VA/ DoD CLINICAL PRACTICE GUIDELINE FOR MANAGEMENT OF BIPOLAR DISORDER IN ADULTS

1. VA/DoD CLINICAL PRACTICE GUIDELINE FORMANAGEMENT OF BIPOLAR DISORDER IN ADULTS Trisha Suppes, MD, PhD Director, Bipolar and Depression Research Program VA Palo Alto Health Care System Professor, Stanford University 2012 WRIISC Webinar Series September 20, 2012

2. Conflict of Interest Disclosures 2011-2012 • Sources of Funding or Medications for Clinical Grants: AstraZeneca, NIMH, Pfizer Inc., Sunovion Pharmaceuticals, Inc. • Consulting Agreements/Advisory Boards: Sunovion Pharmaceuticals, Inc. • Honoraria from talks: None • Speaking Bureaus: None • Royalties: Jones & Bartlett (formerly Compact Clinicals) • Travel: Sunovion Pharmaceuticals, Inc. • Financial Interests/Stock Ownership: None

3. Objectives • Be able to make a differential diagnosis for PTSD and Bipolar Disorder • Be familiar with common co-occurring illnesses with bipolar disorder, including anxiety disorders • Be familiar with most recent VA guidelines for management and treatment of bipolar disorder

4. The Extraordinary Toll of Medical Illness in Bipolar Disorder • People with serious mental illness die 25 years earlier than the general population • Much attributed to smoking, obesity, substance abuse, and inadequate access to medical care • WHO lists Bipolar Disorder as 6thworldwide all cause morbidity and mortality Colton C & Manderscheid R. PrevChronic Dis 2006;3(2):1-10.

5. Costs Associated with BD in the VA • Total VA direct costs for this illness are over $900,000,000 per year - 2007 Blow F et al. Care in the VHA for Veterans with Psychosis: FY2007

6. Bipolar Disorder • Also known as manic depression, a mental illness that causes a person’s moods to be labile and sometimes swing from extremely happy and energized (mania) to extremely sad (depression) • Chronic illness; can be life-threatening • Most often diagnosed in adolescence or early adulthood

7. Diverse Episodes, Frequencies, PatternsA Mood Chart Is Worth 1000 Words Severe Moderate Mild Mild Moderate Severe Mania Mania* Hypomania Euthymia Hypomania Minor depression Depression Depression * Euphoric or mixed mania

8. Secondary Mania Kim et al. J Neuropsychiatry ClinNeurosci2007.

9. Underdiagnosis of Bipolar Disorder • 600 patients with bipolar disorder; retrospective diagnostic history. • 69% of patients previously misdiagnosed Most common alternative primary diagnoses: Depression 60% Anxiety Disorder 26% Schizophrenia 18% Borderline/Antisocial PD 17% - Patients were misdiagnosed 3.5 times on average - 4 physicians were consulted prior to diagnosis Hirschfield et al. J Clin Psychiatry 2003;64:161-174.

10. Overdiagnosis of Bipolar Disorder --MIDAS Project, Rhode Island (n=700) – 145 patients reported past diagnosis of Bipolar Disorder • 82 of 145 were NOT diagnosed Bipolar when given structured interviews Zimmerman, et al., 2008; Zimmerman, et al., 2010.

11. DSM 5 • One of the goals on the Mood Disorder committee is to decrease false positives • Proposed changes for mood disorders to emphasize: episodic nature of symptoms; importance of activity/energy change in hypo/mania; and evaluating for clusters of symptoms

12. Comorbidity and Symptom Sharing

13. Differential Diagnosis:PTSD and BD • Prominent PTSD mood may be chronic and debilitating anxiety versus episodic symptoms of depression and hypo/mania • PTSD mood can also wax and wane depending on acuteness and individual triggers • Hypomania or mania may be a mixed picture and not only euphoric, e.g. “energized depression”

