Managing Bipolar Depression and Mixed Episodes
Outline
• Diagnosing bipolar disorder with DSM-5
• Treating mixed features of bipolar disorder
• Improving health outcomes in bipolar depression
• Role of psychosocial treatments in bipolar patients
Diagnosis of Bipolar Disorder Can Be Challenging
Initial diagnosis can take ≥10 years
Patients with bipolar disorder more likely to present with
symptoms of depression
Symptom overlap can lead to misdiagnosis as depressive
symptoms are difficult to distinguish from MDD
One-third of patients are misdiagnosed with MDD
Comorbidities (eg anxiety disorder, alcohol and substance
abuse, cognitive or attention disorders, eating disorders)
are common and complicate diagnosis
MDD = major depressive disorder.
Pini et al 2005; Judd et al 2002; Judd et al 2003
Mitchell et al 2008; Hirschfeld et al 2003; Krishnan 2005.
Bipolar and Related Disorders
Changes from DSM-IV:
• Formerly listed under Mood Disorders
• Abnormally and persistently increased goal-directed activity or energy
added as a core symptom of manic and hypomanic episodes
• Mixed Episodes removed and replaced with: “With Mixed Features,” which
can be applied to the current manic, hypomanic, or depressive episode in
bipolar I or II
•
•
•
•
•
Bipolar I disorder
Bipolar II disorder
Cyclothymic disorder
Substance/medication-induced
bipolar and related disorder
Bipolar and related disorder due
to another medical condition
American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition. American Psychiatric Publishing; 2013.
Conceptualization of Pure and Mixed States
in DSM-IV-TR and DSM-5
Core
symptoms
Manic
Depressive
Elevated
mood
>3
<5
Elevated mood +
depressed mood or loss of interest
>3
>5
DSM-IV-TR
Manic
Mixed
DSM-5
Manic
Core
Elevated mood
symptoms
+ energy
Manic
>3
Depressive
<5
Hypomanic/Manic with mixed
features
Elevated mood +
energy
>3
>3
Depressed mood
or loss of interest
<3
>5
Depressive
Depressive with
mixed features
Depressed mood
or loss of interest
>3
>5
Depressive
Depressed mood
or loss of interest
<3
>5
American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition. American Psychiatric Publishing; 2013.
Bipolar Specifiers
• With anxious distress:
– Feeling keyed up or tense
– Feeling unusually restless
– Difficulty concentrating
because of worry
– Fear that something awful
might happen
– Fear that individuals might
lose control of
him- or herself
– Moderate–severe:
4–5 symptoms
– Mild: 2 symptoms
– Severe: 4–5 symptoms +
motor agitation
– Moderate: 3 symptoms
American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition. American Psychiatric Publishing; 2013.
Jail/Prison Has Replaced State Hospitals
State hospital patients
Mentally ill prisoners
Mandersheid RW, Sonnenschen MA, eds. Mental Health, Washington DC:
US Government Printing Office; 1996. DHHS Publication SMA 99-3285.
Mania is an Emergency
• Need rapid, safe stabilization
• Reduction of behavioral agitation
• Sleep restoration and management of withdrawal from
drugs and alcohol
• Antimanic treatment based on
- Manic episode (mixed vs manic)
- Rapid cycling or psychotic symptoms
- Patient’s medication history
- Presence of comorbidities
- Willingness to accept therapy
Goal of Treatment: Mood Stabilization
Mood stabilizers
• Acute treatment or stabilization
of manic/mixed, hypomanic, and
depressive episodes
• Do not induce alternate mood
symptoms (i.e., switch)
• Prevent future relapse or
recurrence of manic/mixed,
hypomanic, or depressive
symptoms or episodes
What Clinicians Actually Prescribe
for Treatment of Bipolar Disorder
75% of patients had at least two psychotropic drugs
for bipolar disorder in the past year
Percentage of patients in the WAVE-bd study who took medication prescribed
for bipolar disorder in the past year
Bipolar I
disorder (%)
Bipolar II
disorder (%)
Anticonvulsants
58
54
Antidepressants
39
66
Antiparkinson drugs
3
0.3
Antipsychotic drugs
70
53
Lithium
31
17
Thyroid therapy
2
4
Other
5
4
The Wide AmbispectiveVE study of the clinical management and burden of bipolar disease (WAVE-bd; NCT01062607) study
recruited patients from: Austria, Belgium, Brazil, France, Germany, Portugal, Romania, Turkey, Ukraine and Venezuela.
