2/25/2011

Case Study: Lisa

32-yr-old, single, partner in an accounting firm
5-year history of returning to PCP every 6-9 months for
STD testing following break-ups with different boyfriends
Distraught, depressed, functions poorly at
work following break-ups

Works 12
12-14
14 hrs/day for 10-14
10 14 weeks
during tax season
Reports high energy, active lifestyle
Susie Adams, PhD, RN, PMHNP, FAANP Reports periods of depression and
Professor & Director Psychiatric Mental Health Nurse Practitioner Program Vanderbilt University School of Nursing

Patricia Hentz, EdD, PMHCNS-

PMHCNS-BC, CRNP
ruminating that she wont find a suitable
Practice Associate Professor & Program Director Advanced Practice Psychiatric Mental Health Nursing Programs mate, fears biological clock is ticking,
University of Pennsylvania School of Nursing
and wants to settle down
STD = sexually transmitted disease
PCP = primary care provider

Symptom Presentation Bipolar Disorders

Most patients with bipolar disorder: 6th leading cause of disability worldwide
Present with depression Lifetime prevalence of 1%
Spend far more time being depressed than
Lifetime suicide risk of 15%
manic,, hypomanic,
yp , or cycling
y g
Exhibit a relapsing and remitting pattern High prevalence of psychiatric & medical
comorbidities
Experience fluctuating moods
(elevation and depression) Symptom profiles overlap with other
Have chaotic relationships; psychiatric diagnoses
impaired quality of life
Stimmel GL. Psychiatr Serv. 2004;55(2):117-118.

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Epidemiology Genetic Risk

Disorder
Lifetime Prevalence Age at Onset Pathophysiology of bipolar disorder still unclear;
(%) (mean year)
family, twin, and linkage studies implicate
Major Depressive
Episode
5-17% - genetic factors
Bipolar I Disorder 1.0% 18.2 Familial connections include:
Bipolar II Disorder 1.1% 20.3 65% to 70% in monozygotic twins
yp
Hypomania Approximately 14% in dizygotic twins
2 4%
2.4% 22 2
22.2
(Subthreshold)
Exploration of bipolar susceptibility genes underway:
Prevalence of bipolar disorder as high as 6.5%, depending on definition
XBP1, a pivotal gene in the endoplasmic reticulum (ER)
Lifetime prevalence rates for major depression are 2:1 for women to
men (post-puberty) stress response, may contribute to the genetic risk factor
Lifetime prevalence rates for bipolar I are equal among men and women Variation at G72 with schizophrenia and bipolar disorder
Manic episodes more common in men; depressive episodes more provides molecular support for the hypothesis that these
common in women two disorders share some of their etiologic background
Appears to occur earlier with a concurrent substance abuse disorder Craddock N, Jones I. J Med Genet. 1999;36:585-594.
Kakiuchi C, et al. Nat Genet. 2003;35(8):171-175.
Merikangas KR, et al. Arch Gen Psychiatry. 2007;64(5):543-552. Schumacher J, et al. Mol Psychiatry. 2004;9:203-207.

Lifetime Comorbid Conditions Bipolar Disorder Symptom Domains

Common in Patients
Domain Symptom
With Bipolar Disorders Manic Mood & Euphoria Risky behaviors (promiscuity,
Behavior Grandiosity spending money, etc.)
Impulsivity Diminished need for sleep
Increased sex
drive/libido
Psychotic Hallucinations
Symptoms Delusions
(grandeurcommon)
Dysphoric Mood Anxiety Hostility
& Behavior Depression Violence or suicide
Irritability
Cognitive Racing/crowded
Symptoms thoughts
Distractibility
Inattention
Disorganization
Krishnan KR. Psychosom Med. 2005;67(1):1-8.

