50
MORE THAN MEETS THE EYE: DIAGNOSING AND TREATING BIPOLAR DEPRESSION
MORE THAN MEETS THE EYE: DIAGNOSING AND TREATING BIPOLAR DEPRESSION
Learning Objectives
• Optimize the differential diagnosis between unipolar and bipolar depression
• Employ evidence-based treatment strategies for patients with bipolar depression
The Mood Disorder Spectrum
• Although categorical classifications may be useful for clinical practice, the overwhelming majority of the evidence points to a dimensional (spectrum) view of mood disorders
• e.g., 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
Depression Mixed
states
Mania with
subsyndromal depression
Depression with
subsyndromal mania
Increasing #/severity of manic symptoms Increasing #/severity of depressive symptoms
Mania
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.
Why is an early, accurate diagnosis important?
• Consequences of not identifying bipolar depression (BD) 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.
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 twice as high for BD compared to MDD
Conus P et al. Bipolar Disord 2014;16(5):548-56;
Holma et al. Bipolar Disord 2014;16(6):652-61.
Risk of Suicide Attempt Depends On Mood Phase
0
10
20
30
40
50
60
70
Euthymic Subthresholddepression
Majordepressive
episode
Mixed episode
Incid
en
ce o
f su
icid
e a
ttem
pt
rela
tive t
o e
uth
ym
ia
Diagnosis of Bipolar Depression
Is it bipolar or unipolar depression?
UNIPOLAR
DEPRESSION
BIPOLAR
DEPRESSION
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.
Excessive
crying
More talkative
Elevated mood
Inflated self-esteem
Decreased need for sleep
Risky behavior
Increased energy
Racing thoughts
Distractibility
Impulsivity
Irritability
Psychomotor agitation
Depressed mood
Loss of interest in previously enjoyable activities
Weight loss or gain
Insomnia
Excessive sleepiness
Loss of energy
Difficulty concentrating
Suicidality
So you think it’s unipolar depression?
• As many as 60% of patients with BPII are initially diagnosed as unipolar
• Correct diagnosis of bipolar disorder (BP) within the first year of symptom onset is made in only 20% of cases
• Over 1/3 of unipolar patients are eventually rediagnosed as bipolar
• Average time between onset of BP symptoms and first appropriate treatment = 10 years
• 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; Conus P et al. Bipolar Disord 2014;16(5):548-56; Kleine-Budde et
al. Bipolar Disord 2014;16(4):337-53; 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.
Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
N=550 individuals followed for >1 year (mean follow-up: 17.5 years) after a diagnosis of major depression at intake.
19.6% of patients converted to bipolar disorder during follow-up
Fiedorowicz JG et al. Am J Psychiatry 2011;168:40-8.
Time to hypomania or mania
Time to hypomania
Pro
po
rtio
n w
ith
ou
t h
yp
om
an
ia o
r m
an
ia
Weeks to follow-up
1.0
0.9
0.7
0 1040 1300 1560
0.8
780520260
Time to mania
Pro
po
rtio
n w
ith
ou
t h
yp
om
an
ia o
r m
an
ia
Weeks to follow-up
1.0
0.9
0.5
0 1040 1300 1560
0.8
780520260
≥3 Symptoms
<3 Manic symptoms
0.6
0.7
Symptoms Most Commonly Seen in Depression With Mixed Features (DMX)
0
10
20
30
40
50
60
Fre
qu
en
cy a
mo
ng
pa
tie
nts
with
DM
X
Takeshima M, Oka T. Psychiatry Clin Neurosci 2015;69(2):109-16.
Excluded from DSM-5
McIntyre RS et al. J Affective Disord 2015;172C:259-64.
Mixed Features: The exception or the rule?
26.0%
34.0% 33.8%
% of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode
n=149 n=65 n=49
MDD BPII BPI
Mixed features commonly encountered in adults with both
major depressive disorder and bipolar disorder:
The International Mood Disorders Collaborative Project
Dudek D et al. J Affective Disord 2013;144(1-2):112-5.
Diagnostic Conversion From MDD to BD
*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
***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
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
IrritabilityFeelings 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.
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 can not be overemphasized
Duffy A et al. BJP 2014;204:122-8; Malhi et al. Bipolar Disord 2014;16(5):455-70;
Wilde A et al. J Affect Disord 2014;158:37-47.
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, euphoric
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.
Mood Disorders Questionnaire (MDQ)
• 13 yes/no self-report answers
• Screens for lifetime history of manic/hypomanicsymptoms
• 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.
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.
Every time.
One of the Most Important Questions to Ask Any Patient With Depression
Any
manic/hypomanic
symptoms
and/or
family history of
bipolar disorder?
Every patient.
Treatment of Bipolar Depression: Efficacy
Mood Stabilizers
• No mood stabilizer is 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
Evidence of
efficacy in DMX
FDA-approved
for BP
depression
FDA-approved
for BP
mania
FDA-approved
for BP
maintenance
FDA-approved
for MDD
Carbamazepine
Lamotrigine
Lithium
Valproate
Stahl SM. Prescriber’s guide. 6th ed. Cambridge University Press; 2018; 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.
Lithium
• Most effective drug for the treatment of recurrent depression and bipolar disorders
• Most stabilizing agent available
• Little risk to worsen depression (like antipsychotics)
• Little risk to worsen mania (like antidepressants)
• Anti-suicidal
• Depression with mixed features is associated with high risk of suicidality
• Lithium has been shown to prevent suicide, regardless of diagnosis
• May have side effects less dangerous than those associated with antipsychotics or other anticonvulsants
• Can be used in populations where mixed states are more prevalent
• Pediatric (age 12+)
• Postpartum
• Protective effect against neurodegenerative changes
• Randomized, controlled studies are lacking but observational studies support the use of lithium in mixed depression
• More clinical studies are needed
Sani G, Fiorillo A. CNS Spectr 2019; Epub ahead of print..
