Efficacy and Behavioral Benefits of the Use of Lamictal in the Treatment the Developmantally Disabled

Finesmith et al., Lamotrigine in patients with refractory epilepsy and mental retardation
Epilepsy and Behavior. 2003 Aug;4(4):386-94.
Efficacy and Tolerability of Lamotrigine as Adjunctive Therapy in
Patients with Refractory Epilepsy and Mental Retardation
Ross Finesmith 1
Theodore R. Sunder,2
Jerry R. McKee 3
1
New York University School of Medicine
2
Southern Illinois University School of Medicine, Springfield, Illinois;
Western Carolina Center, Morganton, North Carolina 3
Key words: lamotrigine, epilepsy, mental retardation, intellectual disability (developmental
disability)
1

Abstract
Objective: This study was conducted to evaluate the efficacy, tolerability, and behavioral effects
of lamotrigine as adjunctive therapy for refractory epilepsy in patients with mental retardation.
Methods: Patients with epilepsy and mental retardation with uncontrolled seizures despite
treatment with other antiepileptic drugs were eligible for this open-label study (n=67). The study
comprised an 8-week pre-lamotrigine Baseline Phase, an 8-week Escalation Phase during which
lamotrigine was titrated to a target dose, an 8-week Maintenance Phase during which doses of
lamotrigine and concomitant antiepileptic drugs were maintained, and a 12-week Optimization
Phase during which doses of lamotrigine and other antiepileptic drugs could be adjusted to
optimize therapy.
Results: Approximately one-quarter (26%) of patients experienced a 75% reduction in seizure
frequency during the Maintenance Phase after addition of lamotrigine; 15% of patients became
seizure-free. A similar pattern of results was reported for the Optimization Phase, during which
doses of several concomitant drugs were reduced. According to investigator assessments, overall
clinical status was improved relative to baseline in 64% of patients at the end of the Maintenance
Phase and 70% of patients at the end of the Optimization Phase. Most patients experienced
improvements relative to baseline in seizure frequency, duration, and intensity during the
Maintenance Phase (60% to 71%) and the Optimization Phase (57% to 67%). Approximately half
of patients were considered to have experienced improvement in social functioning during the
Maintenance Phase (41%) and the Optimization Phase (45%). The Aberrant Behavior Checklist
(ABC) score for lethargy and the mean Habilitative Improvement Scale score were significantly
improved at the ends of the Maintenance and Optimization Phases relative to baseline (p<.01).
Conclusion: Adjunctive therapy with lamotrigine in patients with refractory epilepsy and mental
retardation decreased seizure frequency and improved behavior while permitting a reduction in
dose of concomitant antiepileptic drugs.
2

Introduction
Epilepsy and mental retardation, the 2 most common neurologic impairments among children,1
are frequently comorbid. Approximately 30% to 40% of institutionalized individuals with mental
retardation and 20% of community-dwelling individuals with mental retardation suffer from
epilepsy.2,3
; Braddock D, Hemp R, Bachelder L, Fujiura G. The state of states in
developmental disabilities. 4th ed. Washington. DC. American Association of Mental
Retardation, 1995. The management of epilepsy in patients with mental retardation poses
unique challenges. First, epilepsy in patients with mental retardation may be particularly
refractory to treatment, and patients often experience multiple seizure types.4,5
Because of the
refractory nature of the seizures, patients are frequently maintained on several concomitant
antiepileptic drugs with an attendant high risk of drug interactions and side effects. Second,
whether they are on monotherapy or polytherapy, patients with mental retardation are often more
susceptible than non-retarded individuals to adverse behavioral and psychotropic effects of
medications.5
This heightened susceptibility may arise from neurologic or systemic abnormalities
associated with mental retardation. In addition, psychiatric co-morbidities have been reported
to occur in 25% and severe maladaptive behavior in up to 55% of those meeting criteria
for mental retardation. Ref; Deb S. Mental disorder in adults with mental retardation and
epilepsy. Comp Psych. 1997;(3):179-184.. Many anti-convulsants have shown to have
mood-stabilizing effects and are effective in treating bipolar disorder, mania and
aggressive behaviors. A single patients can benefit from both the antiseizure and mood
stabilizing properties of an anticonvulsant medication. Frequently, healthcare providers or
caregivers may be reluctant to adjust therapy to reduce common side effects ( such as sedation)
not only because of the concern that epilepsy will worsen but also because the patient exhibiting
disruptive behavior may be more easily managed when sedated than when not sedated. Finally,
3

