Original Article CLINICAL
253
Lamotrigine as an Add-on Treatment
for Depersonalization Disorder:
A Retrospective Study of 32 Cases
Mauricio Sierra, MD, PhD, Dawn Baker, DClinPsy,
Nicholas Medford, MRCP, MRCPsych, Emma Lawrence, PhD,
Maxine Patel, MRCPsych, Mary L. Phillips, MD, and Anthony S. David, MD
Abstract
Objectives:
Depersonalization disorder (DPD) is a chronic
condition characterized by the persistent subjec-
tive experience of unreality and detachment from
the self. To date, there is no known treatment.
Lamotrigine as sole agent was not found to be
effective in a previous small double-blind,
randomized crossover trial. However, evidence
from open trials suggests that it may be beneficial
as an add-on medication with antidepressants.
Methods:
We report here an extended series of 32 patients
with DPD in whom lamotrigine was prescribed as an
augmenting medication. Most of the patients were
receiving selective serotonin reuptake inhibitors.
Results:
Fifty-six percent (n = 18) of patients had a more
than or equal to 30% reduction on the Cambridge
Depersonalization Scale score at follow-up. Both
maximum dose of lamotrigine used and before
treatment Cambridge Depersonalization Scale
scores showed positive correlations with the
percentage of response.
Conclusions:
The results of this trial suggest that a significant
number of patients with DPD may respond to
lamotrigine when combined with antidepressant
medication. The results are sufficiently positive to
prompt a larger controlled evaluation of lamotri-
gine as add-on treatment in DPD. phone survey indicated that 19% of 1008
Key Words: depersonalization, derealization,
dissociation, lamotrigine, depression, selective
serotonin reuptake inhibitor, glutamate, CDS
(Clin Neuropharmacol 2006;29:253Y258)
D epersonalization disorder (DPD) is
operationally defined as an alteration
in the perception or experience of the self
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NEUROPHARMACOLOGY
Volume 29, Number 5
September - October 2006
in the Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition, and is
classified along with derealization under
the heading Dissociative Disorders.1 In the
International Classification of Diseases,
10th Revision, the depersonalization-
derealization syndrome is classed as a
separate neurotic disorder. The 2 criteria
are very similar: both note the same core
symptoms, with intact insight.2 Comorbid
anxiety or depressive symptoms often
accompany it, but to make a diagnosis of
DPD, it must be clear that the condition does
not occur exclusively in the presence of the
comorbid condition.1 The onset is in adoles-
cence or early adult life. The condition may
be episodic but is more often chronic and
persistent and may be disabling.3,4
Although the prevalence of DPD in the
general population is unknown, an estimate
of 1% has been suggested on the basis of
community surveys.5 Ross reported a preva-
lence estimate of 2.4% of persistent deper-
sonalization in a nonclinical population in
Canada using a postal survey.6 A large US
Depersonalisation Research Unit,
adults had at least 1 episode of depersonal- Psychological Medicine, Institute
ization in the previous 12 months.7 As a of Psychiatry, London, UK.
Address correspondence and
comorbid condition, its prevalence seems
reprint requests to
much higher. Brauer et al8 found that 80% of Mauricio Sierra, MD, PhD,
212 psychiatric inpatients admitted to Depersonalisation Research Unit,
Psychological Medicine, Institute
present or past depersonalization, whereas of Psychiatry, PO Box 68,
12% reported severe and lasting experiences. Denmark Hill 103, London SE5
8AZ, UK; E-mail:
Similarly, Noyes et al9 found that 40% of 100
psychiatric inpatients endorsed at least 5
features of depersonalization.
M.Sierra-Siegert@iop.kcl.ac.uk
Copyright 2006 by
Lippincott Williams & Wilkins
DOI: 10.1097/01.WNF.0000228368.17970.DA
 CLINICAL Sierra et al
254 NEUROPHARMACOLOGY
Volume 29, Number 5
September - October 2006
Pharmacology of Depersonalization
Depersonalization has a reputation for
being poorly responsive to treatment, and no
definite medication treatment guidelines exist.3
There are historical reports of the use of
barbiturates, amphetamines, neuroleptics,
etcVall with no consistent benefit.10,11 More
recently, case reports of the effectiveness of
antidepressants including selective serotonin
reuptake inhibitors (SSRIs)12 and a small con-
trolled trial clomipramine13 suggested some
sporadic responsiveness. However, this initial
promise has not been supported by a recent
placebo-controlled, double-blind study of fluox-
etine in 54 patients with DPD.14 Despite this,
the fact that depersonalization can be induced
by meta-chlorophenylpiperazine, a potent sero-
tonin receptor agonist,15 and by drugs such as
cannabis,16 lysergic acid diethylamide, and
ecstasy,17 also believed to be serotonin
agonists, suggests that serotonergic mecha-
nisms are important in depersonalization.
Another body of research suggests that
glutamate might be relevant to the pathophysi-
ology of depersonalization and dissociation.18
It has been shown that subanesthetic doses
of the N-methyl D-aspartate receptor antago-
nist ketamine can induce many of the
subjective experiences characteristic of
depersonalization, including a sense of
detachment and emotional numbing. 18
A recent functional magnetic resonance
imaging study found that subjects with
ketamine-induced depersonalization
showed abnormalities in the processing of
emotional stimuli, which were similar to
those previously reported in patients with
DPD.19,20 Subjects with ketamine-induced
depersonalization and those with DPD
showed a lack of activity in limbic areas,
such as the insula and amygdala, and hyper-
activity in prefrontal cortical regions that
may be important for mood regulation.19Y21
It is believed that the altered state of
consciousness induced by ketamine is me-
diated by increased glutamate release
in response to NMDA receptor blockade,
with a consequent excess of glutamate
activity at non-NMDA glutamate recep-
2006 Lippincott Williams & Wilkins
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tors.18,22 In this regard, it has been found
that pretreatment with lamotrigine, a drug
reported to inhibit glutamate release by
action at the presynaptic membrane, 23
attenuates the effects of ketamine on con-
scious experience and cognition.24
In view of the above, we previously
reported the effects of lamotrigine on 11
patients with DPD. Six reported significant
subjective improvement which was reflected
by a drop in the Dissociative Experiences Scale
version II (DES)/depersonalization subscale.25
However, the fact that most of the responders
were also on an SSRI antidepressant (lamo-
trigine was added to their ongoing unsuccess-
ful regimens) left open the possibility that
rather than being effective in its own right,
lamotrigine may be acting as an augmenting
agent.26 In fact, our recent crossover, double-
blind study on 9 patients with DPD, failed to
show any beneficial effects of lamotrigine
when used as the sole medication.27
In this report, we present an expanded
series of patients with DPD in whom lamo-
trigine was prescribed as an addition to
ongoing pharmacological regimens (most
were on SSRIs). This series does not include
the original 11 patients previously reported.
MATERIALS AND METHODS
We assessed a cohort of consecutive
eligible cases who had previously been
prescribed lamotrigine over a 2-year period,
as part of a pragmatic open-label trial. The
follow-up was made by means of the admin-
istration of self-rated questionnaires. The aim
of the survey was to evaluate the efficacy of
lamotrigine in helping reduce symptoms
associated with the disorder.
Participants
Fifty-seven patients who had been
prescribed lamotrigine over the previous 2
years were identified from the DPD clinic
database of the Maudsley Hospital and sent
a follow-up questionnaire and self-rating
scales by post. All patients had received a
formal diagnosis of DPD by means of a

