Fixing the Mix-Up Over Mixed Depression
Transcript of Fixing the Mix-Up Over Mixed Depression
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Fixing the Mix-Up Over
Mixed Depression
Diagnosing and Treating DSM-5 Defined
Mixed Features in Mood Disorders
Handout for the Neuroscience Education Institute (NEI) online activity:
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Learning Objectives
• Utilize evidence-based strategies to identify
patients with mixed depression
• Optimize treatment strategies for patients with
mixed depression
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Overview
• Rationale for supplanting mixed states with
mixed specifier: déjà-vu all over again!
• Clinical implications of mixed features in mood
disorders
• Treating mixed features in mood disorders
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Pre-Poll Question 1
I feel competent diagnosing patients with mixed
depression.
1. 1 (strongly disagree)
2. 2
3. 3
4. 4
5. 5 (strongly agree)
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Pre-Poll Question 2
I feel competent optimizing treatment for patients with
mixed depression.
1. 1 (strongly disagree)
2. 2
3. 3
4. 4
5. 5 (strongly agree)
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Pretest Question 1
In the recently released Diagnostic and Statistical Manual of Mental
Disorders (DSM-5), "mixed states" is replaced with "mixed specifier."
Rationales for this revision include:
1. The real world presentation of mixed states was not captured in
the DSM-IV
2. Rates of misdiagnosis of bipolar disorder were very high based on
DSM-IV criteria
3. Mixed states were being inappropriately treated
4. 1 and 2 only
5. 2 and 3 only
6. All of the above
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Pretest Question 2
Kate is a 26-year-old patient with bipolar depression who is currently
showing some manic symptoms. According to the Systematic
Treatment Enhancement Program for Bipolar Disorder (STEP-BD)
study, the most common subsyndromal manic symptom is:
1. Decreased need for sleep
2. Flight of ideas/racing thoughts
3. Distractibility
4. Increased activity
5. High-risk activity
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Considerations for the Mood Spectrum
MDE, major depressive episode;
MDD, major depressive disorder;
BD NOS, bipolar disorder not otherwise specified.
• Subthreshold hypomania during MDE in MDD
MDD
• Capture subthreshold episode types
• Spectrum
BD NOS • Increased energy/activity
• Duration, symptom count
• Allow mixed hypomania
Bipolar II
• Increased energy/ activity
• Unipolar mania
Bipolar I
• Subthreshold features in MDD
• Specifier "with mixed features"
• Cyclothymia and other subthreshold presentations
• Developmental issues
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Kraepelin Conceptualized Affective States
as a Continuum
Marneros A, Goodwin F. Bipolar Disorders: Mixed States, Rapid Cycling and Atypical Forms.
Cambridge University Press, 2005:1-44.
Kraepelin conceptualized not only mood cycling up and
down, but also thought processes and volition
6 types of mixed states were identified
Depressive or anxious mania (depressed
mood but elevated will and thought)
Excited depression (depressed mood and
will but elevated thought)
Manic with thought poverty (elevated mood
and will but decreased thought)
Manic stupor (elevated mood but
decreased will and thought)
Depression with flight of ideas (depressed
mood and thought but elevated will)
Inhibited mania (elevated mood and
thought but decreased will)
1 4 6 5 7 2 1
1 2 3 5 6 8 1
Thought
disturbance
Mood
disturbance
Volition
disturbance
Pure mania (flight of ideas,
euphoria, hyperactivity)
Pure depression (thought inhibition,
depressive mood, weakness of volition)
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Conceptualization of Pure and Mixed States in
DSM-IV-TR and DSM-5
Manic Mixed Depressive DSM-
IV-TR
Core
symptoms
Manic
Depressive
Elevated
mood
>3
<5
Elevated mood +
depressed mood or loss of interest
>3
>5
Depressed mood
or loss of interest
<3
>5
Core
symptoms
Manic
Depressive
Elevated mood
+ energy
>3
<5
Depressed mood
or loss of interest
>3
>5
Depressed mood
or loss of interest
<3
>5
Elevated mood
+ energy
>3
>3
Manic Depressive Manic with mixed features Depressive with
mixed features DSM-5
APA. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Rev. 2000;
APA. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. 2013.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Main Changes For "Bipolar and Related
Disorders" in DSM-5 Compared to DSM-IV-TR
DSM-IV-TR DSM-5
Specific chapter No Yes
Increased activity/energy Not core mania
criteria
Yes, core mania
criteria
Mixed episodes Mania subtype
categorical
Modifier* (specifier?)
