Transcript Mania with depressive symptoms

The challenge of
managing patients
with bipolar I disorder
beyond the manic
episode
International Review of Psychosis &
Bipolarity (IRPB), Lisbon, Portugal
27th April 2015
Chaired by: Allan Young, UK
Welcome and
introduction
Allan Young
Centre for Affective Disorders
Institute of Psychiatry, Psychology
& Neuroscience
King’s College London
UK
Requests
For your comfort…
 Please switch mobile phones, and all
other electronic devices, OFF or to silent
Requests…
 If you have questions, please fill in
a question card and hand it to one
of the staff during the symposium
 Additionally, please complete the
evaluation form, and hand this into
a member of staff as you leave
3
Agenda
Epidemiology and assessment of suicide risk in bipolar
disorder
Suicide risk in bipolar I disorder related to mania with
depressive symptoms, and implications for treatment
How to use anxiety, irritability, and agitation (AIA)
symptoms for diagnosing mania with depressive
symptoms – asenapine patient case
Maurizio Pompili
Italy
Allan Young
UK
Andrea Fagiolini
Italy
Led by Allan Young
UK
Panel discussion (including Q&A)
4
Participate during the interactive sessions
 Network name: Spotlight
1. Visit: www.lundbecksymposium.com
2. Follow the instructions on your device’s screen
3. Answer the interactive questions and polls
4. Responses will be projected on the symposium screen
5
Q
What proportion of your manic patients with depressive
symptoms suffer from suicidal ideation?
Maurizio Pompilí, Italy
% of patients
0%
15%
30%
50%
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
70%
85%
100%
Epidemiology and
assessment of suicide
risk in bipolar disorder
Maurizio Pompili
Professor of Suicidology and Psychiatry
Faculty of Medicine and Psychology
Sapienza University
Rome, Italy
Conflict of interest statement
Honoraria/expenses
AstraZeneca, Lundbeck
Consultancy/Advisory board
Ferrer
Funded research
AstraZeneca, Servier
8
Q
What proportion of your manic patients with depressive
symptoms suffer from suicidal ideation?
Maurizio Pompilí, Italy
% of patients
0%
15%
30%
50%
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
70%
85%
100%
Q
What proportion of your manic patients with depressive
symptoms attempt suicide during an episode?
Maurizio Pompilí, Italy
% of patients
0%
15%
30%
50%
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
70%
85%
100%
Q
What proportion of your bipolar I patients experience
≥3 depressive symptoms?
Maurizio Pompilí, Italy
% of patients
0%
15%
30%
50%
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
70%
85%
100%
Preventing suicide is a global imperative
Dr Margaret Chan
Director-General of the
World Health Organization
“Unfortunately, suicide all too often fails to be
prioritised as a major public health problem.
Despite an increase in research and knowledge
about suicide and its prevention, the taboo and
stigma surrounding suicide persist and often
people do not seek help or are left alone. And
if they do seek help, many health systems and
services fail to provide timely and effective
help. Yet, suicides are preventable. This
report encourages countries to continue the
good work where it is already ongoing and to
place suicide prevention high on the
agenda, regardless of where a country stands
currently in terms of suicide rate or suicide
prevention activities”
4th September 2014
12
Preventing suicide: a global imperative. WHO 2014
Consequences of suicidality
 For every suicide death:
 There are 5 hospitalisations
 There are 22 emergency department
visits for suicidal behaviour
 Implies more than 844,000 visits
in 2010, and almost 192,000
hospitalisations
13
US Department of Health and Human Services.
National strategy for suicide prevention. 2001
Suicidal risk in selected disorders
Disorder
SMR
Percent per year
Percent total
Bipolar disorder
21
0.31
15.5
Severe major depression
19
0.29
14.6
Mixed drug abuse
19
0.28
14.7
Dysthymia
11
0.17
8.6
Obsessive–compulsive disorder
11
0.14
8.2
Panic disorder
11
0.16
7.2
Schizophrenia
8
0.12
6
Personality disorder
6.7
0.1
5.1
Alcohol abuse
5.3
0.08
4.2
1
0.015
0.72
General population
SMR=standardised mortality ratio
14
Adapted from: Harris & Barraclough. Br J Psychiatry 1997;170:205–208;
Tondo et al. CNS Drugs 2003;17:491–511
15
When do patients with major mood
disorder commit or attempt suicide?
Especially in mixed states, when depression escalates into mania and when volatile and erratic
moods are associated with dysphoria and agitation, clinicians should treat this condition carefully,
monitoring suicide risk at all times1
Mania
Mania with
depressive symptoms
Depression
Mania
9–16%2-4
Dysphoric (mixed)
mania
Normal fluctuation
Major depression
(pure or mixed)
73–79%2-4
Depression
16
1. Pompili et al. Rev Neurother 2009;9(1):109–136;
2. Isometsä et al. Amer J Psychiat 1994;151:1020–1024;
3. Tondo et al. J Clin Psychiat 1998;59:405–414;
4. Valtonen et al. J Clin Psychiatr 2005;66:1456–1462
17
Suicide risk factors in patients with
bipolar disorder
Studies,
n
Subjects,
n
Pools OR or RD
(95% CI)
p-value
(z-score)
Risk of attempt (F>M)
20
44,242
1.54 (1.44–1.66)
<0.0001 (11.7)
Risk of suicide (M>F)
11
75,055
1.83 (1.41–2.39)
<0.0001 (4.48)
Younger onset [RD]
16
11,659
2.99 (2.20–3.78)
<0.0001 (7.41)
Depressive first episode
7
4,686
1.92 (1.39–2.65)
<0.0001 (3.98)
Current depression
3
1,238
5.99 (1.75–20.5)
0.004 (2.85)
Anxiety disorder
13
40,968
1.81 (1.66–1.97)
<0.0001 (13.7)
Any
18
39,139
1.81 (1.31–2.50)
0.0004 (3.57)
Alcohol
16
12,535
1.60 (1.31–1.97)
<0.0001 (4.51)
Drug
11
10,573
1.72 (1.23–2.39)
0.001 (3.20)
5
1,293
2.51 (1.91–3.31)
<0.0001 (6.55)
Risk of attempt
11
7,452
1.69 (1.25–2.27)
0.0006 (3.44)
Risk of suicide
4
7,023
2.91 (1.54–5.48)
0.001 (3.30)
Factor
Sexa
Substance abuse
Personality disorder (B)
Family history of suicide
aRates:
male attempts (1,379/16,231=8.50%); suicides (605/28,694=2.11%); A/S=8.50/2.11=4.03;
female attempts (3,002/28,011=10.7%); suicides (544/46,361=1.17%); A/S=10.7/1.17=9.15;
OR=odds ratio; RD=risk difference; CI=confidence interval
18
Adapted from: Schaffer et al. Bipolar Disord 2015;17:1–16
Bipolar I patients with/without mixed
states
Non-mixed
Mixed
Relative risk
p-value
(χ2 or t)
84
60
–––
–––
10.7%
46.7%
4.36
<0.001 (21.9)
0.21±0.71
0.88±1.28
4.19
<0.001 (16.1)
29.8%
66.7%
2.24
<0.001 (12.2)
Depressions
5.65±4.99
9.78±6.96
1.73
<0.001 (17.2)
Manias
3.01±3.21
3.60±3.38
1.20
NS (1.12)
Rapid-cycling
13.1%
30.0%
2.29
0.019 (6.22)
Employed
51.2%
26.7%
1.92
0.004 (8.70)
Characteristic
Cases (n)
Suicide attempted
Attempts per person
Suicidal ideation
Recurrences per person
