79
Supported by an educational grant from Allergan.
Supported by an educational grant from Allergan.
Faculty
Vladimir Maletic, MD, MSClinical Professor of Psychiatry and Behavioral Science
University of South Carolina School of MedicineGreenville, South Carolina
Faculty Disclosure
• Dr. Maletic: Consultant—Alkermes, Inc., Allergan, Lundbeck A/S, Otsuka America Pharmaceutical, Inc., Shire, Sunovion Pharmaceuticals Inc., Supernus Pharmaceuticals, Inc., Takeda Pharmaceutical Company Limited, Teva Pharmaceutical Industries Ltd.; Speakers Bureau—Alkermes, Inc., Allergan, H. Lundbeck A/S, Otsuka America Pharmaceutical, Inc., Sunovion Pharmaceuticals Inc., Takeda Pharmaceutical Company Limited, Teva; Speakers Bureau (spouse)—Otsuka.
Disclosure
• The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational use(s) of drugs, products, and/or devices (any use not approved by the US Food and Drug Administration).– The off-label and investigational use of mood stabilizers (lithium, valproate, and
lamotrigine), antidepressants (SSRIs, SNRIs, and MAOIs), aripiprazole, asenapine, brexpiprazole, cariprazine, bright light, transcranial direct current stimulation, ketamine, and minocycline for the treatment of bipolar depression will be discussed.
• Applicable CME staff have no relationships to disclose relating to the subject matter of this activity.
• This activity has been independently reviewed for balance.
Learning Objectives
• Discuss current clinical challenges in the management of bipolar depression in terms of its pervasiveness, patient impact, and response to traditional bipolar disorder pharmacotherapies
• Apply insights from dopamine receptor physiology and pharmacology to evaluate potential therapeutic targets in the treatment of bipolar depression
• Assess the mechanisms of action, efficacy, and safety of available and emerging pharmacotherapies for the treatment of bipolar depression
• Translate the latest clinical data and pathophysiologic understanding of bipolar depression into informed and individualized strategies for bipolar disorder management
Advances in Neurobiology and Treatment of Bipolar Depression
Mood Disorders: Introduction
• Mood disorders are a product of complex interactions between several “vulnerability” genes and environmental factors
• Mood disorders are not only chronic and recurrent conditions, they may be progressive
• Sustained functional changes in the brain may precipitate a change in structure
• Mood disorders are associated with changes in endocrine, immune, and autonomic function
Hamer D. Science. 2002;298(5591):71-72. Kendler KS, et al. Am J Psychiatry. 2000;157(8):1243-1251. Maletic V, et al. Int J Clin Pract. 2007;61(12):2030-2040.
Differential Diagnosis and Screening
GWAS in Mood Disorders: Disappointments, Insights, and Surprises
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; BPD = borderline personality disorder; CNS = central nervous system; GWAS = genome-wide association studies; MDD = major depressive disorder; SCZ = schizophrenia; SNP = single nucleotide polymorphism.
MDD Working Group of the Psychiatric GWAS Consortium. Mol Psychiatry. 2013;18(4):497-511. Lubke GH, et al. Biol Psychiatry. 2012;72(8):707-709. Yang J, et al. Nat Genet. 2010;42(7):565-569. Cross-Disorder Group of the Psychiatric Genomics Consortium. Nat Genet. 2013;45(9):984-994.
MDD has significant shared genetic etiology with schizophrenia (rg SNP = .43), bipolar disorder (rg SNP = .47), and ADHD (rg SNP = .32). MDD genes not enriched for those expressed primarily in the CNS.
0
10
20
30
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50
Per
cen
t (%
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P-B
ase
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erit
abil
ity
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0.25
0
0.15
-0.05
0.30
0.05
-0.10
0.20
0.10
Heritabilities
Coheritabilities
AD
HD
AS
D-A
DH
D
BP
D
SC
Z
MD
D
AS
D
SC
Z-B
PD
BP
D-M
DD
SC
Z-M
DD
MD
D-A
DH
D
SC
Z-A
SD
SC
Z-A
DH
D
BP
D-A
DH
D
MD
D-A
SD
BP
D-A
SD
The largest mega-analysis yet conducted has failed to find any SNP or gene definitely associated with depression. Nonetheless, recent mathematical strategies for examining the combined effect of all available genomic SNPs suggests that approximately 30% of the risk for depression results from these multiple polymorphisms.
Early Adversity and Bipolar Disorders
***P<.001. Hx = history.Post RM, et al. Focus. 2007;5(1):73-97.
The influence of early adversity ( ) and family history on age of first symptoms of bipolar disorder ( ).
(n=149) (n=26) (n=253) (n=96)12
14
16
18
20
22
24
Ag
e o
f F
irs
t S
ymp
tom
s
Physical Abuse
P.Abuse: Yes Yes No No
Positive Family Hx: Yes No Yes No
(n=153) (n=32) (n=253) (n=96)14
16
18
20
22
24
Ag
e o
f F
irs
t S
ymp
tom
s
Sexual Abuse
S.Abuse: Yes Yes No No
Positive Family Hx: Yes No Yes No
*** ***
Mood State at Presentation across the Life Cycle
N=889.Kraepelin E. Manic-Depressive Insanity and Paranoia. Edinburgh: ES Livingstone; 1921:169.
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
15 20 25 30 35 40 45 50 55 60 65
%
Age
Melancholia Mixed Mania
DSM-5 Field Trials Inter-rater Reliability
Freedman R, et al. Am J Psychiatry. 2013;170(1):1-5.