14. cont’d • Careful history taking regarding insomnia and energy levels is key • Bipolar hypo/mania will have less sleep but more energy • Always evaluate for CLUSTERS of symptoms to make the differential or diagnose co-occurring conditions

15. cont’d • Increased arousal associated with PTSD can mimic hypo/mania; numbing and avoidance can appear as depression • In many cases, symptoms of anxiety may co-exist with those of bipolar disorder • Extensive co-occurrence of anxiety disorders, including PTSD, and bipolar disorder

16. Psychiatric Co-Occurrence inBipolar Disorder • Common psychiatric co-occurrences • Substance abuse • Anxiety disorders • Eating disorders • Co-occurrence is a marker for bipolarity

17. Co-occurring disorders is Important Consideration for Veterans • In 2002-2008, about 1/3 vets with MH disorders had 2 co-occurring & 1/3 had 3 or more (Seal, 2009). • A 2005 report showed that 38% of vets with BD have a co-occurring anxiety disorder (Kilbourne, 2005). • BD and PTSD are among the highest rates of co-occurring illnesses. Kilbourne et al. Bipolar Disord 2005;7:89-97; Seal et al., Am J Public Health 2009;99:1651-1658.

18. Prevalence of Psychiatric Co-Occurrence: STEP-BD 1000 • Number of Co-occurring Disorders: 1 – 72%; 2 – 20%; 3 – 15%; 4 – 17% Simon et al. J ClinPsychopharmacol2004.

19. Comorbid anxiety associated with: • earlier age of illness onset; • higher rates of mixed states, depressive symptoms, suicidality, substance use, and psychosis; • LONGER TIME TO REMISSION; • more severe medication side effects; • lower quality of life; • POOR RESPONSE to treatment. Freeman et al., 2002; McElroy et al., 2001; Frank et al., 2002, Feske et al., 2000 , Kauer-Sant’Anna et al, 2007 .

20. PTSD in the VAPAHCS • 2010, > 40% of veterans seen in MH division diagnosed with an anxiety disorder: • PTSD 39% • anxiety state 16% • 2010, there were 7,089 (39%) active veterans with PTSD as primary or secondary MH diagnosis • A total of 49,235 encounters • Veterans 2010 with PTSD, 9% or 638 also have a BD diagnosis.

21. Bipolar Disorder & PTSD

22. Increased Risk of Suicide • Patients with BD + anxiety are at higher risk of suicide. • Where does that leave veterans with BD + anxiety? MacKinnon et al. Bipolar Disord 2005; Kilbane et al. J Affect Disord 2009; Kaplan et al. J Epidemiol Community Health 2007; McCarthy et al. Am J Epidemiol 2009.

23. Veterans and Suicide • Veterans are at a higher risk for suicide than the general population. • Recent study - Veterans with BD among the highest risk of committing suicide ; those with anxiety disorders (including PTSD) in top six groups at risk for suicide. • Sample size - 3,291,891 Veterans Kaplan et al. J Epidemiol Community Health 2007;61(8):751; McCarthy et al. Am J Epidemiol 2009;169(8):1033-8; Ilgen et al. Arch Gen Psychiatry 2010;67(11):1152-1158.

24. Veterans and Suicide Risks

26. Why treatment guidelines?

27. Historical Analysis -NIMH Bipolar *N=178, 131 BPD, 47 UP Frye et al. J ClinPsychiatry 2000;61:9-15.

28. Everyone “Just Doing Their Best”

29. Guidelines: Aligning the Arrows

30. What are treatment guidelines? • Treatment options based on research evidence, clinical experience, and/or expert opinion. • Can include pharmacological, psychosocial, or other treatment approaches. • Published guidelines vary in their organization, commitment to evidence-base, and flexibility. • Guidelines must be updated regularly to reflect changes in available evidence.

