Handout for the Neuroscience Education Institute (NEI) online activity:

Mood Disorders:
A "Spectrum" Analysis
 Learning Objectives

Utilize evidence-based strategies to identify

where patients lie on the mood disorder
spectrum
Optimize treatment strategies for patients based
on where they lie along the mood disorder
spectrum
 PrePoll Question

How many patients do you see with symptoms of

mixed depression each week?

1. 0
2. 1-5
3. 6-10
4. 11-15
5. 16-20
6. 21 or more
 Pretest Question 1

Sarah is a 20-year-old patient who presents with symptoms of

depression (including sadness, feelings of worthlessness, and
suicidal ideation) occurring every day for the past month. Which
class of medication would be most suitable for this patient?

1. An antidepressant
2. A mood stabilizer
3. An antipsychotic
4. Either 1 or 2
5. There is not enough information about this patient's case to
make an informed treatment decision
 Pretest Question 2

Clinical interview with Sarah reveals that she has a maternal

aunt with bipolar disorder I. Further assessment reveals that
Sarah feels distracted and as though her thoughts are racing.
Upon speaking with her mother, it is discovered that Sarah has
at times been more talkative than usual and irritable with her
friends and family. Which class of medication would NOT be
recommended as monotherapy for this patient?

1. An antidepressant
2. A mood stabilizer
3. An antipsychotic
4. There is not enough information about this patient's case to
make an informed treatment decision
 Pretest Question 3

Stacey is a 25-year-old patient with bipolar depression who

tends to endorse some manic symptoms during depressive
episodes. Of the following symptoms, which is the most common
subsyndromal mania symptom in patients with mixed
depression?

1. Decreased need for sleep

2. Inflated self-esteem
3. Distractibility
4. Increased goal-directed activity
5. High-risk activity
 Pretest Question 4

A 33-year-old obese patient with treatment-resistant depression

has agreed to a trial of an atypical antipsychotic. Considering
this patient's current weight and the wish to avoid any treatment-
induced weight gain, which of the following approved treatments
would be the least optimal treatment for this patient?

1. Lurasidone
2. Olanzapine/fluoxetine combination
3. Quetiapine
 The Mood Disorder Spectrum
Depression Depression with Mixed Mania with Mania
subsyndromal mania states subsyndromal depression

Increasing #/severity of manic symptoms Increasing #/severity of depressive symptoms

Although categorical classifications may be useful for

clinical practice, the overwhelming majority of the
evidence points to a dimensional (spectrum) view of
mood disorders
eg, treatment response (antidepressant vs. mood stabilizing
agent) and links with family history of BP
Individuals with unipolar depression and "a little bit of
mania" are more likely to have an eventual diagnostic
conversion to bipolar disorder
Benazzi F. Eur Psychiatry 2008;23:40-8; Hu J et al. Primary Care Companion CNS
Disord 2014;16(2):PCC.13r01599; Sato T et al. J Affective Disord 2004;81:103-13;
Vieta E, Valenti M. J Affective Disord 2013;148:28-36.
So You Think It's Unipolar Depression?

Over one-third of unipolar patients are eventually re-

diagnosed as bipolar
As many as 60% of patients with BPII are initially
diagnosed as unipolar
Presence of even subthreshold (hypo)mania
symptoms is strongly associated with conversion to
bipolar disorder
Each (hypo)mania symptom increases risk by ~30%

Akiskal HS, Benazzi. J Affective Disord 2003;73:113-22; Dudek D et al. J Affective

Disord 2013;144(1-2):112-5; Fiedorowicz JG et al. Am J Psychiatry 2011;168:40-8.
Progression to Bipolar Disorder From MDD
With Subthreshold Hypomania

Time to Hypomania or Mania <3 Manic symptoms

1.0 Time to Hypomania 1.0 3 Symptoms
Time to Mania

Hypomania or Mania
Hypomania or Mania

Proportion Without
Proportion Without

0.9

0.9
0.8

0.7
0.8

0.6

0.7 0.5
0 260 520 780 1040 1300 1560 0 260 520 780 1040 1300 1560
Weeks to Follow-up Weeks to Follow-up

19.6% of patients converted to bipolar disorder during follow-up

N=550 individuals followed for >1 year (mean follow-up: 17.5 years) after a diagnosis of major depression at intake.

Fiedorowicz JG et al. Am J Psychiatry 2011;168:40-8.

