bipolar depression: misdiagnosis leads to...
TRANSCRIPT
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Bipolar Depression:
Misdiagnosis Leads to
Mistreatment
Handout for the Neuroscience Education Institute (NEI) online activity:
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Learning Objectives
• Apply evidence-based strategies to differentially
diagnose patients presenting in depressive
states
• Apply evidence-based treatment strategies to
the management of patients with bipolar
disorder
• Optimize treatment for bipolar disorder based on
the long-term needs of the patient
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Pre-Poll Question 1
I feel competent diagnosing patients with bipolar
depression.
1. 1 (strongly disagree)
2. 2
3. 3
4. 4
5. 5 (strongly agree)
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Pre-Poll Question 2
I feel competent optimizing treatment for patients with
bipolar depression.
1. 1 (strongly disagree)
2. 2
3. 3
4. 4
5. 5 (strongly agree)
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Pretest Question 1
A 28-year-old obese woman presents with a depressive episode. She
has previously been hospitalized and treated for a manic episode but is
not currently taking any medication. The agent with the lowest risk of
cardiometabolic side effects is:
1. Lithium
2. Lurasidone
3. Valproate
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Pretest Question 2
Janet is a 43-year-old patient with bipolar disorder. She is currently
depressed with some features of hypomania. Practice guidelines
recommend treatment with an antidepressant in patients with bipolar
disorder under the following conditions:
1. As adjunct for acute bipolar I or II depressive episode with ≥2
concomitant manic symptoms, psychomotor agitation, or rapid
cycling
2. During manic and depressive episodes with mixed features
3. In patients with predominantly mixed states
4. All of the above
5. None of the above
DIFFERENTIAL DIAGNOSIS
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
We Can Do Better
• Correct diagnosis of BP within the first year of symptom
onset is made in only 20% of cases
• Average time between onset of BP symptoms and first
appropriate treatment = 10 years
• Undiagnosed BP = 49%
• Misdiagnosed BP = As high as 60%
• 78% of PCPs fail to detect or misdiagnose BP
• Up to 12.5% of individuals diagnosed with MDD will
experience a manic or hypomanic episode over an
11-year period
Conus P et al. Bipolar Disord 2014;16(5):548-56; Kleine-Budde et al. Bipolar Disord 2013; Epub
ahead of print; Knezevic V, Nedic A. Eur Rev Med Pharmacol Sci 2013;17:1542-5; Philips ML,
Kupfer DJ. Lancet 2013;381:1663-71; Sasdelli A et al. Psychiatry J 2013;2013:548349.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Why Is An Early, Accurate Diagnosis
Important?
• Consequences of not identifying bipolar depression
early:
– Worse quality of life
– Inaccurate and potentially harmful treatment
– Increased cycling and risk of relapse
– Reduced treatment response (e.g., lithium)
– Increased risk of suicide
– Increased subsequent morbidity
– High economic costs
Conus P et al. Bipolar Disord 2014;16(5):548-56.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Increased Risk of Cycling and Relapse
Knezevic V, Nedic A. Eur Rev Med Pharmacol Sci 2013;17:1542-5.
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Properly Diagnosed Wrongly Diagnosed
Mean
# o
f E
pis
od
es O
ver
5 Y
ears
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Suicide
• 29% of patients with BD attempt suicide at least
once in their life
• 10–20% of patients with BD take their own life
• Suicide rates are 20X higher for BD compared to the
general population
• Suicide rates are 2X higher for BD compared to
MDD
Conus P et al. Bipolar Disord 2014;16(5):548-56.
Holma KM et al. Bipolar Disord 2014;16(6):652-61.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Risk of Suicide Attempt Depends On Mood
Phase
0
10
20
30
40
50
60
70
Euthymic Subthreshold depression
Major depressive episode
Mixed episode
Inc
ide
nce
of
Su
icid
e A
tte
mp
t R
ela
tive
to
Eu
thym
ia
Holma KM et al. Bipolar Disord 2014;16(6):652-61.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Depressed Manic Mixed
•2X higher risk of
suicide
•2X higher risk of
Axis-II comorbidity
•Depressive or mixed
1st episode
•Longer duration to
diagnosis
•Female
•Ever in a mixed state
•Ever married
•Ever received ECT
Predominantly
Depressed Predominantly
Depressed + Mixed
Predominantly
Manic
•4X higher risk of
suicide
•3X higher risk of
Axis-II comorbidity
•Depressive or mixed
1st episode
•Longer duration to
diagnosis
•Female
•Ever in a mixed state
•Ever married
•Ever received ECT
•1.38 higher risk of
drug abuse
•Manic or psychotic
1st episode
•12 years or more of
education
•Family history of an
affective illness
Predominantly
Manic + Mixed
•1.28 higher risk of
drug abuse
•Manic or psychotic
1st episode
•12 years or more of
education
•Family history of an
affective illness
Baldessarini RJ et al. Acta Psychiatr Scand 2012;125:293-302.
