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:


Learning Objectives

• Utilize evidence-based strategies to identify

patients with mixed depression

• Optimize treatment strategies for patients with

mixed depression


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


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)


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)


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


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


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


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)

http://www.google.co.uk/url?sa=i&rct=j&q=Kraepelin+bipolar&source=images&cd=&cad=rja&docid=4GLDOGyassH8AM&tbnid=bKVJFVGivNnJyM:&ved=0CAUQjRw&url=http://www.sciencemuseum.org.uk/broughttolife/people/emilkraepelin.aspx&ei=16SUUZiRJMnA0QWDmYDoCg&bvm=bv.46471029,d.ZWU&psig=AFQjCNE_TKP1-TKLra_1Wd8SUWEc0NH9-w&ust=1368782389018891


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.


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




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)


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


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.


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


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.


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


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


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


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


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


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.


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


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;


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


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



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



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. 5th ed. 2013.


DSM-5: Not Included in Mixed Specifier

Symptoms that could overlap on either pole:

• Distractibility

• Irritability

• Insomnia or hypersomnia per se

• Indecisiveness

• Anxiety


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)


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)


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.


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.


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


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


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.


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.


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


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)



*

**

***

***

******

-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



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.



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.



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.



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.


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.


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).


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)


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


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)


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).


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.


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.


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

fixing the mix-up over mixed depression

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