Navigating the Spectrum of Bipolar Disorder:

New Options with Novel Mechanisms of Action

Julie Carbray, PhD, APRN, FPMHNP-BC Craig Chepke, MD, DFAPA

Clinical Professor of Psychiatry and Nursing Adjunct Associate Professor of Psychiatry,
Director Pediatric Mood Disorder Clinic Atrium Health
Institute for Juvenile Research, Medical Director,
Department of Psychiatry Excel Psychiatric Associates
University of Illinois Chicago

Supported by an educational grant from Intra-Cellular Therapies, Inc.

 Faculty Disclosures
• Craig Chepke: Advisory Board—AbbVie, Acadia, Alkermes, Axsome, Biogen, Corium, Idorsia,
Intracellular, Janssen, Karuna, Lundbeck, Moderna, Neurocrine, Noven, Otsuka, Sage, Sumitomo,
Teva; Advisory Board (Spouse)—Otsuka; Consultant—AbbVie, Acadia, Alkermes, Axsome,
Biogen, Corium, Intracellular, Janssen, Karuna, Lundbeck, MedinCell, Moderna, Neurocrine,
Noven, Otsuka, Sage, Sumitomo, Teva; Grant Research/Support—Acadia, Axsome, Harmony,
Neurocrine, Teva; Speaker’s Bureau—AbbVie, Acadia, Alkermes, Axsome, Corium, Intracellular,
Janssen, Karuna, Lundbeck, Merck, Neurocrine, Noven, Otsuka, Sunovion, Teva.

• Julie Carbray: Advisory Board—Supernus, Karuna, Alkermes; Consultant—Karuna, Otsuka.

 Learning Objectives
• Summarize the challenges associated with recognition and
diagnosis/classification of BD, including distinguishing it from other mental
health conditions and accurately characterizing its features
• Describe the burden of cardiometabolic symptoms, such as weight gain, and
other AEs associated with conventional BD treatments, and their impact on
patient outcomes
• Discuss the safety and efficacy of newer and novel agents for BD
management and their respective treatment implications, including their
potential to mitigate AEs and/or address specific BD features
• Implement appropriate patient-centered strategies for BD management to
improve treatment outcomes and patient quality of life
 Introduction to Bipolar Disorder

Julie Carbray PhD, FPMHNP-BC, PMHCNS-BC, APRN

Clinical Professor of Psychiatry and Nursing
Director Pediatric Mood Disorder Clinic
Institute for Juvenile Research,
Department of Psychiatry
University of Illinois Chicago
 Bipolar Disorder and Disability
Global burden of disability over last 20 years increased
by 45 million

Bipolar Disorders 6th leading cause of disability

More gender variation in depression/anxiety F>M

GBD 2019 Mental Disorders Collaborators. Lancet Psychiatry. 2022; 9(2):137-150. Copyright © 2022 The Author(s). Published by Elsevier
Ltd. This is an Open Access article under the CC BY 4.0 license Terms and Conditions.
MyDisbilityJobs.com. Bipolar Disorder Employment Statistics – Update 2023. Accessed August 18,2023.
https://mydisabilityjobs.com/industry-news/bipolar-disorder-employment-statistics.
 Burden of Illness

Burkhardt E, et al. Clinical Risk Constellations for the Development of Bipolar Disorders. Medicina. 2021;57(8):792.
 Bipolar Disorder and the
Vast Variety of Its Presentations

The Core Patterns of BD

i = bipolar I disorder; ii = bipolar II disorder; iii = subsyndromal bipolar symptoms;
iv = mixed states; v = rapid cycling; red = hypo-mania; blue = depression; green = euthymia.

Malhi GS, et al. Bipolar Disord. 2012;14 Suppl 2:66-89.

 Bipolar Disorder Is Often Complex to Diagnose
Tips on Differentiating BD from MDD
Disorders Most Difficult to Differentiate From Bipolar Best Predictors for Achieving Differential Diagnosis between
Disorder MDD vs BD

Accurate Family History

13% Boderline Personality Corroborating Evidence

Disorder 20
29 from Family
36% Unipolar Depression
20% Clinical Presentation
ADHD
24
Schizophrenia Evidence of Early Age at
31% 27 Onset of Depressive
Symptoms

N = 154 N = 168

McIntyre RS, et al. J Clin Psychiatry. 2019;80(3).

 Psychiatric Comorbidities in
Bipolar Disorder
Borderline Personality
Addictive Disorders a ADHD b
Disorder c
• 56% of patients with • 5-10% of patients with • Seven-fold higher
BD1 will be diagnosed ADHD will progress to likelihood of comorbid
with a SUD BD diagnosis borderline personality
• Patients with comorbid disorders
• 1 in 10 patients will ADHD have worse
experience problem performance on
gambling executive functions,
verbal learning and
memory domains
compared to ADHD
alone
a. Preuss U, et al.Medicina. 2021;57(11):1256; b. Hossain S, et al. Cureus. 2019;11(9):e5636; c. Comparelli A, et al. Front. Psychiatry. Sec.
Mood Disorders. 11 August 2022;13.
Jones L, et al. 2015; The British Journal of Psychiatry. 2015;07(4):328–333.
 Bipolar I and II:
Examining the Differences Between Manic & Hypomanic Episodes

Bipolar I Bipolar II
• Abnormally & persistently elevated, expansive or • Abnormally & persistently elevated, expansive or
irritable mood & abnormally or persistently irritable mood & abnormally or persistently
increased goal-directed activity increased goal-directed activity
• Lasting at least 7 days, most • At least 4 days, most of the day, nearly every day
of the day, nearly every day
(unless hospitalized)

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. American
Psychiatric Publishing; 2013.
 Bipolar I and II:
Examining the Differences Between Manic & Hypomanic Episodes