–0.10 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80
0.78
0.67
0.61
0.59
0.56
0.56
0.54
0.50
0.48
0.46
0.46
0.43
0.40
0.40
0.36
0.31
0.28 0.21
0.20
–0.004
Kappa:
Major Neurocognitive Disorder
Posttraumatic Stress Disorder
Complex Somatic Symptom Disorder
Revised Hoarding Disorder
Bipolar I Disorder
Binge Eating Disorder
Borderline Personality Disorder
Schizoaffective Disorder
Mild Neurocognitive Disorder
Schizophrenia
Attenuated Psychotic Symptoms Syndrome
Mild Neurocognitive Disorder Alcohol Use Disorder
Bipolar II Disorder
Mild Traumatic Brain Injury (TBI)
Obsessive-Compulsive Personality Disorder
Major Depressive Disorder
Antisocial Personality Disorder
Generalized Anxiety Disorder
Mixed Anxiety-Depressive Disorder
AnitaPresentationPresentation HistoryHistory TreatmentTreatment Follow-UpFollow-Up
• 32-year-old married female• PCP referral for treatment of depression • Patient self-reports history of several failed past treatment attempts with
antidepressants• On at least 2 occasions antidepressants made her “feel worse”, including an
induction of mood lability• She is currently employed as a teller at a community bank and has a 5-year-
old daughter• First depressive episode occurred after a breakup with a boyfriend during
senior year in high school• One of the depressive episodes occurred after childbirth 5 years ago
AnitaPresentationPresentation HistoryHistory TreatmentTreatment Follow-UpFollow-Up
• Currently, she has complaints of: – Feeling sad and tired most days– Anhedonia; loss of interest in work and hobbies– Periods of insomnia, alternating with hypersomnolence– Even if she doesn’t sleep well, she “can still somehow make it
through the day”– She reports “moving slowly” with difficulty at work and caring for her
daughter – She had occasionally been “thinking about death” but had no specific
plan for suicide• Anita has a history of migraines
Anita’s Responses to the Mood Disorder Questionnaire (MDQ)
The above is an example of a completed MDQ from a fictional patient.Hirschfeld RM, et al. Am J Psychiatry. 2000;157(11):1873-1875.
Yes No1. Has there ever been a period of time when you were
not your usual self and…
…you felt so good or so hyper that other people thought you were not your normal self or you were so hyper that you got into trouble?…you were so irritable that you shouted at people or started fights or arguments?…you felt much more self-confident than usual?…you got much less sleep than usual and found you didn’t really miss it?…you were much more talkative or spoke much faster than usual?…thoughts raced through your head or you couldn’t slow your mind down?…you were so easily distracted by things around you that you had trouble concentrating or staying on track?…you had much more energy than usual?…you were much more active or did many more things than usual?…you were much more social or outgoing than usual, for example you telephoned friends in the middle of the night?…you were much more interested in sex than usual?…you did things that were unusual for you or that other people might have thought were excessive, foolish, or risky?…spending money got you or your family into trouble?
Anita’s Responses to the Mood Disorder Questionnaire (MDQ) (cont’d)
The above is an example of a completed MDQ from a fictional patient.Hirschfeld RM, et al. Am J Psychiatry. 2000;157(11):1873-1875.
2. If you checked YES to more than one of the above, have several of these ever happened during the same time period?
3. How much of a problem did any of these cause you – like being unable to work; having family, money, or legal troubles; getting into arguments or fights? Please circle one response only.
4. Have any of your blood relatives (ie, children, siblings, parents, grandparents, aunts, uncles) had manic-depressive illness or bipolar disorder?
5. Has a health professional ever told you that you have manic-depressive illness or bipolar disorder?
Yes No
No problem Minor problem Moderate problem Serious problem
Anita: Summary
• Question 1: 9 “yes” responses • Question 2: “yes”• Question 3: “moderate” • Positive screen
• Symptoms are consistent with a past and present major depressive episode– Current passive suicidal ideation– Anita reported an “unusual” experience during college:
During 1 of the periods of elevated energy she smoked some “pot” to relax. For several days afterwards she felt “paranoid” and “heard voices”
– Responses to MDQ and self-description of history are suggestive of possible manic episode in the past
– Self-description suggests early and sudden onset of symptoms
– There is a positive family history of bipolar disorder
MDQ score: Other diagnostic considerations:
What is your diagnosis?
A. Major depressive disorder without psychosis
B. Bipolar I disorder depressive episode
C. Bipolar II disorder depressive episode
D. Major depressive disorder with mixed features
E. Dysthymia
Which is an accurate statement about depressive and manic episodes in a bipolar I disorder patient?
A. Nearly 10% of the time is spent in manic episodes; 3 × as long is spent in major depressive episodes
B. An even distribution of time is spent in asymptomatic, depressive, and manic episodes
C. Depression is the initial episode in women about 50% of the time
D. About 75% of the time is spent in manic episodes, 20% is spent in depressive episodes, and only 5% asymptomatic
Patients were incorrectly diagnosed with:• Unipolar depression 60%• Anxiety disorders 26%• Schizophrenia 18%• Borderline or antisocial PD 17%• Alcohol or substance abuse 14%• Schizoaffective disorder 11%
Misdiagnosis in Patients with Bipolar Disorder: NDMDA 2000 Survey
NDMDA = National Depressive and Manic-Depressive Association; PD = personality disorder.Hirschfeld RM, et al. J Clin Psychiatry. 2003;64(2):161-174.
• For 35% of those with prior misdiagnosis, lapse in time from first treatmentseeking to accurate diagnosis was 10 years or longer
• On average, people with bipolar disorder who were previously misdiagnosedreceived 3.5 misdiagnoses and consulted 4 physicians before receiving anaccurate diagnosis
69% Previously Misdiagnosed
Gender Differences in the Onset of Bipolar Disorder May Delay Correct Diagnosis
IQR = interquartile range.Kawa I, et al. Bipolar Disord. 2005;7(2):119-125.
100
0
Pa
tien
ts (
%)
40
60
20
Manic
22
Depressive
7880
First Episode in Womenwith Bipolar I Disorder
Type of Episode
100
0
Pa
tien
ts (
%)
40
60
20
Manic
44
Depressive
56
80
First Episode in Menwith Bipolar I Disorder
Type of Episode
Females (n=121)Median Age (IQR) Age
Males (n=90)Median Age (IQR)
25 (18, 32)18 (16, 25)
Age at first manic or hypomanic episodeAge at first depressive episode
22 (18, 31)20 (16, 30)
Characteristics of Women Who Have Reproductive Cycle-Associated Bipolar Symptoms
• 77% of women reported increases in mood symptoms during perimenstrual, postnatal, or menopausal periods
• Women who had reproductive cycle-associated symptoms also experienced earlier age of onset for depressive and hypo/manic episodes and a greater likelihood of comorbid anxiety disorders, rapid cycling, and mixed mood compared to those who did not have these symptoms
Perich TA, et al. Aust N Z J Psychiatry. 2017;51(2):161-167.
