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The diagnosis and treatment of bipolar mixed states

The diagnosis and treatment of bipolar mixed states. Eduard Vieta, MD, PhD. Disclosure: Eduard Vieta , MD, PhD. Ferdinand VI of Spain (1713-1759). Andrés Piquer. Donkey milk Turtle soup with frogs, calf and snakes Enemas Lime tea with cherries Mother-of-pearl dust Fumaria. Head baths

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The diagnosis and treatment of bipolar mixed states

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  1. The diagnosis and treatment of bipolar mixed states Eduard Vieta, MD, PhD

  2. Disclosure: Eduard Vieta, MD, PhD

  3. Ferdinand VI of Spain (1713-1759)

  4. Andrés Piquer

  5. Donkey milk Turtle soup with frogs, calf and snakes Enemas Lime tea with cherries Mother-of-pearl dust Fumaria Head baths Deer antler jelly with tender vipers Violet Diet Borage potion Pimpernel Agrimony Treatments Assayed for Bipolar Disorder During the XVIII Century in His Majesty Ferdinand VI of Spain Piquer, 1759; Vieta & Barcia, 2000

  6. Classification of Mixed states • Depression with racing thoughts • Excited depression • Depressive-anxious mania • Improductive mania • Inhibited mania • Manic stupor Kraepelin, 1921

  7. Symptom domains in maniaand mixed mania Manic Mood and Behaviour Dysphoric or Negative Mood and Behaviour • Euphoria • Grandiosity • Pressured Speech • Impulsivity • Excessive Libido • Recklessness • Diminished Need for Sleep • Depression • Anxiety • Irritability • Hostility • Violence or Suicide Cognitive Symptoms • Racing Thoughts • Distractibility • Poor Insight • Disorganization • Inattentiveness • Confusion Psychotic Symptoms • Delusions • Hallucinations • Sensory Hyperactivity

  8. Discriminatory “Depressive” Symptoms in Dysphoric Mania • Depressed mood • Irritability • Mood lability • Anhedonia • Hopelessness/helplessness • Suicidal ideation and/or attempt • Guilt • Fatigue Akiskal et al. J Affect Disord 2000

  9. Affective states in 908 patients during 7 years of follow-up % Percentage of total visits Depression Hypomania Euthymia Mixed Hypomania Suppes et al, Arch Gen Psychiatry, 2005

  10. Distribution of the number of lifetime MOODS-SR manic / hypomanic items 30 Patients (%) Bipolar disorder Recurrent major depression 20 10 0 0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45+ Number of manic / hypomanic spectrum items Recurrent major depression, n=117; bipolar disorder, n=106MOODS-SR, Mood Spectrum-Self Report questionnaire Cassano et al 2002

  11. Mixed states are the best proof of the need of a dimensional approach to complement the categorical diagnosis • Tonality of mood more important than polarity • Mixed states too restrictively defined in DSM-IV • A dimensional module should be included in the upcoming DSM-V and ICD-11 classifications • Depressive mixed states poorly studied because of limited potential economic benefit Henry et al, 2007; Vieta & Phillips, 2007

  12. NOT EASY!

  13. Rates of Mixed States Study Patients (N) Percent Winokur et al (1969) 61 16 Kotin & Goodwin (1972) 20 65 Himmelhoch et al (1976) 84 31 Akiskal & Puzantian (1979) 60 25 Nunn (1979) 112 36 Prien et al (1988) 103 67 Post et al (1989) 48 46 Dell’Osso et al (1991) 108 45 McElroy et al (1995) 71 40 Cassidy et al (1998) 273 14 Akiskal et al (1998) 104 37 Dilsaver et al (1999) 105 40 Total 1149 43%

  14. The EMBLEM Study NETHERLANDS 41 Invs 168 Pts NORWAY 7 Invs 30 Pts FINLAND 10 Invs 34 Pts BELGIUM 11 Invs 78 Pts DENMARK 6 Invs 23 Pts • 14 Countries • 530 Investigators • 3536 Patients • 833 (24%) Mixed UK & IRELAND 35 Invs 203 Pts GERMANY 116 Invs 535 Pts SWITZERLAND 12 Invs 95 Patients PORTUGAL 20 Invs 74 Pts FRANCE 126 Invs 795 Pts SPAIN 32 Invs 312 Pts ITALY 56 Invs 555 Pts GREECE 58 Invs 634 Pts Haro JM, et al. Acta Psychiatrica Scand, 2006; Goetz I, et al.Bipolar Disord, 2007; Vieta et al, J Affect Disord, 2007.