Bipolar I Bipolar II
• 3 or more of the following; 4 if irritable: • 3 or more of the following; 4 if irritable:
– Inflated self esteem or grandiosity – Inflated self esteem or grandiosity
– Decreased need for sleep – Decreased need for sleep
– More talkative than usual – More talkative than usual
– Flight of ideas or racing thoughts
– Flight of ideas or racing thoughts
– Distractibility
– Distractibility
– Increase in goal-directed activity or psychomotor agitation
– Increase in goal-directed activity or psychomotor agitation – Activities with painful consequences
– Activities with painful consequences – Unequivocal change in functioning; observable by
– Marked impairment, hospitalization needed, or psychosis others
– Not due to substance or other medical condition – No marked impairment, hospitalization needed, or
psychosis
– Not due to substance or other medical condition

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. American
Psychiatric Publishing; 2013.
“Is this Major Depression or Bipolar II Depression?”
Some Risk Factors
The prodromal elements below increase the risk that what we are seeing is
Bipolar II Depression vs Major Depression

Patients with BD-II, as compared to Major Depression

experienced:

• Experience both insomnia and hypersomnia during the Bipolar II Major

Depression
depressive episode (p=.04) Depression

• More likely to have experiences > 5 previous mood

episodes 61 % vs 12% (p<.0001)

• Earlier age of onset (p =.003)

Rastelli CPB, et al. J Affect Disord. 2013 September 25;150(3):1120–1124.

 Strategies to Accurately Identify
BP-I Depression and BP-II Depression
• Never make a diagnosis of Major • Use screening instruments such as the
Depression without proactively MDQ
assessing for mania/hypomania is
past/currently • Look for family history – BD is a highly
genetic disorder
• Acquire collateral information from
family/friends • Early onset, multiple episodes of
depression, poor response to anti-
• If patient presents with irritability, depressants (amongst others) are all
distractibility, insomnia, substance markers of accurate Bipolar Disorder
misuse (amongst other) symptoms,
proactively look for Bipolar Disorder • Watch out for hypomanic episodes! They
are tricky to detect. Yet, its crucial to look for
them to establish an accurate dx of Bipolar
Disorder Type II

Phillips ML, et al. Lancet. 2013 May 11;381(9878):1663-71.

Key Learning Points
• The diagnosis of BD-I requires a manic episode that
lasts at least 7 days, whereas BD-II requires a
hypomanic episode for least 4 days
• Mania in BD-I always causes marked impairment in
functioning
• In BD-II, hypomania does not cause marked impairment,
which can make it more difficult to detect; but the
depressive episodes cause profound impairment
• Patient treatment priorities may not highlight symptom
clusters without collateral
Understanding Bipolar Disorder with Mixed Features
 Bipolar Depression with Mixed Features
• Mixed= symptoms of > 3 or =
symptoms of mania and depression
occurring simultaneously • Prevalence across MDD and Bipolar
Conceptualization of Bipolar Mixed States in DSM-IV-TR vs DSM-5 Editions Disorder is 11%-70%

• Heterogeneous presentation can

increase risk of misdiagnosis

• Prescence of mixed features

increases complexity of treatment,
morbidity risk and leads to poorer
outcomes
DSM-IV-TR=Diagnostic and Statistical Manual of Mental Disorders, 4th Ed., Text Revision; DSM-5=Diagnostic and Statistical Manual of Mental Disorders, 5th Ed.
Figure: Used with permission from Hu J, et al (2014) Prim Care Companion CNS Disord 16(2).
McIntyre R, et al. J Clin Psychiatry. 2023;84(3). McIntyre R, et al. CNS Spectr. 2020;25(4):502-510. McIntyre R, et al. J Affect Disord. 2015;172:259-264. Hu J, et al.
Prim Care Companion CNS Disord. 2014;16(2). Baldessarini RJ, et al. Journal of Affective Disorders. 2010;126(1-2):299-302.
 Mixed Episodes Across Bipolar Disorder
Prevalence of DSM-5 Mixed Features Specifier in Adults with • 25-45% of patients with BPD I, II
Major Depressive Disorder of Bipolar Disorder
and MDD have mixed episodes

• Those with mixed episodes also

have higher rates of SUDs, and
comorbid cardiovascular disease

• First do no harm

• Unmet need for treatment for mixed

episodes

BD=bipolar disorder; MDD=major depressive disorder; MFS=mixed features specifier.

McIntyre R, et al. J Clin Psychiatry. 2023;84(3). McIntyre R, et al. J Affect Disord. 2015;172:259-264. Jain R, et al al. J Clin Psychiatry. 2017;78(8)
1091-1102.
 Screening Tools
• Young Mania Rating Scale - YMRS • Mixed episode criteria >1, 2, 3
• Montgomery Asberg Depression symptoms of each depression and
Rating Scale - MADRS mania/hypomania
• Hamilton Depression Rating Scale -
HAMD -17 item
• Mood Disorder Questionnaire –MDQ
• Rapid Mood Screener
Tools help elicit the signature of episodes

McIntyre R, et al. J Clin Psychiatry. 2023;84(3). McIntyre R, et al. J Affect Disord. 2015;172:259-264. Jain R, et al al. J Clin Psychiatry. 2017;78(8)
1091-1102. Thase M, et al. Prim Care Companion CNS Disord. 2023;25(2).
 BPD and Anxious Distress
• Estimated lifetime prevalence of at
least one anxiety disorder 40-60%

• Patients with comorbid anxiety have:

– More depressive and
manic/hypomanic episodes
– Shorter periods of euthymia No approved
medication for
Current options
to treat anxiety
More research is
needed to
– Shorter time to relapse BPD and Anxiety in BPD may be
contraindicated
address how to
address anxious
– More suicidal behavior Off label
distress

– Increased substance abuse issues medications are

often used
Polypharmacy is
common
– Greater risk of residual symptoms
– Reduced quality of life and
functioning
McIntyre R, et al. Curr Med Res Opin. 2020;(35):1993-2005. Sylvia LG, et al. Int J Bipolar Disord. 2017;5(1):10. Pennix B, et al. Lancet
2021;397(10277): 914-927. Yatham LN, et al. Bipolar Disord. 2018;20(2):97-170. Jain R, et al. Inter Clin Psychopharm. 2024;39(2):82-92.
Key Learning Points
• Mixed features can be present across mood
disorders and can result in more polypharmacy,
poorer outcomes and prognosis
• Anxious distress with bipolar illness is a
common feature and complicates the treatment
approach
• Screening tools can help clinicians and their
patients determine personalized treatment
targets to address their bipolar illness
Appreciating the Weight Gain and
Cardiometabolic Challenges in
Bipolar Disorder
 Weight Gain is the One Adverse Event Causing the
Highest Discontinuation Rates
DBSA Survey. 896 participants completed
the survey 49.9% unipolar depression and
50.1% bipolar depression