NIMH Collaborative Depression Study, 13 Years
BD-IDepression:Mania 3:1 (N=146)
BD-II Depression:Hypo-Mania 37:1 (N=71)
Higher Morbidity, Chronicity
% of Weeks % of Weeks
Depressed31.9
Manic9.3
Depressed50.3
Hypomanic1.3
Asymptomatic58.8
Asymptomatic48.4
Time Spent Depressed: BD-I vs BD-II
BD-I = bipolar I disorder; BD-II = bipolar II disorder; NIMH = National Institute of Mental Health.Judd LL, et al. Arch Gen Psychiatry. 2002;59(6):530-537. Judd LL, et al. Arch Gen Psychiatry. 2003;60(3):261-269.
Consider Bipolar When Seeing Treatment-Resistant Depression
Sharma V, et al. J Affect Disord. 2005;84(2-3):251-257.
Later Re-evaluation Within 1 Year
Re-evaluation of Referred Patients Who Had Failed≥ 2 Adequate Trials of Antidepressants (N=61)
Initial Re-evaluation Using Structured Clinical
Interview for DSM-IV
35% 59%65% 41%
Major depressive disorderBipolar disorder
Features Differentiating Bipolar from Unipolar Depressive Episodes
DeMuri-Maletic B, Maletic V. Scientific American Psychiatry. 2018; In press.
Initial episode in teenage years Greater risk of hospitalization Presence of psychotic features
Rapid onset and offset of
depressive episodesGreater risk of suicide attempts
Family history of bipolar
disorders
Greater episode frequency
Greater risk of comorbid
substance use disorders, anxiety
disorders, and eating disorders
More mixed symptoms
Antidepressant misadventures
(poor response, syndromal
shifts, induction of mood lability
or rapid cycling)
Greater likelihood of seasonal
pattern of depressive episodesHigher rates of substance use
MDQ
Hirschfeld RM, et al. Am J Psychiatry. 2000;157(11):1873-1875.
How to ScorePositive Screen – All 3 of the following criteria must be met:
Question 1: 7 out of 13 positive (yes) responses
Question 2: Positive (yes) response
Question 3: “Moderate” or “Serious” response
Functional and Structural Brain Changes in Bipolar Disorder
Neurobiology of Mood Disorders
ELA = early life adversity.Maletic V, et al. Front Biosci. 2009;14:5291-5338.
Neuropsychiatric Symptoms
• Emotional• Cognitive• Behavioral• Physical
Systemic Manifestations
“Network” Level: Dysregulation of Neural Circuitry
• Functional changes• Structural changes
Neuroendocrine, Autonomic, and Immune Dysregulation
Cellular and Subcellular Level Impact on
• Intracellular signaling• Gene transcription• Neurotrophic support
Epigenetic Modulation
Clinical Presentation
Epigenome
GeneticEpistasis
ELA
Stress
D E V E L O P M E N T
Etiology Pathophysiology
Functional Brain Changes in Bipolar Disorder
Brain areas associated with cognitive control, which manifest reduced responsiveness, are labeled blue (dorsal ACC, DMPFC, DLPFC). By contrast, limbic and para-limbic brain areas involved in emotional regulation, associated with greater responsiveness, are labeled in red (amygdala, VLPFC, ventral ACC).
Maletic V, et al. Front Psychiatry. 2014;5:98.
Functional Changes in Bipolar Disorder
Langan C, et al. Mol Psychiatry. 2009;14(9):833-846.
Key Functional Differences between Bipolar and Unipolar Depression
fMRI = functional magnetic resonance imaging.Grotegerd D, et al. Eur Arch Psychiatry Clin Neurosci. 2013;263(2):119-131.
Strong feature weights were observed in the amygdala for the negative faces condition, which were specific to unipolar depression, whereas higher amygdala features weights during the positive faces condition were observed, specific to bipolar patients. Medial prefrontal and orbitofrontal regions contributed to classifications specific to unipolar depression, whereas stronger feature weights in dorsolateral prefrontal areas contribute to classifications as bipolar. The pattern classification yielded up to 90% accuracy rates discriminating the 2 groups.
Unipolar Bipolar3.00
2.50
2.00
1.50
1.00
0.50
0.00Happy Happy
fMR
I C
on
tras
t V
alu
e
ValenceNegative Negative
DLPFC Activity is Associated with Bipolar Depression Severity
HAM-D = Hamilton Rating Scale for Depression; MADRS = Montgomery-Åsberg Depression Rating Scale.Fernandez-Corcuera P, et al. J Affect Disord. 2013;148(2-3):170-178.
41 bipolar depressed patients and 41 matched normal controls underwent fMRI scanning while performing baseline, 1-back and 2-back versions of the n-back task. The patients showed failure to de-activate in the medial prefrontal cortex, an area corresponding to the anterior medial node of the default mode network.
15 25
60
40
20
0
-20
20 30 35
Act
ivat
ion
HAM-D
15 25
50
30
10
0
-10
20 30 35
Act
ivat
ion
MADRS
40
20
40
Cortical Gray Matter Changes in Bipolar Depression
Anterior surface rendering illustrating (in blue) areas in which depressed bipolar participants (n=17) showed lower gray matter density relative to euthymic bipolar participants (n=16). MRI study.
Brooks JO 3rd, et al. Psychiatry Res. 2009;172(3):200-204.