for either depressive
or manic episodes
Antidepressant switching Not bipolar Bipolar
Additional "specifiers" Anxiety, suicide
Other bipolar disorders NOS Other unspecified
bipolar and related
disorders
APA. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Rev. 2000;
APA. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. 2013.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Reasons for Supplanting "Mixed States" with
"Mixed Specifier"
• Real world presentation of mixed states
not aligned with DSM-IV-TR description
• Bipolar disorder: high rates of
misdiagnosis
• Suicidality and mixed states
• Inappropriate treatment of mixed states
(e.g., antidepressants)
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Individuals With DSM-5 Defined Mixed Features:
High Unemployment Rate
MFS, DSM-5 defined mixed features.
McIntyre et al. International Mood Disorders Collaborative Project. 2014.
Unemployment rate for patients with pure mania vs. mania with MFS
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Individuals With DSM-5 Defined Mixed Features:
More Cardiovascular Disease
MFS=DSM-5 defined mixed features
McIntyre et al. International Mood Disorders Collaborative Project. 2014.
Prevalence of cardiovascular disease in patients with pure mania vs. mania with MFS
MFS, DSM-5 defined mixed features.
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Evidence Base Supporting Dimensionality in Mood
Disorders
NIMH, National Institute of Mental Health;
STEP-BD, Systematic Treatment Enhancement Program for Bipolar Disorder;
BRIDGE, Bipolar Disorders: Improving Diagnosis, Guidance and Education.
Stanley Network Studies
Munich Study
NIMH Depression Collaborative Study
BRIDGE Study
STEP-BD Study
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Subsyndromal, Minor Depressive, and
Hypomanic Symptoms Predominate
146 Bipolar I Patients
Followed for 12.8 years
86 Bipolar II Patients
Followed for 13.4 years % wks
Major
depression/
mania
Subsyndromal,
minor depressive,
hypomanic
symptoms
% wks
Major
depression/
mania
Subsyndromal,
minor depressive,
hypomanic
symptoms
10
20
30
40
50
10
20
30
40
50
Judd LL et al. Arch Gen Psychiatry 2002;59:530-7;
Judd LL et al. Arch Gen Psychiatry 2003;60:261-9.
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Progression to Bipolar Disorder From MDD
With Subthreshold Hypomania
N=550 individuals followed for >1 year (mean follow-up: 17.5 years) after a diagnosis of major depression at intake.
19.6% of patients converted to bipolar disorder during follow-up
Fiedorowicz JG et al. Am J Psychiatry 2011;168:40-8.
Time to Hypomania or Mania
Time to Hypomania
Pro
po
rtio
n W
ith
ou
t
Hyp
om
an
ia o
r M
an
ia
Weeks to Follow-up
1.0
0.9
0.7
0 1040 1300 1560
0.8
780 520 260
Time to Mania
Pro
po
rtio
n W
ith
ou
t
Hyp
om
an
ia o
r M
an
ia
Weeks to Follow-up
1.0
0.9
0.5
0 1040 1300 1560
0.8
780 520 260
≥3 Symptoms
<3 Manic symptoms
0.6
0.7
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Goldberg JF et al. Am J Psychiatry 2009;166:173-81.
Specific DSM-IV Manic Symptoms During an Index
Episode of Bipolar Depression in STEP-BD
0
5
10
15
20
25
30
35
0 1 2 3 4 5 6 7
Percent of
Patients
No mania (31.2%)
Subsyndromal mania (54.0%)
Full mixed episode (14.8%)
Number of DSM-IV Manic Symptoms
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Goldberg JF et al. Am J Psychiatry 2009;166:173-81.
