Bipolar Disorder:

Where are we now?

Prof RN Mohan
 Disclosure

• Received educational grants and speaker fees from Eli Lilly,

Sanofi-synthelabo, Astra Zeneca,BMS-Otsuka, Jansen-Cilag, Pfizer,
ShirePharma, Wyeth, Lundbeck

• Sat on advisory boards – Eli Lilly, Sanofi, Shire Pharma,

Pfizer/Eisai, Astra Zeneca

• Not in receipt of any retainers from any pharmaceutical company

• Investment in pharmaceuticals companies – None

• Prof.R.N.Mohan
Issues in the diagnosis and understanding of
Bipolar Disorders

 Classification of Bipolar Disorders including subtypes

and course specifiers
 Epidemiology of Bipolar disorders
 Diagnostic issues
 Suicide and Bipolar Disorders
 Clinical features
 Comorbidities
 Biological markers
 Syndromal recovery vs functionality
“ ‘Manisch-Depressive Irresein’
includes … the whole domain of so-
called periodic insanity … mania,
the greater part of melancholia …
lastly we include here certain
colorings of mood, some of them
periodic, some of them continuously
morbid …
[which] pass over without boundary
into the domain of personal
disposition.”
(E. Kraepelin, 1899)
The Traditional Kraepelinian Dichotomy

Aetiologic
al divide?

Dementia Manic-
praecox depressive
illness
Challenges to the Kraepelinian Unitary affective
concept- Unipolar / bipolar distinction

 Clinical studies: showing that bipolar disorder is misdiagnosed as

unipolar disorder and mistreated (Akiskal et al 2000; Ghaemi et al
1999)
 Theoretical studies
(Blacker & Tsuang 1992; Kendler & Gadner 1998)
 Epidemiological studies (Angst)
 Familial and genetic studies: familial aggregation of bipolar and
unipolar disorder. Severe unipolar depression is partly due to
genetic factors
(Duffy et al 2000; McGuffin & Katz 1999)
 Unipolar

Dichotomy

Bipolar

Jules Angst, (1966) ; Carlo Perris (1966) ; George Winokur et Paula Clayton (1967)
 Bipolar Disorder: Symptomology
in a Constant State of Flux

● Extremes of exaggerated
Severe mania
mood
● Depressive symptoms Hypomania (mild to
most common moderate mania)

● Mixed episodes
Balanced mood (euthymia)
– state of mind
Mild to moderate
most fragile
depression
– greatest risk
of suicide Severe
depression

Goodwin & Jamison 1990

 Overview of Bipolar Disorder

● A lifelong recurrent, episodic illness

● Characterized by manic or depressive episodes
followed by symptom-free periods?
● Classification systems (ICD-10 & DSM-IV-TR)
describe discrete subtypes of bipolar disorder
● Current medical treatment of bipolar disorder aims to:
– Control acute manic, depressed or mixed episodes
– Stabilize and then maintain patients in a symptom-free state
– At all times, minimize risk of switching to opposite symptom
pole

American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR).
American Psychiatric Press;2000:382–401; APA. Practice guideline for the treatment of patients with bipolar disorder.
Am J Psychiatry 2002;159(Suppl. 4):1–50; World Health Organization International Statistical Classification of Diseases and Related
Health Problems, 10th Revision. Online Version for 2007 available at: http://www.who.int/classifications/apps/icd/icd10online
 Summary of DSM-IV-TR
Classification of Bipolar Disorders

Bipolar Disorder
Bipolar I Bipolar II Cyclothymic Not Otherwise
Specified

One or more manic One or more At least 2 years of Bipolar features that
or mixed episodes, major depressive numerous periods do not meet criteria
usually episodes of hypomanic and for any specific
accompanied by accompanied depressive bipolar disorders
major depressive by at least one symptoms*
episodes hypomanic episode

* Symptoms do not meet criteria for manic and depressive episodes.

First, ed. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text
Rev. Washington, DC: American Psychiatric Association; 2000:345-428.
 Bipolar Disorder NOS

 Patients with clear symptoms but not long enough to

make a diagnosis of Bipolar I or Bipolar II or
cyclothymia
 DSM- Durational Criteria

 Hypomania-4 days
 Mania-1 week
 Depression-2 weeks
Problems with the DSM-IV-TR™ criteria for bipolar II
disorder

 Mixed symptoms are excluded from the definition

 Four-day duration for hypomania may be too long
 Cognitive symptoms are not included in the definition
 Drug-induced hypomania is excluded
 No account is taken of family history and biological
markers

Vieta et al. Bipolar Disorders: Mixed states, rapid cycling, and atypical forms.
Cambridge: Cambridge University Press, 2005; Suppes et al 2005
 DSM-IV Criteria1 for Mixed
Bipolar Episode
A MIXED episode meets criteria A and B for at least 1 week
A. Major Depressed Episode
5 or more of the following symptoms,
including at least 1 marked with an
asterisk (*):
 *Depressed mood
 *Anhedonia
 Weight loss or gain
 Sleep disturbance (insomnia
or hypersomnia)
 Psychomotor agitation/retardation
 Fatigue (loss of energy)
 Guilt/worthlessness
 Inability to concentrate or indecisiveness
 Suicidal ideation (recurrent thoughts of death)
B. Manic Episode
Abnormally and persistently
elevated, expansive, or irritable
mood. Presence of 3 or more of
the following symptoms (4 if
irritable only):
 Inflated self-esteem or grandiosity
 Decreased need for sleep
 Increased goal-directed activity
 Increased or pressured speech
 Flight of ideas/racing thoughts
 Distractibility
 Risk-taking behavior
 DSM V--Changes

 The DSM-IV diagnosis of bipolar I disorder, mixed

episode, requiring that the individual simultaneously
meet full criteria for both mania and major depressive
episode, has been removed.

