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Lamotrigine in Psychiatry: Pharmacology and Therapeutics


James W. Jefferson, MD


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CNS Spectr. 2005;10(3):224-232

 

Dr. Jefferson is Distinguished Senior Scientist at the Madison Institute of Medicine and clinical professor of psychiatry in the Department of Psychiatry at the University of Wisconsin Medical School in Madison.

Disclosure: Dr. Jefferson has received grant/research support from Abbott, Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Novartis, Organon, Pfizer, Roche, Solvay, UCB, and Wyeth; he is a consultant to GlaxoSmithKline, Novartis, Roche, Shire, Solvay, and UCB; he has received honoraria from Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Organon, Novartis, Pfizer, Solvay, and Wyeth; and he is also a minor shareholder in Bristol-Myers Squibb, GlaxoSmithKline, and Principal Healthcare Technology Systems, Inc. This article was submitted on January 5, 2004, and accepted on June 28, 2004.

Please direct all correspondence to: James W. Jefferson, MD, Madison Institute of Medicine, Inc., 7617 Mineral Point Road, Suite 300, Madison, WI  53717; Tel: 608-827-2451, Fax: 608-827-2444; E-mail: jjefferson@healthtechsys.com.


 

Focus Points

  • Since 1994, lamotrigine has seen progressively greater application in psychiatry, particularly as a treatment for bipolar disorder.
  • Clinically meaningful drug interactions with lamotrigine occur.
  • Lamotrigine rash risk can be minimized but not eliminated.

 

Abstract

Following the introduction of lamotrigine in 1994 as a treatment for epilepsy in the United States, the drug has seen progressively greater application in psychiatry, particularly as a treatment for bipolar disorder. This review critically evaluates the support for lamotrigine use across a broad range of psychiatric disorders as well as discuss its pharmacology, side-effect profile, and interactions with other medications.


Introduction

First synthesized in the 1970s, lamotrigine was studied initially as an antiepileptic drug (AED) and entered the United States market in 1994 as an adjunctive treatment for partial seizures in adults with epilepsy. As has been the case of virtually all AEDs, there has been considerable interest in exploring the drug’s potential for psychiatric indications. Subsequently, lamotrigine has been evaluated in a number of large multicenter trials1 and has been the subject of many less rigorous, smaller reports.1-3 Its Food and Drug Administration approval in June 2003 for maintenance use in bipolar I disorder established it as the first AED and only the second drug since lithium (approved in 1974) with this indication (olanzapine was approved more recently). Some other countries had already approved lamotrigine for bipolar maintenance in late 2002 and early 2003. While the focus of this review is on the psychiatric uses of lamotrigine, its pharmacologic, side-effect,  and tolerability profiles, and its interactions with other medications will also be discussed.

 

Pharmacology

Among AEDs, lamotrigine has a unique phenyltriazine structure and is known by purists as 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine.4 Its specific mechanism of action in epilepsy and even more so in psychiatry is unknown. It does have inhibitory effects on voltage-sensitive sodium channels and modulating effects have been noted on calcium and potassium channels.5 According to the package insert,4 sodium channel inhibition stabilizes neuronal membranes and modulates release of excitatory amino acid neurotransmitters. In a recent review, Ketter and colleagues6 acknowledged “multiple mechanisms of action” and focused on neuroprotective and antiglutamatergic effects as promising contributors to its mood stabilizing activity. Observations that lamotrigine reduced γ-aminobutyric acid (GABA) A receptor-mediated neurotransmission in rat amygdala7 suggest that a GABAergic mechanism may also be involved, although this concept is not without controversy.6,8

 

Lamotrigine does not have pronounced effects on any of the usual neurotransmitter receptors (adrenergic, dopamine D1 and D2, muscarinic, GABA, histaminergic H1, serotonin 5-HT2, and N-methyl-D-asparate). Inhibitory effects on 5-HT, norepinephrine, and dopamine transporters are weak.4,9

 

Lamotrigine is a weak inhibitor of dihydrofolate reductase, but whether this effect is sufficient to contribute to a mechanism of action or increases risk to the fetus during pregnancy is not known.

 

Pharmacokinetics

Absorption of lamotrigine is not influenced by food. Protein binding is relatively low at 55% and protein displacement interactions with other drugs do not appear to be problematic. Linear pharmacokinetics have been demonstrated across the conventional dose range of the drug (blood levels increase in direct proportion to change in dose). Unlike the majority of psychiatric drugs, lamotrigine is metabolized outside the cytochrome P450 system of enzymes; rather, it undergoes Phase II conjugation mainly to a 2-N-glucuronide that is inactive. This suggests a lesser potential for drug interaction mischief, but as discussed later, some interactions do occur. Studies in volunteers4 found that the drug had some tendency towards autoinduction (speeding up its own metabolism) early in the course of treatment, but this has not been problematic clinically. With multiple dosing and in the absence of drug interactions, the elimination half-life (T1/2) is ~25 hours (the range was between 11.6 and 61.6 hours in a study of normal volunteers).4