Clinical Characteristics
(at least 25% more prevalent compared to opposite pole)
Clinical Characteristics and Implications of Polarity
Categorization
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Dudek D et al. J Affective Disord 2013;144(1-2):112-5.
Diagnostic Conversion From MDD to BD
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
*p<0.05
Dudek D et al. J Affective Disord 2013;144(1-2):112-5.
Characteristics of Patients With Diagnostic
Conversion From MDD to BD
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
***p<0.0005
Dudek D et al. J Affective Disord 2013;144(1-2):112-5.
Characteristics of Patients With Diagnostic
Conversion From MDD to BD
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
***p<0.0005
Dudek D et al. J Affective Disord 2013;144(1-2):112-5.
Characteristics of Patients With Diagnostic
Conversion From MDD to BD
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Subthreshold Hypomania in MDD
• Up to 40% of patients diagnosed with unipolar
depression have symptoms of hypomania
– Most common symptoms include:
• Irritability, mental overactivity, psychomotor agitation,
talkativeness
– Individuals with subthreshold hypomania have a more severe
illness course
• High impulsivity increases the rate of conversion
• BPII versus MDD: distinct disorders or continuity on the
mood spectrum?
Alloy LB et al. J Abnorm Psychol 2012;121(1):16-27; Angst J et al. Arch Gen Psychiatry
2011;68(8):791-9; Benazzi F. Prog Neuropsychopharmacol Biol Psychiatry 2006;30:1043-50;
Benazzi F. Psychiatry Clin Neurosci 2005;59:570-5; Mazza et al. J Nerv Ment Dis
2013;201(5):435-7; Phillips ML, Kupfer DJ. Lancet 2013;381:1663-71.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Progression to Bipolar Disorder In Patients
With 3+ Hypomanic Symptoms
Fiedorowicz JG et al. Am J Psychiatry 2011;168(1):40-8.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Why Is Making An Early and Accurate
Diagnosis of Bipolar Depression So Difficult?
• Most patients present when depressed
• Hypomania is often pleasant for patients and may not be
mentioned
• Strict diagnostic criteria in DSM-IV
– DSM-5 now recognizes the importance of changes in activity as
well as mood
– Mixed specifiers now acknowledge depression with hypomanic
features as well as hypomania with depressive features
• Mania is often atypical (especially in youth) with
irritability and flight of ideas rather than euphoria and
grandiosity
Conus P et al. Bipolar Disord 2014;16(5):548-56.
Phillips ML, Kupfer DJ. Lancet 2013;381:1663-71.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Long-term Symptomatic Status of Patients
With Bipolar II Disorder
Judd LL et al. Arch Gen Psychiatry 2003;60:261-9.
Euthymic 46%
Depressed 50%
Hypomanic 2%
Cycling/Mixed 2%
How
patients
typically
present
What you must
search for
Finding a Needle In the Haystack…
THE PROBABILISTIC APPROACH
TO DIFFERENTIAL DIAGNOSIS
Beyond Symptoms of Mania/Hypomania:
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Mood reactivity
Overeating/weight gain
Hypersomnia
Melancholic
features
Catatonic
features
Family history
of BP
More previous
depressive
episodes
Psychotic
symptoms
Psychomotor
agitation (BP-II)
Psychomotor
retardation (BP-I)
Early age of
onset (<25
years)
Restlessness
History of
suicide
attempts
Irritability Feelings of
guilt Comorbid
substance use
disorder
Comorbid
personality
disorder
Shorter
depressive
episodes
Morning
worsening of
symptoms
Early morning
insomnia
Family history of
substance abuse
More Common In Bipolar Depression
Benazzi F. Prog Neuropsychopharmacol Biol Psychiatry 2006;30:1043-50; Schaffer A et al. J Affect Disord
2010;125:103-10; Motovxky B, Pecenak J. Psychiatr Danub 2013;25(1):34-9; Mitchell P et al. Br J Psychiatr
2011;199:303-9; Moreno C et al. Bipolar Disord 2012;14:271-82; Galvão F et al. Comp Psychiatry
2013;54:605-10; Mitchell PB et al. Bipolar Disord 2008;10:144-52; Noto MN et al. Expert Rev Neurother
2013;13(7):795-806.
