Recent Advances in Treating Bipolar Depressive
Spectrum Disorders
Supported by educational grants from AbbVie, Intra-Cellular Therapies,
Neurocrine Biosciences, and Sunovion.

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Faculty
Joseph F. Goldberg, MD
Clinical Professor of Psychiatry
Icahn School of Medicine
Mount Sinai
New York City, New York
Roger McIntyre, MD, FRCPC
Professor of Psychiatry and Pharmacology
Department of Psychiatry/Pharmacology
University of Toronto
Head, Mood Disorders Psychopharmacology Unit
Department of Psychiatry
Toronto, Canada

Faculty Disclosures
The faculty reported the following financial relationships or relationships
to products or devices they or their spouse/life partner have with
commercial interests related to the content of this CME/CE activity:
Joseph F. Goldberg, MD, has disclosed that he as received consulting fees
from BioXcel, Lundbeck, Otsuka, and Sunovion; and has received fees for
non-CME/CE services from Allergan, Intra-Cellular Therapies, and
Sunovion.
Roger McIntyre, MD, FRCPC, has disclosed that he has received
consulting fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Allergan,
Takeda, Neurocrine, Sunovion, Eisai, Minerva, Intra-Cellular, and Abbvie
and has ownership interest in AltMed.

Overview
 Accurately diagnose depressive episodes in individuals with bipolar
disorder, recognize clinical sub-characteristics that may influence
treatment outcome
 Recognize the limited role for use of antidepressants in bipolar
depression and risk for lack of efficacy vs. treatment-emergent
affective switch (TEAS)
 Understand the antidepressant properties of mood stabilizers, second
generation antipsychotics, and emerging novel therapeutics for
depression in bipolar disorder
Slide credit: clinicaloptions.com

Screening for Bipolar Disorder: Rapid Mood Screener
Item Response
1. Have there been at least 6 different periods of time (at least 2 weeks) when you felt deeply
depressed?
Yes No
2. Did you have problems with depression before the age of 18? Yes No
3. Have you ever had to stop or change your antidepressant because it made you highly irritable or
hyper?
Yes No
4. Have you ever had a period of at least 1 week during which you were more talkative than normal
with thoughts racing in your head?
Yes No
5. Have you ever had a period of at least 1 week during which you felt any of the following: unusually
happy; unusually outgoing; or unusually energetic?
Yes No
6. Have you ever had a period of at least 1 week during which you needed much less sleep than usual? Yes No
Tool Sensitivity Specificity PPV NPV
RMS 0.88 0.80 0.80 0.88
MDQ 0.86 0.78 0.78 0.86
4/6 items need to be positive
McIntyre et al., Curr Med Res Opin 2021; 37: 135-144 Slide credit: clinicaloptions.com

Mood Episodes in Bipolar Disorder
Grande et al., Lancet 2016; 387: 1561-1572 Slide credit: clinicaloptions.com
Time
Mixed state
Severity
of
mania
Severity
of
depression
Mania
Hypomania
Euthymia
Subthreshold depression
Major depression

Depression-Polarity Proneness
STEP-BD:
 Over half of patients had 1st
episode polarity=depression
 Associated with more
subsequent lifetime
depressive than manic
episodes
 Higher comorbid anxiety
disorders, PTSD
Perlis et al., Biol Psychiatry 2005; 58: 549-553 Slide credit: clinicaloptions.com
Mania-onset
Depression-onset
Lifetime depressive episodes, by
polarity at onset
30
25
20
15
10
5
0
%
of
Subjects
Number of episodes
0 1 2 3-4