  15. 0.0 0.2 0.4 Cumulative Proportion ofPatients Remitted ** 0.6 Mixed/cycling (n=35) * 0.8 Depressed (n=79) Manic (n=37) 1.0 0 10 20 30 40 50 Weeks of Preliminary Phase Treatment Mixed episodes are difficult to treat *p<0.0001 vs. manic **p<0.0001 vs. manic and p<0.05 vs. depressed Kupfer et al. 2000

  16. Keller MB et al. JAMA. 1986;255:3138-3142. Mixed Episodes Carry More Chronicity 35 32 30 25 22 20 % Remaining Ill at 1 Year 15 10 7 5 0 Pure Mania Pure Depression Mixed Index Episode N = 155.

  17. Long-term Characteristics of Mixed States • Female preponderance (Dell’Osso et al, 1991; Perugi et al, 1997; Akiskal et al, 1998) • Frequent in children and adolescents (Birmaher & Axelson 2006) • Alcohol & neuropsychiatric comorbidity (Himmelhoch et al, 1976) • More past depressive than manic episodes (Perugi et al, 2000; Colom et al, 2006) • Family history more often depressive than manic (Dell’Osso et al, 1991; Perugi et al, 2000) • High switch risk to depression (Salvatore et al, 2007) • High suicide risk (Dilsaver et al, 1993; Strakowski et al, 1996; Goldberg et al, 1998) • Includes agitated depression (Benazzi, 2004) • May respond better to antipsychotics than to antidepressants (Vieta, 2005)

  18. Response to lithium and divalproate in pure and mixed mania SADS-C Criteria * Mania * Improvement vs. Comparator 0.18 6.94 5.08 *p<0.05 Swann et al. 1997

  19. Risperidone in Bipolar Mixed States *During 3 week double-blind phase

  20. 35 Schizoaffective (n=183) Mania (n=249) Bipolar II (n=45) Depression (n=33) Mixed (n=31) 30 25 * 20 YMRS Score * 15 * 10 * * * 5 0 30 25 * 20 * HDRS Score 15 * * * * 10 5 0 Baseline Day 7 Day 14 Week 4 Week 6 Month 3 Month 6 Risperidone in the treatment of bipolar subtypes *p<0.001 vs. baseline Vieta et al. 2001

  21. Olanzapine in patients with a Mixed Episode vs Placebo3 weeks vs Placebo4 weeks vs Valproate3 weeks vs Risperidone 3 weeks vs Placebo3 weeks Cotherapy vs Mono6 weeks vs Haloperidol Adol 38.5% n=5 -5.92 -7.46 % of Patients -7.42 n=12 Mean Change in YMRS Score -8.39 16.7% n=54 n=12 -9.56 -9.96 n=2 n=23 n=50 n=25 -12.88 -12.92 -13.6 -14.0 -13.96 n=56 n=121 n=90 n=95 n=23 Remission Rates -19.66 p=.378 n=61 Olanzapine Placebo p<.001 p=.588 p=.274 p=.184 p=.203 p<.001 Haloperidol OLZ + Li or VPA Valproate Li or VPA Risperidone

  22. Olanzapine Placebo Time to Relapse (Any Mood Episode) Mixed Index Episode Manic Index Episode p<.001 p<.001 n=144 n=76 n=88 n=45 Tohen M et al. Presented at: 24th CINP Meeting; June 20-24, 2004; Paris, France.

  23. Manic Index Episode Mixed Index Episode n=144 n=76 n=88 n=45 p<.001 p<.001 Olanzapine Placebo Time to Manic Relapse Tohen M et al. Presented at: 24th CINP Meeting; June 20-24, 2004; Paris, France.

  24. Olanzapine Placebo Time to Depressive Relapse Manic Index Episode Mixed Index Episode p=.001 p=.002 n=144 n=76 n=88 n=45 Tohen M et al. Presented at: 24th CINP Meeting; June 20-24, 2004; Paris, France.

  25. Time to Mixed Relapse Olanzapine Placebo Manic Index Episode Mixed Index Episode n=144 n=88 n=76 n=45 p<.001 p=.48 Tohen M et al. Presented at: 24th CINP Meeting; June 20-24, 2004; Paris, France.

  26. Quetiapine in rapid cycling bipolar disorder Maximum and endpoint doses according to index episode N=14 rapid cycling bipolar patients Follow-up: 112 days; Mixed n=3 Vieta et al. 2002

  27. Adjunctive quetiapine as a long-term treatment for bipolar I disorder Stabilisation treatment phase Randomised treatment phase Up to 104 weeks Enrolment 12 to 36 weeks Up to 7 days Quetiapine plus mood stabiliser Stabilisation quetiapine plus mood stabiliser Placebo plus mood stabiliser Enrolment Visit S1 Stabilisation treatment phase entry Visit 1 Randomisation Visit 23 Final visit Vieta E, Suppes T, et al. ECNP. Vienna. 2007.