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DIG FAST Manic Episode

A Mnemonic of Mania Symptoms Distinct period of abnormally/persistently elevated,
expansive, or irritable mood lasting at least 1 week
Distractibility: Tasks unfinished
During the period of mood disturbance, 3 or more
Insomnia: need for sleep DIG FAST symptoms persist (4 if one is irritability)
y self-worth
Grandiosity: Causes marked impairment in usual function,
function
Flight of ideas: Racing thoughts relationships, hospitalization to prevent harm to self
or others, or presence of psychotic features
Activity: Increased
Symptoms not due to substance use, general
Speech: Pressured medical condition, or activation by antidepressant
medication
Thoughtless risk: Sex, money, travel
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision.
Washington, DC, American Psychiatric Association, 2000.

Hypomanic Episode Recognizing Hypomania

Distinct period of abnormally/persistently elevated,
expansive, or irritable mood lasting at least 4 days Mood elevation is not necessary for
hypomania; it can present as
During the period of mood disturbance, 3 or more
DIG FAST symptoms persist (4 if one is irritability) overactivity, irritability, etc.
Episode not severe enough to cause marked Look for changes in personality (eg,
functional impairment what is normal for the individual and
Mood disturbance/change in function observable what is not)
by others
The individual rarely has self-awareness
Symptoms not due to substance use, general
medical condition, or activation by antidepressant of the episode; they may not perceive it
medication as a problem
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision.
Washington, DC, American Psychiatric Association, 2000.

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Bipolar Disorder I: Bipolar Disorder II

Diagnostic Subtypes Characterized by depressive episodes and
Bipolar I Single Manic Episode hypomanic episodes, but the episodes of manic-
9 Presence of only 1 manic episode and no past major like symptoms do not quite meet diagnostic
depressive episodes
9 Manic episode not accounted for by schizophrenia, delusional criteria for full manic syndrome
disorder, or psychotic disorder NOS Presence/history of at least 1 major depressive episode
9 Recurrence is either a change in polarity from depression or
an interval
i t l off att least
l t 2 months
th without
ith t manic
i symptoms
t Presence/history of at least 1 hypomanic episode
Bipolar I Most Recent Episode Manic No history of a manic or mixed episode
Bipolar I Most Recent Episode Hypomanic Symptoms cause clinically significant distress or
Bipolar I Most Recent Episode Depressed impairment in function
Bipolar I Most Recent Episode Mixed
Clinical features are those of a major depressive
Bipolar I Most Recent Episode Unspecified disorder combined with hypomanic episode(s)
Bipolar I Rapid Cycling (4 manic episodes/year)
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision.
NOS = not otherwise specified Washington, DC, American Psychiatric Association, 2000.

Bipolar DisorderNOS Bipolar Spectrum Disorders

& Major Depressive Disorder (MDD)
Bipolar symptoms present, but do not meet diagnostic
criteria for bipolar I, bipolar II, or cyclothymic disorder
Bipolar I Bipolar II Bipolar NOS MDD
Early stage of diagnosis warrants further evaluation
to reach conclusive diagnosis In clinical settings, only the patients history, family history,
Symptoms of mania and depression, but the episodes and future course can help differentiate between bipolar I
are too
t short
h t to
t qualify
lif as an actual
t l episode
i d disorder depressive episodes and MDD episodes
15-yr follow-up study of young adults hospitalized with
Episodes of hypomania, but no depressive episode
unipolar depression found 27% developed hypomania and
Symptoms of hypomania and depression, 19% experienced at least 1 manic episode
but they dont last long enough to qualify as High rates of unrecognized bipolar disorder in treatment-
cyclothymic disorder resistant depression. One study found 40% of young adults
Suspect that symptoms are caused by drugs, alcohol, with recurrent MDD met diagnostic criteria for bipolar disorder
or a general medical condition Goldberg JF, et al. Am J Psychiatry. 2001;158:1265-1270.
Smith DJ, et al. J Affect Disord. 2005;84(2-3):167-168.
Smith DJ. Current Psychiatry. 2009;8(7):41-48.