Current pharmacotherapy of Bipolar

Disorder is sub-optimum in. terms of
tolerability –

Top Side effects –

• Weight gain
• Lethargy
• Sleepiness
• Blunted emotions
• Anxiety
• etc
Rosenblat JD, et al. Journal of Affective Disorders. 2019;243:116–120.
 Weight Gain Can Be a “Dealbreaker” Side Effect
70
Reasons for Treatment Discontinuation
Reported Side Effects as Very or
Percentage of Participants who

60
Extremely Bothersome

50

40

30

20

10

0
Weight Trouble Feeling Sexual Anxiety Feeling Restless- Dry Involuntary Feeling Digestive Dizziness/
gain concentrating drowsy dysfunction (n=158) like a ness mouth spasms lack of problems fainting
(n=150) (n=141) or tired (n=133) “zombie” (n=146) (n=150) (n=123) emotion (n=135) (n=123)
(n=165) (n=137) (n=157)

A separate survey by DBSA found that people with BP-I cited weight gain as
the most common side effect that caused medication discontinuation (56%)
BD = Bipolar Disorder; DBSA = Depression and Bipolar Support Alliance.
Bessonova, L, et al. BMC Psychiatry. 2020;20:354. DBSA Survey Center – Depression Experiences and Treatments Survey. May 2017. Accessed
2/15/2024. https://www.dbsalliance.org/wp-content/uploads/2019/02/DBSASurveyCenterDepressionExperiences.pdf.
 Bipolar Disorder and Health Outcomes
“BMI adversely affects disease “Bipolar disorder increases
course in bipolar illness” mortality risk more than smoking”
• STEP-BD study, a 7-year, longitudinal
study conducted across 22 academic
psychiatric centers in the United States
• Monitored symptoms, outcomes
across patients with Bipolar Disorder
• In those with Bipolar Disorder elevated
BMI was associated with worsening
clinical features, including higher rates
of suicidality, comorbidities, and core
depression symptoms.

BMI=body mass index.

Yocum AK, et al. Psychiatry Research. 2023;330:0165-1781. Kadriu B, et al. Bipolar Disord. 2023 Aug 3:doi.org/10.1111/bdi.13370
 Risks and Factors
Contributing to Obesity

Bio Psycho Social

• Metabolism • Sleep quality • Availability of processed
• Hormonal regulation • Anhedonia foods
• Age, gender • Low motivation • Social norms
• Genetic factors • Attitudes toward weight • Work and family
• Baseline activity level and health obligations
• Hedonic threshold • Inpatient treatment • Neighborhood walkability
• Medical conditions and • Coping skills and • Level of non-exercise
medication emotional regulation physical activity
• Comorbid substance use
disorders
 Role of Endogenous Opioid System
CNS-Targeting Pharmacological Interventions for the Metabolic Syndrome

Image: Stemmer K, et al. J Clin Invest. 2019;129(10):4058-4071. doi: 10.1172/JCI129195

 Off-Label Strategies to Address Weight Gain
Intervention Outcomes Limitations
Diet, exercise,
9 lb. weight loss @ 6 months in STRIDE Adherence and access challenges
lifestyle management
Meta-analysis of 12 randomized trials in GI side effects, lactic acidosis risk,
Metformin
schizophrenia: mean weight reduction = 7.2 lb. works best as prevention
GLP-1 receptor liraglutide: 11.7 kg weight loss from Daily-weekly subcutaneous injections,
agonists antipsychotics in schizophrenia coverage limited without T2DM diagnosis
Topiramate or Modest reported mean weight loss (~3-6 lb.) Frequent CNS side effects,
Zonisamide across agents over several months including cognitive changes
7–8 lb. weight loss in patients with
Naltrexone/bupropion GI side effects common, coverage
schizophrenia with antipsychotic-associated
combination challenges
weight gain

GI=gastrointestinal; GLP-1=glucagon-like peptide-1; SC=subcutaneous.

Green CA, et al. Am J Psychiatry. 2015;172(1):71-81. de Silva VA, et al. BMC Psychiatry. 2016;16(1):341. Larsen JR, et al. JAMA Psychiatry.
2017;74(7):719-728. Zheng W, et al. J Clin Psychopharmacol. 2017;37(3):341-346. Tek C, et al. J Clin Psychopharmacol. 2014;34(5):608-612.
 Lifestyle Interventions
• Eat a varied, whole-food, plant-
based diet
• Increase physical activity • Eat a varied, whole-food, plant-
• Improve sleep quality based diet
• Maintain quality relationships
• Increase physical activity
• Avoid substance use
• Manage stress • Improve sleep quality
• Maintain quality relationships
• Avoid substance use
• Manage stress

Image: Am. College of Lifestyle Medicine. 2022. Accessed May 31, 2023. https://lifestylemedicine.org/
Key Learning Points

• Weight gain is a common cause of

discontinuation for medications used to treat
bipolar disorder
• Treatment plans should be designed keeping
this - and other common causes of
discontinuation - in mind
 Understanding Limitations in the
Landscape of Treatment Options in
Bipolar Disorder
Craig Chepke, MD, DFAPA
Adjunct Associate Professor of Psychiatry, Atrium Health
Medical Director, Excel Psychiatric Associates
Huntersville, North Carolina
 Outpatient Bipolar Disorder Treatment:
20-Year Trends
70
SGAs
60 Any Mood Stabilizer
Lithium
50 Non-lithium Antiepileptic
Mood Stabilizers
Percent (%)

Antidepressants
40

30 Comparing 2015-16 to 1997-98

Lithium scripts fell by almost 50% while
20 Antipsychotic prescriptions nearly tripled

