Journal of Clinical Neuroscience 20 (2013) 1316

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Journal of Clinical Neuroscience

journal homepage: www.elsevier.com/locate/jocn

Review

Lamotrigine in epilepsy, pregnancy and psychiatry a drug for all seasons?

Frank J.E. Vajda a,, Seetal Dodd b,c, David Horgan b
a
Departments of Neuroscience and Medicine, University of Melbourne, Royal Melbourne Hospital, Grattan Street, Parkville 3050, Victoria, Australia
b
Department of Psychiatry, University of Melbourne, Parkville, Victoria, Australia
c
School of Medicine, Deakin University, Geelong, Victoria, Australia

a r t i c l e i n f o a b s t r a c t

Article history: Lamotrigine has been demonstrated to be effective as both an antiepileptic drug and a mood stabiliser.
Received 16 May 2012 For epilepsy it is less efcacious than valproate in primary generalised epilepsy, but it is comparable
Accepted 19 May 2012 to some traditional drugs in partial epilepsy. In psychiatry it has signicant advantages over other mood
stabilisers for the treatment and prevention of depressive phases of bipolar illness, but not for the treat-
ment of mania. It has a more benign adverse effect prole than older antiepileptic agents and is not a pro-
Keywords: ven teratogen. Risk of adverse reactions is reduced by commencing treatment at a markedly reduced dose
Epilepsy
that is gradually increased.
Lamotrigine
Pregnancy
2012 Elsevier Ltd. All rights reserved.
Psychiatric indications

1. Introduction around 3 lg/mg with no signicant adverse events. Subsequent

Lamotrigine (LTG) is both an antiepileptic drug (AED) and a
mood stabiliser. Since the 1980s it has evolved from being a second
line drug against partial seizures to a major AED in monotherapy,
for primary generalised as well as partial epilepsy. Later it was tar-
geted particularly at women and claimed to be ideal for women
with epilepsy in pregnancy. More recently it has been used as a
mood stabiliser, advocated as an alternative to valproate (VPA) or
lithium in bipolar disorders, especially for those patients whose ill-
ness has a predominantly depressive pole.
Lamotrigine is the product of Wellcome Research Laboratories
(Beckenham, Kent, England). The cost of its development was re-
puted to be a fraction of the cost of vigabatrine, which was devel-
oped somewhat earlier, but which was plagued by problems of
suspected demyelination in animal models.
The mechanism of action of LTG was initially thought to be re-
lated to the suggestion that folate was a proconvulsant, and LTG
was synthesised as one of a sequence of folic acid antagonists.
However, LTG acts mainly by inhibiting excitatory amino acid re-
lease and hence stabilising neuronal membranes via voltage-sensi-
tive sodium channels.1,2 The clinical pharmacology of LTG was
reported by AW Peck, a member of the team of Wellcome scientists
who developed the drug.3
The pharmacokinetics and pharmacodynamics of LTG were
studied in healthy volunteers. In an open dose-escalating study,
an LTG dose of 240 mg produced peak plasma concentrations of
Corresponding author. Fax: +61 3 9819 3056.
E-mail address: vajda@netspace.net.au (F.J.E. Vajda).
pharmacokinetic studies revealed complete oral absorption, rst-
order kinetics with a mean half-life of approximately 1 day, and
an elimination pathway mainly as a glucuronide in the urine.
Early studies in patients with epilepsy revealed more rapid
metabolism when given with enzyme-inducing AED and delayed
metabolism by VPA. These studies have shown LTG to have desir-
able and predictable pharmacokinetic properties. Pharmacody-
namic effects were absent, suggesting a high therapeutic index.
The glucuronidation pathway for LTG uses the same enzyme
system as phenytoin; hence, in combination with phenytoin, the
doses of LTG need to be raised, but in the presence of VPA, doses
need to be lowered.
2. Use in epilepsy
2.1. Early clinical and regulatory trials
The acute effects of LTG in persons with epilepsy were reported
by Binnie.4 Sixteen patients took single doses of LTG, 120 mg or
240 mg. Six photosensitive patients showed reduction (with aboli-
tion in two) in photosensitivity and ve patients with frequent
interictal spikes showed reduction in spike frequency during
24 hours after LTG administration. The half-life (t1/2) of LTG in sub-
jects taking sodium valproate was prolonged, whereas the t1/2 in
patients taking carbamazepine and/or phenytoin was reduced.
In Australia LTG was approved at the same time as vigabatrin.
Because of the greater efcacy of the latter, its reimbursement
was to be higher than for LTG, but this did not take account of
the better safety prole of LTG. Consequently the approval terms