No. of Trials Agent vs. Placebo Author Primary Outcome
1 Lithium Young et al., 2010 Negative
5 Lamotrigine Calabrese et al., 2008 All 5 Negative
2 Aripiprazole Thase et al., 2008 Negative
2 Olanzapine Tohen et al., 2012 Positive
2 Ziprasidone Lombardo et al .,2012 Negative
5 Quetiapine † Calabrese et al., 2005, Thase et al., 2006, Young et
al., 2010, McElroy 2010;Suppes et al., 2010
All 5 Positive
1 Paroxetine McElroy et al., 2010 Negative
1 Lurasidone Loebel et al., 2014 Positive
4 Cariprazine Yatham et al., 2020; Durgam et al., 2016; Earley et
al., 2020
1 Negative / 3 Positive
2 Lumateperone † Durgam et al., 2021 1 Positive / 1 Negative
Total 25 Only 12 out of 25 positive
Young et al., J Clin Psychiatry 2010;71:150-152; Calabrese et al., Bipolar Disord. 2008;10:323-333; Thase J Clin Psychopharmacol. 2008;28:13-20; Tohen et al., Arch Gen
Psychiatry, 2003;1079-88; Tohen et al., Br J Psychiatry, 2012; 376-382; Lombardo et al., J Clin Psychopharm, 2012;2: 470-478; Calabrese et al., Am J Psychiatry 2005;162:
1351-1369; Thase et al., Clin Psychopharmacol. 2006;26: 600-609; McElroy et al., J Clin Psychiatry 2010; 71:163-174; Loebel et al., Am J Psychiatry 2014; 171: 160-168;
Yatham et al., Int Clin Psychopharmacol 2020; 35: 147-156; Durgam et al., Am J Psychiatry 2016; 173: 271-278; Earley et al., Am J Psychiatry 2019; 176: 439-448; Suppes
et al., J Affect Disord. 2010; 121: 106-115; Durgam, et al., Poster presented at the American Society of Clinical Psychopharmacology Ann Meeting May 29-30, 2020;
Intracellular Therapies Press release 7/12/19
Monotherapy Randomized Trials in Acute Bipolar
Depression
†positive findings in both BP I and BP II depression FDA-approved indication
Slide credit: clinicaloptions.com

Agent Author Primary Outcome
Paroxetine + lithium vs. lithium Nemeroff et al., 2001 Negative
Paroxetine or bupropion + MS vs. MS +
placebo
Sachs et al., 2007 Negative
OFC vs. placebo or olanzapine Tohen et al., 2003 Positive
Lamotrigine + Li+ vs. placebo + Li+ Van der Loos et al., 2009 Positive
Armodafinil vs. placebo Frye et al., 2007, Calabrese et al., 2010;
Calabrese et al 2014
Positive/Negative/Positive
Levetiracetam Saricicek et al., 2011 Negative
Ziprasidone Sachs et al., 2011 Negative
Agomelatine Yatham et al., 2015 Negative
Lurasidone Loebel et al., 2014 Positive
Negative
Lumateperone Intracellular Therapies press release, 2/22/21 Positive
Total 13 6 out of 13 positive
Nemeroff et al., Am J Psychiatry. 2001;158:906; Sachs N Engl J Med. 2007;356:1711; Tohen Arch Gen Psychiatry. 2003;60: 1079; Van der Loos Tijdschr Psychiatr.
2007;49:95; Frye Am J Psychiatry 2007;164:1242; Calabrese et al J Clin Psychiatry. 2010;71:1363; Calabrese et al., J Clin Psychiatry 2014; 75: 1054-1061; Sachs J Clin
Psychiatry. 2011;72:1413; Sericicek J Clin Psychiatry. 2011;72:744; Yatham et al., Br J Psychiatry 2016; 208; 78-86; Loebel et al., Am J Psychiatry 2014; 171: 169-177
Augmentation Randomized Trials in Bipolar Depression
Slide credit: clinicaloptions.com
FDA-approved indication