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Is It Bipolar II or MDD? Indicators of Bipolarity

Differential Diagnostic Keys in Seeming Unipolar Depression
Bipolar II MDD Atypical features
Distractibility Distractibility First-degree relative with bipolar disorder
Mood instability Mood instability
Decreased need for sleep Decreased need for sleep Antidepressant-induced mania or hypomania
Racing/crowded thoughts
Psychomotor agitation
Racing/crowded thoughts
Psychomotor agitation
Multiple family member with major depression
Ch i iirritability
Chronic it bilit I it bl mood
Irritable d Early onset of depression (before age 25)
Mean age of first MDE: 22.8 Mean age of first MDE: 31.9 Lack of response to 3 antidepressant trials
>50% patients have positive family Psychotic features (before age 35)
history of bipolar I and/or II
Mixed depressive episodes
When probing history for past hypomanic episodes, ask first Brief but frequent episodes of depression
about behavioral activation, which facilitates patients recall of
euphoria and/or irritability during these activated periods
Complex comorbidity (anxiety, drug/ETOH misuse,
previous diagnosis of borderline personality disorder)
It is critical to obtain information from significant others
MDE = major depressive event
Smith DJ. Current Psychiatry. 2009;8(7):41-48. Smith DJ. Current Psychiatry. 2009;8(7):41-48.

Bipolar Spectrum Disorders & Borderline Is It Bipolar or BPD?

Personality Disorder (BPD) Differential Diagnostic Keys
Bipolar BPD
Bipolar I Bipolar II Bipolar NOS MDD Impulsivity Impulsivity
Mood instability Mood instability
Inappropriate anger Inappropriate anger
The mood lability of BPD is similar to that seen in bipolar Suicidal behavior
Unstable relationships
Suicidal behavior
Unstable relationships
p
Bipolar disorders are considered clinical disorders or Most patients with mania ultimately Self-mutilation or self-injurious behavior without
experience depression suicidal intent are particularly common
brain disease understood as a broken mood thermostat
Elation to depression or vice versa Roller coaster moods shift rapidly over minutes to
(bipolar I) hours
BPD is characterized by enduring and inflexible pattern
of maladaptive thoughts, feelings, and behaviors linked Chronic irritability (bipolar II) Higher levels of impulsiveness and hostility
to fear of abandonment
Symptoms of BPD that are confined to clearly defined episodes of mood
Behaviors displayed by patients with BPD are disturbance (& absent during euthymia) do not meet BPD diagnosis
conceptualized as arising from their unstable mood Life history is critical: ask about notable life transitions (eg, leaving
school, job loss, divorce)
Fiedorowicz JG, Black DW. Current Psychiatry. 2010;9(1):21-32.
Gunderson JG. Am J Psychiatry. 1996;153(6):752-758.
Wilson ST, et al. J Clin Psychiatry. 2007;68(10):1533-1539. Wilson ST, et al. J Clin Psychiatry. 2007;68(10):1533-1539.

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Screening for Bipolar Disorders:

Keys to Clarifying a Diagnosis
Mood Disorder Questionnaire (MDQ)
1 Has there ever been a period of time when you were not your usual self and... YES NO Obtain a thorough life history/
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?
timeline of events
You felt much more self-confident than usual?
You got much less sleep than usual and found you didnt really miss it?
Obtain collateral information (eg, from a
You were much more talkative or spoke faster than usual? loved one or a family member)
Thoughts raced through your head or you couldnt slow your mind down?
You were so easily distracted by things around you that you had trouble concentrating or staying on track? Develop a genogram
You had much more energy than usual?
You were much more active or did many more things than usual? Establish a symptom timeline
You were much more social or outgoing than usual, (eg, you telephoned friends in the middle of the night?)
You were much more interested in sex than usual? Ask patient to create a daily mood chart
You did things that were unusual for you or that others might have thought were excessive, foolish, or risky?
Spending money got you or your family into trouble? Ask patient about response to prior
2 If you checked YES to more than one of the above, have several of these ever happened during the same
period of time? Please check one response only.
treatment (if any)
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.
No Problem Minor Problem Moderate Problem Serious Problem

Hirschfeld RM, et al. Am J Psychiatry. 2000;157(11):1873-1875.

