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Update on Depression and Mixed Symptoms
Trisha Suppes, MD, Ph.D. Stanford University School of Medicine
VA Palo Alto Health Care System Palo Alto, California
Mood Disorder Day, 2016
Disclosures 2015–2016 • Sources of funding research: NIMH; Sunovion PharmaceuJcals Inc,
Elan Pharma InternaJonal Limited, VA CSP, Pathway Genomics, Stanley Medical
• ConsulJng agreements/speaking engagements: Sunovion PharmaceuJcals Inc, H. Lundbeck A/S, Merck & Co
• ConJnuing medical educaJon: Medscape, Global Medical EducaJon, CMEology
• Speakers bureaus: None
• RoyalJes: Jones & BartleW, UpToDate
• Travel: H. Lundbeck A/S, Sunovion PharmaceuJcals Inc, Merck & Co
• Financial interests/stock ownership: None
This presentaJon contains off-‐licence material for full exchange of scienJfic informaJon
What Was Wrong With the DSM-‐IV Criteria for Mixed Episode?
3
Spectrum of Mixed States Ma
nic S
ympt
oms
Depressive Symptoms
Classic Manic Episode
Euthymia MDE
DSM-IV Mixed
Episode
History of Mixed States
• Jules Falret (1861): First to use term “mixed state” • Mixed episodes were recognized by Weygandt and Kraepelin in 1899
• • DSM-‐IV (1994): Requires coexistence of the full symptomatology of a manic and depressive episode
• Other descripJons include: depressive or anxious mania, excited depression, and agitated depression
5 Swann , et al. Am J Psychiatry 2013; 170: 31-‐42; Angst J, et al. Biol Psychiatry 2000;48(6):445-‐457; Montgomery SA, et al. J Affect Disord. 2000;59(suppl 1):539-‐556; DSM-‐IV®-‐TR, APA, 2000.
Bipolar I disorder is a dimensional disease
Mania Mania with
depressive symptoms Depression
Normal fluctua=on
Mania
Depression
Kraepelin. Psychiatrie: Ein Lehrbuch für Studierende und Ärzte, Psychiatrie. 6th ed., Leipzig; 1899; Weygandt. Über die Mischzustände des
Manisch-‐depressiven Irreseins, Munich; 1899 6
Bipolar disorder – symptoms
Hopelessness
Loss of energy
Diminished pleasure
Suicidal thoughts
Dysphoria
Depressed mood
Worthlessness
High ac=vity/energy level
Diminished need for sleep
Elevated mood Disordered thoughts
Euphoria
Extremely talka=ve
Impulsivity
Anxiety
Irritability Agita=on
Insomnia
7
Consequences of not recognizing Mixed Symptoms – problems w DSM-‐IV
• UnderesJmaJon of suicide risk
• Inappropriate treatment selecJon
• Failure to idenJfy those with unipolar disorder at increased risk of progression to bipolar disorder
8
29.8
66.7
10.7
46.7
0
20
40
60
80
PaJe
nts (%)
PaJents with depressive symptoms in manic episodes have a higher suicide risk than those with pure manic episodes
ValenJ M et al. Bipolar Disord 2011;13:145-‐54
Non-‐mixed bipolar disorder
Mixed bipolar disorder
(n=60) (n=84)
Non-‐mixed bipolar disorder
Mixed bipolar disorder
(n=60) (n=84)
Suicidal ideaJon Suicide aWempts
***p<0.001
***
***
Suicidal ideaJon and suicide aWempts in bipolar disorder
A study of 144 paJents with bipolar disorder followed for ≤20 years
How did we get to DSM 5
• Long history in European case series and reports of mixed symptoms not being confined to manic episodes
• We just needed the data to demonstrate this
4925 visits 448 visits 596 visits 8359 visits
Depressed Hypomanic* Mixed Hypomanic Euthymic
IDS-‐C >=15 YMRS <12 YMRS >=12 YMRS>=12
IDS-‐C >=15 IDS-‐C <15 YMRS <12
Series1 34 3.1 4.2 58
0 10 20 30 40 50 60
Percen
t of T
otal Visits
*Does not include Mixed Hypomania Suppes et al. Arch Gen Psychiatry 2005; 62: 1089-1096.
