Key words
lamotrigine - therapeutic levels - mood disorders
Introduction
Lamotrigine has a modest but significant antidepressant effect [1]
[2]
[3]
[4] and a prophylactic effect particularly for depressive relapse in bipolar disorders
[5]
[6]
[7]. The number needed to treat for prevention of any mood episode was calculated as
5–11 [8]. However, given the negative trial of manic state and the length of time for titration
up to a therapeutic dose, lamotrigine is not indicated for the acute treatment of
mania [9]. Therefore, lamotrigine has a different therapeutic profile compared to other mood
stabilizers such as lithium, valproate and carbamazepine.
Although therapeutic drug monitoring (TDM) of lamotrigine for epilepsy is recommended
and the therapeutic levels are reported to be 3–14 μg/mL [10], so far, no specific reference range has been reported for mood stabilizing effects
of lamotrigine [10]. In the present study, we hypothesized that lamotrigine may have a therapeutic window
for mood disorders.
Patients and Methods
This is a naturalistic and retrospective study. In April 2013, we identified 25 patients
who suffered from mood disorders, received lamotrigine for more than one year, and
measured plasma lamotrigine levels at least once. First, their mental state was retrospectively
and as regularly as possible assessed at 1 month before, just before, 1, 3, 6, 12
months after starting lamotrigine, and thereafter at 18, 24, 30, 36, 42, and 48 months
until its discontinuation. The assessment was performed using each patient’s clinical
records close to the above scheduled months by a blinded researcher (i. e., Y.K. showed
the anonymous clinical records without stating the dates to T.T. who assessed the
mental state independently and blindly) using Clinical Global Impression – Severity
scale (1=normal, 2=borderline mentally ill, 3=mildly ill, 4=moderately ill, 5=markedly
ill, 6=severely ill, 7=the most extremely ill [11]. Secondly, Y.K. identified the last lamotrigine levels on or close to the date
when the last clinical records were described for the aforementioned retrospective
CGI-S assessment. If the day of measuring lamotrigine and the date when the clinical
records for the CGI-S assessment were described were different, the difference was
permitted if lamotrigine dose was unchanged between the day of measuring lamotrigine
and the date when the clinical records for the CGI-S assessment were described. CGI-S
scores were blind to lamotrigine TDM (by Y.K.) and CGI-S ratings (by T.T.) and were
never influenced by lamotrigine TDM.
Subjects
As shown in [Table 1], subjects were 25 patients (15 males and 10 females), aged between 26 and 69 years
(mean=44.9, SD=12.9). 18 patients had bipolar II disorder (BPII), 2 had bipolar I
disorder (BPI) and 5 had major depressive disorder (MD). Their CGI-S scores at 1 month
before and just before starting lamotrigine ranged from 2 to 5 (mean=3.5, SD=0.8)
and 3–5 (mean=4.2, SD=0.7), respectively. Just before starting lamotrigine, 18 patients
had mood stabilizers other than lamotrigine, 15 patients had antidepressants, and
6 patients had antipsychotics. Lamotrigine was started in combination with these drugs.
The starting dose of lamotrigine ranged from 12.5 to 50 mg/day (mean=19.5, SD=8.9),
which was gradually increased to 50–400 mg/day (mean=256.0, SD=99.0) at the last observation.
Table 1 Patient demographics and lamotrigine levels and CGI-S scores.