Cellular and Molecular Pathophysiology of Bipolar Disorder
A Psychosocial stress,social isolation, personality
factors
IL-1, TNF-, IL-6IL-6
EuthymiaStress resilience
Major depression sickness behavior
G
Immunoregulation
t
HP
A -
axi
s
IL-10, TGF-
NE /-AR
IL-1, TNF-, IL-6
NF-B
ACh TLR
7nAChr GR
Infection, tissue trauma, neoplasm Macrophage GCs
IL-10, TGF-
Stress and Inflammation in MDD
α7nAChR = α7 nicotinic acetylcholine receptor; Ach = acetylcholine; α/β-AR = α- or β-adrenoreceptor; GC = glucocorticoid; HPA = hypothalamic–pituitary–adrenal; NE = norepinephrine; NF-κβ = nuclear factor-κβ; TGF-β = transforming growth factor β; TNF-α = tumor necrosis factor α; TLR = toll-like receptor.Raison CL, et al. Arch Gen Psychiatry. 2010;67(12):1211-1224.
TNF-
Depressed(n=9)
Manic(n=12)
Controls(n=42)
10
0
20
30
40
TNF- Plasma Concentration
pg
/mL
P≤.001
2.5
2.0
1.5
pg
/mL
1.0
0.5
0.0
Depression Mania Control
IL-8 Concentration
IL-8
Bipolar Depression May Be Associated with Elevation of Inflammatory Cytokines
O’Brien SM, et al. J Psychiatr Res. 2007;41(3-4):326-331.
Interactions at the Glia–Synaptic Junction
Maletic V, et al. Front Psychiatry. 2014;5:98.
Length of IllnessB
DN
F0 5 10 15 20 25
1.20
1.00
0.80
0.60
0.40
0.20
0.00
Duration of Bipolar Disorder May Be Reflected in the Levels of TNF-α and BDNF
Early stage = within 3 years of the first diagnosis; Late stage = ≥ 10 years since diagnosis.BDNF = brain derived neurotophic factor.Kauer-Sant’Anna M, et al. Int J Neuropsychopharmacol. 2009;12(4):447-458.
r=-0.67P<.001
60 BD-I Patients compared with 60 Healthy Controls
BIP BIPCONT CONT
P<.01
60
50
40
30
20
10
0
TN
F-α
(pg
/mL
)
Early Stage Late Stage
Elevation of Inflammatory Cytokines in CSF May Alter 5-HT and Dopamine Metabolism
• Inflammatory cytokines and monoamine metabolites were compared in 63 suicide attempters and 47 healthy controls
• MADRS scores correlated significantly with CSF IL-6 levels• IL-6 and TNF-a correlated with CSF 5-HIAA and HVA• Higher cytokine levels were associated with increased suicidality
5-HT = serotonin; CSF = cerebrospinal fluid; HIAA = hydroxyindoleacetic acid; HVA = homovanillic acid; LN = natural log.Lindqvist D, et al. Biol Psychiatry. 2009;66(3):287-292.
5.04.5 5.5 6.04.0
3
4
2
1
0
-2
-1
3.5
LN
IL-6
LN 5-HIAA100 300 500
4
3
2
1
0
-2
-1
0 200 400 600
LN
IL-6
HVA
Cholinergic/Catecholaminergic Balance in Bipolar Disorder
External stimuli such as stress may decrease AChE activity, thereby increasing extracellular ACh and the inhibitory effect on DA and NE activity resulting in depression (B). Other stimuli such as increased photoperiod exposure can increase TH, which is the precursor to DA and NE, potentially leading to a switch into manic behavior (C).
Ach = acetylcholine; AChE = acetylcholinesterase; DA = dopamine; DAT = DA transporter; NE = norepinephrine; TH = tyrosine hydroxylase.van Enkhuizen J, et al. Eur J Pharmacol. 2015;753:114-126.
Dopamine Hypothesis of Bipolar Disorder
Elevation in striatal D2/3 receptor availability would lead to increased dopaminergic neurotransmission and mania, whilst increased striatal DAT levels would lead to reduced dopaminergic function and depression. Thus, it can be speculated that a failure of dopamine receptor and transporter homoeostasis might underlie the pathophysiology of this disorder
Ashok AH, et al. Mol Psychiatry. 2017;22(5):666-679.
Dopamine SynthesisPsychotic mania?Non-psychotic mania ↔Euthymia?Bipolar depression?
D2/3 Receptor DensityPsychotic mania ↑Non-psychotic mania ↔Euthymia ↔Bipolar depression?
Dopamine ReleasePsychotic mania?Non-psychotic mania?Euthymia ↔Bipolar depression?
Dopamine TransporterMania?Euthymia ↑Depression ↑
D1 DensityMania?Euthymia ↔Depression?
Psychosis is Associated with Increased DA Synthesis in Striatum
Increased striatal dopamine synthesis capacity was evident in the bipolar psychosis group (n=22) relative to the control group (n=22). The color bar shows the t-statistic. The most significant increase was in the right caudate.
Relationship Between Striatal Dopamine Synthesis Capacity and Positive Psychotic Symptom Rating in the Bipolar Group Relative to the Schizophrenia Group.
PANSS = Positive and Negative Syndrome Scale.Jauhar S, et al. JAMA Psychiatry. 2017;74(12):1206-1213.
Bipolar
Schizophrenia
Whole Striatal Kicer, × 10-3 min-1
18
0
10
10
14 1612
20
40
PA
NS
S P
osi
tive
Su
bs
cale
Sco
re
r=0.52, P=.003
30
Negative and Depressive Symptoms Correlate with D3 Expression
Negative schizophrenic or depressive symptoms seemed to correlate with higher DRD3 levels [MADRS scores: apparent sadness (r=.67, P=.012), reduced sleep (r=.67, P=.011), lassitude (r=.74, P=.004); Brief Psychiatric Rating Scale: tension (r=.89, P=.003), depressive mood (r=.61, P=.027); Scale for the Assessment of Negative Symptoms: latency of response (r=.71, P=.027).
*P=.023; **P=.009.Sokoloff P, et al. Eur J Neurosci. 2017;45(1):2-19.Vogel M, et al. Neuropsychobiology. 2004;50(4):305-310.
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rR
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10-4
5
2
0
1
3
Healthy12 1113
4
n =
Schizophrenic Bipolar Disorder
**
*
Regulation of Synaptic DA Concentration
D3 presynaptic receptors provide more refined control of tonic dopamine release than D2 because they are the higher affinity receptors.
Stahl SM. CNS Spectr. 2017;22(4):305-311.