0967-5868/$ - see front matter 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jocn.2012.05.024
14 F.J.E. Vajda et al. / Journal of Clinical Neuroscience 20 (2013) 1316
were changed after adverse effects related to vigabatrin were taken
into account.
Placebo-controlled clinical trials have demonstrated the efcacy
of LTG in patients with refractory partial seizures.59 In these trials
20% to 30% of patients achieved a 50% reduction in seizures.10
Anecdotal reports, case studies, uncontrolled studies,1113 and a pi-
lot study in juvenile myoclonic epilepsy provided support for the
efcacy of LTG in primary generalised epilepsy14 and one clinical
trial showed its efcacy in the Lennox Gastaut syndrome.15 The
limitations of many of these trials were that seizure efcacy rather
than a syndromic diagnosis of epilepsy was the basis of selection
and assessment.
The rst placebo-controlled clinical trial in patients with refrac-
tory generalised epilepsy was carried out in Australia, reported in
Epilepsia by Beran et al.10 This study used LTG as add-on therapy
in patients, all of whom received VPA. It demonstrated that LTG
was effective in controlling both absence and tonicclonic seizures
in patients with primary generalised epilepsy, refractory to treat-
ment with VPA monotherapy.
Subsequently Brodie and Yuen carried out the rst rigorously
controlled trial on the synergism to highlight the pharmacody-
namic as well as pharmacokinetic interaction between LTG and
VPA.16 A total of 347 patients whose epilepsy was not fully con-
trolled with VPA, carbamazepine, phenytoin or phenobarbital
monotherapy, were recruited into a LTG substitution study. The
addition of LTG to VPA (64% responders) produced a signicantly
better response (p < 0.001) than adding it to other drugs; this effect
was seen for partial as well as tonicclonic seizures. These data
demonstrated a therapeutic synergy between LTG and VPA.
Although the regulatory clinical trial data of LTG suggested an
excellent efcacy of about 50% reduction of seizures in two-
thirds of patients, this measure does not translate accurately in
clinical practice where seizure freedom is required. LTG pro-
vided seizure freedom in about 4% of patients, which was com-
parable to other drugs in a population of people with refractory
epilepsy already treated by a minimum of two drugs before
entering the trials.
2.2. Interactions
Lamotrigine may interact with other drugs. Phenytoin, carbam-
azepine, oxcarbazepine and olanzapine increase the metabolism of
LTG, resulting in reduced serum levels, whereas VPA, sertraline and
uoxetine inhibit its metabolism, resulting in raised serum
levels.17
2.3. Comparative clinical trials
In order to assess the comparative efcacy of LTG compared to
traditional and second-generation AED, two major studies were
performed.18,19 The SANAD study of the effectiveness of carbamaz-
epine, gabapentin, LTG, oxcarbazepine, or topiramate for treatment
of partial epilepsy was an unblinded randomised controlled trial
aimed to assess efcacy of LTG with regard to longer-term out-
comes, quality of life, and health economic outcomes compared
to the new AED. This study recruited 1721 patients for whom car-
bamazepine was deemed to be standard treatment, and they were
randomly assigned to receive the above-mentioned drugs. Primary
outcomes were time to treatment failure, and time to 12-month
remission, and assessment was by both intention to treat and per
protocol.19 Interpretation of this study indicated that LTG was clin-
ically better than carbamazepine, the standard drug treatment, for
time-to-treatment failure outcomes and was therefore deemed to
be a cost-effective alternative for patients diagnosed with partial
onset seizures.
The second SANAD study compared the long-term effectiveness
of VPA, LTG and topiramate in patients with generalised onset sei-
zures or seizures that were difcult to classify.18 This trial recruited
716 patients for whom VPA was considered to be the standard
treatment. Patients were randomly assigned to VPA, LTG or topira-
mate. Primary outcomes were time-to-treatment failure, and time-
to-1-year remission. Analysis was by both intention to treat and
per protocol. The interpretation of this study was that VPA was
better tolerated than topiramate and more efcacious than LTG,
and should remain the drug of rst choice for many patients with
generalised and unclassied epilepsies. However, because of the
known potential adverse effects of VPA during pregnancy, the ben-
ets for seizure control in women of childbearing years should be
considered.
The limitations of LTG in treatment of epilepsy are due to its rel-
atively modest efcacy compared to VPA in primary generalised
epilepsy, but it is comparable to the traditional drugs in partial
