This document provides an overview of bipolar disorder and some of the challenges involved in accurately diagnosing it. It discusses how Aretaeus of Cappadocia in the 2nd century AD provided early descriptions of complex conditions including mania and melancholia. Diagnosing bipolar disorder can be difficult due to problems with cross-sectional and longitudinal evaluation of patients. Symptom overlap between unipolar depression and bipolar disorder can lead to misdiagnosis. The document examines factors that can complicate and delay an accurate diagnosis of bipolar disorder.

1. Bipolar Disorder:
A complex diagnosis
E Timuçin Oral, MD
Prof Psychiatry
Istanbul Commerce University
Department of Psychology

2. X Galen
X Soranus
X Hippocrates
X Aretaeus

3. Aretaeus of Cappadocia (AD 81–138)
Early description of complex conditions
Named diseases:
– Diabetes (“a flowing through a siphon”)
– Heterocrania/hemicrania (“half skull”)
– Koiliakos (“coeliac disease”)
!
! Defined phenomena:
– Mania-melancholia
– Bronchospasm
– Asthma
!
Marneros & Goodwin,Cambridge University Press, 2005.
Aydemir & Malhi, Acta Neuropsychiatrica. 2007:19;62

4. Aretaeus of Cappadocia (AD 81–138)
‘‘I think that melancholia is the
beginning and a part of mania…
The development of mania is really
a worsening of the disease rather
than a change into another...
The symptoms [of melancholia] are not
unclear: [the melancholics] are
either quiet or dysphoric, sad or
apathetic. Additionally, they could
be angry without reason and
suddenly awake in panic”
Marneros & Goodwin,Cambridge University Press, 2005
ARETAEUS of Cappadocia (fl. ca A.D. 50). Libri septem - RUFUS of Ephesus (fl. 1st century A.D.) De corporis humani
partium appellationbus libri tres. in Latin by Junius Paulus Crassus (ca 1500-75). Venice: Giunta Press, 1552.

5. Problems in diagnosing BPD:
“Cross-sectional & longitudinal”

6. Problems in diagnosing BPD:
“Cross-sectional evaluation”
Patients more likely
to present with symptoms of
depression
Unipolar/bipolar depression?
Mixed Symptoms
Symptom overlap

7. Depressive episodes and symptoms
predominate in first-episode BD-I
M-type (mania, hypomania, psychosis)
Judd 2002
(n=146)
D-type (depression, dysthymia,
dysphoric mixed states)
Post 2003
(n=258)
Total
Morbidity from
D-type symptoms
is approximately
3 times greater
than from M-type
symptoms
Joffe 2004
(n=138)
Paykel 2004
(n=204)
Baldessarini 2010
(n=303)
Overall, 5 studies
(n=1049)
Total morbidity = 54%
0
25
50
75
100
Time ill (%)
Baldessarini Bipolar Disord. 2010;12:264.
.

8. Reclassifying major depressive
episodes into a bipolar spectrum
50,0
37,5
Patients (%)
33.8% bipolar spectrum
25,0
12,5
0,0
Bipolar I
(n=25)
Reclassification using Semi-structured
Interview for Depression (SID)
Bipolar II
(n=107)
Bipolar III
(n=5)
Recurrent
depressive
(n=174)
Single
episode
(n=94)
SID subtype
Cassano Psychopathology. 1989;22:278.

9. Bipolar disorder in patients with a major
depressive episode: BRIDGE study
DSM-IV criteria
16% (903 patients) met criteria
for bipolar disorder
Bipolar specifier
47% (2647 patients) met criteria
for bipolar disorder
53%
MDD
N=5635
Bipolar I disorder
Bipolar II disorder
Angst Arch Gen Psychiatry. 2011;68;791.

10. Independent risk factors for bipolar
disorder (DSM-IV-TR): BRIDGE study
≥2 Prior mood episodes
Hypomania/mania in first-degree relatives
Age at first psychiatric symptoms <30 y
Current depressive episode ≤1 mo
Mood lability with antidepressants
Current mixed state
Current psychotic features
History of suicide attempts
Seasonality of mood episodes
Current atypical depression
Current anxiety disorder
Borderline personality disorder
Current substance use disorder
Female
Manic/hypomanic with antidepressants
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5
Odds ratio
903 patients with bipolar disorder (BP I: 685; BP II: 218)
Angst Arch Gen Psychiatry. 2011;68;791.