10
Antidepressants were prescribed
for people with bipolar disorder
0 almost twice as often as lithium
’97–’98 ’99–’00 ’01–’02 ’03–’04 ’05–’06 ’07–’08 ’09–’10 ’11–’12 ’13–’14 ’15–’16
in 2015-2016
Year
SGA = second-generation antipsychotic.
Rhee TG, et al. Am J Psychiatry. 2020;177(8):706-715.
 Limitations of Treatments for Bipolar Disorder
Lamotrigine Carbamazepine Lithium Divalproex
•Risk of SJS/TEN •Risk of SJS/TEN •Narrow therapeutic •Hepatotoxicity
•Slow titration •Aplastic anemia, index (blood levels) •Pancreatitis
restart if >5d missed agranulocytosis •Long-term thyroid •Very teratogenic
•Class warning of SI •Class warning of SI and kidney damage •Class warning of SI
•Hormonal treatment •Teratogenic •Tremor, GI issues •Tremor, GI issues
interaction •Extensive drug-drug •Hair loss •Hair loss, Sedation
•Only effective against interactions •Weight gain •Weight gain
depressive episodes •Benefit in mania

Antipsychotics
•FGAs may induce depression •Drug-induced movement disorders
•Prolactin elevation •Metabolic disorders
•Sedation •Weight gain
GI = gastrointestinal; SI = suicidal ideation; SJS/TEN = Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis. FGA = First-Generation Antipsychotic.
Ghaemi SN. Clinical Psychopharmacology: Principles and Practice. Oxford University Press; 2019. Altshuler L, et al. Am J Psychiatry. 2003;160(7):
1252-1262. El-Mallakh RS, et al. J Affect Disord. 2015;184:318-321. Pacchiarotti I, et al. Am J Psychiatry. 2013 Nov;170(11):1249-62. Kane JM. J Clin
Psychiatry. 2004;65 Suppl 9:16-20. Correll CU, et al. JAMA Psychiatry. 2014;71(12):1350-1363. Gigante AD, et al. CNS Drugs. 2012;26(5):403-420.
 Mechanisms of Action in the
Treatment of Bipolar Disorder
 Receptor Targets for Bipolar Disorder:
Looking for Ties that Bind
H1
Antimanic Effects

blockade
D1
blockade
D1 D2 D3 5-HT1A 5-HT2A 𝛂1 H1/M1 SERT NET
Receptor Affinities (ki, nM)
Olanzapine-
56.6 30.8 38.1 2063 4.0 19 High High -
NE 5-HT1A Fluoxetine
reuptake agonism
Quetiapine 428 626 394 1040 38 14.6 High - -
Antidepressive Effects

M
blockade norquetiapine 99.8 489 - 45 2.9 46.4 High - High
alpha-1 5-HT2A
Lurasidone 262 0.66 15.7 6.75 2.03 47.9 Low - -
blockade blockade
D2/D3 Cariprazine - 0.49 0.09 2.6 18.8 - Low - -
blockade
Lumateperone 41 32 - - 0.54 31-73 Low Mod -

Ach/DA balance interaction

Among all medications studied for bipolar depression,
the receptor bindings present in the highest ratio of
5-HT2A, 𝛂1,
NE/Ach balance interaction efficacious : non-efficacious medications were: D1, and D2
NE/5-HT balance interaction

Fountoulakis, KN et al. European Neuropsychopharmacology. 2024;8:1-9. Goldberg JF, et al. Practical Psychopharmacology. Cambridge
University Press; 2021:17-19. Quetiapine XR - Prescribing Information. AstraZeneca; 2020. Li P, et al. Journal of Medicinal Chemistry.
2014;57(6):2670-2682. Snyder GL, et al. Psychopharmacology. 2015;232(3):605-621.
Potential Receptor Effects Mediating Efficacy in BD:
An Ensemble Cast
Receptor Activity Potential Effects
5-HT1A partial agonism Increases dopamine in medial PFC; anxiolytic & antidepressant action
5-HT2A antagonism Increases DA in PFC/striatum: ↑attention/working memory; antidepressant effect
5-HT2C antagonism Increases dopamine and norepinephrine in cortex; antidepressant effect
5-HT3 antagonism Indirectly facilitates release of acetylcholine, dopamine, and norepinephrine
5-HT7 antagonism Enhances serotonin and glutamate release; antidepressant & procognitive effects
𝛂1 antagonism Similar to (and can be synergistic with) 5-HT2A antagonism
𝛂2 antagonism Enhances release of monoamines
D1 modulation May indirectly increase glutamate signaling; ↑ learning, reward, neuroplasticity
D2 antagonism/partial agonism Antimanic effect
D3 antagonism/partial agonism May increase signaling in reward pathway

DA = dopamine; PFC = prefrontal cortex.

Goldberg JF, et al. Practical Psychopharmacology. Cambridge University Press. 2021:17-19. Stahl, SM. Stahl’s Essential
Psychopharmacology. Cambridge University Press, 2021.
Potential Receptor Effects Implicated in Weight Gain
Receptor Activity Potential Effects
H1 antagonism Appetite/weight increase (especially when paired with 5-HT2C antagonism)
M3 antagonism May interfere with cholinergic actions on insulin secretion
5-HT2C antagonism Appetite/weight increase (especially when paired with H1 antagonism)
5-HT2A antagonism May interfere with serotonergic actions on insulin secretion
𝛂1 antagonism May decrease insulin secretion
D2 antagonism Facilitates pancreatic insulin release, leading to insulin resistance

Some neurotransmitter systems implicated in

energy homeostasis may overlap with those
involved in therapeutic action of antipsychotics

Raben AT, et al. Frontiers in Neuroscience. 2018:741. Hahn M, et al. Schiz Research. 2011;131(1-3):90-5. Matsui-Sakata A, et. al.
Drug Metabolism and Pharmacokinetics. 2005;20(5): 368-378.
Novel Treatment Options to Address Challenges in
The Management of BD
Olanzapine-Samidorphan
 Efficacy of Olanzapine Monotherapy in
Acute Manic and Mixed Episodes of Bipolar I Disorder
Network Meta-Analysis of All-Cause
Discontinuation in Acute Manic/Mixed Episodes
3-Week Acute Pivotal Study 4-Week Acute Pivotal Study
Mean change in YMRS Mean change in YMRS
vs placebo = -5.4 (P=0.02) vs placebo = -6.7 (P<0.001)
Response rate Also Response rate
49% vs 24%; NNT=4 2 positive 65% vs 43%; NNT=5
studies
adjunct to
Mean weight change Li/VPA Mean weight change
olanzapine: +3.63 lb olanzapine: +4.86 lb
placebo: -0.97 lb placebo: +0.99 lb