semistructured interview (see later)4 and had
been prescribed lamotrigine either alone or
as an addition to their ongoing unsuccessful
medication regimens (usually SSRI anti-
depressants but also other types; Table 2)
for at least 6 weeks before the survey. At the
onset of the trial, patients gave their consent
to take the medication after possible adverse
effects of lamotrigine were explained to
them and after being explained that lamo-
trigine was not officially licensed as a treat-
ment of depersonalization.
Assessments
Demographic details along with medi-
cal and psychiatric history were obtained
from all participants. A detailed history
of the nature and course of their deperson-
alization was recorded, by means of a semi-
structured interview. The clinical assessment
incorporated the Present State Examina-
tion. 28 The Present State Examination
includes specific well-defined probes for
depersonalization and derealization, each
scoring 0, not present; 1, moderately intense
or transient; and 2, intense and persistent.
Participants were included only if they met
Diagnostic and Statistical Manual of Men-
tal Disorders, Fourth Edition, criteria for
DPD (300.6). Lifetime prevalences of comor-
bid diagnoses were as follows: major depres-
sion, 11 (34%); generalized anxiety disorder,
2 (6.3%); obsessive-compulsive disorder, 4
(12.5%); and panic disorder, 3 (9.4%).
Outcome Measures
The following scales were administered
as part of the initial assessment at the onset of
the trial and at follow-up: Beck Anxiety
Inventory29 and Beck Depression Inventory
(range 0Y63),30 DES (range, 0Y100)31 and its
depersonalization/derealization subscale
(items 7, 11, 12, 13, 27, and 28), and
Cambridge Depersonalization Scale (CDS)
(range, 0Y290).32 A percentage of improve-
ment was calculated as the difference
between CDS scores at baseline and follow-
up and used as the outcome measure.
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Lamotrigine in Depersonalization CLINICAL
NEUROPHARMACOLOGY
255
Volume 29, Number 5
September - October 2006
RESULTS
Of the 57 eligible cases, 15 failed to reply
(response rate, 74%). Of those who replied, 3
refused, 7 admitted they had never taken the
drug despite it being prescribed, and the
remaining 32 people agreed to participate.
Demographic Characteristics
The mean age of the 32 participants
(19 men and 13 women) was 37.13 years
(range, 18Y73 years). The mean age of onset
was 22.6 years (range, 4Y67 years), and
duration of illness was a mean of 12.1 years
(range, 6 monthsY50 years); however, 50%
reported the duration of illness as 5 years or
less. There were no statistically significant
differences in mean age (t = j1.01, P =
0.32), age at onset (t = j0.16, P = 0.8),
duration of illness (t = j0.24, P = 0.8), or
sex (x2 = 1.86, P = 0.39) between those
individuals that choose to participate and
those that failed to reply, refused, or failed to
adhere to their prescribed medication.
Treatment
Mean duration of lamotrigine treatment
was 13.7 months (range, 6Y21 months). Lamo-
trigine dose was increased by 25 mg every 2
weeks to an average of 209.8 mg daily (range,
25Y600 mg/d) in divided doses. This range of
doses reflected the fact that some patients
improved on relatively small doses; others
could not get beyond a certain dose because
of adverse effects. Hematologic and metabolic
parameters were monitored.
As can be seen in Table 1, paired t tests
comparing scale scores before and after
lamotrigine treatment in the whole sample
revealed a significant score drop in the CDS,
Beck Depression Inventory, and Beck Anxi-
ety Inventory. Improvement on the DES did
not reach significance, although improvement
on the DESYdepersonalization/derealization
6-item subscale31 mean score (range, 0Y100)
was near significant.
The medication taken in conjunction
with lamotrigine (68.7% of the cases) was
predominantly serotonin-norepinephrine
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256 NEUROPHARMACOLOGY
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TABLE 1. Comparison of Scale Global Scores Before and After Lamotrigine Treatment
t Test
Statistic (P),
Psychopathology Measure Prelamotrigine Postlamotrigine df = 31