11. Bipolar vs unipolar depression:
differentiating characteristics
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
Psychomotor activity
More common
Retardation > agitation
Less common
Agitation > retardation
Sleep
Hypersomnia > insomnia Insomnia > hypersomnia
Family history of BPD
High
Low
Family history of UPD
High
High
Adapted by Dunner D. with permission from: Akiskal J Affect Disord. 2005;84:107.

12. Melancholia, by Dürer
Melancholia, by Cranach

13. Problems in diagnosing BPD:
“Longitudinal evaluation”
Delayed diagnosis
Initial diagnosis can take ≥10 years
Hirschfeld J Clin Psychiatry. 2003;64:161.

14. Bipolar disorder:
age at onset predicts initial polarity
80
Depression
72%
Mania
Frequency (%)
70
P=0.001*
60
55.5%
50
40
30
20
10
Early AAO
Intermediate AAO
(< 20 years)
(20-39 years)
*Type of first episode (early AAO vs intermediate AAO)
AAO, age at onset
Biffin Acta Neuropsych. 2009;21:191.

16. Problems in diagnosing BPD:
“Cross-sectional evaluation”
“Missed”
diagnosis
1/3 of patients are
misdiagnosed
Hirschfeld J Clin Psychiatry. 2003;64:161.

17. Why is it important to get the
diagnosis right?
!
Misdiagnosis associated with ineffective
treatment – worse outcome
!
Potential risk of antidepressant switching
!
Treatment approaches are different
Perlis Am J Manag Care. 2005;11:S271; Singh Psychiatry. 2006;3:57;
Marcus Psychiatr Serv. 2009;60:617; Awad Prim Care Comp J Clin Psychiatry. 2007;9:195.
!

18. Costs associated with potential
misdiagnosis of bipolar disorder
Pharmacy
Outpatient
Emergency room
Inpatient
Annual direct
costs per patient (US$ 2004)
10000
7500
5000
2500
54%
P<0.01
30%
0
Potentially misdiagnosed (n=94)
Correctly diagnosed (n=2398)
Kamat AMCP. 2007.

19. Problems in diagnosing BPD:
“Cross-sectional evaluation”
Psychotic symptoms
Mixed symptoms

20. Proposed three-dimensional model of
mood-psychotic disorders
Lifetime Mania
Bipolar II
Bipolar I
Schizoaffective disorder,
Bipolar
Cyclothymia
Schizophrenia
Subclinical BP
Lifetime
Psychosis
Minor depression
Schizophrenia
Lifetime
Depression
Major depression
Schizoaffective disorder,
Depressive
Altınbaş Nöropsikiyatri Arşivi. 2011;48:167.

21. Painting “Mania"
Florencio Yllana
Rybakowski J Affect Disord. 2011;128:319.

22. Mixed states vs pure mania in the
EMBLEM study: outcome at 24 months
Pure mania
Mixed episodes
Patients (%)
70
53
*
35
18
0
Relapse
Recurrence
Remission
Based on 771 French patients followed for 24 months; *P=0.006
Recovery
Azorin BMC Psychiatry. 2009;9:33.

23. Problems in diagnosing BPD:
“Cross-sectional evaluation”
Residual
symptoms

24. Subthreshold depressive symptoms in bipolar,
unipolar and healthy subjects in remission
50
Healthy control
Bipolar disorder
MDD
***
Patients (%)
40
*
30
20
*
10
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17-Item Hamilton Depression Rating Scale
*P<0.05; ***P<0.000
Vieta J Affect Disord. 2008;107:169.

25. Progression from unipolar depression
to bipolar disorder
Proportion without
hypomania or mania
1.0
0.9
0.8
0.7
Time to either hypomania or mania
Time to hypomania
Time to mania
0.6
0.5
0
5
10
15
20
Years of Follow Up
25
30
Number of subthreshold hypomanic symptoms associated
with onset of threshold mania or hypomania
550 patients with diagnosis of major depression
followed for mean of 17.5 years
Fiedorowicz Am J Psychiatry. 2011;168:40