WAVE-bd, Study of the Clinical Management of Bipolar Disease.
Vieta, et al. 2011.
FDA Approved Bipolar Disorder Treatments*
Manic
Mixed
Aripiprazole
+
+
–
+
Asenapine
+
+
–
–
Paliperidone-ER
–
–
–
–
Lurasidone
–
–
+
–
Olanzapine
+
+
–
+
Olanzapine/Fluoxetine
–
–
+
–
Quetiapine/XR
+
+
+
+
Risperidone (Oral/IM)
+
+
–
Ziprasidone
+
+
–
+
Chlorpromazine
+
–
–
–
Carbamazepine ER
+
+
–
–
Divalproex DR/ER
+
+
–
–
Lamotrigine
–
–
–
+
Lithium
+
–
–
+
Agent
Depression Maintenance
+ (IM)
*Aripiprazole, asenapine, olanzapine, quetiapine, risperidone indication as
monotherapy and adjunct to Li or DVPX and with/without psychosis.
Efficacy of Anti-Manic Agents Compared with Placebo
Mania score changes in 55 drug/placebo comparisons,
based on random effects meta-analysis
Favors placebo
Magnitude of
the pooled
effect size
Favors drug
Tamoxifen
Risperidone
Carbamazepine
Haloperidol
Cariprazine
Olanzapine
Ziprasidone
Asenapine
Quetiapine
Lithium
Paliperidone
Valproate
Aripiprazole
Licarbazepine
Verapamil
Lamotrigine
Topiramate
Yildiz A, et al. Neuropsychopharmacology. 2011;36:375-389.
Cipriani Meta Analysis
Aim
Evaluate comparative effects
of all antimanic drugs
Methods
Multiple treatments meta-analysis
(accounts for direct
and indirect comparisons)
Sample
68 RCTs
Jan 1, 1980–Nov 25, 2010
16,073 subjects
All comparisons ITT population
BMJ. 2011;343:bmj.d5616. ©2011 by British Medical Journal Publishing Group.
Variable Lithium Response Rate
Based on Bipolar Subtype
Rapid
Poor
Cycling
Response
30%
Mixed
Mania
Nonrapid Euphoric
Good
Mania
Cycling
Response
70%
Substance (-) Family
Abuse
History
>3
Episodes
DMI
Pattern
M
D
(+) Family Few Lifetime
No
Episodes
Substance History
Abuse
MDI
Pattern
M
D
DMI=Depression, Mania, Interval
MDI=Mania, Depression, Interval
Frye MA et al. J Affect Disord. 1998;48:91-104.
Atypical Antipsychotics in Acute Mania
Pros
• As a class, effective in acute mania
• Rapid control of acute mania/mixed, rapid cycling,
psychosis/no psychosis
• Sustained improvement of symptoms
Cons
• Tardive dyskinesia, neuroleptic malignant syndrome
• Weight gain
TD=tardive dyskinesia; EPS=extrapyramidal symptoms.
Cariprazine in Patient With Acute Mania
Associated with Bipolar I Disorder
Calabrese JR, et al. J Clin Psych. Nov 2014 (epub ahead of print)
Cariprazine in Patients With Acute Mania
Associated with Bipolar I Disorder
Mean dose 7.5mg/day
Not FDA approved for mania.
Sachs GS et al. J Affective Dis. 2015
Typical Antipsychotics in Acute Mania
Pros
• Efficacious for acute mania
• Haloperidol more efficacious than olanzapine,
quetiapine, ziprasidone
Cons/adverse effects
• Acute EPS, TD, akathisia, NMS
Negative impact on course of illness
• ↑ post manic depressive symptom severity
• ↑ frequency of major depressive episodes
Vieta et al. 2010.
