1. Unipolar or Bipolar: Clues to Misdiagnosis AACP Chicago 2010

2. 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

3. 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?

4. 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

5. Underdiagnosis of Bipolar Disorder Iowa 500 study Sample A: Personal interview only Sample B: Personal interview and/or hospital chart Tsuang MT et al. Br J Psychiatry. 1980;137:497–504.

6. 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

7. Mania/ hypomania Rapid cycling Patients (%) 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 = 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 55 23

8. How Long Does Diagnosis Take? UP vs BP, t = -2.8, P =.007; differences between BP subtypes, F = 2., P =.09 Ghaemi SN et al. J Clin Psychiatry. 2000;61:804–808. Years to correct diagnosis Years

9. Historical evolution of the MDI construct and the unipolar-bipolar distinction Falret and Bailarger (1854) Griesinger (1867) Kahlbaum (1882) Kraepelin (1913) Kleist (1950) Circular insanity and insanity of double form Mania and melancholia emerging from a single disorder Cyclothymia as a group of circular disorders Manic-depressive insanity (includes recurrent melancholia) Bipolar vs. unipolar manic- depressive subtypes Adapted from Baldessarini et al., 2000

10. Historical evolution of the MDI construct and the unipolar-bipolar distinction Leonhard (1957) Angst and Perris (1960’s) Dunner Gershon and Goodwin (73) Akiskal (1980) Goodwin and Jamison (1990;2007) DSM IV (1994) Elaborated the polarity hypothesis Further elaborated the polarity conept Type II bipolar disorder (depression + hypomania) Broad “bipolar spectrum” concept Manic-Depressive Illness (BP & Recurrent Unipolar) Bipolar-II, cyclothymia, and rapid cycling included Baldessarini et al., 2000

11. Kraepelin’s Manic Depressive Illness

12. As originally formulated by Leonhard, and by Angst, Perris, Winokur, Goodwin and their colleagues, both unipolar and bipolar described patients with a phasic or cyclic course of recurrent episodes characterized by autonomous “endogenous” features. As originally formulated by Leonhard, and by Angst, Perris, Winokur, Goodwin and their colleagues, both unipolar and bipolar described patients with a phasic or cyclic course of recurrent episodes characterized by autonomous “endogenous” features.

13. DSM-IV Classification of Mood Disorders Mood disorders Bipolar disorders Depressive disorders Bipolar I disorder Bipolar II disorder Bipolar disorder NOS Cyclothymic disorder Recurrent (>1 episode) Recurrent (>1 episode) Depressive disorder NOS Single episode Dysthymic disorder Major depressive disorder DSM-IV. 4th ed. Washington, DC: American Psychiatric Association; 1994.

14. By separating out the Bipolar subtype from the top as a distinct illness, DSM IV and the draft of V depart from Kraepelin and the originators of the UP – BP distinction by placing the primary emphasis on polarity at the expense of cyclicity or recurrence. Goodwin and Jamison 2007

15. Highly Recurrent Unipolar Depression (Cyclic Depression) Bipolar family history Bipolar 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 antidepressants Manic/hypomanic switch with antidepressants Prophylaxis with lithium > imipramine Prophylaxis with lithium > imipramine (Lithium is anti-cyclic, not just anti-bipolar) (Lithium is anti-cyclic, not just anti-bipolar) UNFORTUNATELY DSM-IV (and the draft of V) HAVE NO SUCH CATEGORY UNFORTUNATELY DSM-IV (and the draft of V) HAVE NO SUCH CATEGORY Goodwin FK, Jamison KR. Manic Depressive Illness. 2nd ed. New York, NY: Oxford University Press; 2007.

16. Why has polarity trumped cyclicity? Bipolarity can be determined on the basis of a single manic (or hypomanic) episode, and a UP diagnosis can be made with some confidence if age of onset is >35 or, if an earlier age of onset, after 2 - 3 depressions without a mania/hypomania. Bipolarity can be determined on the basis of a single manic (or hypomanic) episode, and a UP diagnosis can be made with some confidence if age of onset is >35 or, if an earlier age of onset, after 2 - 3 depressions without a mania/hypomania. The quantification of Cyclicity (recurrence) requires long periods of observation, ideally prospectively. This is especially difficult to accomplish in countries with high population mobility, such as the Unites States. The quantification of Cyclicity (recurrence) requires long periods of observation, ideally prospectively. This is especially difficult to accomplish in countries with high population mobility, such as the Unites States. DSM IV and V(draft) diagnoses are cross-sectional DSM IV and V(draft) diagnoses are cross-sectional

17. Recurrent (episodic) > 3 episodes; onset < age 30 (Kraepelin’s manic-depressive illness) Non- Psychotic Bipolar Unipolar Psychotic Depressive disorder N.O.S. Depressive disorders < 3 episodes; onset < age 30 Dysthmia Non- Psychotic Psychotic Major Depression “The Bipolar Spectrum” BPI BP N.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.