 Clues Across The Spectrum
Unipolar Bipolar
Family history of bipolar disorder

Early age at onset of first depressive episode (<25 years)

# of lifetime affective episodes

Clinical
History

Postpartum depressive episodes

# of hospitalizations

Rapid onset of depressive episodes

Greater severity of depressive episodes

Treatment
History

Worse response to antidepressants

Antidepressant-induced hypomania

Psychotic features

Atypical depressive symptoms

Symptoms

Subsyndromal hypomanic symptoms

Impulsivity
Aggression

Hostility

Comorbid SUD
Dervic K et al. Eur Psychiatry 2015;30(1):106-13; Angst J et al. Arch Gen Psychiatry 2011;68(8):791-9;
Musetti L et al. CNS Spectrums 2013;18(4):177-87.
Which Patients With Unipolar Depression Will
Convert to Bipolar Disorder?

Converters
32.8%

Non-Converters
67.2%

Dudek D et al. J Affective Disord 2013;144(1-2):112-5.

Which Patients With Unipolar Depression Will
Convert to Bipolar Disorder?

44
Age of Illness Onset (yrs)

42

40

38 *
36

34
Non-Converters Converters

Dudek D et al. J Affective Disord 2013;144(1-2):112-5.

Which Patients With Unipolar Depression Will
Convert to Bipolar Disorder?

*
8.5
# of Depressive Episodes

7.5

6.5

6
Non-Converters Converters

Dudek D et al. J Affective Disord 2013;144(1-2):112-5.

Which Patients With Unipolar Depression Will
Convert to Bipolar Disorder?

***
40
% of Patients Resistant
to Antidepressants

30

20

10

0
Non-Converters Converters

Dudek D et al. J Affective Disord 2013;144(1-2):112-5.

Which Patients With Unipolar Depression Will
Convert to Bipolar Disorder?

4 ***
3.5
# of Hospitalizations

3
2.5
2
1.5
1
0.5
0
Non-Converters Converters

Dudek D et al. J Affective Disord 2013;144(1-2):112-5.

Which Patients With Unipolar Depression Will
Convert to Bipolar Disorder?

30 ***
Psychiatric Hospital
Weeks Spent in a

25
20
15
10
5
0
Non-Converters Converters

Dudek D et al. J Affective Disord 2013;144(1-2):112-5.

DIAGNOSIS ALONG THE
SPECTRUM
 A Rose By Any Other Name
Depression Depression with Mixed Mania with Mania
subsyndromal mania states subsyndromal depression

Increasing #/severity of manic symptoms Increasing #/severity of depressive symptoms

"With mixed features" if subthreshold "With mixed features" if subthreshold

(hypo)manic symptoms co-occur depressive symptoms co-occur with
with depressive episodes manic episodes

Major Bipolar disorder II Bipolar disorder I

depressive
disorder
(unipolar
depression) DSM-5
DIAGNOSIS
 Evolution of the DSM

DSM-IV mixed episode

Diagnostic criteria for major depression and mania
met at the same time
DSM-5 mixed features specifier
Recognizes the presence of subthreshold
(hypo)manic symptoms during a depressive episode
Specifier may be applied to major depressive
disorder, bipolar II, or bipolar I

APA Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Rev. 2000;
APA Diagnostic and Statistical Manual of Mental Disorders. 5th ed. 2013.
 DSM-5 Mixed Features Specifier

Full criteria for a MDE and 3 of these manic symptoms:

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 (socially, at work or
school, or sexually)
Increased or excessive involvement in activities that have a high
potential for painful consequences (eg, engaging in unrestrained
buying sprees, sexual indiscretions, foolish business investments)
Decreased need for sleep

Diagnosis may be complicated by comorbid conditions, including

untreated ADHD, personality disorders, and substance abuse
APA Diagnostic and Statistical Manual of Mental Disorders. 5th ed. 2013.
Mixed Features: The Exception or the Rule?

Mixed Features Commonly Encountered in Adults With Both

Major Depressive Disorder and Bipolar Disorder:
The International Mood Disorders Collaborative Project

% of Individuals Who Met Criteria For Mixed Features During

an Index Major Depressive Episode

34.0% 33.8%
26.0%

n=149 n=65 n=49

MDD BPII BPI

McIntyre RS et al. J Affective Disord 2015;172C:259-64.