Melancholic
features Family
history of BP
Comorbid
personality
disorder
Early age of
onset (<25
years)
More
previous
depressive
episodes Catatonic
features Morning
worsening of
symptoms
Family history
of substance
abuse
Psychomotor
retardation
(BP-I)
Feelings of
guilt Irritability
Restlessness
UNIPOLAR
DEPRESSION Comorbid
substance use
disorder
Psychomotor
agitation (BP-II) Hypersomnia Shorter
depressive
episodes
Psychotic
symptoms History of
suicide
attempts Overeating/
weight gain
Mood reactivity Early
morning
insomnia
BIPOLAR
DEPRESSION
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
The Probabilistic Approach:
Diagnostic Guidelines
Suspect Bipolar Depression If 5+ Are
Present:
Suspect Unipolar Depression If 4+ Are
Present:
Hypersomnia and/or increased daytime
napping
Initial insomnia/reduced sleep
Hyperphagia and/or increased weight Appetite loss and/or weight loss
Other atypical depressive symptoms (e.g.,
leaden paralysis)
Psychomotor retardation Normal or increased activity level
Psychotic features and/or pathological guilt Somatic complaints
Mood lability
Early onset of first depression
(<25 years?)
Later onset of first depression
(>25 years?)
Multiple prior episodes (>4?) Long duration of current episode
(>6 months?)
Positive family history of bipolar disorder Negative family history of bipolar disorder
Mitchell PB et al. Bipolar Disord 2008;10:144-52.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Potential Caveats to the Probabilistic
Approach: Psychomotor Disturbance
• Some studies find psychomotor retardation more
common in bipolar depression than unipolar
depression, other studies do not
• Some studies find psychomotor agitation more
common in bipolar depression than unipolar
depression, other studies do not
• Psychomotor retardation may be more indicative of
BP-I
• Psychomotor agitation may be more indicative of
BP-II
Mitchell P et al. Br J Psychiatry 2011;199:303-9; Benazzi F. Prog Neuropsychopharmacol Biol
Psychiatry 2006;30:471-7.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Potential Caveats to the Probabilistic
Approach: Sleep Disturbance
• Some studies have found that patients with BP
depression have hypersomnia, whereas patients
with MDD have initial insomnia and reduced sleep
• One recent study in women showed:
– Patients with MDD reported either insomnia or
hypersomnia
– Patients with BP II complained of both insomnia and
hypersomnia
. Noto et al. Exper Rev Neurother 2013;13(7):795-807; Rastelli CPB et al. J Affect Disord
2013;150:1120-24.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Family History
• Although the majority of patients with BP depression
do not have a family history of BP, family history of
BP is arguably the most robust and reliable risk
factor for BP depression
• Individuals with a first-degree relative with BP
disorder are at an 8X greater risk of developing BP
disorder compared to the general population
• The importance of questioning depressed patients
about family history of affective disorders cannot be
overemphasized
Duffy A et al. BJP 2014;204:122-8; Mahli et al. Bipolar Disord 2014;16(5):455-70;
Wilde A et al. J Affect Disord 2014;158:37-47.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Bipolar Depression Rating Scale (BDRS)
• Clinician administered 20–item scale including 3
subscales
– Psychological Depression
• Anxiety, guilt, suicidality, worthlessness, irritability, etc
– Somatic depression
• Sleep disturbance, energy reduction, reduced
concentration, etc
– Mixed
• Psychotic symptoms, lability, increased speech, etc
• http://www.barwonhealth.org.au/bdrs
Berk M et al. Bipolar Disord 2007;9:571-9; Galvão F et al. Comp Psychiatry 2013;54:605-10.