31. Clinical elements relatively unique to bipolar disorder • Majority of patients on 3-5 medications. Combinations often necessary to achieve mood stabilization. • Drug holidays never recommended. • Other medical and co-occurring illness must be considered throughout period of treatment

32. Clinical Practice Guidelines • Updated regularly • Website: • Or try Google…. www.healthquality.va.gov/Management_of_Bi.asp

33. VA/DoD Clinical Practice Guidelines – Bipolar Disorder • Published in May 2010, first update since 1999. • Based on most recent research evidence, ranked according to quality and strength. • Workgroup included experts from the VA, DoD, and academia.

34. Workgroup Membership

35. Evidence Rating System

36. Content of Guideline • Module A: Acute Mania, Hypomania or Mixed Episode • Module B: Acute Depressive Episode • Module C: Maintenance Phase • Module D: Psychosocial Interventions • Module E: Pharmacotherapy Interventions • Module F: Specific Recommendations for Management of Older Persons with BD

39. Pharmacology for Patients experiencing Mania, Hypomania or Mixed Episodes • Stop manic-inducing medications; • Use medication proven to effectively treat manic and mixed manic symptoms; • Consider using the agent(s) that have been effective in treating prior episodes;

40. Cont’d • Consider other psychiatric and medical conditions and try to avoid exacerbating them; • If diabetes or obesity are present, consider the risk and benefit of utilizing medications that are associated with weight gain.

41. If mania/mixed symptoms are severe, with or without psychosis: • Use a combination of an antipsychotic and either Li or DVP. • If severe mania - olanzapine, quetiapine, aripiprazole, or risperidone [B] and ziprasidone [I] • If severe mixed - aripiprazole, olanzapine, risperidone, or haloperidol [B] and quetiapine or ziprasidone [I]

42. If monotherapy is insufficient… • ADJUST medications if there is no response within 2 – 4 weeks on an adequate dose; • Consider SWITCHING to another monotherapy [I]; • Consider COMBINATION therapy (see guidelines for choices for severe mania and/or mixed symptoms);

43. Cont’d • Consider Clozapine, particularly if it has been successful in the past or if other antipsychotics have failed [I]; • Electroconvulsive therapy (ECT) may be considered [C]; • Risks and benefits of specific long-term pharmacotherapy should be discussed prior to starting medication and throughout all treatment [A]

44. Summary of 15 Acute Mania Monotherapy StudiesResponse Rates Mood Stabilizers Atypical Antipsychotics Placebo 60 50 40 Percent responders (≥ 50% mania rating decrease) 30 20 1950 mg/d N = 134 1694 mg/d N = 255 707 mg/d N = 223 4.9 mg/d N = 273 16 mg/d N = 304 575 mg/d N = 208 121 mg/d N = 268 28 mg/d N = 260 10 N = 1265 0 Lithium Divalproex Carbamazepine Risperidone Olanzapine Quetiapine Ziprasidone Aripiprazole Placebo Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. APA Press (2005).

45. Bipolar Depression • Patients should be treated with medications with demonstrated efficacy in depressive episodes - minimizing the risk of switch; • Consider agent(s) effective in treating prior episodes; • Riskfor mood destabilization to mania should be monitored closely for emergent symptoms [I]; • For patients with psychotic features, an antipsychotic should be started [I];

46. cont’d • Consider adding an evidence based psychotherapeutic intervention to improve adherence and patient outcome [B]; • Consider other psychiatric and medical conditions and try to avoid exacerbating them; • If diabetes or obesity are present, consider the risk and benefit of utilizing medications that are less associated with weight gain.

49. Recommendations for Treatment of Depressive Episodes • If patient is having intolerable side effects switch to another effective treatment [I]; • Ensure that medication(s) are in therapeutic range, and raise until improvement, side effects or the dose manufacturer’s suggested upper limits [I]; • If no response within 2 – 4 weeks on a good dose then augment, switch, or consider ECT;

50. Cont’d • Any discontinuation of medication should be tapered and the patient should be monitored for mood destabilization [I]; • If mania/hypomania/mixed symptoms occur, go to Module A [I]; • Risks and benefits of long term pharmacotherapy should be discussed prior to starting medication and throughout treatment [A].