 Instead, a new specifier, “with mixed features,” has

been added that can be applied to episodes of mania
or hypomania when depressive features are present,
and to episodes of depression in the context of major
depressive disorder or bipolar disorder when features
of mania/hypomania are present.
DSM V-Changes-Other Specified Bipolar and
Related Disorder

 DSM-5 allows the specification of particular conditions

for other specified bipolar and related disorder,
including categorization for individuals with a past
history of a major depressive disorder who meet all
criteria for hypomania except the duration criterion
(i.e., at least 4 consecutive days).
 A second condition constituting an other specified
bipolar and related disorder is that too few symptoms
of hypomania are present to meet criteria for the full
bipolar II syndrome, although the duration is sufficient
at 4 or more days.
DSM V-Changes-Other Specified Bipolar and
Related Disorder

 Anxious Distress Specifier In the chapter on bipolar

and related disorders and the chapter on depressive
disorders, a specifier for anxious distress is
delineated. This specifier is intended to identify
patients with anxiety symptoms that are not part of the
bipolar diagnostic criteria.
Concept of Bipolar spectrum
 Versions of the ‘bipolar spectrum’
Akiskal 1977 Cyclothymia-bipolar continuum

Angst 1978 Bipolar sub-types along a spectrum

Klerman 1981 Categories I-VI

Akiskal and Pinto 1999 Categories I-IV (including 1.5, 2.5 and 3.5)

Ghaemi 2002 “Bipolar Spectrum Disorder”

Angst 2003 Added Minor Bipolar Disorders

Sachs 2004 ‘Bipolarity Index’ (100 point)

27
 Akiskal’s Conundrum

 Bipolar ½: Schizobipolar disorder

 Bipolar I: mania with depression
 Bipolar I ½: depression with protracted hypomania
 Bipolar II: depression with hypomanic episodes
 Bipolar II ½: cyclothymic disorder
 Bipolar III: hypomania due to antidepressant drugs
 Bipolar III ½: hypomania and/or depression associated with substance use
 Bipolar IV: depression associated with hyperthymic temperament
 Bipolar V: recurrent depressions without discrete hypomania, but mixed
hypomanic episodes (irritability/agitation/racing thoughts) during
depression
 Bipolar VI: Bipolarity" in the Setting of Dementia
 The bipolar spectrum concept
(Angst, BJPsych, 2007)

• Kretschmer (1921):
– Dimensional (severity) concept, from normal to
pathological:
Cyclothymic Cycloid Manic-depressive
temperament ‘psychopathy’ disorder

• Kleist (1937):
– Proportional model (major and minor mood disorders):
Major Depression and Manic Depression versus mild
depression and minor bipolar disorder
30
 Miro Dali

Churchill Rossini

Balzac

Lincoln
Hemingway Schumann 32
Life course of the disease and creativity of
Robert SCHUMANN
(Zwickau, 1810 - Endenich, 1856)

33
A difficult diagnosis (cont’d)
Wolfgang Amadeus Mozart

Born Salzburg, 27 January 1756

Died Vienna, 5 December 1791

‘When I am . . . completely
myself, entirely alone, of good
cheer . . . my ideas flow best
and most abundantly. Whence
and how they come, I know not;
nor can I force them’ 1

1
341952
Ghiselin B. The Creative Process. New York: Mentor,
 Alfred, Lord Tennyson
(1809-1892)

 English Poet
The charge of the light brigade
 Experienced .

debilitating Half a league, half a league,

Half a league onward,
depression Into the valley of Death
Rode the six hundred.
and "Forward, the Light Brigade!
"Charge for the guns!" he said:
hypomanic Into the valley of Death
Rode the six hundred
spells
 Mood instability in the Tennysons

Recurrent depressive illness Elizabeth Mary Charles

b. 1776 b. 1777 1784-1861
Rage, unstable moods and/or insanity
Bipolar disorder

Elizabeth Fytche George Clayton Tennyson

1781-1865 1778-1831

George Charles Mary Edward Septimus Cecilia

Died in 1808-1879 1813-1890 1815-1866 1817-1909
1810-1884
infancy,
1806

Frederick Emily Arthur Matilda Horatio

1807-1898 1811-1889 1814-1899 1816-1913 1819-1899
Alfred
1809-1892
Jamison 1997
 Kay R Jamison
Author of ‘An unquiet mind’
Suffers from bipolar disorder

“I have often asked myself whether, given the choice, I would choose
to have manic-depressive illness. ... Strangely enough, I think I
would choose to have it. It's complicated.”

“Depression is awful beyond words or sounds or images ...”

“But, normal or manic, I have run faster, thought faster, and loved faster
than most I know. And I think much of this is related to my illness –
the intensity it gives to things"
 Bipolar Spectrum-clinical usefulness?
 Not very useful due to lack of treatment
studies
 However bipolar I and II distinction is
important and there are treatment studies to
guide us.
 Most studies are on Bipolar I and only
recently Bipolar II.
 Most patients seen in clinical practice are
Bipolar II
 Most studies exclude P’s with substance
misuse comorbidity
Bipolar disorder: It’s many faces
P a tte rn s o f I lln e s s A m o n g 2 5 8 S F B N P a tie n ts T r e a te d a n d F o llo w e d
P r o s p e c tiv e ly fo r O n e Ye a r
G r o u p I : > ¾ y e a r ill 2 6 %
A P lu s U ltra d ia n

B D e p r e s s io n
p r e d o m in a te s

C M a n ia
p r e d o m in a te s

C h r o n ic
D d e p r e s s io n

G r o u p I I : E p is o d ic a lly I ll 4 0 %

E D e p r e s s io n +
f u ll- b lo w n m a n ia

D e p r e s s io n +
F h y p o m a n ia

D e p r e s s io n + n o
G m a n ia

M a n ia s
H p r e d o m in a te

G r o u p I I I : M in im a lly I m p a ir e d 3 3 %
I ll f irs t 1 /3 y e a r,
I w e ll s e c o n d 2 /3