K (
nM
) fo
r D
op
am
ine
Dopamine Receptor Affinities1,0000
100
1
10
1,000
Hig
her
Aff
init
y
Dopamine Receptor
D1 D2 D4 D5D3
Comparing the 3 partial D2 agonists: (1) Aripiprazole has the greatest affinity for 5-HT2CR; it has the weakest affinity for H1R. Theoretically, this suggests it may be less associated with metabolic symptoms and perhaps elevate monoamines for better antidepressant effects, therapeutically speaking. It may be the least sedating. (2) Brexpiprazoleshows the greatest affinity for D2R, 5-HT1AR, 5-HT2AR, 5-HT7R, H1R, and α1R; it has the weakest affinity for D3R. This suggests the possibility that it can both inhibit and enhance dopamine activity to a higher degree, treating either psychosis or depression. The serotonin modulation is highly suggestive of antidepressant activity. (3) Cariprazine shows the greatest affinity for D3R; it is the weakest in affinity for D2R, 5-HT1AR, 5-HT2AR, 5-HT7R, and α1R. This may promote a fair amount of dopamine activity and act as an antidepressant. The serotonin modulation is highly suggestive of antidepressant activity.EPS = extrapyramidal symptoms; NMS = neuroleptic malignant syndrome. Frankel JS, et al. Ther Adv Psychopharmacol. 2017;7(1):29-41.
Binding Affinities of Partial D2 Agonists and the Clinical Properties of the Receptors
AripiprazoleKi (nM)
BrexpiprazoleKi (nM)
CariprazineKi (nM)
Therapeutic Effects Adverse Effects
D2 0.34 0.30 0.49 AntipsychoticEPS, tardive dyskinesia, akathisia, NMS
hyperprolactinemia
D3 0.8 1.1 0.085Antipsychotic (including negative
symptoms), antimanic, antidepressant
5-HT1A 1.7 0.12 2.6 Antidepressant, anxiolytic
5-HT2A 3.4 0.47 18.8 Anti-EPS
5-HT2C 15 34 134 Antidepressant
5-HT7 29 3.7 111 Antidepressant
H1 61 19 23.2 Anxiolytic, anti-insomnia Weight gain sedation
M1 >1000 >1000 >1000 Opposes EPSXerostomia, constipation, blurry vision,
cognitive dysfunction, falls (eg, older adults)
α1 57 3.8 155 Antihypertensive Sedation, orthostasis
Pharmacologic Treatment
What is the Best Treatment for Bipolar Disorder?
• Treatment that results in the fewest, briefest, or mildest episodes and side effects; and does not induce switch
• Primary therapeutic objectives:– Treat acute mania, depression, mixed episodes to remission– Prevent recurrences of illness– Restore function
• Combination treatment often required during acute and maintenance treatment
Pharmacotherapy of Bipolar Depression
• Mood stabilizers, including lithium, valproate, and lamotrigine (risk of inefficacy and/or side effects)
• Certain atypical antipsychotics (risk of more severe side effects)• Antidepressants, including SSRIs, SNRIs, and MAOIs (risks of
inefficacy, hypo/manic switch)• Novel treatments (risk of inefficacy)
MAOI = monoamine oxidase inhibitor; SNRI = serotonin nonepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor.
Antidepressants in Bipolar Disorders are either Bad or Neutral ...
Antidepressants Most Common Initial Treatments for Patients with Bipolar Disorder in United States in 2002–2003
N=7760.*Anticonvulsant = 17%; Lithium = 8%.Baldessarini RJ, et al. Psychiatr Serv. 2007;58(1):85-91.
60
50
40
30
20
0
10
Antidepressants MoodStabilizers*
Sedatives Antipsychotics
Init
ial
Pre
scri
pti
on
Rat
e (%
) 50
25
1511
Adjunctive Use of Antidepressants Conferred No Additional Benefit Than Mood Stabilizers Alone in Bipolar I or II Depression:
6-month primary effectiveness outcome
Bupropion, paroxetine, carbamazepine, and valproate are not FDA approved for the treatment of bipolar depression.Durable recovery = 8 weeks euthymia (no more than 2 depressive or 2 manic symptoms) over 6 months. Switch = DSM criteria for hypomania or mania or required treatment; mood stabilizer (MS) = lithium, carbamazepine, valproate, or any approved atypical; adjunctive antidepressant (AD) = bupropion or paroxetine. Sachs GS, et al. N Engl J Med. 2007;356(17):1711-1722.
Ou
tco
me
s A
cco
rdin
g t
oTr
eatm
en
t G
rou
p (
%)
P-value is non-significantbetween groups
30
10
20
5
0
15
25
BD-I similar to BD-II
Adjuvant AD (n=179)
MS Alone (n=187)
Durable Recovery Switch Rates
27.3
23.5
10.710.1
Polarity Switches are Common with Adjunct Antidepressants
Leverich GS, et al. Am J Psychiatry. 2006;163(2):232-239.
Rat
io o
f T
hre
sh
old
Sw
itch
es
to
Su
bth
res
ho
ldB
rief
Hyp
om
ania
s
More Subthreshold
thanThreshold
Phenomena
MoreThreshold
than Subthreshold Phenomena
Acute AntidepressantTrials (10 weeks)4.0
0.5
0.0
2.0
3.0
1.5
1.0
2.5
3.5
50
Continuation AntidepressantTrials (≥1 year)
N= 50 59 50 50 59
Bupropion
Sertraline
Venlafaxine
Patients with BD-I are More Likely to Have a Mood Switch with Adjunct Antidepressants
Leverich GS, et al. Am J Psychiatry. 2006;163(2):232-239.
Time to Switch (Days)
Cu
mu
lati
ve P
rop
ort
ion
wit
ho
ut
a S
wit
ch
1.0
0.8
0.6
0.4
0.2
0
1000 200 300 400 500
Patients with BD-I (N=115)Patients with BD-II (N=44)Censored
More Suicide Attempts during Antidepressant Monotherapy than with Mood Stabilizer
P=.001.Pacchiarotti I, et al. J Affect Disord. 2011;129(1-3):321-326.