although some side effects such as sedation are easily detected in the patient with mental
retardation, other side effects may be difficult to discern—either because they are not physically
manifest and the patient is unable to communicate about them or because they are difficult to
distinguish from the patient’s behavioral pathology.
Achieving the optimum balance of efficacy and tolerability in antiepileptic drug therapy for this
patient population is important in minimizing the influence of factors, such as intellectual
disability induced by medication or arising from frequent or prolonged seizures, that may
exacerbate the patient’s inherent intellectual impairment.5
This goal, as well as the universal
objectives of ensuring patients’ safety and improving their well-being and that of their family
members, has motivated the search for therapies to improve outcomes in the treatment of epilepsy
in patients with mental retardation.2,6
The antiepileptic drug lamotrigine, which combines broad-spectrum efficacy with favorable
tolerability in pediatric and adult patients with epilepsy,7-20
may be a particularly good candidate
for the treatment of epilepsy in individuals with mental retardation. Lamotrigine is effective as
monotherapy for partial seizures in both newly-diagnosed patients and patients switching from
older antiepileptic drugs because of inadequate seizure control or poor tolerability14-16
and as
adjunctive therapy for partial seizures,7-13
absence seizures,13,17
and generalized tonic-clonic
seizures.13,18
Furthermore, lamotrigine effectively controls multiple seizure types in patients with
seizures intractable to other pharmacotherapies.9,18,20-31
For example, lamotrigine is efficacious as
monotherapy or adjunctive therapy in refractory childhood epileptic syndromes—including
Lennox-Gastaut syndrome,18,27
infantile spasms,29
and Rett syndrome30,31
—that are often
associated with intellectual impairment. Besides conferring broad-spectrum efficacy, lamotrigine
is well-tolerated. Compared with carbamazepine and phenytoin, lamotrigine is associated with a
4

lower incidence of neurologic adverse events such as asthenia, dizziness, and somnolence;15,16
and
it does not impair cognitive function.19
In fact, lamotrigine has been observed to enhance mood,
social interaction, and well-being in patients with epilepsy.32,33
While lamotrigine has been suggested, in several small studies, to be effective in intellectually
impaired patients with epilepsy,34-37
its antiepileptic and behavioral effects in patients with mental
retardation have not been thoroughly assessed to date. This open-label study was conducted to
evaluate the efficacy, tolerability, and behavioral effects of adjunctive lamotrigine in patients
with mental retardation and refractory epilepsy.
5

Methods
Patients
Patients at least 12 years of age and weighing at least 25 kg were eligible for the study if they had
a diagnosis of epilepsy with seizures classifiable by the International Classification of Seizures38
and mild, moderate, severe, or profound mental retardation based on Diagnostic and Statistical
Manual-IV (DSM-IV) criteria.39
To be eligible for enrollment, patients also needed to be
receiving stable doses of up to 3 antiepileptic medications at enrollment and to have experienced
at least 2 seizures per month in the 3 months prior to enrollment. Patients were excluded from the
study if they had used any investigational drug within 4 weeks of initiation of the study or had
been previously exposed to lamotrigine; were pregnant, breast-feeding, attempting to become
pregnant, or capable of bearing children but not using acceptable contraception; adhered to the
ketogenic diet; had non-epileptic seizures; had severe organic disease or unstable or uncontrolled
psychiatric illness that in the investigator’s judgment would interfere with the conduct of the
study; had a history of alcohol or other drug abuse or dependence; or planned during the study
period to undergo vagal stimulation or surgery to control seizures. All patients provided written,
informed consent.
Procedures
The protocol for this open-label study (Glaxo Wellcome protocol SCAA4003) was approved by
an institutional review board for each of the United States study sites. The study comprised
• A 2-week Screening Phase during which eligibility was verified and baseline physical and
seizure assessments were obtained;
• An 8-week Baseline Phase during which seizure frequency was assessed while the number
and dosages of concomitant antiepileptic drugs were maintained with no addition of
lamotrigine. To be eligible for continuation in the study after the Baseline Phase, patients
6

