VA/ DoD CLINICAL PRACTICE GUIDELINE FOR - PowerPoint Presentation

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

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

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

The Extraordinary Toll of Medical Illness in Bipolar DisorderPeople 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 6 th worldwide all cause morbidity and mortality Colton C & Manderscheid R. Prev Chronic Dis 2006;3(2):1-10 .

Costs Associated with BD in the VATotal 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

Bipolar DisorderAlso 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

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

Secondary Mania Post-TBI Bipolar Symptoms Nosology Sleeplessness, impaired judgment, grandiosity, irritability, pressured speech in 80%--100% of cases; hyperactivity in 65% and hypersexuality in 50% Epidemiology Incidence 9.1% Prevalence 0.83—22.2% Risk Factors Prolonged post injury amnesia Seizures Multifocal lesions Frontal lesions Orbitofrontal lesions Temporal lesions Non-dominant hemispheric lesions Kim et al . J Neuropsychiatry Clin Neurosci 2007.

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.

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.

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

Comorbidity and Symptom Sharing MANIA DEPRESSION ANXIETY Elated Mood Irritability Irritability Irritability Increased Energy Agitation Restlessness/Agitation Distractibility Poor Concentration Difficulty in Concentration Flight of Ideas Grandiosity Poor Judgment Reduced Sleep Insomnia Insomnia

Differential Diagnosis:PTSD and BDProminent PTSD mood may be chronic and debilitating anxiety versus episodic symptoms of depression and hypo/maniaPTSD 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”

cont’dCareful history taking regarding insomnia and energy levels is keyBipolar hypo/mania will have less sleep but more energy Always evaluate for CLUSTERS of symptoms to make the differential or diagnose co-occurring conditions

cont’dIncreased arousal associated with PTSD can mimic hypo/mania; numbing and avoidance can appear as depressionIn many cases, symptoms of anxiety may co-exist with those of bipolar disorderExtensive co-occurrence of anxiety disorders, including PTSD, and bipolar disorder

Psychiatric Co-Occurrence inBipolar Disorder Common psychiatric co-occurrencesSubstance abuseAnxiety disordersEating disorders Co-occurrence is a marker for bipolarity

Co-occurring disorders is Important Consideration for VeteransIn 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.

Prevalence of Psychiatric Co-Occurrence: STEP-BD 1000 Simon et al. J Clin Psychopharmacol 2004 . Number of Co-occurring Disorders: 1 – 72%; 2 – 20%; 3 – 15%; 4 – 17%

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 .

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 diagnosisA total of 49,235 encounters Veterans 2010 with PTSD, 9% or 638 also have a BD diagnosis. PTSD in the VAPAHCS

Bipolar Disorder & PTSD Merikangas et al (2007) n =9282 (408 w /BD) Simon et al (2004) n =475 McElroy et al (2001) n =288 Bauer et al (2005) n=328 Veterans Lifetime 98 (24%) 81 (17%)19 (7%)93 (28%)Current---24 (5%)12 (4%)82 (25%)

Increased Risk of SuicidePatients 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.

Veterans and SuicideVeterans 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.

Veterans and Suicide Risks

Why treatment guidelines?

Historical Analysis -NIMH Bipolar Frye et al. J Clin Psychiatry 2000;61:9-15. *N=178, 131 BPD, 47 UP Mean Number of Medications at Discharge % of Patients on 3 or more Meds at Discharge 1974-1979 1.5 3.3% 1980-1984 1.5 9.3% 1985-1989 2.5 34.9% 1990-1995 3.0 43.8%

Everyone “Just Doing Their Best”

Guidelines: Aligning the Arrows

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.

Clinical elements relatively unique to bipolar disorderMajority 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

Clinical Practice GuidelinesUpdated regularlyWebsite: Or try Google…. www.healthquality.va.gov/Management_of_Bi.asp

VA/DoD Clinical Practice Guidelines – Bipolar DisorderPublished 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.

