomized trials did

not exceed that of placebo, rash is generally recognized as the side effect most likely to significantly complicate

lamotrigine’s clinical use (see “Rash” subsection below).

A unique feature of lamotrigine in comparison with other agents used in the management of bipolar disorder is its

weight-neutral tolerability profile. Among 583 patients with bipolar disorder treated with lamotrigine, lithium, or

placebo for 52 weeks, a pooled analysis showed that the percentage of patients with a greater than 7% increase in

weight or change in weight did not differ between those treated with lamotrigine and those treated with lithium or

placebo (Sachs et al. 2006). A higher percentage of lamotrigine-treated subjects than of lithium-treated subjects

lost more than 7% of their body weight. A post hoc analysis revealed that nonobese patients taking lamotrigine are

unlikely to experience a change in weight. However, obese patients are significantly more likely to lose weight with

lamotrigine and to gain weight with lithium (Bowden et al. 2006).

Clinical case reports made since the release of lamotrigine have included rare associations with Tourette’s syndrome

(Lombroso 1999); obsessionality in the form of intrusive, repetitive phrases (Kemp et al. 2007); nephritis with

colitis (Fervenza et al. 2000); eosinophilic hepatitis (Fix et al. 2006); visual loss due to cicatrizing conjunctivitis

(McDonald and Favilla 2003); female sexual dysfunction (Erfurth et al. 1998a); lupus erythematosus (Sarzi-Puttini

et al. 2000); stupor (Sbei and Campellone 2001); and hyponatremia in patients with diabetes insipidus (Mewasingh

et al. 2000). Hypersensitivity reactions (multiorgan failure/dysfunction, hepatic abnormalities, disseminatedPrint: Chapter 39. Lamotrigine

http://www.psychiatryonline.com/popup.aspx?aID=432147&print=yes…

8 of 14

10/05/2009 16:19

intravascular coagulation) have also occurred with lamotrigine use.

Rash

Incidence and Prevalence

In early epilepsy trials, rash led to hospitalization and treatment discontinuation or Stevens-Johnson syndrome in

0.3% of adults treated with lamotrigine. During the controlled phase of 12 multicenter trials, no cases of serious

rash occurred in lamotrigine-treated subjects (Calabrese et al. 2002). Among 1,955 patients treated with

lamotrigine in an open-label setting, there was 1 case of mild Stevens-Johnson syndrome and 2 cases of serious

rash. Both cases of serious rash resolved uneventfully upon lamotrigine discontinuation, with one case requiring

additional treatment with oral steroids.

The annual incidence of serious drug-based skin reactions associated with lamotrigine was highest in 1993 (4.2%)

but steadily declined and had stabilized by 1998 (0.02%). This is likely attributable to the manufacturer’s dosage

revision in 1994, which advised a more protracted titration schedule (Calabrese et al. 2002; Messenheimer et al.

1998). It is well documented that the risk of rash is heightened in children younger than 12 years, by the

coadministration of valproic acid, or by exceeding the recommended initial dosage or rate of dosage escalation of

lamotrigine.

Clinical Management

The most common lamotrigine-associated rash is an exanthematic maculopapular or morbilliform eruption that is

benign. However, a clinically similar eruption may be associated with more rare and serious systemic

hypersensitivity reactions (Guberman et al. 1999). Thus, all patients who develop a rash during the first few months

of lamotrigine therapy should be instructed to hold the next dose and immediately seek medical consultation. The

greatest risk of rash appears to be during the first 8 weeks of treatment. A rash during the first 5 days of therapy is

usually due to a nondrug cause.

Figure 39–2 presents a decision-making algorithm for the management of benign and serious rashes. A serious

lamotrigine rash is usually confluent with prominent facial and neck involvement. The rash may be tender or have a

purpuric or hemorrhagic appearance. It is accompanied or preceded by fever, malaise, pharyngitis, anorexia, or

lymphadenopathy (Guberman et al. 1999). Rashes with any feature(s) suggestive of a serious reaction necessitate

immediate drug cessation, followed by monitoring for hepatic, renal, and hematological involvement. Tavernor et al.