Anticonvulsants in Acute Mania
Pros
• Effective in manic and mixed episodes
• Effective in alcohol withdrawal and relapse prevention
• Several effective in migraine prevention
Cons
• Ineffective in acute mania (LTG, TPX, GBP)
• P450 3A4 heteroinduction
• Weight gain and endocrine disturbances (VAL)
• Teratogenicity (VAL, CBZ)
• Rash risk
CBZ=carbamazepine; VAL=valproate; LTG=lamotrigine; GBP=gabapentin; OLZ=olanzapine;
DVPX=divalproex; TPX=topiramate
Novick et al, 2009; Goodwin et al, 2010; Frye et al, 2006;
Harden et al, 2009; Goodwin et al, 2009, Jiang et al, 2009.
ECT for Acute Mania
•
•
Electroconvulsive therapy (ECT) is a mood stabilizer
2 controlled studies of acute mania
- ECT vs lithium
- ECT vs lithium + haloperidol
•
ECT reported significant benefits for acute mania
Mukherjee et al, 1988. Small et al. 1998.
Target Dose Range for Acute Mania/Mixed
AGENT
MONO
Lithium
0.8–1.2 mmol/L
Divalproex
90–125 mg/L
Carbamazepine
4–12 mcg/ml vs 800 mg
Asenapine
10 mg BID sublingual
Olanzapine
10–20 mg/day
Risperidone
4–5 mg/day
Quetiapine
600–800 mg/day
Ziprasidone
80–120 mg/day
Aripiprazole
15–30 mg/day
Clozapine
150–450 mg
Mood Stabilizer Safety and Tolerability Concerns
Lithium
Valproate
Carbamazepine
Lamotrigine
Gastrointestinal
Gastrointestinal
Gastrointestinal
Gastrointestinal
Weight gain
Weight gain
Rash
Rash
Neurotoxicity
Tremor
Neurotoxicity
Headache
Renal toxicity
Hepatotoxicity
Hepatotoxicity
Dizziness
Thyroid toxicity
Thrombocytopenia
Thyroid changes
Pruritis
Hair Loss
Hair Loss
Blood dyscrasias
Dream abnormality
Cardiac toxicity
Pancreatitis
Cardiac toxicity
Acne, Psoriasis
PCOS
Hyponatremia
Teratogen
Teratogen
Teratogen
Teratogen
Suicidality (?)
Suicidality (?)
Suicidality (?)
= boxed warning in prescribing information; (?) = recent alert
All Mood Stabilizers Have at Least One Boxed Warning
In: Ketter TA (ed). Advances in the Treatment of Bipolar Disorder. 2005.
Physician’s Desk Reference. 2008.
Mania/Mixed Episodes Matter
• Treat the illness
– Short-term high-dose benzodiazepine, sleep restoration,
containment
• Individualize treatment
– Right medication to the right patient
• Improved psychoeducation
• Enhanced treatment adherence and minimize side-effect
burden
Depressed State is Much More Frequent in Bipolar
Patients than Hypomania
NIMH Collaborative Depression Study:
13-year follow-up of 146 bipolar patients
Judd LL et al. Arch Gen Psychiatry. 2002;59:530-537.
Probabilistic Approach to Bipolar Depression
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 depressions (≥5 episodes)
Family History
Bipolar disorder (OR=2.6)
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):144-152.
Progression to Bipolar Disorder from MDD with
Subthreshold Hypomania
Time to Hypomania or Mania
Time to Hypomania
Time to Mania
Proportion Without
Hypomania or Mania
Proportion Without
Hypomania or Mania
1.0
0.9
0.8
<3 Manic symptoms
≥3 Symptoms
1.0
0.9
0.8
0.7
0.6
0.7
0.5
0
260 520 780 1040 1300 1560
Weeks to Follow-up
0
260 520 780 1040 1300 1560
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;168:40-48.
.
Specific DSM-IV Manic Symptoms During an Index
Episode of Bipolar Depression in STEP-BD
35
No
mania
(31.2%)
Subsyndromal mania
(54.0%)
30
Full mixed episode
(14.8%)
25
Percent of 20
Patients
15
10
5
0
0
1
2
3
4
5
6
7
Number of DSM-IV Manic Symptoms
American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition. American Psychiatric Publishing; 2013.
