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Program Title Here

Subtitle Here

Improving Diagnostic Certainty in Depressive

Episodes: When Is It Bipolar Disorder?
Sara Jones, PhD, APRN
Psychiatric Mental Health Nurse Practitioner, Board Certified
Fellow of the American Academy of Nurse Practitioners
Journey Wellness Clinic, PLLC

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Clinical Case
PSYCHIATRIC HISTORY
• Began experiencing major depression at age 16
- Comorbid agitation, anxiety with panic states, and cutting behavior
• Experienced at least 3 major depressive episodes by age 18

Caroline
26-year-old EXPERIENCE WITH ANTIDEPRESSANTS
Female • Escitalopram
- Increased agitation and anxiety
• Bupropion
- Used for an overdose that resulted in an inpatient stay
• Sertraline
- Made her depressions more intense and seemed to drive panic states

Clinical Case
FAMILY HISTORY
• Mother with one prior episode of major depressive disorder (MDD) (untreated)
• Maternal grandfather with bipolar disorder (lithium responder)

ADDITIONAL HISTORY
• First presented to Dr. Manning at age 18 while in college
Caroline • Depressions had continued and worsened with emergence of impulsive periods
26-year-old of risk taking, decreased need for sleep, talkativeness and racing thoughts
Female - Energetic periods lasted from 4 to 7 days with abrupt endings into severe
psychomotor retarded depressions
- No psychotic symptoms per se but she remarked that her thinking during
elevated energy was “very confused and scattered”
- Dominant mood during periods of energy was often depressed rather than
elated with suicidal ideation (SI) masked by talkativeness and excitement
seeking
• Addition of aripiprazole to sertraline was not helpful

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Importance of Obtaining an Accurate Diagnosis

70% Misdiagnosed on initial visits Failure to diagnose results in:

Untreated illness may affect

prognosis
Mean number of psychiatric

4 consultations needed to correctly

diagnose bipolar illness
Exposure to adverse effects of
medications for inaccurately
diagnosed conditions

Highest lifetime suicide risk in Decreased quality of life and

32%
misdiagnosed bipolar
increased risk for suicide
depression

Hirschfeld RM, et al. J Clin Psychiatry. 2003;64(2):161-174; Goldberg JF, Ernst CL. J Clin Psychiatry. 2002;63(11):985-991; McCormick U,
et al. J Am Assoc Nurse Pract. 2015;27(9):530-544; Grande I, et al. Lancet. 2016;387(10027):1561-1572.

RMEI Patient Experience Survey

RMEI surveyed 159 patients with BPD. This is what they've reported about their experience getting a diagnosis:

40% 29% Did not have 53%

their diagnosis
Were not Were not provided with
explained to
diagnosed in a the proper educational
them
timely manner support after diagnosis

47%
56% Initially
misdiagnosed Were not
provided with
64%
Felt alone when they
the proper were diagnosed
emotional
support after
Abbrev: BPD Bipolar depression diagnosis
All data are based on patient report.
Data on File. RMEI 2023.

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Characterizing Episodes
Depressive Episodes

≥3 of the following symptomsb

≥5 of following symptoms during the
same 2-week period
• Inflated self-esteem or
• Depressed mood, looks grandiosity
depressed/expresses
• Decreased need for sleep
sadness
• Anhedonia
• More talkative than usual
• Weight loss or gain • Flight of ideas, racing
≥5%/month; appetite changes thoughts
• Sleep changes • Distractibility
• Psychomotor agitation or Mixed Features • Increased goal-directed
retardation (Overlapping and activity or psychomotor
• Fatigue, loss of energy intertwining of
agitation
• Worthlessness, excessive/ symptoms)
inappropriate guilt
• Excessive involvement in
• Decreased concentration pleasurable activities, high
• Recurrent thoughts of death, potential for negative
suicidal ideation (SI) consequences
Symptoms must result in clinically significant distress and impaired
functioning and cannot be caused by medical or substance use
conditions
a Mania = ≥1 week: Severe symptoms that causes marked impairment in functioning, Hypomania = 4 days: Change in functioning uncharacteristic for individual, but not severe enough to cause marked

impairment in functioning; noticed by others. Cannot be caused by medical or substance use conditions. bDuring mood disturbance; 4 if only irritable. American Psychiatric Association. (2013). Diagnostic and
Statistical Manual of Mental Disorders (5th Ed). Arlington, VA: American Psychiatric Assoc.

Differentiating Bipolar from Unipolar Depression

Unipolar Major Depression (MD)
• Symptoms of unipolar and bipolar MD are identical
• Most depressed youth referred to care are experiencing 1st episode of depression; difficult to differentiate
• Follow longitudinally with ongoing assessment!

Conventional Diagnostic Classification

BP not Cyclo- Bipolar Bipolar

Unipolar
otherwise thymic Disorder Disorder
Depression
specified Disorder Type II Type I

Depressive Subthreshold Hypomania, Hypomanic and Presence of

episodes hypomania, subthreshold major mania (at any
subthreshold depression depressive time)
depression episodes

American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th Ed).
Arlington, VA: American Psychiatric Assoc.