 

The pharmacokinetics of lamotrigine are altered in several populations. For example, while moderate cirrhosis does not alter pharmacokinetics, severe cirrhosis with or without ascites was associated with a substantially reduced oral clearance and prolonged elimination half-life.10 On the other hand, chronic renal failure appears to have little effect on the plasma level of lamotrigine, although its elimination half-life was prolonged somewhat.11

 

Oral clearance rates were considerably higher in the very young (body weight <30 kg) suggesting the need for a relatively higher dose in this age group. On the other hand, population kinetic studies in adults did not find an influence of age on clearance12,13 although data from the very old are sparse. Gender and obesity have not been shown to alter lamotrigine clearance, but pregnancy has. Four studies of 14, 12, 9, and 1 pregnancies, respectively,14-17 were consistent in finding a substantial decrease in blood level of lamotrigine as pregnancy evolved and an increase following delivery. Consequently, dose increase may be necessary during pregnancy to maintain a therapeutic effect and dose reduction following delivery to avoid toxicity.

 

Blood Levels

Because a relationship between plasma concentration of lamotrigine and clinical response has not been established for either epilepsy or psychiatric disorders, routine monitoring of blood levels is not recommended. Rather, oral dose should be established by tolerability and clinical response.4,18 Despite the lack of finding of a constant relationship between plasma concentration and toxicity or lack of response, a tentative target range in epilepsy has been proposed for lamotrigine, namely, 10–60 micromol/L.19

 

Because it is not particularly difficult to measure plasma concentrations of lamotrigine, one can expect wider use of this modality and, hopefully, more extensive research to resolve these unanswered questions. When dealing with individual patients, measuring plasma concentrations could be useful to address issues of noncompliance, drug interactions, and other potentially destabilizing events.

 

Psychiatric Uses

At present, the only FDA-approved indication for lamotrigine is “the maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy.”4 Furthermore, the package insert states that the drug’s effectiveness “in the acute treatment of mood episodes has not been established.”

 

Interest in lamotrigine for use in psychiatry evolved, in part, from observations in epilepsy trials of improved mood and well-being that were not necessarily associated with reduction in seizure frequency.20 In a 1994 presentation at the American Psychiatric Association Annual Meeting, Weisleer and colleagues21 described two treatment-resistant bipolar patients who responded dramatically to add-on lamotrigine therapy. Shortly thereafter, a series of large-scale, multicenter, double-blind, placebo-controlled trials4 were conceptualized and initiated.

 

Bipolar Efficacy Studies

Acute Mania

Despite encouraging results from a small double-blind, lithium (but not placebo) controlled study of acute mania,22 lamotrigine was found to be no more effective than placebo in two large company-sponsored controlled trials.1

 

Acute Bipolar Depression

In the one published study of lamotrigine monotherapy in bipolar I depression,23 195 patients were randomized to either lamotrigine 50 mg/day, lamotrigine 200 mg/day (reached by gradual titration), or placebo for 7 weeks. While the 50 mg/day group bested placebo on some outcome measures, the 200 mg/day group was more consistently effective. Efficacy was assessed using the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impression-Severity (CGI-S) and Improvement (CGI-I) scales using both observed and last observation carried forward (LOCF) data (Table 1).

Response was defined as ≥50% improvement on the 17-item HAM-D or MADRS, or a very much or much improved rating on the CGI-I. A statistically significant response was found for the 200 mg/day group on the MADRS and the CGI-I and for the 50 mg/day group on the MADRS. The percent of responders on the MADRS was 54% (200 mg/day group), 48% (50 mg/day group), and 29% (placebo group).

 

Adverse event dropouts were 15% on placebo, 18% on lamotrigine 50 mg/day, and 16% on lamotrigine 200 mg/day. The most common adverse event was headache, occurring about twice as often with lamotrigine as with placebo. Rash incidence was 11% to 14% across the three groups. No rash was considered serious.

 

Lamotrigine 200 mg/day was effective on most outcome measures, and both doses were well tolerated. The 7-week duration of the study may have been too short to maximize the benefit of lamotrigine given the gradual titration schedule (the graphic representation of change over time shows that improvement on lamotrigine had not plateaued at Week 7). The results of additional acute bipolar I depression studies have not yet been published.