Depression With Mixed Features (DMX)

Associated with:
Family history of BP
Suicidality
Antidepressant-induced The prognosis for depression
mania with co-occurring
Young age of onset (hypo)mania (DMX) is much
Long duration of illness worse than for pure unipolar
Poor prognosis depression or bipolar
Severe depression depression without mixed
Antidepressant resistance features
Females
Comorbid anxiety
Comorbid SUD
Impulse control
Akiskal HS, Benazzi F. J Affective Disord 2003;73:113-22; Angst J et al. Am J
Psychiatry 2010;167:1194-201; Goldberg JF et al. Am J Psychiatry 2009;166:173-81.
Symptoms Most Commonly Seen in DMX

Irritability Rumination
Distractibility Initial or middle insomnia
Psychomotor agitation Dramatic expressions of
Racing/crowded suffering
thoughts Impulsivity
Increased talkativeness Risky behaviors
Emotional lability

Akiskal HS, Banazzi F. J Affective Disord 2005;8:245-58; Benazzi F, Akiskal HS. Psychiatry Res
2006;141:81-8; Koukopoulos A, Sani G. Acta Psychiatr Scand 2014;129:4-16; Faedda GL et al. J Affective
Disord 2015;176:18-23; Goldberg JF et al. Am J Psychiatry 2009;166:173-81; Olgiati P et al. Depression
Anxiety 2006;23:389-97; Maj M. J Clin Psychiatry 2015;76(3):e381-2; Perugi G et al. J Clin Psychiatry
2015;76(3):e351-8; Sani G et al. J Affective Disord 2014;164:14-8; Suppes T et al. Am J Psychiatry 2015;
Epub ahead of print; Takeshima M, Oka T. Psychiatry Clin Neurosci 2015;68:109-16.
Symptoms Most Commonly Seen in DMX

60
Patients With DMX
Frequency Among

50

40

30

20

10

Takeshima M, Oka T. Psychiatry Clin Neurosci 2015;69(2):109-16.

 DMX Diagnostic Criteria

Although irritability, distractibility, and

psychomotor agitation are among the
most common symptoms of DMX, they
are excluded from DSM-5 mixed features
criteria due to the overlap of these
symptoms with other disorders (eg,
anxiety disorders) and between mania
and depression
Some argue that these 3 particular
symptoms are the defining features of
DMX and that excluding them will lead to
misdiagnosis and dangerous treatment
strategies
Imagine if we excluded psychosis as a
diagnostic feature of schizophrenia?

Takeshima M, Oka T. Psychiatry Clin Neurosci 2015;69(2):109-16; Koukopoulos A, Sani G.

Acta Psychiatr Scand 2014;129:4-16; Mahli GS et al. J Affective Disord 2014;158:8-10.
 Non-DSM Criteria for DMX

Do not exclude agitation, irritability, or distractibility

Benazzi criteria
Koukopoulos criteria
Research-based diagnostic criteria
Consider family history
Consider age of onset of depression

Koukopoulos A, Sani G. Acta Psychiatr Scand 2014;129:4-16; Benazzi F. Eur

Psychiatry 2008;23:40-8; Mahli GS et al. J Affective Disord 2014;158:8-10; Takeshima
M, Oka T. Psychiatry Clin Neurosci 2015;69(2):109-16; Perugi G et al. J Clin Psychiatry
2015;76(3):e351-8.
 Non-DSM Criteria for DMX
4X as many cases of DMX identified using
research-based diagnostic criteria
30%

29.1%
% of Depressed Patients Identified as DMX

25%

20%

15%

7.5%
10%

5%

0%
DSM-5 CRITERIA RBDC CRITERIA

Perugi G et al. J Clin Psychiatry 2015;76(3):e351-8.

 Non-DSM Criteria for DMX

All patients
100% 100.0%
identified as
90% 87.2% ~10% of patients
DMX will indeed
80%
have DMX identified as
70%
DMX will not
HOWEVER, 60% 55.1%
50%
actually have
%

Only 5.1% of DMX

40%
individuals who 30% Less than 50%
have DMX will 20% 5.1%
at risk of
be identified 10%
receiving
0%
~95% at risk of inappropriate
DSM-5 CRITERIA BENAZZI CRITERIA
receiving treatment
Specificity Sensitivity
Specificity Sensitivity
Sensitivity
inappropriate
treatment

Which is potentially more detrimental?

