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1 MANIA

2 Your footnote

3 Your footnote Cipriani A, Barbui C, Salanti G et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. The Lancet 2011; 378:

4 Your footnote Cipriani A, Barbui C, Salanti G et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. The Lancet 2011; 378:

5 BIPOLAR DEPRESSION

6 BIPOLAR DEPRESSION Most episodes Longer duration than mania Most of psychosocial impairment 89% of severe or completed suicide attempts YET Despite recent improvements, bipolar depression is usually misdiagnosed and until recently there has been no established acute or long term treatment Lish et al J Affective Disord 1994; 31: ; MacQueen et al Acta Psychiatr Scand 2000; 101:

7 Depression is THE Problem Asymptomatic 53% Bipolar I (Judd et al. Archives of General Psychiatry 59: , 2002) Symptomatic 47% Depressed 67% Manic/ hypomanic 20% Mixed 13% Bipolar II (Judd et al. Archives of General Psychiatry 60: , 2003) Asymptomatic 46% Symptomatic 54% Depressed 94% Hypomanic 2% Mixed 4%

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9 Sidor et al. Antidepressants for the acute treatment of bipolar depression: a systematic review and meta-analysis. J Clin Psychiatry 2010; doi: /jcp.09r05385gre

10 Br J Psychiatry Jan;194(1):4-9

11 Improvement QUETIAPINE Study Week Study Week LS Mean Change From Baseline Quetiapine 300 mg (n=172) Quetiapine 600 mg (n=170) Placebo (n=169) Quetiapine 300 mg (n=155) Quetiapine 600 mg (n=151) Placebo (n=161) BOLDER I BOLDER II p<0.001 vs placebo Calabrese et al 2005 Thase et. al. J Clin Psychopharmacol 2006;26: ITT, LOCF

12 Acta Psychiatr Scand 2008;118:

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14 RESULTS 29 RCTs (double blind) 8,331 subjects Individual drugs or combinations (used as combinations)

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16 SUCRA and 95% CIs for efficacy (SMD) in rank order Olan+Fluox Olanzapine Valproate SSRI Lurasidone TCA Quetiapine Lamotrigine Lithium Risperidone Aipiprazole Ziprasidone MAOI Placebo 0 SUCRA SMD SUCRA: surface under the cumulative ranking curve (SUCRA), higher value is favourable

17 SUCRA and 95% CIs for Switch to Mania in rank order Ziprasidone Quetiapine TCA SSRI MAOI Placebo Lithium Olan+Fluox Valproate Risperidone Olanzapine Lurasidone Lamotrigine Aipiprazole SUCRA: surface under the cumulative ranking curve (SUCRA), higher value is favourable

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19 SUCRA and 95% CIs for response in rank order Olan+Fluox Lurasidone Valproate Quetiapine Lamotrigine Olanzapine SSRI Lithium Risperidone TCA Aipiprazole Ziprasidone Placebo MAOI SUCRA: surface under the cumulative ranking curve (SUCRA), higher value is favourable

20 SUCRA and 95% CIs for withdrawal in rank order Olan+Fluox Risperidone Ziprasidone Olanzapine Valproate TCA SSRI MAOI Placebo Lithium Quetiapine Lamotrigine Lurasidone Aipiprazole SUCRA: surface under the cumulative ranking curve (SUCRA), higher value is favourable

21 Summary of rankings Symptom score change (effect size highest first) Response (highest likelihood first) Switch to mania (lowest risk first) Withdrawal (lowest risk first) Olanzapine+fluoxetine Olanzapine+fluoxetine Ziprasidone Olanzapine+fluoxetine Olanzapine Lurasidone Quetiapine Risperidone Valproate Valproate TCA Ziprasidone SSRI Quetiapine SSRI Olanzapine Lurasidone Lamotrigine MAOI Valproate

22 ADJUNCTIVE ANTIDEPRESSANT TREATMENT IN BIPOLAR DEPRESSION (STEP-BD): 26 WEEK RCT % of subjects MS + AD MS + PBO 0 Trans. Rem. Durable Rec. 50% impr. Aff. Sw. D/C AE Sachs G et al, NEJM 356: , 2007

23 BEST FOR BIPOLAR DEPRESSION? Olanzapine + fluoxetine Olanzapine Lurasidone Quetiapine Valproate SSRIs?

24 GUIDELINES ON BIPOLAR DEPRESSION BAP 2016 NICE 2015 Consider the use of an antidepressant with an antimanic drug in Bipolar I patients Consider quetiapine or olanzapine monotherapy Consider lamotrigine as monotherapy in bipolar II disorder Consider adding lamotrigine to quetiapine or lithium Consider ECT in refractory depression Consider the strategy for long term treatment as patient recovers Offer fluoxetine combined with olanzapine or quetiapine monotherapy. If the person prefers, consider either olanzapine (without fluoxetine) or lamotrigine monotherapy. If there is no response to fluoxetine combined with olanzapine, or quetiapine, consider lamotrigine monotherapy. Within 4 weeks of resolution of symptoms, discuss with the person, and their carers if appropriate, whether to continue psychological or pharmacological treatment for bipolar depression or start long-term treatment

25 PROPHYLAXIS

26 OLANZAPINE VS PLACEBO TOHEN ET AL, AM J PSYCH, 163, , 2006

27 Probability of Remaining in Remission (%) MS +/- OLANZAPINE IN MAINTENANCE? * * P= Time to Recurrence of Mania or Depression (Days) Olanzapine + Lithium or Valproate (n=30) Li=.78, VPA = 69.2 Placebo + Lithium or Valproate (n=38) Li=.75, VPA=67.6 Subjects had reached remission on combination treatment and were randomized to have olanzapine withdrawn or continued Tohen et al, Br J Psychiatry 2004;184:337-45

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33 Ghaemi SN, Wingo AP, Filkowski MA et al. Long-term antidepressant treatment in bipolar disorder: meta-analyses of benefits and risks. Acta Psychiatr Scand 2008;118:

34 SUMMARY OF PROPHYLACTIC ACTIVITY Drug Prevents mania Prevents depression Lithium ++ + Valproate + + Aripiprazole ++ + Olanzapine ++ + Quetiapine Lamotrigine x + Risperidone depot ++ X Antidepressants X?

35 REFRACTORY MANIA Clozapine Tamoxifen Verapamil

36 CALABRESE JR ET AL AM J PSYCHIATRY JUN;153(6): CLOZAPINE FOR TREATMENT-REFRACTORY MANIA. 80% 70% 60% 50% 40% 30% 20% 10% 0% 72% YMRS improvement 32% BPRS improvement Clozapine N=25 Clozapine

37 Clozapine

38 All subjects failed CPZ 500mg + Li

39 DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED 6-WEEK STUDY ON THE EFFICACY AND SAFETY OF THE TAMOXIFEN ADJUNCTIVE TO LITHIUM IN ACUTE BIPOLAR MANIA Journal of Affective Disorders, Volume 129, Issues 1 3, March 2011,

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41 SUMMARY Mania DA antagonists Depression Olanzapine+fluoxetine; quetiapine; lamotrigine Prophylaxis DA antagonist; lithium Refractory Clozapine