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Managing Bipolar I Disorder With LAMICTAL ® (lamotrigine). Please see complete Prescribing Information. Classification of Bipolar Disorder. Summary of DSM-IV-TR Classification of Bipolar Disorders. Bipolar I. Bipolar II. Cyclothymic. Bipolar Disorder Not Otherwise Specified.

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Managing bipolar i disorder with lamictal lamotrigine l.jpg

Managing Bipolar I Disorder With LAMICTAL® (lamotrigine)

Please see complete Prescribing Information.



Summary of dsm iv tr classification of bipolar disorders l.jpg
Summary of DSM-IV-TR Classification of Bipolar Disorders

Bipolar I

Bipolar II

Cyclothymic

Bipolar DisorderNot OtherwiseSpecified

One or more manic or mixed episodes, usually accompanied by major depressive episodes

One or more major depressive episodes accompanied by at least one hypomanic episode

At least 2 years of numerous periods of hypomanic and depressive symptoms*

Bipolar features that do not meet criteria for any specific bipolar disorders

* 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; 2000:345-428.


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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; 2000:345-428.


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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; 2000:345-428.


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Rapid Cycling Specifier in Bipolar Disorder

  • 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; 2000:345-428.


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Bipolar Disorder in Bipolar Disorder—Impact and Challenges


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Estimated Total Lifetime Cost per Case in Bipolar Disorderby Prognosis Group

Thousands of dollars, 1998

Begleyet al. Pharmacoeconomics. 2001;19(5 pt 1):483-495.


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Bipolar Disorder in 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. 2002;4:9-11.

2. Goodwin & Jamison. Manic-Depressive Illness. New York, NY: Oxford University Press; 1990.

3. Goodwin. J Clin Psychiatry. 2002;63(suppl 10):5-12.


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Mood Disorder Questionnaire in Bipolar Disorder—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. 2002;4:9-11.

Hirschfeld et al. Am J Psychiatry. 2000;157:1873-1875.


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Mood Disorder Questionnaire in Bipolar Disorder

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 didn’t really miss it?

… you were much more talkative or spoke much faster than usual?

… thoughts raced through your head or you couldn’t slowyour mind down?

Hirschfeld. Prim Care Companion J Clin Psychiatry. 2002;4:9-11.


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Mood Disorder Questionnaire (cont’d) in Bipolar Disorder

… 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. 2002;4:9-11.


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Minor problem in Bipolar Disorder

Moderate problem

Serious problem

No problem

Mood Disorder Questionnaire (cont’d)

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. 2002;4:9-11.


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Prevalence of Bipolar Spectrum in the US in Bipolar Disorder—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 >80,000 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; 64:53-59.


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Bipolar Disorder in 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; 64:53-59.


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Symptoms of Bipolar Disorder in Bipolar Disorder—Heavy Impact on Daily Life

*

*

*

Percent

* P<0.0001

Calabrese. J Clin Psychiatry. 2003;64:425-432.


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MDQ-Positive Patients — in Bipolar DisorderPrevious Diagnosis by Physician

Percent of patients

Hirschfeld et al. J Clin Psychiatry. 2003; 64:53-59.


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Bipolar Disorder in Bipolar Disorder —A Diagnostic Challenge

Hirschfeld et al. J Clin Psychiatry. 2003;64:161-174.


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Treatment-Resistant Bipolar Depression in Bipolar Disorder—More Pervasive Than Mania (n=258)

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 NeurosciRes. 2002;2:142-157.


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Patients with bipolar I disorder experienced mood symptoms nearly half of the time during a 12.8-year follow-up period.

  • Depressive symptoms were predominant

  • Depression was 3.5-fold more frequent than mania

  • 90% of patients had at least 1 week of depressive symptoms

  • Depression (but not mania) predicted greater future illness burden

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. 2002;59:530-537.


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It Is Important to Recognize and nearly half of the time during a 12.8-year follow-up period.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 antimanic—rather than antidepressant—properties2

1. Post et al. Clin Neurosci Res. 2002;2:142-157.

2. Ketter et al. J Clin Psychiatry. 2002;63:146-151.


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Treatment Objectives for nearly half of the time during a 12.8-year follow-up period.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. 2002;63(suppl 10):18-22.

2. Hirschfeld et al. Am J Psychiatry. 2002;159(4 suppl):1-50.


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FDA-Approved Treatment Options Indicated for Bipolar Disorder—Until Lamotrigine

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.


Bipolar depression management challenges and needs l.jpg
Bipolar Depression Disorder —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


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Definition of Mood Stabilizer Disorder

  • 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. 2002;159(4 suppl):1-50.


