Managing Bipolar I Disorder With LAMICTAL

1
Managing Bipolar I Disorder With LAMICTAL
(lamotrigine)
Please see complete Prescribing Information.
2
Classification of Bipolar Disorder
3
Summary of DSM-IV-TR Classification of Bipolar
Disorders
Bipolar DisorderNot OtherwiseSpecified
Cyclothymic
Bipolar II
Bipolar I
Bipolar features that do not meet criteria for
any specific bipolar disorders
At least 2 years of numerous periods of hypomanic
and depressive symptoms
One or more major depressive episodes
accompanied by at least one hypomanic episode
One or more manic or mixed episodes, usually
accompanied by major depressive episodes
Symptoms do not meet criteria for manic and
depressive episodes.
First, ed. Diagnostic and Statistical Manual of
Mental Disorders. 4th ed. Text Rev. Washington,
DC American Psychiatric Association
2000345-428.
4
Summary of DSM-IV-TR Criteria forManic Episodes
in Bipolar Disorder

• Abnormally and persistently elevated, expansive,
  or irritable mood for at least 1 week
• Inflated self-esteem or grandiosity
• Decreased need for sleep
• Pressured speech
• Flight of ideas or racing thoughts
• Distractibility
• Increase in goal-directed activity or psychomotor
  agitation
• Excessive involvement in pleasurable activities
  that have a high potential for painful
  consequences

This symptom must be present.
First, ed. Diagnostic and Statistical Manual of
Mental Disorders. 4th ed. Text Rev. Washington,
DC American Psychiatric Association
2000345-428.
5
Summary of DSM-IV-TR Criteria for Major
Depressive Episodes in Bipolar Disorder

• Depressed mood
• Markedly diminished interest or pleasure
• Significant weight loss or gain or appetite
  increase or decrease
• Insomnia or hypersomnia
• Observable psychomotor agitation or retardation
• Fatigue or loss of energy
• Feelings of worthlessness or excessive or
  inappropriate guilt
• Diminished ability to think, concentrate, or make
  decisions
• Recurrent suicidal ideation, thoughts of death, a
  suicide attempt, or a specific plan for
  committing suicide

At least one of these symptoms must be present.
First, ed. Diagnostic and Statistical Manual of
Mental Disorders. 4th ed. Text Rev. Washington,
DC American Psychiatric Association
2000345-428.
6
Rapid Cycling Specifier

• ?4 episodes of depression, mania, mixed, or
  hypomania in previous 12 months
• Episodes demarcated by
• a period of full or partial remission for ?2
  months
• OR
• a switch to an episode of opposite polarity
• Distinct course modifier associated with poor
  clinical outcome

First, ed. Diagnostic and Statistical Manual of
Mental Disorders. 4th ed. Text Rev. Washington,
DC American Psychiatric Association
2000345-428.
7
Bipolar Disorder Impact and Challenges
8
Estimated Total Lifetime Cost per Case by
Prognosis Group
Thousands of dollars, 1998
Begley et al. Pharmacoeconomics. 200119(5 pt
1)483-495.
9
Bipolar Disorder Challenges

• Bipolar patients who present depressed may be
  diagnosed as having major depressive disorder and
  may be treated accordingly1
• This can result in treatment delay, inappropriate
  or undertreatment, and can lead to worsening of
  symptoms by switching into mania or cycle
  acceleration2
• The needs for treatment of bipolar disorder are
  substantial despite the risk of recurrence, the
  focus tends to be on short-term treatment.³ This
  creates problems over the long term
  inappropriate treatment may have a negative
  impact on patients2
• In the absence of large-scale and
  well-documented, positive clinical trials,
  management of bipolar depression has been mostly
  empirical

1. Hirschfeld. Prim Care Companion J Clin
Psychiatry. 200249-11. 2. Goodwin Jamison.
Manic-Depressive Illness. New York, NY Oxford
University Press 1990. 3. Goodwin. J Clin
Psychiatry. 200263(suppl 10)5-12.
10
Mood Disorder Questionnaire A Validated
Screening Tool

• Comprises 13 yes/no symptom questions, 1
  co-occurrence question, and 1 functional
  impairment question
• MDQ positive cases
• 7 or more symptoms AND
• co-occurrence during same time period AND
• moderate to severe functional impairment
• Positive screens indicate the need for a full
  clinical evaluation
• Can be accessed online at www.dbsalliance.org