 

Bipolar Maintenance

Two large 18-month multicenter bipolar I maintenance studies24,25 compared lamotrigine with placebo and lithium (serum lithium concentration: 0.8­—1.1 mEq/L). One entered patients (n=175) who had been recently manic/mixed or hypomanic and used a flexible dose design for lamotrigine 100–400 mg/day (mean=211 mg/day),24 and the other entered patients (n=463) who had been recently depressed and used a fixed-dose design (50, 200, or 400 mg/day).25 Both studies had an 8–16 week open-label phase involving treatment with “doctor’s choice” medication followed by phasing over to lamotrigine monotherapy for a minimum of 1 week. Eligible patients were then randomized into the double-blind phases of the studies. In the “recently manic” study,24 both lamotrigine and lithium bested placebo in improving time to intervention for any mood episode, while only lamotrigine was more effective in prolonging time to a depressive episode and only lithium in prolonging time to a manic, mixed or hypomanic episode. Similar results were found in the “recently depressed” study.25

 

While neither study found lamotrigine effective in delaying onset of manic, mixed or hypomanic episodes, a pooled analysis of the two studies did just that,26 although, as stated in the package insert, “The finding was more robust for depression.”4

 

In the “recently manic” study25 which was terminated before reaching the planned number of patients because of slow enrollment, the percent of patients completing the full 18 months was 31% for lamotrigine, 23% for lithium, and 16% for placebo. The full completion rate in the “recently depressed” study was 17% for lamotrigine and lithium and 10% for placebo. In the open-label phase of each study, one serious rash occurred involving lamotrigine. There were no serious rashes in the double-blind phases. In the double-blind phase of both studies, the only adverse event that was significantly more common on lamotrigine than placebo was rash in the “recently depressed” study (7% versus 2%, P<.05). Bear in mind that patients in the double-blind phase had already been treated with lamotrigine open-label, which could have introduced a selection bias favoring lamotrigine tolerability during the double-blind phase. In neither study was there evidence to suggest that lamotrigine increased the risk of a manic, mixed, or hypomanic episode.

 

Of interest was the dosing recommendation that evolved from these two studies as stated in the package insert: The target dose of lamotrigine “is 200 mg/day (100 mg/day in combination with valproate and 400 mg/day in combination with carbamazapine or other enzyme-inducing drugs).”4 Because patients treated with lamotrigine 400 mg/day in the “recently depressed” study had no greater benefit than the lamotrigine 200 mg/day group, the package insert states that “doses above 200 mg/day are not recommended.” From a clinician’s perspective, this certainly does not mean that there will not be individual patients who both tolerate and respond to doses >200 mg/day.

 

Rapid Cycling

Open-label case series27,28 suggest a benefit from lamotrigine either alone or as an augmenter for rapid cycling (≥4 episodes/year) bipolar patients. A 6-month, double-blind, flexible-dose, placebo-controlled study29 took these observations a step further. Outpatients (n=324) were first treated open-label with lamotrigine. Concurrent psychiatric medications, when present, were tapered and discontinued, and those patients remaining stable on lamotrigine alone for 2 weeks were randomized to the double-blind phase (n=182). In this phase, lamotrigine dosing ranged between 100 mg/ day and 500 mg/day (mean [n=2]: 288 mg/day).

 

On the primary outcome measure, time to additional mood symptom pharmacotherapy, the median survival was 18 weeks for lamotrigine and 12 weeks for placebo, a difference that did not reach statistical significance. On the other hand, the percent of patients who remained stable for 6 months on lamotrigine (41%) was significantly greater (P=.03) than those on placebo (26%). Of particular interest was that it was only in the subgroup with bipolar II disorder that lamotrigine outdid placebo in terms of relapse-free completers. On the primary outcome measure, the bipolar II subgroup showed a strong trend towards statistical significance (P=.073) and a significant difference for overall study survival (P=.015).

 

One can conclude from this study that lamotrigine shows promise as a monotherapy approach to rapid cycling bipolar disorder, but that the promise lies predominantly with bipolar II patients. As is the case with most bipolar patients requiring long-term treatment, greatest benefit seems to require a combination of medications.

 

It should be noted that both of the 18-month maintenance studies contained a substantial cohort of rapid cyclers (defined as 4–6 episodes/year)­—28% of the “recently manic” and 30% of the “recently depressed” groups. A post-hoc analysis of these subpopulations would be a worthwhile contribution to the rapid cycling literature.

 

Treatment-Resistant Bipolar Disorder

A number of open-label case series have suggested benefit from lamotrigine as add-on therapy for treatment-refractory bipolar disorder.30-33 A complex placebo-controlled, crossover comparison of lamotrigine and gabapentin in a mixed sample (bipolar I [n=11], bipolar II [n=14] with 23/25 being rapid cyclers, and unipolar [n=6]) of treatment-refractory patients found significant overall benefit from lamotrigine but not from gabapentin. But, as the authors stated, “Given the severity, treatment resistance, and heterogeneity of our population in conjunction with the novel double crossover design, one should view these results as preliminary rather than definitive.”34

 

Major Depressive Disorder

The efficacy of lamotrigine as a treatment for major depressive disorder (MDD) was explored in two multicenter, placebo-controlled comparisons (one with desipramine),35,36 the results of which are available only in abstract form. There apparently was a statistically significant improvement on lamotrigine versus placebo, although the magnitude of difference was not striking.

 

Lamotrigine has also been investigated as an augmenting agent for MDD with the usual open-label reports of success.37-39 The harsh reality of the placebo-controlled, double-blind, however, was far-less encouraging with two studies40,41 producing essentially negative results. Nonetheless, both sets of authors found room for optimism in their analysis of the results (“might have antidepressive properties,” “suggesting potential efficacy”).