Values are ±SD
19
Adapted from: Valenti et al. Bipolar Disord 2011;13:145–154
Mixed states represent a severe
presentation of bipolar disorder
– higher suicide risk
Suicidal ideation and suicide attempts in bipolar I disorder
Suicidal ideation
Suicide attempts
***
80
Patients (%)
66.7
***
60
46.7
40
29.8
20
10.7
0
Non-mixed
bipolar disorder
(n=84)
Mixed bipolar
disorder
(n=60)
Non-mixed
bipolar disorder
(n=84)
Mixed bipolar
disorder
(n=60)
***p<0.001 vs non-mixed patients
Mixed episode defined according to DSM-IV criteria; a study of 144
patients with bipolar disorder followed for ≤20 years
20
Valenti et al. Bipolar Disord 2011;13:145–154
Mania with depressive symptoms
– higher risk of suicide
 184 inpatients with bipolar I
disorder
Prevalence of suicidality among patients
with mixed mania or pure mania
70
Percentage of patients
 77 with pure mania
 107 with mixed mania
 Patients with mixed mania met
full criteria for a bipolar I manic
episode and had two or more
prominent depressive features
(other than current suicidality)
60
57.9
50
40
30
20
10
1.3
0
Mixed mania
21
Pure mania
Goldberg et al. Am J Psychiatry 1998;155:1753–1755
Early onset and suicidality are associated
with high mixed state index scores
Relationships between mixed state index scores
and complications of bipolar disorder
6
Absent
***
n=19
Present
5
MSI score
*
n=29
*
n=33
4
n=17 n=38
3
n=23
n=39
n=22
2
1
Onset <16
Substance
abuse
Head
trauma
Suicide
attempt
*p<0.05, ***p<0.001
MSI=Mixed State Index (measure of how strongly mixed an episode is);
note: rate of substance use disorder was very high throughout the entire
study population (~70%), therefore this characteristic may not have been
useful in delineating subtypes of illness
22
Swann et al. World Psychiatry 2009;8:166–172
Suicide risk in unipolar major depression,
bipolar I and bipolar II disorder
All suicidal acts
0.53
Attempts
0.48
Suicides
1.66
1.52
0.05
0%
0.98
0.14
20%
Unipolar major depression (n=1,983)
Overall risk is based on analysis of clinical records of 2,826
major affective disorder patients in Sardinia
0.82
0.16
40%
60%
Risk rates (% per year)
Bipolar I disorder (n=529)
23
80%
100%
Bipolar II disorder (n=314)
Tondo et al. Acta Psychiatr Scand 2007;116:419–428
Bipolar II and suicide risk
 BP-II acounts for 30–58% of all major depressions in psychiatric
practice
 5% prevalence of BP-II spectrum in the general population
 Mixed states are very common in the BP-II spectrum
 The cyclothymic temperament is the most prevalent temperament in
BP-II, and has been shown to be a predictor of suicide
 Rapid mood shifts are the hallmark of BP-II
 BP-II suicides are the most likely to be lethal – they use the most
aggressive methods
BP=bipolar disorder
24
Akiskal. Acta Psychiatr Scand 2007;116(6):395–402
Diagnostic distribution of suicide victims
with current primary major depression
Both studies
(n=125)
54
Rihmer et al.
1995 (n=25)
2
56
Rihmer et al.
1990 (n=100)
8
53
0%
20%
Unipolar major depression
44
1
40%
60%
Completed suicides
Bipolar I disorder
25
36
46
80%
100%
Bipolar II disorder
Rihmer et al. J Affect Disord 1990;18:221–225;
Rihmer et al. J Affect Disord 1995;35:147–152
Lifetime prevalence
Lifetime prevalence of suicide attempts in
unipolar major depression, bipolar I and
bipolar II disorder
35%
33%
30%
Range
18–61%
26%
25%
Range
10–50%
20%
15%
13%
10%
Range
9–30%
5%
0%
Unipolar major
depression (n=1,328)
Data taken from 10 studies, total of 3,187 patients
Bipolar I disorder
(n=1,319)
Bipolar II disorder
(n=340)
Pompili et al. Expert Rev Neurother 2009;9(1):109–136; Individual studies:
Coryell et al. 1987; Cassano et al. 1992; Dunner et al. 1976; Endicott et al. 1985;
Judd & Akiskal. 2003; Lewerich et al. 2003; Marneros et al. 2004; Oedegaard &
Fasmer. 2005; Slama et al. 2004; Tondo et al. 1999; Vieta et al. 1997
26
Distribution of mood disorders
n
Prevalence
(%)
Suicide
attempt (%)
1,273
57.6
1.0
Minor bipolar disorder
382
17.3
7.2
Pure major depressive disorder
286
12.9
5.8
Mild depression
171
7.74
–
Bipolar disorder
98
4.43
26.5
Bipolar II
65
2.94
31.5
Bipolar I
33
1.49
17.3
2,210
100
–
Diagnosis
None
Total
Study was led by University of Munich, involving 2,210
subjects followed for 10 years (final diagnoses shown)
27
Adapted from: Zimmermann et al.
Arch Gen Psychiatry 2009;66:1341–1352
Risk of suicide attempt in patients with bipolar I
vs bipolar II disorder
– alarming rates in bipolar spectrum
Dittman et al. 1976
Dunner et al. 1976
Coryell et al. 1985
Endicott et al. 1985
Coryell et al. 1987
Cassano et al. 1989
Vieta et al. 1997
Leverich et al. 2003
Dalton et al. 2003
Sakamoto & Fukunga. 2003
Joyce et al. 2004
Moreno & Andrade. 2005
Angst et al. 2005
Balazs et al. 2006
Valtonen et al. 2006
Rihmer et al. 2006
Pompili et al. 2006
Galfalvy et al. 2006
Bader et al. 2007
Lopez et al. 2007
Tondo et al. 2007
Pooled risk ratio [95% CI]:
1.09 [0.93–1.28]
(BP-I:32.4%; BP-II:27.4%)
-0.5
0.0
0.5
1.0
1.5 2.0 2.5 3.0
Risk ratio [95% CI]
4.0
4.5
5.0
BP-I risk higher
Null=RR of 1.0
BP=bipolar disorder; RR=risk ratio
3.5
28
Adapted from: Novick et al. Bipolar Disord 2010;12:1–9
Suicidal behaviour during phases of
bipolar disorder: a cross-sectional study
25%
23%
Suicide attempts (%)
21%
20%
20%
15%
10%
5%
0%
0%
Depressive
Depressive mixed
Mixed
(Hypo)manic
χ2=9.1, p=0.03
29
Valtonen et al. J Affect Disord 2007;97:101–107
Mood state during suicide attempt
15.6%
Depressive
11.1%
Manic
Mixed-dysphoric
73.3%
Sample is 310 patients with bipolar I or II
30
Tondo et al. J Clin Psychiat 1998;59:405–414;
Baldessarini et al. J Clin Psychiatry 1999;60(Suppl 2):77–84
 Patients die from suicide, on average, 10 years earlier than from
other causes
31
Angst et al. J Affect Disord 2002;68:167–181
Follow-up of suicide risk in mood
disorders according to the function of age
Patients die from suicide, on average, 10 years earlier than from other causes
100%
80%
60%
40%
Natural deaths (n=261)
Completed suicides (n=44)
20%
0%
20
30
40
50
60
70
80
Age
Dotted line shows line of best fit for completed suicides
32
Angst et al. J Affect Disord 2002;68:167–181
33
Angst et al. Arch Suicide Res 2005;9(3):279–300
Suicide in 406 patients with major mood
disorder – a 40–44 year follow-up
Percent of
total deaths
Percent of
patients
SMR
Unipolar major depression (n=186)
17.5
14.5
26.4
Bipolar (n=220)
10.2
8.2
11.7
Manic (n=30)
5.0
4.7
Bipolar I (n=130)
12.0
13.6
Bipolar II (n=60)
8.3
10.6
SMR=standardised mortality ratio
34
Angst et al. Arch Suicide Res 2005;9(3):279–300
Suicide in 406 patients with major mood
disorder – a 40–44 year follow-up
Survival curves of suicide in
subtypes of mood disorders