Hirschfeld. Prim Care Companion J Clin
Psychiatry. 200249-11. Hirschfeld et al. Am J
Psychiatry. 20001571873-1875.
11
Mood Disorder Questionnaire
Has there ever been a period of time when you
were not your usual self and
you felt so good or so hyper that other people
thought you were not your normal self or you were
so hyper that you got into trouble? you were so
irritable that you shouted at people or started
fights or arguments? you felt much more
self-confident than usual? you got much less
sleep than usual and found you didnt really
miss it? you were much more talkative or spoke
much faster than usual? thoughts raced through
your head or you couldnt slowyour mind down?
Hirschfeld. Prim Care Companion J Clin
Psychiatry. 200249-11.
12
Mood Disorder Questionnaire (contd)
you were so easily distracted by things around
you that you had trouble concentrating or staying
on track? you had much more energy than
usual? you were much more active or did many
more thingsthan usual? you were much more
social or outgoing than usual for example, you
telephoned friends in the middle of the night?
you were much more interested in sex than
usual? you did things that were unusual for
you or that other people might have thought were
excessive, foolish, or risky? spending money
got you or your family into trouble?
Hirschfeld. Prim Care Companion J Clin
Psychiatry. 200249-11.
13
Mood Disorder Questionnaire (contd)
If you checked YES to more than one of the above,
have several of these ever happened during the
same period of time? How much of a problem
did any of these cause you like being unable to
work having family, money, or legal troubles
getting into arguments or fights? (Please circle
one response only.)
Hirschfeld. Prim Care Companion J Clin
Psychiatry. 200249-11.
14
Prevalence of Bipolar Spectrum in the US A
Large-Scale Epidemiological Study

• Objective to estimate rate of positive screens
  for bipolar I and II disorder among adults in the
  US
• The MDQ was mailed to 100,000 households
• Nationwide sample of gt80,000 respondents,
  representing broad age range and all regions
• Magnitude of public health problem further
  examined by estimating proportion of population
  reported to be undiagnosed or incorrectly
  diagnosed

Hirschfeld et al. J Clin Psychiatry. 2003
6453-59.
15
Bipolar Disorder 3.4 of the US Population
Screened Positive by MDQ
Weighted Percent
Overall Prevalence
Age Group
Income
Weighted to match US census data.
Hirschfeld et al. J Clin Psychiatry. 2003
6453-59.
16
Symptoms of Bipolar Disorder Heavy Impact on
Daily Life



Percent
Plt0.0001
Calabrese. J Clin Psychiatry. 200364425-432.
17
MDQ-Positive Patients Previous Diagnosis by
Physician
Percent of patients
Hirschfeld et al. J Clin Psychiatry. 2003
6453-59.
18
Bipolar Disorder A Diagnostic Challenge
Total
Base (n) 600
Misdiagnosis () 69
Times misdiagnosed 3.5
MDs consulted before Dx 4
Misdiagnosed as ()
Depression 60
Anxiety disorder 26
Schizophrenia 18
Borderline personality or antisocial personality disorder 17
Hirschfeld et al. J Clin Psychiatry.
200364161-174.
19
Treatment-Resistant Bipolar Depression More
Pervasive Than Mania (n258)
Total 121 days
Mean of days ill per year
Total 39.6 days
Time spent depressed exceeded time spent manic by
a factor of 3
Post et al. Clin Neurosci Res. 20022142-157.
20
Long-term Frequency of Depressive
Symptoms(Percent of Follow-up Weeks)
Mixed 13
Weeks With Symptoms 47
Weeks Without Symptoms 53
Manic/ Hypomanic 20
Depressed 67
Judd et al. Arch Gen Psychiatry. 200259530-537.
21
It Is Important to Recognize and Treat Bipolar
Depression

• Bipolar depression is more pervasive than mania1
• Mean duration of the depressive episode in
  bipolar disorder is longer than manic episodes2
• Depression is chronic in more than 20 of
  patients with bipolar disorder2
• Recently introduced medications (anticonvulsants
  and atypical antipsychotics) have predominantly
  antimanicrather than antidepressantproperties2

1. Post et al. Clin Neurosci Res.
20022142-157. 2. Ketter et al. J Clin
Psychiatry. 200263146-151.
22
Treatment Objectives for Bipolar Disorder

• Bipolar disorder is a lifelong illness
  therefore, maintenance treatment is the core of
  management1
• Treatment choice should be made by collaborative
  effort between patient and physician2
• The goal of acute therapy is to stabilize acute
  episodes with the goal of remission2
• The goal of maintenance therapy is to optimize
  protection against recurrence of episodes2
• Concurrently, attention needs to be devoted to
  maximizing patient functioning and minimizing
  subthreshold symptoms and adverse effects of
  treatment2

1. Calabrese et al. J Clin Psychiatry.
200263(suppl 10)18-22. 2. Hirschfeld et al. Am
J Psychiatry. 2002159(4 suppl)1-50.
23
FDA-Approved Treatment Options Indicated for
Bipolar DisorderUntil Lamotrigine
Drug Indication
Lithium1 Indicated in treatment of manic episodes Maintenance therapy prevents or diminishes intensity of subsequent episodes in those patients with a history of mania
Divalproex/ valproate2 Indicated for treatment of manic episodes Effectiveness for long-term use in mania (gt3 wks) has not been systematically evaluated in controlled clinical trials long-term usefulness for individual patients should be continually reevaluated
Olanzapine3 Indicated for short-term treatment of acute manic episodes associated with bipolar I disorder Effectiveness for long-term use in mania (gt4 wks) has not been systematically evaluated in controlled clinical trials risk and benefit in long-term use (gt4 wks) should be periodically reevaluated for the individual patient
1. Lithium prescribing information. 2. Depakote
prescribing information. 3. Zyprexa prescribing
information.
The brands listed are trademarks of their
respective owners and are not trademarks of the
GlaxoSmithKline Group of Companies. The makers of
these brands are not affiliated with and do not
endorse GlaxoSmithKline or its products.
24
Bipolar Depression Management Challenges and
Needs