Baseline Manic Symptom Severity in Depression Prior
to Antidepressant Treatment
5
2.0
*
YMRS
Score
†
4
1.6
3
2
CGI 1.2
Severity
Mania 0.8
1
0.4
0
0
TEM
(n=44)
ADR
(n=84)
ADNR
(n=44)
*F(2,169)=4.5; P<0.01
TEM
(n=44)
ADR
(n=84)
†F(2,169)=3.4;
ADNR
(n=494)
P=0.04
TEM=treatment-emergent mania; ADR=antidepressant responder; ADNR=antidepressant nonresponder.
Frye MA, Helleman G, McElroy SL, et al. Am J Psychiatry. 2009;166(2):164-172.
Increased Rates of Metabolic Syndrome in Bipolar
Disorder: an International Observation
NHANES III – prevalence of NCEP III-defined
metabolic syndrome in general population: 23.7%
Estimates of metabolic syndrome in
bipolar disorder population: 20%‒66%
NHANES III=Third National Health and Nutrition Examination Survey.
NCEP III=National Cholesterol Education Program Adult Treatment Protocol.
McIntyre et al. 2010.
Phenotype
Obesity + MDD
Obesity + BD
• 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
The Needs of Patients with Bipolar Disorder
Aspects of care patients would most like to see improved
Better treatment of depression
Lower risk of weight gain
Prevention of relapse in depression
Improved functionality/quality of life
Lower risk of sleeping difficulties
Lower risk of suicidal thoughts
Lower risk of diabetes
Lower risk of muscle stiffness
Lower risk of sedation
0
5
10
15
20
25
30
35
40
Respondents (%)
Understanding patients' Needs, Interactions, Treatment, and Expectations (UNITE)
global survey of 1300 patients with bipolar disorder.
McIntyre 2009.
45
MADRS Response Rates Across Six Lamotrigine
Acute Bipolar Depression Studies
Patients
(%)
p=0.005
p=0.89
p=0.36
1996–1997
Bipolar I
1997–1998
Bipolar I & II
2000–2002
Bipolar I
p=0.21
p=0.03
2003–2005
Bipolar II
2003–2006
Bipolar I & II
p=0.42
2003–2005
Bipolar I
Response: ≥50% improvement over baseline. Pooled relative risk of response: 1.22; confidence interval (CI) 1.06, 1.41;
P=0.005. MADRS=Montgomery Åsberg Depression Rating Scale.
Calabrese et al 2008; Geddes et al 2009; Van der Loos et al 2009.
Bipolar I Depression: MADRS Total Score Over 8 Weeks
for Olanzapine, OFC, or Placebo
Time (weeks)
0
1
2
3
4
5
6
7
8
0
Placebo (n=355)
Olanzapine (n=351)
OFC (n=82)
-5
LSM
Change in
MADRS
Total Score -10
-15
*
*
*
*
*
*
-20
*
*
*
*†
*†
*†
*p<0.001 vs placebo for olanzapine and OFC.
†p<0.05 vs olanzapine for OFC (ITT; MMRM).
Tohen et al. 2003.
Bipolar Depression: MADRS Total Score Over
8 Weeks for Quetiapine Vs Placebo
BOLDER I & II and EMBOLDEN I & II Pooled Data
Time (weeks)
0
1
2
3
4
5
6
7
8
0
Quetiapine 300 mg/day (n=811)
Quetiapine 600 mg/day (n=816)
Mean
Change in
MADRS
Total
Score
Placebo (n=580)
-5
***
-10
-15
***
***
***
***
***
***
***
***
***
-20
***p<0.001 vs placebo (ITT; LOCF)
Pooled analysis from four randomised, double-blind, placebo-controlled studies in
patients with bipolar I or II depression: BOLDER I, 5077US/0049; BOLDER II,
D1447C00135; EMBOLDEN I, D1447C00001; EMBOLDEN II, D1447C00134.
Young et al 2009.
Lurasidone Monotherapy for Bipolar Depression
• 6-week trial of lurasidone or placebo
• Bipolar I depressed patients, with or without rapid
cycling
Change in MADRS
from Baseline
0
-5
-10.7
-10
-15
-15.4
-15.4
d = .45
d = .45
-20
20-60 mg (n=166)*
80-120 mg
(n=160)†
Placebo (n=170)
modal dose 34.9mg/day. †Mean modal dose = 92.3 mg/day.
Loebel A, et al. Am J Psychiatry. 2014;171(2):160-168.