J H y p o m a n ia s o n ly

M ild d e p r e s s io n s
K o n ly

V ir tu a lly w e ll
L
 Why does this matter?
• Diagnosis is critical for planning treatment:
– MDD is currently defined by the absence of hypomania
– Life-long risk of conversion to bipolar disorder is 1.25%
per year
– Earlier bipolar diagnosis should greatly improve
prognosis

• Research:
– Nosology/classification
– Genetics
– Neuroimaging
– Evaluating new treatments

• Antidepressants for bipolar depression:

– Effective, ineffective, safe, dangerous? 41
 Diagnosing bipolar spectrum disorders:

Uncritical over-
inclusiveness

Diagnostic
conservatism
 Three groups of patients as ‘bipolar spectrum’:
• Depressed patients who have experienced hypomania soon after taking
antidepressants

• Depressed patients with a history of ‘subthreshold’ manic symptoms

which fall below the DSM-IV diagnostic threshold for hypomania

• Depressed patients who have never experienced manic symptoms but

who have several other indicators of bipolarity, eg:
• first-degree relative with bipolar disorder
• early-onset depression
• high recurrence rate
• atypical depressive symptoms
• depressive mixed states
• high comorbidity
• Psychotic symptoms
• Post partum onset, seasonal presentation
43
Current diagnostic scheme:

Bipolar Disorder
1%

Unipolar
Depression

20%

46
Current diagnostic scheme:

Bipolar Disorder
1%

The grey area of bipolarity

(Bipolar Spectrum)
Unipolar
Depression

20%

47
 Epidemiology: Distribution by Sex

 Distribution by sex is equal overall

 Most males start with a manic episode
 Female predominance among patients with
– Rapid cycling
– Bipolar II
– Dysphoric mania/mixed states
– Depressive episodes

Goodwin and Jamison. Manic-Depressive Illness; 2007:168; McElroy et al. Am J Psychiatry.

1992;149: 1633-1644.
Subtypes and course specifiers
 Mixed States

● DSM-IV – Meet criteria for mania and major

depressive episode
● Heterogeneous and changing presentations
● Female preponderance
● 1st episode often late in life
● Early episodes tend to be depressive
● Higher rates of suicide and co-morbidity
● Greater association with organicity
● Worsening by antidepressants
 Mixed States

 Mixed states:
– Operationalised as a stable/static construct by DSM-IV
– Inpictures
reality they are complex, fluctuating and unstable clinical
5

– May be better defined along a continuum/spectrum of “mixity”

 Dysphoric mania 1

Traditional conceptualization of Mixed States: Depressed/dysphoric

mood intrudes into dominant mania
 Agitated depression2,3
Converse mix: Presence of manic features in a dominantly
depressive presentation
 Treatment
1. Berk M, et al. AustResistant
NZ J Psychiatry Depression
2005; 39:215-221. 4
2. Koukopoulos A. Psychiatr Clin North Am 1999; 22: 547-564.
3. Benazzi, F. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 1279–1285
4. Sharma V, et al. J Affect Disord. 2005; 84: 251-57
5. Kruger S, et al. Bipolar Disorders 2005; 7: 205-215
 Treatment Studies of Mixed States

 Most studies are designed to treat pure manic

episodes, not mixed episodes specifically

 Patients with mixed states are usually a small subset

of the total number of patients studied

 Even double-blind, placebo-controlled studies have to

be interpreted with caution

 Maintenance treatment studies are limited

Kruger S, et al. Bipolar Disord 2005;7:205-215.

 Rapid Cycling bipolar disorder

 Concept introduced by Dunner and Fieve (1974)1

 Introduced as a course specifier in DSM-IV
– Defined as 4+ episodes of illness per year
– 2 months period of partial or full remission between episodes or switch
from one pole to another
– Arbitrary – episode frequency a strong proxy of disease severity2
 Prevalence of 13-20%1,2
 Depression is the major burden
 Disputes as to whether more common in BPI or BPII 2,4
 Associated with greater morbidity and poorer treatment response compared to
non-RC bipolar disorder1

1. Dunner & Fieve (1974) Arch Gen Psychiatry 30: 229-233

2. Kupka et al. (2005) Am J Psychiatry 162: 1273-1280
3. Kukopulos et al. Pharmakopsychiatrie Neuro-Psychopharmakologie 13: 156-167
4. Kupka et al. (2003) J Clin Psychiatry 64: 1483-1494.
 Rapid Cycling Bipolar Disorder

● Female preponderance
● Association with sub clinical hypothyroidism
● Higher rates in Bipolar II
● No genetic basis
● Not related to menstrual cycles
● Perhaps related to circadian rhythms
 Rapid Cycling and antidepressants

 RC associated with prior exposure to

antidepressants1
– ? Because of association with more severe depression 2
– ? Causative in acceleration
 Report of 73% of TCA treated patients with RC3

1. Kupka et al. (2003) J Clin Psychiatry 64: 1483-1494

2. Kukopulos et al. Pharmakopsychiatrie Neuro-Psychopharmakologie 13: 156-167.
3. Wehr & Goodwin FK (1987) Am J Psychiatry 144: 1403-1411
Prevalence of psychotic symptoms in
Bipolar I- disorder (n = 352)

50
42 41
40
34

30
25
%

22
20

11
10
6
4 3 3 3 2
0
Hallucination Delusion Thought disorder Negative symptoms

auditory visual taktile

Ideas of reference Grandeur paranoia
desorganized speech desorganized behavior Hyperaktivity
Apathic poverty of speech poverty of affect
Keck et al, Comprehensive Psychiatry 2003; 44: 263-269
 Age of Onset

 Peak: 15 to 19 years

 Earlier onset and more severe course in

substance abusers

 Later onset (eg, in elderly) may occur as a result of other

conditions (e.g. neurological conditions)