Misdiagnosing someone who is "pure unipolar" as DMX?
or
Treating unidentified DMX with antidepressants?
Benazzi F. Eur Psychiatry 2008;23:40-8; Takeshima M, Oka T. Psychiatry Clin Neurosci 2015;69(2):109-16.
 Consequences of Misdiagnosis/
Inappropriate Treatment

Years (often a decade or more) of unnecessary

suffering
Treatment resistance?
Reduced likelihood of responding to eventual
appropriate mood stabilizer treatment
Treatment-emergent activation syndrome
(TEAS)
Suicidality

.
 Treatment Resistance

Patients with DMX are less likely to respond to treatment-as-usual

for major depressive disorder
Diagnostic conversion from unipolar to bipolar is significantly related
to treatment resistance
As many as two-thirds of patients whose diagnosis is converted from
unipolar to bipolar disorder are treatment resistant
Approximately half of patients with treatment-resistant "unipolar"
depression may actually be bipolar
Repeated exposure to antidepressants may lead to resistance to
mood stabilizers and poorer outcomes in patients without "pure
unipolar" depression
It may also be that patients with more antidepressant trials were
always going to be resistant
Angst J et al. Am J Psychiatry 2010;167:1194-201; Dudek D et al. J Affective Disord 2013;144(1-
2):112-5; Sharma V et al. J Affective Disord 2005;84(2-3):251-7; Rihmer Z, Gonda X. Depression
Res Treatment 2011;2011:906426; Amsterdam JD, Shults J. J Affective Disord 2009;115(1-2):234-
40; Post RM et al. J Clin Psychiatry 2012;73(7):924-30.
Treatment-Emergent Activation Syndrome
(TEAS)

(Hypo)mania Over 20% of patients may experience

Agitation TEAS related to antidepressants
Most common with serotonin-
Anxiety
norepinephrine reuptake inhibitors
Panic attacks (SNRIs) and tricyclic antidepressants
Irritability (TCAs)
Hypothetically related to high
Hostility/aggression
noradrenergic potency
Impulsivity
The presence of even minor,
Insomnia subthreshold (hypo)mania during a
depressive episode increases the risk of
Suicidality
TEAS

Angst J et al. Arch Gen Psychiatry 2011;68(8):791-9; Fountoulakis KN et al. Eur Arch
Psychiatry Clin Neurosci 2012;262(suppl 1):S1-48; Post RM et al. J Clin Psychiatry
2012;73(7):924; Akiskal HS et al. J Affective Disord 2005;8:245-58.
 Higher Risk of TEAS

Bipolar I > bipolar II TCA or SNRI use

History of antidepressant- Absence of antimanic
induced mania mood stabilizer
Mixed depression Genetic factors
Low TSH with TCA use Comorbid alcoholism
Hyperthymic Female gender +
temperament comorbid anxiety disorder

TSH: thyroid-stimulating hormone.

Bond DJ et al. J Clin Psychiatry 2008;69:1589-601; Frye MA et al. Am J Psychiatry

2009;166:164-72; Salvadore G et al. J Clin Psychiatry 2010;71:1488-501.
 DMX and Suicidality

Non-euphoric (hypo)manic symptoms (including

psychomotor agitation, impulsivity, irritability, and
racing/crowded thoughts) combined with depressive
symptoms (ie, DMX) = recipe for suicidality
Presence of mixed features increases risk of suicidality
by 4X in both unipolar and bipolar depression
DMX may underlie the connection between
antidepressant use and suicidality
Most notably in the pediatric population, in which DMX is often
the rule rather than the exception
Both young age of onset of depression and DMX symptoms
indicate bipolarity
Akiskal HS, Benazzi F. Psychopathology 2005;38:273-80; Balazs J et al. J Affective Disord 2006;91:133-8;
Benazzi F. Lancet 2007;369:935-45; Olgiati P et al. Depression Anxiety 2006;23:389-97; Swann AC et al.
Bipolar Disord 2007;9(3):206-12; Rihmer Z, Gonda X. Depression Res Treatment 2011;2011:906426.
One of the Most Important Questions to
Ask Any Patient With Depression

Any
mania/hypomania
symptoms
and/or
family history of
bipolar disorder?

Every patient. Every time.

 DMX and Family History

Family history of BP
4X higher in DMX than in "pure" unipolar depression
Highly associated with patients who have 2+
(hypo)manic symptoms during major depressive
episodes (MDEs)
As common in DMX as in BP
Supports the idea of DMX as a "soft" bipolar disorder
and a dimensional rather than a categorical view of
mood disorders

Prieto ML et al. J Affective Disord 2015;172:355-60;

Axelson D et al. Am J Psychiatry 2015;172(7):638-46.
 Tools for Assessing DMX

See APPENDIX for more details on each

assessment tool
Bipolar Depression Rating Scale (BDRS)
Clinician-administered assessment of current symptoms
Mini International Neuropsychiatric Interview (MINI)
Patient self-report assessing current (hypo)manic symptoms
Clinically Useful Depression Outcome Scale with DSM-5
Mixed (CUDOS-M)
Patient self-report assessing current (hypo)manic symptoms
Hypomania Checklist (HCL-32)
Patient self-report that screens for lifetime (hypo)manic
symptoms
TREATMENT ALONG THE
SPECTRUM
 Major Depressive Episodes:
A Trace of Depression Means Treat With an Antidepressant