were to have experienced at least 2 seizures including at least 1 convulsive seizure and fewer
than 12 major motor seizures (i.e., clonic, tonic, or tonic-clonic) during each 4-week interval
of the Baseline Phase;
• An 8-week Escalation Phase during which lamotrigine was introduced and titrated to a target
of 100 to 200 mg/day for patients on valproate or 300 to 500 mg/day for patients on enzyme-
inducing antiepileptic drugs while the number and dosages of concomitant antiepileptic drugs
were maintained;
• An 8-week Maintenance Phase during which lamotrigine dose was maintained unless a
change was necessary because of intolerable side effects or poor seizure control. As in the
Baseline and Escalation Phases, the number and dosages of concomitant antiepileptic drugs
were maintained during the Maintenance Phase; and
• A 12-week Optimization Phase during which doses of lamotrigine and concomitant
antiepileptic drugs could be adjusted to optimize the patient’s therapy. Concomitant
antiepileptic drugs, but not lamotrigine, could be withdrawn during the Optimization Phase.
The primary measurements obtained during the study included
• Seizure counts by type of seizure. Seizure counts were recorded daily by caregivers
throughout the study and reviewed by the investigator at clinic visits conducted at least once
during the Screening and Baseline Phases and every 4 weeks during the Escalation,
Maintenance, and Optimization Phases.
• Investigator-rated clinical status of patients at the end of the Escalation, Maintenance, and
Optimization Phases on the following specific indices: seizure frequency, seizure duration,
seizure intensity, adverse events, social functioning, intellectual functioning, and motor
7

functioning. Clinical status was rated as mild, moderate, or marked deterioration; no change;
or mild, moderate, or marked improvement;
• Scores on the Aberrant Behavior Checklist, a 58-item instrument completed by the caregiver
during the Screening Phase and at the end of the Baseline, Escalation, Maintenance, and
Optimization Phases. The Aberrant Behavior Checklist measures inappropriate and
maladaptive behaviors (irritability, lethargy, stereotypy, hyperactivity, inappropriate speech)
over the past 4 weeks. Questions on the behaviors are scored on a 4-point scale: 0=not at all
a problem; 1=a slight problem; 2=a moderately serious problem; 3=a severe problem. The
checklist has been demonstrated to be reliable and valid in mentally retarded populations40,41
and has frequently been used in clinical trials and clinical practice to assess the effects of
medications on behavior of mentally retarded individuals;
• Scores on the Habilitative Improvement Scale, a 14-question, 7-point scale completed by the
caregiver during the Screening Phase and at the end of the Baseline, Escalation, Maintenance,
and Optimization Phases. The Habilitative Improvement Scale, a relatively new instrument
that has not yet been widely employed in clinical trials, measures degree of change in 5
domains of daily functioning during the past 5 weeks: adaptive skills, social/communication
skills, mood/behavior, care provision, and health/safety. The instrument was specifically
designed to detect behavioral change attributed to treatment interventions. Responses are
scored on a 7-point scale ranging from no improvement (0) to significant improvement (6)
with an additional non-numeric score for no impairment (NI); and
• Adverse events, defined as any untoward medical occurrence whether or not it was considered
to be attributed to the study medication. Adverse events were recorded by caregivers
throughout the study and reviewed by the investigator at clinic visits conducted at least once
during the Screening and Baseline Phases and every 4 weeks during the Escalation,
Maintenance, and Optimization Phases.
8

Data Analysis
The main efficacy endpoint was the percentage of patients with reductions in seizure frequency
(to no seizures or by at least 25%, 50%, or 75%) during the Maintenance Phase and the
Optimization Phase compared with the Baseline Phase. Other endpoints, computed for both the
Maintenance Phase and the Optimization Phase, included
• The percentage of patients rated by investigators as mildly, moderately, or markedly
improved on the clinical status items;
• Mean change from baseline scores on the Aberrant Behavior Checklist. The Aberrant
Behavior Checklist is scored by summing the scores for each item contributing to each of the
5 behaviors to yield a score for each behavior.36,37
The lower the score for each behavior, the
greater the improvement in behavior;
• Mean change from baseline score on the Habilitative Improvement Scale. The Habilitative
Improvement Scale is scored by summing the scores for all items to yield a total score. The
higher the score, the greater the improvement in behavior; and
• The incidence of adverse events considered by the investigator to be possibly, probably, or
definitely drug-related.
All data were summarized using descriptive statistics. No formal statistical analyses were
performed for the seizure data or the tolerability data. Although the study was not statistically
powered to examine behavioral measures, mean Aberrant Behavior Checklist scores and
Habilitative Improvement Scale scores were compared between the Baseline and Maintenance
Phases and the Baseline and Optimization Phases using paired t-tests. The low statistical power of
the study for detecting behavioral change notwithstanding, it was reasoned that large behavioral
changes might be reflected in statistically significant results.
9