Goodwin FK. 1990:127-156. Brady KT. J Clin Psychiatry. 1995;56(suppl 3):19-24. Ghaemi SN. J Clin Psychiatry.
2000;61:804-808.
 Rates of Clinical Diagnoses of Bipolar Disorder
Among U.S. Inpatients, ‘96-’04
• Data from the National Hospital Discharge Survey (CDC). Excludes long-term care facilities.
• Population adjusted: Rates per 10,000 of each age group’s total population based on U.S.
Census.
Children
30
Discharges per 10,000 Children

25

20

15

10

1996 1997 1998 1999 2000 2001 2002 2003 2004

Year

5-13 year-olds (+421%)

1996: 1.4 per 10,000 -> 2004: 7.3 per 10,000

Substance Depression Bipolar

Anxiety Conduct Problems Psychosis
Developmental Cognitive Psychophys
Other

Blader & Carlson, Biol Psychiatry 2007

 Rates of Clinical Diagnoses of Bipolar Disorder
among U.S. Inpatients, ‘96-’04 (Cont)

Adolescents
90
Discharges per 10K Adolescents

80
70
60
50

40
30
20

10
0
1996 1997 1998 1999 2000 2001 2002 2003 2004

14-19 year-olds (+300% ) Year

1996: 5.1 per 10,000 -> 2004: 20.4 per 10,000

Substance Depression Bipolar

Anxiety Conduct Problems Psychosis
Developmental Cognitive Psychophys
Other

Blader & Carlson, Biol Psychiatry 2007

 Rates of Clinical Diagnoses of Bipolar Disorder
Among U.S. Inpatients, ‘96-’04 (Cont)
Adults
140

120
Discharges per 10K Adults
100

80

60

40

20

0
1996 1997 1998 1999 2000 2001 2002 2003 2004
20-64 year-olds (+46%)

1996: 10.4 per 10,000 -> 2004: 16.2 per 10,000

Substance Depression Bipolar
Anxiety Conduct Problems Psychosis
Developmental Cognitive Psychophys
Other
Blader & Carlson, Biol Psychiatry 2007
 DD

 ADHD
 Conduct Disorder
 DSM V-deliberations

 Birmaher a CP decribed a study which showed that

58% of children diagnosed according to DSM IV
criteria have Bipolar 1 disorder (classic MDP)

 Interestingly 41% of children diagnosed as Bipolar

Disorder NOS progressed to a Bipolar I or II in
longitudinal follow up

 Use of adult criteria seem legitimate/reasonable!

 HOW COMMON IS IT?

BIEDERMAN (1996)

AMONG REFERRED CHILDREN WITH ADHD, ABOUT 19% HAVE BPD

ADHD & JUVENILE MANIA: AN OVERLOOKED CO-MORBIDITY?

J.OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT
PSYCHIATRY, 35: 997-1008.
 HOW COMMON IS IT?

 OVERRALL LIFETIME PREVALENCE OF ADHD IN

PEOPLE WITH BPD IS
9.5%

Nierenberg et al (2005)
Clinical & Diagnostic implications of lifetime ADHD co-morbidity in Adults
with Bipolar Disorder: data from the first 1000 STEP-BD participants.
Biological Psychiatry, 57, 1467-1473
 MAKING A DIAGNOSIS

 CAN BE DIFFICULT
 BOTH ADHD AND BPD SHARE PRIMARY
FEATURES OF:
 MOOD INSTABILITY
 BURSTS OF ENERGY AND RESTLESSNESS
 TALKATIVENESS
 “RACING THOUGHTS”
 IMPULSIVITY
 IMPATIENCE
 IMPAIRED JUDGEMENT
 IRRITABILITY
 ADHD-pointers

 Very early onset

 Pervasive
 Non episodic
 TREATMENT

 ALWAYS TREAT THE MOOD DISORDER FIRST

 ONCE MOOD IS STABILISED, CONSIDER

TREATMENT FOR ADHD, IF IT IS NECESSARY
 DSM V

 To address concerns about potential overdiagnosis

and overtreatment of bipolar disorder in children, a
new diagnosis, disruptive mood dysregulation
disorder, is included for children up to age 18 years
who exhibit persistent irritability and frequent
episodes of extreme behavioral dyscontrol.
On average, how long does it take from the onset
of major mood symptoms to the diagnosis of
Bipolar Disorder?

 A) 2 years
 B) 10 years
 C) 5 years
 D) 6 months
Diagnosis of BPD
 How Long Does Diagnosis Take?
Years to correct diagnosis
14
11.6 12
12
10 8.9
8
Years

5.9
6
4 3.3
2
0
UP All BP BP I BP II BP NOS
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.
 Misdiagnosis of Bipolar Disorder

2000 National Depressive and Manic-Depressive Association

(DMDA)* Bipolar Survey (n=600)

Were you ever How many times were

misdiagnosed? you misdiagnosed?

31% 30%
No >4 times
69% 70%
Yes 1-3 times

35% were symptomatic

Most frequent diagnosis: >10 years before
unipolar depression correct diagnosis

*Renamed as the Depressive and Bipolar Support

Alliance (DBSA) Hirschfeld et al 2003
 The Earlier the Onset of Bipolar Illness The
Longer the Delay to First Treatment
First Symptoms
Years Delay to First Treatment

17.5 YRS DEPRESSION

MANIA
15.7
BOTH IN SAME YR.
15.3
12.4
10.9
11.5

6.0

4.0
2.1

2.9 1.9
2.1

Onset
Age Range: ≤ 12 13-18 19-29 30 +
Onsets in: Childhood Adolescence Adult Adult 83
(Early) (Late) Post et al 06
 Pre-puerbetal mania
 Kraepelin described it and said it is rare!