|
Patient #
|
Gender
|
Age
|
Dx
|
Lamotrigine levels (μg/mL) at the last observation
|
Within 5–11 μg/mL or not
|
Lamotrigine administration period until the last observation (months)
|
CGI-S at baseline
|
CGI-S at the last observation
|
|
1
|
m
|
46
|
MD
|
7.21
|
y
|
12
|
5
|
2
|
|
2
|
m
|
38
|
BPII
|
4.24
|
n
|
18
|
5
|
3
|
|
3
|
m
|
62
|
MD
|
5.18
|
y
|
18
|
5
|
1
|
|
4
|
m
|
35
|
BPII
|
11.28
|
n
|
36
|
5
|
2
|
|
5
|
f
|
39
|
BPII
|
11.86
|
n
|
24
|
5
|
3
|
|
6
|
f
|
36
|
BPII
|
6.05
|
y
|
6
|
4
|
2
|
|
7
|
f
|
38
|
BPII
|
9.31
|
y
|
24
|
4
|
3
|
|
8
|
m
|
52
|
BPII
|
7.29
|
y
|
18
|
3
|
2
|
|
9
|
m
|
26
|
BPII
|
10.36
|
y
|
18
|
4
|
2
|
|
10
|
m
|
52
|
BPII
|
10.83
|
y
|
24
|
4
|
2
|
|
11
|
m
|
46
|
BPII
|
8.84
|
y
|
48
|
5
|
2
|
|
12
|
f
|
28
|
MD
|
14.13
|
n
|
12
|
4
|
4
|
|
13
|
f
|
60
|
BPII
|
5.85
|
y
|
48
|
5
|
3
|
|
14
|
m
|
35
|
BPII
|
3.83
|
n
|
18
|
4
|
2
|
|
15
|
m
|
38
|
BPII
|
4.26
|
n
|
42
|
4
|
4
|
|
16
|
f
|
69
|
BPI
|
6.89
|
y
|
36
|
3
|
2
|
|
17
|
m
|
61
|
BPII
|
2.22
|
n
|
12
|
3
|
2
|
|
18
|
f
|
63
|
BPII
|
12.78
|
n
|
18
|
4
|
4
|
|
19
|
m
|
65
|
BPII
|
5.37
|
y
|
24
|
4
|
2
|
|
20
|
f
|
26
|
BPII
|
1.71
|
n
|
24
|
4
|
2
|
|
21
|
f
|
44
|
MD
|
5.02
|
y
|
12
|
5
|
2
|
|
22
|
m
|
53
|
BPI
|
4.50
|
n
|
18
|
4
|
3
|
|
23
|
m
|
41
|
BPII
|
7.09
|
y
|
12
|
3
|
3
|
|
24
|
f
|
30
|
MD
|
6.11
|
y
|
18
|
4
|
3
|
|
25
|
m
|
39
|
BPII
|
7.28
|
y
|
18
|
4
|
2
|
BP I=bipolar I disorder, BP II=bipolar II disorder, MD=major depressive disorder,
CGI-S=Clinical Global Impression-Severity Scale scores (1=normal, 2=borderline mentally
ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severely ill, 7=the most extremely
ill)
Measurement of plasma lamotrigine levels
All the blood samples for measurement of plasma lamotrigine levels were taken approximately
12 h after the last dose of lamotrigine. All lamotrigine doses were unchanged for
more than the 6 days which are required to obtain lamotrigine levels in a steady state.
Valproate was combined with lamotrigine in 7 patients while carbamazepine was combined
with lamotrigine in 2 patients, but their doses were unchanged for more than 2 months
and their effects on lamotrigine levels also seemed to be in a steady state. The measurement
of lamotrigine was performed using a HPLC system by a third party. The inter- and
intra-assay coefficients of variation were 2.79 and 0.58%, respectively.
Statistical analyses
In order to investigate our hypothesis that lamotrigine may have a therapeutic window
for mood disorders, we depicted the relationship between the last lamotrigine level
and the last CGI score in 25 patients. If any, using the potential therapeutic window,
repeated measures of analysis of variance (ANOVA) were performed using the CGI-S scores
at baseline (i. e., just before starting lamotrigine) and the last CGI-S scores as
a dependent factor with the last lamotrigine levels (within the potential therapeutic
window or not) as an independent factor. Secondly, the last CGI-S scores were compared
between patients whose lamotrigine levels were within the potential therapeutic window
and patients whose lamotrigine levels were not within the window by unpaired t-test.