0
0.2
0.4
0.6
0.8
1
AD Alone (N=61) AD + MS (N=34)
Nu
mb
er
of
Att
em
pts
Lithium Decreases Risk of Suicide
N=339Baldessarini RJ, et al. J Clin Psychiatry. 1999;60 Suppl 2:77-84.
Su
icid
al A
cts
per
100
Pa
tien
t-Y
ear
s
20-fold difference
8
2
4
1
0
3
5
BeforeLithium
Treatment
7.11
2.3 2.29
4.86
0.355
6
7
DuringLithium
Treatment
AfterLithium
Treatment
FirstYear OffLithium
LaterYears OffLithium
13.7-folddifference
6.48-folddifference
Immune Genes Associated with Schizophrenia May Predict Poor Lithium Response in Patients with Bipolar Affective Disorder
Trends in the ORs for favorable treatment response to lithium for patients with BPAD in the low SCZ deciles (first to ninth) compared with patients in the highest SCZ PGS decile (10th), estimated at the most significant P value thresholds (P<5 x 10−2)(n=2586). In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines.
BPAD = bipolar affective disorder; OR = odds ratio; PGS = polygenic score; SCZ = schizophrenia. International Consortium on Lithium Genetics (ConLi+Gen), et al. JAMA Psychiatry. 2018;75(1):65-74.
4.0
Deciles
2nd 4th
1.5
3.5
0.5
OR
of
Fav
ora
ble
Li
Res
po
nse
1st 10th
0
2.5
3.0
2.0
1.0
3rd 7th5th 8th6th 9th
Antidepressants in Bipolar Disorders are either Bad or Neutral ...
Except When They are Good and Beneficial
Number of Weeks Until Relapse
Pro
po
rtio
n o
f P
arti
cip
ants
N
ot
Re
lap
sin
g
0 8 16 24 32 40 480.0
0.2
0.4
0.6
0.8
1.0
Medication continuation 6–12 months
Medication discontinuation group (n=43)
Medication continuation > 12 months
Time to Relapse among Participants with Bipolar Disorder Who Discontinued Antidepressant Treatment Within 6 Months of Depressive Episode Remission or
Continued Treatment for 6–12 Months or Beyond 12 Months
Altshuler L, et al. Am J Psychiatry. 2003;160(7):1252-1262.
Long-Term Treatment with Antidepressants in BD-I and BD-II
Vöhringer PA, et al. J Clin Psychopharmacol. 2015;35(5):605-608.
0.00
0.25
0.50
0.75
1.00
0 20 40 60 80
Weeks to first any mood episode
AD continuation/BD-II
AD discontinuation/BD-II
AD continuation/BD-I
AD discontinuation/BD-I
Pro
po
rtio
n o
f P
arti
cip
ants
N
ot
Re
lap
sin
g
BD-I (n=21) BD-II (n=49)
Antidepressant Use in Bipolar Depression: ISBD Task Force Report
• Adjunctive use when there is a history of prior response• Adjunctive use for maintenance if a patient relapses into
depression after stopping the antidepressant• Antidepressant monotherapy should be avoided in BD-I• Avoided in BD-I or BD-II depression with ≥ 2 core manic
symptoms• Antidepressant should be completely avoided in manic and mixed
episodes
ISBD = International Society for Bipolar Disorders.Pacchiarotti I, et al. Am J Psychiatry. 2013;170(11):1249-1262.
Role of Atypical Antipsychotics in Bipolar Depression
Industry-Sponsored Acute Bipolar Depression Trials• Monotherapy Quetiapine vs placebo 5 +• Monotherapy Lamotrigine vs placebo 0 +• Adjunctive Lamotrigine vs placebo 1 +• Monotherapy Aripiprazole vs placebo 2 -/failed• Mono/Adj Ziprasidone vs placebo 2 -/failed• Adjunctive Armodafinil vs placebo 1 +/2 failed• Adjunctive Levetiracetam vs placebo 1 -• Monotherapy Olanzapine vs placebo 2 +• Adjunctive Agomelatine vs placebo 2 -/failed• Mono/Adj Lurasidone vs placebo 2 +/1 failed• Monotherapy Lurasidone vs placebo (pediatric pts) 1 +• Monotherapy Cariprazine vs placebo 2 +/1 failed/underpowered
Calabrese JR, et al. Am J Psychiatry. 2005;162(7):1351-1360. Thase ME, et al. J Clin Psychopharmacol. 2006;26(6):600-609. Suppes T, et al. J Affect Disord. 2010;121(1-2);106-115. Young AH, et al. J Clin Psychiatry. 2010;71(2):150-162. McElroy SL, et al. J Clin Psychiatry. 2010;71(2):163-174. Geddes JR, et al. Br J Psychiatry. 2009;194(1):4-9. Calabrese JR, et al. J Clin Psychiatry. 1999;60(2):79-88. Calabrese JR, et al. Bipolar Disord. 2008;10(2):323-333. Van der Loos ML, et al. J Clin Psychiatry. 2009;70(2):223-231. Thase ME, et al. J Clin Psychopharmacol. 2008;28(1):13-20. Lombardo I, et al. J Clin Psychopharmacol. 2012;32(4):470-478. Sachs GS, et al. J Clin Psychiatry. 2011;72(10):1413-1422. Calabrese JR, et al. J Clin Psychiatry. 2010;71(10):1363-1370. Calabrese JR, et al. J Clin Psychiatry. 2014;75(10):1054-1061. Saricicek A, et al. J Clin Psychiatry. 2011;72(6):744-750. Tohen M, et al. Arch Gen Psychiatry. 2003;60(11):1079-1088. Tohen M, et al. Br J Psychiatry. 2012;201(5):376-382. Yatham LN, et al. Br J Psychiatry. 2016;208(1):78-86. Loebel A, et al. Am J Psychiatry. 2014;171(2):169-177. DelBello MP, et al. J Am Acad Child AdolescPsychiatry. 2017;56(12):1015-1025. Durgam S, et al. Am J Psychiatry. 2016;173(3):271-281. ClinicalTrials.gov Identifier: NCT02670538.
