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Recognition and Diagnosis of Bipolar Disorder and Its Spectrum

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Title: Recognition and Diagnosis of Bipolar Disorder and Its Spectrum


1
  • Section 1
  • Recognition and Diagnosis of Bipolar Disorder and
    Its Spectrum

2
Spectrum of Bipolar Disorders
  • Bipolar I and II
  • Hypomania
  • Bipolar NOS
  • Cyclothymia
  • Rapidly changing mood swings
  • Major depression with a strong family history of
    bipolar disorder
  • Antidepressant-induced mania and hypomania
  • Secondary mania, due to other illness or drugs

Adapted from American Psychiatric Association.
Practice Guideline for the Treatment of Patients
with Bipolar Disorder. 2nd ed. Washington, DC
2002.
3
Bipolar Terminology
  • A distinct period of abnormally and persistently
    elevated, expansive, or irritable mood
  • Mania
  • Lasting at least 1 week with a significant
    decline in function
  • Hypomania
  • Lasting at least 4 days, (clearly different from
    the usual non-depressed mood), but without a
    significant decline in function and no psychosis

American Psychiatric Association Diagnostic and
Statistical Manual of Mental Disorders, Fourth
Edition, Text Revision. Washington, DC American
Psychiatric Association 2000.
4
Bipolar Terminology (cont)
  • Mixed Episode
  • The criteria are met both for a manic episode and
    for a major depressive episode (bipolar I
    disorder)
  • Cyclothymia
  • Alternating mood states that do not meet full
    criteria for depressive, manic, or mixed episode
    for at least 2 years
  • Bipolar NOS
  • A mood episode that does not meet specific
    criteria for any specific bipolar disorder

American Psychiatric Association Diagnostic and
Statistical Manual of Mental Disorders, Fourth
Edition, Text Revision. Washington, DC American
Psychiatric Association 2000.
5
296.80 Bipolar Disorder NOS
The Bipolar Disorder Not Otherwise Specified
category includes disorders with bipolar features
that do not meet criteria for any specific
bipolar disorder. Examples include
  • Very rapid alternation (over days) between manic
    symptoms and depressive symptoms that meet
    symptom threshold criteria but not minimal
    duration criteria for manic, hypomania, or major
    depressive episodes
  • Recurrent hypomanic episodes without intercurrent
    depressive symptoms
  • A manic or mixed episode superimposed on
    delusional disorder, residual schizophrenia, or
    psychotic disorder not otherwise specified
  • Hypomanic episodes, along with chronic depressive
    symptoms that are too infrequent to qualify for a
    diagnosis of cyclothymic disorder
  • Situations in which the clinician has concluded
    that bipolar disorder is present but is unable to
    determine whether it is primary, due to a general
    medical condition, or substance induced

American Psychiatric Association Diagnostic and
Statistical Manual of Mental Disorders, Fourth
Edition, Text Revision. Washington, DC American
Psychiatric Association 2000.
6
(No Transcript)
7
Diagnostic Criteria for Major Affective Disorders
(DSM-IV)
NOS Not otherwise specified
Adapted from the American Psychiatric
Association Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition, Text Revision.
Washington, DC American Psychiatric Association
2000345-428.
8
Diagnosing Bipolar Disorder Challenges
  • Variability of age of onset and presentation
  • Commonly presenting in the depressed phase and
    being misdiagnosed as unipolar depression
  • Prepubertal onset depression or dysthymia carries
    a 2040 risk of bipolar illness
  • Symptom overlap with other psychiatric conditions
  • Previous misdiagnosis common
  • Many clinically prominent psychiatric and medical
    comorbidities

Thomas P. J Affect Disord. 200479(suppl
1)S3-S8. Berk M, et al. Med J Aust.
2006184459-462.
9
The Bipolar Spectrum Stronger
Bipolar I
? 1 week
Bipolar II
? 4 Days
Bipolar NOS
lt 4 Days
Bipolar III
Antidepressant-related hypomania
Adapted from Akiskal HS, Pinto O. Psychiatr Clin
North Am. 199922517-534.
10
The Bipolar Spectrum Weaker
Hyperthymic
Bipolar IV
Depressive Mixed State IV ½
Recurrent Unipolar Depression Bipolar V
Adapted from Akiskal HS, Pinto O. Psychiatr Clin
North Am. 199922517-534. Akiskal HS, et al. J
Affect Disord. 200696197-205.
11
Bipolar Missed States! (Mixed States)
  • Bipolar mixed states depression and mania
    co-occurring
  • Dysphoric mania common especially in women
  • Depressive mixed states
  • Core of depression, but with racing thoughts
  • Mixed hypomania

Berk M, et al. Aust N Z Psych. 200539215-221. Su
ppes T, et al. Arch Gen Psychiatry.
2005621089-1096.
12
Self-Rated Screening ToolThe Mood Disorder
Questionnaire (MDQ)
  • Hyper or more energetic than usual
  • Predominately or thematically irritable
  • Distinctly self-confident, positive or
    self-assured
  • Less sleep than usual
  • More talkative or speaking faster than usual
  • Racing thoughts
  • Easily distracted
  • Problems at work and socially
  • More interest in sex
  • Taking unusual risks
  • Excessive spending

Hirschfeld RM, et al. J Clin Psychiatry.
20036453-59.
13
Bipolar Disorder Diagnosis Is Often Missed
  • gt 85,000 US adults surveyed
  • Positive screen rate for bipolar illness 3.7
    (gt 6 million people in US)
  • For those with positive screen

Diagnosed withbipolar disorder
20
Neither bipolar disorder nor depression diagnosis
49
Diagnosed with depressionbut not bipolar disorder
31
Only 20 of those with a positive screen had been
told by their doctors that they had bipolar
disorder
Hirschfeld RM, et al. J Clin Psychiatry.
20036453-59.
14
Unipolar Misdiagnosis May Lead to Inappropriate
Treatment
Bipolar disorder misdiagnosed as unipolar
depression in 37 of patients (N 85)
100
80
55
60
Patients ()
40
23
20
n 38
n 35
0
RapidCycling
Mania/Hypomania
Development of mania/hypomania or rapid cycling
while taking antidepressants.
Ghaemi SN, et al. J Clin Psychiatry.
200061804-808.
15
The Hazards of Misdiagnosis and Delayed
Diagnosis in Bipolar Disorder
  • Increased risk of
  • Rapid cycling or mixed features
  • Suicide attempts or completion
  • Violent behavior impulsive behavior
  • Sexual and other indiscretions
  • Worsening substance abuse
  • Loss of job or significant other
  • Treatment resistant

16
Self-Report Diagnostic Tools For Screening
Bipolar Disorder
17
Clinician-Administered Diagnostic Tools For
Screening Bipolar Disorder
18
Subthreshold Bipolar Disorder(The Soft Bipolar
Spectrum)
  • Boundaries of bipolarity have expanded over the
    past decade
  • Suggest that the diagnostic criteria for
    hypomania need revision
  • Further study is needed to evaluate the hard
    and soft definitions of bipolar II, minor
    bipolar disorder, and hypomania
  • A more expansive definition of bipolar II yields
    a cumulative prevalence rate of 10.9, compared
    to 11.4 for broadly defined major depression