There were higher rates of suicide
among depressive patients (17.5%)
than among patients with bipolar I
disorders (12.0%) and bipolar II
disorders (8.3%)

Suicides were lowest in the
preponderantly manic group of patients

These findings are confirmed by the
SMRs, which were more than five times
lower for manic patients (4.7) than for
major depressive patients (26.4),
whereas bipolar I (13.6) and bipolar II
(10.6) disorders took intermediate
positions
Cumulative proportion surviving
1.00
0.95
0.90
0.85
Mania and mania with
mild depression (n=30)
Bipolar II disorder (n=60)
Bipolar I disorder (n=130)
Depression (n=186)
0.80
0.75
0
10
20
30
40
Years since onset of first prospective episode
Mood disorder n=406, suicides n=45, p=0.15
35
Angst et al. Arch Suicide Res 2005;9(3):279–300
Mortality of 403 patients with mood
disorders 48–52 years after their
psychiatric hospitalisation
Kaplan–Meier survivor function
Survival curves of suicide in subtypes of mood
disorders
1.00
Maniaa
0.95
Bipolar II disorder
Bipolar I disorder
0.90
MDD
0.85
0.80
0.75
0
10
20
30
40
50
Years since onset of first prospective episode
aOr
mania with minor depressive syndromes;
MDD=major depressive disorder
36
Angst et al. Eur Arch Psychiatry Clin Neurosci 2013;263(5):425–434
Columbia-Suicide Severity Rating Scale
(C-SSRS)
37
Columbia-Suicide Severity Rating Scale.
http://www.cssrs.columbia.edu
Columbia-classification algorithm for
suicide assessment (C-CASA): codes
Suicidal
Indeterminate
Non suicidal
1
Completed suicide
2
Suicide attempt
3
Preparatory actions towards imminent suicidal behaviour
4
Suicidal ideation
5
Self-injurious behaviour intent unknown
6
Not enough information: death
9
Not enough information: non-death
7
Self-injurious behaviour without suicidal intent
8
Other (accident, psychiatric, medical)
38
FDA. Guidance for industry, suicidality. 2010;
Posner et al. Am J Psychiatry 2007;164(7):1035–1043
Moving from a categorical to a
dimensional approach
Manic
DSM-IV
DSM-5
Manic
Mixed
Manic with mixed features
Depressive
Depressive with
mixed features
Depressive
DSM-5 has been updated to include a new ‘with mixed features’
specifier for hypomanic, manic or depressive episodes
39
American Psychiatric Association. Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition, Text Revision. Arlington, VA, 2000;
American Psychiatric Association: Diagnostic and Statistical Manual of
Mental Disorders, Fifth Edition. Arlington, VA, 2013
‘With mixed features’ specifier in DSM-5
 Use a specifier indicating the presence of symptoms of
the opposite pole
 Applicable to episodes of both depression and
(hypo)mania
 Applicable in the context of both unipolar and bipolar
lifetime diagnoses
 Addresses convergence of predominantly depressive
and manic mixed states
40
American Psychiatric Association: Diagnostic and
Statistical Manual of Mental Disorders, Fifth Edition.
Arlington, VA, American Psychiatric Association, 2013
The new M.I.N.I. patients’ module for the
DSM-5 ‘with mixed features’ specifier
Since you have been experiencing your current manic episode, have you almost every day
had times when:
Q1
You felt sad, empty, tearful, down, or depressed?
Q2
a) You were less interested in most activities?
b) You had less pleasure doing the activities you used to enjoy?
Q3
You were slowed down in your speech, thoughts or movements?
Q4
a) You had fatigue?
b) You felt without energy?
Q5
a) You had feelings of worthlessness?
b) You felt excessively guilty?
Q6
You wished you were dead, considered hurting yourself, made plans to commit
suicide or attempted suicide?
For questions that were split into two parts for patients (M.I.N.I. module questions 2, 4
and 5), patients were counted as having that symptom if ‘yes’ was selected for at least
one part; if patients answered ‘yes’ to both parts of the question, it was counted as only
one symptom to correspond with the DSM-5 criteria count
41
Hergueta & Weiller. Int J Bipolar Disord 2013;1:21
Warning signs – IS PATH WARM
I
Ideation – threatened or communicated
S
Substance abuse – excessive or increased
P
Purposeless – no reasons for living; anhedonia
A
Anxiety – agitation/insomnia
T
Trapped – feeling no way out; perceived burdensomeness
H
Hopelessness
W
Withdrawal – from friends, family, society
A
Anger (uncontrolled)/rage/seeking revenge
R
Recklessness – risky acts; unthinking
M
Mood changes (dramatic)
42
American Association of Suicidology, www.suicidology.org
Traditional directive model
Depression
Lack of sleep
Poor appetite
Anhedonia…
? Suicidality ?
Therapist
Patient
43
Jobes. Suicide Life Threat Behav 2000;30(1):8–17
Collaborative approach
Suicidality
Agitation
Pain
Hopelessness
Stress
Self hate
Reasons for living vs reasons for dying
Therapist & patient
44
Jobes. Suicide Life Threat Behav 2000;30(1):8–17
A suicidal person may…
 Talk about suicide, death, and/or
having no reason to live
 Make statements such as these:
 Most suicidal individuals give
definite warnings of their suicidal
intentions, but significant others are
either unaware of the significance
of these warnings or do not know
how to respond to them
45

“I can’t go on any longer”

“I hate this life”

“There’s no point to this stupid life”

“Everyone would be better off
without me”

“Life is not worth living”

“Nothing matters anymore”

“I don’t care about anything
anymore”

“I want to die”

