Bipolar Disorder
In Primary Care Settings
Christopher Schneck, M.D.
Associate Professor of Psychiatry
Director, Outpatient Consultation Services
University 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
21%
MDQ+
649
Hirschfeld RM, et al. J Am Board Fam Pract. 2005;18:233-239.
Waiting Room Patients
in a Family Practice
Bipolar 8%
10% MDQ+
Neither 12%
Depression 80%
1146 Outpatients
Das AK, et al. JAMA. 2005;293(8):956.
Challenges in the Diagnosis and
Treatment of Bipolar
Disorder
•Unrecognized
•Untreated
Often
•Misdiagnosed
•Inadequately
treated
•Worsened by
wrong treatment
Ghaemi SN, et al. Can J Psychiatry. 2002;47:125-134.
Misdiagnosis
of Bipolar Disorder
Percent
70
60
50
40
30
20
10
0
u
Ab
B
er
st
lu
oh
Et
C
ty
ie
nx
se
a
ni
re
n
io
ss
re
ep
ph
zo
hi
Sc
A
D
Initial Diagnosis
Hirschfeld RM, et al. J Clin Psychiatry. 2004;65(suppl 15):5-9.
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
Manic Mood and Behavior
• Euphoria
• Grandiosity
• Pressured speech
• Impulsivity
• Excessive libido
• Recklessness
• Social intrusiveness
• Diminished need
for sleep
Psychotic Symptoms
• Delusions
• Hallucinations
Dysphoric or Negative Mood
and Behavior
•
•
•
•
•
BIPOLAR
DISORDER
Depression
Anxiety
Irritability
Hostility
Violence or suicide
Cognitive Symptoms
•
•
•
•
Racing thoughts
Distractibility
Disorganization
Inattentiveness
Slide courtesy of Keck PE Jr.; adapted from Goodwin FK, Jamison KR. Manic-Depressive Illness.
Oxford University Press: New York, NY; 1990.
Time Depressed vs. Manic
37:1
60
Weeks depressed
Weeks manic
Percent of Weeks
50
40
3:1
30
20
10
0
BP I
(n=146)
BP II
(n=71)
1. Judd LL et al. Arch Gen Psychiatry. 2002; 59:530-537. 2. Judd LL et al. Unpublished data.
Psychosocial Impairment:
Depression More Impairing than Mania
Percent With Disruption*
Due to depressive symptoms
Due to manic symptoms
35
32
30
25
20
27
23
20
22
17
15
10
5
0
Work/School
P < 0.01
Social/Leisure
P < 0.0001
*Marked or extreme over past 4 weeks
Hirschfeld RM. Eur Neuropsychopharmacol. 2004;14(suppl 2):S83-S88.
Family Life
P < 0.0001
Mania
Depression
Mania
Depression
Mania
Depression
Mania
Depression
Bipolar I
vs Bipolar
Bipolar I
II
Bipolar II
• Manic or mixed episode
• Hypomania + major
•
•
•
•
depression
• Female:male = 2:1
• Diagnostic challenges:
Highly familial
Female:male = 1:1
Suicide: 10%–15%
60% Comorbid substance
– 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 w/
strong family hx of
bipolar disorder
Antidepressant-induced
manias & hypomanias
Rapidly changing
mood swings
Bipolar II
Secondary manias
Bipolar I
Cyclothymia
Major Depression
Bipolar Spectrum Disorders
Gorman JM, Sullivan G. J Clin Psychiatry. 2000;6(1 Suppl 1):13-16.
Bipolar
Difficulties in Diagnosis:
Bipolar Patients Previously Diagnosed with
Unipolar MDD (N=29)
19.6
24.7
25.2
30
33.2
34.3
Depression
DX: Bipolar
Mania
9.1 years
Ghaemi SN et al. J Clin Psych 61:10, 2000
Consequences of Misdiagnosis
ATD
Monotherapy
Switches,
Cycling
↑ Suicide
Attempts
↑ Comorbidity
↑ Mortality
↑ Psychosocial Impairment
Goldberg JF, Ernst CL. J Clin Psychiatry. 2002;63:985-991. Goldberg JF, Truman CJ. Bipolar Disord. 2003;5:407-420.
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
Substance Abuse
Family History
First Episode < 25 yrs
Postpartum Illness
Psychosis < 35 yrs
Atypical Features
Rapid On/Off Pattern
Recurrent MDE (> 3)
Bipolar
Unipolar
Very High
Moderate
Almost Uniform
Sometimes
Very Common
Sometimes
Very Common
Sometimes
Highly Predictive
Uncommon
Common
Occasional
Typical
Unusual
Common
Unusual
Brief MDE (avg < 3 months) Suggestive
MDE = major depressive episode
Kaye NS. J Am Board Fam Pract. 2005;18:271-281.
Uncommon
Screening
for Bipolar
Disorder
Bad day at the office
The Mood Disorder
Questionnaire (MDQ)
+
-
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
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.
