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Managing Bipolar I Disorder With LAMICTAL ® (lamotrigine)

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)

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  1. Managing Bipolar I Disorder With LAMICTAL® (lamotrigine) Please see complete Prescribing Information.

  2. Classification of Bipolar Disorder

  3. Summary of DSM-IV-TR Classification of Bipolar Disorders Bipolar 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.

  4. Summary of DSM-IV-TR Criteria forManic Episodes in Bipolar Disorder • Abnormally and persistently elevated, expansive, or irritable mood for at least 1 week* • Inflated self-esteem or grandiosity • Decreased need for sleep • Pressured speech • Flight of ideas or racing thoughts • Distractibility • Increase in goal-directed activity or psychomotor agitation • Excessive involvement in pleasurable activities that have a high potential for painful consequences * This symptom must be present. First, ed. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Rev. Washington, DC: American Psychiatric Association; 2000:345-428.

  5. Summary of DSM-IV-TR Criteria for Major Depressive Episodes in Bipolar Disorder • Depressed mood* • Markedly diminished interest or pleasure* • Significant weight loss or gain or appetite increase or decrease • Insomnia or hypersomnia • Observable psychomotor agitation or retardation • Fatigue or loss of energy • Feelings of worthlessness or excessive or inappropriate guilt • Diminished ability to think, concentrate, or make decisions • Recurrent suicidal ideation, thoughts of death, a suicide attempt, or a specific plan for committing suicide * At least one of these symptoms must be present. First, ed. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Rev. Washington, DC: American Psychiatric Association; 2000:345-428.

  6. Rapid Cycling Specifier • 4 episodes of depression, mania, mixed, or hypomania in previous 12 months • Episodes demarcated by: • a period of full or partial remission for 2 months OR • a switch to an episode of opposite polarity • Distinct course modifier associated with poor clinical outcome First, ed. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Rev. Washington, DC: American Psychiatric Association; 2000:345-428.

  7. Bipolar Disorder —Impact and Challenges

  8. Estimated Total Lifetime Cost per Case by Prognosis Group Thousands of dollars, 1998 Begleyet al. Pharmacoeconomics. 2001;19(5 pt 1):483-495.

  9. Bipolar Disorder — Challenges • Bipolar patients who present depressed may be diagnosed as having major depressive disorder and may be treated accordingly1 • This can result in treatment delay, inappropriate or undertreatment, and can lead to worsening of symptoms by switching into mania or cycle acceleration2 • The needs for treatment of bipolar disorder are substantial; despite the risk of recurrence, the focus tends to be on short-term treatment.³ This creates problems over the long term; inappropriate treatment may have a negative impact on patients2 • In the absence of large-scale and well-documented, positive clinical trials, management of bipolar depression has been mostly empirical 1. Hirschfeld. Prim Care Companion J Clin Psychiatry. 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.

  10. Mood Disorder Questionnaire —A Validated Screening Tool • Comprises 13 yes/no symptom questions, 1 co-occurrence question, and 1 functional impairment question • MDQ positive cases • 7 or more symptoms AND • co-occurrence during same time period AND • moderate to severe functional impairment • Positive screens indicate the need for a full clinical evaluation • Can be accessed online at www.dbsalliance.org Hirschfeld. Prim Care Companion J Clin Psychiatry. 2002;4:9-11. Hirschfeld et al. Am J Psychiatry. 2000;157:1873-1875.

  11. Mood Disorder Questionnaire Has there ever been a period of time when you were not your usual self and… … you felt so good or so hyper that other people thought you were not your normal self or you were so hyper that you got into trouble? … you were so irritable that you shouted at people or started fights or arguments? … you felt much more self-confident than usual? … you got much less sleep than usual and found you 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.

  12. 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.

  13. 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.

  14. Prevalence of Bipolar Spectrum in the US —A Large-Scale Epidemiological Study • Objective: to estimate rate of positive screens for bipolar I and II disorder among adults in the US • The MDQ was mailed to 100,000 households • Nationwide sample of >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.