 

At present, more convincing evidence will be required before lamotrigine can be considered a treatment for MDD.

 

Other Psychiatric Uses

A small open-label schizophrenia study42 found Brief Psychiatric Rating Scale improvement from lamotrigine augmentation of clozapine but not olanzapine, haloperidol or flupenthixol. Three patient with schizomanic episodes improved with lamotrigine treatment.43 The future of lamotrigine as a treatment for schizophrenia spectrum disorders remains to be determined.

 

An open-label study of eight patients with borderline personality disorder (“meeting seven or more of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for bipolar disorder without concurrent major mood disorders”)­45 reported a response to lamotrigine in six and sustained remission in 444. Improved cognition and mood was noted in a study of five patients on long-term corticosteroid therapy who received lamotrigine.

 

Uncontrolled case reports46 described benefit from lamotrigine in epileptic psychosis (n=2); post-stroke pathological laughing and crying (n=1)47; aggression in dementia (n=1)48; aggression with brain trauma (n=1)49; and self-injurious behavior associated with mental retardation (n=1).50 On the other hand, a placebo-controlled study51 found no benefit from single-dose pretreatment with lamotrigine in protecting against naloxone-precipitated heroin withdrawal.

 

Six of 11 patients with depersonalization disorder improved on open-label lamotrigine (add-on in five of six patients),52 but a double-blind, placebo-controlled crossover monotherapy study by the same investigators in nine patients with depersonalization disorder was negative.53

 

With one exception (neuropathic pain),54 double-blind, placebo-controlled studies55-60  have found lamotrigine useful in treating a variety of pain syndromes (including trigeminal neuralgia, diabetic neuropathy, human immunodeficiency virus-associated sensory neuropathics, postoperative pain, and cold-induced pain).

 

Side Effects and Toxicity

The package insert for lamotrigine is replete with adverse event data from premarketing studies of epilepsy (adult and pediatric; adjunctive and monotherapy) and bipolar disorder (monotherapy maintenance).4 The adverse event discontinuation rates in these studies were as follows: epilepsy: adult adjunctive 11%, adult monotherapy 10%, and pediatric adjunctive 11.5%; bipolar disorder 16%, with the most common single event being rash in 3% to 5%. These figures lack the all-important correction for background noise (placebo discontinuation rates). For example, in the double-blind phase of the two pivotal bipolar maintenance studies,24,25 13% on lamotrigine and 16% on placebo dropped out due to adverse events (admittedly this phase of the study included only those patients who had tolerated open-label lamotrigine). A recent presentation of data from four long-term and four short-term placebo-controlled bipolar I studies61 reported adverse event discontinuation rates for lamotrigine of 12% versus 10% for placebo. Side effects that appear to be dose-dependent include ataxia, blurred vision, diplopia, dizziness, nausea, and vomiting.

 

Neurological

There have been reports of several patients with epilepsy and mental retardation in whom treatment with lamotrigine had negative effects on behavior (aggression, irritability, hyperactivity).62,63 Tics were induced by lamotrigine in several children with epilepsy.64,65 A 23-year-old with MDD became hypomanic when lamotrigine was added to bupropion.66 In a study of normal volunteers, lamotrigine 150 mg/day had fewer adverse cognitive and behavior effects than carbamazapine (mean: 696 mg/day).67

 

Hepatic

There have been rare cases of hepatitis, some fatal, associated with lamotrigine therapy.68,69 Under such circumstances, a cause-and-effect relationship may be difficult to establish. Routine monitoring of hepatic function is not necessary with lamotrigine.

 

Hematologic

Reports of agranulocytosis, neutropenia, and anemia have usually involved lamotrigine and other medications, are quite uncommon, and have been difficult to assess with regard to causality70-72 (personal communication, GlaxoSmithKline Medical Information Department, June 2003). Hematologic monitoring is not a routine requirement with lamotrigine.

 

Endocrine

Lamotrigine has not been associated with hyperinsulinemia, hyperandrogenism or polycystic ovaries.73-76

 

Weight

Weight neutrality appears to be the rule with lamotrigine.77 A retrospective review of 32 epilepsy trials involving 463 patients treated for at least 6 months78 found a mean weight increase of 0.5±5 kg. A 32-week comparison of lamotrigine and valproate70 found a mean weight gain of 1.3 pounds with the former and 12.8 pounds with the latter. When the two 18-month bipolar I studies80 were analyzed after 52 weeks, obese patients on lamotrigine actually lost a mean of 2.96 kg compared with gains with placebo (1.46 kg) and lithium (3.3 kg). As with any drug, a finding of weight neutrality does not exclude the possibility of substantial weight gain in an exceptional patient.