0
10
20
30
40
50
60
Full mixed episode (n = 204)
Subsyndromal mania (n = 745)
Percent of
Patients
Specific DSM-IV Manic Symptoms During an Index
Episode of Bipolar Depression in STEP-BD
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3-Fold Higher Rate of Bipolar Disorder Among
Individuals With MDD When Using Bipolar Specifier
Angst J et al. Arch Gen Psychiatry 2011;68:791-8.
No. (%)
Country Patients,
No.
Hospitalized,
%
Age, Mean (SD),
y
Male Sex,
%
Bipolar DSM-IV-
TR
Bipolar
Specifier
Bosnia
Bulgaria
China
Egypt
Georgia
Germany
Iran
Korea
Macedonia
Morocco
Netherlands
Pakistan
Portugal
Slovakia
Spain
Taiwan
Ukraine
Vietnam
Total
200
300
727
306
254
251
313
212
224
317
220
265
311
297
655
420
297
66
5635
46.5
46.0
45.9
24.2
18.5
59,4
37.4
25.5
26,8
20.8
12.7
37.0
11.9
57,6
25,5
14.8
73.7
37.9
34.4
46.3 (10.9)
49.8
39.7 (14.4)
37.7 (12.8)
46.5 (15.0)
48.0 (12.3)
38.4 (12.3)
45.0 (14.5)
47.5 (13.3)
39.7 (11.5)
46.1 (13.7)
38.2 (12.0)
45.9 (13.0)
48.4 (13.2)
47.2 (13.9)
45.3 (12.7)
46.9 (13.1)
40.7 (11.1)
44.1 (13.7)
32.5
36.5
39.1
49.0
32.9
36.8
33.9
27.8
28.6
38.3
40.0
50.4
25.7
38.0
33.1
27.2
29.6
51.5
35.5
45 (22.5)
56 (18.7)
105 (14.4)
42 (13.7)
39 (15.4)
29 (11.6)
57 (18,2)
15 (7.1)
29 (12.9)
55 (17.4)
28 (12.7)
60 (22.6)
45 (14.5)
50 (16.8)
100 (15,3)
64 (15.2)
65 (21.9)
19 (28.8)
903 (16.0)
111 (55.5)
171 (57.0)
290 (39.9)
144 (47.1)
103 (40.6)
102 (40.6)
169 (54.0)
55 (25.9)
107 (47.8)
148 (46.7)
81 (36.8)
158 (59.6)
172 (55.3)
166 (55.9)
324 (49.5)
149 (35.5)
156 (52.5)
41 (62.1)
2647 (47.0)
Demographic Features of the Study Sample
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McIntyre RS et al. J Affective Disord 2015;172C:259-64.
MDD BD-I BD-II
26.0%
34.0% 33.8%
% of individuals who met criteria for MFS during an index major depressive episode
n=149 n=65 n=49
Mixed features specifier (MFS) was operationalized as a score ≥1 on 3 or more select items on the Young
Mania Rating Scale (YMRS) or ≥1 on 3 select items on the Montgomery-Åsberg Depression Rating Scale
(MADRS) or the Hamilton Depression Rating Scale (HAMD-17) during an index major depressive episode
(MDE) or a hypo/manic episode, respectively.
*Data from a post hoc analysis of participants who met criteria for a current mood episode as
part of MDD (n=506) or BD (BD-I: n=216, BD-II: n=130)
Mixed Features Commonly Encountered in Adults With Both
Major Depressive Disorder and Bipolar Disorder:
The International Mood Disorders Collaborative Project
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MDD and Subthreshold Bipolarity
• 10-year prospective study; n=2,210 subjects
(14–24 years at baseline)
• Subthreshold BD = MDD + hypo/manic symptoms, but never having
met criteria for (hypo)mania
• Among 488 respondents with MDD, 60% had pure MDD and 40%
had subthreshold BD
• Subthreshold BD cases had:
– Significantly increased family history of mania
– Higher rates of nicotine dependence, alcohol use disorder, and panic
disorder
• Subthreshold BD converted more often to BD than to pure MDD
BD, bipolar disorder;
MDD, major depressive disorder.
