Bipolar DisorderIn Primary Care Settings

Christopher Schneck, M.D.Associate Professor of Psychiatry

Director, Outpatient Consultation ServicesUniversity of Colorado Denver Depression Center

Aurora, CO

Disclosure:Funding Sources

NIMH

No pharmaceutical funding

Case Example

Patient L.R.

• 33 year old single female, presents with chronic depression.– Depressed for 15 years– Current symptoms: hypersomnic, eating

more, craves carbohydrates/sweets, feels like she is “nailed to the bed in the mornings,” crying spells, not suicidal but sometimes “prays she will not wake up,” irritable, anxious.

– Never psychotic; no suicide attempts.

Patient L.R.

• Denies manic symptoms. At times, can feel more self-confident, “project a different self,” more impulsive.

• No family history of mood disorder• Past Medical Hx:

– Appendectomy – Mild asthma

• Working 3 jobs; wants to return to graduate school

• Intermittent alcohol problems• In psychotherapy

Patient L.R.

• All antidepressants “work for a while, then stop.”– Paroxetine (Paxil)– Fluoxetine (Prozac)– Sertraline (Zoloft)– Venlafaxine (Effexor)– Buproprion (Wellbutrin)– Amphetamine/d-amphetamine (Adderall)– Escitalpram (Lexapro)– Nefazodone (Serzone)

Next Step?

Diagnosis?

Treatment?

Bipolar Disorder in Patients Treated for Depression in a Family Medicine Clinic

649

21%MDQ+

Hirschfeld RM, et al. J Am Board Fam Pract. 2005;18:233-239.

Waiting Room Patients in a Family Practice

1146 Outpatients

10% MDQ+

Depression 80%

Bipolar 8%

Neither 12%

Das AK, et al. JAMA. 2005;293(8):956.

Challenges in the Diagnosis and

Treatment of Bipolar Disorder

Ghaemi SN, et al. Can J Psychiatry. 2002;47:125-134.

Often

•Unrecognized

•Untreated

•Misdiagnosed

•Inadequately treated

•Worsened by wrong treatment

Misdiagnosis of Bipolar Disorder

0

10

20

30

40

50

60

70

Depression

Anxiety

Schizophrenia

Cluster B

Etoh Abuse

Per

cen

t

Hirschfeld RM, et al. J Clin Psychiatry. 2004;65(suppl 15):5-9.

Initial Diagnosis

Possible Red Flags

• Antidepressant Failure• Increased

irritability/agitation on antidepressants

• Post-partum depression• Seasonal mood changes• Legal, interpersonal,

occupational chaos

Marchand WR. Hosp Physician. 2003;39:21-30. Manning JS. Curr Psychiatry. 2003;2:6-9.Geller B, Luby J. J Am Acad Child Adolesc Psychiatry. 1997;36:1168-1176. Akiskal HS, et al. J Affect Disord. 1983;5:115-128.

Possible Red Flags

• Rapid onset/offset• “Too many to

count”• Psychosis• Family history• Substance abuse

Clinical Features of Bipolar Disorder

Symptom Domains of Bipolar Disorder

• Racing thoughts• Distractibility• Disorganization• Inattentiveness

• Delusions• Hallucinations

• Euphoria• Grandiosity• Pressured speech• Impulsivity• Excessive libido• Recklessness• Social intrusiveness• Diminished need

for sleep

• Depression • Anxiety• Irritability• Hostility• Violence or suicide

Cognitive SymptomsPsychotic Symptoms

Dysphoric or Negative Mood and BehaviorManic Mood and Behavior

BIPOLARDISORDER

Slide courtesy of Keck PE Jr.; adapted from Goodwin FK, Jamison KR. Manic-Depressive Illness. Oxford University Press: New York, NY; 1990.

0

10

20

30

40

50

60

BP I (n=146) BP II (n=71)

Time Depressed vs. Manic

1. Judd LL et al. Arch Gen Psychiatry. 2002; 59:530-537. 2. Judd LL et al. Unpublished data.

Weeks depressedWeeks manic

Per

cent

of

Wee

ks

3:1

37:1

Psychosocial Impairment: Depression More Impairing than Mania

*Marked or extreme over past 4 weeks

Hirschfeld RM. Eur Neuropsychopharmacol. 2004;14(suppl 2):S83-S88.

2327

32

1720

22

0

5

10

15

20

25

30

35

Work/School Social/Leisure Family Life

Due to depressive symptoms Due to manic symptoms

P < 0.01 P < 0.0001P < 0.0001

Per

cen

t W

ith

Dis

rup

tion

*

Mania

Depression

Mania

Depression

Mania

Depression

Mania

Depression

Bipolar I vs Bipolar II

Bipolar I Bipolar II

• Manic or mixed episode• Highly familial• Female:male = 1:1• Suicide: 10%–15% • 60% Comorbid substance

• Hypomania + major depression• Female:male = 2:1 • Diagnostic challenges:

– Hypomania not experienced

as “abnormal”

– Prior hypomania often not

reported

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000.