 There is over diagnosis in the USA

84
In general, Bipolar Disorder is:
A) More under-diagnosed than over-
diagnosed

B) More over-diagnosed than under-

diagnosed

85
 Under-recognition of bipolar II patients
presenting with major depression (France)
Visit 1 (n=537) Visit 2 (n=493)
First diagnosis Systematic evaluation of hypomania

Unipolar Unipolar
72% 54%

Other
6%
Bipolar II
Bipolar II
40%
22%
Other
6%

Hantouche et al 1998; Allilaire et al 2001

 Replication-Hantouche

 North Africa, Far East and Europe

 5800 patients

 Major depression, Angst HCL 32

 After careful evaluation significant % were Bipolar II’s.

 Bipolar disorder has little cross national variation!

 Is Bipolar disorder under-diagnosed or over-
diagnosed?

 There are 5 well designed major studies of Bipolar I

patients indicating that for each one properly diagnosed
there is one improperly diagnosed (primarily as unipolar
depression) – i.e. 50% under-diagnosis
 This is not to say that some over-diagnoses is not going on,
but under-diagnosis is clearly the predominant problem
 Problem of self diagnosis for secondary gain eg. Debt,
trouble with the law….. Or simply socially acceptable or
even fashionable
“We can safely assume that the prevalence of
bipolar disorders is seriously under-reported and
that the burden of bipolar disorder, estimated by
the WHO to be much lower than that of depression,
will as a consequence have to be reassessed.”
 Summary

 Many patients with apparently unipolar depression

may suffer from a clinically relevant bipolar spectrum
disorder

 This has important implications for mood disorders

research and more importantly clinical practice

 Future classifications of mood disorder should include

dimensional assessments of symptoms and affective
temperament
Which phase of Bipolar Disorder contributes
most to disability?

A) Manic episodes

B) Mixed episodes

C) Depressive episodes
 Residual Morbidity
in Treated BP-I Patients
60

50
Percent of Time Ill

Judd et al. 2002

40 Post et al. 2003

Joffe et al. 2004
Baldessarini et al. 2006
30

from 1st
episode
20

10

0
"Manic" "Depressive" Total Morbidity
Morbidity
THE FIRST SYMPTOM OF BIPOLAR
DISORDER IN APPROXIMATELY HALF THE
PATIENTS IS DEPRESSION

Stanley Foundation bipolar treatment outcome

network

SUPPES et al 1998
The Stanley Foundation Bipolar Network (SFBN): Sites and principal investigators

Stanley Data
Coordinating
(Grosvenor
Center (DCC) Lane, Bethesda)

Cincinatti Bethesda Utrecht

Paul Keck Willem Nolen
Kirk Denicoff
Los Angeles Susan McElroy
Gabriele Leverich Ralph Kupka
Lori Altshuler Robert Post
Mark Frye Dallas
John Rush
Trisha Suppes Munich
Heinz Grunze
Network sites Freiburg
Jörg Walden
THE FIRST SYMPTOM OF BIPOLAR
DISORDER IN APPROXIMATELY HALF THE
PATIENTS IS DEPRESSION

Stanley Foundation bipolar treatment outcome

network

SUPPES et al 1998
 Barriers to Correct Diagnosis
● Patients may not seek help due to
– lack of understanding / recognition of illness,
embarrassment, stigma, denial of illness

● Diagnosis can be difficult

– variation in symptoms
– multiple phases of illness
– a spectrum of patient types
– overlap with psychotic and other affective illnesses
– comorbidity with other psychiatric illnesses
– symptoms due to other causes eg alcohol or drug abuse

● Diagnostic criteria have important limitations

Bowden 2001
 Barriers to Diagnosis

 Current diagnostic classification failings

 Failure of clinicians to recognise hypomanic
symptoms
 Failure of patients to report hypomanic symptoms
(state dependent memory distortion)
Early, Accurate Diagnosis Impacts Outcomes

● Missed diagnosis can lead to inappropriate

treatment, aggravated course and future treatment
resistance1, 2, 3
● Delaying correct diagnosis is associated with
increased risk of suicide attempts4
● Inappropriate antidepressant use in bipolar disorder
can induce mania or rapid cycling3

1
Angst J. Psychopathology. 1985;18(2-3):140-154; 2Goldberg JF, Harrow M, Whiteside JE, et al.
Am J Psychiatry. 2001(Aug);158(8):1265-1270; 3Goodwin AK, Jamison KR. Evolution of the
bipolar-unipolar concept. In: Manic-Depressive Illness, New York, NY: Oxford University Press;
1990; 4Dunner DL, Fleiss JL, Fieve RR. Am J Psychiatry. 1976(Aug);133(8):905-908
 Steps to Improve Diagnosis

● Accurate history taking ● Education of physicians

– family history on recognising bipolar II
– obtain information from ● Increase patients’
family awareness
and friends
of the symptoms of bipolar
– longitudinal follow-up disorder, particularly mild
(use of mood diaries)
mood elevations
● Education of physicians
on the importance of
correct diagnosis

Bowden 2001
 Improving Detection Rates

● Mood Disorder Questionnaire (MDQ)

● Self rated 13 item questionnaire , yes/no questions

regarding manic/hypomanic symptoms

● Bipolar Spectrum disorders Questionnaire by Ghaemi

(Emory University, Atlanta)

● Angst HCL 32

Hirshfeld AJP 2000

 Antidepressant-Induced Mania:
Meta-Analysis from Clinical Trials

14
% of Patients Switching to Mania

12 TCAs
11.20%
SSRIs
10
Placebo
8

4 3.70% 4.20%

2
0.52% 0.72% 0.21%
0
Unipolar Depression Bipolar Depression

Significance: TCA=SSRI >Placebo TCA >SSRI=Placebo

Peet M. Br J Psychiatry. 1994;164(4):549-550.