Mixed
States

Mania with Depression with

subsyndromal subsyndromal
depression mania

Mania Depression
 Major Depressive Episodes:
A Trace of Mania Means Treat With an Antipsychotic

Mixed
States

Mania with Depression with

subsyndromal subsyndromal
depression mania

Mania Depression
 Issues With Existing
Treatment Guidelines for DMX

Any existing guidelines (and FDA approvals) for mixed

bipolar disorder refer to DSM-IV criteria (co-occurring
threshold-level MDE + threshold-level mania)
Recommendations are to treat as mania
A diagnosis of MDD implies the use of unipolar
depression treatment guidelines
Possibly ineffective and potentially harmful
Treatment guidelines for bipolar depression are likely the
most applicable to DMX
Many are not up to date with the latest clinical trial data (ie,
atypical antipsychotics with mood-stabilizing properties)
Very few studies have yet to focus specifically on DMX
.
 Bipolar Spectrum-Based First-Line
Monotherapy Treatment Recommendations
Depression Depression with Mixed Mania with Mania
subsyndromal mania states subsyndromal depression

Increasing #/severity of manic symptoms Increasing #/severity of depressive symptoms

Unipolar depression?
Bipolar disorder?
Only those patients Does it matter in terms of choosing the best treatment?
with essentially NO
symptoms of
(hypo)mania should
Mood
be considered for
antidepressant Stabilizer
monotherapy
Atypical
Antipsychotic

Antidepressant
 Treatment Algorithm for
Depression Without Mixed
Features
Any
mania/hypomania
Antidepressant symptoms and/or Yes
No
monotherapy family history of
BP?

Therapeutic Any
mania/hypomania
response to Yes
Yes No symptoms and/or
antidepressant family history of
monotherapy? BP?
See DMX
Any
treatment
mania/hypomania guidelines
symptoms and/or Yes
family history of
BP?

Follow APA
treatment
No Continue guidelines but
antidepressant consider DMX
monotherapy treatment
No guidelines

Switch to Resistant to 2
alternate antidepressant
antidepressant monotherapy
monotherapy trials
Treatment Algorithm for
Depression With Mixed
Features (DMX)

Discontinue/taper Patient on antidepressant

Yes No
antidepressant monotherapy?

Initiate atypical Therapeutic

antipsychotic response?

Add or switch to
mood stabilizer
Therapeutic
No or switch to No
response?
different atypical
antipsychotic

Add Therapeutic
Yes
antidepressant response?

No
Continue as
maintenance
Consider ECT and therapy
novel/experimental options
 Atypical Antipsychotics
Evidence of FDA- FDA- FDA- FDA-
Efficacy in Approved for Approved for Approved for Approved for
DMX BP BP BP MDD
Depression Mania Maintenance
Aripiprazole (adjunct)
Asenapine
Lurasidone
Olanzapine
(with fluoxetine) (with fluoxetine)

Quetiapine (adjunct)
Risperidone
Ziprasidone
Cerullo M et al. CNS Spectrums 2013;18(4):199-208; Fountoulakis KN et al. Eur Arch Psychiatry
Clin Neurosci 2012;262(suppl 1):S1-48; Fountoulakis KN et al. Int J Neuropsychopharmacol
2012;15:1015-26; Grunze H, Azorin JM. World J Biol Psychiatry 2014;15(5):355-68; Vieta E, Valenti
M. J Affective Disord 2013;148:28-36; Fornaro M et al. Int J Mol Sci 2016;17(2):241.
doi:10.3390/ijms17020241; Stahl SM. Prescriber's Guide. 5th ed. Cambridge University; 2014.
 Asenapine in DMX

Berk M et al. J Clin Psychiatry 2015;76(6):728-34.

 Asenapine in Mania With Depressive
Symptoms (DSM-5 Specifier)
Improvement of depressive symptoms at Week 3
Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms
70 70 70
* ** *
60 60 60
Remission rate (%)

Remission rate (%)

Remission rate (%)

50 50 50

40 40 40

30 30 30

20 20 20

10 10 10

0 0 0
Placebo (n=69) Placebo (n=40) Placebo (n=12)
Asenapine (n=113) Asenapine (n=56) Asenapine (n=12)
Olanzapine (n=132) Olanzapine (n=66) Olanzapine (n=16)
*p0.05, **p0.01 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
items), 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.

