CHAIR SUMMIT 7TH ANNUAL #CHAIR2014. Master Class for Neuroscience Professional Development. September 11 13, Westin Tampa Harbour Island

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1 #CHAIR2014 7TH ANNUAL CHAIR SUMMIT Master Class for Neuroscience Professional Development September 11 13, 2014 Westin Tampa Harbour Island Sponsored by

2 #CHAIR2014 Bipolar Depression: Putting the End Goal at the Front of Your Mind Robert M.A. Hirschfeld, MD University of Texas Medical Branch Galveston, TX

3 Robert M. A. Hirschfeld, MD Disclosures Consultant: Equinox; GlaxoSmithKline; GME Global Medical; Merck Manual Editorial Board Royalties: Jones and Bartlett

4 #CHAIR2014 Learning 1 Objective Initiate an individualized treatment plan for bipolar depression that considers efficacy, side-effect profile, and metabolic impact

5 #CHAIR2014 Learning 2 Objective Regularly implement the use of validated rating scales and questionnaires to objectively measure the clinical status of patients being treated for bipolar depression

6 Bipolar Disorder (Manic Depressive Illness) A recurrent and sometimes chronic illness involving episodes of depression and mania or hypomania 1 Polarity of Symptoms Euthymia Longitudinal Course Mania Hypomania Subsyndromal Depression Depression Depression 1. Hirschfeld RMA. Adv Stud Med No PMID

7 History of Concept of Bipolar Disorder Kraepelin! Separation of manic depressive insanity from dementia praecox Bipolar Disorder! Leonhard, Angst, Winokur Bipolar II! Dunner, Gershon, Goodwin Notion of Bipolar Spectrum! Akiskal, Klerman, Cassano

8 DSM-5 Mood Disorders Bipolar Disorder Bipolar I Disorder Bipolar II Disorder Cyclothymic Disorder Depressive Disorders Disruptive Mood Dysregulation Disorder Major Depressive Disorder Persistent Depressive Disorder (Dysthymia) Premenstrual Dysphoric Disorder

9 Mood Disorders (Goodwin) Manic Depressive Illness Recurrent (episodic) >3 episodes; onset < age 30 Depressive Unipolar Disorders <3 episodes; onset < age 30 Goodwin FK, Jamison KR. Manic Depressive Illness. 2nd ed. New York, NY: Oxford University Press, 200

10 Why is Polarity More Important than Cyclicity in the Current Nomenclature? It s simple and easy bipolarity can be determined on the basis of a single manic (or hypomanic) episode Determining cyclicity is time consuming and complicated the quantification of cyclicity (recurrence) requires long periods of observation, ideally prospective

11 The Crux of this Debate Is there a group of recurrent depressives who are actually manic depressive? OR Have these patients simply not demonstrated their true bipolarity?

12 Recurrent Depression as Part of Manic Depressive Illness Bipolar family history Early age of onset (teens to early 20s) High episode frequency Manic/Hypomanic switch with antidepressants Prophylaxis with lithium > imipramine! (Lithium is anti-cyclic, not just anti-bipolar) Goodwin FK, Jamison KR. Manic Depressive Illness. 2nd ed. New York, NY: Oxford University Press, 2007

13 Predictors of Subsequent Bipolar Disorder in Patients with Episodes of Depression (13 year Follow-up) Family history of Bipolar Disorder Age of onset earlier than 25 4 previous depressive episodes Suicidal acts Cyclothymic temperament Substance abuse Male Tondo L, et al. J Affect Disord. 2014;167:44-49.

14 Long Term Course of Bipolar Disorder! Number of Episodes over 25+ years! 5-9 Time spent ill! Well 53%! Depressed 38%! Manic/Hypomanic 9% Mortality! Most Frequent Natural Causes! Cardiovascular Disease and Cancer! Suicide! 30 times higher than general population Angst, J. (1966) Zur Aetiologie und Nosologie Endogener Depressiver Psychosen. Eine genetische, Sociologische und Klinische Studie. Berlin: Springer. Marneros A. et al. Acta Psychiatr Scand, 1990, 82, PMID: ; Judd, LL, et al. Arch Gen Psychiatry, 59(6), PMID:

15 Long Term Course of Bipolar Disorder FDA Approved Treatments for Bipolar Maintenance (8/2014) Lithium Aripiprazole Olanzapine Quetiapine Lamotrigine Ziprasidone (adjunctive only) Risperidone Long Acting Injection

16 Maintenance Studies in Bipolar Disorder (vs. Placebo) 8/ Monotherapy At least 4 weeks stable, with exception of olanzapine (which was 2 weeks) All enriched, with exception of lithium All have abrupt discontinuation * Frequently relapsing Bipolar Disorder Prevent a Recurrence of Any Mania Depression Lithium P P P Atypical Antipsychotics Aripiprazole P P - Quetiapine P P P Olanzapine P P P Risperidone Long Acting Injection* P P - Anticonvulsants Lamotrigine P +/- P

17 Maintenance Studies in Bipolar Disorder (vs. Placebo) 8/2014 Combined Treatment with Lithium or Divalproex At least 4 weeks stable with exception of olanzapine (which was 1 visit) All enriched All have abrupt discontinuation into the placebo group Prevent a Recurrence of Any Mania Depression Quetiapine P P P Risperidone Long Acting Injection* P P - Olanzapine P?? Ziprasidone P P - Aripiprazole P P - * Frequently relapsing Bipolar Disorder

18 Psychosocial Interventions in the Long Term Treatment of Bipolar Disorder Psychoeducation Regularize biorhythms Crisis management Family intervention Support and advocacy groups Supportive psychotherapy Behavior management