Rising Use of Antidepressants and Antidepressants
without Mood Stabilizers in Bipolar Disorder
Rhee et al., Am J Psychiatry 2020; 177: 706-715
Antidepressants
without a mood
stabilizer
increased from
17.9% (‘97-’00)
to 40.9% (‘13-’16)
Slide credit: clinicaloptions.com
Percent
70
60
50
40
30
20
10
0
Year
‘97-’98 ‘99-’00 ‘01-’02 ‘03-’04 ‘05-’06 ‘07-’08 ‘09-’10 ‘11-’12 ‘13-’14 ‘15-’16
Data are from the National Ambulatory Medical Care Survey. 1997-2016. AD = antidepressant;
AP=antipsychotic; MS=lithium and antiepileptic mood stabilizers.
Any AD
AD without MS
AD without AP
AD without MS and AP
Prescribing trends for antidepressants in the treatment of bipolar
disorder in office-based visits to psychiatrists, 1997-2016

How Impactful Are Treatments for Bipolar Depression?
Bahji et al., J Affect Disord 2020; 269: 154-184 Slide credit: clinicaloptions.com
Whaa??
Favors drug Favors Placebo
-3 -2 -1 0 1 2 3
Random Effects Model SMD 95%-CI P-Score
Direct
Comparisons
Contrast
to Placebo
Fluoxetine
Divalproex
Lurasidone
Moclobemide
Cariprazine
Imipramine
Olanzapine
Phenelzine
Tranylcypromine
Quetiapine
OFC
Escitalopram
Sertraline
Lithium
Venlafaxine
Paroxetine
Aripiprazole
Lamotrigine
Ziprasidone
Carbamazepine
Gabapentin
1.00
3.00
2.00
0.00
2.00
2.00
3.00
1.00
0.00
11.00
2.00
1.00
0.00
1.00
0.00
1.00
2.00
6.00
4.00
1.00
1.00
0.87
0.85
0.82
0.75
0.70
0.70
0.65
0.65
0.55
0.54
0.48
0.47
0.43
0.42
0.39
0.31
0.31
0.31
0.26
0.19
0.01
-1.41 [-2.55; -0.27]
-1.25 [-2.03; -0.47]
-1.15 [-1.92; -0.37]
-1.09 [-2.64; 0.45]
-0.85 [-1.62; -0.08]
-0.86 [-1.72; 0.01]
-0.72 [-1.35; -0.09]
-0.77 [-1.91; 0.38]
-0.55 [-1.87; 0.77]
-0.48 [-0.82; -0.14]
-0.39 [-1.02; 0.24]
-0.33 [-2.00; 1.34]
-0.24 [-1.75; 1.26]
-0.24 [-1.21; 0.72]
-0.14 [-1.63; 1.35]
-0.18 [-1.15; 0.79]
-0.04 [-0.82; 0.73]
-0.07 [-0.51; 0.37]
0.05 [-0.54; 0.64]
0.40 [-0.78; 1.58]
1.84 [0.67; 3.01]
SMD for depression severity change

Fluoxetine Monotherapy in Bipolar II Depression
But: the results pertain to initial
fluoxetine responders
 148 received open-label
fluoxetine monotherapy for 12
weeks
 49.7% recovered and were then
randomized to fluoxetine (mean
dose 34 mg/day) vs lithium
(mean dose 1027 mg/day, mean
serum [Li+]=0.69 mEq/L) vs
placebo
Amsterdam et al. Am J Psychiatry 2010; 167(7): 792-800 Slide credit: clinicaloptions.com
Days
Proportion
of
Patients
Without
Relapse
1.00
0.75
0.50
0.25
0.00
400
0 100 200 300
Fluoxetine
Lithium
Placebo
Number
at risk
28
26
27
14
8
9
12
7
6
10
5
4
0
0
1

Antidepressants for Bipolar Depression
 Meta-analysis of 6 randomized trials, n=1383
 Response: not significant (OR=1.158, 95% CI=0.840-1.597)
 Remission: not significant (OR=1.220, 95% CI=0.874-1.703)
 Small improvement in clinician-rated depressive symptom scores
(standardized mean differences 0.165 [95% CI=0.051-0.278], p=0.004)
 Acute treatment not associated with an increased risk of treatment-
emergent mania or hypomania (0.926 [0.576–1.491], p=0.753)
 But: 52-week extension periods were associated with an increased risk
(1.774 [1.018 – 3.091], p=0.043)
McGirr et al., Lancet Psychiatry 2016; 3: 1138-1146 Slide credit: clinicaloptions.com