 

Dysgusia

Altered taste sensation was associated with lamotrigine in three patients (bitter taste and hypersalivation, bitter taste and hyposalivation, salty taste and hypersalivation).81

 

Overdose

Findings associated with overdose include ataxia, nystagmus, coma, seizure worsening, and intraventricular conduction delay.4 A 32-year-old overdosed on lamotrigine 4,500 mg/day together with clonazepam 2 mg/day and alcohol. Severe ataxia, nystagmus, and slurred speech were noted together with a peak plasma concentration of 35.8 mg/day. The electrocardiogram was normal and recovery was complete.82

 

Withdrawal

In general, a withdrawal syndrome has not been associated with the abrupt discontinuation of lamotrigine, although a single case report83 described minor symptoms suggestive of such a reaction.

 

Pregnancy and Breastfeeding

Data continue to be gathered on the effects of lamotrigine exposure during pregnancy. Physicians can enroll such patients in the Lamotrigine Pregnancy Registry (1-800-336-2176) and patients can enroll themselves in the North American Antiepileptic Drug Pregnancy Registry (1-888-233-2334).

 

An interim report from the International Lamotrigine Pregnancy Registry84 included 168 cases of monotherapy and 166 cases of polytherapy exposure to lamotrigine during the first trimester. Major birth defects occurred in 1.8% of the monotherapy exposures (3/168), 10% of exposures also involving valproate (5/50), and 4.3% of combined exposures without valproate (5/116). There were no characteristic abnormalities noted. The sample size, thus far, is too small to allow generalizations, although the monotherapy finding is reassuring given the incidence of major malformation in the general population of 2% to 3%. The drug is in FDA Pregnancy Category C. Generous folate supplementation is recommended for women of childbearing potential who are taking lamotrigine.

 

Lamotrigine does appear in breast milk and measurable serum levels have been noted in a few infants,16,85 none of whom had adverse effects. Whether lamotrigine-exposed infants are at risk for drug-induced rash is unknown.

 

Dermatologic

The package insert4 (June, 2003) for lamotriginecontains a black box warning about the risk of serious rash, including Stevens-Johnson syndrome and toxic epidermal necrolysis, associated with use of the drug and presents the incidence figures shown in Table 2.

These figures must be considered far from static as data continue to accrue. Fortunately, the identification and modification of risk factors have resulted in a considerably reduced likelihood of serious rash.

 

Benign rashes, usually morbilliform, are far more common with lamotrigine, occurring (according to the package insert) in 10% of all exposed patients in the epilepsy trials and 14% in the bipolar disorder trials. Interestingly, “most rashes resolved even with continuation of treatment,” but, at the same time, the package insert also advises that the drug “should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not drug related.” Opinion varies in this regard: “The benign rash is just that and should not be a reason for withholding a medication.”86 “Unfortunately, a morbilliform eruption is often the initial presentation of more serious reactions.”87 There is consensus that drug discontinuation is imperative if a severe reaction is suspect (eg, “[T]he presence of urticaria, blisters, mucosal involvement, facial edema, ulcers, palpable or extensive purpura, fever, or lymphadenopathy...”87).

 

It should be noted that all rash occurring in clinical trials is not attributable to the medication under study. For example, non-serious rash in the two lamotrigine bipolar maintenance studies4 was 7% of lamotrigine and 5% for placebo. If a non-serious rash is clearly an allergic reaction and the drug is discontinued, there may be circumstances under which rechallenge would be appropriate, which is not the case with a severe reaction. There are many examples where rechallenge has been accomplished successfully, but reactivation of rash has also been reported; consequently, a decision to reintroduce the drug should not be taken lightly.88

 

Rashes, both serious and non-serious, most commonly occur during the first 8 weeks of treatment with lamotrigine.88-92

 

Risk factors for a lamotrigine rash include high starting dose, rapid dose escalation, use with valproate, and use in children. Additional considerations include a history of multiple drug allergies, immunologic disorders, and a family history of severe reaction to the drug in question.93

 

The introduction of progressively more conservative dosing schedules in the 1990s appears to have substantially reduced the risk of serious rash (it is less clear if the incidence of non-serious rash has been altered). For example, the current recommended dosing for lamotrigine in adults in the absence of valproate or enzyme inducers is 25 mg/day for 2 weeks and then 50 mg/day for an additional 2 weeks with continued gradual titration thereafter. Patients must be aware that if lamotrigine is discontinued for more than five half-lives, it will usually be necessary to repeat the entire titration process. A recent study challenged this recommendation by successfully restarting 24 such patients with a single oral loading dose of ~6.5 mg/kg.94 Nonetheless, the more conservative approach is still advised, particularly for psychiatric patients.

 

While much has been written about lamotrigine and rash, the risk of serious rash is actually quite low (eg, 0.08% in adults on monotherapy in the mood disorder trials), and serious rash is certainly not unique to lamotrigine.95,96 Patient and clinician education and close attention to dosing guidelines should do much to minimize the likelihood of a serious skin reaction.

 

Drug Interactions

Because lamotrigine is metabolized by glucuronidation, pharmacokinetic drug interactions that alter lamotrigine blood levels are likely to do so through this phase II metabolic process.97,98 The cytochrome P450 enzyme system has no clinically meaningful involvement in lamotrigine metabolism.

