efficacy and behavioral benefits of the use of lamictal in the treatment the developmantally...

Finesmith et al., Lamotrigine in patients with refractory epilepsy and mental retardationEpilepsy 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

2Southern 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

lower incidence of neurologic adverse events such as asthenia, dizziness, and somnolence;15,16 and

4


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

functioning. Clinical status was rated as mild, moderate, or marked deterioration; no change;

or mild, moderate, or marked improvement;

7


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.

Data Analysis

8


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).

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

11


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

appropriately the newfound energy associated with removal of the sedating antiepileptic drug and

the institution of lamotrigine therapy.

15


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

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

16


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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21


Figure 1. Patient disposition

22


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

80Pe

rcen

tage

of P

atie

nts

Maintenance PhaseOptimization Phase

Seizure Free75% Reduction50% Reduction25% 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

114 2

9 8 11

2631

50

70 7064

2319

915

19

37

72

13

41

71

64 60

0

20

40

60

80

100

Ove ra ll Sta tus

Se izure Fre quency

Se izure Dura tion

Se izure Intensity

Adve rse Eve nts

Socia l Function

Inte lle ctua l Function

Motor Function

M ild, M oderate, or M arked DeteriorationNo Change

M ild, M oderate, or M arked Im provem ent

Optimization Phase

158 7

11

3 3

21

33

45

65 6870

10 1317

38

71

2932

14

45

67

60 57

0

20

40

60

80

100

Ove ra ll Sta tus

Se izure Fre quency

Se izure Dura tion

Se izure Intensity

Adve rse Eve nts

Socia l Function

Inte lle ctua l Function

Motor Function

M ild, M oderate, or M arked DeteriorationNo Change

M ild, M oderate, or M arked Im provem ent

24

Per

cent

age

of P

atie

nts

Per

cent

age

of P

atie

nts

Maintenance Phase


Figure 4. Mean Aberrant Behavior Checklist scores at the end of the Baseline,

Maintenance, and Optimization Phases. Decreases in scores signify improvement.

25

* p<.05 vs Baseline Phase** p<.01 vs Baseline Phase


Table 1. Demographics and Patient Characteristics

Variable ValueGender, 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±45358±118

188±56403±87

26

efficacy and behavioral benefits of the use of lamictal in the treatment the developmantally...

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