Zimmermann et al. Arch Gen Psychiatry 2009;66:1341-52.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
MDD → BD Continuum
• Approximately 20–55% of MDD cases are
characterized by lifetime symptoms of some
degree of subthreshold hypomania
• Compared to those with "pure" depression,
those with lifetime subthreshold hypomanic
symptoms may have more complex illness and
less favorable course and outcome
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Low Level of Agreement on the Diagnostic Phenotype of
MDD: Mixed Features Point of Confusion
Pooled data presented from DSM-5 field trials sites, except for the diagnosis of complex
somatic symptoms disorder revised, hoarding disorder, binge eating disorder, schizoaffective
disorder, attenuated psychotic symptoms syndrome, bipolar II disorder, obsessive–compulsive
disorder, antisocial personality disorder, and generalized anxiety disorder
Regier et al. Am J Psychiatry 2013;170:59-70;
Freedman et al. Am J Psychiatry 2013;170(1):1-5;
APA. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. 2013.
DSM-5: inter-rater reliability of diagnoses from the initial field trials (adult diagnoses)
Kappa
-0.004
0.20
0.21
0.28
0.31
0.36
0.40
0.40
0.46
0.46
0.48
0.50
0.54
0.56
0.56
0.59
0.61
0.67
0.78
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8
Mixed anxiety-depressive disorder
Generalized anxiety disorder
Antisocial personality disorder
Major depressive disorder
Obsessive–compulsive personality disorder
Mild traumatic brain injury
Bipolar II disorder
Alcohol use disorder
Attenuated psychotic symptoms syndrome
Schizophrenia
Mild neurocognitive disorder
Schizoaffective disorder
Borderline personality disorder
Binge eating disorder
Bipolar I disorder
Hoarding disorder
Complex somatic symptom disorder revised
Posttraumatic stress disorder
Major neurocognitive disorder
Adult diagnosis
Kappa:
Very good agreement
Good agreement
Questionable agreement
Unacceptable agreement
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Changes in New DSM-5 Criteria:
MDE With Mixed Features Specifier
• Elevated, expansive mood
• Inflated self-esteem or grandiosity
• More talkative than usual or pressure to keep talking
• Flight of ideas or racing thoughts
• Increase in energy or goal-directed activity (either socially, at work or
school, or sexually)
• Increased or excessive involvement in activities that have a high potential
for painful consequences (e.g., engaging in unrestrained buying sprees,
sexual indiscretions, or foolish business investments)
• Decreased need for sleep
Full criteria for an MDE and ≥3 of these manic symptoms
APA. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. 2013.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Anxiety Distress Specifier Also Frequently
Applies to BD and MDD
• With anxious distress:
– Feeling keyed up or
tense
– Difficulty concentrating
because of worry
– Fear that individual
might lose control of
him- or herself
– Mild: 2 symptoms
– Moderate: 3 symptoms
– Feeling unusually restless
– Fear that something awful
might happen
– Moderate-severe: 4-5
symptoms
– Severe: 4-5 symptoms +
motor agitation
APA. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. 2013.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Commonly Used Terminology
Diagnostic criteria
Describing patients
Mixed episode (DSM-IV)
State in which the full criteria for both
a manic and a depressive episode are met
simultaneously
Mixed features (DSM-5)
A specifier that can be added to manic,
hypomanic, or depressive episodes
e.g., "manic episode with mixed
(depressive) features"
Mixed mania/mania with
subsyndromal depression
Presence of depressive symptoms during
a manic episode
Mixed depression/depressive
episode with subsyndromal mania
Presence of manic symptoms during a
depressive episode
Manic/hypomanic episode with
depressive symptoms
MDE with hypomanic symptoms
MDE, major depressive episode.
APA. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Rev. 2000;
APA Diagnostic and Statistical Manual of Mental Disorders. 5th ed. 2013.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
DSM-5: Not Included in Mixed Specifier
Symptoms that could overlap on either pole:
• Distractibility
• Irritability
• Insomnia or hypersomnia per se
• Indecisiveness
• Anxiety
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Probabilistic Approach to
Bipolar Depression
Confirmation of specific numbers requires further study.
