Lamotrigine in bipolar affective disorder
Denise Duncan, Harry W. McConnell and David Taylor
Psychiatric Bulletin 1998, 22:630-632.
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DRUG INFORMATION QUARTERLY
Lamotrigine in bipolar affective
disorder
Denise Duncan, Harry W. McConnell and David Taylor
Aims and method The study aimed to assess the
available data on the use of lamotrigine as a mood
stabilising agent. We reviewed
all published and
unpublished data available to us through a Mediine
search from 1987-1998 and from our own files, which
include reference materials presented at conferences
as well as published reports.
Results Most of the data found were derived from
case reports or open trials. We could find no published
double-blind,
placebo-controlled
studies. The data
from initial open trials suggest that lamotrigine may be
effective
in bipolar disorder, but futher data are
required before specific treatment recommendations
can be made.
Clinical implications At this early stage, there are too
few data to recommend lamotrigine for first or second
line therapy in bipolar disorder. However, initial reports
are very promising and this agent may eventually be
unequivocally
shown to be useful in treating mania,
hypomania,
depression, rapid cycling and mixed
affective states in people with bipolar disorder.
Lamotrigine, an anticonvulsant. is licensed in the
UK as monotherapy for the treatment of partial
seizures and primary and secondary generalised
tonic-clonic seizures. It is believed to act by
inhibiting the release of excitatory neurotransmitters (glutamate and aspartate) by blocking
voltage-dependent sodium channels and by sta
bilising presynaptic neuronal membranes (McKee
& Brodie, 1996). It may also have effects on
calcium channels. As well as being useful in the
treatment of epilepsy, lamotrigine, like other
anticonvulsants,
has also been reported to be
useful in the treatment of refractory bipolar
disorder and rapid-cycling bipolar disorder. A
few reports of improvement in quality of life
measures when used in people with epilepsy
prompted the use of this drug in patients with
psychiatric illness. Data about its psychotropic
effects are, however, largely reported as case
histories and open trials and are discussed below.
Clinical studies
and case reports
In the first published case report, a 49-year-old
man with a long-standing history of rapid cycling
630
disorder presented while in the depressed phase
of his illness (Calabrese et al, 1996). The patient
had previously not responded to lithium and was
unable to tolerate carbamazepine.
Lamotrigine
was started at 25mg/day for two weeks and
increased to 200mg/day over five weeks. Over a
20-week period the patient's Hamilton Rating
Scale for Depression (HAM-D: Hamilton, 1960)
score fell from 46 to nine and his Global
Assessment Scale (GAS; Endicott, 1976) score
increased from 32 to 69. Eleven months later the
patient remained euthymic. The authors postu
lated that lamotrigine has antidepressant effects
and will not induce mania in patients with rapidcycling bipolar disorder.
In a case report where lamotrigine was added
to valproate therapy (Waiden et al, 1996), a 39year-old man presented while in the manic phase
of bipolar affective disorder. He had previously
been treated with various neuroleptics, antidepressants and lithium. He was admitted and
initially treated with neuroleptics. benzodiazepines and carbamazepine (1500mg/day). This
regimen proved to be ineffective and so the
carbamazepine was changed to valproate (up to
2700mg/day).
Some improvement was noted,
although a mixed dysmorphic
manic state
persisted. The patient was discharged on valpro
ate and 10 weeks later lamotrigine was added at
25mg twice a day which was slowly increased to
150 mg/day. The patient responded well.
In the following year. Kusumaker & Yatham
(1997a) described seven patients with rapidcycling bipolar disorder who were also treated
with lamotrigine. Six of these patients were newly
diagnosed and started on lamotrigine 25 mg twice
a day. This was increased to 50 mg twice a day
one week later and to 75 mg twice a day three
weeks later if required. Four patients responded:
all by the third week. The seventh patient (an
elderly woman) had an eight-year history and had
previously been treated with lithium, carbama
zepine and valproate (divalproex). She was most
recently taking valproate which controlled her
hypomania but not her depressive symptoms.
During a depressive episode lamotrigine was
started and symptoms resolved in a week. The
dose was not stated but the patient developed a
Psychiatric Bulletin (1998). 22. 630-632
DRUG INFORMATION QUARTERLY
rash four weeks later. Lamotrigine was discon
tinued but recommenced four days later and the
patient has remained well.