• Challenges
• None of the available antidepressants are
  indicated by the FDA for use in bipolar
  depression
• The labeling of many antidepressants has been
  changed for the class to clarify that their
  indication is specifically for major depressive
  disorder (unipolar depression)
• Needs include
• A maintenance agent that
• delays mood episodes, especially depression
• can delay the relapse into both mania and
  depression
• has a favorable tolerability profile

25
Definition of Mood Stabilizer

• Several definitions of what constitutes a mood
  stabilizer have been proposed and include
• proven efficacy for the treatment of mania or
  depression,
• absence of exacerbation of manic or mixed
  symptoms,
• OR
• prophylactic efficacy
• Lamotrigine is the first drug since lithium to be
  indicated for the maintenance treatment of
  bipolar disorder

Hirschfeld et al. Am J Psychiatry. 2002159(4
suppl)1-50.
26
Acute Treatment vs Long-term Management

• Many patients continue to experience subthreshold
  symptoms even after recovering from an acute mood
  episode1
• Frequency and number of episodes can be reduced
  with maintenance therapy1
• Successful management of bipolar disorder
  requires a mood stabilizer with long-term
  efficacy across the spectrum of moods2

1. Goodwin. J Clin Psychiatry. 200263(suppl
10)5-12. 2. Calabrese et al. J Clin Psychiatry.
200263(suppl 10)18-22.
27
Lamotrigine Historical Milestones

• 1981 Epilepsy studies initiated
• 1990 First marketing approval for epilepsy
  granted (Ireland)
• 1994 FDA grants marketing approval in US as
  adjunctive therapy for partial seizures in
  adults with epilepsy
• 1995 First bipolar study initiated
• 1996 US IND for bipolar disorder filed
• 1997 18-month pivotal studies initiated in
  bipolar disorder
• 2002 First global approval for use in bipolar
  disorder
• 2003 FDA grants marketing approval for
  adjunctive therapy for partial seizures in
  pediatric patients ?2 years of age
• 2003 FDA grants marketing approval for the
  maintenance treatment of adults with bipolar I
  disorder to delay the time to occurrence of
  mood episodes in patients treated for acute mood
  episodes with standard therapy

28
Managing Bipolar I Disorder With Lamotrigine

• Bipolar medications such as lithium,
  divalproex/valproate, and olanzapine have been
  proven effective in acute mania
• Lamotrigine is the first approved maintenance
  treatment in bipolar disorder since lithium
• Lamotrigine has been proven effective in
  extending stability by delaying mood episodes in
  adults with bipolar I disorder in 2 long-term (18
  months) clinical trials
• Lamotrigine is now approved by the FDA for use in
  adults as maintenance treatment of bipolar I
  disorder to delay the time to occurrence of mood
  episodes (depression, mania, hypomania, mixed
  episodes) in patients treated for acute mood
  episodes with standard therapy

29
LamotrigineClinical Trials
30
Lamotrigine A New Approach to Long-term Mood
Stabilization With Proven Long-term Efficacy,
Especially for Bipolar Depression

• Indicated for the maintenance treatment of
  bipolar I disorder to delay the time to
  occurrence of mood episodes (depression, mania,
  hypomania, mixed episodes) in patients treated
  for acute mood episodes with standard therapy
• Offers long-term stability for mood episodes,
  with particular efficacy in depression as shown
  in 2 landmark maintenance trials of 18 months
  duration
• Combined, these trials represent the largest
  (n1,305) prospectively defined,
  placebo-controlled data set in bipolar disorder1

1. Data on file, GlaxoSmithKline.
31
A Placebo-Controlled 18-MonthTrial of
Lamotrigine and Lithium Maintenance Treatment in
Recently Manic or Hypomanic Patients With Bipolar
I Disorder
Landmark Maintenance Trial M
Bowden et al. Arch Gen Psychiatry.
200360392-400.
32
Study DesignCurrently or Recently
Manic/Hypomanic Patients
SCREEN
OPEN LABEL Lamotrigine 100-200 mg/day
DOUBLE-BLIND
Concomitant psychotropics
Bipolar I currently or recently
manic/hypomanic
Lamotrigine 100-400 mg/day (n59)
Lithium 0.8-1.1 mEq/L (n46)
Placebo (n70)
Stable pts randomized
2 weeks
8-16 weeks
76 weeks
Bowden et al. Arch Gen Psychiatry.
200360392-400.
33
Study DesignCurrently or Recently
Manic/Hypomanic Patients (contd)

• 78 of all patients utilized other psychiatric
  medications during the open-label phase1
• Concomitant psychotropic medications included
  benzodiazepines, selective serotonin reuptake
  inhibitors (SSRIs), atypical antipsychotics
  (including olanzapine), valproate, or lithium1,2
• Patients with CGI-S score ?3 for gt4 weeks,
  including at least the final week on monotherapy
  with lamotrigine, were randomized1

1. Bowden et al. Arch Gen Psychiatry.
200360392-400. 2. Data on file, GlaxoSmithKline.
34
Inclusion CriteriaCurrently or Recently
Manic/Hypomanic Patients