The Placebo Conundrum in Interpreting Trials in Bipolar
Depression
Response: citalopram=48%
Placebo=46% 1
1 Ghaemi et al., J Clin Psychiatry 2021; 81(1):19m13136
2 Ellegaard et al. J Affect Disord. 2019;245:1043-1051
Response: NAC=44%
Placebo=56% 2
CITALOPRAM N-ACETYLCYSTEINE
Slide credit: clinicaloptions.com
30
25
20
15
10
Mean
MADRS
Score
Week
6
0 1 2 3 4 5
Placebo
Citalopram
30
25
20
15
10
Mean
MADRS
Score
Week
24
Baseline
Placebo
NAC
2 10 20

Factors That Favor or Discourage Antidepressant Use
Favors Antidepressant Use Discourages Antidepressant Use
BP II BP I
Pure depressed episodes Mixed features
Absence of rapid cycling Past year rapid cycling
Absence of recent mania/hypomania Mania/hypomania in past 2-3 months
Absence of comorbid alcohol/substance use disorders Alcohol or substance use comorbidity
Prior favorable antidepressant response Suboptimal responses to prior antidepressants
No history of antidepressant-induced mania History of antidepressant-induced mania/hypomania
SLC6A4 l/l genotype SLC64 s/s genotype
Goldberg and Stahl, Practical Psychopharmacology, Cambridge Univ. Press, 2021 Slide credit: clinicaloptions.com

Quetiapine and Olanzapine/Fluoxetine Combination in
Bipolar Depression
Quetiapine
300 or 600 mg/day comparable
efficacy ~58% response rate (vs.
36% placebo)
Dropout due to adverse events:
Quetiapine: 13.1-23.3%
Placebo: 11.9%
OFC
6/25, 6/50, 12/50 mg/day
56% response rate (vs. 30%
placebo)
Dropout due to adverse events:
OFC: 2.3%
Placebo: 5.0%
1 Calabrese et al., Am J Psychiatry 2005; 162: 1351-1360;
2 Tohen et al., Arch Gen Psychiatry 2003; 60: 1079-1088 Slide credit: clinicaloptions.com

*P<0.05
**P<0.01
***P<0.001
Mean baseline
MADRS = ~30-31
Placebo + Li/VPA (n=161)
Lurasidone + Li/VPA (n=179)
Cohen’s d effect size: 0.34 (MMRM)
-13.5
**
*
***
***
-17.1
LS
Mean
Change
from
Baseline
Baseline Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Wk 6
-20.0
-15.0
-10.0
-5.0
0.0
Adjunctive Design
-20.0
-15.0
-10.0
-5.0
0.0
Baseline Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Wk 6
-10.7
-15.4
-15.4
*
*
**
***
***
**
**
***
***
***
Monotherapy Design
Cohen’s d effect size: 0.51 (MMRM)
Lurasidone 20-60 mg (n=161)
Lurasidone 80-120 mg (n=162)
Placebo (n=162)
Loebel et al., Am J Psychiatry. 2014;171(2): 160-168
Loebel et al., Am J Psychiatry. 2014 Feb;171(2): 169-717
Acute Efficacy of Lurasidone in Bipolar I Depression:
MADRS (MMRM) – Primary Efficacy Endpoint
Discontinuation due to adverse events: 5.9-6.6%
Discontinuation due to adverse events: 6.0%
Slide credit: clinicaloptions.com