(1995) reported successfully restarting patients on lamotrigine after mild isolated rash; however, re-titration should

progress slowly and begin at 5–12.5 mg/day. Patients should not be rechallenged if they have had a serious rash,

such as a reaction associated with systemic symptoms or internal toxicity (Besag et al. 2000). Because immune

tolerance to lamotrigine is lost following interruption of dosage for more than 1 week, patients should be instructed

to resume lamotrigine at the prior initial start-up dose and gradually titrate upwards whenever therapy has been

interrupted for more than a few days.

FIGURE 39–2. Clinical management of rash related to lamotrigine treatment.Print: Chapter 39. Lamotrigine

http://www.psychiatryonline.com/popup.aspx?aID=432147&print=yes…

9 of 14

10/05/2009 16:19

CBC = complete blood count; LFT = liver function test.

Source. Reprinted from Calabrese JR, Sullivan JR, Bowden CL, et al: “Rash in Multicenter Trials of Lamotrigine in Mood

Disorders: Clinical Relevance and Management.” Journal of Clinical Psychiatry 63:1012–1019, 2002. Copyright 2000, Physicians

Postgraduate Press. Used with permission.

To explore whether the incidence of dermatological reactions could be mitigated by adherence to a series of

dermatological precautions, Ketter et al. (2006) led an intervention study that randomly assigned patients to usual

precautionary care versus dermatological precautionary care prior to initiation of lamotrigine therapy. Outpatients

13 years of age and older received 12 weeks of open-label lamotrigine and were instructed not to exceed the

recommended initial dosage or dosage-escalation schedule. Those in the dermatological precautions group were

instructed not to ingest new food, receive immunizations, or use new conditioners, cosmetics, soaps, detergents, or

fabric softeners and to reduce exposure to poison ivy. Among 1,139 subjects enrolled into the trial, none

experienced a serious rash. The incidence of nonserious rash did not differ between the usual care group (8.8%)

and those advised to follow dermatological precautions (8.6%).Print: Chapter 39. Lamotrigine

http://www.psychiatryonline.com/popup.aspx?aID=432147&print=yes…

10 of 14

10/05/2009 16:19

Attention must be drawn to the black box warning in the prescribing information, which instructs prescribers to

ordinarily discontinue lamotrigine “at the first sign of rash, unless the rash is clearly not drug related” because “it is

not possible to predict reliably which rashes will prove to be serious or life threatening” (GlaxoSmithKline 2007).

Overdose

Among 493 cases of lamotrigine toxicity in overdose, the majority of patients (52.1%) experienced no toxic clinical

effects (Lofton and Klein-Schwartz 2004). Common symptoms included drowsiness, vomiting, nausea, ataxia,

dizziness, and tachycardia. Rare cases of coma, seizures, heart conduction delay, and respiratory depression have

been reported in overdose. Some ingestions of lamotrigine involving quantities up to 15 grams have been fatal.

Use During Pregnancy

Lamotrigine may represent an option for women with bipolar disorder during pregnancy due to its favorable

tolerability profile and maintenance effects against bipolar depression. An observational study by Newport et al.

(2008) examined risk of illness recurrence in pregnant women with stable bipolar disorder who continued

lamotrigine treatment during pregnancy ( n = 10) versus those who discontinued mood stabilizer therapy during

pregnancy (n = 16). The risk of illness recurrence was 3.3 times lower when lamotrigine was continued (30.0%

recurrence [3/10] vs. 100% recurrence [16/16] when patients discontinued mood stabilizers; P <0.0001; odds

ratio = 23.2; 95% confidence interval = 1.5–366). A reduced risk of depressive recurrence, as well as of manic or

hypomanic recurrence, was observed with continued lamotrigine treatment. It remains unclear, however, whether

lamotrigine carries a lower risk of major teratogenic defects compared with other mood-stabilizing medications.