Bipolar Depression: OFC Combination
*P<.05 vs PBO. †P<.05 vs OLZ.LOCF = last observation carried forward; OLZ = olanzapine; OFC = olanzapine-fluoxetine combination; PBO = placebo. Tohen M, et al. Arch Gen Psychiatry. 2003;60(11):1079-1088.
–20
–18
–16
–14
–12
–10
–8
–6
–4
–2
0 1 2 3 4 5 6 7 8
Week
OLZ (n=351)
PBO (n=355)
OFC (n=82)
*
*
** *
*
† † †
** * * *
*Vis
it-w
ise
Imp
rove
me
nt
fro
m
Bas
elin
e i
n M
AD
RS
(L
OC
F)
Acute Bipolar Depression: Quetiapine BOLDER Trials
*Values are least squares mean. †P<.01 vs placebo, ‡P<.001 vs placebo. QUE = quetiapine.Calabrese JR, et al. Am J Psychiatry. 2005;162(7):1351-1360. Thase ME, et al. J Clin Psychopharmacol. 2006;26(6):600-609.
Mean Change from Baseline*
Imp
rove
me
nt
-20
-16
-12
-8
-4
01 2 43 65 7 80
QUE 600 mg/day (n=170)Placebo (n=169)
QUE 300 mg/day (n=172)
Study Week
BOLDER 1
‡
‡‡
‡ ‡
‡
‡
‡
‡
‡‡
‡
‡
‡‡
‡
ITT, LOCF
-20
-16
-12
-8
-4
01 2 43 65 7 80
Study Week
BOLDER 2
QUE 600 mg/day (n=151)Placebo (n=161)
QUE 300 mg/day (n=155)
‡
‡‡
‡‡
‡
‡
‡
‡
‡
‡
‡
‡
‡
†
‡
MADRS Total Score
Bipolar Depression: Quetiapine XRMADRS Mean Change from Baseline
aP<.001 vs placebo; MITT, LOCF.Suppes T, et al. J Affect Disord. 2010;121(1-2):106-115.
-20
-15
-10
-5
0
1 2 3 4 5 6 7 8
Placebo (n=137)
Quetiapine XR 300 mg/day(n=133)
LS
Mea
n C
han
ge
fro
m
Bas
elin
e
Week
a
aa
a aa a
a
Bipolar Depression: Lurasidone Monotherapy
-20
-15
-10
-5
0
20-60 mg (n=166)* 80-120 mg(n=160)**
Placebo (n=170)
• 6-week trial of lurasidone or placebo
• Bipolar I depressed patients, with or without rapid cycling
Loebel A, et al. Am J Psychiatry. 2014;171(2):160-168.
d=.45 d=.45
-15.4-15.4
-10.7
*Mean modal dose= 34.9 mg/day
**Mean modal dose= 92.3 mg/day
Most common AEs:HeadacheNauseaAkathisia
Ch
ang
e in
MA
DR
Sfr
om
Bas
elin
e
Bipolar Depression: Add-on Lurasidone
-20
-15
-10
-5
0
Lurasidone (n=183) Placebo (n=165)
6-week trial of lurasidone (20 to 120 mg/day) or placebo added to lithiumor divalproex in bipolar I depression
MMRM: P<.01.Loebel A, et al. Am J Psychiatry. 2014;171(2):169-177.
-17.1
-13.5
Ch
ang
e in
MA
DR
Sfr
om
Bas
elin
e
Pediatric Bipolar Depression: Lurasidone
P<.05; **P<.001; ***P<.0001.CDRS-R = Children’s Depression Rating Scale, Revised.DelBello MP, et al. J Am Acad Child Adolesc Psychiatry. 2017;56(12):1015-1025.
Pediatric Patients (10 to 17 Years) with Bipolar Depression
*
****
******
-25
-20
-15
-10
-5
0
Placebo (n=170) Lurasidone 20-80 mg/day (n=173)
Week 1
Week2
Week3
Week4
Week 5
Week6Baseline
IMP
RO
VE
ME
NT
ES=0.45
LS
Mea
n C
han
ge
in
CD
RS
-R T
ota
l Sc
ore
Weeks
Bipolar I Depression: Cariprazine
ClinicalTrials.gov Identifier: NCT02670538.
Placebo
Cariprazine, 1.5 mg/day
Cariprazine, 3.0 mg/day
Table 1. Study RGH-MD-54: Efficacy Endpoints – ITT
Cariprazine
Placebo (N=156)
1.5 mg/day (N=154)
3 mg/day (N=164)
Primary Endpoint: MADRS Total Score – MMRM
Baseline, Mean ± SDChange at Week 6, LS Mean (SE)LSMD vs PlaceboP-value vs PlaceboAdjusted I-value vs Placebo
30.2 ± 4.4-12.6 (0.76)
30.7 ± 4.3-15.1 (0.77)
-2.5 (-4.6, -0.4).0204.0331
31.0 ± 4.9-15.6 (0.76)
-3.0 (-5.1, -0.9).0052.0103
4
-20
Baseline
-10
2 61
0
-5
LS
Me
an C
han
ge
in
MA
DR
S T
ota
l S
core
-15
LS
Me
an C
han
ge
fro
m B
asel
ine
Bipolar I Depression: Cariprazine
Multi-site controlled trial in 571 patients suffering from bipolar idepression,141 in the placebo group and 140, 145, and 145 in the cariprazine 0.75-, 1.5-, and 3.0-mg/day groups.
CGI-S = Clinical Global Impressions severity subscale. Cariprazine 0.75 mg/day compared with placebo: *P<.05; **P<.01; ***P<.001. Cariprazine 1.5 mg/day compared with placebo: †P<.05; ††P<.01; †††P<.001. Cariprazine 3.0 mg/day compared with placebo: #P<.05; ##P<.01; ###P<.001.Durgam S, et al. Am J Psychiatry. 2016;173(3):271-281.