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Screening Tools
Risk Factors for Bipolar Disorder
Clinician-administered Rating Scales
1st degree family member with an
• Structured Clinical Interview for DSM-IV established bipolar diagnosis
(SCID)
• Young Mania Rating Scale (YMRS) Presence of psychosis

Self-report Rating Scales History of treatment-resistant

depression
• General Behavior Inventory (GBI)
• Mood Disorder Questionnaire(MDQ) Mixed features of mania and
• Patient Health Questionnaire (PHQ-9) depression
• 6-item Rapid Mood Screener (RMS)
Significant agitation/aggression in
response to psychostimulant or
Also Helpful: antidepressant

• CIDI 3.0 Bipolar Screener, brief structured Symptoms of mania attributable to

interview an antidepressant
• For a list of public domain screening tools:
www.div12.org/assessment-repository History of suicidal ideation/attempt

Miller CJ, et al. Clin Psychol (New York). 2009;16(2):188-201: McCormick U, et al. J Am Assoc Nurse Pract. 2015;27(9):530-544; Grande I, et al. Lancet.
2016;387(10027):1561-1572. McIntyre RS, et al. Curr Med Res Opin. 2021;37(1):135-144. Kessler RC, et al. J Affect Disord. 2006;96(3):259-269.

Trauma: Another Consideration

Limbic System
Amygdala
Emotions
Complex
Automatic Behavior

Kato T. Psychiatry Clin Neurosci. 2019;73(9):526-540; McCormick U, et al. J Am Assoc Nurse Pract.
2015;27(9):530-544; Grande I, et al. Lancet. 2016;387(10027):1561-1572.

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Clinical Case

DIAGNOSIS

• Careful history confirmed a diagnosis of Bipolar II

Caroline
26-year-old
Female • Tapered off MDD antidepressant therapy

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Optimizing Treatment
James Sloan Manning, MD
Family Physician
High Point, North Carolina

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Clinical Case

Treatment at 18 years of age

• Lurasidone
• Lamotrigine (1st maintenance therapy)
Caroline • Mood instability persisted at therapeutic doses both
26-year-old
Female medications
• Panic attacks and generalized anxiety also persisted

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Bipolar Depression

Goals of Treatment Treatment Challenges

Undertreatment
1 Alleviate depression

Inappropriate treatment

2
Provide long-term
mood stabilization
Limited treatment options

Merikangas KR. Arch Gen Psychiatry. 2007;64(5):543-552.

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Treating Bipolar Depression

Quetiapine Lurasidone
Week 8: Mean Change from Baseline MADRS Week 6: Mean Reduction from Baseline MADRS

BOLDER I1 BOLDER II2 Monotherapy4 Adjunctive Therapy5

* * PLO 80-120 mg 20-60 mg Li/VAL+ PLO Li/VAL + LUR
57.6% 58.2% QUE 600 Results from
36.1% BOLDER II were
QUE 300
confirmatory2
PLO

*P<.001 vs PBO
-10.7
-10.7

Olanzapine/Fluoxetine -15.4 -15.4 -17.1

* * P<.01
Week 8: Mean Reduction from Baseline MADRS3 * P<.001 vs. PBO

OFC Similar reduction in CGI-BP depression severity scores were

OLZ observed4,5
PLO
-11.9 -15
*P<.001 vs PBO
* -18.5
*
Abbrev: CGI-BP: Clinical Global Impressions Scale for use in bipolar illness, Li/VAL: Lithium/Valproate, LUR: Lurasidone, MADRS: Montgomery-Åsberg Depression Rating Scale, QUE: Quetiapine,
OFC: Olanzapine/Fluoxetine combination, OLZ: Olanzapine, PLO: Placebo 1. Calabrese JR, et al. Am J Psychiatry. 2005;162(7):1351-1360; 2. Thase ME, et al. J Clin Psychopharmacol.
2006;26(6):600-609; 3.Tohen M, et al. Arch Gen Psychiatry. 2003;60(11):1079-1088; 4. Loebel A, et al. Am J Psychiatry. 2014;171(2):160-168; 5. Loebel A, et al. Am J Psychiatry. 2014;171(2):169-177.

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Treating Bipolar Depression: Recent Developments

Cariprazine Lumateperone3
Week 6: Mean MADRS Reduction from Baseline Week 6: Mean Reduction from Baseline

Study 11 Study 22
MADRS CGI-BP-S Total Score
0 0
PLO 0 0
-5 -5 LUM
1.5 mg
-10 -10 -10 PLO -10
3.0 mg -2.6 -3.5
-15 -15 -12
-12.6 -12.4 -14.1 -20 -20
-20 -15.1 -15.6 -20 -14.8 -16.7

LS Mean difference LS Mean difference LS Mean difference vs PBO: LS Mean difference vs PBO:
1.5 mg vs PBO: -2.5, P=.0204 1.5 mg vs PBO: -2.5, P=.0208 -4.6, P<.0001 -0.9, P<.0001
3.0 mg vs PBO: -5.1, P=.0052 3.0 mg vs PBO: -1.8, P=.1051

1. Earley WR, et al. Am J Psychiatry. 2019;176(6):439-448.

2. Earley WR, et al. Bipolar Disorders. 2020;22(4):372-384.
3. Calabrese JR, et al. Am J Psychiatry. 2021;178(12):1098-1106.