Individual susceptibility to treatment emergent
mania and cycle acceleration

 Female gender
 Bipolar 1
 Personal or family history of AD induced
mania
 Substance misuse comorbidity
 Family or personal history of BPD
 Early onset <25
 Antidepressant monotherapy is commonly
used for treatment of bipolar disorder
First 70
prescribed
60
drug
50
class 50
(%)
40

30

20 17 15
11
10 8

0
Anti- Anti- Lithium Sedative Anti-psychotic
depressant convulsant

Most antidepressants do not control manic episodes and may induce mania

n=7,760 receiving a new pharmacotherapy as monotherapy

(representing 63% of 12,237 patients with bipolar disorder initially
identified); based on Commercial and Medicare claims in the USA 110
Baldessarini et al 2007
 Recent changes in Bipolar illness
(1st edition of MDI [1990] vs 2nd [2007])

 More cycling, mixed states, and lithium resistance

 Younger age of onset and increased prevalence among the
young
 Role of Antidepressants ?

– 10 fold increase (per capita) in antidepressant

scripts since the “second generation”
– TCA/MAOI : 85% of scripts by psychiatrists vs.
86% of 2nd gen AD scripts by non-psychiatrist
– Most adult bipolar patients have already been
on ADs by the time they see a psychiatrist

111
Treatment emergent affective switches (TEAS)
 Avoid AD or AP induced switches

 Prone to error as causality cannot be proven beyond doubt

 Some doubt this and argue that switches are a natural part of the illness

 Pre-treatment switch rates they say are no different to now

 They quote antidepressant withdrawal mania

 They say switches if at all attributed to SSRI’s are much lower than
 TCA’s

 Some recent studies (STEP BD, Gijsman and Geddes meta-analysis) have not
shown such high swtich rates into mania or cycle acceleration
 Antidepressant vs Placebo (Add-on)
in Bipolar I or II Depression (Including Mixed States*)
Duration of treatment
100%  16 weeks
Dropout
Recovery
Percent of Patients in

Treatments
Treatment Group

75% Response
 Paroxetine, bupropion, or placebo
Switch
 In addition to mood stabilizer (lithium,
50% cbz, valp, aAP) and other medication

25% Outcome criteria

 Durable recovery: ≥8 weeks euthymia
 Response: ≥50% improvement without
0%
hypomania
MS + AD MS + Pbo
 Switch: DSM-IV criteria for hypomania,
N=179 N=187 or intervention

Sachs et al 2007. N Engl J Med. 356,17:1711-1722

*See Goldberg et al 2009. Am J Psychiat,166:173-181
Predominant mood disturbance in BPD is
depression
 Course
Course over15
over15 Year
Year Follow-up
Follow-up
BPI
BPI n=135
n=135 BPII
BPII n=71
n=71
Judd et al 52%
NIMH CDS, 2001

37:1
31%
BP II

BPI 10%

BPI 1.4%
BPII
% weeks % weeks
Depression Manic Spectrum
Significance of subsyndromal symptoms
• Contributes to earlier relapse

• Psychosocial and cognitive impairment

(poor work performance)
 Mood State at Presentation
Across the Life Cycle (N = 899)
Mania Mixed Melancholia
100

80
Percent

60

40

20

0
15 20 25 30 35 40 45 50 55 60 65
Years
E. Kraepelin. Manic-Depressive Insanity and Paranoia. Edinburgh, Scotland:
E. & S. Livingstone; 1921:169.
Suicidality
 Risk of Suicide in Bipolar Disorder
 Suicide as cause of death
– 10% to 20% of persons with either bipolar or
recurrent depressive disorders
– 19% of deaths in bipolar patients due to suicide.
Recent data, reflecting more outpatients (and
perhaps the impact of treatment) is 8-10%

 Serious, life threatening suicide attempts

– 19% to 50% of bipolar patients (16 studies reviewed)

Goodwin and Jamison 2007

8025
 Bipolar Disorder: Untreated vs. Treated
Standardized Mortality Ratios
Adapted from 29.2*
Angst, 2000 Zurich Cohort,
n=406
1959-1997
* p< 0.001 Untreated
† p< 0.05 Treated

6.4
2.2* 1.6† 2.0* 2.2*
1.4* 1.7 1.3 1.6 2.0 1.3 1.3
0.6

Neoplasm Cardio- Cerebro- Accidents Suicide Other All Causes

vascular vascular
 Suicidality

 It is estimated that there is a lower ratio of attempted

suicides to completed suicides in Bipolar disorder as
compared to the general population

 This suggests that the suicidal behaviour in bipolar

disorder is highly lethal.

 Baldassrini RJ CNS Spectr 2008

Suicidal risks vs. DSM-IV diagnosis
—————————————————————————————————————————

Measures BP-I BP-II MDD

—————————————————————————————————————————
Cases 529 314 1983
At-risk (yrs) 13.2 16.3 9.30
Suicidal rates (%/yr)
Suicides 0.14 0.16 0.05
Attempts 1.52 0.82 0.48
All acts 1.66 0.98 0.53
Suicide SMR 12.8 14.7 4.59
Lethality (A/S) 10.8 5.12 9.60
—————————————————————————————————————————
Tondo. Lepri, Baldessarini Acta Psychiatr Scand 2007; 116:419–428 (N=2829).
SMR = ratio of observed vs. local general population suicide rate: 10.9/100k/yr.
General population A/S ca. 25. Note: Rates of acts do not differ by Dx among
ever-hospitalized patients, but BPD risk is much greater if never hospitalized.
132
 35
Suicidal Acts in 2826 Major
30 Affective Disorder Patients
% of Suicidal Patients

vs. Years from Illness-Onset

25 [Tondo & Baldessarini 2007]

20

15

10

0
0–1 2–5 6–10 11–15 16–20 21–25 >26
Years from Illness Onset 133
 Suicides-episode type

 Most occur during the depressive phase of the illness.

 dysphoric/irrtable mixed states is a risk factor

 Balderssarini RJ CNS Spectr 2006

 NIMH CDS-risk factors for suicide

 Only prospective data

 1000 patients followed for 10 years

 Estimating at 1 year- risk factors for suicide

Risk Factors for Suicide in Bipolar
Adults (Current)

 Severe depression with anxiety, agitation,

global insomnia
 Mixed—dysphoric mania
 Mood cycling in episode
 Substance abuse
 Transition periods/early recovery stage
 Impulsive and/or violent behavior

Goodwin and Jamison 2007.

