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WHAT’S REALLY NEW IN BIPOLAR DISORDER, OCTOBER 2005

WHAT’S REALLY NEW IN BIPOLAR DISORDER, OCTOBER 2005. OR WHAT I THINK IS IMPORTANT AND NEW (AND SOME OLD STUFF TOO). WHO AM I? WHERE AM I?. MEDICAL DIRECTOR OF DAY HOSPITAL, PALOMAR HOSPITAL, ESCONDIDO, CALIFORNIA; PSYCHIATRIST, PSYCHIATRIC CENTERS OF SAN DIEGO, ESCONDIDO

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WHAT’S REALLY NEW IN BIPOLAR DISORDER, OCTOBER 2005

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  1. WHAT’S REALLY NEW IN BIPOLAR DISORDER, OCTOBER 2005 OR WHAT I THINK IS IMPORTANT AND NEW (AND SOME OLD STUFF TOO)

  2. WHO AM I? WHERE AM I? MEDICAL DIRECTOR OF DAY HOSPITAL, PALOMAR HOSPITAL, ESCONDIDO, CALIFORNIA; PSYCHIATRIST, PSYCHIATRIC CENTERS OF SAN DIEGO, ESCONDIDO Pinnacle Of Career: Admission to Medical School Joining PCSD

  3. $$$ DISCLOSURES $$$ RESEARCH, LECTURES, CONSULTANT • Lilly, Janssen, Wyeth-Ayerst, Servier, FHH Foundation, Lundbeck, Organon, Alberta Heritage Foundation Research, Astra-Zeneca, Biovail • Inspiration: Dr. Ron Remick, Dr. Ernie McCrank, My patients

  4. MY DAILY AFFIRMATIONS • Just for today…I won’t sit in my living room all day in my underwear; I’ll move the computer into the bedroom

  5. HISTORICAL REVIEW • Aretaeus • Kraepelin • Leonhard • Goodwin • Akiskal • Gorman met McCrank

  6. WHAT I LEARNED IN MY FIRST RESEARCH PROJECT • NOTHING IN LIFE OCCURS IN A VACUUM, NOT EVEN HEART DISEASE

  7. MOOD DISORDERS ARE DISORDERS WITH CYCLICAL CHANGES IN MOOD, ENERGY AND BEHAVIOR • It seems to me that it is more likely that Mood Disorders are primarily energy disorders with secondary mood and behavior dimensions

  8. DIAGNOSTIC ISSUES • DSM IV puts primary emphasis on polarity (i.e. history of mania or hypomania) rather than cyclicity or recurrence • Depressive disorders are thus a meaningless category because of: 1. Defined by “not bipolar” 2. Too heterogeneous, patient with 2 episodes in lifetime vs. someone with episodes every 12 to 24 months

  9. HIGHLY RECURRENT UNIPOLAR DEPRESSION (Clinical Features) • Family history of Bipolar Disorder (BD) • Bipolar like age of onset (teens and 20’s) • High episode frequency (every 18-24 mo) • Represents 25-35% of unipolar cases • May convert to BD, but many don’t, unless receiving antidepressants without mood stabilizer • Patients respond to Li better than imipramine • No category for these patients in DSM IV

  10. POTENTIAL BIPOLAR DIATHESIS • Recurrent major depressive episodes • Early age of onset (40% of patients before age 20 BD, of remaining 60%, most have highly recurrent unipolar depression) • Family history of BD • Atypical depressive symptoms • Brief depressive episodes • Psychotic Depressive episodes • Post Partum Depression • AD induced hypomania/mania • AD non-response or wear off

  11. PNEMONIC FOR MANIC SYMPTOMS - DIGFAST • Distractibility • Indiscretion (pleasurable activities) • Grandiosity • Flight of ideas • Activity increase • Sleep deficit (decreased need) • Talkativeness (pressured speech)

  12. ALL QUESTIONS POSED TO BIPOLAR PATIENTS, ARE BEST POSED TO THEIR RELATIVES …At Least When It Comes To Mania

  13. 2% 1% 6% 9% 46% 53% 50% 32% % of Weeks Asymptomatic Depressed Manic/hypomanic Cycling / mixed Bipolar Disorder Symptoms areChronic and Predominantly Depressive 146 bipolar I patientsfollowed 12.8 years 86 bipolar II patientsfollowed 13.4 years Judd et al (2002) Archives of General Psychiatry (59) 530-537 Judd et al (2003) Archives General Psychiatry. (60) 261-269

  14. ANTIDEPRESSANT (AD) TREATMENT IN BIPOLAR VS. UNIPOLAR DEPRESSION • Ghaemi SN et. al.; Am J Psychiatry 161:163-165,2004 • Long term safety and effectiveness of AD’s is well established for unipolar, but not BD patients. Short term efficacy is clear. • Tricyclic’s are not as effective for recurrence as Li has been demonstrated • This study compared modern and older AD’s in Bipolar depression (41 patients) vs. Unipolar depression (37 patients)