Responder criteria: ≥50% reduction from baseline in MADRS at LOCF-endpoint
Number needed to treat (NNT) = 1 / % responders on active compound - % responders on PBO
Proportion
of
Patients
(%)
Placebo + Li/VPA
(N = 161)
Lurasidone + Li/VPA
(N = 179)
NNT = 7
Placebo
(N = 162)
Lurasidone
20-60 mg
(N = 161)
NNT = 5
Lurasidone
80-120 mg
(N = 162)
NNT = 5
Adjunctive Design Monotherapy Design
**P<0.01
***P<0.001
Lithium level & modal dose - 0.7 mEq/L & 900mg/d
Valproate level & modal dose - 75 ug/ml &1000mg/d
Acute Responder Efficacy of Lurasidone in BD I Depression
Loebel et al., Am J Psychiatry. 2014;171(2):160-168
Loebel et al., Am J Psychiatry. 2014 Feb;171(2):169-177 Slide credit: clinicaloptions.com
100
80
60
40
20
0
42%
**
57%
100
80
60
40
20
0
***
51%
***
53%
30%

Evidence-Based Treatments for Pediatric Bipolar
Depression
Other evidence-based pharmacotherapies:
 Lithium 6-week open label (+) trial
 Lamotrigine 8-week open label (+) trial 3
Detke HC et al. JAACAP, 2015; 54(3):217-224; Chang et al., J Am Acad Child Adolesc Psychiatry 2006; 45: 298-304
*Key Takeaway: Lurasidone and Olz/Flx are the only agents approved for Ped BPD
Slide credit: clinicaloptions.com
FDA-Approved Agents: NNT NNH (>7% weight gain)
Olanzapine-fluoxetine combination 6 3
Lurasidone 5 20

*
**
*
n=141
n=140
n=145
n=145
n=163
n=162
n=153
n=156
n=154
n=164
Logistic regression with LOCF, ITT Population
ClinicalTrials.gov IdentifierNCT02670538 (RGH-MD-53); Durgam et al., Am J Psychiatry, 2016 Mar 1;173: 271-281
Earley et al., Am J Psychiatry, 2019 176:439-448
Cariprazine: MADRS Response at Week 6 (≥50% MADRS
Total Score Reduction)
Dropout due to Adverse events:
8.2-11.6%
Dropout due to Adverse events:
4.5-5.5%
Slide credit: clinicaloptions.com
MADRS
Response
(%)
RGH-MD-56 RGH-MD-53 RGH-MD-54
60
40
20
0
Placebo
Cariprazine 0.75 mg/d
Cariprazine 1.5 mg/d
Cariprazine 3.0 mg/d

Cariprazine in Bipolar Depression With or Without
Manic Symptoms
 Pooled analysis of 3 randomized trials
McIntyre et al., CNS Spectrums 2020 Aug;25(4):502-510 Slide credit: clinicaloptions.com
*P < 0.05
**P < 0.01
***P ≤ 0.001
Placebo
Cariprazine 1.5 mg/d
**
*
***
***
LS
Mean
Change
from
Baseline
Baseline Wk 2 Wk 4 Wk 6
-16
-2
0
Patients With Manic Symptoms Patients Without Manic Symptoms
-4
-6
-8
-10
-12
-14
Cariprazine 3 mg/d
Placebo
Cariprazine 1.5 mg/d
LS
Mean
Change
from
Baseline
Baseline Wk 2 Wk 4 Wk 6
-16
-2
0
-4
-6
-8
-10
-12
-14
Cariprazine 3 mg/d
***
*
*
***
***
***
**
**

Cariprazine Efficacy in Bipolar Depression Across Clinical
Moderators
Patel et al., Int Clin Psychopharmacol 2021; 36: 76-83 Slide credit: clinicaloptions.com
*P < 0.05
**P < 0.01
***P < 0.001 versus placebo
Placebo
Cariprazine 1.5-3 mg/d
0
-2
-4
-6
-8
-10
-12
-14
-16
LS
Mean
Change
From
Baseline
Duration of
Current Episode
Number of Previous
Manic/Mixed Episodes
Number of Previous
Depressive Episodes
Predominant
Episode Pole
≤ 2.77
Months
> 2.77
Months
≤ 2
Episodes
> 2
Episodes
≤ 4
Episodes
> 4
Episodes
Manic ≥
Depressive
Manic <
Depressive
N= 237 454 223 469 190 414 266 506 224 232
469 450 152 297 308 626
LSMD -2.4 -2.9 -1.9 --3.3 -2.4 -2.9 -2.2 -2.9
*** *** *** ***
** **
*
*
-12.0
-14.4
-12.1
-15.0
-12.4
-14.4
-11.7
-15.0
-12.2
-14.6
-11.8
-14.8
-13.0
-15.2
-11.6
-14.5