Results
Demographics and Patient Characteristics
The number of patients who enrolled in the study was 95, 67 of whom met study eligibility
criteria and entered the Escalation Phase (Table 1; Figure 1). The mean age of patients entering
the Escalation Phase was 28.5 years (minimum 14 years; maximum 54 years); the majority were
white (81%) males (57%). More than two-thirds of patients were severely (12%) or profoundly
(58%) retarded. Approximately half (46%) of patients were institutionalized; the remainder
resided in group or cluster homes or with their families.
Patient Disposition
Of the 67 patients entering the Escalation Phase, 54 completed the study (Figure 1). Thirteen (13)
patients discontinued because of adverse events (9 patients), protocol violations (3 patients), or
other reasons (1 patient). The numbers of patients discontinuing during the Escalation,
Maintenance, and Optimization Phases were 3, 6, and 4, respectively. All 67 patients entering the
Escalation Phase and taking at least 1 dose of lamotrigine were included in the data summaries.
Use of Antiepileptic Drugs
At study entry, patients were taking a median of 2 antiepileptic drugs, the most common of which
were carbamazepine and valproate (Table 1). The percentages of patients taking 1, 2, and 3
antiepileptic drugs at study entry were 31%, 52%, and 16%, respectively.
From the Maintenance Phase to the Optimization Phase, the mean lamotrigine dose was increased
from 151 mg/day to 188 mg/day among those receiving valproate and from 358 mg/day to 403
mg/day among those not receiving valproate (Table 1). During the Optimization Phase, the mean
10

doses of gabapentin, phenobarbital, and valproate were decreased by 41%, 15%, and 13%,
respectively; the mean doses of other concomitant antiepileptic drugs remained relatively stable.
Seizure Frequency
Substantial proportions of patients experienced reduction in seizure frequency during the
Maintenance Phase after lamotrigine had been added to the antiepileptic drug regimen (Figure 2).
Approximately one-quarter (26%) of patients experienced a 75% reduction in the frequency of
seizures relative to baseline; 15% of patients were seizure-free while they used lamotrigine during
the Maintenance Phase. A similar pattern of results was reported for the Optimization Phase
(Figure 2).
Investigator-Rated Clinical Status
According to investigator assessments, overall clinical status was improved relative to the
Baseline Phase in 64% of patients at the end of the Maintenance Phase (Figure 3) and 70% of
patients at the end of the Optimization Phase (Figure 3). Furthermore, the majority of patients
experienced improvements in seizure frequency, duration, and intensity during both the
Maintenance Phase (60% to 71% of patients; Figure 3) and the Optimization Phase (57% to 67%
of patients; Figure 3). Most patients (72% during the Maintenance Phase and 71% during the
Optimization Phase) were considered to have experienced no change in adverse events.
Approximately half of patients were considered to have experienced improvement in social
functioning during the Maintenance Phase (41%) and the Optimization Phase (45%); intellectual
and motor functioning were unchanged relative to the Baseline Phase for most patients (Figure 3).
11