Potential adverse effects to the developing fetus of mothers receiving lamotrigine are beginning to emerge upon

examination of data from international pregnancy registries (Cunnington and Tennis 2004; Holmes et al. 2006). As

with any mood stabilizer, lamotrigine use during pregnancy represents an inherent dilemma for clinicians and

expectant mothers, who must balance the risks associated with untreated bipolar disorder with the potential for

occurrence of major congenital malformations. During treatment with valproate or carbamazepine, neural tube

defects are estimated to occur in 1%–5% of neonates after first-trimester exposure. However, the risk for

malformations with newer antiepileptic drugs, including lamotrigine, is less well characterized. Preliminary data

from the North American Antiepileptic Drug Pregnancy Registry suggests a possible association between

first-trimester exposure to lamotrigine monotherapy and cleft lip and/or cleft palate (Holmes et al. 2006). The

documented oral clefts were not part of a syndrome that included other birth defects. A total of 5 cases of oral cleft

occurred among 564 pregnant women, resulting in a total prevalence of 8.9 cases per 1,000. This contrasts with

0.37 per 1,000 cases in an unexposed group, representing a 24-fold increase in risk. As this association requires

confirmation from other prospectively collected registries or ongoing research, the validity of the findings are

uncertain. An International Lamotrigine Registry, maintained by GlaxoSmithKline since 1992, recorded a total of 14

congenital malformations among 414 outcomes (2.9%) involving a first-trimester monotherapy exposure

(Cunnington and Tennis 2004). This is similar to the background risk of 2%–3% for congenital malformations in the

general population. Likewise, a more recent population-based case–control study found no evidence of increased

risk for orofacial clefts relative to other malformations due to lamotrigine monotherapy (Dolk et al. 2008).

Lamotrigine is listed as Pregnancy Category C in terms of teratogenic effects.

DRUG–DRUG INTERACTIONS

Lamotrigine is not known to inhibit the activity of the cytochrome P450 2D6 enzyme. However, the addition of

adjunctive lamotrigine to enzyme inducers such as carbamazepine, phenytoin, primidone, and phenobarbital

decreases lamotrigine plasma concentrations by approximately 40%–50% (Hahn et al. 2004). The inducing effect of

oxcarbazepine is approximately half that of carbamazepine (Weintraub et al. 2005). Because lamotrigine is nearly

exclusively metabolized by glucuronidation, the introduction of adjunctive valproate (an enzyme inhibitor) results in

immediate and successful competition for metabolism, with resultant increases in half-life. The steady-state half-life

for lamotrigine in the presence of valproate is 69.6 hours (Yau et al. 1992), compared with a multidose mean

half-life of 25.4 hours with lamotrigine monotherapy (GlaxoSmithKline 2007). Mixed results have been found on the

composite effect of administering lamotrigine in combination with valproate plus an enzyme-inducing antiepileptic

drug. Some studies have found no difference in lamotrigine clearance from that associated with monotherapy (May

et al. 1996), while others have found the inhibitory effects of valproate to predominate, resulting in lower

lamotrigine clearance (May et al. 1996; Weintraub et al. 2005).

Evidence has emerged that oral contraceptives containing estrogen have the potential to decrease serum

concentrations of lamotrigine by up to 64% (Sabers et al. 2001, 2003). During the long-term treatment of bipolar

disorder, use of ethinyl estradiol–containing compounds may require an increase in the maintenance dose of

lamotrigine by as much as twofold over the recommended target maintenance dose. Conversely, stopping

estrogen-containing oral contraceptives, including during the “pill-free” week, may increase lamotrigine levels to a

clinically significant range. It appears that progestogen-only compounds do not influence lamotrigine levels,

regardless of whether administered by the oral, intramuscular, subdermal, or intrauterine modes (Reimers et al.

2005). Despite the potential for increased metabolism of lamotrigine when used in combination with oral

contraceptives, the manufacturer does not recommend any dosage adjustments to the initial titration schedule.Print: Chapter 39. Lamotrigine

http://www.psychiatryonline.com/popup.aspx?aID=432147&print=yes…

11 of 14

10/05/2009 16:19

CONCLUSION

The mechanism by which lamotrigine achieves its therapeutic effect in the treatment of bipolar disorder is unknown.

