Unipolar or Bipolar: Clues to Misdiagnosis AACP Chicago 2010.
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Transcript of Unipolar or Bipolar: Clues to Misdiagnosis AACP Chicago 2010.
Unipolar or Bipolar: Clues to Misdiagnosis
AACP
Chicago 2010
Outline• (1) Consequences of missing bipolarity and/or
cyclicity and the major reasons for it:– Failure to include a family member in the initial
evaluation
– DSM IV & V (draft) confound polarity and cyclicity
(2) Formal studies of UP – BP differences
(3) Clinical clues to bipolarity and/or cyclicity
In the interest of time some slides are hidden, but you will receive the full set by email
• A widely publicized recent study purports to show overdiagnosis in adults; it does not
• 5 studies of bipolar I adults diagnosed by research criteria suggest that the frequency of underdiagnosis is approximately 50%
Goodwin FK, Jamison KR. Manic Depressive Illness. 2nd ed. New York, NY: Oxford University Press; 2007.
Is Bipolar Disorder Overdiagnosed, Underdiagnosed, or Both?
Overdiagnosis in Adults?
• N = 700 outpatients, mean age 39.9
• Overdiagnosis?– Self-report of prior BD diagnosis = 20.7%– SCID BD = 12.9%– SCID confirmation of prior BD diagnosis = 43.4%
• BD underdiagnosis?– Self-report of no prior BD diagnosis = 70%– SCID BD = 30%
• The published paper emphasizes overdiagnosis, though it might just as well have emphasized underdiagnosis
• It really reflects neither: It is simply a study of reliability
M Zimmerman et al, J Clin Psychiatry, June 2008, 69: 935-40
Underdiagnosis of Bipolar Depression: The NIMH Experience
Gershon ES et al. Arch Gen Psychiatry. 1988;45:328–336.
• Patients admitted with major depression– Screened for bipolar disorder by 2 separate
1-hour psychiatric interviews – Family member interviewed by another
investigator interested in genetics– Input from the family resulted in twice as many
bipolar I diagnoses as the patient interviews
0
20
40
60
80
100
Mania/Mania/hypomaniahypomania
RapidRapidcyclingcycling
Pa
tie
nts
(%
)P
ati
en
ts (
%)
Percent of misdiagnosed bipolar patients who developed mania/hypomania or rapid cycling while taking antidepressants
Ghaemi SN et al. J Clin Psychiatry. 2000;61:804–808.
N = 38N = 38
Unipolar Misdiagnosis May Lead to Inappropriate Treatment
• Naturalistic study done with chart review of 85 patients
• Bipolar depression misdiagnosed as unipolar in 56% of patients
• Antidepressants used earlier and more often than mood stabilizers
5555
2323
3661revGoodwin 2010
Kraepelin’s Manic Depressive Illness
As originally formulated by As originally formulated by Leonhard, and by Angst, Perris, Leonhard, and by Angst, Perris, Winokur, Goodwin and their Winokur, Goodwin and their colleagues, both unipolar and colleagues, both unipolar and bipolar described patients with a bipolar described patients with a phasic or cyclic course of phasic or cyclic course of recurrent episodes characterized recurrent episodes characterized by autonomous “endogenous” by autonomous “endogenous” features. features.
DSM-IVDSM-IV Classification of Classification of Mood DisordersMood Disorders
Mood disordersMood disorders
Bipolar disordersBipolar disorders Depressive disordersDepressive disorders
Bipolar IBipolar Idisorderdisorder
Bipolar IIBipolar IIdisorderdisorder
BipolarBipolardisorderdisorderNOSNOS
CyclothymicCyclothymicdisorderdisorder
Recurrent (>1 episode)Recurrent (>1 episode)
DepressiveDepressivedisorderdisorderNOSNOS
SingleSingleepisodeepisode
DysthymicDysthymicdisorderdisorder
MajorMajordepressivedepressivedisorder disorder
DSM-IV. 4th ed. Washington, DC: American Psychiatric Association; 1994.