Progressive Nature of Case Study: Lisa

Assessment
Bipolar Disorder Administer MDQ
Based on the concepts of kindling, plasticity, Ask about family history of affective disorders
Ask about family history of ETOH/substance abuse
and learning, severity of symptoms are
Ask about her use of ETOH/substances
believed to be progressive. Do you use alcohol to relax/de-stress?
How much? How often?
Single manic and depressive episodes Ask about when she was especially
may progress to mixed episodes and productive or active for 2 days or more;
finally toward rapid-cycling and treatment ask about euphoria or irritability during
these high activation (high energy) periods
resistance.
Keys to Lisas Diagnosis
Bipolar disorder requires continual Admits that she becomes irritable when friends or
assessment and monitoring of treatment. co-workers dont meet her expectations
Brother diagnosed with bipolar disorder
Stahl, SM. Depression and Bipolar Disorder: Stahl's Essential Psychopharmacology. 3rd ed.
New York, NY: Cambridge University Press; 2008.
and ETOH dependence

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Patient-Centered Treatment Approach

Multiphase Treatment Strategy
Acute Continuation Maintenance
Identify various presentations of bipolar disorders/spectrum
Duration 3 - 8 Weeks 2 - 6 Months Indefinite
Identify symptoms, track symptom progression/response to Tx
Symptoms Syndromal Subsyndromal/Absent Absent/Subsyndromal
Treatment aims:
Overt/Covert
Prevent relapse Episode Overt Absent / Overt
(Partially/Fully Suppressed)
Minimize and manage side effects
Response Recovery,
Treat residual symptoms Goals Remission Relapse Prevention
Recurrence Prevention
Identify and manage comorbidities F ll F
Full Function
ti
(ideally) Improved Function
Encourage adherence to treatment Efficacy - Tolerability
Priority Efficacy Tolerability
Assessment tools for monitoring: Balance

Hamilton Depression Rating Scale (HAM-D) Continue, Decrease, Optimize, Address

Medications Increase, Add
Increase Prodromes
MDQ
Young Mania Rating Scale (YMRS) Support/structure Adherence Adherence
Psychosocial Education Cognitive, Behavioral, Optimize Adaptation
Encourage self monitoring: eg, mood chart, sleep records Involve Family Family, Institute Monitoring Anticipate Prodromes
Incorporate psychotherapy approaches to improve functioning
Ketter TA (ed). Handbook of Diagnosis and Treatment of Bipolar Disorder. Arlington, VA: American Psychiatric Publishing, Inc.; 2009.;
Provide patient and family support and education Keller MB. J Clin Psychiatry. 2004;65(Suppl 15):10-14.; Sachs GS. J Clin Psychopharmacol. 1996;16(suppl 1):32S-47S.; Sachs GS.
J Clin Psychiatry. 2003;64(Suppl 8):35-40.; Swann AC. J Clin Psychiatry. 2005;66(Suppl 1):7-12.

FDA-Approved Agents for FDA-Approved Agents for

Bipolar Disorder Bipolar Disorder
ACUTE MANIA ACUTE DEPRESSION MAINTENANCE Agent Side Side effects: EPS Notes
Year Drug Year Drug Year Drug effects: Weight gain
1970 Lithium 2003 Olanzapine + fluoxetine 1974 Lithium Sedation
combination
Aripiprazole - - + Akathisia
1973 Chlorpromazine 2006 Quetiapine, XR (2008) 2003 Lamotrigine
Asenapine ++ ++ ++
1994 Divalproex, ER (2005) 2004 Olanzapine
p
Carbamazepine +++ ++ ++
2000 Olanzapine* 2005 Aripiprazole Chorpromazine +++ ++ ++
2003 Risperidone* 2008 Quetiapine, XR Divalproex +++ ++ -
(adjunct)
Lamotrigine - - -
2004 Quetiapine, XR 2009 Risperidone LAI*
(2008)* Lithium ++ ++ _
2004 Ziprasidone 2009 Ziprasidone (adjunct) Olanzapine ++ +++ +/- Dose-related akathisia
2004 Aripiprazole* Quetiapine +++ ++ -
2004 Carbamazepine ERC Risperidone ++ ++ ++
2009 Asenapine Ziprasidone + - +

*Adjunctive and monotherapy; LAI = Long-acting injectable EPS = extrapyramidal symptoms

Ketter TA (ed). Handbook of Diagnosis and Treatment of Bipolar Disorder. Arlington, VA: American Psychiatric Publishing, Inc.; 2009. Stahl, SM. Stahls Essential Psychopharmacology 3rd ed. Cambridge University Press. 2008.