However, its discovery has provided investigators with a novel AED for empirical validation in the routine treatment

of bipolar disorder. Although initial results from trials of lamotrigine in the treatment of mania were unfavorable,

subsequent maintenance studies have provided compelling data to show that lamotrigine prevents the recurrence of

mood episodes and displays antidepressant efficacy, albeit most convincingly for the prophylaxis against depression

in contrast to the acute diminution of depression. Even with its ability to stabilize mood from below baseline,

lamotrigine appears to have a switch rate to mania or hypomania that is similar to treatment with placebo.

Lamotrigine’s neutral effects on body weight and favorable side-effect profile make it appealing for use in patients

with comorbid metabolic syndrome or when other treatments have resulted in poor tolerability. At present,

lamotrigine remains the only AED mood stabilizer with more established efficacy in the depressed illness phase than

in mania or hypomania. Future controlled investigations should determine whether lamotrigine is effective in

comorbid populations, such as individuals with substance use disorders, where it may act to both stabilize mood and

decrease drug consumption. Trials are also needed to explore the use of lamotrigine in combination with other mood

stabilizers or atypical antipsychotics, providing insight into whether combination treatment is superior to

monotherapy in preventing mood relapse and recurrence.

REFERENCES

Anand A, Charney DS, Oren DA, et al: Attenuation of the neuropsychiatric effects of ketamine with lamotrigine:

support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists. Arch Gen Psychiatry

57:270–276, 2000 [PubMed]

Ayala G, Matsumoto H, Gumnit R: Excitability changes and inhibitory mechanisms in neurocortical neurons during

seizures. J Neurophysiol 33:73–85, 1970 [PubMed]

Besag F, Ng G, Pool F: Successful re-introduction of lamotrigine after initial rash. Seizure 9:282–286, 2000 [PubMed]

Bourin M, Masse F, Hascoet M: Evidence for the activity of lamotrigine at 5-HT(1A) receptors in the mouse forced

swimming test. J Psychiatry Neurosci 30:275–282, 2005 [PubMed]

Bowden CL, Calabrese JR, Ascher J, et al: Spectrum of efficacy of lamotrigine in bipolar disorder: overview of

double-blind, placebo-controlled studies. Presented at the American College of Neuropsychopharmacology (ACNP)

Annual Meeting, San Juan, PR, December 2000

Bowden CL, Calabrese JR, Sachs G, et al: 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 60:392–400, 2003

[PubMed]

Bowden CL, Asnis GM, Ginsberg LD, et al: Safety and tolerability of lamotrigine for bipolar disorder. Drug Saf

27:173–184, 2004 [PubMed]

Bowden CL, Calabrese JR, Ketter TA, et al: Impact of lamotrigine and lithium on weight in obese and nonobese

patients with bipolar I disorder. Am J Psychiatry 163:1199–1201, 2006 [Full Text] [PubMed]

Bradburn NM: The Structure of Psychological Well-Being. Chicago, IL, Alpine, 1969

Brown EB, McElroy SL, Keck PE Jr, et al: A 7-week, randomized, double-blind trial of olanzapine/fluoxetine

combination versus lamotrigine in the treatment of bipolar I depression. J Clin Psychiatry 67:1025–1033, 2006

[PubMed]

Brown ES, Perantie DC, Dhanani N, et al: Lamotrigine for bipolar disorder and comorbid cocaine dependence: a

replication and extension study. J Affect Disord 93:219–222, 2006 [PubMed]

Calabrese JR, Bowden CL, McElroy SL, et al: Spectrum of activity of lamotrigine in treatment-refractory bipolar

disorder. Am J Psychiatry 156:1019–1023, 1999a

Calabrese JR, Bowden CL, Sachs GS, et al: A double-blind placebo-controlled study of lamotrigine monotherapy in

outpatients with bipolar I depression. J Clin Psychiatry 60:79–88, 1999b

Calabrese JR, Suppes T, Bowden C, et al: A double-blind, placebo-controlled, prophylaxis study of lamotrigine in

rapid-cycling bipolar disorder. J Clin Psychiatry 61:841–850, 2000 [PubMed]