  28. Quetiapine plus lithium or valproate in the long-term treatment of bipolar disorder: time to recurrence of a mood event 1.0 Quetiapine plus lithium or divalproex (n=646) 0.9 Placebo plus lithium or divalproex (n=680) 0.8 0.7 0.6 Proportion of patients event free 0.5 0.4 0.3 0.2 HR: 0.30; 95% CI: 0.24, 0.37; p<0.0001 0.1 0.0 0 10 20 30 40 50 60 70 80 90 100 110 Time (weeks) ITT population Vieta E, Suppes T, et al. ECNP. Vienna. 2007.

  29. Incidence of Mood, Mania, or Depression Event by Index Episode Outcome ***Time to next mood episode hazard ratio p<0.0001 vs placebo ITT population Vieta et al 2007; Suppes et al, 2007.Study 126 + 127

  30. Ziprasidone in Manic and Mixed Episodes Change in MRS Score (LOCF) Mixed Episode Manic Episode ** * ** * * ** ** * ** Mean dose = 122 mg/day Pooled Studies *P<0.05, **P<0.01 Potkin S et al. APA 2004.

  31. Aripiprazole in mixed mania(Pooled data from 3 placebo-controlled trials) YMRS p=0.044 Jody et al. 2004

  32. Electroconvulsive therapy Mania Harin et al. 1993 Mixed Episodes Ciaparelli et al. 2001 Rapid Cycling Kho. 2002 Bipolar Depression Grunhaus et al. 2002 Valenti et al. 2008

  33. Control Group Psychoeducation Group Psychoeducation and prevention of mixed and depressive episodes N=120 % Relapsed Patients p=0.0006 p=0.003 p=0.01 Colom et al. 2003

  34. Antidepressant related switch (n=48) Antidepressant non-response (n=50) Antidepressant response (n=94) ** * 40 4 35 3.5 30 3 25 2.5 20 2 15 1.5 10 1 5 0.5 0 0 IDS YMRS *F (2,186)=6.36 **F (2,187)=5.33 , p=0.006 Sub-threshold mixed symptoms predict Antidepressant-Related Mania YMRS Items higher in the ADRM group: #2 motor activity #6 speech # 8 thought content. Frye et al. Presented at the ASBD 2006, Melbourne

  35. Antidepressants in mixed bipolar depression: findings from the STEP-BD • 335 bipolar depressed patients with at least 2 concurrent manic symptoms from the first 2000 STEP-BD participants • Adjunctive antidepressant use was associated with significantly higher mania symptom severity at 3-month follow-up • No significant effect of antidepressants on recovery likelihood Goldberg et al, 2007

  36. Problems regarding the initial treatment of bipolar disorders Firstprescribeddrug class(%) Antidepressant monotherapy twice as common as mood stabilizers Sedative Lithium Anticonvulsant Antidepressant Antipsychotic n=7,760 (63% of 12,237 received monotherapy); based on Commercial and Medicare claims. Baldessarini R, et al. Psychiatr Serv 2007;58(1):85-91.

  37. EMBLEM Study: Antidepressant Medication Rosa et al, submitted a* = before b* = after change in oral medication

  38. Summary of the APA guidelines for mixed bipolar episodes • Treatment of Mixed Episodes • Severe: lithium or divalproate + antipsychotic • Mild: lithium, divalproate or olanzapine • Resistant: carbamazepine/oxcarbazepine, clozapine, ECT Hirschfeld et al. 2002

  39. Recommendations for the treatment of mixed bipolar episodes • General rules: • Predominant symptoms/subtype • Screening and treatment of physical and psychiatric co-morbidities (i.e. substance abuse) • Discontinue antidepressants and use BZD if severe anxiety • Assess suicide risk and provide support Vieta. 2005

  40. Recommendations for the treatment of mixed bipolar episodes • Specific treatment: • Low/moderate doses of atypical antipsychotics • Combination with divalproate (or carbamazepine?) • Lithium still has a role • Avoid antidepressants except in very particular cases • ECT often necessary Vieta. 2005

  41. Effective for mixed mania: Divalproate Olanzapine Aripiprazole Ziprasidone Possibly effective for mixed mania: Lithium Carbamazepine Oxcarbazepine Quetiapine Risperidone Clozapine ECT Not effective for mixed mania: Lamotrigine Topiramate Gabapentin Antidepressants Possibly effective for mixed depression Quetiapine Olanzapine ECT Conclusions ADVICE: COMBINATION! Vieta. 2005

  42. THANK YOU! www.bipolarclinic.org F. Panicali F. Colom JM.Goikolea I. Pacchiarotti A. Benabarre E. Popova E. Vieta C. Daban M. Reinares A. Martinez-Aran C. Torrent M. Comes J. Sanchez-Moreno N. Cruz • A.R. Rosa • C.M. Bonnin • P. Castro • C. Franco • M. Valenti

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