32-Item Hypomania Checklist (HCL-32) I need less sleep I am more flirtatious and/or am more sexually active
I feel more energetic and more active I talk more
I am more self-confident I think faster
I enjoy my work more I make more jokes or puns when I am talking
I am more sociable (make more phone calls, go out more) I am more easily distracted
I want to travel and/or do travel more I engage in lots of new things
I tend to drive faster or take more risks when driving My thoughts jump from topic to topic
I spend more money/too much money I do things more quickly and/or more easily
I take more risks in my daily life (in my work and/or other
activities)
I am more impatient and/or get irritable more easily
I am physically more active (sport, etc) I can be exhausting or irritating for others
I plan more activities or projects I get into more quarrels
I have more ideas, I am more creative My mood is higher, more optimistic
I am less shy or inhibited I drink more coffee
I wear more colorful and more extravagant
clothes/make-up
I smoke more cigarettes
I want to meet or actually do meet more people I drink more alcohol
I am more interested in sex, and/or have increased sexual
desire
I take more drugs (sedatives, anti-anxiety pills, stimulants)
15-Item Hypomania Checklist (HCL-15) Less sleep
More drive or energy
More self-confidence
Increased social activity and work motivation
Increased physical activity
More plans and ideas
Less shy, less inhibited
More talkative than usual
More puns and jokes, faster thinking, laughing more
More irritable, impatient
Increased consumption of coffee, cigarettes
Increased consumption of alcohol
Extremely happy mood, overeuphoric
Increased sex drive, interest in sex
Over-activity (e.g., shopping, business, telephone calls, travelling, visiting people)
He et al. Gen Hosp Psychiatry 2014;36(3):347-51.
A depressed
patient who
endorses less
than 7 items has a
93% likelihood of
having MDD
rather than BPII
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Mood Disorders Questionnaire (MDQ)
• 13 yes/no self-report answers
• Screens for lifetime history of manic/hypomanic
symptoms
• Shorter and possibly more accurate than the
HCL-32
• However, the HCL may be better for detecting
subthreshold hypomania symptoms
Sasdelli A et al. Psychiatry J 2013;548349.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Mood Swings Questionnaire (MSQ)
• Score of 22 or more warrants detailed clinical
assessment
• Available as an anonymous online self-test at:
www.blackdoginstitute.org.au
• 35% of patients who consulted a health care
professional following an online MSQ positive
screen had a diagnosis of BP confirmed
• Superior sensitivity and specificity compared to the
MDQ
Parker G, Fletcher K. J Affect Disord 2013;150:276-83; Parker G et al. J Affect Disord
2012;138:104-9.
TREATMENT OF BIPOLAR
DEPRESSION: EFFICACY
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Study MADRS WMD (95% CI)
Calabrese et al. 2005 -6.47 (-8.67; -4.27)
Thase et al. 2006 -4.07 (-6.03; -2.11)
Young et al. 2010 -4.29 (-6.28; -2.3)
McElroy et al. 2010 -3.71 (-6.22; -1.2)
Quetiapine 600 pooled -4.64 (-5.82; -3.46)
Heterogeneity: Q=3.64; p=0.303
Overall: Z=-7.71; p=0; n=1396
Calabrese et al. 2005 -6.13 (-8.33; -3.93)
Thase et al. 2006 -5.01 (-6.95; -3.07)
Young et al. 2010 -3.55 (-5.55; -1.55)
McElroy et al. 2010 -3.59 (-6.1; -1.08)
Suppes et al. 2010 -5.51 (-7.88; -3.14)
Quetiapine 200 pooled -4.76 (-5.75; -3.76)
Heterogeneity: Q=4.19; p=0.381
Overall: Z=-9.37; p=0; n=1661
Quetiapine in Bipolar Depression
Chiesa A et al. Int Clin Psychopharmacol 2012;27(2):76-90.
Favors: QUET PBO
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
OFC in Bipolar Depression
Data from two 8-week randomized clinical trials for bipolar depression. Primary measure was
change in MADRS; OFC was significantly superior to both OLZ and PBO.
OFC: n=86, mean daily dose 7.4 mg/39.3 mg. OLZ: n=370, mean daily dose 9.7 mg. PBO: n=377.