Workgroup Membership VA Eileen P. Ahearn, MD, PhD Thomas J. Craig, MD, MPH Jennifer Hoblyn , MD, MPH Amy M. Kilbourne , PhD, MPH Todd. P. Semla , PharmD Alan C. Swann, MD Trisha Suppes , MD, PhD - Co-Chair Michael Thase, MDDoDAaron Bilow , PharmDGary Southwell, PhD LTC, USARandon S. Welton MD. LtCol, USAF - Co-ChairOffice of Quality and Performance, VHACarla Cassidy, RN, MSN, NPQuality Management DivisionUS Army Medical CommandErnest Degenhardt, RN, MSN, ANP-FNPJoanne Ksionzky BSN, RN, CNOR, RNFAMary Ramos, PhD, RNFACILITATOROded Susskind, MPHResearch Team – ECRIVivian H. Coats, MPHEileen G. ErinoffKaren Schoelles, MDDavid Snyder, PhD Healthcare Quality InformaticsMartha D’Erasmo, MPH Rosalie Fishman, RN, MSN, CPHQJoanne Marko, MS, SLP

Evidence Rating System SR (Strength of Recommendation) A A strong recommendation that clinicians provide the intervention to eligible patients. B A recommendation that clinicians provide (the service) to eligible patients. C No recommendation for or against the routine provision of the intervention is made. D Recommendation is made against routinely providing the intervention to asymptomatic patients. I The conclusion is that the evidence is insufficient to recommend for or against routinely providing the intervention.

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

Likely to be Beneficial [SR] Trade off between Benefit and Harm [SR] Mania Lithium, valproate , carbamazepine , aripiprazole , olanzapine , quetiapine , risperidone , or ziprasidone [A] Combining (lithium or valproate) with aripiprazole, olanzapine, quetiapine, or risperidone [A]Clozapine [I]Oxcarbazepine [I]MixedEpisodeValproate, carbamazepine,aripiprazole, olanzapine,risperidone, or ziprasidone [A]Clozapine [I]Oxcarbazepine [I]Quetiapine [I]Lithium [I]

Unlikely to be Beneficial OR May be Harmful [SR] Mania Lamotrigine [D] Topiramate [D] Gabapentin [D] Antidepressant monotherapy [C] Mixed Episode Lamotrigine [D] Topiramate [D] Gabapentin [D]

Pharmacology for Patients experiencing Mania, Hypomania or Mixed EpisodesStop 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;

Cont’dConsider 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.

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]

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);

Cont’dConsider 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]

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

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

cont’dConsider 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.

Likely to be Beneficial [SR] Trade off between Benefit and Harm [SR] Acute Depressive Episodes Lithium [B] Quetiapine (in BD types I & II) [A] Lithium with adjunctive lamotrigine [A] Olanzapine/Fluoxetine [B] Olanzapine [C] Lamotrigine [B] Augmentation with SSRI, SNRI, buproprion , andMAOI [C]

Unknown Unlikely to be Beneficial OR May be Harmful [SR] Acute Depressive Episode Carbamazepine Clozapine Haloperidol Oxcarbazepine Risperidone Topiramate Valproate Ziprasidone Aripiprazole monotherapy [D] Gabapentin [D] Antidepressant monotherapy [D]

Recommendations for Treatment of Depressive EpisodesIf 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;

Cont’dAny 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].

* * * * * * * * * * * * * * * * * P < 0.001 vs placebo 1 2 4 3 6 57 8 Study Week Mean Change from Baseline Quetiapine 600 mg (n = 170) Quetiapine 300 mg (n = 172) Placebo (n = 169)    -20 -15 -10 -5 0 Quetiapine vs Placebo in BD Depression Quetiapine recommended in Stage 2 based on a single, robust, large, well-designed randomized clinical trial, with the proviso that replication studies are needed. Intent to treat (ITT); last observation carried forward (LOCF) Calabrese JR et al. APA 2004.