26. Problems in diagnosing BPD:
“Longitudinal evaluation”
Rapid cycling
Ineffective treatment = worse outcome, poor QoL

27. Rapid cycling vs non-rapid cycling:
course of illness
Rapid Cyclers
(n=86)
Nonrapid Cyclers
(n=872)
p
Mean age at onset (years)
26.31±10.24
28.21±10.30
0.04
Mean delay (years)
Symptom onset to current episode
20.38±11.88
15.90±10.92
0.0005
Illness progression, (%)
Episodes with free intervals
59.3
72.6
0.009
Stressors (current episode), (%)
83.7
89.6
0.09
First episode polarity, (%)
Depression
52.2
35.9
0.01
19±16.54
7.09±6.40
<0.0001
44.2
14
37.6
6.5
0.22
0.01
10.5
4.5
0.004
Mean previous episodes
Suicide attempts, (%)
Lifetime (at least 1)
Past year (at least 1)
Previous hospitalisations, (%)
Multiple
Azorin CNS Spectrum. 2008;13:780.

28. “Tree of Life”
by Selen Şanlı

29. Problems in diagnosing BPD:
“Longitudinal evaluation”
Comorbidities
Almost the rule
Severity, complications, worse outcome, poor QoL

30. Comorbidities complicate diagnosis and
management of bipolar disorder
Complicates
diagnosis and
treatment
Decreased
QoL
Impaired
psychosocial
functioning
Comorbid
condition
Greater risk of
depressive and mixed
episodes, and suicidal
behaviour
Possible
earlier age
of onset
More severe
disease course
Poorer treatment
adherence
Colom J Clin Psychiatry. 2000;61:549; Pollack Subst Abus. 2000;21:193;
Vieta Bipolar Disord. 2001;3:253; Keller J Clin Psychiatry. 2006;67(suppl 1);5.

31. Time to remissiona (weeks)
Anxiety symptoms delay time to remission
in patients with bipolar I disorder
No anxiety
Anxiety
Log rank=1.45
df=1, P=0.29
70
Log rank=2.95
df=1, P=0.09
53
35
Log rank=4.37
df=1, P=0.04
18
0
n=23
n=7
Manic
n=24
n=11
n=18
Depressed
n=9
Mixed
Polarity treated in acute phase
aBased
on Kaplan-Meier survival analysis;
Anxiety-related correlates included history of panic attacks, diagnosis of
lifetime threshold or sub-threshold anxiety disorder, baseline Hamilton
Rating Scale for Depression (HAM-D) psychic and somatic anxiety
Feske Am J Psychiatry. 2000;157:956.

32. Problems in diagnosing BPD:
“Longitudinal evaluation”
Switching

33. “Illusion of Rising”
by Tamer Ertuna

34. Revised DSM-5 criteria for mood disorder
Mixed features
!
Full criteria for manic or
hypomanic episode, plus 2–3
of the following symptoms
nearly every day for at least
1 week:
–
–
–
–
–
–
Depressed/down
Decreased interest or pleasure
Psychomotor retardation
Fatigue
Worthlessness/guilt
Death/suicide
!
Full criteria for major
depressive episode, plus 2–3
of the following nearly every
day for at least 1 week
–
–
–
–
–
–
–
–
Expansive or irritable
Grandiose
Increased/pressured speech
Flight of ideas
Increased/excessive involvement
in activities with high potential
for painful consequences
Increased goal-directed activity
Increased energy
Decreased need for sleep
American Psychiatric Association. http://www.dsm5.org/ProposedRevisions/Pages/proposedrevision.aspx?rid=428.
Accessed April 20, 2010.

35. Bipolar disorder: a complex diagnosis

36. Bipolar disorder: a complex diagnosis
Psychotic symptoms
! Delusions
! Hallucinations
Manic mood and behaviour
! Delusions
! Euphoria
! Grandiosity
! Pressured speech
! Impulsivity
! Excessive libido
! Recklessness
! Social intrusiveness
! Diminished need for sleep
Cognitive symptoms
! Racing thoughts
! Distractability
! Disorganisation
! Inattentiveness
Dysphoric or negative
mood and behaviour
! Depression
! Anxiety
! Irritability
! Hostility
! Violence or suicide

37. Summary
!
Bipolar disorder is a chronic, frequent and
debilitating illness
!
Although it is one of the well- and first-known
disorders, it is still misdiagnosed frequently
!
Appropriate diagnosis is the first step in
choosing the best treatment available
!
Rational psychopharmacology is a sine qua
non for prevention and is possible

38. Questions?