Citrome L. Expert Opinion Pharmacother 2011;12(17):2751-8.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Lurasidone in Bipolar Depression:
Monotherapy
*p<0.05 **p<0.01 ***p<0.001
Placebo (n=162) Lurasidone 20–60 mg (n=161) Lurasidone 80–120 mg (n=162)
Baseline mean = 30.5 Baseline mean = 30.3 Baseline mean = 30.6
Loebel A et al. Am J Psychiatry 2014;171(2):160-8.
Change From Baseline in MADRS (MMRM)
Effect size (MMRM)
Lurasidone 20–60 mg: 0.51
Lurasidone 80–120 mg: 0.51
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Lurasidone in Bipolar Depression:
Adjunct
*p<0.05 **p<0.01 ***p<0.001
Placebo + Li/VPA (N=161) Lurasidone + Li/VPA (N=179)
Baseline mean = 30.8 Baseline mean = 30.6
Mean daily dose of lurasidone: 66.3 mg (90% of participants received ≥60 mg)
Loebel A et al. Am J Psychiatry 2014;171(2):169-77.
Change From Baseline in MADRS (MMRM)
Effect size: 0.34 (MMRM)
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Bipolar Depression: NEI Practice Guideline
On VAL On Li On atypical
antipsychotic
(QUE or LUR)
Not on
medication
Add/
switch to
Li, LAM,
QUE, or
LUR
Add/
switch to
LAM,
QUE, or
LUR
Add/
switch
to
LAM
Add/
switch
to Li
Switch
to OLZ
+SSRI
Add
VAL
Add
Li +
VAL
Add/
switch
to Li
Add/
switch
to LAM
Add Li
or
LAM
Add
Li or
LAM
Goodwin GM. J Psychopharmacol 2009;23(4):346-88; Goodwin GM et al. Eur Neuropsychopharmacol
2008;18(7):535-49; Grunze H et al. World J Biol Psychiatry 2010;11:81-109; Hirschfeld RMA et al. American
Psychiatric Association 2002; Kasper S et al. J Clin Psychiatry 2008;69:1632-46; Yatham LN et al. Bipolar Disord
2009;11(3):225-55..
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Recommended Doses in Bipolar Depression
Drug Daily dose
lamotrigine (mono) 100–200 mg
lithium 0.6–1.0 mEq/L
lurasidone 20–120 mg
olanzapine-fluoxetine 6–12/25–50 mg
quetiapine 300 mg
valproate 70–90 mg/L
Drug Daily dose
aripiprazole 15–30 mg (maint)
asenapine 5–10 mg (maint)
carbamazepine 4–15 mg/L (maint)
iloperidone 12–24 mg (maint)
oxcarbazepine 1200–2400 mg (mania)
paliperidone 6 mg (schiz)
risperidone 25–50 mg IM q2wks
(maint)
ziprasidone 80–160 mg (maint)
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
What's the Role of Antidepressants?
Recent Recommendations From ISBD
• When to avoid ADs
– As adjunct for acute bipolar I or II depressive episode
with ≥2 concomitant manic symptoms, psychomotor
agitation, or rapid cycling
– As monotherapy in bipolar I disorder
– As monotherapy in bipolar II depression with ≥2
concomitant manic symptoms
– During manic and depressive episodes with mixed
features
– In patients with predominantly mixed states
10th International Conference on Bipolar Disorders (ICBD). Abstract 13. 2013.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
What's the Role of Antidepressants?
Recent Recommendations From ISBD
• When to consider ADs
– As adjunct for acute bipolar I or II depressive episode
in patients with a history of good AD response
– As maintenance (adjunct) for patients who relapse
into a depressive episode after stopping an AD
10th International Conference on Bipolar Disorders (ICBD). Abstract 13. 2013.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Bipolar Depression: NEI Practice Guideline
Cautiously consider adding bupropion
Add modafinil, armodafinil, or pramipexole
Replace one or both agents with alternate
first- or second-line agents
Consider ECT, third-line agents, and
novel or experimental options
Add-on Novel or Experimental Agents
Stahl SM. CNS Spectrums; in press.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Armodafinil in Bipolar Depression:
Adjunct 150 mg
46.2
5.6 1.6
34.2
3.5 4.4
0 5
10 15 20 25 30 35 40 45 50
Response Rates AE Discontinuation ≥7% Weight Gain
armodafinil
placebo
Ketter TA et al. Presented at US Psychiatric Mental Health Congress; 2012.