Lumateperone in Bipolar I and II Depression
Durgam, et al., Poster presented at the American Society of Clinical Psychopharmacology
Ann Meeting May 29-30, 2020 Slide credit: clinicaloptions.com
Mean Change from Baseline to Day 43 in MADRS Total Score
LS
Mean
Change
from
Baseline
(SE)
0
-2
-4
-6
-8
-10
-12
-14
-16
-18
-20
ITT Bipolar I Bipolar II
n 188 188 150 150 38 38
Placebo
Lumateperone 42 mg
****
LSMD: -4.58
Effect size: -0.56
****
LSMD: -3.95
Effect size: -0.49
****
LSMD: -7.04
Effect size: -0.81
***P < .001, ****P < .001 LSMD vs. Placebo. MMRM
Effect size calculated as LSMD/pooled estimate of within subject error standard deviation.
ITT, intent-to-intent; LS, least squares; LSMD, least squares mean difference; MADRS, Montgomery-Asberg Depression Rating Scale; MMRM, mixed-
effects model for repeated measures; SE, standard error

Lumateperone in Bipolar I and II Depression
Durgam, et al., Poster presented at the American Society of Clinical Psychopharmacology
Ann Meeting May 29-30, 2020 Slide credit: clinicaloptions.com
Placebo
Lumateperone 42 mg
100
80
60
40
20
0
Patients
%
Responders
≥ 50% Decrease from Balance
Remitters
Total Score ≤ 12
37%
***
51%
34%
*
40%
MADRS Response and Remission at Day 43 in the ITT
*P < .05, ***P < .001 vs placebo in the ITT population. Responder and remitter analysis based on logistic
regression analysis with terms for site, treatment, and the bipolar disorder stratification at screening.
ITT, intent-to-treat; MADRS, Montgomery-Asberg Depression Rating Scale.

Evidence-Based Second Generation Antipsychotic Preparations
for Bipolar Depression: Most Common Adverse Effects
Agent Most Common Adverse Effects Weight Gain >7%
Drug Placebo
Quetiapine Somnolence (52%), dry mouth (37%), dizziness (13%),
constipation (8%)
8% 1 2.0% 1
OFC Weight gain (25%), dry mouth (15%), somnolence
(14%), fatigue (12%)
22% 2 1.8% 2
Lurasidone Somnolence (11%), akathisia (11%), nausea (14%),
EPS (14%)
2.4% 3 0.7% 3
Cariprazine Restlessness (2-7%), akathisia (6-10%), somnolence
(6-7%), insomnia (7-10%)
3.0% 4 1.0% 4
Lumateperone Headache (18%), somnolence (9%) 1.1% 5 1.1% 5
OFC=olanzapine-fluoxetine combination
1 Manufacturers Product Information, AstraZeneca; 2 Manufacturers Product Information, Eli Lilly & Co.;
3 Manufacturers’ Product Information, Sunovion; 4 Manufacturers’ Product Information, Allergan;
5 Durgam, et al., Poster presented at the American Society of Clinical Psychopharmacology
Ann Meeting May 29-30, 2020 Slide credit: clinicaloptions.com

First Generation Antipsychotics May Induce Depression After
Mania
2-fold ↑risk with haloperidol
vs. olanzapine 1
1 Tohen et al., Arch Gen Psychiatry 2003; 60: 1218-1226;
2 Zarate and Tohen, Am J Psychiatry 2004; 161: 169-171
Depression Relapse Over 6 Months
After Index Mania
Slide credit: clinicaloptions.com
21.1%
0%
25
20
15
10
5
0
MS+Perphenazine
(n = 19)
MS+Placebo
(n = 18)
Time to Switching to Depression, d
Probability
of
Not
Switching
to
Depression
1.0
0.8
0.6
0.4
0.2
0
100
0 10 20 30 40 50 60 70 80 90
Olanzapine
Haloperidol