In the same year these same authors (Kusumaker & Yatham, 1997b) also reported on 22
patients with bipolar depression who had lamo
trigine added to their valproate therapy in an
open naturalistic setting. Sixteen of these pa
tients had a 50% or greater reduction in their
HAM-D score by week 6 and no patient switched
to mania.
Fogelson & Stembach (1997), have further
reported an open trial of lamotrigine in refractory
patients. Six patients had treatment-refractory
bipolar I disorder (four with rapid cycling) and one
patient had bipolar schizoaffective disorder. All
patients had failed an adequate trial of at least six
antidepressants, mood stabilisers or other combi
nations. Lamotrigine was given in maintenance
doses between 50 mg and 400 mg/day. in addition
to various other therapies
(carbamazepine.
lithium, acetazolamide, risperidone, dexamphetamine and trazodone). At eight-week follow-up,
three of the four rapid-cycling patients had
marked improvement (complete remission of
symptoms) and one showed no improvement and
discontinued at eight weeks because of nausea.
The bipolar schizoafTective patient did not respond
and the other two bipolar I patients had a
moderate response (significant amelioration of
symptoms). The longer-term outcome (i.e. be
tween 14 and 65 weeks) was less promising with
only two of the rapid-cycling patients sustaining a
marked improvement. One now showed a moder
ate response and only one of the bipolar I patients
still showed a moderate response.
Fatemi et al (1997) also studied the use of
lamotrigine, in a naturalistic
setting, in five
patients with treatment-resistant
rapid-cycling
bipolar disorder. Lamotrigine was given for a
mean of 225.8 days, either as monotherapy or as
add-on therapy (mean dose= 185mg/day). Data
were analysed using a random regression model.
Depressive symptoms and social functioning
improved in a dose- and time-dependent man
ner.
A retrospective study also recently reported the
outcome of 16 patients with bipolar disorder (13
bipolar 1. three bipolar II) not satisfactorily
controlled by standard mood stabilisers, who
had been treated with lamotrigine for a period of
2-6 weeks (mean five weeks) (Sporn & Sachs,
1997). At the beginning of treatment,
nine
patients were depressed, six were in a mixed
state and one was diagnosed with mania. Eight
patients were considered
to be responders
(Clinical Global Impressions scale (CGI: Guy,
1976)^2). Those who responded were either in
the depressed or mixed phase; all had an
improvement
in their depressive symptoms.
Unfortunately, two of the people with depression
Lamotrigine
in bipolar affective disorder
who did not respond switched to either mania or
a mixed state and one responder switched from a
mixed state to hypomania. The maximum dose of
lamotrigine
reached was between 50 and
250 mg/day with a mean dose of 141 mg/day
for responders.
In the most recent case report (Labbate &
Rubey, 1997), lamotrigine was given to a 48-yearold gentleman with treatment refractory bipolar
disorder (depressed phase). While remaining on
various psychotropics. he was started on 25 mg/
day which was increased to 500 mg/day over six
weeks. Treatment was considered successful
with improvement in his mood and allowing the
discontinuation of most of his psychotropics.
Preliminary data on two unpublished
trials
have recently been presented. Bowden et al (at
the American Psychiatric Association
151st
Annual Meeting, 1998: further details available
from the author upon request) has outlined the
results of a placebo-controlled
open trial. He
recruited from 21 centres in the US and Europe,
192 out-patients with bipolar I disorder who
were depressed on entry into the study. Lamo
trigine (200 mg/day) showed clear evidence of
antidepressant efficacy as assessed by the HAMD: with a lesser effect seen with 50 mg/day thus
suggesting a dose-related response. Calabrese
(at the American Psychiatric Association 151st
Annual Meeting, 1998: further details available
from the author upon request) also reported on
his unpublished 48-week open-label, prospective
trial of 75 treatment-refractory
patients. Of 41
people with depression
in this study, 68%
showed significant improvement. Of 31 presen
ting with a manic, mixed or hypomanic presen
tation. 84% improved.
Adverse
effects
Alongside these reports of the positive psychotropic effects, lamotrigine has also been asso
ciated with adverse psychiatric effects. Delirium
has been described in one case report of a 39year-old woman when the lamotrigine dose was
increased to 150 mg/day, resolving when the dose
was lowered to 100 mg/day (Sporn & Sachs.