  15. Bipolar Disorder — 3.4% of the US Population Screened Positive by MDQ Weighted Percent * Overall Prevalence Age Group Income * Weighted to match US census data. Hirschfeld et al. J Clin Psychiatry. 2003; 64:53-59.

  16. Symptoms of Bipolar Disorder —Heavy Impact on Daily Life * * * Percent * P<0.0001 Calabrese. J Clin Psychiatry. 2003;64:425-432.

  17. MDQ-Positive Patients —Previous Diagnosis by Physician Percent of patients Hirschfeld et al. J Clin Psychiatry. 2003; 64:53-59.

  18. Bipolar Disorder —A Diagnostic Challenge Hirschfeld et al. J Clin Psychiatry. 2003;64:161-174.

  19. 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.

  20. 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.

  21. It Is Important to Recognize and Treat Bipolar Depression • Bipolar depression is more pervasive than mania1 • Mean duration of the depressive episode in bipolar disorder is longer than manic episodes2 • Depression is chronic in more than 20% of patients with bipolar disorder2 • Recently introduced medications (anticonvulsants and atypical antipsychotics) have predominantly 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.

  22. Treatment Objectives for Bipolar Disorder • Bipolar disorder is a lifelong illness; therefore, maintenance treatment is the core of management1 • Treatment choice should be made by collaborative effort between patient and physician2 • The goal of acute therapy is to stabilize acute episodes with the goal of remission2 • The goal of maintenance therapy is to optimize protection against recurrence of episodes2 • Concurrently, attention needs to be devoted to maximizing patient functioning and minimizing subthreshold symptoms and adverse effects of treatment2 1. Calabrese et al. J Clin Psychiatry. 2002;63(suppl 10):18-22. 2. Hirschfeld et al. Am J Psychiatry. 2002;159(4 suppl):1-50.

  23. 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.

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

  25. Definition of Mood Stabilizer • Several definitions of what constitutes a mood stabilizer have been proposed and include: • proven efficacy for the treatment of mania or depression, • absence of exacerbation of manic or mixed symptoms, OR • prophylactic efficacy • Lamotrigine is the first drug since lithium to be indicated for the maintenance treatment of bipolar disorder Hirschfeld et al. Am J Psychiatry. 2002;159(4 suppl):1-50.

  26. Acute Treatment vs Long-term Management • Many patients continue to experience subthreshold symptoms even after recovering from an acute mood episode1 • Frequency and number of episodes can be reduced with maintenance therapy1 • Successful management of bipolar disorder requires a mood stabilizer with long-term efficacy across the spectrum of moods2 1. Goodwin. J Clin Psychiatry. 2002;63(suppl 10):5-12. 2. Calabrese et al. J Clin Psychiatry. 2002;63(suppl 10):18-22.

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

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

  29. Lamotrigine—Clinical Trials

  30. Lamotrigine — A New Approach to Long-term Mood Stabilization With Proven Long-term Efficacy, Especially for Bipolar Depression • Indicated for the maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy • Offers long-term stability for mood episodes, with particular efficacy in depression as shown in 2 landmark maintenance trials of 18 months’ duration • Combined, these trials represent the largest (n=1,305) prospectively defined, placebo-controlled data set in bipolar disorder1 1. Data on file, GlaxoSmithKline.

  31. A Placebo-Controlled 18-MonthTrial of Lamotrigine and Lithium Maintenance Treatment in Recently Manic or Hypomanic Patients With Bipolar I Disorder Landmark Maintenance Trial M Bowden et al. Arch Gen Psychiatry. 2003:60:392-400.

  32. Study DesignCurrently or Recently Manic/Hypomanic Patients SCREEN OPEN LABEL Lamotrigine 100-200 mg/day DOUBLE-BLIND Concomitant psychotropics Bipolar I currently or recently manic/hypomanic Lamotrigine 100-400 mg/day (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.

