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

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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

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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

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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

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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 6th worldwide all
  cause morbidity and mortality

Colton C Manderscheid R. Prev Chronic Dis
20063(2)1-10.
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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
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Bipolar Disorder

• Also known as manic depression, a mental illness
  that causes a persons 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

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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
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Secondary Mania
Post-TBI Bipolar Symptoms Post-TBI Bipolar Symptoms 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 0.8322.2
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.
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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
200364161-174.
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Overdiagnosis of Bipolar Disorder

• --MIDAS Project, Rhode Island (n700)
• 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.
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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

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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
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Differential DiagnosisPTSD 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

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contd

• 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

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contd

• 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

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Psychiatric Co-Occurrence inBipolar Disorder

• Common psychiatric co-occurrences
• Substance abuse
• Anxiety disorders
• Eating disorders
• Co-occurrence is a marker for bipolarity

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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 2005789-97
Seal et al., Am J Public Health 2009991651-1658.
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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 Clin Psychopharmacol 2004.
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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-SantAnna et al, 2007 .
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PTSD in the VAPAHCS

• 2010, gt 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.

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Bipolar Disorder PTSD
Merikangas et al (2007) n9282 (408 w/BD) Simon et al (2004) n475 McElroy et al (2001) n288 Bauer et al (2005) n328 Veterans
Lifetime 98 (24) 81 (17) 19 (7) 93 (28)
Current --- 24 (5) 12 (4) 82 (25)
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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.
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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
200761(8)751 McCarthy et al. Am J Epidemiol
2009169(8)1033-8 Ilgen et al. Arch Gen
Psychiatry 201067(11)1152-1158.
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Veterans and Suicide Risks
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Why treatment guidelines?
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Historical Analysis -NIMH Bipolar
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
N178, 131 BPD, 47 UP
Frye et al. J Clin Psychiatry 2000619-15.
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Everyone Just Doing Their Best
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Guidelines Aligning the Arrows
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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.

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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

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Clinical Practice Guidelines

• Updated regularly
• Website
• Or try Google.

www.healthquality.va.gov/Management_of_Bi.asp
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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.

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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, MD DoD Aaron Bilow, PharmD Gary Southwell, PhD LTC, USA Randon S. Welton MD. LtCol, USAF - Co-Chair
Office of Quality and Performance, VHA Carla Cassidy, RN, MSN, NP Quality Management Division US Army Medical Command Ernest Degenhardt, RN, MSN, ANP-FNP Joanne Ksionzky BSN, RN, CNOR, RNFA Mary Ramos, PhD, RN
FACILITATOR Oded Susskind, MPH FACILITATOR Oded Susskind, MPH
Research Team ECRI Vivian H. Coats, MPH Eileen G. Erinoff Karen Schoelles, MD David Snyder, PhD Healthcare Quality Informatics Martha DErasmo, MPH Rosalie Fishman, RN, MSN, CPHQ Joanne Marko, MS, SLP
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Evidence Rating System
SR (Strength of Recommendation) 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.
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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

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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
Mixed Episode Valproate, carbamazepine, aripiprazole, olanzapine, risperidone, or ziprasidone A Clozapine I Oxcarbazepine I Quetiapine I Lithium I
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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
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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

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Contd

• 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.

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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

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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)

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Contd

• 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

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

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contd

• 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.

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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, and MAOI C
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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
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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 manufacturers suggested upper limits
  I
• If no response within 2 4 weeks on a good dose
  then augment, switch, or consider ECT

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Contd

• 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.

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Quetiapine vs Placebo in BD Depression
Intent to treat (ITT) last observation carried
forward (LOCF)

• Quetiapine recommended in Stage 2 based on a
  single, robust, large, well-designed randomized
  clinical trial, with the proviso that replication
  studies are needed.

Calabrese JR et al. APA 2004.
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Olanzapine Plus FluoxetineEffective in Bipolar I
Depression
0

-5


Mean Change in MADRS Scores


-10

PBO
OLN 9.7 mg
-15
OLN 7.4 mg FLX 39.3 mg



-20
0
1
2
3
4
6
8
Week
Plt.05 vs OLN, OLNFLX. Plt.05 vs OLN.
MADRS Montgomery-Asberg Depression Rating
Scale. Tohen M, et al. Arch Gen Psychiatry.
2003601079-1088.
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Maintenance Treatments
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/hypomania
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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
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Maintenance Therapy

• A 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

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

• Patients who have had gt1 manic episode, or 1
  manic and depressive episode, or gt2 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.

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• 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 patients family and
  community support C.

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Adjunctive Psychoeducation

• Psychoeducation 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.

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Contd

• With the patients 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.

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Adjunctive Psychotherapies

• CBT for those who have achieved remission from an
  acute manic episode and who have had lt12 previous
  acute episodes A
• IPSRT for those who have achieved remission from
  an acute manic episode and are maintained on
  prophylactic medication B

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Contd

• Structured 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.

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Applying this Guideline to Patients with BD and
PTSD
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RCTs of BD w/co-occurring Anxiety
Citation Duration Subgroup Outcome
Sheehan et al., 2009 8-week Panic disorder or GAD (n111) Risperidone placebo on CGI-Anxiety Severity
Tohen et al., 2007 8-week Co-occurring anxiety symptoms (n833) OLZ and OFC gt PBO for response and remission rates
Hirschfeld et al., 2006b 8-weeks Co-occurring anxiety symptoms (n542) QTP gt PBO for reduction in HAM-A
Maina et al., 2008 12 weeks Comorbid anxiety disorder (n47) OLZ or LTG Li both effective in reducing HAM-A
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In sum

• Clinical treatment studies critically needed on
  VA priority population of individuals with
  bipolar disorder, PTSD, and, often, substance
  use/abuse
• Differential diagnosis critical to providing best
  treatments