OR = odds ratio from Othmer E et al. J Clin Psychiatry 2007;68(1):47-51.
Mitchell PB et al. Bipolar Disord 2008;10(1, pt 2):144-52.
Bipolar I depression more likely if ≥5:
Symptomatology
Hypersomnia
Hyperphagia
Psychomotor retardation
Other "atypical" symptoms
Psychosis and/or pathological guilt (OR=3.3)
Mood lability or manic symptoms
Onset and Course
Earlier onset (<25 years) (OR=1.9)
Multiple (≥5) depressive episodes
Family History
Bipolar disorder (OR=2.6)
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
TEM, treatment-emergent mania; ADR, antidepressant responder; ADNR, antidepressant non-responder.
Subsyndromal Hypomanic Symptoms
Increase Risk of Switching
Frye MA et al. Am J Psychiatry 2009;166(2):164-72.
*F(2,169) = 4.5; P < 0.01
YMRS Score
0
1
2
3
4
TEM (n = 44)
ADNR (n = 44)
ADR (n = 84)
5
*
†F(2,169) = 3.4; P = 0.04
CGI Severity Mania
0
0.4
0.8
1.2
1.6
2.0
†
TEM (n = 44)
ADNR (n = 494)
ADR (n = 84)
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Higher Risk for Treatment-Emergent
Affective Switching
• Bipolar I > bipolar II
• History of antidepressant-
induced mania
• Mixed depression
• Low TSH with TCA use
• Hyperthymic
temperament
• TCA or SNRI use
• Absence of antimanic
mood stabilizer
• Genetic factors
• Comorbid alcoholism
• Female gender +
comorbid anxiety disorder
SNRI, serotonin-norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant; TSH, thyroid-stimulating hormone.
Bond DJ et al. J Clin Psychiatry 2008;69:1589-1601; Frye MA et al. Am J Psychiatry 2009;166:164-
72; Salvadore G et al. J Clin Psychiatry 2010;71:1488-1501.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Obesity Changes Phenotype of Mood
Disorder
• Atypical features
• More severe (e.g., suicide risk)
• Poor cognitive performance
• Predominance of depressive symptoms
• More severe (e.g., suicide risk)
• Anxiety symptoms
• Poor cognitive performance
Obesity + MDD
Obesity + BD
Rosenblat and McIntyre, 2015.
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Antidepressant Use in
Bipolar Disorder
1. Adjunctive antidepressants for acute bipolar depression
a. Permissible if history of positive antidepressant response
b. Avoid in the presence of ≥2 core manic symptoms, psychomotor
agitation, or rapid cycling
2. Antidepressant monotherapy for acute bipolar depression
a. Avoid in bipolar I disorder
b. Avoid in bipolar II disorder in the presence of ≥2 core manic symptoms
3. Adjunctive antidepressants for bipolar maintenance
a. Permissible if patient relapses into depressive episode after stopping
antidepressant therapy
Pacchiarotti I et al. Am J Psychiatry 2013;170(11):1249-62; Vieta E.
Antidepressant Use in Bipolar Disorder: The ISBD Task Force Consensus Report.
Presented at International Conference on Bipolar Disorders. 2013.
See ISBD Task Force description at http://www.isbd.org/task-forces/past-task-forces.
ISBD Task Force Recommendations
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Antidepressant Use in
Bipolar Disorder (cont)
4. Antidepressant-Induced Switching to Mania/Hypomania or Mixed Features and
Rapid Cycling
a. Monitor patient and discontinue antidepressants in response to emergent mania,
hypomania, or psychomotor agitation
b. Discourage antidepressants if there is a history of antidepressant-emergent
mania/hypomania or mixed episodes
c. Avoid if there is high mood instability or a history of rapid cycling
5. Antidepressant Use in Mixed States
a. Avoid during manic or depressive episodes with mixed features
b. Avoid in patients with predominantly mixed states
c. Discontinue if a mixed state emerges
6. Antidepressant Classes and Increased Risk of Mood Switching (SNRIs and TCAs)
a. Permissible only after trials of other antidepressants tried and if patient is closely
monitored for switch or mood destabilization
See ISBD Task Force description at http://www.isbd.org/task-forces/past-task-forces.