Calabrese JR, Sullivan JR, Bowden CL, et al: Rash in multicenter trials of lamotrigine in mood disorders: clinical

relevance and management. J Clin Psychiatry 63:1012–1019, 2002 [PubMed]

Calabrese JR, Bowden CL, Sachs G, et al: A placebo-controlled 18-month trial of lamotrigine and lithium maintenance

treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry 64:1013–1024, 2003 [PubMed]

Calabrese JR, Goldberg JF, Ketter TA, et al: Recurrence in bipolar I disorder: a post hoc analysis excluding relapses

in two double-blind maintenance studies. Biol Psychiatry 59:1061–1064, 2006 [PubMed]

Calabrese JR, Huffman RF, White RL, et al: Lamotrigine in the acute treatment of bipolar depression: results of fivePrint: Chapter 39. Lamotrigine

http://www.psychiatryonline.com/popup.aspx?aID=432147&print=yes…

12 of 14

10/05/2009 16:19

double-blind, placebo-controlled clinical trials. Bipolar Disord 10:323–333, 2008 [PubMed]

Cheung H, Kamp D, Harris E: An in vitro investigation of the action of lamotrigine on neuronal voltage-activated

sodium channels. Epilepsy Res 13:107–112, 1992 [PubMed]

Crumrine RC, Bergstrand K, Cooper AT, et al: Lamotrigine protects hippocampal CA1 neurons from ischemic damage

after cardiac arrest. Stroke 28:2230–2236, 1997 [PubMed]

Cunnington M, Tennis P: International Lamotrigine Pregnancy Registry Scientific Advisory Committee: Lamotrigine

and the risk of malformations in pregnancy. Neurology 64:955–960, 2004

Daly K, Fatemi S: Lamotrigine and impulse behavior. Can J Psychiatry 44:395–396, 1999 [PubMed]

Davanzo P, King B: Open trial of lamotrigine in the treatment of self-injurious behavior in an adolescent with

profound mental retardation. J Child Adolesc Psychopharmacol 6:273–279, 1996 [PubMed]

Devarajan S, Dursun S: Aggression in dementia with lamotrigine treatment. Am J Psychiatry 157:1178, 2000 [Full

Text] [PubMed]

DeVeaugh-Geiss J, Ascher J, Brook S, et al: Safety and tolerability of lamotrigine in controlled monotherapy trials in

mood disorders. Presented at the American College of Neuropsychopharmacology (ACNP) Annual Meeting, San Juan,

PR, December 2000

Dolk H, Jentink J, Loane M, et al: Does lamotrigine use in pregnancy increase orofacial cleft risk relative to other

malformations? Neurology 71:714–722, 2008 [PubMed]

Dubovsky SL: Calcium antagonists in manic-depressive illness. Neuropsychobiology 27:184–192, 1993 [PubMed]

Erfurth A, Amann BA, Grunze H: Female genital disorder as adverse symptom of lamotrigine treatment: a

serotonergic effect? Neuropsychobiology 38:200–201, 1998a

Erfurth A, Walden J, Grunze H: Lamotrigine in the treatment of schizoaffective disorder. Neuropsychobiology

38:204–205, 1998b

Fervenza FC, Kanakiriya S, Kunau RT, et al: Acute granulomatous interstitial nephritis and colitis in anticonvulsant

hypersensitivity syndrome associated with lamotrigine treatment. Am J Kidney Dis 36:1034–1040, 2000 [PubMed]

Fix OK, Peters MG, Davern TJ: Eosinophilic hepatitis caused by lamotrigine. Clin Gastroenterol Hepatol 4:xxvi, 2006

Gabriel A: Lamotrigine adjunctive treatment in resistant unipolar depression: an open, descriptive study. Depress