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Acute Treatment vs Long-term Management Disorder

  • 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. 2002;63(suppl 10):5-12.

2. Calabrese et al. J Clin Psychiatry. 2002;63(suppl 10):18-22.


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Lamotrigine Disorder – 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


Managing bipolar i disorder with lamotrigine l.jpg
Managing Bipolar I Disorder DisorderWith 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



Slide30 l.jpg
Lamotrigine Disorder— 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 (n=1,305) prospectively defined, placebo-controlled data set in bipolar disorder1

1. Data on file, GlaxoSmithKline.


Slide31 l.jpg

A Placebo-Controlled 18-Month DisorderTrial 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. 2003:60:392-400.


Study design currently or recently manic hypomanic patients l.jpg
Study Design DisorderCurrently 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 (n=59)

Lithium 0.8-1.1 mEq/L (n=46)

Placebo (n=70)

Stable pts randomized

8-16 weeks

2 weeks

76 weeks

Bowden et al. Arch Gen Psychiatry. 2003:60:392-400.


Study design currently or recently manic hypomanic patients cont d l.jpg
Study Design DisorderCurrently or Recently Manic/Hypomanic Patients (cont’d)

  • 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 >4 weeks, including at least the final week on monotherapy with lamotrigine, were randomized1

1. Bowden et al. Arch Gen Psychiatry. 2003:60:392-400.

2. Data on file, GlaxoSmithKline.


Inclusion criteria currently or recently manic hypomanic patients l.jpg
Inclusion Criteria DisorderCurrently 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. 2003:60:392-400.


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Baseline Psychiatric Profile DisorderCurrently 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. 2003:60:392-400.


Slide36 l.jpg

Baseline Psychiatric Profile DisorderCurrently or Recently Manic/Hypomanic Patients (cont’d)

  • 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. 2003:60:392-400.


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Study Endpoints DisorderCurrently 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. 2003:60:392-400.


Slide38 l.jpg
Lamotrigine Delayed Time to Intervention Disorderfor 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 (n=58)

Placebo (n=69)

44

Percent of patients

15

Estimated % of pts intervention-free

18 mo

LTG vs PBO, P=0.02

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. 2003:60:392-400.

Data on file, GlaxoSmithKline.


Slide39 l.jpg
Lamotrigine Increased Median Number of Days to Intervention for a Mood EpisodeCurrently 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.


Slide40 l.jpg
More Patients Taking Lamotrigine Remained Intervention-Free for a Depressive EpisodeCurrently or Recently Manic/Hypomanic Patients

90

80

70

60

50

40

30

20

10

0

83

Lamotrigine 100-400 mg (n=58)

Placebo (n=69)

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, P=0.015

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. 2003:60:392-400.

Data on file GlaxoSmithKline.


Time to intervention for a manic episode currently or recently manic hypomanic patients l.jpg
Time to Intervention for a Manic Episode for a Depressive EpisodeCurrently or Recently Manic/Hypomanic Patients

100

90

80

70

60

50

40

30

20

10

0

Lamotrigine 100-400 mg (n=56)

Placebo (n=69)

Estimated % of pts intervention-free*

LTG vs PBO, P=0.280

0

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 manic episode.

  • * Some patients considered intervention-free for manic episodes could have had intervention for depressive episodes.

Bowden et al. Arch Gen Psychiatry. 2003:60:392-400.


Slide42 l.jpg

Adverse Events ( for a Depressive Episode10%) Currently or Recently Manic/Hypomanic Patients

Bowden et al. Arch Gen Psychiatry. 2003:60:392-400.


Summary landmark maintenance trial m currently or recently manic hypomanic patients l.jpg
Summary: Landmark Maintenance Trial M for a Depressive EpisodeCurrently 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. 2003:60:392-400.


Slide44 l.jpg

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.


Study design currently or recently depressed patients l.jpg
Study Design Lithium Maintenance Treatment in Recently Depressed Patients With Bipolar I DisorderCurrently or Recently Depressed Patients

SCREEN

OPEN LABEL

Lamotrigine 100-200 mg/day

DOUBLE-BLIND

Placebo (n=121)

Concomitant

psychotropics

Lamotrigine 400 mg/day (n=47)

Bipolar I

currently

or recently

depressed

Lamotrigine 200 mg/day (n=124)

Lamotrigine 50 mg/day (n=50)

Lithium 0.8-1.1 mEq/L (n=121)

Stable pts randomized

2 weeks

8-16 weeks

76 weeks

Calabrese JR et al. J Clin Psych. In press.