• Moderate to severely ill bipolar I disorder
  patients
• Currently or recently manic or hypomanic (DSM-IV
  criteria)
• OR
• Had been manic or hypomanic within 60 days of
  screening, had manic or hypomanic symptoms at
  enrollment, and had ?1 additional manic or
  hypomanic episode and 1 depressed episode
  (including mixed episodes according to DSM-IV
  criteria) within 3 years of enrollment
• Outpatients
• 18 years or older
• No significant thyroid disease
• No significant general health problems

Bowden et al. Arch Gen Psychiatry.
200360392-400.
35
Baseline Psychiatric ProfileCurrently or
Recently Manic/Hypomanic Patients

• 66 of patients required psychiatric
  hospitalization during their lives
• 29 of patients had attempted suicide
• 28 of patients had rapid-cycling disorder (4-6
  episodes per year)
• Patients had experienced a mean of 1.0
  depressive, 1.4 manic, 0.3 hypomanic, and 0.2
  mixed episodes in the past 12 months

Bowden et al. Arch Gen Psychiatry.
200360392-400.
36
Baseline Psychiatric ProfileCurrently or
Recently Manic/Hypomanic Patients (contd)

• Patients mean age at first depressive and manic
  episode was 23 and 26 years, respectively
• Average age at trial entry was 41 years
• Thus, the average patient in the study had been
  living with the disorder for 15-18 years

Bowden et al. Arch Gen Psychiatry.
200360392-400.
37
Study Endpoints Currently or Recently
Manic/Hypomanic Patients

• Primary endpoint was time to intervention
  (pharmacologic or ECT) for mood episodes (relapse
  or recurrence of a depressive, manic, hypomanic,
  or mixed episode)
• Secondary endpoints included
• time to intervention for a depressive episode
• time to intervention for a manic, hypomanic, or
  mixed episode
• This trial was not designed to demonstrate a
  difference on the secondary endpoints

Bowden et al. Arch Gen Psychiatry.
200360392-400.
38
Lamotrigine Delayed Time to Intervention for
Mood Episodes Currently or Recently
Manic/Hypomanic Patients
70 60 50 40 30 20 10 0
100 90 80 70 60 50 40 30 20 10 0
Lamotrigine 100-400 mg (n58) Placebo (n69)
44
Percent of patients
15
Estimated of pts intervention-free
18 mo
LTG vs PBO, P0.02
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Month
Bowden et al. Arch Gen Psychiatry.
200360392-400. Data on file, GlaxoSmithKline.
39
Lamotrigine Increased Median Number of Days to
Intervention for a Mood Episode Currently or
Recently Manic/Hypomanic Patients
141 days
Lamotrigine
66 more intervention-free days
85 days
Placebo
0
20
40
60
80
100
120
140
160
180
Median time to intervention (days)
Data on file, GlaxoSmithKline.
40
More Patients Taking Lamotrigine Remained
Intervention-Free for a Depressive Episode
Currently or Recently Manic/Hypomanic Patients
90 80 70 60 50 40 30 20 10 0
83
Lamotrigine 100-400 mg (n58) Placebo (n69)
100 90 80 70 60 50 40 30 20 10 0
40
Percent of patients
Estimated of pts intervention-free
18 mo
LTG vs PBO, P0.015
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Month
Note the study was not designed to demonstrate
a difference in time to intervention for a
depressive episode. Some patients considered
intervention-free for depressive episodes could
have had intervention for manic episodes.
Bowden et al. Arch Gen Psychiatry.
200360392-400. Data on file GlaxoSmithKline.
41
Time to Intervention for a Manic Episode
Currently or Recently Manic/Hypomanic Patients
100 90 80 70 60 50 40 30 20 10 0
Lamotrigine 100-400 mg (n56) Placebo (n69)
Estimated of pts intervention-free
LTG vs PBO, P0.280
1
2
3
4
5
6
7
8
9
10
11
12
13
0
14
15
16
17
18
Month
Note the study was not designed to demonstrate
a difference in time to intervention for a manic
episode. Some patients considered
intervention-free for manic episodes could have
had intervention for depressive episodes.
Bowden et al. Arch Gen Psychiatry.
200360392-400.
42
Adverse Events (?10) Currently or Recently
Manic/Hypomanic Patients
Bowden et al. Arch Gen Psychiatry.
200360392-400.
 
43
Summary Landmark Maintenance Trial M Currently
or Recently Manic/Hypomanic Patients

• Lamotrigine was more effective than placebo at
  prolonging the time to
• intervention for a mood episode of any polarity
  in patients who were currently or recently
  manic/hypomanic
• intervention for a depressive episode
• There was no evidence of worsening of manic
  symptoms compared with placebo, as measured by
  MRS score change from baseline
• Lamotrigine demonstrated a favorable tolerability
  profile
• When initiated in currently or recently
  manic/hypomanic bipolar I patients, lamotrigine
  is an effective long-term mood stabilizer,
  especially for delaying depression