Weeks8
-18
0
-14
4 62
-8
0MADRS Total Score
Cariprazine, 1.5 mg/dayCariprazine, 3.0 mg/day
-12
-4
-6
-2
-16
-10
73 51
Baseline MADRS: 30.3–31.1
(A)
PlaceboCariprazine, 0.75 mg/day
LS
Me
an C
han
ge
fro
m B
asel
ine
Weeks8
-1.8
0
-1.4
4 62
-0.8
0CGI-S Score
-1.2
-0.4
-0.6
-0.2
-1.6
-1.0
73 51
Baseline CGI-S: 4.4
(B)
Primary Analysis Time Point Primary Analysis Time Point
**†
#
**††
##
**†††
### ††
# ††
#
#
††
##
*†††
##††
#
††
Asenapine in Bipolar I Mixed Depressive Episodes
aError bars indicate standard error. *P<.05 vs placebo; †P<.05 vs olanzapine.Berk M, et al. J Clin Psychiatry. 2015;76(6):728-734.
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
Placebo
Asenapine
Olanzapine
n = 19 20 31 19 19 29 26 31 39 Day 7 Day 21 Endpoint (LOCF)
LS
Mea
n C
han
ge
fro
m B
ase
line
in
MA
DR
S T
ota
l S
co
rea
*†
*
*
MADRS > 20, DSM-IV mixed state, BL MADRS = 24–26
Antipsychotics: Adverse Events
ARI = aripiprazole; ASE = asenapine; CLZ = clozapine; ILE = iloperidone; LUR = lurasidone; OLZ = olanzapine; QTP = quetiapine; RIS = risperidone; ZIP = ziprasidone; +/0 = minimal risk; ± = equivocal; DD = dose dependent; ISF = insufficient data.Cha DS, et al. Expert Opin Pharmacother. 2012;13(11):1587-1598.
Adverse Event ARI ASE CLZ ILE LUR OLZ QTP RIS ZIP
MetabolicWeight gainDyslipidemiaGlucose dysregulation
+/0±±
++/0+/0
++++++++
++±+
+/0+/0+/0
+++++++
++++
++++
+/0±±
NeurologicalSomnolence/sedationEPS
+DD
++DD
+++++
+±
DDDD
+++DD
+++0/+
++DD
+DD
HormonalProlactin ± ± +/0 ± ISF ± ± DD ±
Novel Treatments for Bipolar Depression
Bright Light as Adjunct Treatment of Bipolar Depression
• Significant difference in remission rates between the active treatment group (68.2%) and the inactive treatment group (22.2%) (OR=7.50, 95% CI=1.80, 31.28, P=.003; adjusted OR=12.64, 95% CI=2.16, 74.08, P=.004)
• Bipolar I and II depressed patients were randomly assigned to treatment with either 7000-lux bright white light or 50-lux dim red placebo light (N=23 for each group)
Sit DK, et al. Am J Psychiatry. 2018;175(2):131-139.
Week
4 6
0
40
0
20
2 51
70
30
60
Pa
tien
ts R
em
itte
d (
%)
3
50
10
Active Treatment
Inactive Treatment
Transcranial Direct Current Stimulation (tDCS)
59 adults with BD-I or BD-II in a major depressive episode and receiving a stable pharmacologic regimen with HAM-D-17 scores > 17.
HAM-D-17 = 17-item Hamilton Depression Rating Scale.Sampaio-Junior B, et al. JAMA Psychiatry. 2018;75(2):158-166.
Time
Week 2 Week 4
10
25
20
5
HA
M-D
-17
Sco
re
Baseline
Sham tDCS
Active tDCS
Week 6
15
MA
DR
S
Adjunct Ketamine Helps Anxious and Non-Anxious Bipolar Depression
36 patients with anxious (n=21) and non-anxious (n=15) treatment-resistant bipolar depression (types I and II; concurrently treated with either lithium or valproate) received a single infusion of ketamine (0.5 mg/kg) over 40 minutes. Significant drug effects (all P<.001) suggested that both anxious and non-anxious groups had an antidepressant response to ketamine.
Ionescu DF, et al. Bipolar Disord. 2015;17(4):438-443.
Time (Post-infusion)
Day14
0Base-line
Day2
80Min
15
40
Non-anxious/KetamineAnxious/KetamineNon-anxious/PlaceboAnxious/Placebo
Day10
Day1
120Min
Day3
40Min
Day7
230Min
5
25
10
30
20
35
HA
M-D
Time (Post-infusion)
Day14
0Base-line
Day2
80Min
25
Day10
Day1
120Min
Day3
40Min
Day7
230Min
10
15
5
20
Adjunct Minocycline in Treatment of Bipolar Depression
Observed mean reduction in symptom severity in the mITT sample (n=20). **P≤.01 associated with a paired t-test comparing MADRS score at a given time point to baseline. Change in depression symptom severity over time for treatment responders (n=10) and non-responders (n=10). The mean minocycline dose at study end was 256 mg daily (Range: 100–300 mg, SD: 71 mg).
Murrough JW, et al. J Affect Disord. 2018;230:56-64.
Weeks
8
0
0
10
4 62
20
30
MA
DR
S S
core
Responders (n=10)
Non-Responders (n=10)
Weeks
8
0
0
10
4 62
20
30
MA
DR
S S
core
****
** **
Improvement in Cognition with Adjunct Minocycline Treatment in Bipolar I and II Depression
8-week, open-label study with adjunctive minocycline (100 mg bid).
Soczynska JK, et al. Bipolar Disord. 2017;19(3):198-213.
Change from Baseline to Endpoint in MADRS (%)
60 100
-60
0
-20
-40
20 800
40
-20
20
Ch
ang
e in
Ver
ba
l M
emo
ry (
%)
R2 Linear=0.274R2 Quadratic=0.478
Verbal Memory(A)
40
Change from Baseline to Endpoint in MADRS (%)
60 100
-20
10
-20
-10
20 800
40
0
30
Ch
ang
e in
Ps
ych
om
oto
r S
pee
d (
%)
R2 Linear=0.506
Psychomotor Speed(B)
40
20
In Conclusion
• Bipolar depression is a tremendous health burden in primary care patients
• Screening patients presenting with depressive symptoms, anxiety symptoms, insomnia symptoms, and substance/alcohol use is critical
• Both nonpharmacologic and pharmacologic treatments are recommended
• Wise treatment selection, along with thorough monitoring for efficacy and tolerability is indicated