*Mean
Add-on Lurasidone for Bipolar Depression
Change in MADRS
From Baseline
6-week trial of lurasidone (20–120 mg/day) or placebo added to
lithium or divalproex in bipolar I depression
MMRM:
P<0.01
-13.5
-17.1
Loebel A, Cucchiaro J, Silva R, et al. Am J Psychiatry. 2014;171:169-177.
Lurasidone Efficacious in Bipolar Depression
with Subsyndromal Hypomania
McIntyre RS, et al. Presented at: 166th Annual Meeting of the APA;
May 18-22, 2013; San Francisco, CA.
Lurasidone for Mixed Depression
RESOLVE Study
•
•
•
•
•
•
•
211 MDD patients with 2 or 3 manic symptoms
Lurasidone 20-60mg/day or placebo (mean 36.2 mg/day)
MADRS primary efficacy measure
CGI-S, YMRS, HAM-A secondary efficacy measures
NNT was 3 and 4 for response and remission resp.
Lurasidone better than placebo on all measures
Nausea, insomnia, headache commonest SE
Am J Psychiatry. 2015 Nov 10:appiajp201515060770. [Epub ahead of print]
RESOLVE Study
MADRS (MMRM) – Primary Endpoint
LS Mean Change from Baseline
Baseline
Wk 1
Wk 2
Wk 3
Wk 4
Wk 5
*
Wk 6
Effect Size = 0.80
**
***
***
***
***
*p<0.05
**p<0.01
***p<0.001
ITT Population
BL mean = 33.3
BL mean = 33.2
Am J Psychiatry. 2015 Nov 10:appiajp201515060770. [Epub ahead of print]
Bipolar I Depression: MADRS Total Score Over 8
Weeks for Aripiprazole or Placebo
Weeks
0
1
2
3
4
5
6
7
8
-2.0
-4.0
-6.0
-8.0
-10.0
-12.0
-14.0
PBO (n=177)
ARI (n=162)
Baseline
28.49
29.07
Study
1
PBO (n=176)
ARI (n=175)
29.35
29.56
Study
2
**
*
*
**
*
*
*
*
**
*
P=NS at Week 8; * P ≤.05; ** P <.01; vs BPO.
ARI=aripiprazole. ARI unapproved for acute bipolar depression.
Thase ME, Jonas A, Khan A, et al. J Clin Psychopharmacol. 2008;28:13-20.
Improvement
Mean Change in MADRS
Total Score
0.0
Ziprasidone Monotherapy Not Efficacious
in Acute Bipolar Depression
0
1
2
Study 1
Study 2
Weeks
Weeks
3
4
5
Mean Change in MADRS
0
0
1
2
3
4
5
0
ZIP (120–160 mg/d)
ZIP (40–80 mg/d)
PBO
-2
-4
-6
-8
6
ZIP (40–160 mg/d)
-2
PBO
-4
-6
*
-8
-10
-10
-12
-12
-14
-14
-16
-16
-18
-18
*
*
*
* P<.05. ZIP=ziprasidone. ZIP unapproved for acute bipolar depression.
Lombardo I, Sachs G, Kolluri S, et al. J Clin Psychopharmacol. 2012;32:470-478.
6
Conventional Antipsychotics Increase Severity
of Depression/Dysphoria
60
Perphenazine
50
Percentage of
patients
Placebo
40
30
20
10
0
Discontinued
from study
Relapse
total
Relapse
depression
Relapse
mania
Side
effects
Zarate CA Jr, Tohen M. Am J Psychiatry. 2004;161:169-171.
Antidepressant Use in Bipolar Disorder:
The ISBD Task Force Consensus Report
Jadad
scorea
Evidence
levelb
Antidepressant monotherapy
3
D
Adjunctive antidepressants: short-term efficacy in acute depression
4
B
Predictors of initial response to adjunctive antidepressants
3
D
3.5
C
Predictors of long-term responsiveness to adjunctive antidepressant
treatment
3
D
Antidepressant use in mania and mixed states
3
D
Antidepressants and affective switch (mania, hypomania, or mixed)
4
C
Are newly emerging or increasing irritability and agitation, subclinical
mixed states during antidepressant treatment a form of mood
switching?