19 #CHAIR2014 Recent Acute and Maintenance Trials

20 Lurasidone Approved for Monotherapy Bipolar I Depression June 2013 Change From Baseline in Key Efficacy Measures Loebel A, et al. Am J Psychiatry. 2014;171(2): PMID:

21 Lurasidone Approved as Adjunctive Therapy with Lithium or Valproate Bipolar I Depression June 2013 Change From Baseline in Key Efficacy Measures Loebel A, et al. Am J Psychiatry. 2014;171(2): PMID:

22 Metabolic Considerations Long-term View Lurasidone The diagnosis of bipolar disorder is associated with high rates of metabolic syndrome and an increase in the risk of cardiovascular disease 1. The metabolic profile of lurasidone in the bipolar depression studies is consistent with prior schizophrenia studies and suggests that it may be associated with low cardiometabolic risk in this vulnerable clinical population. Lurasidone extended use and bipolar maintenance studies adjunctive to lithium or divalproex in progress Goldstein B, et al. Bipolar Disord. 2009;11(6): ; Sunovion Lurasidone Extended Use Study. ClinicalTrials.gov Identifier: NCT ; Sunovion Bipolar Maintenance Study of Lurasidone Adjunctive to Lithium or Divalproex. ClinicalTrials.gov Identifier: NCT

23 Novel Treatment of Bipolar Depression Two Ketamine* Trials 18 and 15 patients with treatment resistant bipolar depression and BP I or II depression on therapeutic levels of lithium or valproate A single IV infusion of ketamine (an NMDA antagonist glutamate system) or placebo 18 Treatment Resistant Bipolar Depression Patients * * * * * * * 15 Bipolar I or II Depression Patients ** ** ** ** ** * Minutes Days Time After Infusion Minutes *Not an FDA approved agent for bipolar disorder Diazgranados N et al, Arch Gen Psychiatry. 2010; 67(8): PMID: Zarate CA et al. Biol Psychiatry. 2012; 71(11): PMID: Days

24 Cariprazine* Monotherapy for Acute Mania Cariprazine atypical antipsychotic with potent dopamine D 3 + D 2 receptor partial agonist 21 day multicenter, randomized, placebo controlled, flexible dose study of efficacy and safety of cariprazine in 238 Bipolar I patients with acute mania Primary outcome variable! YMRS change from baseline *Not an FDA approved agent for bipolar disorder Durgam S, et al. Bipolar Disord Jul 24. [Epub ahead of print]. PMID:

25 Cariprazine* Monotherapy for Acute Mania 0$!2$!4$!6$!8$!10$!12$!14$!16$!18$!20$ 0$ 2$ 4$ 7$ 11$ 14$ 21$ Placebo$ Cariprazine$ Response % 25 48*** Remission % 23 42** ***$ ** ** *** 6$ *Not an FDA approved agent for bipolar disorder ** p <.01 *** p <.001 YMRS response: 50% Reduction from Baseline; YMRS Remission: Total Score 12 Durgam S, et al. Bipolar Disord Jul 24. [Epub ahead of print]. PMID:

26 Cariprazine* Monotherapy for Acute Mania Safety (Treatment Emergent AEs 10%) Cariprazine % Placebo % Extrapyramidal disorder 25* 9 Headache Akathisia 19* 6 Constipation 15 9 Nausea *Not an FDA approved agent for bipolar disorder *Not an FDA approved agent for bipolar disorder Dyspepsia 13 7 *Not an FDA approved agent for bipolar disorder p <.001 vs. placebo Durgam S, et al. Bipolar Disord Jul 24. [Epub ahead of print]. PMID:

27 Paliperidone* Monotherapy Maintenance Trial in Bipolar Disorder I 766 Bipolar I (manic or mixed) patients were randomized (4:1) to paliperidone ER or olanzapine for 3 weeks Continuation Phase: 12 stable weeks Maintenance Phase! Olanzapine responders (n = 48) sayed on olanzapine! Paliperidone ER responders (N = 300) randomized to paliperidone ER or placebo! Primary Outcome variable time to recurrence of any mood episode *Not an FDA approved agent for bipolar disorder Berwaertz J, et al. J Affective Disord. 2012;138(3): PMID:

28 Paliperidone* Monotherapy Maintenance Trial in Bipolar Disorder I Recurrence of Manic Symptoms! PCB > Paliperidone > Olanzapine Recurrence of Depressive Symptoms! Placebo non-significantly better than paliperidone Olan/Olan (N = 82) Pali/Pali (N = 146) p =.017 Pali/Placebo (N = 144) *Not an FDA approved agent for bipolar disorder Berwaertz J, et al. J Affective Disord. 2012;138(3): PMID:

29 Lamotrigine Monotherapy vs. Combination in Maintenance Treatment of Bipolar Disorder Open Phase:! Bipolar I or II patients currently (or within past 6 months) depressed were administered LTG + DVPX open label. Patients whose depression resolved for at least 4 weeks were eligible for the maintenance phase 86 patients randomized to 8 months of LTG + placebo or LTG + DVPX Bowden CL, et al. Acta Psychiatr Scand. 2012;126(5): PMID:

30 Lamotrigine Monotherapy vs. Combination in Maintenance Treatment of Bipolar Disorder Results Time to depressive episode did not differ between the groups Significantly more patients in LTG monotherapy had at least one MADRS score 15 (67%) than combo (44%) Combination therapy was superior to LTG monotherapy for manic symptoms Bowden CL, et al. Acta Psychiatr Scand. 2012;126(5): PMID:

31 Conclusions Bipolarity probably more important than cyclicity Early onset, family history and recurrence are important predictors of subsequent bipolarity Several choices for maintenance treatment of bipolar disorder.! These work better for preventing mania than depression Management of side effects important in long term management of bipolar disorder patients

32 Questions & Answers #CHAIR2014