epilepsy.
3. The role of LTG in psychiatry
LTG is a relatively new drug in psychiatry, originally developed
as an anticonvulsant with a favourable adverse effect prole com-
pared to phenytoin.20 Early clinical trials showed that LTG had a
benecial effect on mood.9 The limitations of LTG in psychiatry
are not yet fully ascertained and its capacity to make patients
euthymic, rst noted 20 years ago, may render it useful as a mood
stabiliser.21 By the middle to late 1990s the efcacy of LTG as a
treatment for bipolar disorder had been established.2225
LTG is indicated for the maintenance treatment for bipolar dis-
order in people aged 18 years and over.26 LTG demonstrates ef-
cacy in bipolar maintenance treatment to prevent relapse to both
depressive and manic phases27; however, it is less effective than
lithium for preventing mania during maintenance treatment.28
Although off indication, there is evidence of treatment efcacy of
LTG for acute bipolar depressive episodes,25,29 refractory bipolar
disorder30 and as an augmentation agent for treatment resistant
unipolar depression.31,32 LTG is superior to placebo for the treat-
ment of rapid cycling bipolar disorder.33 There is little evidence
for efcacy of LTG to treat acute manic episodes.34 Compared to
other mood stabilisers, LTG is often better tolerated. In randomised
clinical trials it has been associated with fewer adverse effects than
lithium.35
LTG has been investigated for other psychiatric disorders with
mixed results. A study of 28 patients with borderline personality
disorder suggested that LTG may reduce impulsivity associated
with this disorder.36 A separate study demonstrated that it may re-
duce aggression in women with borderline personality disorder.37
A study of patients with schizophrenia receiving antipsychotic
treatment did not benet from conjunctive treatment with LTG.38
LTG did not differ from placebo for the treatment of binge eating
with obesity,39 cocaine dependence40 and autistic disorder.41 LTG
is superior to placebo for the treatment of depersonalization disor-
ders42 and post-traumatic stress disorder.43
In clinical psychiatric practice, there is an increasing emphasis
on bipolar illness and the use of mood stabilisers. Lithium is less
widely used than previously, due to concerns about its true ef-
cacy, the possibility of permanent renal problems, and its known
teratogenesis. Second-generation antipsychotics have problems
of weight gain and sedation, as well as cost restrictions. VPA
has problems of sedation, weight gain, alopecia and the polycys-
tic ovary (PCO) syndrome. Carbamazepine can inactivate oral
contraceptives and other agents by enzyme induction. LTG pre-
sents an attractive therapeutic alternative option. It is not gener-
ally associated with the above side-effects, except the association
 F.J.E. Vajda et al. / Journal of Clinical Neuroscience 20 (2013) 1316
with a possible severe rash on rapid introduction. The presence
of signicantly fewer side-effects is an important consideration
when we seek patient compliance.
4. Women and pregnancy
A relatively early phase in marketing of this drug was focussed
on women in childbearing age and pregnancy. Teratogenesis is an
ever-present spectre in women of childbearing age. VPA and car-
bamazepine have been widely used as mood stabilisers and AED,
but with grave apprehensions among informed doctors and pa-
tients about teratogenesis. There is concern that the risks associ-
ated with VPA, especially in high dose, are not reected in
prescribing patterns by some non-neurologists.44 The International
Registry of Antiepileptic Drugs and Pregnancy (EURAP) study45 of
more than 4000 pregnancies showed that LTG at doses up to
300 mg daily had the lowest rate of fetal malformations of the
commonly used AED. LTG was marketed as the anticonvulsant
drug ideal for pregnancy, claiming to be equally effective to VPA
and free from causing foetal malformations.
This hope was only partly realised. LTG appears free of causing
signicant malformations, and has not been shown to affect cogni-
tive development of the foetus, but it appears to be less effective
for the treatment of epilepsy than VPA in pregnancy, as well as
in monotherapy in general.46 There are Issues such as the induction
of the elimination of LTG by the oral contraceptive pill, and resul-
tant loss of effectiveness. Doses of LTG are to be raised routinely in
each trimester to counter this effect, and requiring dose reduction
after delivery. This makes it a complex drug to use in pregnancy.
The main problem with the use of LTG is the slow introductory
dose schedule, which is necessary to prevent serious, occasionally
catastrophic, adverse effects. This requires 8 weeks to elapse before
a stable starting dose is reached. Trying to replace VPA with LTG in