Inclusion criteria currently or recently depressed patients l.jpg
Inclusion Criteria Lithium Maintenance Treatment in Recently Depressed Patients With Bipolar I DisorderCurrently 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.


Baseline psychiatric profile currently or recently depressed patients l.jpg
Baseline Psychiatric Profile Lithium Maintenance Treatment in Recently Depressed Patients With Bipolar I DisorderCurrently 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.


Baseline psychiatric profile currently or recently depressed patients cont d l.jpg
Baseline Psychiatric Profile Lithium Maintenance Treatment in Recently Depressed Patients With Bipolar I DisorderCurrently or Recently Depressed Patients (cont’d)

  • 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.


Study endpoints currently or recently depressed patients l.jpg
Study Endpoints Lithium Maintenance Treatment in Recently Depressed Patients With Bipolar I DisorderCurrently 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.


Lamotrigine delayed time to intervention for mood episodes currently or recently depressed patients l.jpg
Lamotrigine Delayed Time to Lithium Maintenance Treatment in Recently Depressed Patients With Bipolar I DisorderIntervention 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 (n=165)

Placebo (n=119)

36

Percent of patients

27

Estimated % of pts intervention-free

18 mo

LTG vs PBO, P=0.029

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.


Slide51 l.jpg
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.


Slide52 l.jpg
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 (n=165)

Placebo (n=119)

51

41

Percent of patients

Estimated % of pts intervention-free*

18 mo

LTG vs PBO, P=0.047

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.


Time to intervention for a manic episode currently or recently depressed patients l.jpg
Time to Intervention for a Manic Episode for a Depressive EpisodeCurrently or Recently Depressed Patients

Lamotrigine 200 and 400 mg (n=165)

Placebo (n=119)

100

90

80

70

60

50

40

30

20

10

0

Estimated % of pts intervention-free*

LTG vs PBO, P=0.339

0

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 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.


Adverse events 10 currently or recently depressed patients l.jpg
Adverse Events ( for a Depressive Episode10%)Currently or Recently Depressed Patients

* Lamotrigine 200 and 400 mg/day groups combined.

Calabrese JR et al. J Clin Psych. In press.


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Summary: Landmark Maintenance Trial D for a Depressive EpisodeCurrently 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 (n=966) 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.


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  • Prospective Analysis of Combined Landmark Maintenance Trials M and D


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    Lamotrigine Delayed Time to Intervention for Mood Episodes Currently/Recently Depressed or Manic Bipolar I PatientsCombined Analysis

    70

    60

    50

    40

    30

    20

    10

    0

    100

    90

    80

    70

    60

    50

    40

    30

    20

    10

    0

    Lamotrigine 100-400 mg (n=223)

    Placebo (n=188)

    37

    Percent of patients

    22

    Estimated % of pts intervention-free

    18 mo

    LTG vs PBO, P<0.001

    1

    2

    3

    4

    5

    6

    7

    8

    9

    10

    11

    12

    13

    14

    15

    16

    17

    18

    Month

    Data on file, GlaxoSmithKline.


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    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.


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    39% for a Mood Episode

    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 (n=233)

    Placebo (n=188)

    Percent of patients

    Estimated % of pts intervention-free*

    18 mo

    LTG vs PBO, P=0.009

    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.


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    22% for a Mood Episode

    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 (n=223)

    Placebo (n=188)

    Percent of patients

    Estimated % of pts intervention-free*

    18 mo

    LTG vs PBO, P=0.034

    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.


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    Treatment-Emergent Adverse Events for a Mood Episode Combined Analysis — Open-Label Phase*

    Incidence (5% and Numerically Greater During DoseEscalation Phase) of Treatment-Emergent Adverse Events

     * When patients may have been receiving concomitant psychotropic medications.


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    Treatment-Emergent Adverse Events for a Mood Episode Combined Analysis – Randomized Phase

    Incidence (5% and Numerically Greater Than Placebo) of Treatment-Emergent Adverse Events

    Adverse event

    Lamotrigine (n=227)

    %

    Placebo (n=190)

    %

    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


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    Incidence of Mania/Hypomania/Mixed for a Mood Episode Episodes Reported as Adverse EventsCombined Analysis

    25

    20

    15

    Percent of patients

    10

    5

    0

    Lamotrigine (n=227)

    Lithium (n=166)

    Placebo (n=190)

    In all bipolar control trials, adverse events of mania were reported as 5% lamotrigine, 3% lithium, and 4% placebo.


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    Summary: for a Mood Episode Prospectively DefinedCombined 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.