Aberrant Behavior Checklist Scores
The mean Aberrant Behavior Checklist score for lethargy was significantly improved at the end
of the Maintenance Phase relative to the end of the Baseline Phase (p<.05). Additional
improvement in the score for lethargy over that observed during the Maintenance Phase was
observed at the end of the Optimization Phase (p<.01 versus Baseline Phase; Figure 4). Although
scores for irritability and stereotypic behavior demonstrated a similar pattern of improvement
over the Maintenance and Optimization Phases, no statistically significant changes were observed
for irritability or for hyperactivity or inappropriate speech.
Habilitative Improvement Scale
The mean Habilitative Improvement Scale score was significantly improved at the end of the
Escalation Phase (19.7) relative to the end of the Baseline Phase (7.6; p=.0005) and again at the
end of the Maintenance Phase (21.0; p=.0004) and the Optimization Phase (23.4; p<.0001).
Adverse Events
The only adverse events that investigators considered to be possibly, probably, or definitely drug-
related and that occurred in at least 5% of patients during the Escalation Phase (n=67), the
Maintenance Phase (n=64), or the Optimization Phase (n=58) were somnolence (6% Escalation,
5% Maintenance, 3% Optimization), dizziness (4% Escalation, 5% Maintenance, 2%
Optimization), ataxia (3% Escalation, 5% Maintenance, 0% Optimization), and emotional lability
(6% Escalation, 2% Maintenance, 0% Optimization).
12

Discussion
The results of this study show that adjunctive use of lamotrigine in patients with mental
retardation and refractory epilepsy decreased seizure frequency while permitting a reduction in
dose of concomitant antiepileptic drugs including phenobarbital, gabapentin, and valproate.
During the Maintenance Phase, 44% of patients on lamotrigine experienced at least a 50%
reduction in the frequency of seizures relative to pre-lamotrigine baselines; 15% became seizure
free. Similarly, during the Optimization Phase, when doses of several concomitant antiepileptic
drugs were reduced at the investigator’s discretion, 39% of patients experienced at least a 50%
reduction in the frequency of seizures relative to pre-lamotrigine baselines; 11% were seizure-
free. Investigator ratings of patients’ clinical status corroborated these data derived from
caregiver diaries: the majority of patients were judged to have exhibited improvement in overall
clinical status as well as in seizure frequency, duration, and intensity during both the Maintenance
Phase and the Optimization Phase.
These data corroborate those from several other studies conducted in patients with mental
retardation or other intellectual impairment and epilepsy.20,34-37
For example, in an open-label
study of 45 patients ages 1 to 20 years with intractable epilepsy, 80% of whom were mentally
retarded, adjunctive use of lamotrigine for 4 to 35 months was associated with a greater than 30%
reduction in seizures in 36% of patients; 11% became seizure-free.20
Caregivers of more than half
(24) of patients reported behavioral improvements including increased contact, attention, and
alertness and less irritability while patients were taking lamotrigine. Similarly, Coppola and
Pascotto found that adjunctive use of lamotrigine for a median of 7 months among patients with
refractory epilepsy and mental delay was associated with a greater than 50% reduction in seizure
frequency relative to pre-lamotrigine baselines among 14% of patients; 22% of patients became
seizure-free.34
In another study of patients with intractable epilepsy and intellectual and/or
13

physical disability, lamotrigine as adjunctive therapy or monotherapy for 6 months to 2 years was
associated with a greater than 50% reduction in seizures for 77% of patients; 35% became
seizure-free.35
Concomitant antiepileptic drugs were discontinued in 36% of patients in this study,
and 22 of the 34 patients exhibited positive behavioral effects including increased alertness and
responsiveness. The more robust effects of lamotrigine on seizure frequency in this 34-patient
study compared with other studies including the current one may be attributed to that study’s
excluding patients who had failed to respond to lamotrigine or experienced significant side effects
with it.
These studies consistently demonstrate improvement in patients’ behavior and mood during
lamotrigine therapy although the behavioral data are primarily anecdotal and subjective. The
current study extends these previous findings by showing that besides reducing the frequency of
seizures lamotrigine improved objective behavioral measures in patients with mental retardation
and refractory epilepsy. Mean scores on the lethargy and stereotypy dimensions of the Aberrant
Behavior Checklist as well as the mean Habilitative Improvement Scale score significantly
improved over the course of lamotrigine therapy. Moreover, investigators rated social function as
having improved relative to pre-lamotrigine baselines in nearly half of patients on adjunctive
lamotrigine therapy. The magnitude of improvement in Aberrant Behavior Checklist scores
occurring with adjunctive use of lamotrigine is within the range considered to be clinically
meaningful.40,41
. The magnitude of change in score constituting a clinically meaningful change
has not yet been determined for the Habilitative Improvement Scale. These improvements in
behavior may be secondary to improved control of seizures with adjunctive use of lamotrigine.
Alternatively or in addition, lamotrigine may have mood-stabilizing and behavior-enhancing
properties independent of its antiseizure effects. The latter speculation is consistent with
lamotrigine’s established mood-stabilizing effects in bipolar disorder42
and with previous
14