the rst trimester of an established pregnancy leaves the change-
over too late to inuence foetal development that occurs in the rst
trimester. Introductory dose schedules evolved after some disas-
ters were noted on rapid introduction, especially in presence of
VPA. A slow introduction regimen with LTG may start with doses
of 12.5 mg on alternate days, for 2 weeks, then progressively dou-
bled each week, until 200 mg per day has been reached.
The value of serum level measurements of anticonvulsants is
controversial.47 Most practitioners do not measure serum LTG lev-
els. An exception may be advised in the case of pregnancy where
these measurements may aid the stabilisition of protective levels
attained by a given LTG dose, adjusted in each term. Methods of as-
say for plasma levels are available.48
The limitations of LTG use in pregnancy are a relative lack of
efcacy in epilepsy, changes in dose requirements which require
adjustments and the fact that slow introduction fails to provide
seizure protection in the critical period of the rst trimester. LTG
toxicity may be expected following delivery if the dose of LTG is
not reduced to pre-pregnancy levels. The clinical manifestations
are nystagmus, ataxia, mental obtundation, slurred speech, nausea
and malaise. Alternative second-generation drugs are not more ter-
atogenic than the older ones, but LTG is not regarded a signicant
teratogenic AED.49
As regards lactation, human milk is not simply a food. Rather, it is
a complex, sophisticated, and highly integrated human infant sup-
port system that provides the infant with protection, information,
and nutrition. The ability of lactation to provide this support to the
infant results from its provision of both non-nutritive and food/
nutritive components.50 LTG is excreted in considerable amounts
into breast milk. Early reports show that most full-term babies seem
to have little problem with breastfeeding, but close monitoring for
toxicity, especially in small or preterm babies, is advised.51
15
4.1. Safety concerns
The most notable safety concern with LTG is rash. A benign rash
can occur in approximately 10% of patients and a serious rash in
0.1% of patients.35,52 The rash can resolve with discontinuation of
LTG.53 Instances of StevensJohnson syndrome or toxic epidermal
necrolysis may be life threatening, but are very rare. The Ste-
vensJohnson syndrome and lesser degrees of erythema multi-
forme exudativa manifest as a severe rash and exudation
affecting skin and mucous membranes. This may be fatal. Low dose
introduction of LTG, and slow escalation lowers the risks of this ad-
verse event markedly,1 especially if the patient is taking concomi-
tant VPA.
A case report of fatal hepatic necrosis has been documented.54
LTG is capable of producing new seizure types, but only in gen-
eralised epilepsy. It is also capable of aggravating myoclonus.5557
The development of PCO syndrome was reported from Finland
to be associated with the use of VPA, LTGs main competitor. VPA
may cause infertility, hyperinsulinism, hirsutism and menstrual
abnormalities. LTG was claimed to be free from this effect.58 The
PCO claim has been disputed and it appears that it is of multifacto-
rial causation, including a genetic susceptibility; VPA, however,
may inuence its development.59 LTG has also been reported from
Finland to have no effect on sperm count or motility in contrast to
other traditional AED, for example VPA, which were claimed to af-
fect sperm count, lower motility or cause increase in viscosity of
the spermatic uid. Although male fertility has been claimed to
be impaired by traditional AED, this claim is also controversial.60,61
4.2. Therapeutic range
LTG has no well-dened therapeutic range, and exhibits what
has been termed an individual therapeutic range (that is, it is
characteristic for each person taking the drug). This range is inu-
enced by numerous factors but it may serve as a marker to adjust
medication.62,63
5. Conicts of interest/Disclosures
F.J.E.V. received support for running the Australian Pregnancy
Register from The Royal Melbourne Hospital Neuroscience Founda-
tion, The Epilepsy Society of Australia, UCB, Sano, Novartis, Jans-
sen and Sci Gen.
S.D. has received grant/research support from the Stanley Med-
ical Research Institute, NHMRC, Beyond Blue, ARHRF, Simons Foun-
dation, Geelong Medical Research Foundation, Eli Lilly,
GlaxoSmithKline, Organon, Mayne Pharma and Servier, speakers
fees and advisory board fees from Eli Lilly and conference travel
support from Servier.
D.H. has received speaker fees, advisory board fees and travel
grants from multiple pharmaceutical companies.
Acknowledgment
We thank Janet Graham for her assistance.
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