Both monotherapy studies showed olanzapine has equal efficacy

in two difficult-to-treat populations: with or without psychotic
features and those with mixed vs. pure manic episodes
Fewer all-cause discontinuations
Weight gain, somnolence, dry mouth, and dizziness
were common adverse events in both trials;
Olanzapine is hard to beat in monotherapy for acute
Pooled D/C due to AE: olanzapine=2% and placebo=2% mania/mixed episodes: robust efficacy and effectiveness

YMRS = Young Mania Rating Scale; NNT = Number Needed to Treat; VPA =valproic acid; D/C = discontinuation; AE = adverse event.
Tohen M, et al. Am J. Psych. 1999;156(5):702-709. Tohen M, et al. Arch Gen Psych. 2000;57(9):841-849. Yildiz, A, et al. Psychol Med. 2015;45(2):299-317.
 Olanzapine Monotherapy Prevents All 3 Types of
Mood Episodes in Maintenance of Bipolar I
1.0 Time to Symptomatic Relapse
Into Any Mood Episode
Responders to 6-12 weeks of open-label olanzapine
were randomized to placebo or continued treatment
0.8
Median time to relapse into any Mean dose

More relapses
NNT=3 mood episode for olanzapine vs 12.5 mg 0.6
for relapse placebo: 174 days vs. 22 days
prevention
Olanzapine monotherapy significantly reduced 0.4
the risk of all 3 types of mood episodes:
manic, depressive, and mixed
0.2
Olanzapine (N=225)
Placebo (N=136)
Mean weight change in open-label 0
Discontinuation due 0 50 100 150 200 250 300 350 400
stabilization: +6.6 lb to adverse events
In double-blind maintenance: for those taking
olanzapine +2.2 lb, placebo = -4.4 lb olanzapine = 7.6% Olanzapine is the only medication with efficacy as
monotherapy to prevent relapse into manic, depressive,
and mixed episodes in patients with an index mixed episode
NNT = Number needed to treat.
Tohen M, et al. Am. J. Psychiatry. 2006;163(2):247-256. Yatham LN, et al. Bipolar Disorders. 2018;20(2):97-170.
 Weight Gain with Olanzapine Use in Adults:
Findings from 86 Clinical Trials
Amount 6 Weeks 6 Months 12 Months 24 Months 36 Months
Gained (N=7465) (N=4162) (N=1345) (N=474) (N=147)
≤0 lb 26.2% 24.3% 20.8% 23.2% 17.0%

More weight gain

0 to ≤11 Ib 57.0% 36.0% 26.0% 23.4% 25.2%
11 to ≤22 Ib 14.9% 24.6% 24.2% 24.1% 18.4%
22 to ≤33 lb 1.8% 10.9% 14.9% 11.4% 17.0%
33 to ≤44 Ib 0.1% 3.1% 8.6% 9.3% 11.6%
44 to ≤55 Ib 0% 0.9% 3.3% 5.1% 4.1%
55 to ≤66 Ib 0% 0.2% 1.4% 2.3% 4.8%
>66 lb 0% 0.1% 0.8% 1.2% 2%

≤2% 2% to <10% 10% to <20% 20% to <33% >33% For some people,
olanzapine weight gain
can’t stop, won’t stop

Zyprexa (olanzapine) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2020. Millen BA, et. al. J. Psychopharmacol. 2011;25(5):639-645.
The Role of Opioid Receptor Antagonists in
Mitigating Weight Gain
Samidorphan MOA Video Placeholder
 Opioid Receptor Antagonism:
Different Receptors, Different Effects
Food
Mu antagonist

Blocking mu-opioid receptors in the VTA

β-EP inhibits dopamine release in the NAc,
Mesolimbic
reducing the excessive reward signaling of
Pathway hedonic eating for highly rewarding foods.
Dopamine
GABA GABA
interneuron
VTA NAc

Mu Knockout Mice Kappa Knockout Mice Delta Knockout Mice

Effects of Opioid •Reduced weight gain/fat mass •Reduced weight gain/fat mass •Reduced weight gain per
Receptor Knockouts despite a high-energy diet despite a high-energy diet Calorie consumed
in Mouse Models of •Protective against insulin •Elevated levels of spontaneous •Greater energy expenditure
Metabolism resistance in aging mice fed a locomotor activity, no increase •Greater thermogenesis in
high-fat diet in thermogenesis brown adipose tissue.

MOR = Mu Opioid Receptor; VTA = ventral tegmental area; Nac = Nucleus Accumbens; β-EP = β-endorphins
McIntyre RS, et al. CNS Spectrums. 2023;28(3):288-299. Glass MJ, et al. Neuropeptides. 1999;33(5):360-368. Czyzyk TA, et al. The FASEB
Journal. 2012;26(8):3483. Heilig M, et al. Nature Reviews Neuroscience. 201112(11):670-684.
 Opioid Receptor Antagonists:
Different Medications, Different Results
Naltrexone Samidorphan
HEAT
Half-Life 4 hours 7-9 hours
Bioavailability 5%–40% 69%

Ratio of Receptor Blockade Potency

for Samidorphan vs Naltrexone Mitochondrion

0 2 4 6 8 10 12 14 16 18 20
Delta opioid antagonism may
5.5x increase energy expenditure,
mu
mu Greater than
naltrexone
in part, via thermogenesis in
Brown Adipocyte brown adipose tissue
3.4x
kappa
kappa Greater than
naltrexone
Brown Adipose Tissue

18.8x Samidorphan and naltrexone have

delta
delta Greater than distinct pharmacokinetic and pharmacodynamic
naltrexone properties and are not interchangeable