Anxiety 23:485–488, 2006 [PubMed]

Geddes JR, Calabrese JR, Goodwin GM: Lamotrigine for treatment of bipolar depression: an independent

meta-analysis and meta-regression of individual patient data from 5 randomized trials. Br J Psychiatry Br J

Psychiatry 194:4–9, 2009 [PubMed]

Ghaemi SN, Pardo RB, Hsu DJ: Strategies for preventing the recurrence of bipolar disorder. J Clin Psychiatry 65

(suppl):16–23, 2004

GlaxoSmithKline: Lamictal (lamotrigine) prescribing information. Research Triangle Park, NC, GlaxoSmithKline, May

2007. Available at: http://us.gsk.com/products/assets/us_lamictal.pdf

Goodwin GM, Bowden CL, Calabrese JR, et al: A pooled analysis of 2 placebo-controlled 18-month trials of

lamotrigine and lithium maintenance in bipolar I disorder. J Clin Psychiatry 65:432–441, 2004 [PubMed]

Grunze H, von Wegerer J, Greene RW, et al: Modulation of calcium and potassium currents by lamotrigine.

Neuropsychobiology 38:131–138, 1998 [PubMed]

Guberman A, Besag F, Brodie M, et al: Lamotrigine-associated rash: risk/benefit considerations in adults and

children. Epilepsia 40:985–991, 1999 [PubMed]

Hahn CG, Gyulai L, Baldassano CF, et al: The current understanding of lamotrigine as a mood stabilizer. J Clin

Psychiatry 65:791–804, 2004 [PubMed]

Harrison N, Simmonds M: Quantitative studies on some antagonists of N-methyl-D-aspartate in slices of rat cerebral

cortex. Br J Pharmacol 84:381–391, 1985 [PubMed]

Hertzberg M, Butterfield M, Feldman M, et al: A preliminary study of lamotrigine for the treatment of posttraumatic

stress disorder. Biol Psychiatry 45:1226–1229, 1999 [PubMed]

Holmes LB, Wyszynski DF, Baldwin EJ, et al: Increased risk for nonsyndromic cleft palate among infants exposed to

lamotrigine during pregnancy. Birth Defects Res A Clin Mol Teratol 76:318, 2006

Jawad S, Richens A, Goodwin G, et al: Controlled trial of lamotrigine (Lamictal) for refractory partial seizures.

Epilepsia 30:656–663, 1989

Kemp DE, Gilmer WS, Fleck J, et al: An association of intrusive, repetitive phrases with lamotrigine treatment inPrint: Chapter 39. Lamotrigine

http://www.psychiatryonline.com/popup.aspx?aID=432147&print=yes…

13 of 14

10/05/2009 16:19

bipolar II disorder. CNS Spectr 12:106–111, 2007 [PubMed]

Ketter TA, Greist JH, Graham JA, et al: 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 67:400–406, 2006

[PubMed]

Lang D, Wang C: Lamotrigine and phenytoin interactions on ionic channels present in N4TG1 and GH3 clonal cells.

Soc Neurosci Abs 17:1256, 1991

Lang D, Wang C, Cooper B: Lamotrigine, phenytoin, and carbamazepine interactions on the sodium current present

in N4TG1 mouse neuroblastoma cells. J Pharmacol Exp Ther 266:829–835, 1993 [PubMed]

Laurenza A, Asnis G, Beaman M, et al: A double-blind, placebo-controlled study supporting the efficacy of

lamotrigine in unipolar depression. Bipolar Disord 1 (suppl):39–40, 1999

Leach MJ, Marden CM, Miller AA: Pharmacological studies on lamotrigine, a novel potential antiepileptic drug, II:

neurochemical studies on the mechanism of action. Epilepsia 27:490–497, 1986 [PubMed]

Leach MJ, Lees G, Riddall DR: Lamotrigine: mechanisms of action, in Antiepileptic Drugs, 4th Edition. Edited by Levy