Akiskal HS. Curr Psychiatry Rep.
200241-3. Angst J, et al. J Affect Disord.
200373133-146.
19
The Rule of 3 Hinting at Soft Bipolarity (NOS) in
a Clinically Depressed Person
  • Three or more
  • Major depressive episodes
  • Failed marriages
  • Failed antidepressants trials
  • Distinct professions
  • First degree relatives (or generations) with
    affective illness
  • Fields of eminence in the family
  • Substances of abuse
  • Impulsive behaviors (gambling, car racing,
    sexual, etc.)
  • Individuals dated simultaneously
  • Simultaneous jobs
  • Languages (for US-born citizens)
  • Triad of past histrionic, psychopathic, or
    borderline diagnoses
  • Triad of red car, necktie, or belt

Akiskal HS. J Affect Disord. 200584279-290.
20
Importance of Interviewing the Patient and Their
Family
  • Patients admitted with major depression
  • NIMH study
  • Step 1 Patient screened for bipolar disorder
  • Step 2 Family member interviewed (by another
    investigator interested in genetics)
  • Result Twice as many bipolar I diagnoses from
    interviewing both the patient and a family member

Blehar MC, et al. Psychopharmacol Bull.
199834239-243.
21
Physicians Must Use Patient Perspectives to
Improve Diagnosis and Care
  • Factors Necessary for Recovery
  • Communication between patient and physician best
    chance for recovery when patient feels hes being
    heard physician must try to understand how the
    world looks through patients eyes
  • Treatment plans that include patient input and
    preferences physician must discuss all options
    so patient has complete understanding of illness
  • Recovery-oriented treatment based on mutually
    agreed goals so patient feels like a partner in
    care

Lewis L, et al. Adm Policy Ment Health.
200532497-503.
22
Take Home Messages
  • Bipolar disorder can masquerade in different or
    mixed mood states
  • Bipolar disorder is often misdiagnosed as
    depression due to the prevalence of depressive
    episodes often as the presenting phase
  • Misdiagnosis can have serious detrimental effects
    on treatment effectiveness and outcomes

23
  • Section 2 Comorbidities

24
ComorbiditiesThe Rule Not the ExceptionThe
Multidimensionality of Bipolar Disorder
DiabetesMellitus
Cardio-vascular
PainDisorders
Obesity
Migraine
Comorbidities Medical Psychiatric
BipolarDisorder
Substance Abuse
PersonalityDisorders
EatingDisorders
ADHD
AnxietyDisorders
ImpulseControl
McIntyre RS, et al. Human Psychopharmacol.
200419369-386.
25
Psychiatric Comorbid Conditions in Bipolar
Disorder Patients
Allergies, asthma, migraine, and chronic fatigue
1. Hilty DM, et al. Psychiatr Serv.
199950201-213. 2. Krishnan KRR. Psychosomatic
Med. 2005671-8. 3. Brown ES. Psychiatr Clin N
Am. 200528421-425. 4. Singh JB, et al. Bipolar
Disord. 20068696-709.
26
Psychiatric Comorbidities Occur Frequently and
Can Complicate Diagnosis of Bipolar Disorder
  • Additional axis I disorder
  • 65 of bipolar patients have 1 or more
  • Nearly 25 have 3 or more
  • Lifetime prevalence
  • 61 substance abuse
  • 42 anxiety disorders
  • Comorbid conditions can mimic mood symptoms, mask
    them, or exacerbate them

McElroy SL, et al. Am J Psychiatry.
2001158420-426.
27
High Number of Lifetime Comorbid Axis I
Disorders in Both Bipolar I and II Patients
Percent
McElroy SL, et al. Am J Psychiatry.
2001158420-426.
28
Bipolar Disorder and Prevalence of Anxiety
Disorder
  • An anxiety disorder is the most prevalent
  • Social phobia generalized anxiety disorder
    panic disorder obsessive-compulsive disorder
    posttraumatic stress disorder
  • Co-occurrence of anxiety disorder associated
    with
  • Earlier age of onset of mood symptoms
  • Greater number of depressive symptoms
  • Suicidality
  • Greater comorbidity of substance abuse and eating
    disorders
  • Keck PE, et al. J Clin Psychiatry. 200667(suppl
    1)8-15.
  • Simon NM, et al. Am J Psychiatry.20041612222-222
    9.

29
Bipolar Disorder and Frequency ofAnxiety Disorder
McIntyre RS, et al. Bipolar Disord.
20068665-676.
30
Bipolar Disorder and Posttraumatic Stress
Disorder
  • Prevalence rates vary from 5401,2,3,4,5
  • More likely in women, separate course from
    bipolar disorder 4
  • Arises in about 1/3 of adults with bipolar
    disorder who survived severe childhood abuse3
  • In 137 patients with bipolar disorder following
    September 11 terrorist attacks, PTSD was
    associated with hypomanic, manic, or mixed mood
    state at the time of trauma6
  • Manic symptoms may predispose to adverse sequelae
    following traumatic event

1. Kessler R, et al. Arch Gen Psychiatry.
1995521048-1060. 2. McElroy SL, et al. Am J
Psychiatry. 2001158420-426. 3. Goldberg JF, et
al. J Psychiatr Res. 200539595-601. 4.
Strakowski SM, et al. J Clin Psychiatry.
199859465-471. 5. McIntyre RS, et al. Bipolar
Disord. 20068665-676. 6. Pollack MH, et al. J
Clin Psychiatry. 200667394-399.
31
Treatment of Bipolar Disorders and Psychiatric
Comorbidities
Antidepressants may trigger mania or destabilize
bipolar disorder
Keck PE, et al. J Clin Psychiatry. 200667(Suppl
1)8-15.
32
Bipolar Disorder and ADHD
  • Common features
  • Impulsivity
  • Attention problems
  • Conduct problems
  • Substance use
  • Poor school or work performance
  • Relationship problems

Distinguishing features
Comorbidity more common in childhood than adult
onset bipolar disorder.
Slide courtesy of Roger McIntyre, MD and Robert
M. Post, MD.
33
Lifetime Prevalence of Substance Use Highest in
Bipolar Disorder
9
70
8
61
60
7
48
47
50
6
36
5
40
33
Percent
31
Odds Ratio
27
4
30
3
20
2
10
1
0
0
Major Depression
OCD
Panic
Bipolar I
Bipolar II
Dysthymia
Schizophrenia
Regier DA, et al. JAMA. 19902642511-2518.
34
Course of Substance Use Disorder During Bipolar
Disorder
  • Drug use primarily cannabis
  • Alcohol use always associated with affective
    symptoms
  • Cannabis use somewhat common in the absence of
    affective symptoms
  • Locked cycling relatively unusual


 Strakowski SM, et al. J Clin Psychiatry.
199859465-471.
35
Substance Use Disorder Onset With Bipolar
Disorder Onset
  • SUD precedes BPD in
  • 69 (Strakowski et al 1996, 1998)
  • 53 (Winokur et al 1995)
  • 91 (Kovasznay et al 1993)
  • 59 (Feinman Dunner 1996)
  • SUD is commonly antecedent
  • Does relative age at onset affect course?

