Journal of Affective Disorders 115 (2009) 241 – 245

www.elsevier.com/locate/jad

Brief report
Lamotrigine in bipolar disorder: Results of a mirror-image evaluation
using the NIMH Lifechart-Methodology ☆
C. Born a,⁎, B. Bernhard a , S. Dittmann a , F. Seemüller a , H. Grunze a,b
a
Department of Psychiatry, Ludwig Maximilians-University, Nußbaumstr. 7, D-80336, Munich, Germany
b
School of Neurology, Neurobiology and Psychiatry, Newcastle University, Leazes Wing, Royal Victoria Infirmary, Queen Victoria Road,
Newcastle upon Tyne NE1 4LP, Tyne and Wear, United Kingdom

Received 9 December 2007; received in revised form 18 July 2008; accepted 19 July 2008
Available online 5 September 2008

Abstract

Background: Lamotrigine (LTG) is characterized by prophylactic efficacy against bipolar depression (BPD). We evaluated retro-
and prospectively the naturalistic treatment outcome with LTG analysing lifecharts of patients from the bipolar outpatient clinic.
Methods: Lifechart-data of 20 patients routinely treated with LTG for the first time were evaluated, comparing number and duration
of manic, depressive and mixed episodes prior to LTG and after initiation of treatment (mirror-image evaluation). The mean
prospective evaluation period based on the lifechart was 18.1 months. Also we compared the number and severity of “switches”
from depression in mania. Additionally, CGI-BP, YMRS, IDS-C and GAF scores at the monthly visits were compared for time after
LTG initiation.
Results: We found no significant differences in the absolute number of manic, depressive and mixed episodes, respectively, before
and after initiation of LTG. The number of “switches” did not differ significantly. A significant difference in duration of time
patients suffered from a depressive state before and after initiation of LTG was observed in favour of LTG treatment (p = .006). A
similar finding was observed for the time spent in mixed episodes (p b .001). No significant difference was observed for scores of
mood scales at the monthly visits (CGI-BP, YMRS, IDS-C, GAF).
Limitations: Generalizability of these results is limited due to the uncontrolled design and the issues in comparing prospective and
retrospective data.
Conclusion: These data underline not only the antidepressant profile of LTG, but also the usefulness of the Lifechart-Methodology
(LCM) in the evaluation of treatment outcome under routine conditions.
© 2008 Elsevier B.V. All rights reserved.

Keywords: Bipolar disorder; Mania; Depression; Lamotrigine; Lifechart-Methodology