Bowden et al. Arch Gen Psychiatry.
200360392-400.
44
A Placebo-Controlled 18-Month Trial of
Lamotrigine and Lithium Maintenance Treatment in
Recently Depressed Patients With Bipolar I
Disorder
Landmark Maintenance Trial D
Calabrese JR et al. J Clin Psych. In press.
45
Study DesignCurrently or Recently Depressed
Patients
SCREEN
OPEN LABEL Lamotrigine 100-200 mg/day
DOUBLE-BLIND
Placebo (n121)
Concomitant psychotropics
Lamotrigine 400 mg/day (n47)
Bipolar I currently or recently depressed
Lamotrigine 200 mg/day (n124)
Lamotrigine 50 mg/day (n50)
Lithium 0.8-1.1 mEq/L (n121)
Stable pts randomized
2 weeks
8-16 weeks
76 weeks
Calabrese JR et al. J Clin Psych. In press.
46
Inclusion CriteriaCurrently or Recently
Depressed Patients

• Moderate to severely ill bipolar I disorder
  patients
• Currently or recently depressed (DSM-IV criteria)
• OR
• Had been depressed within 60 days of screening,
  had depressive symptoms at enrollment, and had ?1
  additional manic or hypomanic episode and 1
  depressed episode (including mixed episodes
  according to DSM-IV criteria) within 3 years of
  enrollment
• Outpatients
• 18 years or older
• No significant thyroid abnormalities
• No significant general health problems

Calabrese JR et al. J Clin Psych. In press.
47
Baseline Psychiatric ProfileCurrently or
Recently Depressed Patients

• 81 of all patients utilized other psychotropic
  medications during the open-label phase
• 66 of patients required psychiatric
  hospitalization during their lives
• 37 of patients had attempted suicide
• 30 of patients had rapid-cycling disorder (4-6
  episodes per year)
• Patients had experienced a mean of 1.7
  depressive, 0.9 manic, 0.3 hypomanic, and 0.1
  mixed episodes in the past 12 months

Calabrese JR et al. J Clin Psych. In press.
48
Baseline Psychiatric ProfileCurrently or
Recently Depressed Patients (contd)

• Patients mean age at first depressive and manic
  episode was 23 and 27 years, respectively
• Average age at trial entry was 42 years
• Thus, the average patient in the study had been
  living with the disorder for 15-19 years

Calabrese JR et al. J Clin Psych. In press.
49
Study Endpoints Currently or Recently Depressed
Patients

• Primary endpoint was time to intervention
  (pharmacologic or ECT) for mood episodes (relapse
  or recurrence of a manic, hypomanic, mixed, or
  depressive episode)
• Secondary endpoints included
• Time to intervention for a depressive episode
• Time to intervention for a manic, hypomanic, or
  mixed episode
• This trial was not designed to demonstrate a
  difference on the secondary endpoints

Calabrese JR et al. J Clin Psych. In press.
50
Lamotrigine Delayed Time to Intervention for
Mood Episodes Currently or Recently Depressed
Patients
70 60 50 40 30 20 10 0
100 90 80 70 60 50 40 30 20 10 0
Lamotrigine 200 and 400 mg (n165) Placebo (n119)
36
Percent of patients
27
Estimated of pts intervention-free
18 mo
LTG vs PBO, P0.029
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Month
Data on file, GlaxoSmithKline. Calabrese JR et
al. J Clin Psych. In press.
51
Lamotrigine Increased Median Number of Days to
Intervention for a Mood EpisodeCurrently or
Recently Depressed Patients
200 days
Lamotrigine
115 more intervention-free days
93 days
Placebo
0
20
40
60
80
100
120
140
160
180
200
Median time to intervention (days)
Data on file, GlaxoSmithKline.
52
More Patients Taking Lamotrigine Remained
Intervention-Free for a Depressive
EpisodeCurrently or Recently Depressed Patients
70 60 50 40 30 20 10 0
100 90 80 70 60 50 40 30 20 10 0
Lamotrigine 200 and 400 mg (n165) Placebo (n119)
51
41
Percent of patients
Estimated of pts intervention-free
18 mo
LTG vs PBO, P0.047
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Month
Note the study was not designed to demonstrate
a difference in time to intervention for a
depressive episode. Some patients considered
intervention-free for depressive episodes could
have had intervention for manic episodes.
Data on file, GlaxoSmithKline. Calabrese JR et
al. J Clin Psych. In press.
53
Time to Intervention for a Manic
EpisodeCurrently or Recently Depressed Patients
Lamotrigine 200 and 400 mg (n165) Placebo (n119)
100 90 80 70 60 50 40 30 20 10 0
Estimated of pts intervention-free
LTG vs PBO, P0.339
1
2
3
4
5
6
7
8
9
10
11
12
13
0
14
15
16
17
18
Month
Note the study was not designed to demonstrate
a difference in time to intervention for a manic
episode. Some patients considered
intervention-free for manic episodes could have
had intervention for depressive episodes.
Calabrese JR et al. J Clin Psych. In press.
54
Adverse Events (?10)Currently or Recently
Depressed Patients
Lamotrigine 200 and 400 mg/day groups combined.
Calabrese JR et al. J Clin Psych. In press.
55
Summary Landmark Maintenance Trial DCurrently
or Recently Depressed Patients