observations showing dissociation of the mood- or behavior-enhancing and the antiseizure effects
of lamotrigine in patients with epilepsy.32,33
While lamotrigine was most often associated in the current study and others with positive effects
on mood and behavior, other studies have reported (albeit infrequently) negative effects of
lamotrigine on behavior in patients with intellectual impairment.36,43
. For example, Huber et al.
reported that although 26% of 125 multi-handicapped, institutionalized patients with treatment-
resistant epilepsy experienced positive psychotropic effects such as improvement in mood and
affect with adjunctive lamotrigine, 8% of patients experienced negative psychotropic effects
including aggression and inappropriate euphoric mood.36
Behaviors such as the latter may
comprise adverse effects of the drug, but it is equally possible that behaviors such as aggression
and euphoria may be manifestations of therapy-associated enhancement of arousal or alertness
during use of lamotrigine. In a subset of these patients , this effect may induce an elevation of
mood in the presence of a pre-existing state of hypomania and manifest in a behavioral
deterioration . This type of effect may occur more frequently in this population because the high
comorbidity of affective disorders in individuals with mental retardation and developmental
disabilities. These associated affective conditions, including hypomania, can be difficult to
assess, because social maladaptive behaviors is part of these disabilities. Previous published
reports on the negative behaviors associated with lamotrigene administration, did not screen or
assess pre-existing psychiatric or personality disorders prior to initiating medication. In addition,
lamotrigine therapy may be unmasking problematic behaviors that were masked during treatment
with sedating antiepileptic drugs. The patient switched from a heavily sedating antiepileptic drug
or drug combination to relatively non-sedating lamotrigine may exhibit a range of behaviors that
were not possible under sedation. In such cases, behavioral training may help in channeling
15

appropriately the newfound energy associated with removal of the sedating antiepileptic drug and
the institution of lamotrigine therapy.
Lamotrigene was well tolerated as adjunctive therapy in this study. The most common adverse
events that investigators considered to be possibly, probably, or definitely related to study
medication were somnolence and dizziness, both of which were reported among 5% or fewer
patients during the Maintenance or Optimization Phases. Despite the fact that lamotrigine was
added to multi-drug antiepileptic regimens, investigators judged that overall clinical status with
respect to adverse events remained unchanged for the majority of patients during lamotrigine
therapy. The adverse-event data suggest that the reduction in dose of concomitant antiepileptic
drugs during optimization of therapy with lamotrigine may have resulted in a decrease in the
incidence of some side effects. All of the most common adverse events occurred at a lower
incidence during the Optimization Phase when doses of some concomitant drugs were being
decreased than they did during the Escalation or Maintenance Phases when doses of the
concomitant antiepileptic drugs were maintained at pre-study levels. For example, during the
Optimization Phase when doses of concomitant drugs were being reduced, the incidence of
somnolence was reduced (3%) compared with either the Escalation Phase (6%) or the
Maintenance Phase (5%). This finding is consistent with previous observations that decreasing
the doses of sedating antiepileptics such as phenobarbital can be effected in patients with mental
retardation without compromising seizure control.2,4, 44
Several authors have emphasized the need
to reduce or eliminate the use of barbiturates, in particular, in patients with epilepsy who are
mentally retarded because of their strong association with somnolence and irritability.2,4
In their 1998 review on the management of epilepsy in individuals with intellectual disability,
Alvarez et al. suggest that
16

The initiation of treatment with broad-spectrum
antiepileptic drugs, or replacing several drugs with one
or two broad-spectrum antiepileptic drugs, may be of
considerable benefit to the individual with intellectual
disability. This management regime may avoid the
pitfall of reducing already limited intellectual resources
with excessive medication.5
The results of this study with broad-spectrum lamotrigine bear out this contention by showing
that adjunctive use of lamotrigine in patients with mental retardation and refractory epilepsy
decreased seizure frequency and improved several aspects of behavioral functioning while
permitting a reduction in dose of concomitant antiepileptic drugs.
17