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Individual Patient Characteristics Assessing Antidepressant Use

for Treatment Consideration in Bipolar Depression
Subtype (bipolar I vs bipolar II) Favors Antidepressant Use
Phase (depressed, manic/mixed, relapse prevention) Bipolar II
Course (rapid cycling vs non-rapid cycling) Depressed (non-mixed) states
Polarity predominance (depressed vs elevated) Absence of rapid cycling
Psychiatric comorbidity (eg, anxiety, substance use disorders) Absence of recent mania or
hypomania
Medical comorbidity (eg, obesity, overweight, metabolic
problems) Absence of comorbid ETOH or
substance use disorder
Treatment resistance (esp. for depressive pole)
Prior favorable antidepressant
Adverse effect sensitivity (esp. central nervous system, response
weight/metabolic) No history of antidepressant-induced
Demographics (eg, age, gender, ethnicity, employment, mania or hypomania
financial status)
Goldberg JF. Current Psychiatry. 2010;9(5):41-49.
Discourages Antidepressant Use
Bipolar I
Mixed manic & depressive features
Presence of rapid cycling
Mania or hypomania in past 2-3
months
Presence of comorbid ETOH or
substance use disorder
Suboptimal responses to prior
antidepressants
History of antidepressant-induced
mania or hypomania

Lithium Divalproex/Valproic Acid

Effective in treating acute mania and for
maintenance; not effective for mixed and
rapid cycling
Reduces suicide risk
Good in combination with other agents
g and
can be used at a lower dose when used in
combination
Has narrow therapeutic window; needs to be
monitored closely
Common side effects: weight gain and sedation
Serious side effects: lithium toxicity, kidney
damage, and cardiac complications
Useful for mania and for bipolar depression
Can be used in combination with lithium or atypical
antipsychotic
Known drug interactions with topiramate
and lamotrigine
Risk of ovarian cysts in women
Risk of birth defects to fetus: should not be
used in pregnant women
Side effects: weight gain and sedation
Serious side effects: rare hepatotoxicity and
pancreatitis that can be fatal

8

Carbamazepine
Useful for bipolar mania, mixed mania,
and bipolar depression
Drug interaction with valproate, others
g g
Risk of weight gain is less than with
agents such as lithium and divalproex
Common side effect: sedation
Serious side effects: rare Stevens-
Johnson syndrome, cardiac problems,
aplastic anemia, and agranulocytosis
Quetiapine
Approved for acute mania, acute
bipolar depression and maintenance
Useful in mixed mania
Low EPS
Common side effects: weight gain
and sedation
Serious side effects: hyperglycemia,
diabetes and dyslipidemia, and rare
neuroleptic malignant syndrome (NMS)
2/25/2011
Lamotrigine
Not useful for acute mania but has
shown to be effective for bipolar
depression, and maintenance
Low risk of weight gain and sedation
Interaction with valproate (if
( f also taking
valproate, give 1/2 the dose of
lamotrigine)
Serious side effects: risk of serious
rash, Stevens-Johnson syndrome,
blood dyscrasia
Risperidone
Used for mania and mixed mania;
may be useful for bipolar depression
and maintenance
Common side effects: weight gain,
sedation, increased prolactin levels,
and EPS
Serious side effects: hyperglycemia,
ketoacidosis, rare NMS, seizures
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Ziprasidone
Approved for acute mania and mixed
mania
May also be useful for bipolar
depression and bipolar maintenance
Risk of weight gain and sedation
are low
Serious side effects: prolonged QT
interval, rare NMS
Olanzapine
Approved for maintenance therapy
to prevent recurrence of mania
Olanzapine monotherapy:
prevention of manic and mixed
p
episodes
Side effects: weight gain