Ethics
The study was approved by the ethics committee of Oita University Faculty of Medicine.
All subjects gave written informed consent.
Results
[Table 1] shows patient demographics, lamotrigine levels and CGI-S scores in 25 patients.
[Fig. 1] shows the relationship between the last lamotrigine levels and the last CGI-S scores
of 25 patients. Our visual inspection indicated the presence of a therapeutic window
of lamotrigine from 5 to 11 μg/mL. Therefore, the following analyses were performed
to use this range (5–11 μg/mL) as a potential therapeutic window.
Fig. 1 The relationship between plasma lamotrigine levels and CGI-S scores at the last observation
of 25 patients. 25 pairs of plasma lamotrigine levels and CGI-S scores were shown
and the shape indicated the presence of the therapeutic window of lamotrigine as 5–11 μg/mL.
The repeated measures of ANOVA revealed a significant tendency of the effect of the
last lamotrigine levels (within 5–11 μg/mL or not) [lamotrigine, F(1,23)=4.0, p=0.058:
CGI-S, F(1,23)=57.6, p<0.0001: lamotrigine×CGI-S, F(1,23)=2.2, p=0.16] ([Fig. 2]).
Fig. 2 The time course of basal CGI-S and the last CGI-S. The repeated measures of ANOVA
revealed a significant tendency of the effect of the last lamotrigine levels.
The last CGI-S scores of the 15 patients whose lamotrigine levels were within 5–11 μg/mL
were significantly lower than those of 10 patients whose lamotrigine levels were not
within 5–11 μg/mL (2.2±0.6 vs. 2.9±0.9, t=2.45, p=0.023). There were no significant
differences in gender rate (6 females and 9 males within 5–11 μg/mL vs. 4 females
and 6 males without 5–11 μg/mL, p> 0.99), age (47.1±12.8 years within 5–11 μg/mL vs.
41.6±13.0 years without 5–11 μg/mL, t=−1.04, p=0.31), psychiatric diagnoses (MD:BPI:BPII;
4:1:10 within 5–11 μg/mL vs. 1:1:8 without 5–11 μg/mL, p=0.59) or lamotrigine administration
period until the last observation (22.4±12.5 months within 5–11 μg/mL vs. 22.2±8.8
months without 5–11 μg/mL, t=−0.042, p=0.97).
Discussion
Our hypothesis that lamotrigine may have a therapeutic window for mood disorders was
supported in the present study. The repeated measures of ANOVA failed to reach a significant
level, but they reached a significant tendency. Moreover, the CGI-S scores at the
last observation of the 15 patients whose lamotrigine levels were within 5–11 μg/mL
were significantly lower than those of 10 patients whose lamotrigine levels were not
within 5–11 μg/mL. Other factors were not significantly different between the groups.
These findings suggest that 5–11 μg/mL may be therapeutic levels of lamotrigine effects
for mood disorders.
Since the therapeutic levels of lamotrigine for epilepsy are reported to be 3–14 μg/mL
[10], this range was also applied to our data. As a result, there were no significant
findings (data not shown). Although a large part of our data were within 3–14 μg/mL,
these findings suggest that 5–11 rather than 3–14 μg/mL may be more appropriate for
the therapeutic levels of lamotrigine for mood disorders.
The main limitation is that this study was a retrospective naturalistic study. Further
prospective studies are required which randomize patients to different doses and evaluate
plasma levels and subsequent response over a defined period. Moreover, it is unclear
whether antidepressant effect and/or prophylactic effect of lamotrigine were assessed
by CGI-S and a CGI-S measure is a limited assessment. Moreover, CGI assessment was
not blind to the hypothesis that lamotrigine may be helping the patients. Also, the
analysis did not control for confounding variables including co-medications.
Conclusion
The present findings suggest that lamotrigine may have a therapeutic window for patients
with mood disorder from 5 to 11 μg/mL.