36
Impact of Substance Abuse on Bipolar Course of
Illness
  • More
  • Early onset - unmasking
  • Suicidality
  • Mixed or dysphoric mania
  • Rapid cycling
  • ER visits and hospitalizations
  • Neuronal loss?
  • Less
  • Compliance
  • Symptom remission
  • Treatment (lithium) response

Goodwin Jamison. Manic Depressive
Illness.1990. Goldberg JF, et al. J Clin
Psychiatry. 199960733-740. Frye MA, et al. Mod
Probl Pharm. 19972588-113. Strakowski SM, et
al. Int J Psychiatry Med. 199424305-328.
37
Treatment of Co-occurring Bipolar Disorder and
Substance Use Disorders
  • Few controlled treatment studies in bipolar
    disorder
  • Must make inferences from data in primary
    substance disorders
  • Combination of psychotherapeutic interventions
    and pharmacotherapies targeting both disorders
    optimally
  • Earlier recognition and treatment of bipolar
    disorder may prevent substance disorder

Levin FR, et al. Biol Psychiatry. 200456738-748.
38
Substance Use Disorder in Bipolar Disorder
Treatment
Bipolar
Substance Drug
Disorder Abuse Lithium /- VPA CBZ
/- TPM -/ Antipsychotics -/? Antidepressa
nts /- /- Naltrexone -/? Disulfiram - AA/Be
havioral /-
Slide courtesy of Stephen M. Strakowski, MD.
39
Bipolar Disorder and Substance Abuse Treatment
Response
  • Tohen et al (1990)
  • 24 lithium-treated BP patients - alcoholism
    predicted shorter remission
  • Weiss et al (1998)
  • Self-report compliance 21 compliance lithium vs
    50 divalproex in 44 bipolar-SUD patients
  • Goldberg et al (1999)
  • 204 substance abusers who received valproate or
    carbamazepine had remission of their bipolar
    disorder more often than substance abusers who
    received lithium alone (P lt 0.05)
  • Salloum IM (2005)
  • VPA found to be effective with co-occurring
    alcohol dependence
  • Weiss et al (2005)
  • Patients with bipolar disorder who experience
    sustained recovery from SUDs have a better QOL
    than with an active SUD
  • Patients with no SUD history had the best QOL

Tohen M, et al. J Affect Disord.
19901979-86. Weiss RD, et al. J Clin
Psychiatry. 199859172-174. Goldberg JF, et al.
J Clin Psychiatry. 199960733-740. Salloum IM,
et al. Arch Gen Psychiatry. 20056237-45. Weiss
RD, et al. J Clin Psychiatry. 200566730-735.
40
Accelerated Cycling Bipolar Disorder and
Borderline Function or Personality Disorder
Distinguishing Features
Slide courtesy of Roger McIntyre, MD.
41
Bipolar Disorder and Borderline Personality
Disorder
  • Only modest association
  • Patients with borderline personality disorder vs
    other personality disorders had higher
    co-occurrence (19.4) of bipolar disorder
  • Those with other personality disorders and
    bipolar disorder had more new onset borderline
    personality disorder (25) than those without
    bipolar disorder (10)

Gunderson JG, et al. Am J Psychiatry.
20061631173-1178.
42
Medical Comorbidity in Bipolar Disorder A
Population-Based Survey
Significantly higher than no bipolar (P lt 0.05)
Adapted from McIntyre RS, et al. Psychiatr Serv.
2006571140-1144.
43
Medical Comorbidities With Bipolar Disorder
  • Cardiovascular disease
  • Increased mortality in male inpatients with
    bipolar disorder 1.87
  • Obesity
  • Central obesity more common, especially with
    antipsychotics
  • Diabetes
  • Increased prevalence 9.9 expected prevalence
    3.4
  • Neurological disorders
  • Migraine prevalence 25 of men, 27 of women
    rate in men is almost 5x general population
  • Chronic pain syndromes

Elmslie JL, et al. J Clin Psychiatry.
200061179-184 Cassidy F, et al. Am J
Psychiatry. 19991561417-1420 Weeke A, et al. J
Affect Disord. 198713287-292 Mahmood T, et al.
J Affect Disord. 199952239-241 Schiffer RB, et
al. Am J Psychiatry. 198614394-95.
44
Correlates of Obesity in Patients With Bipolar
Disorder
  • Hypertension
  • Diabetes mellitus
  • Arthritis
  • Male
  • Exposure to 1 weight-increasing psychotropic
  • Comorbid binge-eating disorder
  • gt 4 manic episodes
  • 1 suicide attempt
  • Limited occupational functioning

Stanley Foundation Bipolar Treatment Outcome
Network (N 644) McElroy SL, et al. J Clin
Psychiatry. 200263207-213.
45
Bipolar Disorder and Type II Diabetes
1. Cassidy F, et al. Am J Psychiatry.
19991561417-1420. 2. Regenold WT, et al. J
Affect Disord. 20027019-26. 3. Ruzickova M, et
al. Can J Psychiatry. 200348458-461. 4.
Kilbourne AM, et al. Bipolar Disord.
20046368-373.
46
Comorbid Restless Leg Syndrome (RLS) and
Iatrogenic Mania
  • Dopamine agonists (such as pramipexole,
    ropinirole, used to treat RLS and Parkinsons
    disease) may induce iatrogenic mania such as
  • Gambling
  • Hypersexuality
  • Impulsive shopping

Singh A, et al. Am J Psychiatry.
2005162814-815. Weintraub D, et al. Arch
Neurol. 200663969-973.
47
Unique Treatment Challenges of Parkinsons
Disease
  • Depression and anxiety are common
  • Motor on-off phenomenon common and associated
    with mood fluctuations
  • Patients with major affective disorder have about
    2-fold increased likelihood of developing
    Parkinsons disease
  • Dopamine agonists may worsen mania in persons
    with co-occurring bipolar disorder
  • Some dopamine agonists, such as pramipexole, also
    have demonstrated antidepressant efficacy as
    adjuncts to mood stabilizers, with low risk of
    inducing mania, in preliminary placebo-controlled
    trials
  • Physicians treating Parkinsons patients should
    be alert for symptoms of bipolar disorder

Ferreri F, et al. Can Med A J. 20061751545-1552.
Nilsson FM, et al. Acta Psychiatr Scand.
2001104380-386. Goldberg JF, et al. Am J
Psychiatry. 2004161564-566. Zarate CE Jr, et
al. Biol Psychiatry. 20045654-60.
48
Medical Comorbidities With Bipolar Disorder
  • Some medications increase risk for weight gain,
    diabetes, metabolic syndrome, and cardiovascular
    disease
  • Measure waist circumference, BMI, weight, blood
    pressure, glucose
  • Encourage diet and exercise
  • Monitoring for drug toxicity is essential
  • Routine monitoring of mood stabilizers
    recommended every 6 months
  • Thyroid function tests for lithium
  • CBC and hepatic function for valproate and
    carbamazepine
  • Triglycerides for atypical antipsychotics

Kilbourne AM, et al. J Affect Disord. Epub ahead
of print. Suppes T, et al. J Clin Psychiatry.
200566870-886.
49
General Principles in Treatment of Comorbidity
in Bipolar Disorder
  • Address bipolar disorder and its comorbidities
    concurrently
  • Use medications that treat both disorders
  • Use medication with least abuse potential and
    least toxicity
  • Use doses that are below the side effects
    threshold
  • Most treatment of psychiatric comorbidities is
    off-label
  • Maximize the use of nonpharmacologic treatment
  • Patients with comorbidities are at greater risk
    for medication nonadherence

50
Section 3 Treatment of Bipolar Disorder
51
Therapies With Bipolar Disorder Indications
Limited data Physicians Desk Reference. 61st
ed. Montvale, NJ Medical Economics Co 2007.
52
TIMA Algorithm for Treatment of Acute Manic
Episodes (Stages 12)
Stage 1 Monotherapy 1ALithium, valproate,
atypicals excluding olanzapine and clozapine
1B Olanzapineor carbamazepine
ResponseContinue with therapy
NonresponseTry alternate monotherapy
Stage 2 Two-drug combination Lithium,
valproate, atypical antipsychoticChoose 2 (not 2
atypicals, not aripiprazole or clozapine)
ResponseContinue with therapy
Use targeted adjunctive treatment as necessary
before moving to next stage. Agitation/Aggression-
clonidine, sedatives Insomnia-hypnotics
Anxiety-benzodiazepines, gabapentin. All agents
in Stage 1A and 1B are indicated for acute mania
associated with bipolar I disorder. Safety and
other concerns led to placement of olanzapine and
carbamazepine as alternate first-stage choices.
Suppes T, et al. J Clin Psychiatry.
200566870-886.
53
TIMA Algorithm for Treatment of Acute Manic
Episodes (Stages 34)
Suppes T, et al. J Clin Psychiatry.
200566870-886.
54
Mixtures of Manic and Depressed Symptoms Are
Commonly Seen
Depressive Mixed States1
Mixed Mania
Dysphoric Mania
Full Mania
Full Mania
2 Mania Symptoms
Mania MDE
2 Depressive Symptoms
Full MDE
Full MDE
MDE major depressive episode 1. Benazzi F.
Psychiatry Res. 2004127247-257. 2. Maj M, et
al. Am J Psychiatry. 20031602134-2140. 3.
Akiskal HS, et al. J Affect Disord.
200585245-258.
Agitated depressions? 2,3
55
Conventional vs Atypical AntipsychoticsSide-Effe
ct Profiles
Key 0 absent ? minimal mild
moderate severe TRZ Thioridazine HAL
haloperidol CLZ clozapine OLZ olanzapine
RIS risperidone QTP quetiapine ZIP
ziprasidone ARI Aripiprazole a Minimal weight
gain in long-term treatment.
Tandon R, Jibson MD. Psychoneuroendocrinology.
200328(suppl 1)9-26. Physicians Desk
Reference. 61st ed. Montvale, NJ Medical
Economics Co 2007.
56
FDA Black Box Warnings
  • Clozapine
  • Agranulocytosis, seizures, hypotension,
    myocarditis
  • Valproate
  • Fetal neural tube defects, hepatic failure,
    hemorrhagic pancreatitis
  • Lamotrigine
  • Serious rashes
  • Lithium
  • Toxicity close to therapeutic levels
  • Carbamazepine
  • Agranulocytosis
  • Aplastic anemia
  • Second generation antipsychotics
  • Increased mortality in elderly patients with
    dementia-related psychosis

Prescribing Information. In Physicians Desk
Reference. 61st ed. Montvale, NJ Medical
Economics Co 2007
57
Treating Bipolar Depression
  • Monotherapy or combination therapy
  • Lithium
  • Novel antipsychotics
  • Anticonvulsants
  • Other strategies
  • Add-on antidepressant (not as monotherapy)
  • Electroconvulsive therapy (ECT)

While monotherapy is the goal of most
practitioners, the inherent nature of bipolar
disorder makes combination therapy the rule
rather than the exception.
Young LT. J Psychiatry Neurosci.
20042987-88. American Psychiatric Association.
Am J Psychiatry. 20021591-50.
58
TIMA Bipolar Treatment of Acute Depressive
Episodes (Stages 13)
Taking no antimanic, with history of severe
and/or recent mania
Taking no antimanic, without history of severe
and/or recent mania
Taking otherantimanic
Taking Li
Increase to 0.8 mEq/L
(continue)
Stage 1
Antimanic LTG
LTG
Stage 2
OFCa or QTPa
Stage 3
Combination from Li, LTG, QTP, or OFC
aNote safety issue described in reference listed
below (ie, olanzapine is associated with weight
gain, quetiapine is associated with sedation and
somnolence). Li lithium LTG lamotrigine OFC
olanzapine-fluoxetine combination QTP
quetiapine.
Suppes T, et al. J Clin Psychiatry.
200566870-886.
59
TIMA Bipolar Treatment of Acute Depressive
Episodes (Stages 45)
Stage 4
Li, LTGb, OFC, VPA, or CBZ SSRIc, BUP, or VEN
or ECT or QTP
Stage 5
MAOIs, tricyclics, pramipexole, other AAPsa,
OXC, other combinations of drugs at stages,
inositol, stimulants, thyroid
aNote safety issue described in reference listed
below (ie, olanzapine is associated with weight
gain, quetiapine is associated with sedation and
somnolence). bLamotrigine has limited antimanic
efficacy and, in combination with an
antidepressant, may require the addition of an
antimanic. cSSRIs include citalopram,
escitalopram, fluoxetine, paroxetine, sertraline,
and fluvoxamine. Evidence supported by
randomized controlled clinical trials with large
effect sizes. AAP atypical antipsychotic BUP
bupropion CBZ carbamazepine CONT
continuation ECT electroconvulsive therapy
Li lithium LTG lamotrigine MAOI
monoamine oxidase inhibitor OFC
olanzapine-fluoxetine combination OXC
oxcarbazepine QTP quetiapine SSRI selective
serotonin reuptake inhibitor VEN venlafaxine
VPA valproate.
Suppes T, et al. J Clin Psychiatry.
200566870-886.
60
Quetiapine Monotherapy for the Treatment of
Bipolar Depression
MADRS Total Score
Study Week
Study Week
1
2
4
3
6
5
7
8
0
1
2
4
3
6
5
7
8
0
0
0
Placebo (n 169)
Placebo (n 161)
Mean Change From Baselinea
QTP 300 mg/d (n 172)
QTP 300 mg/d (n 155)
QTP 600 mg/d (n 151)
QTP 600 mg/d (n 170)
-4
-4

-8
-8





-12
-12

Improvement















-16
-16










BOLDER I N 511
BOLDER II N 467
-20
-20
P lt 0.01 vs placebo, P lt 0.001 vs placebo
aValues are least squares mean
Calabrese J, et al. Am J Psychiatry.
20051621351-1360.
Thase ME, et al. J Clin Psychopharmacol.
200626600-609.
61
BOLDER II MADRS Items
Quetiapine 300 mg (n 155)
Apparent sadness
Quetiapine 600 mg (n 151)
Reported sadness
Placebo (n 161)


Inner tension


Reduced sleep


Reduced appetite

Concentration difficulties


Lassitude

Inability to feel


Pessimisticthoughts


Suicidal thoughts
0
10
20
30
40
50
60
70
80
Improvement from Baseline in Mean Score
N 467 P lt 0.05 P lt 0.01 P lt 0.001 vs
placebo (P-values ANCOVA, change from
baseline) Week 8 assessment
Thase ME, et al. J Clin Psychopharmacol.
200626600-609.
62
Olanzapine-fluoxetine CombinationTreatment for
Bipolar I Depression
Source
Review
0
Placebo (N 355)
-2
Olanzapine (N 351)

-4
OFC (N 82)
-6
Reviewer Memo

-8



Improvement
MADRS Change From Baseline
-10

-12

-14


-16
-18
-20
0
1
2
3
4
5
6
7
8
Week
P lt 0.05 olanzapine vs placebo P lt 0.05 vs OFC
N 788 Tohen M, et al. Arch Gen Psychiatry.
2003601079-1088.
Slide Modified
Memo
63
Comparison of Olanzapine and Olanzapine-Fluoxetin
e in Bipolar I Depression MADRS Items

Apparent sadness
OFC (n 82)
Placebo (n 355)

Reported sadness
Olanzapine (n 351)


Inner tension


Reduced sleep


Reduced appetite

Concentration difficulties

Lassitude

Inability to feel

Pessimistic thoughts
Suicidal thoughts
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
OFC olanzapine fluoxetine N 788 P lt 0.05
vs placebo P lt 0.05 vs olanzapine Week 8
assessment
Mean Change From Baseline in MADRS score
Tohen M, et al. Arch Gen Psychiatry.
2003601079-1088.
64
TIMA Guidelines for Maintenance Treatment Most
Recent Episode Depressed
  • It is an option to remain on well-tolerated,
    effective, acute-phase treatments
  • Available evidence supports the options presented
    for maintenance treatment

Patients With Recent and/or Severe History of
Mania
Lamotrigine Combined With Antimanic Agent
Level I
All Other Patients
Lamotrigine Monotherapy
Level II Lithium
Level III Combination of Antimanic and
Antidepressant That Has Been Effective in the
Past, including Olanzapine/Fluoxetine
Combination1
Level IV Valproate, Carbamazepine,
Aripiprazole,2 Clozapine,1 Olanzapine,1
Quetiapine,2 Risperidone,2 Ziprasidone2
Level V Typical Antipsychotics,1
Oxcarbazepine,2 ECT
1. Safety issues warrant careful consideration of
this option for potential long-term use 2.
Relatively limited information is currently
available on this agent in long-term use
Suppes T, et al. J Clin Psychiatry.
200566870-886.
65
Maintenance Treatment
  • FDA-indicated agents
  • Lithium
  • Lamotrigine
  • Olanzapine
  • Aripiprazole

Physicians Desk Reference. 61st ed. Montvale,
NJ Medical Economics Co 2007.
66
Lithium vs Placebo in Maintenance
1.2
Lithium
1
Placebo
0.8
0.6
Probability of Remaining Well
0.4
0.2
0
0
10
20
30
40
50
60
Follow-Up (weeks)
Keck PE Jr, et al. Biol Psychiatry.
200047756-761.
67
Lithium Reduces Mortality
Cochrane Controlled Trials Registry 32
Randomized Trials 1389 patients randomized to
lithium 2069 randomized to active comparators
Cipriani A, et al. Am J Psychiatry.
20051621805-1819.
68
Lamotrigine or Placebo Time to Intervention for
Any Mood Episode Combined Analysis
70 60 50 40 30 20 10 0
100 90 80 70 60 50 40 30 20 10 0
Lamotrigine 100-400 mg (n 223) Placebo (n 188)
37
of patients
22
Estimated of Pts Intervention-Free
18 months
LTG vs PBO, P lt 0.001
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Month
Goodwin GM, et al. J Clin Psychiatry.
200465432-441.
69
Lamotrigine or Placebo Time to Intervention for
a Depressive EpisodeCombined Analysis
70 60 50 40 30 20 10 0
57
41
of patients
18 months
Some patients considered intervention-free for
depressive episodes could have had intervention
for manic episodes.
Goodwin GM, et al. J Clin Psychiatry.
200465432-441.
70
Lamotrigine or Placebo Time to Intervention for
a Manic Episode Combined Analysis
70 60 50 40 30 20 10 0
65
100 90 80 70 60 50 40 30 20 10 0
53
Lamotrigine 100-400 mg (n 223) Placebo (n 188)
of patients
Estimated of Pts Intervention-Free
18 mo
LTG vs PBO, P 0.034
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Month
Some patients considered intervention-free for
manic episodes could have had intervention for
depressive episodes.
Goodwin GM, et al. J Clin Psychiatry.
200465432-441.
71
Maintenance Treatment Atypical Antipsychotics
  • Olanzapine is recommended as an alternate
    first-line therapy
  • Aripiprazole is recommended as a second-line
    therapy
  • Other atypical antipsychotics (quetiapine,
    risperidone, ziprasidone) are potential
    maintenance treatments

Suppes T, et al. J Clin Psychiatry.
200566870-886. Yatham LN, et al. Bipolar
Disord. 200575-69.
72
Olanzapine Versus Placebo Relapse Into Mania or
Depression
1.0
1.0
0.8
0.8
0.6
0.6
Probability of Remaining Relapse Free
0.4
0.4
Subjects receiving olanzapine (N 225)
Subjects receiving olanzapine (N 225)
0.2
0.2
Subjects receiving placebo (N 136)
Subjects receiving placebo (N 136)
0.0
0.0
0
50
100
150
200
250
300
350
400
50
100
150
200
250
300
350
400
0
Days to Relapse Into Mania Only
Days to Relapse Into Depression Only
P lt 0.001
P lt 0.001
Tohen M, et al. Am J Psychiatry. 2006163247-256.
73
Aripiprazole for Maintenance Treatment of
Bipolar Disorder
Manic Relapse
Depressive Relapse
1.0
1.0
0.9
0.9
0.8
0.8
0.7
0.7
0.6
Proportion of Patients Without Relapse
0.6
Proportion of Patients Without Relapse
0.5
0.5
0.4
0.4
0.3
0.3
0.2
0.2
Aripiprazole (N 77) Placebo (N 83)
Log rank P 0.008 HR 0.309 (95 CI 0.123 to
0.774)
Aripiprazole (N 77) Placebo (N 83)
Log rank P 0.683 HR 0.833 (95 CI 0.345 to
2.011)
0.1
0.1
0.0
0.0
0
28
56
84
112
140
168
196
28
56
84
112
140
168
196
0
Days in Study
Days in Study
Keck PE Jr, et al. J Clin Psychiatry.
200667626-637.
74
Maintenance Treatment Antidepressants
  • Maintenance antidepressants efficacy has been
    established in unipolar but not bipolar
    depression
  • Increased cycling on antidepressants has been
    shown in three placebo-controlled studies
  • Not recommended, but if used, must be used with
    an antimanic agent in bipolar I disorder
  • When antidepressants are used in acute therapy,
    taper and discontinue them after recovery from
    depression maintain them only in those who
    repeatedly relapse soon after discontinuation
    (about 20 of bipolar patients)

Ghaemi SN, et al. Bipolar Disord.
20035421-433. Suppes T, et al. J Clin
Psychiatry. 200566870-886. Yatham LN, et al.
Bipolar Disord. 200575-69.
75
Maintenance Treatment Anxiolytics
  • Systematic evaluation of benzodiazepines as
    prophylactic agents in bipolar disorder has not
    been conducted
  • Issues such as dependence, rebound anxiety,
    memory impairment argue against their long-term
    use

Yatham LN, et al. Bipolar Disord. 200575-69.
76
Maintenance Treatment Mood Stabilizer
Combinations
  • Some efficacy demonstrated
  • Lithium plus valproate
  • Lithium plus carbamazepine
  • Olanzapine-fluoxetine combination has shown
    efficacy
  • Many other combinations are used but with limited
    evidence

Suppes T, et al. J Clin Psychiatry.
200566870-886. Yatham LN, et al. Bipolar
Disord. 200575-69.
77
Relapse Prevention
  • Features associated with increased risk of
    recurrence
  • 20 previous episodes of depression or
    (hypo)mania
  • Residual manic symptoms at response
  • More days depressed/anxious in previous year
    associated with depressive recurrence
  • More time spent in manic/hypomanic state in past
    year associated with shorter time to
    manic/hypomanic/mixed episode recurrence
  • Suggests bipolar disorder remains a highly
    recurrent, predominantly depressive illness
  • Targeting residual symptoms in maintenance
    treatment may reduce risk of recurrence

Perlis RH, et al. Am J Psychiatry.
2006163217-224.
78
The Importance of Subsyndromal Symptoms in
Bipolar Disorder
  • Subsyndromal (subthreshold) symptoms (those that
    fail to meet full diagnostic criteria for mood
    episode) are a significant public health issue
  • May be related to poor outcomes
  • Are associated with deficits in social and
    occupational functioning
  • Increase the risk of relapse
  • Are significantly associated with functional
    impairment in multiple domains

Altshuler LL, et al. J Clin Psychiatry.
2006671551-1560. Marangell LB. J Clin
Psychiatry. 200465(suppl 10)24-27.
79
Subsyndromal Symptoms Are Associated With
Functional Impairment in Over 5075 of Patients
Altshuler LL, et al. J Clin Psychiatry.
2006671551-1560.
80
Treating Subsyndromal Mood Symptoms in Bipolar
Disorder Evaluation of Maintenance Trials
  • Two 18-month, randomized, placebo-controlled
    maintenance trials for bipolar I disorder were
    evaluated for incidence, time course, impact of
    pharmacotherapy on subsyndromal symptoms
  • Subsyndromal symptoms occurred in 25 of all
    visits
  • Compared with placebo (54.8), higher mean
    percentage of visits in remission with
    lamotrigine (63.0, P .020) but not with
    lithium (60.0, P 0.165)
  • Lithium and lamotrigine delayed onset of
    subsyndromal symptoms and time from onset of
    relapse
  • Further studies are needed to assess whether
    treatment interventions can minimize subsyndromal
    symptoms or prevent relapse

Frye MA, et al. J Clin Psychiatry.
2006671721-1728.
81
Treatment-Resistant Bipolar Depression STEP-BD
25
  • Open randomized trial
  • Prior nonresponse to MS AD
  • LTG 150250 mg/day
  • INO 1025 gms/day
  • RIS up to 16 mg/day
  • Up to 16 weeks
  • Recovery lt 2 sxs
  • for 2 mos

20
15
Recovery Rate ()
10
5
0
Lamotrigine (N 21)
Inositol (N 23)
Risperidone (N 23)
Nierenberg AA, et al. Am J Psychiatry.
2006163210-216.
82
Recommendations for Combination Therapy in
Bipolar Disorder
  • Combination therapy is the rule, not the
    exception
  • Use evidence-based data when available
  • Add drugs to the treatment regimen that
    specifically targets residual symptoms

Bowden CL. J Clin Psychiatry. 200465(suppl
15)21-24.
83
Take Home Messages
  • Goal is to stabilize depression without causing
    mania and minimizing side effects
  • Monotherapy antidepressants can destabilize
    bipolar depression
  • Evidence-based treatment for bipolar depression
    includes lithium and lamotrigine
  • Quetiapine is the only approved monotherapy for
    bipolar depression
  • OFC is the only FDA approved combination therapy
    for bipolar depression
  • Some novel antipsychotics may have a role in
    treating bipolar depression as monotherapy while
    stabilizing mania

84
Section 4 Nonpharmacologic Treatment Approaches
85
Goals of Psychotherapy
  • Establish and maintain a therapeutic alliance
  • Provide education about the disease and its
    treatment
  • Promote regular patterns of activity and sleep
  • Identify cognitive distortions linked with
    depression
  • Identify sources of interpersonal discord (eg,
    expressed emotion) and promote healthy responses
    to stress
  • Detect early warning signs of mood episodes
  • Minimize the negative impact of the illness
  • Promote the regular use of medications

86
Enhancement of Adherence and Improving Illness
Outcome in Bipolar Disorder
  • Patients with bipolar disorder are often poorly
    adherent to their medical regimens
  • While psychotherapy for bipolar disorder is known
    to generally improve illness outcome, it has been
    reported that interventions that focus on
    treatment adherence may yield positive results in
    this specific area

Cochran SD. J Consult Clin Psychol.
198452873-878. Colom F. Bipolar Disord.
20024(suppl 1)102.
87
Psychosocial Treatment Options
  • Brief technique-driven interventions 6 to 12
    individual sessions
  • Cognitive therapy
  • Interpersonal social rhythm therapy (IPSRT)
  • Family or couples therapy
  • Group psychoeducation

Scott J, et al. Psychiatr Clin North Am.
200528371-384.
88
Evidence-Based Therapies
  • Impact on relapse and rehospitalization rates
  • Group psychoeducation
  • 25 hospitalized vs 35 in unstructured group1
  • Cognitive behavioral therapy (CBT)
  • 1 year relapse 44 vs 75 usual care2
  • 2-year follow-up found no reduction in relapse
    rates after first 6 months 3
  • Family focused treatment (FFT)
  • 2 year relapse 28 with FFT vs 60 with
    individual support4
  • Perceived criticism may be an indicator 5

1. Colom F, et al. Arch Gen Psychiatry.
200360402-407. 2. Lam DH, et al. Arch Gen
Psychiatry. 200360145-152. 3. Lam DH, et al. Am
J Psychiatry. 2005162324-329. 4. Rea MM, et al.
J Consult Clin Psychol. 200371482-492. 5.
Miklowitz DJ, et al. Psychiatry Res.
2005136101-111.
89
Interpersonal Social Rhythm Therapy Focus
  • IPSRT focuses on
  • The link between mood and life events
  • The importance of maintaining regular daily
    rhythms
  • The identification and management of potential
    precipitants of rhythm dysregulation with
    attention to interpersonal triggers
  • The identification and management of affective
    symptoms

Frank E, et al. Biol Psychiatry. 200048593-604.
90
Benefits of Psychotherapy Interventions
  • Adjustment to Dx and Rx
  • Enhanced adherence
  • Improved self-esteem
  • Reduced risky behaviors
  • Modification of destabilizing biopsychosocial
    factors
  • Management of stressors
  • Learning coping strategies
  • Early recognition
  • Modification attitudes/beliefs

Scott J, Gutierrez MJ. Bipolar Disord.
20046498-503.
91
Psychotherapy Reduces Relapse Rate
0.1
1
10
1
Logarithmic scale of odds ratio
Favors therapy
Significant reduction in relapse rate (40)
compared to standard treatment alone.
Scott J, et al. Intl J Neuropsychopharmacol.
200710123-129.
92
Section 5 Use of Antidepressants in Bipolar
Disorder
93
Treatment of Bipolar Depression
  • Fewer studies than for mania
  • Limited approved treatments
  • Antidepressants lack evidence and may cause mood
    destabilization

Ghaemi SN, et al. J Clin Psychiatry.
200162565-569. Ghaemi SN, et al. Am J
Psychiatry. 2004161163-165.Muzina DJ,
Calabrese JR. Int J Neuropsychopharmacol.
20036285-291.
94
Use of Antidepressants in Bipolar Disorder
  • Bipolar disorder is associated with considerable
    depressive morbidity
  • Risk-to-benefit ratio of antidepressants as
    adjuncts to mood stabilizers is an area of
    controversy and disagreement
  • Antidepressants may increase risk of iatrogenic
    mania, mixed states, rapid cycling
  • APA 2002 guidelines recommend conservative use of
    antidepressants
  • Although evidence of their safety and efficacy is
    limited, antidepressants are commonly used in
    treatment of bipolar depression

Hirschfeld RM et al. Presented at 156th American
Psychiatric Association Annual Meeting May
17-22, 2003 San Francisco, CA. Goldberg JF, et
al. Bipolar Disord. 20035407-420. American
Psychiatric Association. Practice Guidelines for
the Treatment of Patients With Bipolar Disorder.
2nd ed. Washington, DC American Psychiatric
Publishing Group 2002.
95
Bipolar Depression and AntidepressantsGeneral
Clinical Guidelines and Risks
  • Conservative approach to antidepressant use
  • Risk of antidepressant induced mood-cycling in
    about 1530 of patients
  • Mood stabilizers (lithium, lamotrigine) are
    effective in acute and prophylactic treatment of
    depression lithium is effective in suicide
    prevention
  • Antidepressants should be reserved for severe
    cases of acute bipolar depression and not used
    routinely
  • Cost/risk benefit ratio for antidepressant
    treatment of bipolar depression is unfavorable
  • Antidepressants should be discontinued after
    recovery from depressive episode (mixed evidence
    for this recommendation)
  • American Psychiatric Association. Practice
    Guidelines for the Treatment of Patients With
    Bipolar Disorder. 2nd ed. Washington, DC
    American Psychiatric Publishing Group 2002.
  • Ghaemi SN, et al. Bipolar Disord. 20035421-433.
  • Ghaemi SN, et al. Am J Psychiatry.
    2004161163-165.

96
No Antidepressant Advantage For Paroxetine or
Imipramine If Lithium Levels Are Therapeutic
N 15 15 14 7 10 7
60
P NS
P 0.05
50
40
Responders per Hamilton Criterion 7
Li PBO
30
Li PAR
Li IMI
20
10
Switch Rates LiPBO 2.3 LiIMI 7.7 LiPAR 0
0
Overall Efficacy
Li 0.8 mEq/L
PBO Placebo PAR Paroxetine IMI Imipramine
Nemeroff CB, et al. Am J Psychiatry.
2001158906-912.
97
Antidepressant Efficacy Stanley Network
N 32 42 37 15 22
22
68.8
71.0
62.5
55.3
With CGI 1 or 2
48.5
43.0
Leverich GS, et al. Am J Psychiatry.
2006163232-239.
98
Time Until Switch With Antidepressants Stanley
Bipolar Network
1.0
0.8
P 0.03
0.6
Cumulative Proportion Without a Switch
0.5
0.2
Patients with bipolar I disorder (N 115)
Patients with bipolar II disorder (N 44)
Censored
0.0
200
300
100
400
500
0
Time to Switch (days)
Leverich GS, et al. Am J Psychiatry.
2006163232-239.
99
Ratio of Threshold Switches to Subthreshold Brief
Hypomanias
4.0
More Threshold Than Subthreshold Phenomena
3.5
3.0
2.5
Ratio of Threshold Switches to Subthreshold Brief
Hypomanias
2.0
1.5
1.0
More Subthreshold Than Threshold Phenomena
Bupropion
0.5
Sertraline
Venlafaxine
0.0
Acute Antidepressant Trials (10 weeks)
Continuation Antidepressant Trials ( 1 year)
Leverich GS, et al. Am J Psychiatry.
2006163232-239.
100
Maintenance Antidepressants in Bipolar Disorder
  • Maintenance antidepressants efficacy has not been
    established in bipolar disorder
  • Increased cycling on antidepressants has been
    shown in three placebo-controlled studies
  • When antidepressants are used in acute therapy,
    taper and discontinue them after recovery from
    depression
  • Maintain antidepressants only in those who
    repeatedly relapse soon after discontinuation
    (about 20 of bipolar patients)

Ghaemi SN, et al. Bipolar Disord. 20035421-433.
101
TIMA 2005 Bipolar Acute Depression
Stage 1
OtherAntimanic
No Antimanic, Severe or Recent Mania
No Antimanic,No Severe or Recent Mania
Taking Li
(Increase Li to 0.8 mEq/L)
(continue)
Antimanic Lamotrigine
Lamotrigine
  • Lamotrigine is a mood stabilizer not antimanic
  • Lithium is an antimanic
  • If history of recent or severe mania, add or
    optimize antimanic
  • Otherwise, lamotrigine monotherapy may be
    appropriate

Suppes T, et al. J Clin Psychiatry.
200566870-886.
102
TIMA 2005 Bipolar Acute Depression
Partial Response or Nonresponse
Stage 2
Quetiapine or Olanzapine-Fluoxetine
Response
Partial Response or Nonresponse
CONT
Stage 3
Combination from Li, LTG, QTP, or OFC
  • Designed to minimize cycle risk
  • Note no anticonvulsant except LTG until Stage 4
  • Overlap and taper
  • Follow ADA guidelines regarding metabolic
    monitoring

Suppes T, et al. J Clin Psychiatry.
200566870-886.
103
TIMA 2005 Bipolar Acute Depression
Response
CONT
Partial Response Or Nonresponse
Li, LTG, QTP, OFC, VPA, or CBZ SSRI, BUP, or
VEN or ECT
Stage 4
  • Combinations (OFC combinations 3 drugs)
  • Lamotrigine should not be combined with AD
    without antimanic
  • Includes VPA and CBZ at this point
  • SSRIs include CTP, FLX, PRX, SRT, and FLV
  • Some advocate the use of AD earlier but
    evidence is lacking
  • Venlafaxine associated with more mania
    induction

BUP bupropion CBZ carbamazepine CTP
citalopram ECT electroconvulsive therapy Li
lithium LTG lamotrigine OFC
olanzapine-fluoxetine combination QTP
quetiapine SSRI selective serotonin reuptake
inhibitor VEN venlafaxine VPA
valproate Suppes T, et al. J Clin Psychiatry.
200566870-886.
104
Bipolar Depression and Antidepressants General
Guidelines and Risks
  • Always use mood stabilizer in bipolar I patients,
    even while depressed
  • Promptly wean the antidepressant if evidence of
    hypomania or mania emerges
  • Antidepressants may trigger mania (mood
    destabilization) or accelerate mood cycle
  • Up to 33 of patients with bipolar disorder may
    be susceptible to antidepressant-induced manias
  • Possibly less efficacious in bipolar than
    unipolar depression
  • Few standard antidepressants have been studied in
    bipolar depression

Dantzler A, Osser DN. Psychiatr Ann.
199929270-284. Frances AJ, et al. J Clin
Psychiatry. 199859(suppl 4)73-79. Goldberg JF,
Ernst CL. J Clin Psychiatry. 200263985-991. Gold
berg JF, Truman CJ. Bipolar Disord.
20035407-420. Möller HJ, et al. J Affect
Disord. 200167141-146.
105
Complicated Bipolar Relapse
106
Presentation
  • 32-year-old female
  • Brought to ER by police
  • Family called 911 after altercation at
  • home escalated

107
History of Present Illness
  • Sister tells ER doctor that patient has been
    getting more irritable for last 6 weeks
  • Missed outpatient psychiatrist appointment 2
    weeks ago
  • Spent disability check and couldn't afford to
    fill prescription
  • Sister suspects patient has started abusing
    cocaine again

108
Past Psychiatric History
  • Diagnosed with bipolar disorder at age 21
  • 5 prior hospitalizations (3 manic episodes, 2
    depressive episodes with suicidality)
  • Sporadic outpatient attendance with partial
    medication
  • compliance
  • Responded to lithium, but patient discontinued
    due to
  • tremor
  • Responded to valproic acid, but patient
    discontinued
  • due to weight gain
  • Noncompliance associated with cocaine abuse

109
Recent Psychiatric History
  • More irritable
  • Feels her sister is checking on her too much
  • Feels she can make a new start and called
  • CNN and NBC seeking audition as newscaster
  • Poor sleep pattern

110
Past Medical History
  • Hypertension
  • Obesity (BMI 32)
  • Gallstone surgery

111
Social and Family History
  • Social History
  • Cigarette smoker
  • 2 DUIs
  • On disability for bipolar disorder
  • Family History
  • Mother has bipolar disorder
  • First cousin committed suicide
  • Patient has longstanding difficulties in her
    family relationship
  • Divorced twice
  • 1 child has ADHD, 1 cousin with bipolar disorder

112
Mental Status Examination
  • Intoxicated and irritable in ER
  • Angry with her sister, vague threats (she
    better
  • watch out if she continues to be so pushy)
  • Speech pressured
  • Tells ER doctor she doesn't want to be
    hospitalized because she is setting up interview
    with CNN
  • If she doesn't get the job, it will be over

113
Differential Diagnosis
  • Bipolar disorder, manic relapse
  • Polysubstance abuse

114
Laboratory Tests
  • Urinary drug screen positive for cocaine,
    benzodiazepines
  • Pregnancy test negative
  • Glucose and triglycerides normal
  • Cholesterol mildly elevated
  • Liver function tests normal

115
Clinical Course
  • Initially refuses admission and becomes
  • belligerent in ER
  • Calmed by intramuscular (IM) injection of
  • antipsychotic
  • Later on required a second IM injection and
    admitted to the hospital
  • Still irritable, pressured in speech, and
    sleeping
  • 3 hours a night
  • Quetiapine started with gradual titration to
  • 600 mg/day

116
Clinical Course (cont)
  • Patient decided to try lithium monotherapy for
    outpatient care
  • Becomes more agreeable and engaged in treatment
  • Reluctantly agrees to aftercare substance abuse
    day program
  • Says she'll take her medications but that "they
    better not make me fatter"

117
Case Summary
  • Female with dual diagnosis bipolar disorder I
  • Cardiovascular/weight comorbidities
  • Intermittent noncompliance and substance abuse
    underlie poor long-term course and heightened
    risk of injurious behavior
  • Doctor's capacity to achieve persistent clinical
    stability strongly influenced by patient's
    perceived effectiveness (risk versus benefit
    appraisal) of medications

118
Key Messages
  • Therapeutic engagement is a critical first step
    to treatment adherence
  • Careful assessment of
  • Medical and psychiatric comorbidities in bipolar
    disorder
  • Treatment options (agents, formulations) in
    managing acutely agitated bipolar patients
  • Treatment goals (choice agents, risk-benefit
    appraisal) in stabilization of bipolar patients
  • Treatment priorities, decisions, and transition
    to outpatient maintenance therapy

119
The Bland Chef
120
History
  • 37-year-old single female, without children,
    employed as a chef at a local hotel
  • Chief complaint Im depressed and wired
  • Diminished interest in her work, which she
    previously was passionate about
  • No suicidal ideation
  • Hyperphagia, hypersomnia, racing thoughts, feels
    anxious and hyper, irritable with friends,
    severe premenstrual worsening
  • Mood instability admixed with nonrefreshing
    sleep, led to previous diagnosis of major
    depression

121
History of Present Illness
  • Current episode began approximately six months
    ago in the absence of identifiable interpersonal
    stressors
  • Confluence of depressive symptoms, increasing
    severity
  • Has noted decreased sleep by approximately 12
    hours on occasion my mind wont stop when my
    head hits the pillow
  • Has noted panic attacks, generalized anxiety, and
    mood lability woven into depressive symptoms, no
    suicidal ideation, psychotic features, alcohol or
    substance abuse

122
History of Present Illness (cont)
  • Although patient maintains normal working hours,
    spends less time creating new menu items
  • On days off, has been exercising less and
    becoming socially withdrawn
  • Current antidepressant, an SSRI, offers minimal
    symptom relief and may even worsen my anxiety
  • Adherent with medication prescribed 8 weeks ago

123
Past Psychiatric History
  • Recalls being anxious as a child
  • No externalizing behavioral disorder or history
    of trauma
  • Index depressive episode as sophomore, age 21
    after breakup with boyfriend
  • Depressive episodes typically last 24 months in
    duration with suggestion of worsening in the fall

124
Past Psychiatric History (cont)
  • Has received three previous antidepressants, all
    of which she described as not working
  • Further history reveals that previous
    antidepressants worsened anxiety
  • Has been in therapy on one previous occasion for
    three months, but my therapist didnt understand
    me
  • Occasionally takes benzodiazepines when agitation
    is severe
  • No prior hospitalization

125
Recent Psychiatric History
  • Prior to onset of current depression, patient was
    awarded Chef of the Yea
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