Antipsychotic Risk for Depression After Mania in
Depression-Prone Bipolar Patients
Maccariello et al., J Clin Psychiatry 2020; 81(4): 19m12896 Slide credit: clinicaloptions.com
1 10
OR (95% CI)
4.29 (1.30-14.12)
1.28 (1.03-1.58)
1.07 (1.00-1.16)
1.05 (1.01-1.09)
3.87 (1.35-11.09)
Variables
Both FGAs and SGAs
CGI-BP total score at baseline evaluation
Depressive temperament
Age
Depressive predominant polarity
Wald = 24.567. P = .000. Variables not in the equation; FGAs, antidepressants, age at first episode, total
number of previous manic episodes.
Abbreviations: CGI-BP=Clinical Global Impressions scale for use in bipolar illness, FGAs=first-generation
antipsychotics, OR=odds ratio, SGAs=second-generation antipsychotics

Treating Anxiety Symptoms During Bipolar Depression
Agent Outcome
Olanzapine-fluoxetine
combination
Treats BP depression with or without comorbid anxiety, and reduces HAM-A
scores, better than placebo.1,2
Lurasidone Low dose (20-60 mg/day) or high dose (80-120 mg/day) lowers HAM-A
better than placebo 3
Quetiapine 300 mg/day or 600 mg/day lowers HAM-A better than placebo 4
In BP with comorbid panic disorder or GAD, quetiapine (mean dose 186
mg/day) > placebo or divalproex in lowering or CGI-A or HAM-A 5
1 Tohen, et al. 2007 J Affect Disord 104(1-3): 137-146; 2 Tohen et al. 2003 Arch Gen Psychiatry 60: 1079-1088; 3 Loebel, et al., Am J
Psychiatry 2014; 171: 160-168; 4 Hirschfeld, et al., J Clin Psychiatry 2006; 67: 355-362; 5 Sheehan, et al. 2013 J Affect Disord 145: 83-94
HAM-A=Hamilton Rating Scale for Anxiety
CGI-A=Clinical Global Impressions Scale for Anxiety
Slide credit: clinicaloptions.com

Novel Therapeutics

Anti-inflammatory Drugs for Bipolar Depression
Rosenblat et al., Bipolar Disord 2016; 18: 89-101
Agent Dosing Effect Size
Omega-3 fatty acids 1-6 gms/day EPA -0.36 (95% CI= -0.73 to 0.01)
NSAIDs Celecoxib 400 mg/day; aspirin 240 mg/day 0.02 (-0.52 to 0.56)
N-acetylcysteine 1-2 gms/day -0.75 (-1.22 to -0.28)
pioglitazone 15-30 mg/day -0.53 (-1.13 to 0.07)
EPA=eicosopentanoic acid
Slide credit: clinicaloptions.com

Pramipexole in Bipolar Depression
Outcome # Studies Effect Size 95% CI Z score p
Response (RR) 2 4.12 1.40 to 12.15 2.57 0.010
Remission (RR) 2 2.85 0.64 to 12.81 1.37 0.171
Drop-out due to adverse event (RR)
Drop-out due to any cause (RR) 2 1.56 0.21 to 11.64 0.44 0.663
Any scale acute (SMD) 2 -1.16 -1.82 to -0.51 3.49 0.000
Tundo et al., Acta Psychiatr Scand 2019; 140: 116-125 Slide credit: clinicaloptions.com