3.5
D
Antidepressants and cycle acceleration
3.5
D
3
D
Topic
Adjunctive antidepressants: maintenance studies
Antidepressants and suicidality
aThe
Jadad score indicates study methodological quality from 0 to 5, with higher scores indicating higher quality bGrades
for evidence level from A (excellent) to D (poor).
Pacchiarotti et al. 2013.
Adjunctive Levothyroxine in Bipolar Depression:
A Randomized, Double-Blind, Placebo-Controlled Study
Women
(n=32)
Total study group
(n=62)
Placebo (n=31)
Levothyroxine (n=31)
Men
(n=30)
Placebo (n=15)
Levothyroxine (n=17)
Placebo (n=16)
Levothyroxine (n=14)
22
22
20
20
20
18
16
*
14
HAM-D
24
HAM-D
24
HAM-D
Mean
24
HAM-D
22
score
18
16
*
14
0
1
2
3
4
5
6
*
Time (weeks)
0
1
2
3
4
16
14
12
12
18
5
Time (weeks)
6
12
0
1
2
3
4
5
6
Time (weeks)
*p<0.05 vs placebo (ITT; LOCF).
Adjunctive levothyroxine (300 µg/day) or placebo in patients with bipolar I or II disorder.
HAM-D=Hamilton rating scale for depression.
Stamm et al 2013.
Novel Treatments for Bipolar Depression
•
•
•
•
•
•
•
Modafinil/Armodafinil
Pramipexole
N-acetyl cysteine
Ketamine
Riluzole
Insulin sensitizers
Anti-inflammatory agents
All agents unapproved for acute bipolar depression.
Adapted from: McIntyre R, et al. Psychiatric Times. April 11, 2011.
http://www. psychiatrictimes.com/bipolar-disorder/content/article/10168/1846994.
Accessed March 12, 2013.
•
•
8-week randomized
comparison of
armodafinil 150 mg/day
(n=128) vs placebo
(n=129) added to
lithium, olanzapine, or
divalproex for bipolar
depression
Two negative studies
Mean ± SEM IDS-C30 Total Score
Adjunctive Armodafinil in Bipolar Depression
40
Mean ± SEM Change from Baseline in Total Score
on 30-Item Inventory of Depressive Symptomatology,
Clinician-Rated (IDS-C30) for Patients With
Bipolar Depression Receiving Adjunctive Armodafinil
150 mg/d versus Placebo
35
30
25
*
20
**
**
15
10
5
Armodafinil (n=124)
Placebo (n=123)
0
Base- Week Week Week Week
line
1
2
3
4
*P=0.027 (ANCOVA) versus placebo; **P=0.044 (ANOVA) and P=0.074
(ANCOVA) versus placebo. ANCOVA, analysis of covariance, ANOVA,
analysis of variance.
Calabrese JR, Ketter TA, Youakim JM, et al. J Clin Psychiatry.
2010;71(10):1363-1370.
Visit
Week
6
Week
8
Final
Visit
Treatment-Resistant Bipolar Depression: ECT vs
Pharmacological Treatment
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).
Schoeyen H K, et al. Am J Psych. 2015;172(1): 41-51.
Treatment of Acute Bipolar Depression
LEVEL 1A- Established efficacy*
Quetiapine monotherapy (bipolar disorder I & II)
Lurasidone monotherapy (bipolar disorder I)
Lurasidone or quetiapine adjunctive to lithium or divalproex (biopolar
disorder 1)
LEVEL 1B – Established efficacy, but with safety concerns*
Olanzapine + fluoxetine (bipolar disorder I)
*Note. 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
*Note. Efficacy limitations include negative randomized controlled trails but positive meta-analyses.
Florida Medicaid Drug Therapy Management Program for Behavioral Health. January 2014.
Treatment of Acute Bipolar - Depression
LEVEL 3 – If levels 1 and 2 are ineffective or treatment not
tolerated*
Electroconvulsive therapy (ECT)
*Note. 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 treatment not tolerated
Transcranial Magnetic Stimulation (TMS)
Antimanic therapy + (FDA approved medication for major
depression)*
Pramipexole
Adjunctive – modafinil, thyroid, or stimulants
3 drug combination
*Note. There is inadequate information (including negative trials) to recommend adjunctive
antidepressants, aripiprazole, ziprasidone, levetiracetam, armodafinil, or omega-3 fatty acids for bipolar
depression.