18. 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

19. Unipolar – Bipolar Differences Family History (genetics) Epidemiology Natural course Clinical features of depression Personality Biological findings Pharmacological response

20. Bipolar vs. Unipolar Depression: Classical Differentiating Characteristics Goodwin and Jamison Manic-Depressive Illness, 1990, 2007; Akiskal HS. J Affect Disord, 2005. BipolarUnipolar History of mania or hypomania YesNo TemperamentCyclothymicDysthymic Sex ratioEqualWomen > men Age at onsetTeens, 20s, and 30s30s, 40s, 50s Onset of episodeOften abruptMore insidious Number of episodesNumerousFewer Postpartum episodesMore commonLess common Psychotic episodesMore commonLess common Psychomotor activityRetardation > agitationAgitation > retardation Sleep Hypersomnia > insomnia Insomnia > hypersomnia Family history of BPDHighLow Family history of UPDHigh

21. 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

22. 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

23. 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

24. 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

25. Relative Risk for Bipolar Disorder in First-Degree Relatives of Patients with Major Mood Disorders Bipolar (I & II)10.7 All Major Depression2.8 Early Onset Recurrent Depression subgroup 4.5

26. Genetics Among 321 1 st degree relatives of BP probands, more (32%) had a diagnosis of recurrent UP (avg of 7 prior episodes) than a diagnosis of BP I (23%) Among 321 1 st degree relatives of BP probands, more (32%) had a diagnosis of recurrent UP (avg of 7 prior episodes) than a diagnosis of BP I (23%) This same study provided evidence that recurrence was familial, and it was largely independent of polarity This same study provided evidence that recurrence was familial, and it was largely independent of polarity Fisfalen et al Am J Psych 2005

27. Overview of Reported Differences between Bipolar Disorder and Unipolar Depression Bipolar (I and/or II)Unipolar Epidemiology Lifetime Risk1.2-1.5%5-10% Proportion of Major Affective Illness20-50%50-80% Gender RatioF=MF>M Substance AbuseMore frequentLess frequent SuicideUnclear Goodwin and Jamison 2007

28. Overview of Reported Differences between Bipolar Disorder and Unipolar Depression Bipolar (I and/or II)Unipolar Natural Course Age at OnsetYounger Narrower Range Older Broader Range Number of EpisodesMoreFewer Length of Depressive Episode ShorterLonger Cycle LengthShorterLonger Precipitants of EpisodesMore important at illness onset than for later episodes Relation to illness onset not clear Seasonal PatternFall/winter: depression Spring/summer: mania/hypomania Spring: depression (?) Goodwin and Jamison 2007

29. Unipolar – Bipolar Differences Family History (genetics) Epidemiology Natural course Clinical features of depression Personality Biological findings Pharmacological response

30. 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

31. 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

32. Overview of Reported Differences between Bipolar Disorder and Unipolar Depression Bipolar (I and/or II)Unipolar Personality Depression/IntroversionLessMore Impulse ControlLessMore Stimulus SeekingMoreLess Personality ProfileMore normalLess normal Hyperthymic TemperamentMoreLess CyclothymiaMoreLess Goodwin and Jamison 2007

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

34. Overview of Reported Differences between Bipolar Disorder and Unipolar Depression Bipolar (I and/or II)Unipolar Pharmacological Response Response to AntidepressantsLess(?)More(?) Speed of Response to Antidepressants More rapid(?)Less rapid(?) Tolerance to AntidepressantsMore frequentLess frequent Antidepressant Response to Mood Stabilizers More frequentLess frequent Manic/ Hypomanic Response to Antidepressants More frequentLess frequent Prophylactic Response to LithiumEquivalent when bipolar and unipolar cycle lengths are comparable Prophylactic Response to Antidepressants PoorGood? Goodwin and Jamison 2007

35. 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

36. 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

37. 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.

38. Bipolar II Switching in MDD 11-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.

39. Very Low Level Hypomanic Symptoms While Depressed Predict Antidepressant-Related Switch into Mania (In bipolar depressed patients on mood stabilizers) Antidepressant group: Non- response Response no switch Switch into mania (# of patients)(N = 50)(N = 94)(N = 48)  YMRS  SD 2.4  2.5 1.9  2.5 3.8  4.9 YMRS items (P <.05) (#2) Increased MOTOR ACTIVITY/ ENERGY (#6) Increased SPEECH (rate or amount) (#8) CONTENT (questionable plans; new interests) F(2,187) = 5.33 P =.006  Frye MA et al. New research presented at: Annual Meeting of the American Psychiatric Association; May 20–25, 2006; Toronto, Canada. Abstract NR215. Clinical correlates associated with antidepressant-related mania

40. “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.

41. 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.

42. 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).

43. BP-NOS Defined for COBY l Distinct period of Elated Mood plus 2 symptoms or Irritable Mood plus 3 symptoms (1 symptom short) l Mood must be distinct change from usual and symptoms must be associated/intensify with mood change l Change in functioning l Not associated with medication l At least 4 hours meeting above criteria in a 24-hour period to count as “one day” l Lifetime of ≥ 4 days total of meeting criteria (e.g. 4 one-day episodes; 2 two-day episodes, etc.) B Birmaher, ISBD, Pittsburgh, 2009

44. COBY Subjects at Intake 35% 58% 7% B Birmaher, ISBD, Pittsburgh, 2009

45. Why Were the BP-NOS Not BP-I/II? B Birmaher, ISBD, Pittsburgh, 2009

46. 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