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Mood Disorders:
A "Spectrum" Analysis
Learning Objectives
1. 0
2. 1-5
3. 6-10
4. 11-15
5. 16-20
6. 21 or more
Pretest Question 1
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
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
1. Lurasidone
2. Olanzapine/fluoxetine combination
3. Quetiapine
The Mood Disorder Spectrum
Depression Depression with Mixed Mania with Mania
subsyndromal mania states subsyndromal depression
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
# of hospitalizations
Antidepressant-induced hypomania
Psychotic features
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%
44
Age of Illness Onset (yrs)
42
40
38 *
36
34
Non-Converters Converters
*
8.5
# of Depressive Episodes
7.5
6.5
6
Non-Converters Converters
***
40
% of Patients Resistant
to Antidepressants
30
20
10
0
Non-Converters Converters
4 ***
3.5
# of Hospitalizations
3
2.5
2
1.5
1
0.5
0
Non-Converters Converters
30 ***
Psychiatric Hospital
Weeks Spent in a
25
20
15
10
5
0
Non-Converters Converters
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
34.0% 33.8%
26.0%
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
29.1%
% of Depressed Patients Identified as DMX
25%
20%
15%
7.5%
10%
5%
0%
DSM-5 CRITERIA RBDC CRITERIA
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
%
.
Treatment Resistance
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
Any
mania/hypomania
symptoms
and/or
family history of
bipolar disorder?
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
Mixed
States
Mania Depression
Major Depressive Episodes:
A Trace of Mania Means Treat With an Antipsychotic
Mixed
States
Mania Depression
Issues With Existing
Treatment Guidelines for DMX
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)
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
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.
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
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)
49
-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
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
0.0
Mean Change From Baseline
-5.0
-5.4
BL mean = 16.7
-10.0
-9.9***
0.0
-5.0
-6.4
-10.0
-11.2***
BL mean = 20.5
-15.0
BL mean = 19.9
***p<0.001
4
2
0 Treatment-Emergent Mania
PLACEBO LURASIDONE
6
% of Patients
4
0
PLACEBO LURASIDONE
* *
**p=0.002
*p=0.0138
Not significant
(p=0.069)
No
Don't
Seriously, just don't do it
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)
n=145
n=190
1. 0
2. 1-5
3. 6-10
4. 11-15
5. 16-20
6. 21 or more
Posttest Question 1
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
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
1. Lurasidone
2. Olanzapine/fluoxetine combination
3. Quetiapine
APPENDIX
Bipolar Depression Rating Scale (BDRS)
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.