  15. AD TREATMENT TRIAL COMPARISON CONTINUED • Short term non-response for BD at 51.3% vs. Unipolar at 31.6% • Manic switching less in BD patients taking mood stabilizers (31.6% vs. 84.2%) • Cycle acceleration only occurred in BD depression (25.6%), with new rapid cycling in 32.1% of patients • Late response loss, or tolerance was 3.4X’s more frequent in BD depression • Cycle acceleration, rapid cycling and response loss were not prevented by mood stabilizers • In general, modern AD’s did not have lower negative outcomes than Tricyclic's

  16. AD TREATMENT TRIAL COMPARISON CONCLUSION • An unfavorable cost/benefit ratio is indicated for the use of AD therapy in the treatment of Bipolar depression • This studies distressing numbers are significant, considering that many clinicians, and even most guidelines are suggesting both short and long-term use of AD’s for Bipolar depression

  17. A 52 WEEK OPEN-LABEL CONTINUATION STUDY OF Ltg. IN THE TREATMENT OF BIPOLAR DEPRESSION • McElroy SL et. al.; J Clin Psychiatry 65:204-210, 2004 • Bipolar depression is more frequent, lasts longer, and is more difficult to treat than mania • Ltg is a novel anticonvulsant that has been shown to be effective in the acute treatment of Bipolar depression. This study is a 52 week, open-label continuation of that original trial

  18. A 52 WEEK OPEN-LABEL CONTINUATION STUDY OF Ltg. IN THE TREATMENT OF BIPOLAR DEPRESSION CONTINUED • The study group were BD I patients with an episode of Major Depression that had completed a 7 week dbl. bld. Plc. Controlled Ltg. intervention, and were then invited to enter this study, receiving 100-500 mg./day of Ltg. • Of the 135 patients completing the acute study, 124 (92%) entered the continuation study • MADRS, CGI measures were applied at 4, 12, 24, 36, and 52 weeks

  19. A 52 WEEK OPEN-LABEL CONTINUATION STUDY OF Ltg. IN THE TREATMENT OF BIPOLAR DEPRESSION CONTINUED • Of the 124 patients entered, 77 had received Ltg and 47 had received placebo during the acute study • The mean duration of Ltg. exposure was 10.4 months, and mean modal dose was 187 mg/d. • 56% of the patients completed the trial • There was a significant and sustained improvement over time. 84% achieved remission by week 4, and episodes of mania/hypomania were reduced from the previous year • Headache was the most common drug-related adverse event

  20. A 52 WEEK OPEN-LABEL CONTINUATION STUDY OF Ltg IN THE TREATMENT OF BIPOLAR DEPRESSION CONCLUSION • Ltg was effective in 1 year of open label treatment as adjunctive or monotherapy, and provided sustained improvement without mood destabilization • The issue of remission is studied in many psychiatric disorders, but it may be most critical in BD

  21. LAMOTRIGINE RASH • Can cause severe skin reactions (i.e. Steven Johnson Syndrome SJS, Toxic Epidermal Necrolysis TEN) • Recent data from German Rash Registry show only 1/10,000 (almost all neurology patients) • Registry lists many other agents (9 antibiotics, 4 anticonvulsants) ahead of Ltg

  22. CARDIAC DISEASE AND DEPRESSION

  23. PRELIMINARY RANDOMIZED, DBL BLD, PLACEBO CONTOLLED TRIAL OF PRAMIPEXOLE (MIRAPEX) ADDED TO MOOD STABILIZERS FOR TREATMENT RESISTANT BD DEPRESSION • Goldberg et. al. Am J Psychiatry 161:564-566,2004 • Pramipexole, a dopamine agonist, may have AD properties. Efficacy and safety were assessed in this study • 22 depressed outpatients with non-psychotic BD were randomly assigned to placebo or Pramipexole at max. dose of 1.7 mg./d for 6 weeks. HDRS (response at 50% improvement) and CGI were used

  24. PRELIMINARY RANDOMIZED, DBL BLD, PLACEBO CONTOLLED TRIAL OF PRAMIPEXOLE (MIRAPEX) ADDED TO MOOD STABILIZERS FOR TREATMENT RESISTANT BD DEPRESSION CONTINUED • 83% of Pramipexole and 60% of placebo patients completed the study • Response rates in the Pramipexole and placebo groups were 67% and 20% respectively • Pramipexole patients also had greater mean improvements in CGI scores • One patient DC’ed Pramipexole because of the emergence of hypomania (the only adverse effect drop-out)