 Lurasidone in Bipolar Depression With
Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint): Change from baseline in YMRS score groups with
groups with and without subsyndromal hypomania and without subsyndromal hypomania
70 0.5 0.3
Lurasidone Placebo 0.1

LS mean YMRS change score (Week 6)

60 0.0
** ** **
53.2
51.2 51.1
50 -0.5
Responder rate (%)

40 -1.0
32.2 31.1
30 27.8 -1.5

20 -2.0

10 -2.5 -2.3
-2.4 -2.4
Lurasidone

-2.8 Placebo
0 -3.0
Subsyndromal Subsyndromal No subsyndromal Subsyndromal Subsyndromal No subsyndromal
hypomania hypomania (score of hypomania hypomania hypomania (score of hypomania
(baseline YMRS 4) 2 for 2 or more (baseline YMRS 4) 2 for 2 or more
YMRS items) YMRS items)

Lurasidone (20120 mg/day) Lurasidone (20120 mg/day)

**p<0.01

49

McIntyre RS et al. J Clin Psychiatry 2015;76(4):398-405.

 Lurasidone Efficacy in DMX:
Montgomery-sberg Depression Scale (MADRS)

Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

0.0
LS Mean Change From Baseline

-5.0 Effect size = 0.8

*

-10.0
**
-13.0
-15.0 ***
***
-20.0 -20.5
***
***

-25.0
Placebo (N=100) Lurasidone (N=108)
BL mean = 33.3 BL mean = 33.2

*p<0.05; **p<0.01; ***p<0.001.

Mean daily dose of lurasidone was 36.2 mg/day.

Suppes T et al. Am J Psychiatry 2016;173(4):400-7.

 Lurasidone Efficacy in DMX:
Young Mania Rating Scale (YMRS)

Placebo (N=100) Lurasidone (N=108)

0.0
Mean Change From Baseline

-5.0
-4.9

-7.0**
BL mean = 10.3
BL mean = 11.1
-10.0
**p<0.01

Suppes T et al. Am J Psychiatry 2016;173(4):400-7.

 Lurasidone Efficacy in DMX:
Hamilton Anxiety Rating Scale (HAM-A)

Placebo (n=100) Lurasidone (n=108)

0.0
Mean Change From Baseline

-5.0
-5.4

BL mean = 16.7
-10.0
-9.9***

***p<0.001 BL mean = 17.0

-15.0

Suppes T et al. Am J Psychiatry 2016;173(4):400-7.

 Lurasidone Efficacy in DMX:
Sheehan Disability Scale (SDS)

Placebo (n=100) Lurasidone (n=108)

Mean Change From Baseline

0.0

-5.0

-6.4

-10.0

-11.2***
BL mean = 20.5
-15.0
BL mean = 19.9
***p<0.001

Suppes T et al. Am J Psychiatry 2016;173(4):400-7.

 Lurasidone Efficacy in DMX:
Suicide and TEAS
Treatment-Emergent Suicidal
Behavior
8
6
% of Patients

4
2
0 Treatment-Emergent Mania
PLACEBO LURASIDONE
6

% of Patients
4

0
PLACEBO LURASIDONE

Suppes T et al. Am J Psychiatry 2016;173(4):400-7.

Efficacy of Olanzapine Monotherapy in the Treatment
of Bipolar Depression With Mixed Features

* *

n=56 n=93 n=85 n=148 n=17 n=32

Tohen M et al. J Affective Disord 2014;164:57-62.

 Quetiapine Efficacy in DMX:
Clinical Global Impression (CGI-BD)

**p=0.002

Suppes T et al. J Affective Disord 2013;150(1):37-43.

Quetiapine Efficacy in DMX: MADRS

*p=0.0138

Suppes T et al. J Affective Disord 2013;150(1):37-43.

Quetiapine Efficacy in DMX: YMRS

Not significant
(p=0.069)

Suppes T et al. J Affective Disord 2013;150(1):37-43.

 Ziprasidone Monotherapy for DMX:
Improvement in Depressive Symptoms

Patkar A et al. PLOS ONE 2012;7(4):e34757.

 Ziprasidone Monotherapy for DMX:
No Improvement in Manic Symptoms

Patkar A et al. PLOS ONE 2012;7(4):e34757.