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
Observed/Expected
1.8
Malignancy
7.1
Personality D/O
5.9
Alcohol
19.2
Mixed Drugs
8.5
Schizophrenia
Bipolar Disorder
15.0
20.3
Major Depression
History of Suicide
Attempt
38.4
0
0
Inskip H et al. Br J Psych 1998;172:35-37.
5
5
10
10
15
1
5
20
20
25
2
5
30
30
35
3
40
40
5
36
Bipolar Disorder: Untreated vs Treated
Standardized Mortality Ratios
29.2*
*P < 0.001
†P < 0.05
Untreated
Treated
Zurich cohort, n = 406
1959–1997
6.4
1.4*
0.6
Neoplasm
2.2*1.7
1.6† 1.3
1.6 2.0
Cardiovascular
Cerebrovascular
Accidents
Adapted from Angst F et al. J Affect Disorder. 2002;68:167-181.
Suicide
2.0*1.3
2.2*
1.3
Other
All Causes
37
Treatment
Psychotherapy
Medications
Improved
Outcome
Therapies With Bipolar Disorder
Indications
Therapy
Valproic acid
Lithium
Carbamazepine
Divalproex
Bipolar
Mania
√
√
√
√
Lamotrigine
Aripiprazole
Olanzapine
√
√
Olanzapine+fluoxetine (OFC)
Quetiapine
Risperidone
Ziprasidone
*Limited
Bipolar
Depression
Maintenance
Relapse
Prevention
Yes
No
No
No
Yes
No*
Yes
No
No
No
Yes
No*
No
No
No
No**
Yes
No
Yes
No
Yes
No
Yes
No
No
√
√
√
√
√
√
√
√
√
Yes
Yes
√
√
Yes
Yes
Yes
No
No
Yes
No
No
Yes
No
No
No
Yes
No
No
No
Yes
data; **Emerging data
Physicians’ Desk Reference®. 59th ed. Montvale, NJ: Medical Economics Co; 2005.
Treatment of
Mania
Response Rates
in 20 Acute Mania Trials
70%
62%
Percent Responders
60%
50%
50%
42%
40%
29%
30%
20%
10%
0%
Li/DVX/CBZ/Atypicals
From Ketter TA. Review of Psychiatry, vol 24, no. 3
Placebo
Atypical+Li/DVX Combo
Li/DVX Monotherapy
Risperidone vs Placebo in Acute Mania:
Mean Reduction in YMRS Score
Mean Change in Total YMRS Score
Baseline
Day 3
Week 1
Week 2
Week 3
Endpoint
0
LOCF analysis; *P < 0.001 risperidone vs placebo
-2
Placebo (n = 125; BL YMRS = 29.2)
-4
-6
*
-8
Risperidone (n = 134; BL YMRS = 29.1 )
Median dose 4.1 mg/day
-10
*
-12
*
*
BL = Baseline
Hirschfeld RM et al. Presented at ACNP Annual Meeting. San Juan, Puerto Rico. December
2002.
*
Overview of 15 Acute Mania
Monotherapy Studies
Placebo
Percent Responders
60%
Atypical Antipsychotics
Mood Stabilizers
50%
40%
30%
20%
10%
0%
Lithium
1950
Mg/d
DVX
1694
Mg/d
CBZ
707
Mg/d
Risp
4.9
Mg/d
OLZ
16
Mg/d
QUE
575
Mg/d
Zip
Ari
121
Mg/d
28
Mg/d
PCB
Adapted from Ketter TA. Advances in the Treatment of Bipolar Disorder. Review of Psychiatry, vol. 24, no. 3
Treatment of
Bipolar
Depression
Positive Antidepressant Trials with
Adequate Sample Size* in
Bipolar Depression
Slide Courtesy G Sachs
*Statistical Power ≥ 0.8 to detect meaningful
difference at p<.05
Effectiveness of Adjunctive
Antidepressant Treatment for
Bipolar Disorder
NS
30
% Patients
25
27
23.5
20
15
NS
10
11
MS + AD
MS Alone
10
5
0
Durable Recovery
Switch Rates
Sachs GS et al. NEJM 2007; 356(17)
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 Who
Discontinued Antidepressant Treatment Within 6 Months of
Remission or Continued Treatment Beyond 6 Months
Proportion of Subjects Not Relapsing
1.0
Medication Discontinuation
Group
Medication Continuation
Group
0.8
0.6
0.4
0.2
0.0
0
8
16
24
32
Number of Weeks Until Relapse
40
48
Altshuler L et al. Am J Psych 160, 2003
Treatment Response in
Response Rate
Modern Trials with >100 Depressed
Bipolar Subjects
70%
Placebo Response Rate
60%
Active Placebo Difference
50%
22%
22%
40%
29%
25%
29%
30%
20%
35%
35%
36%
36%
25%
10%
24%
19%
11%
4%
0%
QUE 600
mg
QUE 300
mg
LTG 200
mg
OFC
25%
LTG 50 mg
Li Pax
Li IMI
8%
OLZ
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
Refer
When 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?