OLN 9.7 mg PBO OLN 7.4 mg + FLX 39.3 mg Week 0 1 2 3 4 6 8 Mean Change in MADRS Scores -20 -15 -10 -5 0 * * * * * * † † † * P <.05 vs OLN, OLN+FLX. † P <.05 vs OLN. MADRS = Montgomery-Asberg Depression Rating Scale. Tohen M, et al. Arch Gen Psychiatry. 2003;60:1079-1088. Olanzapine Plus Fluoxetine Effective in Bipolar I Depression

Likely to be Beneficial [SR] Trade off between Benefit and Harm [SR] Monotherapy : - Lithium [B*/A**] - Lamotrigine [B*/C**]- Olanzapine [C*/B**] Combination: - Quetiapine as adjunct to lithium or valproate [B] - Olanzapine as adjunct to lithium or valproate [C]Valproate [C]Carbamazepine [C] Aripiprazole [B**]* Prevention of depression** Prevention of Mania/hypomaniaMaintenance Treatments

Maintenance Recommendations (continued) Maintenance benefit unknown Unlikely to be Beneficial OR May be Harmful [SR] Clozapine, Gabapentin, Haloperidol, Olanzapine/Fluoxetine, Oxcarbazepine , Risperidone , Topiramate , Ziprasidone Antidepressant monotherapy [D]

Maintenance TherapyA structured approach is recommended [A];Patients who have had an acute manic episode should be treated for at least 6 months after the initial episode is controlled and encouraged to continue on life-long prophylactic treatment [A]; Risks and benefits of long term pharmacotherapy should be discussed prior to starting medication and should be continued throughout treatment [C];

Suppes et al. Arch Gen Psychiatry 1991. In early 1990s, there were basic questions to answer in treatment of BD, for example, should patients be prescribed drugs continuously?

Cont’dPatients who have had >1 manic episode, or 1 manic and depressive episode, or >2 depressive episodes, should be encouraged to continue on life-long prophylactic treatment, as the benefits outweigh the risks [A]; If medications are to be discontinued, they should be slowly and GRADUALLY TAPERED over at least a 2 to 4 week period, unless medically contraindicated, to prevent a “REBOUND” episode of bipolar disorder and/or increase the risk of suicide [B].

Patients in remission should be seen every 1 to 3 months with ongoing assessment of recent symptoms [I];All patients on medication should be monitored for potential adverse effects [B]; Monitor serum concentrations (as appropriate) and other appropriate blood work every 3 to 6 months to maintain efficacy and avoid toxicity [A/B];For those on APs, monitor weight, waist circumference, blood pressure, BMI, plasma glucose and fasting lipids [C]. Adherence to medication therapy should be routinely evaluated at each visit [A]; Assess any changes in patient’s family and community support [C].

Adjunctive PsychoeducationPsychoeducation should emphasize [B]:The importance of active involvement in treatment The nature and course of their bipolar illness The potential benefit and adverse effects of treatment options The recognition of early signs of relapse Behavioral interventions that can lessen the likelihood of relapse including careful attention to sleep regulation and avoidance of substance misuse.

Cont’dWith the patient’s permission, family members or significant other should be involved in the psychoeducation process [C];A structured group format in providing psychoeducation and care management for patients with clinically significant mood symptoms should be considered [A].

Adjunctive PsychotherapiesCBT for those who have achieved remission from an acute manic episode and who have had <12 previous acute episodes [A]; IPSRT for those who have achieved remission from an acute manic episode and are maintained on prophylactic medication [B];

Cont’dStructured Family therapy can be considered for couples and families who are coping with BD [C];Patients may benefit from chronic care model-based interventions [B], especially when more symptomatic or recently hospitalized [A].

Applying this Guideline to Patients with BD and PTSD

RCTs of BD w/co-occurring Anxiety Citation Duration Subgroup Outcome Sheehan et al., 2009 8-week Panic disorder or GAD ( n =111) Risperidone = placebo on CGI-Anxiety Severity Tohen et al., 2007 8-week Co-occurring anxiety symptoms ( n =833) OLZ and OFC > PBO for response and remission rates Hirschfeld et al., 2006b 8-weeksCo-occurring anxiety symptoms (n=542)QTP > PBO for reduction in HAM-AMaina et al., 200812 weeksComorbid anxiety disorder (n=47)OLZ or LTG + Li; both effective in reducing HAM-A

In sumClinical treatment studies critically needed on VA priority population of individuals with bipolar disorder, PTSD, and, often, substance use/abuseDifferential diagnosis critical to providing best treatments