 

Effects of Other Drugs on Lamotrigine Pharmacokinetics

Valproate reduces lamotrigine clearance by ~50% resulting in a marked prolongation of elimination half-life and doubling of lamotrigine plasma levels.99,100 Awareness of this interaction is critical to the safe use of these drugs in combination. For example, a woman taking lamotrigine 400 mg/day developed a severe encephalopathy (lamotrigine plasma level: 19 mg/L) after phenytoin (an enzyme inducer) was replaced by valproate.101 The risk of serious rash also increases in the presence of valproate unless appropriate dose adjustments are made.

 

A case report described two patients who developed neurotoxicity and doubling of lamotrigine blood levels when sertraline was co-administered.102 In contrast, in vitro sertraline had no effect on lamotrigine metabolism.4 Whether there is a predictable interaction between lamotrigine and sertraline (or selective serotonin reuptake inhibitors in general) is not yet known.

 

Lamotrigine clearance and plasma levels can be reduced substantially by a number of enzyme-inducing drugs, including carbamazepine, phenytoin, phenobarbital, primidone, methsuximide, and rifampicin, and, to a lesser extent, oxcarbazapine.103-105 In addition, plasma levels of lamotrigine were reduced by >50% in the presence of oral contraceptives.106 Such interactions can be managed by dosage modification, but remember, too, that discontinuation of a enzyme inducer will result in a marked increase in lamotrigine plasma level.107

 

Effects of Lamotrigine on Other Drug Pharmacokinetics

In general, there is an absence of clinically meaningful interactions of lamotrigine and other drugs (valproate, carbamazepine, phenytoin, topiramate, levetiracetam, and lithium).108-112

 

There is a single case report of clozapine plasma levels113 tripling in the presence of lamotrigine.113 Whether this is a predictable interaction is unknown. The absence of a pharmacokinetic interaction does not guarantee the absence of a pharmacodynamic interaction as was observed in nine patients who developed neurotoxic symptoms after lamotrigine was added to carbamazepine despite no changes in blood levels of either drug.114

 

There are well-established interactions with valproate (lamotrigine levels doubled) and several enzyme inducers (lamotrigine levels halved). Dosage adjustments of lamotrigine are essential to ensure safety of such combinations (see package insert for details).4

 

Conclusion

Lamotrigine has a well-established role in psychiatry for treating bipolar disorder, particularly as maintenance therapy. While lamotrigine is promising as a treatment for bipolar depression and rapid cycling, further research is necessary to verify this potential. Case reports are suggestive of value for a broader range of psychiatric disorders, although confirmatory studies are required.

 

Lamotrigine is generally well tolerated, but it can cause dose-dependent central nervous system side effects and a benign allergic rash. Serious rash can occur but is quite uncommon with proper attention to dosing. Drug interations are few but can be clinically meaningful with valproate (an inhibitor) and several enzyme inducers.  CNS

 

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44. Pinto OC, Akiskal HS. Lamotrigine as a promising approach to borderline personality: an open case series without concurrent DSM-IV major mood disorder. J Affect Disord. 1998;51:333-343.

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46. De León OA, Furmaga KM. Effect of lamotrigine treatment in epileptic psychosis [letter]. J Clin Psychopharmacol. 1999;19:186.

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48. Devarajan S, Dursun S. Aggression in dementia with lamotrigine treatment [letter]. Am J Psychiatry. 2000;157:1178.

49. Pachet A, Friesen S, Winkelaar D, Gray S. Beneficial behavioural effects of lamotrigine in traumatic grain injury. Brain Inj. 2003;17:715-722.

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51. Rosen MI, Persall HR, Kosten TR. The effect of lamotrigine on naloxone-precipitated opiate withdrawal. Drug Alcohol Depend. 1998;52:173-176.

52. Sierra M, Phillips ML, Labert MV, Senior C, David A, Krystal JH. Lamotrigine in the treatment of depersonalization disorder [letter]. J Clin Psychiatry. 2001;62:826-827.

53. Sierra M, Phillips ML, Ivin G, Krystal J, David AS. A placebo-controlled cross-over trial of lamotrigine in depersonalization disorder. J Psychopharmacol. 2003;17:103-105.

54. McCleane G. 200 mg daily of lamotrigine has no analgesic effect in neuropathic pain: a randomised, double-blind, placebo controlled trial. Pain. 1999;83:105-107.

55. Zakrzewska J, Chaudhry Z, Nurmikko TJ, Patton DW, Mullens EL. Lamotrigine (Lamictal) in refractory trigeminal neuralgia: results from a double-blind placebo controlled crossover trial. Pain. 1997;73:233-230.

56. Eisenberg E, Lurie Y, Braker C, Daoud D, Ishay A. Lamotrigine reduces painful diabetic neuropathy: a randomized, controlled study. Neurology. 2001;57:505-509.