% P
atients
Response: ≥50% decrease in IDS-C30
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Armodafinil in Bipolar Depression:
Adjunct
Frye MA et al. Int J Bipolar Disord 2015;31(1):34.
Response: ≥50% decrease in IDS-C30
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Pramipexole in Bipolar Depression:
Adjunct
Zarate CA Jr et al. Biol Psychiatry 2004;56(1):54-60.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Omega-3 Fatty Acids
• Principal dietary sources include fatty cold water fish
and fish oil supplements
• Increased fish intake is associated with reduced
lifetime prevalence of mood disorders
• 1-4 g/day omega-3 supplementation may:
– Reduce manic and depressive symptom severity
– Reduce BP relapse rates
– Reduce risk of suicide
– Protect against adverse cardiometabolic effects
– Has little safety risk
McNamara RK, Strawn JR. PharmaNutrition 2013;1(2):41-9.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Why Treat Bipolar Disorder With
Psychotherapy?
• Increase adherence to medication
• Enhance social and occupational functioning
• Enhance capacity to manage stressors in the social-occupational milieu
• Enhance protective effects of family and other social supports
• Decrease denial and trauma and encourage acceptance of the disorder
• Decrease the risk of recurrence
Swartz HA et al. Psychotherapy for bipolar disorder. In Stein DJ, Kupfer DJ & Schatzberg AF (eds.)
The American Psychiatric Publishing textbook of mood disorders. 2006;405-420.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Empirically Tested Psychotherapies for
Bipolar Disorder
• Cognitive Behavioral Therapy (CBT)
• Psychoeducation (Group)
• Psychoeducation (Individual)
• Family Focused Therapy (FFT)
• Interpersonal and Social Rhythm Therapy (IPSRT)
Geddes et al. Lancet 2013;381:1672-82.
TREATMENT OF BIPOLAR
DEPRESSION: SAFETY AND
TOLERABILITY
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Metabolic Syndrome and Obesity in Bipolar
Disorder
• 68% of BP patients are overweight
• 32% of BP patients meet criteria for obesity (relative to <
20% of controls)
• Patients with BP are 3X more likely to have metabolic
syndrome compared to healthy controls
– Despite consuming fewer calories, carbohydrates, fats,
and more fiber than healthy controls!
• Thus, although diet and lifestyle are factors, the story is
much more complicated
– Effects of pharmacological agents?
– Common etiology of metabolic syndrome and BP?
Fagiolini A et al. Am J Psychiatry 2003;160(1):112-7;
Bly MJ et al. Bipolar Disord 2014;16(3):277-88.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
0
2
4
6
8
10
12
14
16
18
20
Non-obese BMI 30 BMI 35
Mean
# o
f L
ifeti
me
(Hyp
o)M
an
ic S
ym
pto
ms
Obesity May Predict Bipolarity in Depressed
Patients
Vannucchi et al. J Affect Disord 2014;156:118-22.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Obesity Decreases Time to Depressive
Recurrence C
um
ula
tive P
roport
ion
Rem
ain
ing W
ell
Weeks in Maintenance Treatment
0.0
0.2
0.4
0.6
0.8
1.0
0 20 40 60 80 100 120
Non-obese
Obese
Obese patients had a shorter time to depressive recurrence than non-obese patients
Fagiolini A et al. Am J Psychiatry 2003;160:112-117.
Log Rank Chi-square = 7.33, df = 1, p < 0.007)
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
0
1
2
3
4
5
HTN CVD
Control
Depression
Bipolar
Goldstein et al. Bipolar Disord 2009.
Cardiovascular Disease and Hypertension
Among Adults With Bipolar I Disorder O
dd
s R
ati
o (
ad
justi
ng
fo
r ag
e, sex,
an
d r
ace)
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Other
LMG 0 0 0 0 0 + rash
LI 0 0 ++ ++ 0 0 tremor, GI, acne,
thyroid, renal
LUR + + 0 + 0 0
OLZ + + +++ ++ + ++
QUET 0 0 ++ +++ ++ ++
VAL 0 0 ++ +++ 0 + tremor, GI
Mood Stabilizers: Side Effects
Stahl SM. Stahl's essential psychopharmacology: the prescriber's guide. 4th ed. 2011;
Stahl SM. CNS Spectrums; in press.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Other
ARIP + 0 0 0 0 0 nausea
ASEN + + + ++ + 0 oral
hypoesthesia
CBZ 0 0 + +++ 0 + nausea,
headache, rash
ILOP 0 + + + +++ 0
OXC 0 0 + + 0 0 nausea, rash
PAL ++ +++ ++ + ++ 0
RSP ++ +++ ++ + + 0
ZIP + + 0 + 0 0 activation (low
dose)
Mood Stabilizers: Side Effects (cont.)