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    Lamotrigine for a Mood Episode — An Effective Mood Stabilizer for Long-term Maintenance of Patients With Bipolar IDisorder

    • 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 lamotrigine’s 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. 2003:60:392-400.

    2. Calabrese JR et al. J Clin Psych. In press.


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    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. 2002;159(4 suppl):1-50.


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    Lamotrigine: DisorderConsiderations for Use in the Treatment of Bipolar I Disorder


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    Bipolar Indication Disorder

    • 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


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    Lamotrigine Disorder—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)


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    Lamotrigine Disorder— Pharmacokinetic Profile No Blood Monitoring Required

    • Unlike lithium, no serum level monitoring is required with lamotrigine

      Absorption

      Dose dependent No

      Bioavailability (%) >98

      Tmax (h) 1.4 – 4.8

      Protein binding (%) 55

      Metabolites Inactive

      t1/2 (h) 12 - 70

      Autoinduction Slight


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    Lamotrigine Disorder— 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


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    Lamotrigine — Effect of Oral Contraceptives Disorder

    • 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


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    Lamotrigine — Use During Pregnancy Disorder

    • 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.


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    Pregnancy Registries Disorder

    • Lamotrigine Pregnancy Registry

      • Physician enrollment of patients

      • (800) 336-2176

    • North American Antiepileptic Drug Pregnancy Registry

      • Patient self-enrollment

      • (888) 233-2334


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    Initiation of Treatment With Lamotrigine Disorder

    • 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


    Dosage and administration of lamotrigine in adult bipolar i patients l.jpg

    not taking Disorderenzyme-inducing drugs or valproate

    Weeks 1 & 2

    Weeks 3 & 4

    Week 5

    Week 6

    25 mg/day

    50 mg/day

    100 mg/day

    Target Dose

    200 mg/day

    takingvalproate

    Weeks 1 & 2

    Weeks 3 & 4

    Week 5

    Week 6

    25 mg/every other day

    25 mg/day

    50 mg/day

    Target Dose

    100 mg/day

    takingenzyme-inducing drugs and not taking valproate

    Weeks 1 & 2

    Weeks 3 & 4

    Week 5

    Week 6

    Week 7

    50 mg/day

    100 mg/day

    in divided doses

    200 mg/day

    in divided doses

    300 mg/day

    in divided doses

    Target Dose

    Up to 400 mg/day

    in divided doses

    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.


    Dosing at greater than recommended doses l.jpg
    Dosing at Greater Than DisorderRecommended 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


    Lamotrigine supplied as l.jpg
    Lamotrigine Disorder— Supplied As…

    25 mg

    100 mg

    150 mg

    200 mg


    Lamotrigine sample kits l.jpg
    Lamotrigine Disorder— Sample Kits


    Lamotrigine dispensing errors alert l.jpg
    Lamotrigine Disorder— 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.


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    Lamotrigine: DisorderImportant Safety Information


    Slide82 l.jpg

    Lamotrigine — Important Safety Information Disorder

    • 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 wasapproximately 0.3% in adult epilepsy patients receiving lamotrigine as adjunctive therapy


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    Lamotrigine — Important Safety Information Disorder(cont’d)

    • The rate of serious rash is approximately 0.8% in pediatric patients (age <16 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 <18 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


    Lamotrigine serious rash l.jpg
    Lamotrigine Disorder — 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


    Lamotrigine recommendations concerning rash l.jpg
    Lamotrigine Disorder — 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


    Lamotrigine additional important safety information l.jpg
    Lamotrigine Disorder — 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


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    Case Studies Disorder


    Case 1 l.jpg
    Case 1 Disorder

    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 judgment—one episode led to hospitalization

    • He has a history of occasional substance use


    Case 189 l.jpg
    Case 1 Disorder

    Next steps

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


    Case 2 l.jpg
    Case 2 Disorder

    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


    Case 291 l.jpg
    Case 2 Disorder

    Next steps

    • You conclude that RP probably has bipolar disorder

    • What medication(s) would you initiate?

    • What are the data that support your decision?


    Case 3 l.jpg
    Case 3 Disorder

    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


    Case 393 l.jpg
    Case 3 Disorder

    Next steps

    • You conclude that HM is experiencing an episode of acute mania

    • Would you consider adding an antipsychotic to this patient’s regimen, at least during the acute episode?

    • Would you consider adding lamotrigine for maintenance treatment?


    Case 4 l.jpg
    Case 4 Disorder

    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


    Case 495 l.jpg
    Case 4 Disorder

    Next steps

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


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