57. Simpson DM, McArthur JC, Olney R, et al. Lamotrigine for HIV-associated painful sensory neuropathies: a placebo-controlled trial. Neurology. 2003;60:1508-1514.

58. Bonicalzi V, Canavero S, Gerutti F, Piazza M, Clemente M, Chió. Lamotrigine reduces total postoperative analgesic requirement: a randomized double-blind, placebo-controlled pilot study. Surgery. 1997;122:567-570.

59. Webb J, Kamali F. Analgesic effects of lamotrigine and phenytoin on cold-induced pain: a crossover placebo-controlled study in healthy volunteers. Pain. 1998;76:357-363.

60. Vestergaard K, Andersen G, Gottrup H, Kristensen BT, Jensen TS. Lamotrigine for central poststroke pain: a randomized controlled trial. Neurology. 2001;56:184-190.

61. Asnis G, Bowden C, Calabrese J, Sachs G, Bentley B, Leadbetter R. Safety and tolerability of lamotrigine in bipolar I disorder. Poster presented at: Annual Meeting of the New Clinical Drug Evaluation Unit; May 27-30, 2003. Boca Raton, FL.

62. Ettinger AB, Weisbrot DM, Saracco J, Dhoon A, Kanner A, Devinsky O. Positive and negative psychotropic effects of lamotrigine in patients with epilepsy and mental retardation. Epilepsia. 1998;39:874-877.

63. Beran RG, Gibson RJ. Aggressive behaviour in intellectually challenged patients with epilepsy treated with lamotrigine. Epilepsia. 1998;39:280-282.

64. Sotero de Menezes, MA, Rho JM, Murphy P, Cheyette S. Lamotrigine-induced tic disorder: report of five pediatric cases. Epilepsia. 2000;41:862-867.

65. Lombroso CT. Lamotrigine-induced tourettism. Neurology. 1999;52:1191-1194.

66. Margolese HC, Beauclair L, Szkrumelak N, Chouinard G. Hypomania induced by adjunctive lamotrigine. Am J Psychiatry. 2003;160:183-184.

67. Meador KJ, Loring DW, Ray PG, et al. Differential cognitive and behavioral effects of carbamazepine and lamotrigine. Neurology. 2001;56:1177-1182.

68. Overstreet K, Costanza C, Behling C, Hassanin T, Masliah E. Fatal progressive hepatic necrosis associated with lamotrigine treatment: a case report and literature review. Dig Dis Sci. 2002;47:1921-1925.

69. Sauvé G, Bresson-Hadni S, Prost P, et al. Acute hepatitis after lamotrigine administration. Dig Dis Sci. 2000;45:1874-1877.

70. Esfahani FE, Dasheiff RM. Anemia associated with lamotrigine. Neurology. 1997;49:306-307.

71. Solvason HB. Agranulocytosis associated with lamotrigine [letter]. Am J Psychiatry. 2000;157:1704.

72. Fadul CE, Meyer LP, Jobst BC, Cornell CJ, Lewis LD. Agranulocytosis associated with lamotrigine in a patient with low-grade glioma. Epilepsia. 2002;43:199-200.

73. Isojärvi JIT, Rättyä J, Myllylä VV, et al. Valproate, lamotrigine, and insulin-mediated risks in women with epilepsy. Ann Neurol. 1998;43:446-451.

74. Stephen LJ, Kwan P, Shapiro D, Dominiczak M, Brodie MJ. Hormone profiles in young adults with epilepsy treated with sodium valproate or lamotrigine monotherapy. Epilepsia. 2001;42:1002-1006.

75. Morrell MJ, Isojärvi J, Taylor AE, et al. Higher androgens and weight gain with valproate compared with lamotrigine for epilepsy. Epilepsy Res. 2003;54:189-199.

76. Røste LS, Taubøll E, Berner A, Isojärvi JIT, Gjerstad L. Valproate, but not lamotrigine, induces ovarian morphological changes in Wistar rats. Exp Toxic Pathol. 2001;52:545-552.

77. Biton V. Effect of antiepileptic drugs on bodyweight: overview and clinical implications for the treatment of epilepsy. CNS Drugs. 2003;17:781-791.

78. Devinsky O, Vuong A, Hammer A, Barrett PS. Stable weight during lamotrigine therapy: a review of 32 studies. Neurology. 2000;54:973-975.

79. Biton V, Mirza W, Montouris G, Vuong A, Hammer AE, Barrett PS. Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy. Neurology. 2001;56:172-177.

80. Ginsberg LD, Bowden CL, Calabrese JR, Sachs GS, Ketter TA. Effects of mood stabilizers on body weight in bipolar I disorder. In: 156th Annual Meeting New Research Abstracts. San Francisco, Calif: American Psychiatric Association; 2003;173-174. NR463.

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82. O’Donnell J, Bateman DN. Lamotrigine overdoes in an adult. Clin Toxicol. 2000;38:659-660.