☆
The work has been supported by the Stanley Medical Research
Institute.
⁎ Corresponding author. Department of Psychiatry, LMU Munich,
Nußbaumstr. 7, 80336 Munich, Germany. Tel.: +49 89 5160 5712;
fax: +49 89 5160 5718.
E-mail address: christoph.born@med.uni-muenchen.de (C. Born).
0165-0327/$ - see front matter © 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jad.2008.07.020
1. Introduction
Lamotrigine (LTG) belongs to the so-called new
generation of anticonvulsant drugs (Muzina et al.,
2002). Its molecular mechanism of action partially
differs from that of other anticonvulsants (Calabrese
et al., 1998). First, it demonstrated efficacy in the
242 C. Born et al. / Journal of Affective Disorders 115 (2009) 241–245
treatment of partial complex seizures (Brodie et al.,
1995; Matsuo, 1999). More recent, LTG also showed
mood-stabilizing properties, observed first in the
treatment of patients with epilepsy (Smith et al.,
1993). The clinical profile is furthermore characterized
by activation, tending to yield alertness and potentially
antidepressant effects (Ketter et al., 2003; Smith et al.,
1993) as evaluated in many open and randomised
studies in psychiatric patients (Bowden et al., 2003;
Calabrese et al., 1998, 1999, 2000; Fatemi et al., 1997;
Ketter and Manji, 2003; Kusumakar and Yatham, 1997;
Walden et al., 1996). Distinguishing LTG from other
medications for bipolar disorders it has been labelled as
the first mood-stabilizer “from below” (Calabrese et al.,
2003; Ketter and Calabrese, 2002). LTG is now formally
approved in several countries for the prevention of
depressive episodes in bipolar disorders, in some
countries also for overall prevention of bipolar mood
episodes.
A general short-coming of controlled phase III studies,
however, is a selection bias of patients (Bowden et al.,
1995) not resembling “real-world” bipolar patients.
Therefore, we decided to evaluate post-hoc LTG “real-
world” efficacy analysing lifecharts of patients who were
treated for clinical reasons with LTG at the bipolar
outpatient clinic of the Department of Psychiatry at the
Ludwig Maximilians-University in Munich. All of these
patients also took part in the “Naturalistic follow-up
study” (Nfs) of the “Stanley Foundation Bipolar Net-
work” (SFBN) from 1999 to 2002 and performed
lifecharting as part of the protocol. More in detail, the
procedure of the Nfs and the lifechart method is described
elsewhere (Dittmann et al., 2002; Leverich et al., 2001).
Additionally, we compared the data of prospectively
monthly mood ratings with the Clinical Global Impres-
sion-Bipolar Version (CGI-BP; (Spearing et al., 1997),
Young Mania Rating Scale (YMRS; (Young et al., 1978),
Inventory of Depressive Symptoms-Clinician Version
(IDS-C; (Rush et al., 1986), and the Global Assessment of
Functioning Scale (GAF).
2. Patients and methods
A total of 128 patients were enrolled into the SFBN
Nfs in Munich between 1999 and 2002. 27 (19.9%) of
these patients were treated with LTG when they entered
the Nfs and started lifecharting. Because of lack of
lifechart-data 6 of the 27 patients were excluded from
this analysis and 1 patient was already treated with LTG
before inclusion into Nfs. We evaluated data of the
remaining 20 patients, who never received treatment
with LTG before. 9 (45%) of the 20 patients were
females. The mean age of patients was 40.4 years
(median 34; SD 14.4) at entry into the Nfs. 11 (55%)
were diagnosed as having bipolar-I-disorder and 9
(45%) as having bipolar-II-disorder according to DSM
IV criteria. For 6 (55%) of the patients with bipolar-I-
disorder the retrospective lifechart depicted a rapid-
cycling course in the year before study-entry and
treatment with LTG. Only 1 (11%) patient with
bipolar-II-disorder had a rapid-cycling course in the
year before study-entry. The individual observational
period was determined by the respective duration of the
prospective follow-up from LTG initiation to cessation
of LTG or lost- to follow-up. During the follow-up
period several of these patients had minor changes in
their additional psychotropic medication (mean 1.35
medication changes/patient). Seven patients had no
change and five patients had one change. Four patients
had two, two patients three and two patients had four
changes. Change of medication occurred mainly when
patients became symptomatic despite treatment with
LTG. 7 (35%) patients worsened and refused further
treatment with LTG.
We evaluated the data of these 20 patients by counting
number and duration of manic, depressive and mixed
episodes as well as rapid changes in mood (“switches”)
using the clinician form of the retrospective – before
initiation of LTG – and the prospective lifechart — after
initiation of LTG. Manic, depressive and mixed
episodes were defined according to the criteria of the
DSM IV in this evaluation of the lifechart. Mixed mood
states were marked as depressive and manic at the same
time. A “switch” was defined as a rapid and symptomatic
change of mood to an episode of the opposite state.
2.1. Statistical analysis
The scales extracted from the monthly routine visits
included the CGI-BP, YMRS, IDS-C, and the GAF. To
analyse the lifechart-data and the scores of these scales
we applied the “Last Observation Carried Forward-
Method” (LOCF). We used the chi-square test to test
categorical variables. The Fisher–Yates test, in case of
very small sample size, and the independent t test were
used for dimensional variables.
3. Results
All patients were treated with LTG for the first time.
The mean of maximum daily dosage was 288.8 mg/day
(median 275; SD 114.8; range 100–500) and the mean
for the total administered dosage was 236.8 mg/day
(median 232.5; SD 86.6). Including the taper-in time of
 C. Born et al. / Journal of Affective Disorders 115 (2009) 241–245 243

Table 1 different mode of collection of data (prospective vs.