Aripiprazole Antidepressants
Effective as a monotherapy in the Use with caution after mood
treatment of acute manic and stabilization
mixed manic episodes Risk of treatment-induced switching
Also used for the p
prevention of to mania
mood episode Risk of switching appears less in
Side effects: may be activating (eg, bipolar II
akathisia) Not recommended as monotherapy

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Case Study: Lisa Monitoring

Lamotrigine is prescribed Initially Monthly
At 1st 3
Months
Every 3
Months Annually
25mg/day for 2 weeks, then 50mg/day for
2 weeks, then 100mg/day Personal/family
X X
history
Titrate slowly for higher doses
if needed Weight (BMI) X

Consider adding SSRI if Blood pressure X X

depressive episodes do not remit
Fasting glucose X X X
Rationale: bipolar II
Activation, irritability
Fasting lipid profile X X X
Episodes of depression
No manic or mixed episodes

Prevalence of Risk Factors for Reasons for Nonadherence to

Metabolic Syndrome in Patients Medication in Patients With
With Bipolar Disorder (N = 171) Bipolar Disorder (N = 140)

Krishnan KR. Psychosom Med. 2005;67(1):1-8. Krishnan KR. Psychosom Med. 2005;67(1):1-8.

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Practical Strategies for Practical Strategies to

Addressing Nonadherence Manage Complex Patients
Assess and address primary and
Ensure sufficiently frequent visits secondary problems
Involve significant others Sleep disturbances and anxiety: gabapentin/pregabalin,
benzodiazepines
Ensure adjunctive psychotherapies Weight gain: regular monitoring, nutritional counseling,
exercise,
i ttopiramate
i t
Limit pharmacotherapy complexity
Alcohol dependence: naltrexone, acamprosate
Anticipate adverse effects Nicotine dependence: bupropion
Carefully monitor adverse effects Prescribe treatments with multiple potential benefits
(eg, for mood and migraines)
Match adverse effect profile to patient vulnerabilities
Consider serial trials vs crossover trials vs
Match adverse effect profile to illness combination trials
phase vulnerabilities Look beyond pharmacotherapy

Psychosocial Elements Psychosocial Stress

Psychosocial stress and social support High levels of criticism from relatives
Cognitive behavioral therapy Low levels of parental warmth
Education Life events that disrupt routines
Interpersonal
I t l and
d social
i l rhythm
h th th
therapy Live events that accelerate goal striving
Family-focused therapy Loss of social support; early physical
Mood charting and sexual abuse

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Cognitive Behavioral Therapy Education

Challenge the patients beliefs about Help patient understand bipolar
self, the world, and the future that disorder as a product of biological
contribute to the mood disorder vulnerability and stress

Focus on restructuring g dysfunctional

y Emphasize that monitoring moods
beliefs that are high risk, which can anddd
detecting
t ti early l warning
i signs
i off
relapse are critical
predispose the patient to mania
Include family members in the
education regarding warning signs
of relapse and early intervention
strategies

Interpersonal and
Family-Focused Therapy
Social Rhythm Therapy
Education: caregivers need to know
Stabilize daily routines and sleep- that patients do not have full control
wake cycles over their symptoms
Help patients gain insight into the Reiterate that patients need treatment
bidirectional relationship between and
d needd tto b
be maintained
i t i d on
moods and interpersonal events medication
Provide communication and problem-
Interpersonal inventory to identify
solving skills
interpersonal problem areas (eg,
family, work, interpersonal deficits) Discuss how to recognize early signs
of relapse

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Case Study: Review

Stabilized on lamotrigine 100mg/day x 6 mo

Q&A
Therapy focused on pattern of intense dependent
relationships/desperate search for life partner
Break-up with boyfriend triggered
depressive episode that didnt
g
respond to lamotrigine 200 mg/day
g y
Nonadherence issues; restarted
lamotrigine titrated to 100 mg/day
Added SSRI (sertraline) titrated to 100 mg/day
Hypomania, irritability, and depressive
symptoms stable for past year
Working on life values, desire for child
(biologic vs adopted), less desperate to find mate

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