Ketamine and Esketamine
IV ketamine meta-analysis of 7 trials in MDD or BP depression: 1
 Response OR at 24 hours= 9.9 (95%CI=4.4-22.3)
 Response OR at 1 week= 4.6 (95%=2.1-10.2)
 May reduce suicidal ideation within 4 hours 2
1 Newport, et al., Am J Psychiatry 2015; 172: 950-966
2 Bartoli, et al., Neurosci Biobehav Rev 2017; 77: 232-236
3 McIntyre et al., Am J Psychiatry 2021; Mar 17;appiajp202020081251
2021 International Expert Opinion on Ketamine and Esketamine:
"The high rate of treatment-resistant depression in persons with bipolar disorder, as well as preliminary
evidence supporting the safety and efficacy of ketamine, would justify consideration of ketamine as an
investigational treatment in bipolar disorder “ 3
Slide credit: clinicaloptions.com

Neuromodulation: Vagal Nerve Stimulation in Bipolar
Depression
McAllister-Williams, et al. Int J Bipolar Disord 2020; 8:13 Slide credit: clinicaloptions.com
Time to Initial Response (Months)
Probability
of
Initial
Response
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
VNS+TAU
TAU
66
0 6 12 18 24 30 36 42 48 54 60
VNS + TAU
TAU
97
59
65
43
42
27
31
16
23
14
19
13
16
12
12
11
11
8
9
6
7
3
Treatment Group

Repetitive Transcranial Magnetic Stimulation (rTMS) in
Bipolar Depression
 Meta-analysis 14 randomized trials,
274 participants1
 Crude response rate=50.3%
(vs. 32.5% with sham control) (NNT=5.6)
1 Nguyen et al., J Affect Disord 2021; 279: 250-255
Stimulation Technique OR (Response), 95% CI
High frequency left-sided 2.57 (1.17-5.66)
Bilateral 2.05 (0.50-8.41)
Low frequency right-sided 5.21 (0.96-28.13)
Overall 2.72 (1.44-5.14)
Not FDA-approved in bipolar depression
Slide credit: clinicaloptions.com

Intermittent Theta Burst Repetitive Transcranial
Magnetic Stimulation in Bipolar Depression
4-week trial, 120% motor resting threshold targeting LDLPFC, n=37, iTBS vs. sham
Trial halted for futility (response=16% iTBS, 17% sham)
McGirr et al., JAMA Network Open 2021; 4(3): e210963 Slide credit: clinicaloptions.com
CGI
MADRAS
Time
MADRAS
score
35
30
25
20
15
10
5
0
Baseline 2 wk 4 wk
Sham iTBS
Active iTBS
Time
CGI
score
6
5
4
3
2
1
0
Baseline 2 wk 4 wk
Panel A shows the change in Montgomery-Asberg Depression Rating Scale (MADRS) score from baseline to study end at 4 weeks.
Panel B shows the change in scores on the Clinical Global Impression (CGI) Scale. Circles denote means, and error bars denote
standard error of the mean.

Transcranial Direct Current Stimulation for Bipolar
Depression
Sampaio-Junior et al., JAMA Psychiatry 2018; 75: 158-166
N=59 BP I or II depressed
outpatients on stable med
regimens
Ten daily 30 minute, 2mA,
anodal-left cathodal-right
prefrontal sessions on
weekdays, then 1 session every
fortnight until Week 6
Response: 67.6% (vs. 30.4% sham); NNT=2.69
Slide credit: clinicaloptions.com
Change in Depression Scores Over Time
Time
HDRS-17
Score
25
20
15
10
5
Baseline Week 2 Week4 Week 6
Sham tDCS
Active tDCS

Take-Home Messages
Slide credit: clinicaloptions.com
 Carefully assess and characterize bipolar depression; consider polarity
proneness, concurrent anxiety, severity, chronicity, treatment resistance
 Consider antidepressant “candidacy” criteria - a minority of bipolar pure-
depressed patients
 Variable antidepressant efficacy among “mood stabilizers,” adjunctive
efficacy of lamotrigine
 Robust acute effects for OFC, quetiapine, lurasidone, cariprazine,
lumateperone
 Emerging role for (es)ketamine, possibly other novel glutamatergic agents,
omega-3 fatty acids, pramipexole, neuromodulation

clinicaloptions.com
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