• Lamotrigine was more effective than placebo at
  prolonging the time to
• intervention for a mood episode of any polarity
  in patients who were currently or recently
  depressed
• intervention for a depressive episode
• Lamotrigine demonstrated a favorable tolerability
  profile
• When initiated in currently or recently depressed
  bipolar I patients, lamotrigine is an effective
  long-term mood stabilizer, especially for
  delaying depression
• This is the largest (n966) placebo-controlled
  maintenance study in bipolar disorder in
  currently or recently depressed patients

Data on file, GlaxoSmithKline. Calabrese JR et
al. J Clin Psych. In press.
56
Lamotrigine as a Long-term Mood Stabilizer in
Currently/Recently Depressed or Manic Bipolar I
Patients Prospective Analysis of Combined
Landmark Maintenance Trials M and D
57
Lamotrigine Delayed Time to Intervention for Mood
Episodes Combined Analysis
70 60 50 40 30 20 10 0
100 90 80 70 60 50 40 30 20 10 0
Lamotrigine 100-400 mg (n223) Placebo (n188)
37
Percent of patients
22
Estimated of pts intervention-free
18 mo
LTG vs PBO, Plt0.001
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Month
Data on file, GlaxoSmithKline.
58
Lamotrigine Increased Median Number of Days to
Intervention for a Mood Episode Combined Analysis
197 Days
Lamotrigine
129 more intervention-free days
86 Days
Placebo
0
20
40
60
80
100
120
140
160
180
200
Median time to intervention (days)
Data on file, GlaxoSmithKline.
59
More Patients Taking Lamotrigine Remained
Intervention-Free for a Depressive Episode
Combined Analysis
70 60 50 40 30 20 10 0
57
100 90 80 70 60 50 40 30 20 10 0
41
Lamotrigine 100-400 mg (n233) Placebo (n188)
Percent of patients
Estimated of pts intervention-free
18 mo
LTG vs PBO, P0.009
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Month
Some patients considered intervention-free for
depressive episodes could have had intervention
for manic episodes.
Data on file, GlaxoSmithKline.
60
Time to Intervention for a Manic Episode
Combined Analysis
70 60 50 40 30 20 10 0
65
100 90 80 70 60 50 40 30 20 10 0
53
Lamotrigine 100-400 mg (n223) Placebo (n188)
Percent of patients
Estimated of pts intervention-free
18 mo
LTG vs PBO, P0.034
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Month
Some patients considered intervention-free for
manic episodes could have had intervention for
depressive episodes.
Data on file, GlaxoSmithKline.
61
Treatment-Emergent Adverse Events Combined
Analysis Open-Label Phase
Incidence (?5 and Numerically Greater During
DoseEscalation Phase) of Treatment-Emergent
Adverse Events
Adverse Event Percentage
Headache 25
Rash 11
Dizziness 10
Diarrhea 8
Dream abnormality 6
Pruritus 6
  When patients may have been receiving
concomitant psychotropic medications.
62
Treatment-Emergent Adverse Events Combined
Analysis Randomized Phase
Incidence (?5 and Numerically Greater Than
Placebo) of Treatment-Emergent Adverse Events
Placebo (n190)
Lamotrigine (n227)
Adverse event
Back pain 8 6 Fatigue 8 5 Abdominal
pain 6 3 Nausea 14 11 Constipation 5 2 Vomiting 5
2 Insomnia 10 6 Somnolence 9 7 Xerostomia (dry
mouth) 6 4 Rhinitis 7 4 Exacerbation of
cough 5 3 Pharyngitis 5 4 Rash (non-serious) 7 5
63
Incidence of Mania/Hypomania/Mixed Episodes
Reported as Adverse Events Combined Analysis
25
20
15
Percent of patients
10
5
0
Lamotrigine (n227)
Lithium (n166)
Placebo (n190)
In all bipolar control trials, adverse events of
mania were reported as 5 lamotrigine, 3
lithium, and 4 placebo.
64
SummaryProspectively Defined Combined Analysis

• This prospectively defined combined analysis
  reinforces the finding of the individual trials
  on the primary endpoint for lamotrigine
• In currently or recently depressed, manic, or
  hypomanic bipolar I patients, lamotrigine
• was more effective than placebo in prolonging
  time to intervention for mood episodes
• was effective at prolonging time to intervention
  for depressive episodes
• was effective at prolonging time to intervention
  for manic episodes
• however, findings were more robust for depression
  
• Lamotrigine demonstrated a favorable tolerability
  profile

Data on file, GlaxoSmithKline.
65
Lamotrigine An Effective Mood Stabilizer for
Long-term Maintenance of Patients With Bipolar I
Disorder

• The dichotomous nature of bipolar disorder
  demands that any management plan treat both
  phases of the illness long-term without
  neglecting or exacerbating one phase or the other
• Because of the chronic nature of the disorder,
  treatments that offer the opportunity for
  long-term maintenance are critical
• Two large-scale clinical studies have confirmed
  lamotrigines ability to delay recurrence of mood
  episodes1,2
• Lamotrigine is particularly effective in delaying
  depressive episodes
• Given its favorable tolerability profile and
  effectiveness, lamotrigine is a valuable option
  to manage bipolar disorder long-term