83. Gelisse Ph, Kissani N, Crespel A, Jafari H, Baldy-Moulinier M. Is there a lamotrigine withdrawal syndrome? Acta Neurol Scand. 2002;105:232-234.

84. Tennis P, Eldridge RR. Preliminary results on pregnancy outcomes in women using lamotrigine. Epilepsia. 2002;43:1161-1167.

85. Chaudron LH, Jefferson JW. Mood stabilizers during breastfeeding: a review. J Clin Psychiatry. 2000;61:79-90.

86. Labiner DM. Lamotrigine and rash: scratching beneath the surface. J Clin Psychiatry. 2002;63:1010-1011.

87. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med. 1994;331:1272-1285.

88. Besag FMC. Approaches to reducing the incidence of lamotrigine-induced rash. CNS Drugs. 2000;13:21-33.

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90. Wong ICK, Mawer GE, Sander JW. Factors influencing the incidence of lamotrigine-related skin rash. Ann Pharmacother. 1999;33:1037-1042.

91. Schlienger RG, Shapiro LE, Shear NH. Lamotrigine-induced severe cutaneous adverse reactions. Epilepsia. 1998;39:522-526.

92. Shepherd GM. Hypersensitivity reactions to drugs: evaluation and management. Mt Sinai J Med. 2003;70:113-125.

93. Calabrese JR, Sullivan JR, Bowden CL, et al. Rash in multicenter trials of lamotrigine in mood disorders: clinical relevance and management. J Clin Psychiatry. 2002;63:1012-1019.

94. Lardizabal DV, Morris HH, Hovinga CA, Del Mar Carreña M. Tolerability and pharmacokinetics of oral loading with lamotrigine in epilepsy monitoring units. Epilepsia. 2003;44:536-539.

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96. Ruble J, Matsuo F. Anticonvulsant-induced cutaneous reactions: incidence, mechanisms and management. CNS Drugs. 1999;12:215-236.

97. Liston HL, Markowitz JS, DeVane CL. Drug glucuronidation in clinical psychopharmacology. J Clin Psychopharmacol. 2001;21:500-515.

98. de Leon J. Glucuronidation enzymes, genes and psychiatry. Int J Neuropsychopharmacol. 2003;6:57-72.

99. Kanner AM, Frey M. Adding valproate to lamotrigine: a study of their pharmacokinetic interaction. Neurology. 2000;55:588-591.

100. Anderson GD, Yau MK, Gidal BE, et al. Bidirectional interaction of valproate and lamotrigine in healthy subjects. Clin Pharmacol Ther. 1996;60:145-156.

101. Hennessy MJ, Wiles CM. Lamotrigine encephalopathy [letter]. Lancet. 1996;347:347-348.

102. Kaufman KR, Gerner R. Lamotrigine toxicity secondary to sertraline. Seizure. 1998;7:163-165.

103. Besag FMC, Berry DJ, Pool F. Methsuximide lowers lamotrigine blood levels: a pharmacokinetic antiepileptic drug interaction. Epilepsia. 2000;41:624-627.

104. Ebert U, Thong NQ, Oertel R, Kirch W. Effects of rifampicin and cimetidine on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects. Eur J Clin Pharmacol. 2000;56:299-304.

105. May TW, Rambeck B, Jurgens U. Influence of oxcarbazepine and methsuximide on lamotrigine concentrations in epileptic patients with and without valproic acid comedication: results of a retrospective study. Ther Drug Monit. 1999;21:175-181.

106. Sabeers A, Öhman I, Christensen J, Tomson T. Oral contraceptives reduce lamotrigine plasma levels. Neurology. 2003;61:570-571.

107. Anderson GD, Gidal BE, Messenheimer JA, Gilliam FG. Time course of lamotrigine de-induction: impact of step-wise withdrawal of carbamazepine or phenytoin. Epilepsy Res. 2002;49:211-217.

108. Doose DR, Brodie MJ, Wilson EA, et al. Topiramate and lamotrigine pharmacokinetics during repetitive monotherapy and combination therapy in epilepsy patients. Epilepsia. 2003;44:917-922.

109. May TW, Rambeck B, Jurgens U. Serum concentrations of levetiracetam in epileptic patients: the influence of dose and co-medication. Ther Drug Monit. 2003;25:690-699.

110. Mataringa M-I, May TW, Rambeck B. Does lamotrigine influence valproate concentrations? Ther Drug Monit. 2002;24:631-636.

111. Gidal BE, Rutecki P, Shaw R, Maly MM, Collins DM, Pitterle ME. Effect of lamotrigine on carbamazepine expoxide/carbamazepine serum concentration ratios in adult patients with epilepsy. Epilepsy Res. 1997;28:207-211.

112. Chen C, Veronese L, Yin Y. The effects of lamotrigine on the pharmacokinetics of lithium. Br J Clin Pharmacol. 2000;50:193-195.

113. Kossen M, Selten JP, Kahn RS. Elevated clozapine plasma level with lamotrigine [letter]. Am J Psychiatry. 2001;158:1930.

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