The Spectrum of Bipolar Disorder

Major Depression Bipolar

Rapidly changing mood swings

Major depression w/strong family hx of bipolar disorder

Antidepressant-inducedmanias & hypomanias

Cyclothymia

Secondary manias

Bipolar II Bipolar I

Gorman JM, Sullivan G. J Clin Psychiatry. 2000;6(1 Suppl 1):13-16.

Bipolar Spectrum Disorders

Difficulties in Diagnosis:Bipolar Patients Previously Diagnosed with

Unipolar MDD (N=29)

Ghaemi SN et al. J Clin Psych 61:10, 2000

9.1 years

24.7

Mania

19.6

Depression

25.2 30 34.3

DX: Bipolar

33.2

Consequences of Misdiagnosis

↑ SuicideAttempts

↑ Comorbidity

↑ Psychosocial Impairment

ATDMono-

therapy

↑ Mortality

Goldberg JF, Ernst CL. J Clin Psychiatry. 2002;63:985-991. Goldberg JF, Truman CJ. Bipolar Disord. 2003;5:407-420.

Switches,Cycling

Reasons for Misdiagnosis

• Hypomania hard to identify– Patients typically do not seek care for hypomania

– Patients often omit hypomania from clinical histories

• Patients tend to seek care during depressive episode

• Bipolar II may be common in primary care setting

Zylstra RG, et al. Primary Care Companion J Clin Psychiatry. 1999;1:47-49.

Can you tell the difference

between bipolar & unipolar

depression?

Features Indicative of Bipolar versus Unipolar Depression

UncommonSuggestiveBrief MDE (avg < 3 months)

UnusualCommonRecurrent MDE (> 3)

UnusualTypicalRapid On/Off Pattern

OccasionalCommonAtypical Features

UncommonHighly PredictivePsychosis < 35 yrs

SometimesVery CommonPostpartum Illness

SometimesVery CommonFirst Episode < 25 yrs

SometimesAlmost UniformFamily History

ModerateVery HighSubstance Abuse

UnipolarBipolar

MDE = major depressive episode

Kaye NS. J Am Board Fam Pract. 2005;18:271-281.

Screening

for Bipolar Disorder

Bad day at the office

The Mood Disorder

Questionnaire (MDQ)

Hirschfeld RMA, et al. Am J Psychiatry. 2000;157:1873-1875.Hirschfeld RMA, et al. Am J Psychiatry. 2003;160:178-180.Hirschfeld RMA, et al. J Clin Psychiatry. 2003;64:53-59.

+ Greater than 7 “yes” responses-”yes” to Question 2-”Moderate” or “Serious” to Question 3

- 7 or fewer “yes” responses-no to Question 2-”No problem” or “minor problem” to Question 3

www.psycheducation.org/PCP/handouts/mdq.doc

Bipolar Spectrum Diagnostic Scale

√√

√√

√√ √√

√

√

Ghaemi SN et al. J Affect Dis, vol 84, 2005

“Has there ever been a time in your life, when, for

several days or even weeks, you slept a lot less than usual and found you

didn’t miss it?”

Treatment

Suicide Risk: Various Conditions

0 5 10 1

5

20 2

5

30 3

5

40

38.4

20.3

15.0

8.5

19.2

5.9

7.1

1.8

History of Suicide Attempt

Major Depression

Bipolar Disorder

Schizophrenia

Mixed Drugs

Alcohol

Personality D/O

Malignancy

Observed/Expected

Inskip H et al. Br J Psych 1998;172:35-37.

5 10 15 20 25 30 35 400

36

Bipolar Disorder: Untreated vs Treated Standardized Mortality Ratios

Neoplasm Cardio-vascular

Cerebro-vascular

Accidents Suicide Other All Causes

Untreated

Treated

29.2*

1.4* 2.2* 1.6† 1.6 2.0* 2.2*

*P < 0.001 †P < 0.05 Zurich cohort, n = 406

1959–1997

Adapted from Angst F et al. J Affect Disorder. 2002;68:167-181.37

6.4

0.61.7 1.3

2.0 1.3 1.3

Treatment

Medications Psycho-therapy

ImprovedOutcome

Therapies With Bipolar Disorder Indications

*Limited data; **Emerging dataPhysicians’ Desk Reference®. 59th ed. Montvale, NJ: Medical Economics Co; 2005.