Prevalence of Mixed Hypomania n=14,328 visits in 908 PaJents
11
“The cheerful and mournful or anxious mood are not simple opposites that are mutually
exclusive, but they may mix with each other in the most different
ways”
Emil Kraepelin, 1921
12
MDD/Mixed: A Conceptual Model
MDD BP II BP I
Bipolar Disorder Unipolar/MDD
BPI, bipolar I disorder; BPII, bipolar II disorder; MDE, major depressive episode.
MDE
MDD With Mixed Features
13
Prevalence of DSM-‐5 Mixed Features* During Major Depressive Episodes
0
5
10
15
20
25
30
35
40
MDD (n=149) BP I (n=65) BP II (n=49)
InternaJonal Mood Disorders CollaboraJve Project
McIntyre RS, et al. J Affect Disorders. 2015; 172C: 259–264
* DSM-‐5 Mixed Features specifier defined via extracJng YMRS, MADRS or HAM-‐D items
% 26.0%
34.0% 33.8%
Ziprasidone treatment in depressive mixed states in bipolar disorder type II or MDD
Patkar A et al. PLoS One 2012;7:e34757.
Change from baseline in MADRS score
MADRS, Montgomery–Åsberg Depression Ra=ng Scale; MDD, major depressive disorder
Placebo (n=38)
Ziprasidone (n=35)
-‐2
0
-‐4
-‐6
-‐8
-‐10
-‐12
-‐14 Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 0
Mean chan
ge M
ADRS
from
baseline
***
*
*
*p<0.05 vs. placebo; **p<0.001 vs. placebo
Lurasidone in MDD with mixed features: Change in MADRS total score
-‐25.0
-‐20.0
-‐15.0
-‐10.0
-‐5.0
0.0 Baseline Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Wk 6
LS, least squares; MADRS, Montgomery–Åsberg Depression Ra=ng Scale;
MDD, major depressive disorder
Effect size = 0.80
Suppes T et al. Am J Psychiatry 2016;173:400–7.
LS m
ean chan
ge from
baseline
*p<0.05; **p<0.01; ***p<0.001
***
***
***
***
**
*
Baseline mean = 33.2 Baseline mean = 33.3
Placebo (n=100) Lurasidone (n=108)
Do AnJdepressants Worsen MDD-‐MF?
0
10
20
30
40
50
60
Mixed Features (+) Mixed Features (-‐)
RetrospecJve history of anJdepressant-‐induced mania/hypomania in BRIDGE-‐II-‐Mix Study
%
Perugi et al., Acta Psychiatr Scand 2015 Jun 12. doi: 10.1111/acps.12457. [Epub ahead of print]
n=52 n=135
53.8 %
26.7%
OR=3.21 (95% CI=1.65-‐6.24)
p<.0001
VA Palo Alto Bipolar and Depression Research Program; CCR; and CSP NODES Staff
TRISHA SUPPES, MD, PHD MICHAEL OSTACHER, MD, MPH GRACE FISCHER, BS ELENA NIKOLAEV DAVID GRIMM, BA, BS JEFF NAGY, MS, MHA VICTORIA COSGROVE, PHD KARISHMA RAJU KAREN BRATCHER, RN, MSN ALDA VICENCIO, RN, BSN AMI PATEL, MPH PERRIN FRENCH, MD
• If full criteria are met for a manic episode or hypomanic episode and at least 3 of the following symptoms are present during the majority of days of the current or most recent episode of mania or hypomania (last 1 week or 4 days):
29 American Psychiatric AssociaJon: DiagnosJc and StaJsJcal Manual of Mental Disorders, Fi}h EdiJon. Arlington, VA, American Psychiatric AssociaJon, 2013.
DSM-‐5: Mixed Specifier With Depressive Features
DSM-‐5: Mixed Specifier With Depressive Features
• Prominent dysphoria or depressed mood • Diminished interest or pleasure in all acJviJes • Psychomotor retardaJon • FaJgue or loss of energy • Feelings of worthlessness or excessive/inappropriate guilt
• Suicidal ideaJon, aWempt, or plan
30 American Psychiatric AssociaJon: DiagnosJc and StaJsJcal Manual of Mental Disorders, Fi}h EdiJon. Arlington, VA, American Psychiatric AssociaJon, 2013.
Mixed Specifier With Hypomanic Features
• If predominantly Depressed, full criteria are met for a Major Depressive Episode and at least 3 of the following symptoms are present nearly every day during the episode:
31 Reprinted with permission from the DiagnosJc and StaJsJcal Manual of Mental Disorders, Fi}h EdiJon, (Copyright (c) 2013). American Psychiatric AssociaJon. All rights reserved.
