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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?