VA/DoD CLINICAL PRACTICE GUIDELINE FOR

MANAGEMENT OF BIPOLAR DISORDER IN ADULTS

Trisha Suppes, MD, PhDDirector, Bipolar and Depression Research

ProgramVA Palo Alto Health Care System

Professor, Stanford University

2012 WRIISC Webinar SeriesSeptember 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

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

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 2006;3(2):1-10.

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

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

Diverse Episodes, Frequencies, PatternsA Mood Chart Is Worth 1000 Words

Hypomania

Severe

Moderate

Mild

Mild

Moderate

Severe

Mania*

Depression

Minor depression

EuthymiaHypomania

* Euphoric or mixed mania

Mania

Depression

Secondary ManiaPost-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 amnesiaSeizuresMultifocal lesionsFrontal lesionsOrbitofrontal lesionsTemporal lesionsNon-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 misdiagnosedMost 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 diagnosisHirschfield 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 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

Comorbidity and Symptom Sharing

MANIA DEPRESSION ANXIETY

Elated Mood

Irritability Irritability Irritability

Increased Energy Agitation

Restlessness/Agitation

DistractibilityPoor

ConcentrationDifficulty in

Concentration

Flight of Ideas

Grandiosity

Poor Judgment

Reduced Sleep Insomnia Insomnia

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”

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

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

Psychiatric Co-Occurrence inBipolar Disorder

• Common psychiatric co-occurrences– Substance abuse– Anxiety disorders– Eating disorders

• Co-occurrence is a marker for bipolarity

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.

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 diagnosis– A 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 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.

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.

Veterans and Suicide Risks

Bipolar Disorders

Anxiety Disorders

Substance Use

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 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

Clinical Practice Guidelines

• Updated regularly

• Website:

• Or try Google….

www.healthquality.va.gov/Management_of_Bi.asp

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.

Workgroup MembershipVAEileen P. Ahearn, MD, PhDThomas J. Craig, MD, MPHJennifer Hoblyn, MD, MPHAmy M. Kilbourne, PhD, MPHTodd. P. Semla, PharmDAlan C. Swann, MDTrisha Suppes, MD, PhD - Co-ChairMichael Thase, MD

DoDAaron Bilow, PharmDGary Southwell, PhD LTC, USARandon S. Welton MD. LtCol, USAF - Co-Chair

Office of Quality and Performance, VHACarla Cassidy, RN, MSN, NP

Quality Management DivisionUS Army Medical CommandErnest Degenhardt, RN, MSN, ANP-FNPJoanne Ksionzky BSN, RN, CNOR, RNFAMary Ramos, PhD, RN

FACILITATOROded Susskind, MPH

Research Team – ECRIVivian H. Coats, MPHEileen G. ErinoffKaren Schoelles, MDDavid Snyder, PhD

Healthcare Quality InformaticsMartha D’Erasmo, MPHRosalie Fishman, RN, MSN, CPHQJoanne Marko, MS, SLP

Evidence Rating SystemSR (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 providingthe intervention.

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

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]

MixedEpisode

Valproate, 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 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;

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.

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’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]

Summary of 15 Acute Mania Monotherapy Studies Response Rates

Atypical AntipsychoticsMood Stabilizers

0

10

20

30

40

50

60

Carbamazepine

707mg/dN = 223

Risperidone

4.9mg/dN = 273

Quetiapine

575mg/dN = 208

Ziprasidone

121mg/dN = 268

Aripiprazole

28mg/dN = 260

Placebo

N = 1265

Olanzapine

16mg/dN = 304

Divalproex

1694mg/dN = 255

Lithium

1950mg/dN = 134P

erce

nt

resp

on

der

s(≥

50%

man

ia r

atin

g d

ecre

ase)

Placebo

Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. APA Press (2005).

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];

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.

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

CarbamazepineClozapineHaloperidolOxcarbazepineRisperidoneTopiramateValproateZiprasidone

Aripiprazole monotherapy [D]

Gabapentin [D]

Antidepressant monotherapy [D]

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;

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].

*

*

*

** * * *

*

**

* * * * *

*P < 0.001 vs placebo

1 2 43 65 7 8

Study Week

Mea

n C

han

ge

fro

m B

asel

ine 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

Week0 1 2 3 4 6 8

Mea

n C

han

ge

in M

AD

RS

Sco

res

-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 FluoxetineEffective 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/hypomania

Maintenance 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 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];

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’d• Patients 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 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.

Cont’d

• With 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 Psychotherapies

• CBT 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’d

• 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].

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-weeks Co-occurring anxiety symptoms (n=542)

QTP > PBO for reduction in HAM-A

Maina et al., 2008

12 weeks Comorbid anxiety disorder (n=47)

OLZ or LTG + Li; both effective in reducing HAM-A

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