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patients. Clin Drug Invest 1998;16:263-277.
20

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lamotrigine in patients with epilepsy and mental retardation. Epilepsia 1998;39:874-877.
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21

Figure 1. Patient disposition
22
Discontinuations during Baseline =28
Lack of seizures = 9
Consent withdrawn =6
Protocol violations = 5
Other =8
Discontinuations during Escalation =3
Adverse events =3
Discontinuations during Maintenance = 6
Adverse events =5
Non-compliance with medications =1
Discontinuations during Maintenance = 4
Protocol violations = 3
Adverse events =1
Entered Baseline
N = 95
N = 67
N = 64
N = 54
Completed study
N = 54
Entered Escalation
Entered Maintenance
Entered Optimization

Figure 2. Percentage of patients with at least 25%, 50%, or 75% reduction in seizure
frequency or free of seizures during the Maintenance and Optimization Phases relative to
the pre-lamotrigine Baseline Phase
54
44
26
15
61
39
28
11
0
20
40
60
80
PercentageofPatients
Maintenance Phase
Optimization Phase
Seizure Free≥ 75% Reduction≥ 50% Reduction≥ 25% Reduction
23
Percentage Change from Baseline Seizure Frequency

Figure 3. Percentages of patients rated by investigators as having improved, shown no
change, or deteriorated during the Maintenance Phase (top graph) or the Optimization
Phase (bottom graph) relative to the pre-lamotrigine Baseline Phase
11
4 2
9 8
11
26
31
50
70 70
64
23
19
9
15
19
37
72
13
41
71
64
60
0
20
40
60
80
100
Overall Status
Seizure Frequency
Seizure Duration
Seizure Intensity
Adverse Events
Social Function
Intellectual Function
Motor Function
Mild, Moderate, or Marked Deterioration
No Change
Mild, Moderate, or Marked Improvement
Optimization Phase
15
8 7
11
3 3
21
33
45
65
68
70
10
13
17
38
71
29
32
14
45
67
60 57
0
20
40
60
80
100
Overall Status
Seizure Frequency
Seizure Duration
Seizure Intensity
Adverse Events
Social Function
Intellectual Function
Motor Function
Mild, Moderate, or Marked Deterioration
No Change
Mild, Moderate, or Marked Improvement
24
PercentageofPatientsPercentageofPatients
Maintenance Phase

Figure 4. Mean Aberrant Behavior Checklist scores at the end of the Baseline,
Maintenance, and Optimization Phases. Decreases in scores signify improvement.
Irritability Lethargy Stereotypy Inappropriate
Speech
7.8
2.9
6.4
5.5
2.4
5
1
1.3
5.8
1.2
6.1
4.8*
4.7
2.3
5.1**
0
3
6
9
MeanScore
Baseline
Maintenance Phase
Optimization Phase
Hyperactivity
25
* p<.05 vs Baseline Phase
** p<.01 vs Baseline Phase

Table 1. Demographics and Patient Characteristics
Variable Value
Gender, n(%)
Male
Female
38(57%)
29(43%)
Race, n(%)
Asian
Black
Hispanic
White
1(1%)
7(10%)
5(7%)
54(81%)
Mean age, y (minimum, maximum) 28.5 (14, 54)
Severity of mental retardation, n(%)
Mild
Moderate
Severe
Profound
13(19%)
7(10%)
8(12%)
39(58%)
Habitation of patient, n(%)
Group or cluster home
Institution
Private family
11(16%)
31(46%)
25(37%)
Main seizure types at Screening, n(%)
Simple partial
Complex partial
Partial with secondary generalization
Generalized tonic-clonic
9(13%)
33(49%)
27(40%
27(40%)
Concomitant antiepileptic medications,
n(%)
Carbamazepine
Valproate
Phenytoin
Phenobarbital
Gabapentin
34(51%)
30(45%)
16(24%)
16(24%)
14(21%)
Mean lamotrigine dose, mg/day ±SD
Maintenance Phase
Patients on valproate (n=29)
Patients not on valproate (n=35)
Optimization Phase
Patients on valproate
Patients not on valproate
151±45
358±118
188±56
403±87
26

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