Risk Factors in Bipolar Disorder
(by History)

 Family history of suicide/impulsivity/violence

 Prior suicide attempt
 History of impulsive and/or violent behavior
 History of severe depressions with
anxiety/agitation/global insomnia
 Relatively early in course of illness

Goodwin FK, Jamison KR. Manic-Depressive Illness.

2007.
 Uncovering Bipolar vs Unipolar depression –
symptom profile studies

 Think bipolar
 Early onset
 Psychotic symptoms
 Postpartum onset
 Treatment resistant unipolar depression
 AD induced hypomania/mania
 Cycle induction at the start or stopping AD
 Change in the type of depressive symptoms over time
 Differences in symptom profile alone

 These are suggestive and none shown is

pathognomonic!
 or
 Sufficiently characteristic!

 On a probabilistic basis phenomenology is only subtly

divergent

 To this end current research is focussed on

indentifying early clinical and biological markers
 However as yet no robust or reliable neurobiological marker
of bipolar disorder has been identified

 Clinical diagnosis remains contingent on a history of mania or

hypomania

 This has been the source of much debate as clinically mania and
hypomania do not constitute the predominant mood state and
hypomania is detected often retrospectively
 This is seen as an undue bias toward one aspect of the illness?
 Berk M, M J Aust 2006
Compared to Bipolar II, Bipolar I depressed
patients have:

A) More anxiety symptoms

B) More rapid cycling

C) More psychotic features

D) More episodes and shorter intervals

 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

F. Goodwin 2009
 Bipolar and Cognition

 Core feature
 Occurs in prodromal phase
 More severe during illness phase
 May persist during remission
 Schiz > Bipolar > Unipolar
 Standardised Scores

-3
-2
-1
0

-3,5
-2,5
-1,5
-0,5
0,5
Reading

Counting

ounting backwards

Number symbols

Trail Making Test A

Trail Making Test B

Writing speed

Calculating

Naming
symptoms
symptoms
Bipolar group

Finding similarities
Psychiatric Illnesses

FAS-Fluss
Cognitive Impairment in

Productivity
of writing
Schizophrenia with negative
Schizophrenia without negative
 Drug effects on cognition

 Lithium  Cholinesterase
inhibitors
 Valproate
 Stimulants
 Anti-cholinergics
 Modafanil
 Benzodiazepines
 Noradrenergic
 Topiramate
agents
 Ventricular
Volumes in
Bipolar
Disorder

Strakowski et al. Am J Psychiatry 2002

 Frontal-Limbic
Frontal-Limbic Disconnection?
Disconnection?

Prefrontal
Cortex

Cingulate
Cortex

Hippocampus
Amygdala
 However as yet no robust or reliable neurobiological marker
of bipolar disorder has been identified

 Clinical diagnosis remains contingent on a history of mania or

hypomania

 This has been the source of much debate as clinically mania and
hypomania do not constitute the predominant mood state and
hypomania is detected often retrospectively
 This is seen as an undue bias toward one aspect of the illness?
 Berk M, M J Aust 2006
 Burden Associated with Bipolar Disorder

 Seventh leading cause of disability worldwide

 Considerable economic burden:
– Total annual cost in the UK of £2 billion
– Direct NHS annual cost of £199 million
– Drugs <1% of total costs

● Considerable personal burden; an individual with onset of

bipolar disorder in mid–late 20s effectively loses:
– 9 years of life
– 12 years of normal health
– 14 years of work activity

NHS = National Health Service

World Health Organization, 2001; Montgomery and Cassano. Management of Bipolar Disorder. London, UK: Martin Dunitz Ltd,
1996; Das Gupta and Guest. Br J Psychiatry 2002;180:227–233
 Burden Associated with Bipolar Disorder

 Seventh leading cause of disability worldwide

 Considerable economic burden:
– Total annual cost in the UK of £2 billion
– Direct NHS annual cost of £199 million
– Drugs <1% of total costs

● Considerable personal burden; an individual with onset of

bipolar disorder in mid–late 20s effectively loses:
– 9 years of life
– 12 years of normal health
– 14 years of work activity

NHS = National Health Service

World Health Organization, 2001; Montgomery and Cassano. Management of Bipolar Disorder. London, UK: Martin Dunitz Ltd,
1996; Das Gupta and Guest. Br J Psychiatry 2002;180:227–233
 Multidimensionality of bipolar disorder

Diabetes Diabetes
Cardio-
mellitus mellitus
Pain vascular
Obesity disorders
Hyper-
triglyceridaemia Obesity
Migraine

Oedema Ionotropic Angina Bipolar Substance

abuse
failure Personality
disorder
disorders
Eating
disorder
Hyper- Renal ADHD
tension function Anxiety
Impulse disorders
Hyper-
control
cholesterolaemia
McIntyre et al 2004
 Co-Morbidity

 SFBN (McElroy, 2001)

– Co morbidity around 65%

– DSM IV Axis I additional diagnosis – 23%

– DSM IV Axis I - Two additional diagnosis – 18%

– DSM IV Axis I – Three or more additional diagnosis –

24%

– Substance Use (Alcohol) – 21.4%- 54.5%

– Co morbid anxiety disorder – 42%

 Effect of Substance Abuse
on Course of Bipolar Illness

 Earlier onset
 More frequent episodes and hospitalizations
 Mixed episodes and rapid cycling
 More suicidal behaviors
 Slower symptom remission
 Poor adherence to treatment regimens
 More likely to be lithium refractory