Tolerability of Atypical Antipsychotics

SEDATION WEIGHT GAIN EPS

Best choice Aripiprazole Aripiprazole Clozapine
Brexpiprazole Brexpiprazole Iloperidone
Cariprazine Cariprazine Quetiapine
Iloperidone Lurasidone Aripiprazole
Lurasidone Ziprasidone Brexpiprazole
Paliperidone Asenapine Cariprazine
Risperidone Iloperidone Asenapine
Ziprasidone Paliperidone Lurasidone
Asenapine Risperidone Olanzapine
Olanzapine Quetiapine Ziprasidone
Clozapine Clozapine Paliperidone
Worst choice Quetiapine Olanzapine Risperidone
Patients on atypical antipsychotics should be regularly monitored for side effects, including BMI
 Mood Stabilizers for DMX
Evidence of FDA-Approved FDA-Approved FDA-Approved FDA-Approved
Efficacy in for BP for BP for BP for MDD
DMX Depression Mania Maintenance
Carbamazepine

Lamotrigine

Lithium

Valproate

No mood stabilizer is actually approved for use in depression of any kind
(unipolar, mixed, bipolar)
There are some data for the efficacy of lamotrigine or valproate for bipolar
depression
Lithium is well known for its anti-suicide effects; however, neither lithium nor
carbamazepine monotherapy is recommended for the treatment of bipolar
depression
Stahl SM. Prescriber's Guide. 5th ed. Cambridge University Press; 2014; Goodwin GM et al. J Psychopharmacol
2009;23(4):346-88; Connolly KR, Thase MD. Primary Care Companion CNS Disord 2011;13(4):PCC.10r01097;
Fountoulakis KN et al. Eur Arch Clin Neurosci 2012;262(suppl 1):S1-48; Musetti L et al. CNS Spectrums 2013;18(4):177-87.
Antidepressant Monotherapy for DMX?

No
Don't
Seriously, just don't do it

Antidepressant monotherapy should probably NOT be used in

patients with even the slightest hint of (hypo)mania (or a
family history of bipolar disorder)
You will most likely not know if your depressed patient has
ever had any (hypo)manic symptoms and/or family history of
bipolarity unless you ask
Every patient. Every time.
Any patient on antidepressant monotherapy should be
regularly monitored for response and emergence of
hypomania
 Combination Therapy
The treatment of DMX may require a combination of medications
Common combinations for BP depression include:
Atypical antipsychotic + mood stabilizer
Atypical antipsychotic + antidepressant
Olanzapine-fluoxetine combination in particular
Mood stabilizer + antidepressant
The combination of olanzapine or risperidone and carbamazepine is not
recommended; always check the safety of any particular combination
If an antidepressant is prescribed for DMX, it should be used in
conjunction with a mood-stabilizing agent (atypical antipsychotic or
mood stabilizer)
It is questionable whether adding an antidepressant to a mood stabilizer
or an atypical antipsychotic has any therapeutic benefit
Magiria S et al. In: Ritsner MS, ed. Use of Polypharmacy in the "Real World." New York, NY:
Springer; 2013. Polypharmacy in Psychiatry Practice; vol 2; Nivoli AMA et al. J Affective Disord
2012;140:125-41; Yatham LN et al. Bipolar Disord 2009;11:225-55.
Olanzapine-Fluoxetine Combination in the Treatment
of Bipolar Depression With Mixed Features
(p=0.0006)
***
45
N.S (p=0.065)
40
35
** (p=0.014)
% of Responders

30
25
20
15
10
5 n=166 n=173 n=37
0
PLACEBO OLANZAPINE OFC

Response defined as 50% reduction in the MADRS total score and < 2
concurrent manic/hypomanic symptoms (measured by the YMRS)

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al. J Clin Psychiatry 2009;70(10):1424-31.

No Faster Recovery From Mixed Depression in Bipolar
Disorder When Antidepressants Are Added to Mood
Stabilizers (STEP-BD)
355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Goldberg et al. Am J Psychiatry 2007;164(9):1348-55.

 Other Adjunctive Pharmacological
Treatment Strategies

Modafinil/armodafinil Omega-3 fatty acids

Stimulants may worsen Ramelteon
symptoms (including
irritability, agitation, and Celecoxib
TEAS) in patients with DMX Topiramate for weight
Pramipexole management
Folic acid Benzodiazepines (short-
Inositol term) for anxiety and
agitation
Ketamine
N-acetyl cysteine
Dell'Osso B, Ketter TA. Int J Neuropsychopharmacol 2013;16:55-68; Fountoulakis KN et al. Eur Arch Psychiatry
Clin Neurosci 2012;262(suppl 1):S1-48; Goodwin GM. J Psychopharmacol 2009;23(4):346-88; Grunze H et al.
World J Biol Psychiatry 2010;11(2):81-109; Magiria S et al. In: Ritsner MS, ed. Use of Polypharmacy in the
"Real World." New York, NY: Springer; 2013. Polypharmacy in Psychiatry Practice; vol 2.
 Nonpharmacological Interventions