Pacchiarotti I et al. Am J Psychiatry 2013;170(11):1249-62; Vieta E.
Antidepressant Use in Bipolar Disorder: The ISBD Task Force Consensus Report.
Presented at International Conference on Bipolar Disorders. 2013.
ISBD Task Force Recommendations
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Mixed Features Specifier Common in Bipolar
Depression
• 56.1% met the severity criterion (YMRS score ≥4) for mixed features
• (43.1%) met an alternative item-based criterion (YMRS score ≥2 on 2 or more items)
• Mixed features were more likely
• Female
• White
• Earlier age at onset of bipolar illness
• History of rapid cycling
• Higher baseline levels of anxiety
McIntyre RS et al. J Clin Psychiatry 2015;76(4):398-405.
YMRS, Young Mania Rating Scale.
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Lurasidone Effective in Bipolar Depression
With Hypomanic Symptoms (DSM-5 Specifier)
MADRS responder rates (6-week LOCF-endpoint):
groups with and without subsyndromal hypomania
Change from baseline in YMRS score groups with
and without subsyndromal hypomania
Lurasidone (20–120 mg/day) Lurasidone (20–120 mg/day)
**p<0.01
36
51.2 51.1 53.2
32.2 31.1
27.8
0
10
20
30
40
50
60
70
Subsyndromal hypomania
(baseline YMRS ≥4)
Subsyndromal hypomania (score of
≥2 for 2 or more YMRS items)
No subsyndromal hypomania
Lurasidone Placebo
** ** **
-2.4
-2.8
0.1
-2.3 -2.4
0.3
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
Subsyndromal hypomania
(baseline YMRS ≥4)
Subsyndromal hypomania (score of
≥2 for 2 or more YMRS items)
No subsyndromal hypomania
LS
mean Y
MR
S c
hange s
core
(W
eek 6
) Lurasidone
Placebo
Responder
rate
(%
)
McIntyre RS et al. J Clin Psychiatry 2015;76(4):398-405.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Extension
Study 306
(US Sites)
Placebo
Lurasidone 20–60 mg/day
6 Weeks
Screening
Baselin
e
3–14
Days
Day 1
Double-Blind Phase
Planned N=200 (100/arm)
Study dosing
Days 1–7: 20 mg/day
Days 8–43: flexible, 20–60 mg/day
FPI: Sep 2011
LPO: Oct 2014
12 Weeks
FPI, first patient in; LPO, last patient out; US, United States.
Suppes T et al. Am J Psychiatry 2015; Epub ahead of Print.
Lurasidone for the Treatment of Major Depressive Disorder
With Mixed Features: A Randomized, Double-Blind, Placebo-
Controlled Study
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Key Inclusion Criteria
• All patients (aged 18–75 years) were required to meet criteria for
major depressive disorder plus 2 or 3 of the following manic
symptoms (occurring on most days over the last 2 weeks or longer):
• Elevated, expansive mood
• Inflated self-esteem or grandiosity
• More talkative than usual or pressure to keep talking
• Flight of ideas or subjective experience that thoughts are racing
• Increase in energy or goal-directed activity (socially, at work or school, or
sexually)
• Increased or excessive involvement in activities that have a high potential for
painful consequences (e.g., engaging in unrestrained buying sprees, sexual
indiscretions, or foolish business investments)
• Decreased need for sleep (feeling rested despite sleeping less than usual; in
contrast to insomnia)
Suppes T et al. Am J Psychiatry 2015; Epub ahead of Print.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
*
**
***
***
******
-25.0
-20.0
-15.0
-10.0
-5.0
0.0
Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6
Placebo (N=100) Lurasidone (N=108)
LS
Mea
n C
han
ge
Fro
m B
ase
lin
e
BL mean = 33.2 BL mean = 33.3
*P<0.05; **P<0.01; ***P<0.001.
ITT population.
MADRS scale range, 0-60.
Mean daily dose of lurasidone was 36.2 mg/day.