Florida Medicaid Drug Therapy Management Program for Behavioral Health. January 2014.
Numbers Needed to Treat vs Numbers Needed to Harm
Olanzapine/Fluoxetine
Quetiapine
Lurasidone
NNT
NNH
4 (response)
5 (remission)
7 (weight gain)
9 (diarrhea)
6 (weight gain >7% from
baseline)
6
5 (sedation)
5
17 (nausea)
15 (akathisia)
25 (sedation)
-493 (weight gain)
NNH, number needed to harm; NNT number needed to treat.
Citrome L. Expert Opin Pharmacother. 2011;12(17):2751-2758;
Ketter TA, et al. Acta Psychiatr Scand. 2011;123(3):175-189;
Loebel A, et al. Am J Psychiatry. 2014;171(2):160-168.
Antipsychotics: Adverse Events
Adverse Event
ARI
ASE
CLZ
ILE
LUR
OLZ
QTP
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
++
++
+
+
Hormonal
Prolactin
0
0
0
0
0
+/0
0
++
0
ARI=aripiprazole; ASE=asenapine; CLZ=clozapine; ILE=iloperidone; LUR=lurasidone;
OLZ=olanzapine; QTP=quetiapine; RIS=risperidone; ZIP=ziprasidone.
Cha DS, McIntyre RS. Expert Opin Pharmacother. 2012;13:1587-1598.
Variables Influencing Functional Outcomes
in Bipolar Disorder
Sociodemographic Variables
Age, male gender, low premorbid
psychosocial functioning
Clinical Variables
Age of onset, # of episodes, hospitalizations,
Subthreshold symptomatogy, rapid
cycling, medical or psychiatric comorbidity
Neurocognitive Variables
Neurocognitive dysfunction
(attention, verbal memory,
executive functions)
Environmental Variables
Social and family support, policies,
perceived stigma
Pharmacological Variables
# drugs, side effects
Sánchez-Moreno et al. Psychother Psychosom. 2009.
What Can Be Done to Improve Cognition and
Functioning in Bipolar Disorder?
• Prevention of cognitive impairment
– Effective pharmacotherapy for relapse prevention
– Psychoeducation
• Treatment of cognitive impairment
– Treating subthreshold depression
– Treating comorbidities
– Rational use of drugs
– Cognitive enhancers
– Cognitive remediation
Vieta. Management of bipolar disorder in clinical practice. 3rd Ed. CMG, London. 2013.
Functional Remediation Trial in Bipolar Disorder
Double-blind, randomized design
10 centers
N=239
Bipolar I and II
patients in
remission
Functional Remediation
n=77
Psychoeducation
n=82
FAST >18
A score of 4 or more
in the FAST
cognitive domain
and 2 or more in
another domain
Treatment as usual
n=80
Primary endpoint:
FAST change from
baseline
Randomization
-3 Months
Week 0
Week 21
Torrent et al. Am J Psychiatry. 2013.
Week 52
Functional Remediation in Bipolar Disorder
Changes in Functional Impairment Scores Before and After
Intervention in Patients with Bipolar Disorder
Functional Remediation
Psychoeducation
Treatment as Usual
34
Functioning
Assessment
Short Test
Score,
Mean (SE)
32
30
28
26
24
22
20
0
Pre-treatment
Assessment
Post-treatment
Assessment
Higher scores indicate greater impairment. Functional remediation programme consisting of 21 weekly sessions
lasting 90 minutes. Change for the functional remediation group was significantly different from change for the
treatment-as-usual group (Pillai’s Trace=0.065; F=6.51; P=.002) SE=standard error.
Torrent C, Bonnin Cdel M, Martinez-Aran A, et al. Am J Psychiatry. 2013;170(8):852-859.
Conclusions
• Bipolar depression and mixed episodes are the
predominant presentation
• Atypicals are the choice treatment in mixed features
• All atypicals are not efficacious in bipolar depression
• Psychosocial treatments are critical in most patients
• Attention to physical health outcomes is critical to
preventing and treating bipolar depression: i.e. metabolic
morbidity as brain hazard
Q&A