– And any mention of suicide –
Pompili et al. Rev Neurother 2009;9(1):109–136
Key issues
 Bipolar disorder is associated with a very high risk of completed suicide
and relatively lethal attempts, especially early in the illness when sustained
clinical interventions, and even the diagnosis, may not have been
established
 Depressive and dysphoric–agitated mixed phases of bipolar disorder are
especially life threatening as well as challenging to diagnose and to treat
effectively and safely; volatile and erratic moods associated with dysphoria
and agitation are also associated with higher suicide risk
 Hopelessness is a cognitive trait associated with suicide, leading suicidal
patients to believe that suicide is the only feasible strategy for dealing with
their seemingly insoluble problems
 Proper assessment is fundamental for full management of suicide risk;
do explore suicidal ideation and intent
46
Suicide risk in bipolar
disorder related to
mania with depressive
symptoms, and
implications for treatment
Allan Young
Centre for Affective Disorders
Institute of Psychiatry, Psychology
& Neuroscience
King’s College London
UK
Conflict of interest statement
 Employed by Centre for Affective Disorders, Institute of Psychiatry,
Psychology & Neuroscience, King’s College London; Honorary Consultant
SLaM (NHS)
 Paid lectures and advisory boards for all major pharmaceutical companies
with drugs used in affective and related disorders
 No share holdings in pharmaceutical companies
 Lead Investigator for Embolden Study (AstraZeneca), BCI Neuroplasticity
study and Aripiprazole Mania Study
 Investigator initiated studies from AZ, Eli Lilly, Wyeth
 Grant funding (past and present): NIMH (USA); CIHR (Canada); NARSAD
(USA); Stanley Medical Research Institute (USA); MRC (UK); Wellcome
Trust (UK); Royal College of Physicians (Edin); BMA (UK); UBC-VGH
Foundation (Canada); WEDC (Canada); CCS Depression Research Fund
(Canada); MSFHR (Canada)
48
Q
How many days do your manic patients with depressive
symptoms stay in hospital?
Allan Young, UK
Days in hospital
7
14
21
28
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
35
42
49
Q
What proportion of your manic patients with depressive
symptoms fail to reach remission?
Allan Young, UK
% of patients
0%
15%
30%
50%
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
70%
85%
100%
Q
What proportion of your manic patients with depressive
symptoms attempt suicide during their lifetime?
Allan Young, UK
% of patients
0%
15%
30%
50%
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
70%
85%
100%
Age of onset for selected disorders
Age of onset distributions
Cumulative (%)
100
Anxiety
Depressive disorders
Substance
75
Somatoform
Bipolar
Poss. psychotic
50
Anxiety
Depressive disorders
Substance
Somatoform
Bipolar
Poss. psychotic
25
0
0
10
20
30
40
Age of onset (years)
52
50
Percentile
25
50
75
8
18
31
22
31
42
17
20
28
14
19
30
14
18
25
27
37
48
60
Jacobi et al. Psychol Med 2004;34(4):597–611
Mood state at presentation across the life
cycle
100
Depression
Patients (%)
80
Mixed
60
Mania
40
20
0
Age
DSM-5
n=889
15
Manic
20
25
30
35
40
45
Manic with mixed features
50
55
60
65
Depressive with
mixed features
Depressive
Kraepelin. Manic-Depressive Insanity and Paranoia, 1921; E & S Livingstone,
Edinburgh; American Psychiatric Association: Diagnostic and Statistical
Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric
Association, 2013; Vieta & Valenti. J Affect Disord 2013;148:28–36
53
Incidence of depressive symptoms in manic
episodes is 30–40%
– depending on definition used
Definitions used:
Patients with depressive
symptoms (%)
45
40
35
37
39
a
Mean incidence
from a review of
studies1
b
CGI-BP mania and
CGI-BP depression
scores >32
c
≥2 depressive
symptoms3
d
≥2 depressive
symptoms4
e
DSM-5 criteria5
34
31
30
30
25
20
15
10
5
0
n=981a
n=771b
CGI-BP=Clinical Global lmpression–Bipolar version
n=1,090c
n=104d
n=700e
1. McElroy et al. Am J Psychiatry 1992;149:1633–1644;
2. Azorin et al. BMC Psychiatry 2009;9:33; 3. Hantouche et al. J Affect Disord 2006;96:225–232;
4. Akiskal et al. J Affect Disord 1998;50:175–186; 5. Vieta et al. J Affect Disord 2014;156:206–213
Mixed states represent a severe presentation of
bipolar disorder
– longer hospital stays
Average length of stay in hospital for bipolar subdiagnoses
Manic episodes
(n=15,324)
29.2
Depressive episodes
(n=8,329)
29.9
Mixed episodes
(n=2,379)
42.3
0
10
20
30
40
50
Length of stay (days)
Bipolar disorder episodes categorised according to the ICD10 (International Classification of Diseases, 10th edition)
55
Ösby et al. J Affect Disord 2009;115:315–322
Mania with depressive symptoms
– a high impact on patients
Mania with depressive symptoms is associated with:
 More frequent episodes of longer duration1
 Longer time to achieve symptomatic remission2
 Longer hospital stays3
 Suicidal thoughts more common2
56
1. Vieta & Valentí. J Affect Disord 2013;148(1):28–36;
2. Swann et al. Am J Psychiatry 2013;170(1):31–42;
3. Ösby et al. J Affect Disord 2009;115(3):315–322
Treatments used for bipolar disorder
 Anticonvulsants
 Antipsychotics