Concomitant psychotropic medication. retrospective) as discussed later.
Anticonvulsants Antidepressants Antipsychotics Fig. 2 shows the results for mixed episodes and
and lithium “switches” from a manic to a depressive state and vice
Carbamazepine (2 pat.) Doxepine (1 pat.), Amisulprid (1 pat.) versa.
paroxetine (1 pat.) In general we observed only few mixed episodes.
Lithium (6 pat.) Citalopram (1 pat.), Clozapine (3 pat.)
The duration of mixed episodes was clearly reduced
reboxetine (1 pat.)
Topiramate (2 pat.) Fluoxetine (1 pat.), Olanzapine (3 pat.) after initiation of LTG and the difference compared
sertraline (1 pat.) to changes in manic episodes reached significance
Valproate (3 pat.) Fluvoxamine (1 pat.), Perazine (1 pat.) (p b .001). The reduction of time patients spent in a
thioridazine (1 pat.) mixed state reached also significance when compared to
Mirtazapine (4 pat.), Risperidone (3 pat.)
depressive episodes (p b .001) with a better outcome for
venlafaxine (3 pat.)
mixed episodes. When counting “switches” we noticed
Number of patients treated with each concomitant psychotropic
nearly no change at the end of follow-up.
medication during the follow-up is given in parenthesis.
Additionally, we compared the scores of the scales
prospectively applied at the monthly routine visits during
LTG we prospectively followed-up and evaluated LTG treatment. We found no significant differences of
lifechart-data for a mean of 543.7 days (median 354; the scores of these questionnaires at any time point. The
SD 410.5; range 131–1302 days), corresponding to a greatest, still not significant improvement was observed in
mean of 18.1 months (range 4.4–43.4). More specifi- the GAF with a mean of 65.1 points (median 60; SD 15.2)
cally, the treatment with LTG was followed-up in 6 at study-entry and a mean of 71.1 points (median 70; SD
(30%) patients b6 months, in 4 (20%) patients 6 to 21) at the end of follow-up. The mean score of the YMRS
12 months, in 2 (10%) patients 12 to 18 months, and in 8 was less than 10 points during LTG treatment, however,
(40%) patients 18 to 24 months. some patients had one-time scores up to 30 points
indicative of break-through mania. The mean score of the
3.1. Results from the lifechart IDS-C was less than 20 points at every visit, but some
patients had one-time scores up to 40 points indicative for
As shown in Table 1 the duration of depressive a new depressive episode. The mean score of the CGI-BP
episodes, but not for manic episodes was significantly was around 3 points (range 1–7) at every time point.
reduced after initiation of LTG (p = .006). There was Especially, there was no significant difference when
nearly no change in duration of manic episodes. comparing scores at entry into the study and at last visit of
Interestingly, the total number of episodes after initia- the follow-up period.
tion of LTG appeared to be twofold higher for both types At entry into the study the investigators described for 6
of mood episodes (see Fig. 1) without significant (30%) patients a euthymic state, for 9 (45%) patients a
difference between (sub)depressive and (hypo)manic depressive state, and for 4 (20%) patients a euphoric or
episodes. However, this may be an artefact due to the dysphoric state, while 1 (5%) patient was continuously