TherapyBipolarMania

BipolarDepression

MaintenanceRelapse

Prevention

Valproic acid Yes No No No

Lithium Yes No* Yes Yes

Carbamazepine Yes No No No

Divalproex Yes No* No No

Lamotrigine No No** Yes No

Aripiprazole Yes No Yes No

Olanzapine Yes No Yes Yes

Olanzapine+fluoxetine (OFC) No Yes No No

Quetiapine Yes Yes No No

Risperidone Yes No No No

Ziprasidone Yes No No No

√√√√

√√

√√√

√

√√√

√

√√√

Treatment of

Mania

Response Rates in 20 Acute Mania Trials

50%

29%

62%

42%

0%

10%

20%

30%

40%

50%

60%

70%

Li/DVX/CBZ/Atypicals Placebo Atypical+Li/DVX Combo Li/DVX Monotherapy

From Ketter TA. Review of Psychiatry, vol 24, no. 3

Pe

rce

nt

Re

spo

nd

ers

Risperidone vs Placebo in Acute Mania: Mean Reduction in YMRS Score

BL = Baseline

Hirschfeld RM et al. Presented at ACNP Annual Meeting. San Juan, Puerto Rico. December 2002.

-12

-10

-8

-6

-4

-2

0

Baseline Day 3 Week 1 Week 2 Week 3 Endpoint

Mea

n C

hang

e in

Tot

al Y

MR

S S

core

Risperidone (n = 134; BL YMRS = 29.1 )

Median dose 4.1 mg/day

Placebo (n = 125; BL YMRS = 29.2)

*

*

LOCF analysis; *P < 0.001 risperidone vs placebo

* **

Overview of 15 Acute Mania Monotherapy Studies

0%

10%

20%

30%

40%

50%

60%

Lithium DVX CBZ Risp OLZ QUE Zip Ari PCB1950Mg/d

1694Mg/d

707Mg/d

4.9Mg/d

16Mg/d

575Mg/d

121Mg/d

28Mg/d

Adapted from Ketter TA. Advances in the Treatment of Bipolar Disorder. Review of Psychiatry, vol. 24, no. 3

Mood Stabilizers Atypical Antipsychotics

Placebo

Per

cent

Res

pond

ers

Treatment of

Bipolar Depression

Positive Antidepressant Trials with

Adequate Sample Size* in Bipolar Depression

*Statistical Power ≥ 0.8 to detect meaningfuldifference at p<.05

Slide Courtesy G Sachs

Effectiveness of Adjunctive

Antidepressant Treatment for

Bipolar Disorder

23.5

10

27

11

0

5

10

15

20

25

30

Durable Recovery Switch Rates

% P

atie

nts

MS + ADMS Alone

Sachs GS et al. NEJM 2007; 356(17)

NS

NS

Conversion to Rapid Cycling

Antidepressant

Problems with Antidepressants: Mrs. A

...”After 10 days noticed racing & distorted thoughts, increased irritability, hostility, aggressive behavior and decreased need for sleep. She described feeling “speedy” and began driving aggressively; she later described her state as one of ‘radical agitation.’”

Schneck CD. J Clin Psychiatry 59:12, 1998

Antidepressant Associated with Increased Cycle Rates

Episodes Odds Ratio Statistic

4+ Episodes (N=48) 3.8 95% CI=1.2-2.3, p=0.001

2-3 Episodes (N=225) 2.0 95% CI=1.4-2.9, p=0.0001

One episode (N=263) 1.7 95% CI=1.7-8.5, p=0.001

Schneck et al. Am J Psych 165 (3), 2008

Time to Relapse for Patients with Bipolar Disorder WhoDiscontinued Antidepressant Treatment Within 6 Months of

Remission or Continued Treatment Beyond 6 Months

Number of Weeks Until Relapse

0 8 16 24 32 40 48

1.0

0.8

0.6

0.4

0.2

0.0

Pro

po

rtio

n o

f S

ub

ject

s N

ot

Rel

apsi

ng

Medication DiscontinuationGroup

Medication ContinuationGroup

Altshuler L et al. Am J Psych 160, 2003

Treatment Response in Modern Trials with >100 Depressed

Bipolar Subjects

36% 36%

25% 24%19%

11%4%

8%

22% 22%

29%25%

29%

35%

25%35%

0%

10%

20%

30%

40%

50%

60%

70%

QUE 600mg

QUE 300mg

LTG 200mg

OFC LTG 50 mg Li Pax Li IMI OLZ

Res

pons

e R

ate

Placebo Response Rate

Active Placebo Difference

Adapted from Ketter TA. Advances in the Treatment of Bipolar Disorder. Review of Psychiatry, vol. 24, no. 3

Psychotherapy by (buy) the Book

Be on the look-out for:

• Repeated antidepressant failures• Irritability/agitation on antidepressants• Severe post-partum depression• Rapid onset/offset of mood changes• “Too many to count”• Psychosis• Family history of bipolar disorder• Substance abuse

Ask:• Duration of mood

symptoms• Hypomanic

symptoms• Friends, family• Family history• Prior response to

antidepressants• MDQ or BSDS

ReferWhen Possible….

Patient L.R.

• Diagnosis: Bipolar Spectrum– Collateral information: episodic

irritability, pressured speech at times

• Antidepressants tapered

• Started on lamotrigine

• Dose pushed to 400 mg daily

Questions?