Tan LA, et al. Neuropsychiatric Disease and Treatment. 2022;18:2497-2506. McIntyre RS, et al. CNS Spectrums. 2023;28(3): 288-299.
OLZ-SAM had Significantly Less Weight Gain vs OLZ in a
6-mo Head-to-Head Study of Adults with Schizophrenia
% Change in Body Weight for Olanzapine-Samidorphan vs Olanzapine
7%
% CFB in Body Weight (LS Mean)

6%
Olanzapine
Olanzapine-Samidorphan
6.6% 50%
Lower chance of
gaining ≥7% or
More weight gain

5%
≥10% body
4% weight
4.2%*
3% *P=0.003

2%
Olanzapine-samidorphan’s mean weight change appears
to plateau after ~6 weeks, but olanzapine’s does not
1%

0
0 1 2 4 6 8 12 16 18 24
Week
OLZ (n) 272 269 265 249 244 233 220 202 187 175
OLZ-SAM (n) 266 265 248 236 229 218 214 199 185 177

Adding samidorphan to
A previous study demonstrated that samidorphan did olanzapine mitigates weight gain,
not impair the efficacy of olanzapine in schizophrenia but not antipsychotic efficacy
OLZ = Olanzapine; SAM = samidorphan; CFB = change from baseline; LS =l east-squares
Correll CU, et al. Am J Psychiatry. 2020;177(12):1168-1178. Potkin SG, et al. The Journal of Clinical Psychiatry. 2020;81(2):5960.
 OLZ-SAM Weight Remained Stable in a
1-Year Open-Label Study of Adults with Schizophrenia
Mean Body Weight Over Time
184.8 Prior double-blind study All participants receiving open-label olanzapine-samidorphan
Mean Body Weight, lb

Over the 52-wk open-label period

More weight gain

180.4
Mean weight and metabolics
remained stable
176

≥7% weight gain: 21.5%

171.6 ≥7% weight loss: 21.1%
Olanzapine
OLZ-SAM OLZ-SAM
167.2
Week 0 4 8 12 16 20 24 0 2 4 6 8 12 16 20 24 28 32 36 40 44 48 52
Olanzapine (n) 272 249 233 220 202 187 175 OLZ-SAM (n)
265 255 244 236 225 213 209 201 193 186 180 174 172 168
OLZ-SAM (n) 266 236 218 214 199 185 177 262 250

Further long-term data from 523 participants with bipolar I or schizophrenia

with up to 4 years of open-label treatment with olanzapine-samidorphan
Long-term treatment was associated with Symptoms remained 35.9% completed
minimal changes in lipid/glycemic parameters stable as measured by the 4-year
and weight (mean CFB +3.2 lb) CGI-S (mean CFB -0.28) treatment period

OLZ = Olanzapine; SAM = samidorphan; CFB = change from baseline; CGI-S = Clinical Global Impression of Severity
Kahn RS, et al. Schizophr Res. 2021;232:45-53. Correll CU, et al. Am J Psych. 2020;177(12):1168-1178. Potkin SG, et al. J Clin Psych. 2020;81(2):61-64.
Accessed 2/4/24. https://investor.alkermes.com/news-releases/news-release-details/alkermes-announces-topline-results-long-term-open-label-safety.
Key Learning Points

• Olanzapine is the only medication with efficacy

as monotherapy to prevent relapse into manic,
depressive, and mixed episodes in patients with
an index mixed episode
• Adding samidorphan to olanzapine mitigates its
weight gain, but not its efficacy in schizophrenia
or bipolar I disorder
Lumateperone
 Lumateperone is Approved for a Wide Spectrum
of People with Bipolar I and II Depression
2003 2006 2013 2019 2021

Olanzapine/ Quetiapine Total

Lurasidone Cariprazine Lumateperone
Fluoxetine (IR and XR) Options

Has FDA Approval in

Monotherapy
Bipolar Depression ✓ ✓ ✓ ✓ ✓ 5
Bipolar I Adjunct to
Lithium or ✓ ✓ 2
Valproate

Monotherapy ✓ ✓ 2
Bipolar II Adjunct to
Lithium or ✓ 1
Valproate

Lumateperone. Prescribing information. Intra-Cellular Therapies; 2021. Quetiapine. Prescribing information. AstraZeneca; 2021.
Quetiapine XR. Prescribing Information. AstraZeneca; 2020. Olanzapine/fluoxetine. Prescribing information. Eli Lilly, Inc; 2021.
Lurasidone. Prescribing information. Sunovion Pharmaceuticals Inc; 2019. Cariprazine. Prescribing information. AbbVie plc; 2019.
Lumateperone MOA Video Placeholder
 Lumateperone Mechanism of Action:
Receptor Binding 5-HT :D 2A 2 ratio
0 10 20 30 40 50 60

1 Lumateperone ~60x
Ki (nM, inverse log scale)
Stronger Binding Affinity

Clozapine
Lumateperone acts as a full antagonist
at postsynaptic D2 receptors, but acts as a Iloperidone
partial agonist at presynaptic D2 receptors
10 Risperidone Lumateperone’s 60x greater
selectivity for 5-HT2A to D2
Olanzapine receptor affinity is higher
than that of any other
antipsychotic
Quetiapine
0.54 31 32 33 41 73
100 Lurasidone
5-HT2A
5-HT2A ⍺1A
𝛂1A D
D2
2 SERT
SERT D1
D1 ⍺1B
𝛂1B
antagonist antagonist inhibitor antagonist
Cariprazine
SERT = Serotonin Reuptake Transporter
Caplyta (lumateperone) [Package Insert]. New York, NY: Intra-Cellular Therapies. 2023. Li P, et al. Journal of Medicinal Chemistry.
2014;57(6):2670-2682. Kantrowitz JT. CNS Drugs. 2020;34(9):947-959.
 D1 Indirect Modulation of Glutamate Function
Prefrontal
Cortex
Neuron

Preclinical data shows lumateperone indirectly AMPA

activates both NMDA and AMPA glutamatergic
GLUTAMATE + DEPOLARIZATION
receptors in the PFC via downstream effects NMDA +
from its action on D1 receptors
D1
Lumateperone: Alone enhances NMDA- and AMPA-induced currents
NMDA-induced currents AMPA-induced currents
200 200 ##
*
NMDA-Induced Currents

AMPA-Induced Currents

150 150 **
(% of control)

(% of control)

100 100 Lumateperone’s enhancement of

NMDA and AMPA-induced currents
50 50 is blocked by a D1 antagonist

0 0
ITI-007 30 nM SCH23390 1 μM ITI-007 30 nM SCH23390 1 μM
+ITI-007 30 nM +ITI-007 30 nM

AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA = N-methyl-D-aspartate; PFC = Prefrontal Cortex.