Effect size = 0.8
-13.0
-20.5
Lurasidone Highly Effective in MDD With
Mixed Features
Suppes T et al. Am J Psychiatry 2015; Epub ahead of Print.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Lurasidone Reduces Hypomanic Severity
in Adults With MDD and Mixed Features
-4.7
-7.0**
-10.0
-5.0
0.0
Placebo (N=100) Lurasidone (N=108)
Mean
Ch
an
ge F
rom
Baselin
e
BL mean = 10.3
BL mean = 11.1
**P<0.01.
YMRS, Young Mania Rating Scale.
Suppes T et al. Am J Psychiatry 2015; Epub ahead of Print.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Lurasidone Reduces Anxiety Severity in
Adults With MDD and Mixed Features
-5.6
-9.9***
-15.0
-10.0
-5.0
0.0
Placebo (n=99) Lurasidone (n=106)
Mean
Ch
an
ge F
rom
Baselin
e
BL mean = 16.7
BL mean = 17.0 ***P<0.001
HAM-A, Hamilton Anxiety Rating Scale.
HAM-A, Hamilton Anxiety Rating Scale.
Suppes T et al. Am J Psychiatry 2015; Epub ahead of Print.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Lurasidone Reduces Global Illness Severity in
Adults With MDD and Mixed Features
-6.4
-10.7***
-15.0
-10.0
-5.0
0.0
Placebo (n=80) Lurasidone (n=80)
Mean
Ch
an
ge F
rom
Baselin
e
BL mean = 20.5
BL mean = 19.9
***P<0.001.
SDS, Sheehan Disability Scale.
Suppes T et al. Am J Psychiatry 2015; Epub ahead of Print.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Olanzapine Monotherapy Is Efficacious in the
Treatment of Bipolar Depression With Mixed Features
Remission rate by mixed features category. Abbreviation: NNT=number needed to treat. Mixed feature was defined by the number of baseline Young Mania Rating Scale items with scores ≥1. Remission was defined as the patient whose Montgomery–Åsberg Depression Rating Scale total score was ≤12 at 6 weeks. Treatment comparison p-values are from Fisher׳s exact test. Interaction p-values are from the Breslow–Day test.
Tohen M et al. J Affective Disord 2014;164:57-62.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Bipolar I and II Depression: Quetiapine XR
-25
-20
-15
-10
-5
00 1 2 3 4 5 6 7 8
Quetiapine XR 300 mg/day (n=133)
Placebo (n=137)
Week
LS
M C
han
ge F
rom
Baselin
e
MA
DR
S T
ota
l S
co
re
Imp
rovem
en
t
***
***P<0.001 vs. placebo
XR, extended release.
*** ***
*** *** *** *** ***
Suppes T. J Affective Disord 2010;121:106.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
6-Week, Randomized, Double-Blind, Placebo-Controlled Trial
of Ziprasidone for the Acute Depressive Mixed State
Patkar A et al. PLOS ONE 2012;7(4):e34757.
Ziprasidone vs. placebo: 6-week change in MADRS from baseline. Error bars indicate standard deviation. Treatment response by categorical group was 52.9% for ziprasidone vs. 28.9% for placebo (χ2 = 4.29, df = 1, p = 0.04). Treatment remission by categorical group was 50.0% for ziprasidone vs. 18.4% for placebo (χ2 = 8.05, df = 1, p = 0.0045).
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Asenapine in Mania With Depressive
Symptoms (DSM-5 Specifier)
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.
McIntyre et al. J Affective Disord 2013;150(2):378-83.
*p≤0.05, **p≤0.01 vs. placebo
Placebo (n=69)
Asenapine (n=113)
Olanzapine (n=132)
0
10
20
30
40
50
60
70 *
0
10
20
30
40
50
60
70
0
10
20
30
40
50
60
70
Placebo (n=12)
Asenapine (n=12)
Olanzapine (n=16)
** *
Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms
Improvement of depressive symptoms at Week 3
Re
mis
sio
n r
ate
(%
)
Re
mis
sio
n r
ate
(%
)
Re
mis
sio
n r
ate
(%
)
Placebo (n=40)
Asenapine (n=56)
Olanzapine (n=66)
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Adverse Effect Profiles for Atypical
Antipsychotics
Number of + symbols signifies extent of adverse event; 0 neutral
EPS: extrapyramidal symptoms; CLZ: clozapine; ILE: iloperidone; OLZ: olanzapine; RIS: risperidone; QUE: quetiapine; ZIP: ziprasidone; ARI: aripiprazole; ASE: asenapine; LUR: lurasidone.