By separating out the By separating out the Bipolar subtype from Bipolar subtype from the top as a distinct the top as a distinct
illness, DSM IV and the illness, DSM IV and the draft of V depart from draft of V depart from
Kraepelin and the Kraepelin and the originators of the UP – originators of the UP –
BP distinction by BP distinction by placing the primary placing the primary
emphasis on polarity at emphasis on polarity at the expense of cyclicity the expense of cyclicity
or recurrenceor recurrence. Goodwin and Jamison 2007
Highly Recurrent Highly Recurrent Unipolar Depression Unipolar Depression (Cyclic Depression)(Cyclic Depression)
Bipolar family historyBipolar family history Bipolar-like age of onset (teens and 20s)Bipolar-like age of onset (teens and 20s) High episode frequency High episode frequency Manic/hypomanic switch with Manic/hypomanic switch with
antidepressantsantidepressants Prophylaxis with lithium > imipramineProphylaxis with lithium > imipramine
(Lithium is anti-cyclic, not just anti-(Lithium is anti-cyclic, not just anti-bipolar) bipolar)
UNFORTUNATELY DSM-IVUNFORTUNATELY DSM-IV (and the draft (and the draft of V) HAVE NO SUCH CATEGORYof V) HAVE NO SUCH CATEGORY
Goodwin FK, Jamison KR. Manic Depressive Illness. 2nd ed. New York, NY: Oxford University Press; 2007.
Why has polarity trumped Why has polarity trumped cyclicity? cyclicity?
Bipolarity can be determined on the basis of a Bipolarity can be determined on the basis of a single manic (or hypomanic) episode, and a single manic (or hypomanic) episode, and a UP diagnosis can be made with some UP diagnosis can be made with some confidence if age of onset is >35 or, if an confidence if age of onset is >35 or, if an earlier age of onset, after 2 - 3 depressions earlier age of onset, after 2 - 3 depressions without a mania/hypomania.without a mania/hypomania.
The quantification of Cyclicity (recurrence) The quantification of Cyclicity (recurrence) requires long periods of observation, ideally requires long periods of observation, ideally prospectively. This is especially difficult to prospectively. This is especially difficult to accomplish in countries with high population accomplish in countries with high population mobility, such as the Unites States. mobility, such as the Unites States.
DSM IV and V(draft) diagnoses are cross-DSM IV and V(draft) diagnoses are cross-sectional sectional
Recurrent (episodic)> 3 episodes; onset < age 30
(Kraepelin’s manic-depressive illness)
Non-Psychotic
Bipolar Unipolar
Psychotic
DepressivedisorderN.O.S.
Depressive disorders< 3 episodes; onset < age 30
Dysthmia
Non-Psychotic
Psychotic
MajorDepressio
n
“The Bipolar Spectrum”
BPI
BPN.O.S.
Cyclo-thymia
Mood or Affective Disorders;
A proposal for DSM V
BPII
Goodwin FK, Jamison KR. Manic Depressive Illness. 2nd ed. New York, NY: Oxford University Press; 2007.
Outline
• (1) Consequences of missing bipolarity and/or cyclicity and the major reasons for it:– Failure to include a family member in the initial
evaluation– DSM IV & the draft of V confound polarity and
cyclicity
(2) Formal studies of UP – BP differences
(3) Clinical clues to bipolarity and/or cyclicity
Unipolar – Bipolar Differences
• Family History (genetics)
• Epidemiology
• Natural course
• Clinical features of depression
• Personality
• Biological findings
• Pharmacological response
Bipolar vs. Unipolar Depression:Classical Differentiating Characteristics
Goodwin and Jamison Manic-Depressive Illness, 1990, 2007; Akiskal HS. J Affect Disord, 2005.
Bipolar Unipolar
History of mania or hypomania
Yes No
Temperament Cyclothymic Dysthymic
Sex ratio Equal Women > men
Age at onset Teens, 20s, and 30s 30s, 40s, 50s
Onset of episode Often abrupt More insidious
Number of episodes Numerous Fewer
Postpartum episodes More common Less common
Psychotic episodes More common Less common
Psychomotor activity Retardation > agitation Agitation > retardation
Sleep Hypersomnia > insomnia
Insomnia > hypersomnia
Family history of BPD High Low
Family history of UPD High High
The interpretation of reported UP-BP differences is confounded by heterogeneity in both groups
• For most UP samples, data on the number of prior episodes and on age of onset (mean, range, frequency distribution for each) are not provided.– This is important because, for eg, Benazzi et al found
that when UP and BP samples are matched for age of onset some of the polarity differences disappear.
– Also, as noted earlier, comparably recurrent UP and BP pts have similar responses to prophylactic lithium
• In many of the BP samples BP I and II are lumped together
Goodwin and Jamison 2007
In most of the early UP-BP studies the UP group was more recurrent and the BP group was BP I (thus these differences
are more reliably related to polarity)• Some examples:
– Family history of mania – BP > UP– Symtomatic variability across episodes –
BP > UP– Post-partum episodes - BP > UP– Psychomotor retardation – BP > UP– Psychotic features – BP > UP– Prophylactic response to lithium – BP = UP
Goodwin and Jamison 2007
The interpretation of reported UP-BP differences is confounded by heterogeneity in both groups
• For most UP samples, data on the number of prior episodes and on age of onset (mean, range, frequency distribution for each) are not provided.– This is important because, for eg, Benazzi et al found
that when UP and BP samples are matched for age of onset some of the polarity differences disappear.