RH, Mattson RH, Meldrum BS. New York, Raven, 1995, pp 861–869

Lofton AL, Klein-Schwartz W: Evaluation of lamotrigine toxicity reported to poison control centers. Ann

Pharmacother 38:1811–1815, 2004 [PubMed]

Lombroso C: Lamotrigine-induced tourettism. Neurology 52:1191–1194, 1999 [PubMed]

Maj R, Fariello RG, Ukmar G, et al: PNU-151774E protects against kainate-induced status epilepticus and

hippocampal lesions in the rat. Eur J Pharmacol 359:27–32, 1998 [PubMed]

May TW, Rambeck B, Jurgens U: Serum concentrations of lamotrigine in epileptic patients: the influence of dose and

comedication. Ther Drug Monit 18:523–531, 1996 [PubMed]

McDonald MA, Favilla I: Visual loss in a patient with lamotrigine-induced cicatrizing conjunctivitis. Clin Exp

Ophthalmol 31:541–543, 2003 [PubMed]

Messenheimer JA, Mullens EL, Giorgi L, et al: Safety review of adult clinical trial experience with lamotrigine. Drug

Saf 18:281–296, 1998 [PubMed]

Mewasingh L, Aylett S, Kirkham F, et al: Hyponatraemia associated with lamotrigine in cranial diabetes insipidus.

Lancet 356:656, 2000 [PubMed]

Miller AA, Wheatley P, Sawyer DA, et al: Pharmacological studies on lamotrigine, a novel antiepileptic drug:

anticonvulsant profile in mice and rats. Epilepsia 27:483–489, 1986 [PubMed]

Muzina DJ, Elhaj O, Gajwani P, et al: Lamotrigine and antiepileptic drugs as mood stabilizers in bipolar disorder. Acta

Psychiatr Scand 111 (suppl):21–28, 2005

Newport DJ, Stowe ZN, Viguera AC, et al: Lamotrigine in bipolar disorder: efficacy during pregnancy. Bipolar Disord

10:432–436, 2008 [PubMed]

Ohman I, Vitols S, Tomson T: Lamotrigine in pregnancy: pharmacokinetics during delivery, in the neonate, and

during lactation. Epilepsia 41:709–713, 2000 [PubMed]

Pearlin L, Schooler C: The structure of coping. J Health Soc Behav 19:2–21, 1978 [PubMed]

Pennell PB: Antiepileptic drug pharmacokinetics during pregnancy and lactation. Neurology 61:S35–S42, 2003

Pennell PB, Newport DJ, Stowe ZN, et al: The impact of pregnancy and childbirth on the metabolism of lamotrigine.

Neurology 62:292–295, 2004 [PubMed]

Pinto O, Akiskal H: Lamotrigine as a promising approach to borderline personality: an open case series without

DSM-IV major mood disorder. J Affect Disord 51:333–343, 1998 [PubMed]

Post R, Weiss S, Pert A: Differential effects of carbamazepine and lithium on sensitization and kindling. Prog

Neuropsychopharmacol Biol Psychiatry 8:425–434, 1984 [PubMed]

Post R, Nolen WA, Kupka RW, et al: The Stanley Foundation Bipolar Network, I: rationale and methods. Br J

Psychiatry Suppl 41:S169–S176, 2001

Reimers A, Helde G, Brodtkorb E: Ethinyl estradiol, not progestogens, reduces lamotrigine serum concentrations.

Epilepsia 46:1414–1417, 2005 [PubMed]

Rubio G, Lopez-Munoz F, Alamo C: Effects of lamotrigine in patients with bipolar disorder and alcohol dependence.