1. Bowden et al. Arch Gen Psychiatry.
200360392-400. 2. Calabrese JR et al. J Clin
Psych. In press.
66
Recommendations for Maintenance Treatment of
Bipolar I Disorder(Adapted From APA Guidelines)

If one medication was used to achieve remission
from the most recent episode, it should be
continued level I.
Hirschfeld et al. Am J Psychiatry. 2002159(4
suppl)1-50.
67
LamotrigineConsiderations for Use in the
Treatment of Bipolar I Disorder
68
Bipolar Indication

• Lamotrigine is indicated for the maintenance
  treatment of bipolar I disorder to delay the time
  to occurrence of mood episodes (depression,
  mania, hypomania, mixed episodes) in patients
  treated for acute mood episodes with standard
  therapy
• The effectiveness of lamotrigine in the acute
  treatment of mood episodes has not been
  established

69
Lamotrigine Proposed Mechanism of Action

• The mechanism of action of lamotrigine in bipolar
  disorder or epilepsy is unknown
• In vitro, it has been found to inhibit
  voltage-sensitive sodium currents, thereby
  stabilizing neuronal membranes
• Modulates presynaptic transmitter release of
  excitatory amino acids (eg, glutamate and
  aspartate)

70
Lamotrigine Pharmacokinetic Profile No Blood
Monitoring Required

• Unlike lithium, no serum level monitoring is
  required with lamotrigine
• Absorption
• Dose dependent No
• Bioavailability () gt98
• Tmax (h) 1.4 4.8
• Protein binding () 55
• Metabolites Inactive
• t1/2 (h) 12 - 70
• Autoinduction Slight

71
Lamotrigine Drug Interactions With Commonly
Prescribed Psychotropic Agents
Results of in vitro experiments suggest that
clearance of lamotrigine is unlikely to be
reduced by concomitant administration of a number
of other psychotropic drugs, including
amitriptyline, clonazepam, clozapine, fluoxetine,
haloperidol, lorazepam, phenelzine, risperidone,
sertraline, or trazodone
72
Lamotrigine Effect of Oral Contraceptives

• In women taking lamotrigine, there have been
  reports of decreased lamotrigine concentrations
  following introduction of oral contraceptives and
  reports of increased lamotrigine concentrations
  following withdrawal of oral contraceptives
• Dosage adjustments may be necessary to maintain
  response when starting or stopping oral
  contraceptives

73
Lamotrigine Use During Pregnancy

• Pregnancy Category C
• Risk cannot be ruled out
• Adequate, well controlled human studies are
  lacking, and animal studies have shown a risk to
  the fetus OR are lacking
• Should be used only if the potential benefit of
  treatment justifies the potential risk to the
  fetus
• Physiological changes during pregnancy may affect
  lamotrigine concentrations and/or therapeutic
  effect. There have been reports of decreased
  lamotrigine concentrations during pregnancy and
  restoration of pre-partum concentrations after
  delivery. Dosage adjustments may be necessary to
  maintain clinical response.

74
Pregnancy Registries

• Lamotrigine Pregnancy Registry
• Physician enrollment of patients
• [phone]
• North American Antiepileptic Drug Pregnancy
  Registry
• Patient self-enrollment
• [phone]

75
Initiation of Treatment With Lamotrigine

• In two 18-month double-blind, placebo-controlled
  studies
• Lamotrigine was initiated in patients with
  bipolar I disorder who were
• Currently manic or hypomanic
• Recently (within 60 days) manic or hypomanic
• Currently depressed
• Recently (within 60 days) depressed
• Lamotrigine was initiated based on concomitant
  medications
• For patients not taking CBZ or EIAEDs 25 mg
  daily
• For patients taking VPA 25 mg every other day
• For patients taking CBZ or other EIAEDs 50 mg
  daily
• Can be initiated at any phase of the illness
  (depressed, manic, hypomanic, mixed) for patients
  treated for acute mood episodes with standard
  therapy

76
Dosage and Administration of Lamotrigine in
Adult Bipolar I Patients

• Doses above target dose are not recommended.
• Because of an increased risk of rash, the
  recommended initial dose and subsequent dose
  escalations should not be exceeded.

77
Dosing at Greater Than Recommended Doses

• In the clinical trials, doses up to 400 mg/day as
  monotherapy were evaluated
• No additional benefit was seen at 400 mg/day
  compared with 200 mg/day accordingly, doses
  above 200 mg/day are not recommended
• The safety profile of lamotrigine in labeling
  describes the experience for bipolar patients
  dosed from 100-400 mg/day

78
Lamotrigine Supplied As
25 mg
100 mg
150 mg
200 mg
79
Lamotrigine Sample Kits
80
Lamotrigine Dispensing Errors Alert

• When prescribing lamotrigine, be sure to write or
  say lamotrigine clearly and instruct your
  patients to check their medicine
• Dispensing errors have been reported with
  lamotrigine and other medications, most commonly
  Lamisil, lamivudine, Ludiomil, labetalol, and
  Lomotil
• Patients who do not receive lamotrigine would be
  inadequately treated and could experience serious
  consequences
• Conversely, patients erroneously receiving
  lamotrigine, especially high initial doses, would
  be unnecessarily subjected to a risk of serious
  side effects