Mixed Specifier With Hypomanic Features
• Elevated, expansive mood • Inflated self-‐esteem or grandiosity • More talkaJve or pressured speech • Flight of ideas or thoughts are racing • Increase in energy or goal-‐directed acJvity • Increased acJviJes that have a high potenJal for painful consequences
• Decreased need for sleep
32
Not Included in Mixed Specifier
Symptoms that could overlap on either pole: • DistracJbility • Irritability • Insomnia or hypersomnia per se • Indecisiveness • AgitaJon
3
Irritability group: Lurasidone (n=22) Baseline mean = 34.0
Lurasidone (n=86) Baseline mean = 33.0
Placebo (n=21) Baseline mean = 34.2
Placebo (n=79) Baseline mean = 33.1
Non-‐irritability group:
Effect size = 0.66
Effect size = 1.41
Lurasidone in MDD with mixed features: Efficacy with high levels of irritability
Irritability criteria: YMRS items 5 & 9 ≥2 LS, least squares; MADRS, Montgomery–Åsberg Depression Ra=ng Scale; MDD, major depressive disorder Swann AC et al. Presented at APA 2016, Atlanta, GA, USA; 14–18 May 2016.
0
-‐5
-‐10
-‐15
-‐20
-‐25
Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Baseline
*p<0.05; **p<0.01; ***p<0.001
LS m
ean chan
ge in
MAD
RS to
tal score
***
***
*** ***
***
**
*
*
**
***
Lurasidone in MDD with mixed features: Nature of manic symptoms
0 10 20 30 40 50 60 70 80
Inflated self esteem
Increased involvement in risky ac=vi=es
Elevated mood
Increased energy
Decreased need for sleep
Pressured speech
Flight of ideas
Suppes T et al. Am J Psychiatry 2016;173:400–7. MDD, major depressive disorder
Pa=ents (%)
19.4% 14.9%
7.3%
58.4%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
Percen
tage of T
otal Visits
2774
Pure Dep. (YMRS≤2; IDS-‐C≥15)
2139
Mixed Dep. (2<YMRS<12; IDS-‐C≥15)
1045
Hypomania/ Mania
(YMRS≥12)
8352
Euthymia (YMRS<12; IDS-‐C<15)
Number of Visits
Mood States During 14,310 Visits
Mood State
33.3 35.9
27.3
48.7 45.6
57.6
0
10
20
30
40
50
60
70
Total Non-‐Mixed Mixed
Placebo
Olanzapine
Olanzapine in bipolar I depression with manic symptoms
Tohen M et al. J Affect Disord 2014;164:57–62.
InteracJon p=0.045
Percen
tage of p
a=en
ts in re
mission
p=0.001 p=0.089 p<0.001
n=219 n=228 n=153 n=169 n=66 n=59
Lurasidone treatment of bipolar depression with subsyndromal hypomania: Post hoc analysis
Change from baseline in MADRS score (MMRM; mITT)
McIntyre RS et al. J Clin Psychiatry 2015;76:398–405. LS, least squares; MADRS, Montgomery–Åsberg Depression Ra=ng Scale;
mITT, modified inten=on-‐to-‐treat; MMRM, mixed model for repeated measures
Week 1 Baseline Week 2 Week 3 Week 4 Week 5 Week 6
0
-‐2
-‐4
-‐6
-‐8
-‐10
-‐12
-‐14
-‐16
-‐18
***
*** **
**
*
*
*
*
*
*
With mixed features lurasidone (n=182)
Without mixed features lurasidone (n=141)
With mixed features placebo (n=90)
Without mixed features placebo (n=72)
LS m
ean chan
ge in M
ADRS
score
*p<0.05; **p<0.01; ***p<0.001
Lurasidone Treatment of Bipolar Depression with Mixed Features: Post hoc analysis
McIntyre RS, et al. Clin Psychiatry. 2015;76(4):398-‐405.
Lurasidone for Major Depressive Disorder with Mixed Features
*p<0.05. **p<0.01. ***p<0.001.
ES=0.8
Mean dose=36.2 mg/day
Suppes T et al., AJP in Advance (doi: 10.1176/appi.ajp.2015.15060770)