Valproate

First-generation

Carbamazepine

Clozapine

Lamotrigine

Second-generation
 Lithium
 Antidepressants
(use / cessation)
 ECT
 Support / containment /
risk management
 Psychological treatments
ECT=electroconvulsive therapy;
not all treatment options listed are licensed indications
57
•
Aripiprazole
•
Asenapine
•
Lurasidone
•
Olanzapine
•
Paliperidone
•
Quetiapine
•
Risperidone
•
Ziprasidone
Treatment of mixed states
 Current treatments for bipolar disorder are largely directed towards
ameliorating symptoms and preventing relapse
 A greater understanding of pathophysiological processes is now
required to identify biological markers for bipolar disorder, and
provide more accurate diagnosis and new personalised treatment
approaches1
 Specific targeted therapies, capable of affecting the underlying
disease processes, may prove to be more effective, faster acting,
and better tolerated than existing therapies, therefore providing
better outcomes for the individuals affected by bipolar disorder2
58
1. Yang. Focus 2011;IX(4):423–427;
2. Zarate et al. Biol Psychiatry 2006;59:1006–1020
Current treatment of mixed states
WAVE-bd study – mixed states
100
Lithium
Antipsychotics
Patients treated (%)
80
Venezuela
(n=225)
N=2,896
Belgium
(n=408)
Anticonvulsants
Ukraine
(n=221)
Antidepressants
60
Germany
(n=209)
Anxiolytics
France
(n=480)
Romania
(n=183)
No treatment
40
Brazil
(n=164)
Portugal
(n=512)
Austria
(n=125)
Turkey
(n=369)
20
0
Pharmacological treatment during
mixed state
n=2,896; patients diagnosed with bipolar disorder type I or type II;
WAVE-bd=Wide AmbispectiVE study of the clinical management
and burden of bipolar disorder
59
Vieta et al. Int J Neuropsychopharmacol 2013;16(8):1719–1732
Current drug use in bipolar I patients with
and without depressive symptoms
The MANACOR study
100
Mania without mixed features
Mania with mixed features
Patients treated (%)
90
80
70
60
50
*
40
30
20
*
10
*
0
*p<0.05 vs ‘mania without mixed features’
60
Reinares et al. European Psychiatry. In Press
Atypicals in DSM-IV mixed episodes
 22 studies examined mixed episodes
 2 studies excluded – no data provided for effect size
 1 study excluded – no data on number of atypical/placebo patients
 10 studies excluded – no data on mean YMRS change
 3 studies included – atypical adjunct to mood stabiliser
 6 studies included – monotherapy
 Aripiprazole, asenapine, olanzapine, paliperidone, risperidone,
ziprasidone
YMRS=Young Mania Rating Scale
Please consult full prescribing information for all of the above
products
61
Muralidharan et al. J Affect Disord 2013;150(2):408–414
Second-generation antipsychotics in manic
symptoms in mixed episodes (DSM-IV)
Second-generation
antipsychotic
Placebo
Change in YMRS score
Standard mean difference (95% CI)
Study or
subgroup
SGA
Mean
SD
Total
Mean
SD
Total
Weight,
%
Azorin 2013
Asenapine
-15.0
9.31
107
-11.5
9.75
66
13.5
-0.37 (-0.68, -0.06)
Azorin 2013
Olanzapine
-13.3
9.94
122
-11.5
9.75
66
14.3
-0.18 (-0.48, 0.12)
Berwaerts 2012
Paliperidone ER
-13.1
8.32
39
-10.8
9.42
36
6.2
-0.26 (-0.71, 0.20)
Houston 2009
Olanzapine
-10.15
4.4
100
-7.68
4.42
101
16.2
-0.56 (-0.84, -0.28)
Keck 2003
Ziprasidone
-11.2
10.6
46
-7.8
12.9
24
5.2
-0.29 (-0.79, 0.20)
Khanna 2005
Risperidone
-28.7
20.44
3
-7.9
16.41
8
0.6
-1.09 (-2.54, 0.35)
McIntyre 2009
Asenapine
-11.3
10.92
53
-7.4
10.65
35
6.9
-0.36 (-0.79, 0.07)
McIntyre 2009
Olanzapine
-12.7
10.66
58
-7.4
10.65
35
7.1
-0.49 (-0.92, -0.07)
Sachs 2002
Risperidone
-13.6
11.3
9
-14.2
9.5
10
1.6
0.06 (-0.85, 0.96)
Suppes 2008
Aripiprazole
-11.7
10.61
93
-7.0
9.85
97
15.5
-0.46 (-0.75, -0.17)
Tohen 2002
Olanzapine
-12.92
8.37
121
-7.46
10.15
60
12.9
-0.60 (-0.92, -0.29)
538
100.0
-0.41 (-0.53, -0.30)
Total (95% CI)
751
Monotherapy
Adjunctive therapy with a mood stabiliser
Favours SGA
Favours placebo
Heterogeneity: Tau2=0.00; Chi2=7.65, df=10 (p=0.66); I2=0%; Test for overall effect: Z=7.11 (p<0.00001)
SGA=second-generation antipsychotic;
CI=confidence interval; SD=standard deviation
62
Muralidharan et al. J Affect Disord 2013;150(2):408–414
Second-generation antipsychotics in depressive
symptoms in mixed episodes (DSM-IV)
Study or
subgroup
SGA – depressive
Placebo – depressive
Change in depression score
Standard mean difference (95% CI)
(drug)
Mean
SD
Total
Mean
SD
Total
Weight,
%
Azorin 2013
(olanzapine)
-6.5
8.83
122
-4.5
9.75
66
32.2
-0.22
(-0.52, 0.08)
Azorin 2013
(asenapine)
-8.2
9.31
107
-4.5
9.75
66
30.3
-0.39
(-0.70, -0.08)
Houston
2009
(olanzapine +
divalproex)
-9.37
5.5
100
-7.69
5.43
101
37.5
-0.31
(-0.58, -0.03)
233
100.0
-0.30
(-0.47, -0.13)
Total
(95% CI)
329
Monotherapy
Adjunctive therapy
Favours
SGA
Favours
placebo
Heterogeneity: Tau2=0.00; Chi2=0.61, df=2 (p=0.74); I2=0%; Test for overall effect: Z=3.48 (p=0.0005)
SGA=second-generation antipsychotic;
CI=confidence interval; SD=standard deviation
63
Muralidharan et al. J Affect Disord 2013;150(2):408–414
In patients suffering from mania with depressive
symptoms, asenapine improves manic and
depressive symptoms (DSM-IV)
Effect on manic symptoms
Week 3
Effect on depressive symptoms
Week 3
0
0
n=122
n=66
n=107
LS mean change in MADRS
total score from baseline
LS mean change in YMRS
total score from baseline
n=66
-5
-10
-15
*
-20
-25
n=122
n=107
-2
Placebo
Asenapine
Olanzapine
-4
-6
-8
**
-10
-12
-14
OC (n): n=43
n=67
n=92
OC (n): n=43
n=67
n=92
*p<0.05, **p<0.01 active treatment vs placebo
Mixed episodes defined according to DSM-IV-TR; post-hoc analysis; ITT (intent-to-treat);
OC (observed cases); mean daily dose: asenapine 18.4 mg, olanzapine 15.6 mg; LS=least squares;
MADRS=Montgomery–Åsberg Depression Rating Scale; YMRS=Young Mania Rating Scale
Azorin et al. J Affect Disord 2013;145(1):62–69
Aripiprazole in bipolar I patients with DSM5 defined mixed features specifier
In data pooled from 6 aripiprazole trials in bipolar mania, 34% of patients
satisfied proposed DSM-5 criteria of ‘mixedness’ at baseline
Improvement of manic symptoms at Week 3
ARI
HAL
Li
PBO
Mean change in YMRS at
Week 3 (LOCF)
0
-2
-4
-6
-8
-8.7
-10
-12
-14
-11.3
-11.6
-11.8
-12.8
-11.8
-13.1
Met criteria for mixed features (n=324)
ARI=aripiprazole; HAL=haloperidol; Li=lithium; LOCF=last observation
carried forward; MADRS=Montgomery–Åsberg Depression Rating
Scale; PBO=placebo; YMRS=Young Mania Rating Scale
-8.9
Did not meet criteria for mixed features (n=595)
65
McIntyre et al. APA Annual Meeting, 2013
Lurasidone in bipolar I depression with
hypomanic symptoms (DSM-5 specifier)
Change in manic and depressive symptoms at Week 6 in patients
with and without subsyndromal hypomania
Manic symptoms
Depressive symptoms
70
0.3
Lurasidone
0.1
0.0
60
Responder rate (%)
LS mean YMRS score (Week 6)
0.5
-0.5
-1.0
-1.5
-2.0
-2.5
Lurasidone
-2.4
-2.3
-3.0
-2.4
**
**
53.2
51.1
50
40
32.2
30
31.1
27.8
20
10
Placebo
0
-2.8
Subsyndromal
hypomania
(baseline
YMRS ≥4)
**
51.1
Placebo
No subsyndromal
Subsyndromal
hypomania
hypomania (score
of ≥2 for 2 or more
YMRS items)
Subsyndromal
hypomania
(baseline
YMRS ≥4)
No subsyndromal
Subsyndromal
hypomania
hypomania (score
of ≥2 for 2 or more
YMRS items)
**p<0.01 vs placebo
Lurasidone (20–120 mg/day);
LOCF=last observation carried forward; LS=least squares;
YMRS=Young Mania Rating Scale
66
McIntyre et al. APA Annual Meeting, 2013;
McIntyre et al. J Clin Psychiatry 2015. [Epub ahead of print]
Olanzapine in mania with depressive
symptoms (DSM-5 specifier)
Improvement of manic symptoms at Week 3
Without mixed features