Harvey J, et al. J Neurosci. 1997;17(14):5271-5280. Vanover, KE, et al. European Neuropsychopharmacology. 2017;27:S660-S661.
 5-HT2A Antagonism May Have Positive Effects on
Sleep Architecture
Slow Wave Sleep
Mean Change From Baseline (min)

10
More Time in Deep Sleep

8
6
4 Low-dose lumateperone improved sleep
2
parameters in people with insomnia disorder
0
-2
-4
-6
Placebo LUM 1mg LUM 5mg LUM 10mg Potential Effects of 5-HT2A Antagonism
Wake After Sleep Onset Positive Effects on Sleep Potential Adverse Effects
0
Mean Change From Baseline (min)
Less nighttime awakening

Increased Slow Wave Sleep Dizziness/hypotension

-5
-10 ↓ Wake after sleep onset Fatigue
-15 ↓ Arousals/awakenings Nausea/vomiting
-20
Improved sleep maintenance Headache
-25
-30 Improved sleep efficiency Constipation
-35
Placebo LUM 1mg LUM 5mg LUM 10mg

LUM = lumateperone.
Vanover KE, et al. European Neuropsychopharmacology. 2017;27:S660-S661. Vanover KE, et al. Nature and Science of Sleep.2010;2:139.
 Lumateperone Monotherapy in Major Depressive
Episodes of Bipolar I and II Depression
Day 8 15 22 29 36 43
0
LSM MADRS Change from Baseline

Lumateperone met the primary endpoint of significantly

reducing the MADRS compared to placebo at week 6,
Improvement in Symptoms

-5 and showed nominal separation as early as week 1

†

-10 Differences of >2 points between a

†
medication and placebo on MADRS
†
are considered clinically relevant
-15 †
Placebo
Lumateperone 42 mg *
†=nominally significant, LSM Difference: -4.6 Lumateperone may begin to have effects rapidly,
not controlled for multiplicity Effect size: -0.56
-20 *P<0.0001 and its growing increases in efficacy vs. placebo
may suggest favorable long-term outcomes

MADRS = Montgomery Åsberg Depression Rating Scale; LS=Least-Squares; CFB= Change from baseline; LUM=lumateperone
Calabrese JR, et al. Am J Psychiatry. 2021;178(12):1098-1106. Montgomery SA., et al. Int. Clin. Psychopharmacol. 2009;24(3):111-118. McIntyre RS et
al. Eur Neuropsychopharmacol. 2023;68:78-88.
 Lumateperone Monotherapy in People with
Bipolar I and with Bipolar II Depression
Bipolar I Subgroup Bipolar II Subgroup
Day 8 15 22 29 36 43 Day 8 15 22 29 36 43
0 0

Improvement in Symptoms
Improvement in Symptoms

LS Mean CFB in MADRS

-2 -2
LS Mean CFB in MADRS

-4 -4
-6 -6 †

-8 -8
-10 -10
†
-12 † -12
-14 † -14 †
Placebo Placebo
-16 † †
Lumateperone -16 Lumateperone
-18 †=nominally significant,
-18 †=nominally LSM Difference: -7.0 *
not controlled for multiplicity LSM Difference: -4.6 * significant,
-20 not controlled for multiplicity Effect size: -0.85
Effect size: -0.48 -20 *Nominal P<0.001
*Nominal P<0.0001
Placebo, n 38 37 38 37 36 35 34
Placebo, n 150 148 146 144 140 137 132
LUM, n 38 38 36 35 35 35 34
LUM, n 150 150 142 138 136 135 135

Lumateperone monotherapy demonstrated efficacy in both Bipolar I and II depression,

with numerically greater separation from placebo in Bipolar II

The sample size of those with Bipolar II disorder

is small, but the very strong results are encouraging
LSM = Least-Squares Mean; CFB = Change from baseline; LUM = lumateperone
McIntyre RS, et al. Eur Neuropsychopharmacol. 2023;68:78-88.
 Lumateperone Adjunct to Lithium or Valproate
in People with Bipolar I or II
Lumateperone vs. Placebo for People with
Inadequate Response to Lithium or Valproate

Day 8 15 22 29 36 43
0
-2
-4
Change from Baseline
Improvement in Symptoms

Adjunct lumateperone 42mg

LS Mean MADRS

-6
demonstrated superior efficacy to placebo
-8
in people with inadequate response to
-10 lithium or valproate at week 6
-12
-14
Lumateperone 28 mg (n=171) †p=0.099 †
-16
Lumateperone 42 mg (n=174)
-18 Placebo (n=174) * LSM Difference: -2.4
-20 Effect size: -0.27
*P<0.021

MADRS = Montgomery Åsberg Depression Rating Scale; LSM = least squares mean
Suppes T, et al. Bipolar Disord. 2023;25:478-488.
 Lumateperone Adverse Event Profile Across
6-Week Acute Bipolar Depression Trials
Adjunct to No change in prolactin
Monotherapy lithium/valproate compared to placebo
Lumateperone Placebo Lumateperone Placebo
(n=372) (n=374) (n=177) (n=175)

Somnolence/Sedation 13% 3% 13% 3% Levels of fasting glucose, insulin,

Dizziness 8% 4% 11% 2% cholesterol, and triglycerides
Nausea 8% 3% 9% 4% were similar to placebo
Dry mouth 5% 1% 5% 1%
EPS 1.3% 1.1% 4.0% 2.3%
Akathisia 0% 0.3% 0.6% 0% Mean weight change and
percentage of participants who
gained ≥7% body weight were similar
No single adverse event led to between lumateperone and placebo
discontinuation in >2% of participants