The brands listed are trademarks of their
respective owners and are not trademarks of the
GlaxoSmithKline Group of Companies. The makers of
these brands are not affiliated with and do not
endorse GlaxoSmithKline or its products.
81
Lamotrigine Important Safety Information
82
Lamotrigine Important Safety Information

• Serious rashes requiring hospitalization and
  discontinuation of treatment have been reported
  with lamotrigine, some of which have included
  Stevens-Johnson syndrome
• In clinical trials of bipolar and other mood
  disorders, the incidence of these rashes was
  0.08 in adult patients receiving lamotrigine as
  initial monotherapy and 0.13 in adult patients
  receiving lamotrigine as adjunctive therapy
• The incidence of these rashes was approximately
  0.3 in adult epilepsy patients receiving
  lamotrigine as adjunctive therapy

83
Lamotrigine Important Safety Information
(contd)

• The rate of serious rash is approximately 0.8 in
  pediatric patients (age lt16 years) receiving
  lamotrigine as adjunctive therapy for epilepsy.
  In a prospectively followed cohort of 1,983
  pediatric patients with epilepsy, there was one
  rash-related death
• The safety and effectiveness in patients lt18
  years with bipolar disorder has not been
  established 
• In worldwide postmarketing experience, rare cases
  of toxic epidermal necrolysis and/or rash-related
  death have been reported, but their numbers are
  too few to permit a precise estimate of the rate
• Lamotrigine should ordinarily be discontinued at
  the first sign of rash, unless the rash is
  clearly not drug-related

84
Lamotrigine Serious Rash

• Risk of rash is higher in pediatric patients
• Risk of rash may be increased by
• Coadministration of valproate
• Exceeding the recommended
• Initial dose of lamotrigine
• Dose escalation of lamotrigine
• Because of an increased risk of rash, initial
  dose and subsequent dose escalations of
  lamotrigine should not be exceeded

85
Lamotrigine Recommendations Concerning Rash

• Patients who develop a rash should be promptly
  evaluated
• Lamotrigine should be discontinued at the first
  sign of rash
• Unless rash is clearly not drug-related
• Discontinuation may not prevent a rash from
  becoming a life-threatening situation or
  permanently disabling or disfiguring
• Prior to initiation of treatment with
  lamotrigine, the patient should be instructed
  that a rash or other signs or symptoms of
  hypersensitivity (eg, fever, lymphadenopathy) may
  herald a serious medical event and that the
  patient should report any such occurrence to a
  physician immediately

86
Lamotrigine Additional Important Safety
Information

• Hypersensitivity Reactions
• Hypersensitivity reactions, some fatal or
  life-threatening, have been observed
• Some have included clinical features of
  multiorgan failure/dysfunction, including
  hepatic abnormalities and evidence of
  disseminated intravascular coagulation
• Early manifestations of hypersensitivity (eg,
  fever, lymphadenopathy) may be present even if a
  rash is not evident
• If these symptoms present, the patient should be
  evaluated immediately and lamotrigine should be
  discontinued if an alternative etiology for
  symptoms cannot be established

87
Case Studies
88
Case 1

• History
• EB is a 22-year-old male presenting with a recent
  history of sleeping for 10-12 hours a day,
  difficulty functioning at work and socially, and
  extreme lethargy
• Upon questioning, he reveals that in the last 5
  years he has experienced 2 episodes characterized
  by extremely elevated mood, pressured speech,
  hypersexuality, and poor judgmentone episode led
  to hospitalization
• He has a history of occasional substance use

89
Case 1

• Next steps
• What medication(s) would you prescribe and why?

90
Case 2

• History
• RP is an 18-year-old college student presenting
  with acute depression
• Questioning reveals that in his mid-teens, he
  experienced several depressive episodes,
  alternating with extreme mood swings and
  sometimes aggressive behavior that resulted in
  arrest later in the course of his treatment, he
  was treated for major depressive episodes with
  medication, which he continues to take
  periodically
• Since starting college, he reports more frequent
  mood swings and occasional alcohol use

91
Case 2

• Next steps
• You conclude that RP probably has bipolar
  disorder
• What medication(s) would you initiate?
• What are the data that support your decision?

92
Case 3

• History
• HM is a 33-year-old woman with a 10-year history
  of bipolar disorder
• During a current manic episode, she is arrested
  for indecent public exposure and admitted to the
  psychiatric ward for observation
• During hospitalization, she continues to show
  signs of elevated mood, hypersexuality, and
  decreased need for sleep
• On admission she reports having taken medication
  regularly for her depression and mania

93
Case 3

• Next steps
• You conclude that HM is experiencing an episode
  of acute mania
• Would you consider adding an antipsychotic to
  this patients regimen, at least during the acute
  episode?
• Would you consider adding lamotrigine for
  maintenance treatment?

94
Case 4

• History
• RW is a 30-year-old woman with a history of
  relatively stable depression-predominant bipolar
  disorder for 10 years
• 1 year ago, she started treatment for a major
  depressive episode
• She then began having episodes of mania,
  separated by periods of depression
• She is currently in a depressed phase
• She has a recent history of infectious
  mononucleosis and mild thyroid hypofunction

95
Case 4

• Next steps
• What, if anything, would you remove from or add
  to her treatment regimen?