With mixed features
0
-3
-6
-9
-12
Mean change from baseline
in YMRS total score
Mean change from baseline
in YMRS total score
0
-3
-6
-9
-12
***
-15
-15
-18
***
-18
Placebo (n=153)
Olanzapine (n=169)
Placebo (n=66)
Olanzapine (n=59)
***p<0.001 vs placebo
Post hoc data from three placebo-controlled studies in patients with bipolar I disorder with
manic/mixed episode; cut-offs used to define depressive symptom severity in patients with
≥3 depressive features: Patients were categorised for mixed features by number of
concurrent depressive symptoms at baseline (0, 1, and 2=without mixed features
[322/447=72.0%], and ≥3=with mixed features [125/447=28.0%), as determined by HAMD17 item score ≥1. Depressive symptoms corresponded to 6 HAM-D17 items in the DSM-5
definition of manic episode with mixed features; LOCF endpoint
67
Tohen et al. J Affect Disord 2014;168:136–141
Asenapine in mania with depressive
symptoms (DSM-5 specifier)
Improvement of manic symptoms at Week 3
Mild depressive symptoms
Moderate depressive symptoms
Severe depressive symptoms
0
0
-3
-3
-3
-6
-6
-6
-9
-9
-9
-12
-12
-12
Mean change from baseline
in YMRS total score
0
*
**
*
-15
-15
-15
-18
-18
-18
Placebo (n=76)
Asenapine (n=117)
Olanzapine (n=135)
Placebo (n=43)
Asenapine (n=58)
Olanzapine (n=67)
Placebo (n=12)
Asenapine (n=13)
Olanzapine (n=16)
*p≤0.05, **p≤0.01 vs placebo
Cut-offs used to define depressive symptom severity in patients with ≥3
depressive features: mild (score ≥1 for MADRS items and ≥2 for PANSS item),
moderate (score ≥2 MADRS, ≥3 PANSS) and severe (score ≥3 MADRS, ≥4
PANSS) symptoms; LOCF endpoint
68
McIntyre et al. J Affect Disord 2013;150(2):378–383
Asenapine in mania with severe
depressive symptoms (DSM-5)
Mean change from baseline in
YMRS total score
Improvement of manic symptoms
Asenapine (n=13)
0
Placebo (n=12)
Olanzapine (n=16)
-3
-6
**
††
-9
†
-12
-15
-18
0
2
4
7
14
21
Endpoint
(LOCF)
**p≤0.01 vs placebo; †p≤0.05, ††p≤0.01 vs olanzapine
Severe depressive symptoms: MADRS items ≥3 and PANSS item ≥4;
post-hoc analysis
Please consult full prescribing information for all of the above products
69
McIntyre et al. J Affect Disord 2013;150(2):378–383
Asenapine in mania with depressive
symptoms (DSM-5)
Improvement of depressive symptoms at Week 1
Mild depressive symptoms
Moderate depressive symptoms
70
70
*
40
30
20
*
10
50
40
30
20
10
0
50
40
30
20
10
0
Placebo (n=47)
Asenapine (n=75)
Olanzapine (n=100)
*†
60
Remission rate (%)
50
70
60
Remission rate (%)
Remission rate (%)
60
Severe depressive symptoms
0
Placebo (n=26)
Asenapine (n=39)
Olanzapine (n=55)
Placebo (n=8)
Asenapine (n=8)
Olanzapine (n=13)
*p≤0.05 vs placebo; †p≤0.05 vs olanzapine
Cut-offs used to define depressive symptom severity in patients with ≥3 depressive features: mild (score
≥1 for MADRS items and ≥2 for PANSS item), moderate (score ≥2 MADRS, ≥3 PANSS) and severe
(score ≥3 MADRS, ≥4 PANSS) symptoms; remission defined as MADRS 12; post-hoc analysis
Please consult full prescribing information for all of the above products
70
McIntyre et al. J Affect Disord 2013;150(2):378–383
Asenapine in mania with depressive
symptoms (DSM-5 specifier)
Improvement of depressive symptoms at Week 3
Mild depressive symptoms
*
70
70
**
60
Remission rate (%)
Remission rate (%)
60
Severe depressive symptoms
50
40
30
20
10
50
40
30
20
10
0
50
40
30
20
10
0
Placebo (n=69)
Asenapine (n=113)
Olanzapine (n=132)
*
60
Remission rate (%)
70
Moderate depressive symptoms
0
Placebo (n=40)
Asenapine (n=56)
Olanzapine (n=66)
Placebo (n=12)
Asenapine (n=12)
Olanzapine (n=16)
*p≤0.05, **p≤0.01 vs placebo
Cut-offs used to define depressive symptom severity in patients with ≥3 depressive
features: mild (score ≥1 for MADRS items and ≥2 for PANSS item), moderate
(score ≥2 MADRS, ≥3 PANSS) and severe (score ≥3 MADRS, ≥4 PANSS)
symptoms; remission defined as MADRS 12; post-hoc analysis
71
McIntyre et al. J Affect Disord 2013;150(2):378–383
Early improvement predicts
asenapine response
Asenapine 10–20 mg/day (n=372)
2x
**
Olanzapine 5–20 mg/day (n=391)
Day 2
9x more likely to respond at Week 3
**
Day 7
**
0
1
2
3
4
5
6
7
8
9
10
Odds ratio‡
**p<0.01; ‡an odds ratio indicates the odds of a patient having a response at Week 3 if they have early improvement,
as compared with the chance of response when not experiencing early improvement
Post-hoc analysis; DSM-IV manic or mixed episode; early improvement was measured as ≥15% reduction, and treatment
response as ≥50% reduction, in YMRS total score; ITT, LOCF; asenapine dosed morning and evening;
DSM-IV mixed episode criteria are met for both a manic and a major depressive episode (at least
5 depressive symptoms) nearly every day during at least a 1-week period
Szegedi et al. J Affect Disord 2013;150(3):745–752
72
Early discharge from hospital with
asenapine
Kaplan-Meier estimate of time to readiness to hospital discharge
of patients with symptom improvement at Day 7
Patients ready for discharge (%)
100
98.2%
89.6%
80
76.9%
60
40
Asenapine 10–20 mg/day (n=372)
Olanzapine 5–20 mg/day (n=391)
Placebo (n=197)
20
0
0
5
10
15
Day
20
25
30
p≤0.05 asenapine vs placebo
Post-hoc analysis; DSM-IV manic or mixed episode; early
improvement was measured as ≥15% reduction, and
treatment response as ≥50% reduction, in YMRS total score;
ITT, LOCF; asenapine dosed morning and evening
73
Vieta et al. Poster presented at IFMAD 2012
Adjunctive quetiapine in the long-term
treatment of mixed states
Proportion of patients event free
Time to manic event*
Time to depressed event*
1.0
1.0
0.9
0.9
0.8
0.8
0.7
0.7
0.6
0.6
0.5
0.5
0.4
0.4
0.3
0.3
0.2
0.2
Quetiapine + Li / DVP (n=219)
0.1
Quetiapine + Li / DVP (n=219)
0.1
Placebo + Li / DVP (n=226)
0
Placebo + Li / DVP (n=226)
0
0
20
40
60
Time (weeks)
80
100
0
20
40
60
Time (weeks)
80
100
*p≤0.001 vs placebo + Li / DVP
Randomised treatment phase (ITT);
Li / DVP=lithium or divalproex; Studies 126 and 127
74
Vieta et al. J Affect Disord 2012;142(1-3):36–44
Mean number of days spent on each
episode at 5-year follow-up
Psychoeducation and prevention of mixed
states
700
Psychoeducation group (n=50)
Control group (n=49)
600
500
400
300
200
***
***
100
*
0
Total
Euphoric mania
**
Hypomania
**
Mixed mania
Depression
*p<0.05, **p<0.01, ***p<0.001 vs control
75
Colom et al. Br J Psychiatry 2009;194(3):260–265
Suicide attempt rates are significantly higher in
manic patients with ≥3 depressive symptoms
≥1 suicide attempt
Percentage of patients
100
Patients with 0–2
depressive symptoms
(n=687; lifetime n=534;
current episode n=291)
80
*
60
54
*
38
40
26
20
Patients with ≥3
depressive symptoms
(n=348; lifetime n=294;
current episode n=212)
9
0
Lifetime
Most recent (current) manic
episode
*p<0.05 vs patients with 0–2 depressive symptoms
76
Young & Eberhard. Neuropsychiatr Dis Treat 2015. In press
Reducing the risk of suicide in bipolar I
disorder – recommendations
 Empathic assessment of suicidal behaviour
 Identify and treat mania with depressive symptoms
 Use treatments with broad efficacy to reduce the risk of suicide
 Treatment of comorbidities
 Restricted access to lethal methods
 Involvement of significant others
 Psychotherapy
 Planning of rescue strategies
77
Treatment of mania with depressive
symptoms – conclusions
 Mixed states are associated with high risk, and adverse outcomes
– particularly suicide
 The definition of mixed states has changed; new research will use the DSM5 definition
 There is an absence of primary data:

Secondary analyses offer some guidance in treatment choice

Adequately powered trials in mixed states are urgently required
 The efficacy of anti-manic agents in pure mania cannot be extrapolated to
individuals with mania with depressive symptoms
 Psychoeducation is a helpful treatment component to prevent mania with
depressive symptoms
78
How to use anxiety,
irritability, and agitation
(AIA) symptoms for
diagnosing mania with
depressive symptoms
– asenapine patient case
Andrea Fagiolini
Department of Mental Health,
University of Siena School of Medicine,
Siena, Italy
Conflict of interest statement
Research grants and/or consultant and/or a speaker for:
 Angelini, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim,
Pfizer, Eli Lilly, Janssen, Lundbeck, Novartis, Otsuka, Sigma-Tau,
Takeda and Roche
80
Comorbidity is the rule
 The prevalence and
epidemiology of psychiatric
comorbidities in bipolar
disorder is high
 Stress-sensitive medical
disorder prevalent
 Irritability and agitation may be
both core manic or comorbid
depressive symptoms
 Anxiety is highly prevalent
81
Fagiolini et al. J Affect Disord 2013;148(2–3):161–169;
McIntyre et al. Hum Psychopharmacol 2004;19(6):369–386
Treatment of mixed states
 Current treatments for bipolar disorder are largely directed towards
ameliorating symptoms and preventing relapse
 A greater understanding of pathophysiological processes is now
required to identify biological markers for bipolar disorder, and
provide more accurate diagnosis and new personalised treatment
approaches1
 Specific targeted therapies, capable of affecting the underlying
disease processes, may prove to be more effective, faster acting,
and better tolerated than existing therapies, therefore providing
better outcomes for the individuals affected by bipolar disorder2
82
1. Yang. Focus 2011;IX(4):423–427;
2. Zarate et al. Biol Psychiatry 2006;59:1006–1020
Treatments used for bipolar disorder
 Anticonvulsants
 Antipsychotics
 Valproate
 First-generation
 Carbamazepine
 Clozapine
 Lamotrigine
 Second-generation
•
•
•
•
•
•
•
•
 Lithium
 Antidepressants
(use / cessation)
 ECT
 Support / containment /
risk management
 Psychological treatments
ECT=electroconvulsive therapy;
not all treatment options listed are licensed indications
83
Aripiprazole
Asenapine
Lurasidone
Olanzapine
Paliperidone
Quetiapine
Risperidone
Ziprasidone
How can we treat mania with depressive
symptoms as defined by DSM-5?
84
DSM=Diagnostic and Statistical Manual of Mental Disorders
Evaluating depressive symptoms in
mania
Recognising and identifying anxiety, irritability and
agitation (AIA) symptoms could:
 Provide a means of identifying those individuals who
may have mania with depressive symptoms
 Identify patients who may be suicidal, allowing for
appropriate treatment
85
Q
What proportion of your manic patients with depressive
symptoms experience anxiety, irritability and agitation?
Andrea Fagiolini, Italy
% of patients
0%
15%
30%
50%
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
70%
85%
100%
72% of patients who experienced mania with
depressive symptoms also had symptoms of
anxiety and irritability/agitation
The combination of
anxiety and irritability/
agitation during a manic
episode could be used as
a relevant discriminator for
the presence of depressive
symptoms
27.1%
(n=115/425)
***
72.4%
(n=199/275)
Patients with mania ‘with depressive symptoms’
Patients with mania ‘without depressive symptoms’
***p≤0.001 for symptoms of anxiety, irritability/agitation in mania ‘with depressive symptoms’ vs mania ‘without depressive symptoms’
IMPACT survey: a multicentre online survey of patients with
or without DSM-5 criteria for a manic episode with mixed
features (n=700); mania with ≥3 depressive symptoms
87
Vieta et al. J Affect Disord 2014;156:206–213
Evaluating depressive symptoms in mania: a
real-world study of patients with bipolar I
disorder (the M.I.N.I. survey)
 The objectives of this research were to assess:
 The number of patients presenting with depressive symptoms
according to the DSM-5 specifier ‘with mixed features’ during a
manic episode
 The association between the presence of depressive symptoms
during a manic episode and:
•
•
•
•
Specific mixed symptoms (anxiety, irritability and agitation)
Suicidality
Clinician satisfaction with treatment
Depressive symptoms included in the M.I.N.I. module
88
Young & Eberhard. Neuropsychiatr Dis Treat 2015. In press
34% of patients in the M.I.N.I. survey
had ≥3 depressive symptoms
0 vs ≥1 depressive symptoms
≤2 vs ≥3 depressive symptoms
31%
34%
66%
69%
Patients with 0 depressive symptoms (n=320)
Patients with ≤2 depressive symptoms (n=687)
Patients with ≥1 depressive symptom (n=715)
Patients with ≥3 depressive symptoms (n=348)
Total n=1,035
1,035 patients were included in the study
Total n=1,035
89
Young & Eberhard. Neuropsychiatr Dis Treat 2015. In press
Suicide attempts are significantly higher
in patients with ≥3 depressive symptoms
≥1 suicide attempt
Percentage of patients
100
Patients with 0–2
depressive symptoms
(n=687; lifetime n=534;
current episode n=291)
80
*
60
54
*
38
40
26
20
Patients with ≥3
depressive symptoms
(n=348; lifetime n=294;
current episode n=212)
9
0
Lifetime
Most recent (current) manic
episode
*p<0.05 vs patients with 0–2 depressive symptoms
90
Young & Eberhard. Neuropsychiatr Dis Treat 2015. In press
Patients ‘with mixed features’
Patients with ≥3 depressive symptoms (n=348) were grouped
according to severity of anxiety, irritability and agitation (AIA)

AIA severe: all three symptoms rated ≥4 = 167 patients (48%)

AIA mild: none or one symptom rated ≥4 = 105 patients (30%)

The analysis was performed in a sub-set of patients (n=162) from the AIA
subgroups who had a lifetime history of suicide attempts

The average number of suicide attempts during the current episode was
significantly higher in the AIA severe group than the AIA mild group; 0.84 vs
0.34, respectively (p<0.0006)

Patients with manic episodes with depressive symptoms present a suicidal
risk that is increased when they experience moderately severe to very
severe symptoms of anxiety, irritability and agitation
Poster to be presented today
in the poster session during the lunch break
91
Weiller & Eberhard. Poster at IRPB 2015
Anxiety, irritability and agitation are significantly
more severe in manic patients with ≥3 depressive
symptoms
Average composite severity score
of anxiety, irritability and agitationa
Severity of anxiety, irritability and agitation
7
6
5
*
4.1
4
3.4
3
2
1
Patients with ≥3 depressive
symptoms (n=348)
Patients with 0–2 depressive
symptoms (n=687)
*p<0.05 vs patients with 0–2 depressive symptoms
M.I.N.I. survey: real-world, prospective study of patients with
bipolar I disorder (n=1,035); aseverity of anxiety, irritability
and agitation was scored on a scale from 1–7, where
1=absent and 7=very severe
92
Young & Eberhard. Neuropsychiatr Dis Treat 2015. In press
Notice AIA  check appropriately
 treat accordingly
1
Notice: AIA
3
2
Treat: accordingly
Check: appropriately
Hopelessness
Loss of energy
High activity/energy level
Anxiety
Diminished need for sleep
Disordered thoughts
Worthlessness
Diminished pleasure
Elevated mood
Irritability
Suicidal thoughts
Agitation
Extremely talkative
Euphoria
Depressed mood
Dysphoria
Impulsivity
AIA=anxiety, irritability, agitation
93
Hergueta & Weiller. Int J Bipolar Disord 2013;1:21
Case study
Ilaria
A 22-year-old university student
diagnosed with bipolar I disorder
1 year ago
The patient case report described during this session
is an actual patient case, the details of which have
been modified to preserve anonymity
Asenapine was used according to the EU label
Clinical assessment: history
 22-year-old, single, university student
 Diagnosed with bipolar I and panic disorder 1 year ago, and
currently treated with divalproex (valproate) 1,200 mg/day,
duloxetine 60 mg/day and olanzapine 10 mg/day
 Presents to the outpatient clinic, accompanied by two fellow
students, reporting that she was not doing well at all
 She is only partially oriented (unable to say which day of the week
we are in), distractible, agitated, unable to sit still, unable to
completely follow the conversation
Continued on next slide.
95
Clinical assessment: chief complaint
 Anxious, irritable, easily distracted, restless, and moderately agitated
 Fellow students report that she spent the previous night smoking,
standing in front of her bedroom window and talking about the fact
that she would better off dead and that she wished she had the guts
to ‘put an end to this whole story’
 They also report that she has been quite short tempered lately,
speaking much faster than usual, jumping from one topic to another,
not sleeping, and experiencing several panic attacks
Continued on next slide.
96
Clinical assessment: findings
 Physical exam
 Vital signs within normal limits
 Height 172 cm
 Weight 85 kg
 Psychiatric assessment
 Alert but only partially oriented
 Demeanour is agitated with anxiety, racing thoughts and pressured
speech
97
Mental status examination
 Mood rapidly changing from irritable, to depressed and anxious.
Highly distractible. Experiences a panic attack during the exam.
States that she feels she would be better off dead, and that she
stopped taking olanzapine and divalproex 2 weeks ago, because of
dry mouth, constipation and weight gain
 Psychiatric diagnosis: bipolar I disorder, manic episode, with mixed
features
 Secondary diagnosis: rule out panic disorder
98
Clinical discussion
Q
In your practice, how many manic patients present with ≥1 depressive
symptoms and/or anxiety, irritability, agitation or suicidal ideation?
Andrea Fagiolini, Italy
% of patients
1–15%
16–35%
36–60%
61–75%
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
76–90%
91–99%
A
RESPONSE
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
Q
What is the most important short-term treatment goal for
this patient?
Andrea Fagiolini, Italy
% of patients
Improve her mood
Improve her sleep
Improve her
relationship with
fellow students
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
Attain rapid control
of agitation, anxiety
and impulsivity
A
RESPONSE
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
Q
What is the most important long-term treatment goal for this
patient?
Andrea Fagiolini, Italy
% of patients
Consider tolerability of
treatment so as not to
predispose patient to
non-adherence
Prevent
relapse
Minimise
subthreshold
symptoms
Reduce
suicide risk
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
Decrease cycling
frequency and
mood instability
Improve overall
patient
functioning
A
RESPONSE
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
American Psychiatric Association (APA)
treatment goals for patients with bipolar disorder
Short-term
Long-term
 Attain rapid control of agitation,
anxiety, and impulsivity
 Consider tolerability of treatment so
as not to predispose patient to nonadherence
 Ensure the safety of patients and
those around them
 Prevent relapse
 Stabilise acute episode
 Minimise subthreshold symptoms
 Achieve remission
 Reduce suicide risk