BAI 18.3 (8.81) 14.7 (7.2) 2.09 (0.045)

BDI 22 (9.5) 16 (7.7) 4.1 (0.001)
DES 22.5 (13.6) 19.8 (10.4) 1.2 (0.226)
DESYdepersonalization/derealization subscale 37.08 (19.3) 30.2 (14.7) 1.9 (0.062)
CDS 129.1 (55) 93.3 (43.2) 3.06 (0.004)
BAI indicates Beck Anxiety Inventory; BDI, Beck Depression Inventory.

reuptake inhibitors (fluoxetine, citalopram, (r = 0.74, P G 0.001), which persisted after

sertraline, and paroxetine), tricyclic antide-
pressants, and serotonin-norepinephrine reup-
take inhibitors. Some participants chose to
take lamotrigine as the sole agent (Table 2).
Response
Responsiveness to lamotrigine was as-
sessed as a percentage of decrease on the CDS
score at follow-up. Fifty-six percent (n = 18) had
a score reduction more than or equal to 30%.
As shown in Table 2, although different
combinations of lamotrigine were associated
with a positive response, there was a trend
suggesting that the combination lamotrigine
plus tryciclics was the least effective.
As can be seen in Table 3, there was a
significant correlation between CDS score re-
duction and maximum lamotrigine dose used.
This effect seemed selective, as no significant
correlations were found between decrease in
each of the other administered scales and
lamotrigine dose. There was also a significant
correlation between CDS score at onset of
treatment and percentage of improvement
correcting for regression to the mean artifacts.
The most commonly reported adverse
effects were nausea and/or diarrhea, visual
disturbance, and tremor and cognitive
impairment. None was severe enough to
necessitate stopping the medication. No
serious adverse effects, such as blood dys-
crasias or skin reactions, were noted.
DISCUSSION
Our results are in keeping with our
previous report in which approximately 50%
of patients with DPD benefited from a combi-
nation of lamotrigine plus an antidepressant.25
A subsequent crossover, double-blind trial
on 9 patients failed to show any positive
effects of lamotrigine when taken as a sole
medication.27 In fact, there was not even
evidence of a placebo effect as no single
patient experienced any improvement. None-
theless, it is interesting that 7 of the 9 patients
who took part in the placebo-controlled trial
claimed to have been depersonalized since