Caplyta (lumateperone) [Package Insert]. New York, NY: Intra-Cellular Therapies. 2023. Mates S, et al. Presented at the American College of
Neuropsychopharmacology (ACNP) 2022 Annual Meeting; December 4-7, Phoenix, AZ
Weight and Metabolic Parameters of Lumateperone
Monotherapy in 6-month Open Label Extension

No clinically significant changes

from baseline to end of treatment in
cardiometabolic laboratory
measures

Mean weight change −0.02 lb

3.4% gained ≥7% body weight

6.0% lost ≥7% body weight

Lumateperone appears well-tolerated in the short

and longer-term periods, but ongoing screening for weight,
metabolics, and movement disorders is still necessary

Mates S, et al. Poster Presented at Presented at the American College of Neuropsychopharmacology (ACNP) 2022 Annual Meeting;
December 4-7, Phoenix, AZ
 Additional Study of Lumateperone
Major Depressive Episodes with Mixed Features
Subgroup of People with Bipolar Depression
Subgroup of People with Bipolar Depression with Mixed Features and Anxious Distress
with Mixed Features 8 15 22 29 36 43
0
0
LSM MADRS Change from Baseline

-3
Improvement in Symptoms

Improvement in Symptoms
†

LS Mean MADRS CFB

-4
-6

-9 -8
†
†
-12
†
-12 †
-15 †
†
† †=nominal p, not controlled for multiplicity
-18 †=nominal p, not controlled for multiplicity
-16 †=nominal p, not controlled for multiplicity
* †
Lumateperone 42 mg (n=100) LSM Difference: -5.7 Lumateperone 42 mg (n=52) †
* LSM Difference: -5.5
-21 Placebo (n=99) Effect size: -0.64 Placebo (n=56)
-20 Effect size: -0.59
0 1 2 3 4 5 6 *P<0.0001 *P<0.01
Weeks

Lumateperone was also superior to placebo Lumateperone significantly improved depressive

in the subgroup of MDD with mixed features episodes in populations that are challenging-to-treat

MADRS = Montgomery Åsberg Depression Rating Scale; LSM = least squares mean; CFB=change from baseline
McIntyre RS, et al. J Clin Psychiatry. 2023;84(3): 46804. Durgam S, et al. Poster Presented at the 2023 American College of
Neuropsychopharmacology (ACNP) Annual Meeting, December 3-6, Tampa, FL.
Key Learning Points
• Lumateperone may indirectly activate NMDA
and AMPA glutamate receptors via downstream
effects from its action on D1 receptors
• The most prominent component of
lumateperone’s MOA can be described as high-
affinity serotonin 2A (5HT2A) receptor
antagonism
• It has not been associated with clinically
significant weight gain, cardiometabolic lab
changes, or movement disorders
Personalizing Treatment in Bipolar Disorder
 Developing Treatment Plans Based on Patient and
Disease-Specific Factors
Type of Bipolar Disorder Course of illness, pattern of
symptoms
Appreciate the Some patients with
evidence base for BP-I will have mania
treatments in frequently, but others
BD-II vs BD-I only very rarely

Polarity-specific properties Past treatment responses, Presence of comorbid

of medications past adverse reactions disorders
e.g., meds with e.g., meds with high
e.g., antimanic efficacy high risk for akathisia weight/metabolic risk
less relevant in BD-II are less favorable for are less favorable for
than it is in BD-I patients with a past patients with obesity,
history of akathisia diabetes, etc.

McIntyre RS, et. al. Human Psychopharmacology: Clinical and Experimental. 2004;19(6):369-386. Yatham LN, et al. Bipolar Disorders.
2018;20(2):97-170.
 Considerations for Monitoring Treatment
Olanzapine/ Quetiapine
Lurasidone Cariprazine Lumateperone
Fluoxetine (IR and XR)

Weight & Metabolic Risks High High Low Low Low

Movement Disorder Risks Low Low Moderate Moderate Low

Early onset of weight gain Early movement disorders Both must be

or metabolic changes are (akathisia, dystonia, DIP) monitored closely
usually a harbinger of are risk factors for later in the short and
further problems development of TD long term!

As patients transition from acute treatment to long-term

maintenance, treatment satisfaction is a key factor in adherence!

DIP = drug-induced Parkinsonism; TD = tardive dyskinesia.

Olanzapine/fluoxetine PI. Eli Lilly, Inc; 2021. Quetiapine PI. AstraZeneca; 2021. Quetiapine XR PI. AstraZeneca; 2020. Lurasidone PI.
Sunovion Pharmaceuticals Inc; 2019. Cariprazine PI. AbbVie plc; 2019. Lumateperone PI. Intra-Cellular Therapies; 2021.
Bates JA, et al. The Primary Care Companion for CNS Disorders. 2010;12(5):26157.
 Positive Relationships Create Results
TEAM TALK
Work together,
describe choices,
offer support, and “Let’s work as a team to
ask about goals make a decision that
suits you best”

SHARED
DECISION-MAKING
Clinicians and people
with lived experience
share the best available
evidence. We support
them to consider the People
“Tell me what Clinician options. with lived “Let’s compare the
matters most to you experience
for this decision” DECISION TALK OPTION TALK possible options”
Get to informed Discuss alternatives
preferences, make using risk
preference-based communication
decisions principles

Elwyn G, et al. J Gen Intern Med. 2012;27:1361–7. Elwyn G, et al. BMJ. 2017;359:j4891. Craig Chepke, MD. Personal communication, September
2022.
 Practical Takeaways

• Be vigilant for mixed features in any person presenting with a

mood disorder, as their presence may signal a more challenging
presentation and can inform our treatment decisions

• From the start of treatment planning, keep in mind that weight gain is
a common cause of discontinuation for medications in bipolar disorder
→ “An ounce of prevention is worth a pound of cure”

• Remember to prioritize the efficacy of treatments in an evidence-

based fashion to help give people with bipolar disorder the best
chance to manage their lives!