Defined as a complete return to
baseline level of functioning and a
virtual lack of symptoms
 Decrease cycling frequency and
mood instability
 Improve overall patient functioning
106
APA. Am J Psychiatry 2002;159(Suppl 4):1–50
Q
In your practice, how many patients with bipolar disorder are fully
adherent to the prescribed medication regimen?
Andrea Fagiolini, Italy
% of patients
1–15%
16–35%
36–60%
61–75%
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
76–90%
91–99%
A
RESPONSE
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
Q
Based on this patient’s profile, and other patients that you
have treated, what side effects are of greatest concern?
Andrea Fagiolini, Italy
% of patients
Weight gain
Sedation
Dry mouth,
tremor,
constipation
Akathisia
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
Dyslipidaemia
Hyperprolactinaemia
and/or sexual
dysfunction
Parkinsonism
A
RESPONSE
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
Clinical assessment: history
 This patient stopped taking olanzapine and divalproex 2 weeks ago,
because of dry mouth, constipation and weight gain
Continued on next slide.
111
Muscarinic receptor subtypes
Receptor
subtype
CNS distribution
Non-CNS location
M1
Cerebral cortex, hippocampus,
neostriatum
Salivary glands, sympathetic
ganglia
M2
Throughout the brain
Smooth muscle, cardiac
muscle
M3
Low levels throughout brain
Smooth muscle, salivary
glands, eyes
M4
Abundant in neostriatum, cortex
and hippocampus
Salivary glands
M5
Projection neurons of substantia
Eyes (ciliary muscle)
nigra pars compacta and ventral
tegmental area, and hippocampus
112
Antimuscarinic pharmacologic effects
– peripheral
 Dry eyes
 Heat intolerance
 Urinary retention
 Tachycardia
 Dry mouth
 Decreased sweating
 Constipation
113
Carnahan et al. J Clin Pharmacol 2006;46:1481–1486
Antimuscarinic pharmacologic effects
– central
 Forgetfulness
 Dizziness
 Agitation/confusion
 Drowsiness
 Delirium
 Falls
 Reduced concentration
114
Carnahan et al. J Clin Pharmacol 2006;46:1481–1486
Treatment considerations: Day 1
 Admitted to inpatient unit
 The patient is started on asenapine (10 mg twice a day)
 Duloxetine is discontinued
 The patient is re-started on divalproex (states to not be sexually
active) at 300 mg twice daily
 Given the level of agitation, lorazepam is also (temporarily) added,
at 1 mg twice a day
115
Q
What proportion of your patients do you treat with adjunctive benzodiazepines
when they are experiencing an episode of mania (with or without depressive
symptoms)?
Andrea Fagiolini, Italy
% of patients
1–15%
16–35%
36–60%
61–75%
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
76–90%
91–99%
A
RESPONSE
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
Treatment considerations: Day 2
 The patient tolerates all the medications and slept for 6 hours
 Agitation and anxiety subsided
 Reports mild, yet tolerable, sedation
 States that suicidal ideation has subsided, and denies suicidal
intention
 Asenapine continued at 10 mg twice a day
 Divalproex increased to 300 mg in the morning and 600 mg at
bedtime
 Lorazepam continued at 1 mg twice daily
118
Treatment considerations: Day 3
 The patient slept for 7 hours
 The patient has clearly improved, but is still overly active despite the
fact that she complains of mild sedation
 Divalproex blood level is 43 μg/ml
119
Q
Would you ‘push’ the divalproex dose higher?
Andrea Fagiolini, Italy
% of patients
Yes
No
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
A
RESPONSE
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
Treatment considerations: Day 4
 Divalproex is increased to 500 mg three times daily
 The patient gets gradually better in the days that follow
 Lorazepam is gradually decreased, and then discontinued
 The patient is continued on asenapine 20 mg/day and divalproex
1,500 mg/day, and is discharged to the intensive outpatient program
on Day 8
122
Treatment of mixed states
– summary
 Mania with depressive symptoms represent some of the most challenging
situations encountered in the management of patients with bipolar illness
 Early and accurate diagnosis of mixed states is essential to ensure that the
most optimal treatment is prescribed
 There is an absence of primary data:

Secondary analyses offer some guidance in treatment choice

Adequately powered trials in mixed states are urgently required
 Emerging data, applying DSM-5 methodology, supports the use of
antipsychotic treatment in patients displaying depressive symptoms during
their manic episodes
123
Panel discussion
(including Q&A)
Led by Chairman
Q
What proportion of your manic patients with depressive
symptoms suffer from suicidal ideation?
Maurizio Pompilí, Italy
% of patients
0%
15%
30%
50%
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
70%
85%
100%
A
RESPONSE
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
Q
What proportion of your manic patients with depressive
symptoms attempt suicide during an episode?
Maurizio Pompilí, Italy
% of patients
0%
15%
30%
50%
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
70%
85%
100%
A
RESPONSE
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
Q
What proportion of your bipolar I patients experience
≥3 depressive symptoms?
Maurizio Pompilí, Italy
% of patients
0%
15%
30%
50%
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
70%
85%
100%
Q
RESPONSE
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
Q
How many days do your manic patients with depressive
symptoms stay in hospital?
Allan Young, UK
Days in hospital
7
14
21
28
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
35
42
49
A
RESPONSE
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
Q
What proportion of your manic patients with depressive
symptoms fail to reach remission?
Allan Young, UK
% of patients
0%
15%
30%
50%
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
70%
85%
100%
A
RESPONSE
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
Q
What proportion of your manic patients with depressive
symptoms attempt suicide during their lifetime?
Allan Young, UK
% of patients
0%
15%
30%
50%
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
70%
85%
100%
A
RESPONSE
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
Q
What proportion of your manic patients with depressive
symptoms experience anxiety, irritability and agitation?
Andrea Fagiolini, Italy
% of patients
0%
15%
30%
50%
Submit
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
70%
85%
100%
A
RESPONSE
The challenge of managing patients with bipolar I disorder beyond the manic episode
Monday 27 April 2015 | 11:30 | Grande Auditorio Egas, Edificio Egas Moniz
April 2015 © 2015 H. Lundbeck A/S
The challenge of
managing patients
with bipolar I disorder
beyond the manic
episode
International Review of Psychosis &
Bipolarity (IRPB), Lisbon, Portugal
27th April 2015
Chaired by: Allan Young, UK