Cha D, McIntyre RS. Expert Opin Pharmacother 2012;13(11):1587-98.
Adverse Event ARI ASE CLZ ILE LUR OLZ QUE RIS ZIP
METABOLIC
Weight gain
Dyslipidemia
Glucose dysregulation
+/0
0
0
+/0
0
0
++++
++
++
++
0
0
+/0
0
0
+++
+++
++
++
+
+
++
+
+
+/0
0
0
NEUROLOGICAL
Somnolence/sedation
EPS
+
+
0/+
0
++++
0
+
0
0
0/+
+++
+
+++
0
++
++
+
+
CARDIOVASCULAR Myocarditis/cardiomyopathy
QTc prolongation
0
0
0
0
+/0
+/0
0
+
0
0
0
+/0
0
+
0
+/0
0
+
HORMONAL
Prolactin
0
0
0
0
0
+/0
0
++
0
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Goldberg et al. Am J Psychiatry 2007;164(9):1348-55.
N=145 w/AD
N=190 w/o AD
355 STEP-BD entrants with major depression + 1 or more manic symptoms
No Faster Recovery From Mixed Depression in Bipolar Disorder
When Antidepressants Are Added to Mood Stabilizers (STEP-BD)
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Treatment-Resistant Bipolar Depression: Randomized
Controlled Trial of Electroconvulsive Therapy vs.
Algorithm-Based Pharmacological Treatment
FIGURE 2. Change in Depression Severity in Patients With Treatment-Resistant Bipolar
Depression Randomly Assigned to ECT or Algorithm-Based Pharmacological Therapy
A linear mixed-effects analysis showed that the mean score at 6 weeks was 6.6 points lower in the ECT group (SE=2.05, 95% CI=2.5–10.6, p=0.002).
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
LEVEL 1A: Established efficacy* Quetiapine monotherapy (bipolar disorder I & II) Lurasidone monotherapy (bipolar disorder I) Lurasidone or quetiapine adjunctive to lithium or divalproex (bipolar disorder I)
LEVEL 1B: Established efficacy, but with safety concerns* Olanzapine + fluoxetine (bipolar disorder I) *Tolerability limitations include sedation and weight gain
LEVEL 2: Established tolerability, but limited efficacy* Consult specialist Lithium (bipolar disorder I) Lamotrigine adjunctive to lithium (bipolar disorder I) Lamotrigine (bipolar disorder I) 2-drug combination of above medications *Efficacy limitations include negative randomized controlled trials but positive meta-analyses
Treatment of Acute Bipolar Depression
Florida Medicaid Drug Therapy Management Program for Behavioral Health. 2014.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
LEVEL 3: If levels 1 and 2 are ineffective or treatment not tolerated* Electroconvulsive therapy (ECT) *Consideration merited due to clinical need, despite even greater efficacy/tolerability limitations than level 1 and 2 treatments
LEVEL 4: If levels 1-3 are ineffective or if treatment is not tolerated Transcranial magnetic stimulation (TMS) Antimanic therapy + (FDA-approved medication for major depression)* Pramipexole Adjunctive: modafinil, thyroid, or stimulants 3-drug combination *There is inadequate information, including negative trials, to recommend adjunctive antidepressants, aripiprazole, ziprasidone, levetiracetam, armodafinil, or omega-3 fatty acids for bipolar depression
Treatment of Acute Bipolar Depression
Florida Medicaid Drug Therapy Management Program for Behavioral Health. 2014.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Summary
• Mood disorders are multidimensional
• Zone of delimitation (i.e., division point) between bipolar disorder and MDD does not exist organically
• MDD has prominent hypomanic features
• Antidepressants are hazardous when treating MDE with hypomanic features
• Antipsychotics are preferred in treating MDE with hypomanic features