– Also, as noted earlier, comparably recurrent UP and BP pts have similar responses to prophylactic lithium
• In many of the BP samples BP I and II are lumped together
Goodwin and Jamison 2007
Clinical Difference between Bipolar I and Bipolar II Depression
Compared to BP II, Bipolar I depressed patients have: More Psychotic Features More Hospitalizations More Agitation and Irritability More Severe Depressive Episodes Longer Major Depressive Episodes
Compared to BP I, Bipolar II depressed patients have: More Anxiety Symptoms Longer Periods of Minor/ Subsyndromal Depressions More Episodes and Shorter Intervals More Rapid Cycling More Premenstrual Dysphoria
Goodwin and Jamison 2007
Relative Risk for Bipolar Disorder in First-Degree Relatives of Patients with Major Mood Disorders
Bipolar (I & II) 10.7
All Major Depression 2.8
Early Onset Recurrent
Depression subgroup
4.5
Overview of Reported Differences between Bipolar Disorder and Unipolar Depression
Bipolar (I and/or II) Unipolar
Natural Course
Age at Onset Younger
Narrower Range
Older
Broader Range
Number of Episodes More Fewer
Length of Depressive
Episode
Shorter Longer
Cycle Length Shorter Longer
Precipitants of Episodes More important at illness
onset than for later
episodes
Relation to illness onset not clear
Seasonal Pattern Fall/winter: depression
Spring/summer: mania/hypomania
Spring: depression (?)
Goodwin and Jamison 2007
Unipolar – Bipolar Differences
• Family History (genetics)
• Epidemiology
• Natural course
• Clinical features of depression
• Personality
• Biological findings
• Pharmacological response
Widely Replicated Clinical Differences between Bipolar (Primarily BP I) and Unipolar Depression
Compared to UP, bipolar patients have more: Psychomotor Retardation Inter-episode Mood Lability Psychotic Features Comorbid Substance Abuse
Atypical Features (BPII)
Compared to BP, unipolar patients have more: Anxiety Agitation Insomnia Physical Complaints Anorexia and Weight Loss
Goodwin and Jamison 2007
Other (less widely replicated) Clinical Differences between Bipolar (Primarily BP I) and Unipolar
Depression
Compared to UP, bipolar patients tend to have more: Symptomatic variability across episodes Irritability (BPII) Hypersomnia Late Insomnia Fragmented REM Sleep
Post Partum Episodes
Compared to BP, unipolar patients tend to have more: Initial Insomnia Pain Sensitivity
Goodwin and Jamison 2007
Overview of Reported Differences between Bipolar Disorder and Unipolar Depression
Bipolar (I and/or II) Unipolar
Personality
Depression/Introversion Less More
Impulse Control Less More
Stimulus Seeking More Less
Personality Profile More normal Less normal
Hyperthymic Temperament More Less
Cyclothymia More Less
Goodwin and Jamison 2007
There is no consensus in the literature regarding unipolar – bipolar differences in biological parameters, and this includes the imaging literature
Overview of Reported Differences between Bipolar Disorder and Unipolar Depression
Bipolar (I and/or II) Unipolar
Pharmacological Response
Response to Antidepressants Less(?) More(?)
Speed of Response to Antidepressants
More rapid(?) Less rapid(?)
Tolerance to Antidepressants More frequent Less frequent
Antidepressant Response to Mood
Stabilizers
More frequent Less frequent
Manic/ Hypomanic Response to
Antidepressants
More frequent Less frequent
Prophylactic Response to Lithium Equivalent when
bipolar and unipolar cycle
lengths are comparable
Prophylactic Response to
Antidepressants
Poor Good?