Fig. 1. Duration and number of (hypo-)manic and (sub-)depressive episodes. Episodes were counted and added before and after initiation of
lamotrigine using the “last-observation-carried-forward method" (based on n = 20 patients).
244 C. Born et al. / Journal of Affective Disorders 115 (2009) 241–245
Fig. 2. Duration and number of mixed episodes and “switches”. Total time spent in mixed epsisodes (months) and numbers of mixed episodes and
numbers of “switches” were counted and added up (based on n = 20 patients).
cycling. At the end of follow-up 11 (55%) patients were
categorized as euthymic, 5 (25%) depressed, and 4 (20%)
as euphoric or dysphoric manic. The relation of euthymic
to non-euthymic patients was significantly different com-
paring first and last visits, before and after LTG (p = .04).
7 (35%) patients discontinued treatment with LTG,
because of a depressive (n = 4; 57%) or a manic episode
(n = 3; 43%). These episodes were marked as long
lasting and high moderate to severe in terms of the
lifechart.
4. Discussion
Analysing lifecharts we compared retrospectively
number and duration of manic, depressive and mixed
episodes as well as number of “switches” before and
after initiation of LTG treatment. We found a significant
reduction in the duration of depressive and mixed
episodes, whereas there was no difference in duration of
manic episodes. In addition, there was a numerical, but
not significant difference in the absolute number of any
type of episodes before and after LTG treatment. The
number of “switches” was nearly the same. These results
are in line with the mild antidepressant effects of LTG as
described in controlled clinical trials (Bowden et al.,
2003; Calabrese et al., 1999; Frye et al., 2000).
Additionally, we compared the scores of the psycho-
metric scales routinely used at the monthly visits. We did
not observe any significant differences of the mean of
scores at any time point. However, from clinical obser-
vation, significantly more patients were categorized as
euthymic at the end of the follow-up. In addition to cross-
sectional investigations of bipolar illness with mood scales
for depressive and manic symptoms, there is an obvious
need to depict the longitudinal course of illness (Denicoff
et al., 2000). These longitudinal fluctuations of symptoms
are often missed when using only cross-sectional ratings.
The longitudinal course can be accurately depicted by the
lifechart method (Post et al., 1988). Daily self-ratings are
also essential to pick up recurrent brief episodes of de-
pression and hypomania (Angst et al., 1990, 1998). Re-
liability and validity of the clinician-rated lifechart has been
demonstrated in previous reports (Denicoff et al., 1997,
2000). However, studies based on lifechart-data are still
scarce. With this study, we applied this tool using a mirror-
image of retrospective and prospective lifecharts supplying
information on the clinical profile and potential usefulness
of LTG.
Nevertheless there are some limitations, comparing
retrospective and prospective lifecharts by a mirror-image
has obvious methodological limitations, which has to be
taken into account when interpreting these data. Drawing
a retrospective lifechart, the investigator interviews the
patient and relatives about his history and additionally
uses other sources of information, e.g., hospital reports
from the past. The patient might well not remember every
minor episode, especially subdepressive or hypomanic
phases. Secondly, the time pattern of retrospective
lifecharts is less subtle than of the prospective charts
and does not allow differentiating between single days.
This might contribute to the finding of non-significantly,
but numerically more manic and depressive episodes
during the prospective lifecharting while taking LTG.
Another limitation of this study, and inherited to its
naturalistic design, is clearly the fact the majority of
patients had changes in their co-medication during the
observational period. With the main burden of bipolar
disorder being depression, it can be assumed that a
continuous attempt to optimize other antidepressant
treatments may also have contributed to the reduction of
days spent in depressive mood. However, it is fair to
assume that this was not different before the initiation of
 C. Born et al. / Journal of Affective Disorders 115 (2009) 241–245
LTG, so that this covariant may be equally present
before and after initiation of LTG.
Role of the funding source
The Vada and Theodore Stanley Foundation sponsored the
Naturalistic follow-up study and our clinic took part as one of the
research centers.
The submitted article contains the evaluation of data collected in
Munich within this study. The cohort is part of other evaluations. The
Stanley Foundation had no further role in the writing of the report and
in the decision to submit the paper for publication.
Conflict of interest
All authors acknowledge that they have received direct or indirect
funding from the Vada and Theodore Stanley Foundation.
Heinz Grunze and Sandra Dittmann have received travel support
and honoraria for presentations and/or written materials from
GlaxoSmithKline in the past.
Heinz Grunze also supplied services as a paid consultant to
GlaxoSmithKline in the past.
Acknowledgement
We gratefully acknowledge the support of the Vada
and Theodore Stanley Foundation.
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