Goodwin and Jamison 2007

 Personality disorders in bipolar II

% Patients

35
30
25
20
15
10
5
0
ve

ic
ne

ic

l
id

ta
st
n

zo
si

To
rli

io

i
es

ss

hi
de

tr
bs

Sc
is

ci
or

ar
H
O
B

Vieta et al 1999
 Bipolar Disorder &
Borderline Personality Disorder
Bipolar Disorder Borderline Personality Disorder
Onset in teens or early 20s No defined onset
Mood changes precipitated by internal or
Spontaneous mood changes
external events
Euthymic, dysphoric, anxious and elated Euthymic, dysphoric, anxious and angry mood
mood shifts shifts but elated mood is rare
Episodic impulsivity and risk-taking Chronic impulsivity and risk-taking
Recurrent suicidal gestures associated with
Episodic suicide attempts related to
both depression and internal/external
depressive episodes
precipitants
Self-mutilation rare Self-mutilation common
Endorse ‘depressed mood’ as descriptor Endorse ‘emptiness’ as descriptor
Family history of bipolar I or II or recurrent Family history negative for bipolar I, II and
depression recurrent depression
Adapted from Yatham L, et al. Bipolar Disord 2005: 7 (Suppl. 3): 5–69.
 Bipolar Disorder and Medical
Comorbidities

 Obesity (some related to pharmacol Rx)

 Diabetes prevalence: 9.9% (norm, 3.4%)
 Relative cardiovascular mortality: 1.87
 Migraine prevalence: 25% men, 27% women
 Twice the general health care costs
 Most of the comorbidities assoc w/ depr

Elmslie et al. J Clin Psychiatry. 2000;61:179-184. Cassidy et al. Am J Psychiatry.

1999;156:1417-1420. Weeke et al. J Affect Disord. 1987;13:287-292. Mahmood et al. J
Affect Disord. 1999;52:239-241. Schiffer et al. Am J Psychiatry. 1986;143:94-95.
 Cardiovascular Disease (CVD) Risk Factors

Estimated Prevalence and Relative Risk

Modifiable Risk (RR)
Factors
Schizophrenia Bipolar Disorder

45–55%, 1.5-2X
Obesity 26%5
RR1
Smoking 50–80%, 2-3X RR2 55%6
Diabetes 10–14%, 2X RR3 10%7
Hypertension ≥18%4 15%5
Dyslipidemia 14%, Up to 5X RR8

1. Davidson S, et al. Aust N Z J Psychiatry. 2001;35:196-202. 2. Allison DB, et al. J Clin Psychiatry. 1999; 60:215-220. 3. Dixon L, et
al. J Nerv Ment Dis. 1999;187:496-502. 4. Herran A, et al. Schizophr Res. 2000;41:373-381. 5. MeElroy SL, et al. J Clin Psychiatry.
2002;63:207-213. 6. Ucok A, et al. Psychiatry Clin Neurosci. 2004;58:434-437. 7. Cassidy F, et al. Am J Psychiatry. 1999;156:1417-
1420. 8. Allebeck. Schizophr Bull. 1999;15(1)81-89.
 The Need for Improvement in
Treatment Options
● Almost 50% of patients experience a recurrence despite adequate
treatment for bipolar disorder
– Residual symptoms increase the risk of a recurrence

● Few patients (26%) achieve full symptom resolution

– Remission should be the goal of treatment

● Many patients who show signs of symptom improvement continue

to experience psychosocial and vocational impairments that affect
normal daily living
– Over a 1-year period, functional recovery occurred in only 24% of
patients

● Long-term medication compliance is poor

Keck et al. Am J Psychiatry 1998;155:646–652; Perlis et al. Am J Psychiatry 2006;163:217–224;

Keller. J Clin Psychiatry 2006;67(Suppl 1):5–7
 Longitudinal course

 Tohen et al. Am J Psychiatry. 2003

 Largest study of long-term outcome in pts with 1st
episode BP-1 disorder
 166 pts followed prospectively for 2 to 4 years after
initial hospitalisation for manic or mixed episode
 Naturalistic design
 High recruitment and retention rates
 Recovery in bipolar disorder – the COBY
study
Patients showing recovery 2 years after index episode
(N=173)
98%

72%

43%

Syndromal recovery Symptomatic recovery Functional recovery

Absence of DSM YMRS<5 and HDRS<8* Occupational and residential
criteria status

*Recent recommendation to decrease the cut-off for true remission: Zimmerman M, 2007

174
Tohen M, et al. Am J Psychiatry 2003;160:2099–2107.
 Functionality in Bipolar Disorder-potential
explanations

 Trait neuropathology
 Vestigial effects of the mood state changes
 Effects of untreated comorbid psychiatric conditions
such as GAD, Panic Disorder
 Effects of comorbid medical conditions such as
obesity, CVS disease
 Side effects of ongoing medication
 Or Some combination of the above
 Tohen M, Arch Gen Psych 1990, Malhi GS, Can J
Psychiatry 2004
 Summary and Conclusions

 Bipolar disorders are seriously under-diagnosed

primarily because clinicians fail to include family
members in the evaluation of patients with depression
 The under-recognition of BP disorder and inadequate
treatment of its depressive phase convey substantial
cost to society, primarily through (1) lost productivity
and (2) a doubling of general health care cost
 Psychiatric and medical comorbidities (largely
associated with BP depression) contribute
substantially to overall disease burden.
 The needs of patients with bipolar disorder:
aspects of care patients would most like to see improved

Better treatment of depression

Less risk of weight gain

Prevention of relapse in depression
Improved functionality / quality of life

Less risk of sleeping difficulties

Less risk of suicidal thoughts

Less risk of diabetes

Less risk of muscle stiffness

Less risk of sedation

0 5 10 15 20 25 30 35 40 45
Respondents (%)
Understanding Patients' Needs, Interactions, Treatment, and Expectations (UNITE)
Global Survey of 1300 patients with bipolar disorder McIntyre 2009
Importance of Evidence Based Treatment

 Of this burdensome illness with high co-morbidity and

suicides!

 Highest suicide rate amongst all Axis 1 disorders