Electroconvulsive therapy (ECT)

Transcranial magnetic stimulation (TMS)
Sleep deprivation
Individual or group psychoeducation
Focus on early warning signs of relapse
Interpersonal and family therapy
Cognitive behavioral therapy

Connolly KR, Thase ME. Primary Care Companion CNS Disord

2011;13(4):PCC.10r01097; Goodwin GM. J Psychopharmacol 2009;23(4):346-88;
Grunze H et al. World J Biol Psychiatry 2010;11(2):81-109; Yatham LN et al. Bipolar
Disord 2013;15:1-44.
 Summary

Not all patients with depression should be given an

antidepressant
The inappropriate overprescribing of antidepressants
has contributed to drug-induced (hypo)manic episodes,
treatment resistance, suicidality, and overall poor quality
of life for many patients suffering from depression
If there are any symptoms of (hypo)mania or a family
history of bipolar disorder, an antipsychotic with mood-
stabilizing properties may be the best option
You will not know if a depressed patient has (hypo)manic
symptoms or a positive family history of bipolar disorder
unless you ask! Every patient. Every time.
 PostPoll Question

How many patients do you see with symptoms of

mixed depression each week?

1. 0
2. 1-5
3. 6-10
4. 11-15
5. 16-20
6. 21 or more
 Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of

depression (including sadness, feelings of worthlessness, and
suicidal ideation) occurring every day for the past month. Which
class of medication would be most suitable for this patient?

1. An antidepressant
2. A mood stabilizer
3. An antipsychotic
4. Either 1 or 2
5. There is not enough information about this patient's case to
make an informed treatment decision
 Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal

aunt with bipolar disorder I. Further assessment reveals that
Sarah feels distracted and as though her thoughts are racing.
Upon speaking with her mother, it is discovered that Sarah has
at times been more talkative than usual and irritable with her
friends and family. Which class of medication would NOT be
recommended as monotherapy for this patient?

1. An antidepressant
2. A mood stabilizer
3. An antipsychotic
4. There is not enough information about this patient's case to
make an informed treatment decision
 Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who

tends to endorse some manic symptoms during depressive
episodes. Of the following symptoms, which is the most common
subsyndromal mania symptom in patients with mixed
depression?

1. Decreased need for sleep

2. Inflated self-esteem
3. Distractibility
4. Increased goal-directed activity
5. High-risk activity
 Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression

has agreed to a trial of an atypical antipsychotic. Considering
this patient's current weight and the wish to avoid any treatment-
induced weight gain, which of the following approved treatments
would be the least optimal treatment for this patient?

1. Lurasidone
2. Olanzapine/fluoxetine combination
3. Quetiapine
APPENDIX
Bipolar Depression Rating Scale (BDRS)

Clinician-administered assessment of current symptoms

Severity of Disturbances to:

Mood Motivation Self-worth Mood lability
Sleep Concentration/ Suicidality Motor drive
memory
Appetite Anxiety Guilt Increased speech
Social Anhedonia Psychosis Agitation
engagement
Energy/activity Affect Irritability

Galvao F et al. Compr Psychiatry 2013;54(6):605-10;

http://www.barwonhealth.org.au/bdrs.
 Mini International Neuropsychiatric
Interview (MINI)

Patient self-report assessing current (hypo)manic symptoms

Herqueta T, Weiller E. Int J Bipolar Disord 2013;1:21;

Young AH, Ebergard J. Neuropsychiatr Dis Treatment 2015;11:1137-43.
Clinically Useful Depression Outcome Scale
With DSM-5 Mixed Features (CUDOS-M)
Frequency of each symptom during the prior week
Patient self-report assessing
current (hypo)manic 0 1 2 3 4

symptoms Not at all Rarely Sometimes Often Almost

always
I felt so happy and cheerful, it was like a high
I had many brilliant, creative ideas
I felt extremely self-confident
I slept only a few hours but woke full of energy
My energy seemed endless
I was much more talkative than usual
I spoke faster than usual
My thoughts were racing through my mind
I took on many new projects because I felt I could do everything
I was much more social and outgoing than usual
I did wild, impulsive things
I spent money more freely than usual
I had many more thoughts and fantasies about sex

Zimmerman M et al. J Affective Disord 2014;168:357-62.

 Hypomania Checklist (HCL-32)

Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al. J Affective Disord 2015;172:355-60; Altinbas K et al. J Affective Disord 2014;152-154L478-82;
http://www.oacbdd.org/clientuploads/Docs/2010/Spring%20Handouts/Session%20220b.pdf.