Stahl SM. Stahl's essential psychopharmacology: the prescriber's guide. 4th ed. 2011;
Stahl SM. CNS Spectrums; in press.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Metabolic Changes With Olanzapine and
Quetiapine: Total Cholesterol (mg/dL)
Rummel-Kluge C et al. Schizophr Res 2010;123:225-33.
-40.0 -20.0 0.0 20.0 40.0
Aripiprazole Clozapine
Quetiapine
Risperidone
Ziprasidone
Risperidone
Ziprasidone Quetiapine
FAVORS FAVORS
Olanzapine
Olanzapine
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Metabolic Changes With Olanzapine and
Quetiapine: Glucose (mg/dL)
Rummel-Kluge C et al. Schizophr Res 2010;123:225-33.
-40.0 -20.0 0.0 20.0 40.0
Aripiprazole Clozapine
Quetiapine
Risperidone
Ziprasidone
Olanzapine
Risperidone
Ziprasidone Quetiapine
FAVORS FAVORS
Olanzapine
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
BL Mean 197.4 mg/dL 196.0 mg/dL 202.2 mg/dL 125.2 mg/dL 132.4 mg/dL 133.9 mg/dL
-3.0
0.0
-3.0
-10.0
-8.0
-6.0
-4.0
-2.0
0.0
2.0
4.0
6.0
8.0
10.0 8.0
3.0
-2.0
-10.0
-8.0
-6.0
-4.0
-2.0
0.0
2.0
4.0
6.0
8.0
10.0
Metabolic Changes With Lurasidone
Safety Population
Cholesterol
Me
dia
n C
ha
ng
e
Fro
m B
as
eli
ne
(m
g/d
L)
Me
dia
n C
ha
ng
e
Fro
m B
as
eli
ne
(m
g/d
L)
Triglycerides
Placebo
(n=147)
Lurasidone
20–60 mg
(n=140)
Lurasidone
80–120 mg
(n=144)
Placebo
(n=147)
Lurasidone
20–60 mg
(n=140)
Lurasidone
80–120 mg
(n=144)
Loebel A et al. Poster presented at APA; 2012.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Metabolic Changes With Lurasidone
Safety Population
Me
dia
n C
ha
ng
e F
rom
B
as
eli
ne
(m
g/d
L)
Glucose
0.5
-1.0
0.0
-2.0
0.0
2.0
4.0
6.0
8.0
10.0
Placebo
(n=148)
Lurasidone 20–60 mg
(n=140)
Lurasidone 80–120 mg
(n=143)
BL Mean 94.5 mg/dL 94.3 mg/dL 94.7 mg/dL
Loebel A et al. Poster presented at APA; 2012.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Mood Stabilizers: Monitoring Guidelines
L: lithium D: divalproex C: carbamazepine A: atypical antipsychotic
*Stable patients **For first 3 months of treatment ***For first year of treatment
Mahli GS et al. Bipolar Disord 2012;14(suppl 2):1-21.
