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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

Managing Bipolar I Disorder With LAMICTAL® (lamotrigine)

Please see complete Prescribing Information.

summary of dsm iv tr classification of bipolar disorders
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.

summary of dsm iv tr criteria for manic episodes in bipolar disorder
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.

summary of dsm iv tr criteria for major depressive episodes in bipolar disorder
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.

rapid cycling specifier
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; 2000:345-428.

estimated total lifetime cost per case by prognosis group
Estimated Total Lifetime Cost per Case by Prognosis Group

Thousands of dollars, 1998

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

bipolar disorder challenges
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.

mood disorder questionnaire a validated screening tool
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. 2002;4:9-11.

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

mood disorder questionnaire
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 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.

mood disorder questionnaire cont d
Mood Disorder Questionnaire (cont’d)

… 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.

mood disorder questionnaire cont d13

Minor problem

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.

prevalence of bipolar spectrum in the us a large scale epidemiological study
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 >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.

bipolar disorder 3 4 of the us population screened positive by mdq
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.

symptoms of bipolar disorder heavy impact on daily life
Symptoms of Bipolar Disorder —Heavy Impact on Daily Life

*

*

*

Percent

* P<0.0001

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

mdq positive patients previous diagnosis by physician
MDQ-Positive Patients —Previous Diagnosis by Physician

Percent of patients

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

bipolar disorder a diagnostic challenge
Bipolar Disorder —A Diagnostic Challenge

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

treatment resistant bipolar depression more pervasive than mania n 258
Treatment-Resistant Bipolar Depression —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.

long term frequency of depressive symptoms percent of follow up weeks

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.

it is important to recognize and treat bipolar depression
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 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.

treatment objectives for bipolar disorder
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. 2002;63(suppl 10):18-22.

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

fda approved treatment options indicated for bipolar disorder until lamotrigine
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
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
definition of mood stabilizer
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. 2002;159(4 suppl):1-50.

acute treatment vs long term management
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. 2002;63(suppl 10):5-12.

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

lamotrigine historical milestones
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
managing bipolar i disorder with lamotrigine
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
slide30
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 (n=1,305) prospectively defined, placebo-controlled data set in bipolar disorder1

1. Data on file, GlaxoSmithKline.

slide31

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. 2003:60:392-400.

study design currently or recently manic hypomanic patients
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 (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
Study DesignCurrently 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
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. 2003:60:392-400.

slide35

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. 2003:60:392-400.

slide36

Baseline Psychiatric ProfileCurrently 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.

study endpoints currently or recently manic hypomanic patients
Study EndpointsCurrently 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
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 (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
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
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
Time to Intervention for a Manic 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

Adverse Events (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
Summary: Landmark Maintenance Trial MCurrently 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

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
Study DesignCurrently 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
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.

baseline psychiatric profile currently or recently depressed patients
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.

baseline psychiatric profile currently or recently depressed patients cont d
Baseline Psychiatric ProfileCurrently 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
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.

lamotrigine delayed time to intervention for mood episodes currently or recently depressed patients
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 (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
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
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
Time to Intervention for a Manic 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
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.

summary landmark maintenance trial d currently or recently depressed patients
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 (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.

slide56

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
slide57

Lamotrigine Delayed Time to Intervention for Mood EpisodesCombined 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.

slide58

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.

slide59

39%

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.

slide60

22%

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.

treatment emergent adverse events combined analysis open label phase
Treatment-Emergent Adverse Events 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.

slide62

Treatment-Emergent Adverse Events 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

incidence of mania hypomania mixed episodes reported as adverse events combined analysis
Incidence of Mania/Hypomania/Mixed 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.

summary prospectively defined combined analysis
Summary: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.

slide65
Lamotrigine — 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.

recommendations for maintenance treatment of bipolar i disorder adapted from apa guidelines
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.

bipolar indication
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
lamotrigine proposed mechanism of action
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)
lamotrigine pharmacokinetic profile no blood monitoring required
Lamotrigine — 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

lamotrigine drug interactions with commonly prescribed psychotropic agents
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

lamotrigine effect of oral contraceptives
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
lamotrigine use during pregnancy
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.
pregnancy registries
Pregnancy Registries
  • Lamotrigine Pregnancy Registry
    • Physician enrollment of patients
    • (800) 336-2176
  • North American Antiepileptic Drug Pregnancy Registry
    • Patient self-enrollment
    • (888) 233-2334
initiation of treatment with lamotrigine
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
dosage and administration of lamotrigine in adult bipolar i patients

not takingenzyme-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
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
lamotrigine supplied as
Lamotrigine — Supplied As…

25 mg

100 mg

150 mg

200 mg

lamotrigine dispensing errors alert
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.

slide82

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 wasapproximately 0.3% in adult epilepsy patients receiving lamotrigine as adjunctive therapy
slide83

Lamotrigine — Important Safety Information (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
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
lamotrigine recommendations concerning rash
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
lamotrigine additional important safety information
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
case 1
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 judgment—one episode led to hospitalization
  • He has a history of occasional substance use
case 189
Case 1

Next steps

  • What medication(s) would you prescribe and why?
case 2
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
case 291
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?
case 3
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
case 393
Case 3

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
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
case 495
Case 4

Next steps

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