Goodwin and Jamison 2007
UP – BP differences: Conclusions
• Our current diagnostic system leaves the unipolar category so broadly defined (i.e. not bipolar) as to be almost meaningless
• Even the DSM IV (and the draft of V) category of “recurrent depression” is too broad since it includes anyone with more than one episode
• A bipolar spectrum that includes recurrent UP with a FH of BP risks confounding polarity & cyclicity
• To evaluate UP – BP differences meaningfully, the two groups should be comparably recurrent or cyclic. The majority of reported UP-BP differences do not reflect matched samples
Goodwin and Jamison 2007
Outline
• (1) Consequences of missing bipolarity and/or cyclicity and the major reasons for it:– Failure to include a family member in the initial
evaluation– DSM IV & V confound polarity and cyclicity
(2) Formal studies of UP – BP differences
(3) Clinical clues to bipolarity and/or cyclicity
Clues to a Bipolar or Cyclic Diathesis
• Family history of mania (when positive)• Early age of onset of depression• Recurrent major depressive episodes (> 3)• Atypical depressive symptoms (DSM-IV criteria) • Brief major depressive episodes (avg < 3 mos)• Psychotic major depressive episodes • Postpartum depression
• Antidepressant-induced mania or hypomania • Rapid antidepressant response, then “wear-off”
• Lack of response to 3 adequate antidepressant trials
.Adapted from: Ghaemi SN Goodwin et al. Psychopathology. 2004; 37:222–226.
Bipolar II Switching in MDD11-Year Naturalistic-Prospective NIMH Study
• 48/559 (9%) of Unipolar became BP II
• 3 main factors: 91% sensitivity– Mood lability– Energy-activity– "Daydreaming" (mental activation)
• Mood liability factor alone– 42% sensitivity, 86% specificity
Akiskal HS, Goodwin et al. Arch Gen Psychiatry, 1995;52:114-123.
“The Rule of 3” (or Excesses), Hinting at Soft Bipolarity in a Clinically Depressed Individual
• ≥3 depressive episodes
• ≥3 failed marriages
• ≥3 failed antidepressant trials
• ≥3 distinct professions
• ≥3 first degree relatives with affective illness
• 3 generation family history
• Eminence in ≥3 fields in the family
• Triad of past histrionic, psychopathic, or borderline diagnoses
• Triad of "trait mood lability," "energy activity," and "daydreaming"
• Triad of red car, necktie, and belt (Akiskal works in So. Calif)
• 3 longstanding substances of abuse
• ≥3 impulse control behaviors (e.g., gambling, car racing, skydiving)
• Simultaneous dating of ≥3 individuals
• 3 simultaneous jobs
• Proficiency in ≥3 languages (for U.S.-born citizens)
Akiskal, J Affect Disord, 2005.
3-4 Year Prospective Prediction of Bipolar (BP-I) Outcome in 41 of 205 Depressives
Variable % Sensitivity % Specificity
Pharmacologic hypomania
Bipolar family history
Loaded pedigree
Hypersomnic-retarded
Psychotic depression
Postpartum onset
Onset <26 years
32
56
32
59
42
58
71
100
98
95
88
85
84
68
Akiskal HS, et al. J Affect Disord,1983;5(2):115-128.
Validity of Bipolar II:Association of Cyclothymic Traits with
Positive Family History for Bipolar Disorder (Odds Ratio)
• Rapid shifts in mood & energy (3.42)• Alternating between high & low (2.13)• Alternating between bubbly & sluggish (2.11)• Excessive daydreaming (2.03)• Urge for risky or outrageous behavior (2.31)• Lethargy alternating with eutonia (2.95)• Brooding vs. optimism (2.35)• Variable need for sleep (2.23)• Inertia vs. restless pursuit of activities (2.79)
Hantouche & Akiskal (JAD, 2006).
BP-NOS Defined for COBYBP-NOS Defined for COBY
Distinct period of Elated Mood plus 2 symptoms or Irritable Mood plus 3 symptoms (1 symptom short)
Mood must be distinct change from usual and symptoms must be associated/intensify with mood change
Change in functioning
Not associated with medication
At least 4 hours meeting above criteria in a 24-hour period to count as “one day”
Lifetime of ≥ 4 days total of meeting criteria (e.g. 4 one-day episodes; 2 two-day episodes, etc.)
B Birmaher, ISBD, Pittsburgh, 2009
COBY Subjects at IntakeCOBY Subjects at Intake
35%
58%7%
B Birmaher, ISBD, Pittsburgh, 2009
Why Were the BP-NOS Not BP-I/II?Why Were the BP-NOS Not BP-I/II?
Episode not long enough (74%)
Hypomania, no MDE (17%)
Not Enough Symptoms (3%)
Too Short & Not Enough Sx (6%)
B Birmaher, ISBD, Pittsburgh, 2009
Conclusions
• Our current diagnostic system leaves the unipolar category so broadly defined (i.e. not bipolar) as to be almost meaningless; ditto “recurrent Depression”
• Suspect BP when your depressed patients have:– BP family history (when positive)– Age of onset below 25– More than 2 depressive episodes before 25– Mood lability when depressed– Rapid response to an antidepressant– Antidepressant “wear off” or “poop out”– No response to 3 adequate antidepressant trials
Goodwin and Jamison 2007