Parameter Baseline Monthly 3 Months 6 Months 12 Months
Liver D, C C** D*** D, C
Renal L C** L C
TSH L L
CBC C C** D*** C, D
Menstrual change D***
Calcium L L
Serum levels* L
Weight D, A A** D***, A L L, D, A
BP A A*** A
Fasting lipids A A A
Fasting glucose A A A
BIPOLAR MAINTENANCE
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Major Goals of Treatment in
Bipolar Disorder
• Prevent future episodes of mania
• Prevent mixed episodes
• Prevent episodes of depression
• Diminish the presence of subsyndromal
depression over extended periods of time
• Improve functioning
• Decrease morbidity and mortality
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Bipolar Maintenance:
General Management
• Maintain medication – Educate on chronicity of disorder – Help establish routine for taking medication
• Maintain psychoeducation and psychotherapy – Include caregiver psychoeducation
• Monitor for and address adverse effects
• Encourage regular physical and social activity
• Encourage regular sleep pattern
• Address interepisode impairment – Neurocognitive difficulty with sustained attention – Sleep disturbance
Swan AC. J Clin Psychiatry 2010;71(12):e35.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Bipolar Maintenance:
General Management
• Train to monitor for prodromal symptoms
– Change in motivated activity, sleep cycle, impulsivity,
or interpersonal behavior
– Change in affect (usually later in prodromal stage)
– Usually consistent within individual
• Train to address prodromal symptoms
– Small medication adjustment
– Change in daily routine
– Stress reduction
– Increase in social interaction
Swan AC. J Clin Psychiatry 2010;71(12):e35.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
NEI Practice Guideline:
Choice of Long-term Medications
Continue current medication if effective. Otherwise, consider (alphabetical order):
Stahl SM. CNS Spectrums; in press.
Maintenance Medication to
Prevent
Manic Relapse Depressive
Relapse
Aripiprazole
Carbamazepine
Lamotrigine
Lithium
Lurasidone
Olanzapine
Oxcarbazepine
Quetiapine
Valproate
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Psychiatric assessment
Risk factor assessment
– Weight, BMI, hypertension,
glucose tolerance, lipids,
C-reactive protein
Summary: Assessment and Treatment
of Interepisodic Symptom Domains
Domain Assessment
Abnormal emotional
reactivity
Cognitive
impairment
Sleep and circadian
rhythm disturbances
Psychiatric and medical
comorbidities
Treatment
BMI, body mass index
Affective Lability Scale
Affect Intensity Measure
Sleep diary
Pittsburgh Sleep Quality
Index
Neuropsychological
assessment
Stress management
Relaxation
Treatment to be developed
Psychoeducation
Interpersonal and social
rhythm therapy
Cognitive behavioral
therapy
Cognitive remediation
Treatment of comorbid
psychiatric and medical
disorders
Diet, exercise, and smoking
cessation…
Patient follow-up is pivotal; also important to consider
benefit-risk profile of current or planned psychotropic medication
Leboyer, Kupfer. J Clin Psychiatry 2010;71:1689.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
NEI Practice Guideline:
Residual Symptoms or Relapse
• If the burden of disease is mania
– Consider combining predominantly anti-manic agents
(e.g., lithium, valproate, antipsychotic)
• If the burden of disease is depression
– Lamotrigine, quetiapine, or lurasidone
• Lamotrigine may require combination with an anti-manic
• Consider clozapine in treatment-refractory patients
• Consider long-acting depot antipsychotics for
frequently relapsing bipolar disorder
Stahl SM. CNS Spectrums; in press.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Treatment Nonadherence
• As many as 77% of patients with BP may be
intentionally or unintentionally nonadherent
• Reasons for nonadherence
– Forgetting to take dose
– Side effects
– Insufficient illness knowledge
– Family/friends who advise against medication
– Access problems
– Alcohol and drug use
Sajatovic M. Compr Psychiatry 2011;52:280-7; Pompili M et al. Expert Rev Neurother
2013;13(7):809-25; Gibson S et al. BMC Psychiatry 2013;13:153; Crowe M et al. Int J Nurs Stud
2011;48:894-903; Baldessarini RJ et al. Hum Psychopharmacol 2008;23:95-105.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Interventions to Improve Adherence
• Most effective interventions only lead to small
improvement in adherence or outcomes
– More convenient care
– Reminders
– Self-monitoring
– Reinforcement
– Counseling
– Family therapy
– Psychological therapy
– Crisis intervention
– Telephone follow-up Haynes R et al. Cochrane Database Syst Rev 2005;(4):CD000011; Sylvia LG. J Clin
Psychophamacol 2013;33(3):343-50.
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Summary
• Standard depression rating scales do not differentiate
between bipolar and unipolar depression
• It is essential that all patients presenting with depression
are carefully screened for symptoms and risk factors
associated with bipolar disorder
• The 3 agents with the most evidence of efficacy for
bipolar depression are quetiapine, olanzapine-fluoxetine,
and lurasidone
• Patient and family psychosocial interventions are
integral, particularly for being vigilant for and addressing
prodromal symptoms, as well as improving treatment
adherence