TABLE 2. Comparison of Lamotrigine Efficacy in Different Combinations With Antidepressants

No. Patients With a
CDS Decrease
Lamotrigine Average CDS % Decrease Range of CDS Decrease 930% (%)

Only (n = 10) 32.2 (22.7) 0Y84 4 (40)

+SSRI (n = 11) 45.2 (20.7) 0Y76 9 (81.8)
+Tryciclics (n = 7) 17.5 (15.7) 0Y36.7 2 (28.5)
+SNRI (n = 4) 35.8 (17) 19.2Y53.7 2 (50)
SNRI indicates serotonin-norepinephrine reuptake inhibitors.

2006 Lippincott Williams & Wilkins

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TABLE 3. Correlations Between Maximum
Lamotrigine Dose Used and Percentage of Score
Decrease on Each of the Scales Administered
Lamotrigine Dose (P)
CDS 0.41 (G0.02)
BDI 0.21 (G0.28)
BAI 0.18 (G0.33)
DES 0.15 (G0.43)
BAI indicates Beck Anxiety Inventory; BDI, Beck
Depression Inventory.
their childhood, and this may have biased the
sample to nonresponsiveness.4
It must be acknowledged that this was
neither a blinded nor a randomized controlled
trial; hence, the results must be treated with
caution. However, a number of factors favor
the interpretation that the data reflect a
genuine pharmacological response. Many of
the participants, including those in the res-
ponder group, had a long duration of illness
and had failed to respond to antidepressant
medication (mostly SSRIs). Many had been
tried on several such agents plus benzodiaze-
pines but with no noticeable or lasting
benefit.
In keeping with the previous study, our
findings suggest that, rather than acting on its
own, lamotrigine works better as an add-on
therapy with SSRI antidepressants. This possi-
bility would not be surprising, in view of the
circumstantial evidence reviewed earlier,
which points to an involvement of both
serotonergic and glutamatergic mechanisms
in depersonalization, and previous clinical
experience in the use of lamotrigine.33 If that
is indeed the case, it may be that successful
pharmacological interventions need to target
both neurotransmitter systems. Other condi-
tions for which there is growing evidence of
the effectiveness of lamotrigine include post-
traumatic stress disorder34 and borderline
personality disorder35 in which emotional
blunting and dissociation are observed,
respectively, symptoms which overlap with
those seen in DPD. In addition, there is a
growing body of evidence, from both animal
models and pharmacological and radioimag-
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Lamotrigine in Depersonalization CLINICAL
NEUROPHARMACOLOGY
257
Volume 29, Number 5
September - October 2006
ing studies in humans, that glutamatergic and
GABAergic (+-aminobutyric acid [GABA]) sys-
tems are implicated in the pathogenesis of
mood disorders.36 These 2 neurotransmitter
systems are closely coupled, changes in one
often reflected by changes in the other. A
recent study of patients with major depressive
disorder showed that cortical GABA concen-
trations rose significantly after treatment with
SSRI antidepressants, suggesting a relationship
between glutamate, GABA, and serotonergic
systems.37 Our finding that, in DPD, a lamo-
trigine-SSRI combination was more effective
than either drug alone may point to a similar
relationship in DPD, with the combination of
drugs exerting a synergistic therapeutic action
due to effects on both serotonergic and
glutamatergic pathways.
CONCLUSIONS
The results of this open study looking at
the efficacy of lamotrigine in DPD are encour-
aging, especially given the limited range of
treatment options in the condition. The pos-
itive results reported in this study clearly
warrant further work, in particular placebo-
controlled studies, trials using a combination
of lamotrigine, and SSRI antidepressants.
ACKNOWLEDGMENTS
The authors are grateful for the sup-
port generously provided by a grant from the
Pilkington Family Trusts, the advice given by
John Krystal, and some running costs for an
earlier trial of lamotrigine in depersonaliza-
tion provided by GlaxoWellcome.
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