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


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


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



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


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


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


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 (?)


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


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




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


There is no consensus in the literature regarding unipolar – bipolar differences in biological parameters, and this includes the imaging literature



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?


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


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



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%


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%)


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


Documents

Unipolar or Bipolar: Clues to Misdiagnosis AACP Chicago 2010