1997). She had been given lamotrigine in combi
nation with lithium because of a history of mood
elevation and depression which had previously
not responded well to lithium, cabamazepine,
clonazepam and valproate. Encephalopathy has
also been described in another recent case report
(Hennessey & Wiles, 1996). Apart from 'switching'
into mania (described above), other adverse
psychiatric effects reported in people with epi
lepsy include aggression, confusion, depression
and psychosis, although a causal effect has not
been established (McKee & Brodie. 1996).
631
DRUG INFORMATION QUARTERLY
The rash associated with lamotrigine has
received a great deal of media attention in recent
months because of the potential of developing
Stevens-Johnson
syndrome, toxic epidermal
necrolysis and angiooedema. Predisposing fac
tors include age (more common in childhood),
concomitant valproate therapy and rapid titration. Other common adverse effects include
headache, nausea, vomiting, diplopia and dizzi
ness. Hepatic dysfunction and blood dyscrasias
may also occur less commonly.
At this early stage it appears that lamotrigine
may be useful in bipolar patients with depressive
symptoms as well as those with hypomania,
mania, mixed states or rapid cycling. More
formalised, randomised
controlled trials are
needed. If lamotrigine is to be used, it should
be started at doses recommended in epilepsy by
the manufacturer
and increased according to
instructions.
It should be noted that these
recommendations are more cautious than many
of the regimens described here.
FOGELSON, D. L. & STERNBACH.H. (1997) Lamotrigine
treatment
of refractory
bipolar
disorder
(letter).
Journal of Clinical Psychiatry. 58. 271-273.
GUY. W. (ed.) (1976) ECDEU Assessment
manual for
psychopharmacology:
Publication
ADM 76-338.
pp. 217-222. Rockville. MD: US Department of Health.
Education and Welfare.
HAMILTON,M. (1960) A rating scale for depression. Journal
of Neurology. J.Neurosurgery
Psychiatry.
23. 56-62.
HENNESSEY.M.
& WILES, and
C. M.
(1996)' Lamotrigine
encephalopathy
(letter). Lancet. 347, 974-975.
KUSUMAKAR,V. & YATHAM,L. N. (1997a) Lamotrigine
treatment
of rapid cycling bipolar disorder (letter).
American Journal of Psychiatry. 154. 1171-1172.
—¿& —¿(1997b) An open study of lamotrigine in refractory
bipolar depression. Psychiatry Research. 72. 145-148.
LABBATE,L. A. & RUBEY, R. N. (1997) lamotrigine
for
treatment-refractory
bipolar disorder (letter). American
Journal of Psychiatry, 154. 1317.
McKEE. P. J. W. & BRODIE.M. J. (1996) Lamotrigine. In The
Treatment of Epilepsy (eds S. Shorvon. F. Dreifuss & D.
Fish), pp438-443.
Oxford: Blackwell Science.
SPORN.J. & SACHS.G. (1997) The anticonvulsant lamotrigine
in treatment-resistant
manic-depressive
illness. Journal
of Clinical Psychopharmacology.
17. 185-189.
WALDEN.J., HESSLINGER.B. & VAN CAI.KER. D. (1996)
Addition of lamotrigine
to valproate may enhance
efficacy in the treatment of bipolar affective disorder.
Pharmacopsychiatry. 29. 193-195.
References
CALABRESE.J. R.. FATEMI.S. H. & WOYSHVILLE.
M. J. (1996)
Antidepressant
effects of lamotrigine in rapid cycling
bipolar disorder (letter). American Journal of Psychiatry.
153. 1236.
ENDICOTT.J.. SPITZER.R. L.. FLEISS.J. L., et al (1976) The
Global Assessment Scale: a procedure for measuring
overall severity of psychiatric disturbance.
Archives of
General Psi/chiatn/. 33. 766-771.
FATEMI.S. H.. RAPPORT.D. J.. CALABRESE.
J. R., et al (1997)
Lamotrigine in rapid-cycling bipolar disorder. Journal of
Clinical Psychiatry. 58. 522-527.
CR65
•¿ DeniseDuncan,
Senior Drug Information
Pharmacist. Maudsley Hospital. Denmark Hill,
London SES 8AZ: Harry W. McConnell, Neurology
Research Fellow, Institute of Psychiatry, London
and David Taylor, Chief Pharmacist. Maudsley
Hospital. London
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632
Duncan et al