  25. PRELIMINARY RANDOMIZED, DBL BLD, PLACEBO CONTOLLED TRIAL OF PRAMIPEXOLE (MIRAPEX) ADDED TO MOOD STABILIZERS FOR TREATMENT RESISTANT BD DEPRESSION CONCLUSION • Pramipexole appears to be effective and safe for the treatment of Bipolar depression • Bipolar depression has emerged as one of the most important and difficult conditions to treat. Beyond Ltg., the choices are complex and poorly supported by sufficient data • Larger randomized and controlled studies are now needed to further assess this study

  26. GENERAL PRINCIPLES OF MANAGEMENT • Use life charts to monitor illness • Remember, it is basically a depressive disorder, even though all of the new med’s are anti-manic drugs • Issue is preventing recurrence • AD’s can induce mania and/or cycling • Keep in mind high suicide risk with BD • Never forget the therapeutic relationship

  27. WHAT IS THE THERAPEUTIC RELATIONSHIP? • The psychodynamic features of the pharmacotherapy relationship can never be overlooked • Without attention to elements such as transference, pharmacotherapy can have reduced value • As in all therapeutic relationships, a working alliance must be established to allow the treatment to proceed with greatest effectiveness

  28. WHAT IS THE THERAPEUTIC RELATIONSHIP, CONTINUED? • The pharmacotherapeutic alliance can be tested and strengthened when: discussing goals of treatment; discussing side effects; the potential for abuse with this patient; the clinicians availability for the resolution of medication and non-medication difficulties • Attention to the therapeutic alliance also involves: consistency; availability; willingness to discuss; and explain alternatives

  29. WHAT IS THE THERAPEUTIC RELATIONSHIP, CONTINUED? • Transference issues include: Idealization initially with the physician being authoritative and knowledgeable, and a provider of coherent and non-judgmental explanation, with no confrontation of looking inward or need to face past and present painful experiences • Unfortunately, the inconsistent and sometimes limited results of the medication, can be more than disappointing to the hopeful patient • Some times the initial positive transference can lend itself to the undermining of psychotherapy, and even splitting. If under-recognized, it can undermine all of the treatment

  30. WHAT IS THE THERAPEUTIC RELATIONSHIP, CONTINUED? • Counter-transference needs to be recognized and understood • Issues like: discouragement; the desire for treatment to proceed more quickly or with less pain; to control the patient; or to give some thing tangible to the patient during a hopeless or helpless impasse.

  31. TREATMENT OF BREAKTHROUGH DEPRESSION • Li has modest effect • Lamotrigine (Ltg) has more robust effect • Olanzapine very small effect (perhaps through non-specific anti-anxiety, ant-insomnia effect) • Quetiapine has large effect, that appears to be specific for depression (?study data)

  32. HOW DO YOU DISTINGUISH BIPOLAR FROM BORDERLINE AND FACTITIOUS DISORDER? • Bipolar Spectrum Disorder has considerably more denial • Bipolar Spectrum Disorder has much less interest in any treatment, but particularly psychotherapy

  33. WHY IS THERE SO MUCH DISABILITY IN BIPOLAR DISORDER?

  34. Seroquel is not yet indicated in Canada for the treatment of bipolar disorder Information presented within may contain data not supported by the current product monograph. Please consult the product monograph for prescribing information.

  35. Study Overview • Eight-week, multicenter, double-blind, randomized, fixed-dose, placebo-controlled monotherapy study • Study population: outpatients with DSM-IV bipolar I or bipolar II disorder, with or without rapid cycling, in a major depressive episode • Study groups: quetiapine 600 mg/d, quetiapine 300 mg/d, placebo • Conducted at 39 centers in the United States Calabrese et al, APA 2004

  36.   Quetiapine 600 mg (n=170) Quetiapine 300 mg (n=172) Placebo (n=169) ITT, LOCF Calabrese et al, APA 2004 MADRS: Change From Baseline Study Week 1 2 3 4 5 6 7 8 § Mean Change From Baseline § § § § § § § § § § § § § § § §p<0.001 vs placebo

  37. Quetiapine 600 mg (n=170) Quetiapine 300 mg (n=172) Placebo (n=169) ITT, LOCF Calabrese et al, APA 2004 Response Rate (50% decrease in MADRS) § § § § § § § § § § § § § § † †p<0.01 §p<0.001 vs placebo

  38. Quetiapine 600 mg (n=170) Quetiapine 300 mg (n=172) Placebo (n=169) ITT, LOCF Calabrese et al, APA 2004 Remission Rate (MADRS 12) § § § § § § § § † § § § § § †p<0.01 §p<0.001 vs placebo

  39. AstraZeneca data on file Effect Size: Change in MADRS Large (0.8) Quetiapine 600 mg 0.75 Quetiapine 300 mg 0.64 Medium (0.5) Small (0.2)

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