  33. 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.

  34. Inclusion CriteriaCurrently or Recently Manic/Hypomanic Patients • Moderate to severely ill bipolar I disorder patients • Currently or recently manic or hypomanic (DSM-IV criteria) OR • Had been manic or hypomanic within 60 days of screening, had manic or hypomanic symptoms at enrollment, and had 1 additional manic or hypomanic episode and 1 depressed episode (including mixed episodes according to DSM-IV criteria) within 3 years of enrollment • Outpatients • 18 years or older • No significant thyroid disease • No significant general health problems Bowden et al. Arch Gen Psychiatry. 2003:60:392-400.

  35. Baseline Psychiatric ProfileCurrently or Recently Manic/Hypomanic Patients • 66% of patients required psychiatric hospitalization during their lives • 29% of patients had attempted suicide • 28% of patients had rapid-cycling disorder (4-6 episodes per year) • Patients had experienced a mean of 1.0 depressive, 1.4 manic, 0.3 hypomanic, and 0.2 mixed episodes in the past 12 months Bowden et al. Arch Gen Psychiatry. 2003:60:392-400.

  36. 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.

  37. 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.

  38. Lamotrigine Delayed Time to Intervention for Mood Episodes Currently or Recently Manic/Hypomanic Patients 70 60 50 40 30 20 10 0 100 90 80 70 60 50 40 30 20 10 0 Lamotrigine 100-400 mg (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.

  39. 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.

  40. 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.

  41. 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.

  42. Adverse Events (10%) Currently or Recently Manic/Hypomanic Patients Bowden et al. Arch Gen Psychiatry. 2003:60:392-400.

  43. 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.

  44. A Placebo-Controlled 18-Month Trial of Lamotrigine and Lithium Maintenance Treatment in Recently Depressed Patients With Bipolar I Disorder Landmark Maintenance Trial D Calabrese JR et al. J Clin Psych. In press.

  45. Study DesignCurrently or Recently Depressed Patients SCREEN OPEN LABEL Lamotrigine 100-200 mg/day DOUBLE-BLIND Placebo (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.

  46. Inclusion CriteriaCurrently or Recently Depressed Patients • Moderate to severely ill bipolar I disorder patients • Currently or recently depressed (DSM-IV criteria) OR • Had been depressed within 60 days of screening, had depressive symptoms at enrollment, and had 1 additional manic or hypomanic episode and 1 depressed episode (including mixed episodes according to DSM-IV criteria) within 3 years of enrollment • Outpatients • 18 years or older • No significant thyroid abnormalities • No significant general health problems Calabrese JR et al. J Clin Psych. In press.

  47. Baseline Psychiatric ProfileCurrently or Recently Depressed Patients • 81% of all patients utilized other psychotropic medications during the open-label phase • 66% of patients required psychiatric hospitalization during their lives • 37% of patients had attempted suicide • 30% of patients had rapid-cycling disorder (4-6 episodes per year) • Patients had experienced a mean of 1.7 depressive, 0.9 manic, 0.3 hypomanic, and 0.1 mixed episodes in the past 12 months Calabrese JR et al. J Clin Psych. In press.

  48. Baseline Psychiatric ProfileCurrently or Recently Depressed Patients (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.

  49. Study Endpoints Currently or Recently Depressed Patients • Primary endpoint was time to intervention (pharmacologic or ECT) for mood episodes (relapse or recurrence of a manic, hypomanic, mixed, or depressive episode) • Secondary endpoints included: • Time to intervention for a depressive episode • Time to intervention for a manic, hypomanic, or mixed episode • This trial was not designed to demonstrate a difference on the secondary endpoints Calabrese JR et al. J Clin Psych. In press.

  50. Lamotrigine Delayed Time to Intervention for Mood Episodes Currently or Recently Depressed Patients 70 60 50 40 30 20 10 0 100 90 80 70 60 50 40 30 20 10 0 Lamotrigine 200 and 400 mg (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.

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