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Challenges with Managing Bipolar Depression:

Treatment Safety and Tolerability
FDA Class Warnings/Precautions for Second-Generation Antipsychotics
1. Increased mortality in elderly with dementia-related psychosis (Black Box)
2 Neuroleptic malignant syndrome
3. Tardive dyskinesia
4. Hyperglycemia and diabetes mellitus
5. Orthostatic hypotension ± syncope
6. Leukopenia, neutropenia, and agranulocytosis
7. Seizures
8. Potential for cognitive and motor impairment
9. Body temperature regulation (pyrexia, feeling hot)
10. Suicide (illness-related)
11. Dysphagia
12. Use in patients with concomitant illness

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Additional Therapies*
Data from Large Meta-analyses

Valproate1 Lamotrigine2
Design Design
4 RCTs, N=142 (age range: 18 to 54 years) 5 RCTs, N=1072 (individual participant data
Treatment duration: Either 4 or 8 weeks obtained and analyzed)
Results P=.001
Efficacy: Reduced Depression P=.002
SMD: -0.35, NNT=5 P=.005 1.47 P=.445
1.27 1.22
1.07
Relative Risk
(vs Placebo)

Safety: Adverse Events

Nausea, somnolence, fatigue/muscle weakness,
headache, diarrhea, and dry mouth.
AEs did not differ significantly between groups
HRSD MADRS HRSD >24 HRSD <24
at baseline at basline
*Not FDA approved for bipolar depression

1. Smith LA, et al. J Affect Disord. 2012;122(1-2):1-9.

2. Geddes JR, et al. Br J Psychiatry. 2009;194(1):4-9.

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Antidepressants in Bipolar Depression

Antidepressants

Potential Risks Potential Benefits

• Inefficacy Some may do well
• Intolerability with adjunct antidepressants
- Mood worsening/switching
- Cycle acceleration

Patients at Greatest Risk

• Mixed symptoms
• Rapid cycling
• History of problems with
antidepressant

Viktorin A, et al. Am J Psychiatry. 2014;171(10):1067-1073.

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RMEI Patient Experience Survey

RMEI surveyed 159 patients with BPD. This is what they've reported about their experience with treatment:

75% 35%
Felt included in Reported their provider
treatment did NOT educate them
decision- about their treatment’s
making side effects

39%
73% Said their treatment
plan was consistent
Felt their medication
was not working for
with their values,
them and 23% felt
preferences, and
their treatment plan
needs
was not safe
Abbrev: BPD Bipolar depression
All data are based on patient report.
Data on File. RMEI 2023.

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Comorbidities in Bipolar Disorder

Patients with bipolar disorder should be screened and
systematically monitored for comorbid conditions
Key Management Principles

1. Establishing the diagnosis

2. Continuous risk assessment as
Metabolic
Disorders SOP
3. Establishing appropriate setting for
Pain
Migraine Disorders treatment
4. Chronic disease management
Personality
Disorders
5. Concurrent or sequential treatment
6. Measurement-based care
ADHD Anxiety

Substance Key Consideration

Abuse
Most bipolar disorder patients have
at least 1 comorbid axis I disorder

McElroy SL, et al. Am J Psychiatry. 2001;158(3):420-426; McIntyre RS, et al. Hum Psychopharmacol.
2004;19(6):369-386; McIntyre RS, et al. Ann Clin Psychiatry. 2012;24(2):163-169.

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Clinical Case
Additional Management at 18 years of age
• Lithium added after grandfather’s positive response discovered
• Panic attacks and generalized anxiety treated with benzodiazepines, but
were eventually tapered
• Addition of CBT and DBT were also critical for overall symptom control,
stress management, and resilience
Caroline
26-year-old
Female History Following Initial Recovery
• Stopped treatment after returning to college at age 20
• After getting married at age 23, panic attacks, anxiety, and eventually,
depression returned
• Returned to treatment, and after some adjustments, got back on the
road to recovery
• Currently employed as a social worker
• Recently moved to Boston with her husband

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Patient Experience Survey Results

Demographics: Highlights Insights

We Could Do Better Educating Our Patients

63
Age Group 68%
40 to 45% of patients reported their physician/nurse
Number of Patients

Caucasian
47 did NOT provide them with relevant education about
BPD, their medication, or their treatment options
32 11%
17 Hispanic
Insurance is not enough
About a third of patients report their coverage does
>50 35 to 25 to 18 to 9% not meet their needs and the cost of care is
49 34 24 African unmanageable
American
Accessibility is a Problem
76.7% 25% report their provider is not accessible
Female 36% cannot get an appointment in a timely manner

All data are based on patient report.

Data on File. RMEI 2023.

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