Atypical Antipsychotics
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. 6th ed. Cambridge University; 2017.
Evidence of
efficacy in DMX
FDA-approved
for BP
depression
FDA-approved
for BP
mania
FDA-approved
for BP
maintenance
FDA-approved
for MDD
Aripiprazole
Asenapine
Brexpiprazole
Cariprazine
Lurasidone
Olanzapine
(with fluoxetine)
(with fluoxetine)
Quetiapine
Risperidone
Ziprasidone
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
Olanzapine-Fluoxetine Combination (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.
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. Poster presented at APA; 2012.
Change From Baseline in MADRS (MMRM)
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. Poster presented at APA; 2012.
Change From Baseline in MADRS (MMRM)
Cariprazine for Bipolar Depression
Earley W et al. Am J Psychiatry 2019;176(6):439-48.
What's the role of antidepressants?Recommendations From the International Society for Bipolar
Disorders (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.
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 recurrenceSwartz HA et al. Psychotherapy for bipolar disorder. In: American Psychiatric Publishing Textbook of Mood Disorders. DJ
Stein, DJ Kupfer & AF Schatzberg (eds.) American Psychiatric Press Publishing, 405-420, 2006; McMahon K et al.
Psychiatr Clin North Am 2016;39(1):35-56.
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. The Lancet 2013;381:1672-82.
Treatment of Bipolar Depression: Safety and Tolerability
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.
0
5
10
15
20
Non-obese BMI 30 BMI 35
Mean
# o
f life
tim
e
(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.
Obesity Decreases Time to Depressive Recurrence
Cu
mu
lati
ve
pro
po
rtio
n
rem
ain
ing
well
Weeks in maintenance treatment
0.0
0.2
0.4
0.6
0.8
1.0
0 20 40 60 80 100 120
Nonobese
Obese
Obese patients had a shorter time to depressive recurrence than nonobesepatients
Fagiolini A et al. Am J Psychiatry 160:112-117, 2003.
Log Rank Chi-square = 7.33, df = 1, p < 0.007)
0
1
2
3
4
5
HTN CVD
Control
Depression
Bipolar
Goldstein et al. Bipolar Disord 2009;11(6):657-62.
Cardiovascular Disease and Hypertension Among Adults With Bipolar I Disorder
Od
ds r
ati
o (
ad
justi
ng
fo
r ag
e, sex,
an
d r
ace)
Other
LMG 0 0 0 0 0 + rash
LI 0 0 ++ ++ 0 0tremor, GI, acne,
thyroid, renal
CBZ 0 0 + +++ 0 +nausea,
headache, rash
VAL 0 0 ++ +++ 0 + tremor, GI
BD Treatments: Side Effects
Stahl SM. Stahl's essential psychopharmacology: the prescriber's guide. 5th ed. 2018.
Other
ARIP + 0 0 0 0 0 nausea
ASEN + + + ++ + 0oral
hypoesthesia
CARIP + 0 0 + 0 0
LUR + + 0 + 0 0
ILOP 0 + + + +++ 0
OLZ + + +++ ++ + ++
PAL ++ +++ ++ + ++ 0
QUET 0 0 ++ +++ ++ ++
RSP ++ +++ ++ + + 0
ZIP + + 0 + 0 0activation (low
dose)
BD Treatments: Side Effects (cont.)
Stahl SM. Stahl's essential psychopharmacology: the prescriber's guide. 5th ed. 2018.
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
AripiprazoleClozapine
Quetiapine
Risperidone
Ziprasidone
Risperidone
ZiprasidoneQuetiapine
FAVORSFAVORS
Olanzapine
Olanzapine
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
AripiprazoleClozapine
Quetiapine
Risperidone
Ziprasidone
Olanzapine
Risperidone
ZiprasidoneQuetiapine
FAVORSFAVORS
Olanzapine
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
10.08.0
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 fr
om
b
as
eli
ne
(m
g/d
L)
Me
dia
n c
ha
ng
e fr
om
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.
Metabolic Changes With Lurasidone
Safety Population
Me
dia
n c
ha
ng
e fr
om
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.
Tolerability Profile of Cariprazine
Adverse
Eventb
Bipolar Depressiona Bipolar Mania
Placebo
(n=323)
Cariprazine 1.5 mg
(n=324)
Cariprazine 3 mg
(n=323)
Placebo
(n=442)
Cariprazinec
(n=623)
Akathisia 8 (2.5) 19 (5.9) 24 (7.4) 21 (4.8) 126 (20.2)
Vomiting 0 2 (0.6) 5 (1.5) 19 (4.3) 54 (8.7)
Restlessness 11 (3.4) 6 (1.9) 23 (7.1) 10 (2.3) 42 (6.7)
Extrapyramida
l disorder2 (0.6) 0 5 (1.5) 24 (5.4) 83 (13.3)
Nausea 6 (1.9) 19 (5.9) 23 (7.1) 33 (7.5) 71 (11.4)
aBased on the two fixed-dose studies with similar slow titration protocol (MD-53, -54); boccurring in ≥5%
of patients in the cariprazine treatment groups and twice the incidence of placebo; cdose range of 3–12
mg/d.
Stahl et al. Poster presented at APA; 2019.
Summary
• Unipolar and bipolar depression present with symptoms that are similar
• There are several probabilistic factors that may tip the scale towards a bipolar diagnosis
• Screening for (hypo)mania and asking about family history of bipolar disorders is critical to making the differential diagnosis
• There are several treatment options for bipolar depression available with varying tolerability profiles