Bipolar Disord 8:289–293, 2006 [PubMed]

Saba G, Dumortier G, Kalalou K, et al: Lamotrigine-clozapine combination in refractory schizophrenia: three cases. J

Neuropsychiatry Clin Neurosci 14:1, 2002Print: Chapter 39. Lamotrigine

http://www.psychiatryonline.com/popup.aspx?aID=432147&print=yes…

14 of 14

10/05/2009 16:19

Sabers A, Buchholt J, Uldall P, et al: Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Res

47:151–154, 2001 [PubMed]

Sabers A, Ohman I, Christensen J, et al: Oral contraceptives reduce lamotrigine plasma levels. Neurology

26:570–571, 2003

Sachs G, Bowden CL, Calabrese JR, et al: Effects of lamotrigine and lithium on body weight during maintenance

treatment of bipolar I disorder. Bipolar Disord 8:175–181, 2006 [PubMed]

Sarzi-Puttini P, Panni B, Cazzola M, et al: Lamotrigine-induced lupus. Lupus 9:555–557, 2000 [PubMed]

Sbei M, Campellone J: Stupor from lamotrigine toxicity. Epilepsia 42:1082–1083, 2001 [PubMed]

Schaffer A, Zucker P, Levitt A: Randomized, double-blind pilot trial comparing lamotrigine versus citalopram for the

treatment of bipolar depression. J Affect Disord 96:95–99, 2006 [PubMed]

Shiah IS, Yatham LN, Lam RW, et al: Effects of lamotrigine on the 5-HT1A receptor function in healthy human males.

J Affect Disord 49:157–162, 1998 [PubMed]

Showalter P, Kimmel D: Stimulation of consciousness and cognition after severe brain injury. Brain Inj 14:997–1001,

2000 [PubMed]

Sierra M, Baker D, Medford N, et al: Lamotrigine as an add-on treatment for depersonalization disorder: a

retrospective study of 32 cases. Clin Neuropharmacol 29:253–258, 2006 [PubMed]

Smith D, Chadwick D, Baker G, et al: Seizure severity and the quality of life. Epilepsia 34 (suppl):S31–S35, 1993

Southam E, Pereira R, Stratton SC, et al: Effect of lamotrigine on the activities of monoamine oxidases A and B in

vitro and on monoamine disposition in vivo. Eur J Pharmacol 519:237–245, 2005 [PubMed]

Spearing MK, Post RM, Leverich GS, et al: Modification of the Clinical Global Impressions (CGI) scale for use in

bipolar illness (BP): the CGI-BP. Psychiatry Res 73:159–171, 1997 [PubMed]

Stefani A, Spadoni F, Sinischali A, et al: Lamotrigine inhibits Ca2+ currents in cortical neurons: functional

implications. Eur J Pharmacol 307:113–116, 1996 [PubMed]

Stenbom Y, Tonnby B, Hagberg B: Lamotrigine in Rett syndrome: treatment experience from a pilot study. Eur Child

Adolesc Psychiatry 7:49–52, 1998 [PubMed]

Tavernor S, Wong I, Newton R, et al: Rechallenge with lamotrigine after initial rash. Seizure 4:67–71, 1995

[PubMed]

Tekin S, Aykut-Bingol C, Tanridag T, et al: Antiglutamatergic therapy in Alzheimer’s disease: effects of lamotrigine. J

Neural Transm 105:295–303, 1998 [PubMed]

van der Loos M, Nolen WA, Vieta E, et al: Lamotrigine as add-on to lithium in bipolar depression. Presented at the

fifth European Stanley Conference on Bipolar Disorder, Barcelona, Spain, October 2006

von Wegerer J, Hesslinger B, Berger M, et al: A calcium antagonistic effect of the new antiepileptic drug lamotrigine.

Eur Neuropsychopharmacol 7:77–78, 1997

Weintraub D, Buchsbaum R, Resor SR Jr, et al: Effect of antiepileptic drug comedication on lamotrigine clearance.

Arch Neurol 62:1432–1436, 2005 [PubMed]

Xie X, Hagan RM: Cellular and molecular actions of lamotrigine: possible mechanisms of efficacy in bipolar disorder.

Neuropsychobiology 38:119–130, 1998 [PubMed]

Yau M, Wargin W, Wolf K, et al: Effect of valproate on the pharmacokinetics of lamotrigine at steady state. Epilepsia

33 (suppl):82, 1992

Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved.