Bipolar Disorder:
Complex, chronic, life-long
spectrum of disorders
that are inherited
but are also
strongly influenced by environmental
factors
Stanley Foundation Study
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Prospective study
2/3 rds have symptoms all of the time
Chronic, fluctuating symptoms
Inter-episode: chronic low grade
mixed states…dysphoric hypomania
2
An episodic condition
that often, ultimately
deteriorates into
a chronic,
treatment-resistant
depression
3
Complex:
spectrum of
disorders and
95% have
co-morbidity
Psychiatric
Co-Morbidity
• 50-93% Anxiety Disorder
• 71% Substance Use/abuse
• 30% Binge Eating Disorder
Frequently
Mis-diagnosed
Nat’l. Depression and Bipolar
Support Alliance Survey
(2000)
• 69% Misdiagnosed
as Unipolar MDD
• 35% Symptomatic 10+ years
before correct Dx and Tx
Frequently
Mis-diagnosed
Only 20%:
correct Diagnosis in
first year
and why it matters
8
First Episodes:
Major Depression
• Childhood onset:
70%
• Adolescent / adult onset: 60%
9
Treating Bipolar With
Antidepressants
• Ineffective
• Cause cycle acceleration
• Provoke mania (switching)
10
Chronicity: Bipolar I
Judd et al. 2003; Frey, 2004
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13 year follow-up study
47% of weeks: Symptomatic
32% weeks: Depressed
9%: Manic
6%: Mixed states
Chronicity: Bipolar II
Judd et al. 2003
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13 year follow-up study
54% of weeks: Symptomatic
53% weeks: Depressed
1.3%: hypomanic
Diagnostic
Issues
13
High Index of
Suspicion
With Major
Depressions
Unipolar vs. Bipolar
14
Family History
1st. Degree relatives
• Blood relatives with:
> Substance Abuse
> Psych Hospitalizations
> 3+ Marriages
> Suicides
> 4+ jobs before age 40
> Hyperthymia
•
Hyper-thymia
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Energetic
Talkative
Outgoing
Sleeps < 6 hours/night
Impulsive
Risk-taking
“Natural Grandiosity”
Think Bipolar When…
• Family Hx of Bipolar
• Hx of childhood onset
• Post-partum onset
• Post-hysterectomy
(total hysterectomy)
Think Bipolar When…
• Treatment resistant to
antidepressants
• Antidepressants cause
agitation,irritability
Think Bipolar When…
• History of + response to
antidepressants, but
loss of efficacy after
a month or two
Think Bipolar When…
• Clear Seasonal Pattern
• MDD with racing thoughts
Think Bipolar When…
• Psychotic Symptoms
• Frequent recurrence
more than one a year
….almost 100%
• Atypical Symptoms…
Atypical Depression
• Hyper-somnia
• Extreme Fatigue
• Increased Appetite
> Carbo Craving
> Weight Gain
Atypical Depression
Perugi, Toni, et al., 2003
• 78% ultimately meet
criteria for bipolar
• Especially BP II
Life Charting
National Institute of Mental Health
BIPOLAR SPECTRUM DISORDERS
BIPOLAR I 
Bipolar II (most common)
Bipolar III
Cyclothymia
Substance induced mania
Schizoaffective disorder
Childhood-Onset Bipolar
25
26
27
Bipolar II
New Diagnostic criterion
hypomania: 2+ days
Most commonly misdiagnosed:
as recurrent or chronic
major depression
28
Screening for a History of
Mania or
Hypomania
> Mood Disorder ?aire
29
BIPOLAR SPECTRUM DISORDERS
BIPOLAR III
(Pseudo-unipolar depression)
(highly recurrent major depression)
Substance Induced
Mania
95% have bipolar
Adverse Medication
Effects:
Activation,
Switching,and
Cycle Acceleration
Warning Signs of
Switching:
Racing thoughts
that prevent
sleep onset
Cycle
Acceleration
Antidepressants
The most commonly
Prescribed drugs in
the USA for
Bipolar Disorders
(Hirshfield, et al., 2003)
23%
judged to have had
antidepressants cause
cycle acceleration
MANIA SUBTYPES
• “CLASSIC MANIA”
60%
• MIXED / DYSPHORIC
40% 
Mixed State
• Unrelenting dysphoria
• Marked Irritability
• Severe Agitation / anxiety
• Intractable Insomnia
• High Suicide Risk
Rapid Cycling
• 4 or more episodes
per year
• Ultra-Rapid Cycling:
4 per month
• Ultradian: Daily
Rapid Cycling
(Arch. Gen Psych.)
(Gitlin, 2002)
• N= 919 patients: followed: 7 years
• 19% were Rapid Cyclers
• Of these only 18% had more
than two years of RC
• Only 2% had continuous RC
• “Flair up” not continuous
Rapid Cycling
Associated With:
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Delayed treatment (11 vs 7 years)
History of child abuse
Thyroid disease
Substance Abuse *
Bipolar Disorder:
Age of Onset
NIMH: STEP-BD (2004)
• Pre-pubertal:
• Adolescent (13-18)
• After age 18
27%
38%
35%
By age 15-16
Bipolar Presentation
Is “Adult Onset”
Version
Bipolar in Children
(Anthony, 2001)
• 70% first episode is MDD
• 1% “Classic mania”
• 29% Mixed mania
MANIA in CHILDREN
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NOT EPISODIC
CHRONIC DYSPHORIA
EXTREME IRRITABILITY
INTENSE EPISODIC
RAGES…
Discriminating Symptoms
• Decreased Need for Sleep
(40% vs 6%)
• Hypersexuality (43% vs 6%)
• Intense, prolonged Rage Attacks
(92% vs 0%)
• Morbid Dreams
• Predictable am activity: ADHD
Realistic Medical
Prophylaxis
• Chronic treatment after first
episode
• What is realistic
“I’m doing a lot better now
that I am back in denial”
Realistic Medical
Prophylaxis
• 30% true cessation of episodes
• Realistic Good Outcome:
> 75% reduction in episode
frequencies
> Reduce severity and
hospitalizations
Medication Adherence
Scott and Pope, (2002)
• 18 month study
• Required repeated hospitalizations:
> Partial Adherence:
81%
> Adherent:
9%
• Overall: 50% are compliant
• Main problem: Long-term tolerability
Instability Model
• Goodwin and Jamison
• Marked Circadian
Vulnerability
Circadian Integrity
The Most Critical Features
• Regular Times:
To Bed & Awakening
• Early Morning Bright Light
• Adequate Sleep
Circadian Integrity
The Most Critical Features
• Maintain Social Rhythms
• Eating
• Exercise
• Bright light exposure
for Bipolar
• Shift work
• Time Zone Changes
• Substance Abuse
• Disrupted Sleep
Empirically Validated
Psychotherapies
• Psycho-educational family Tx
• Interpersonal and Social
Rhythm Therapy (IPSRT)
Family focused
Psycho-education
Miklowitz, et al. 2003
• N: 101
• Fewer hospitalizations: 12% vs 60%
(two year follow-up)
• Relapses (one year follow-up):
> Tx as usual:
53%
> Family Tx Psy. Ed.
29%
• Better Med Compliance: p < 0.04
IPSRT
Interpersonal and Social Rhythm Therapy
(Frank and Ehlers)
• Support medication adherence
• Stabilize environmental factors
• Develop and maintain “social
rhythms”
• Manage provocative social
interactions and
Interpersonal problems
Outcomes: IPSRT
(Kupfer, et al., 2000)
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Time to stabilization; N= 151
Treatment as usual:
40 weeks
IPSRT:
22 weeks
Significantly different:
0.05 level
STEP-BD
• Systematic Treatment
Enhancement Program for
Bipolar Disorder
• N: 5000…currently: 1000
• NIMH supported study
Systematic Trials
Aggressive Treatment
vs.
Compliance
Considerations
Episode resolution
vs
Functional Recovery
Average Time to
Full Resolution
NIMH Collaborative Study Data
• Mania:
11 weeks
• Depression: 19 weeks
• Mixed State: 36 weeks*
* up to
Full Resolution of Mania
Time
Adults
6 months 85%
1 year
92%
2 years
98%
Children
14%
36%
65%
Poly-Pharmacology
STEP-BP program:
only 11%: monotherapy
TREATMENT and PHASES of
BIPOLAR DISORDER
Ideal Mood Stabilizer
• Prevents relapse and
cycle acceleration
“do no harm”
Lithium
30% started on:
prevented relapse*
Seroquel
* (Swann, et al., 2002)
FDA Approved
Medications for
Bipolar Disorder
FDA: Acute Mania
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*
1970:
1973:
1995:
2000:
2003:
2004:
2004:
2005:
2005:
Lithium
Thorazine
Depakote
Zyprexa
Risperdal
Seroquel
Abilify
Geodon
Equetro (Tegretol)
FDA: Acute
Bipolar Depression
* 2004: Symbyax
(Prozac and Zyprexa)
* 2007: Seroquel
FDA: Maintenance
* 1974: Lithium: both
* 2003: Lamictal:
depression
* 2004: Zyprexa: both
* 2005: Abilify: both
Off-Label
Use
Acute Mania and
Prophylaxis
• Lithium
• Depakote *
• Tegretol (Equatro) *
• Trileptal *
• Antipsychotics (all)
76
Dysphoric Mania
Depakote, Lithium
or antipsychotics
Rapid Cycling
Lamictal
77
Black Box Warnings
• Depakote: liver failure, birth defects,
pancreatitis
• Tegretol: aplastic anemia, agranulocytosis
• Lithium: birth defects, toxicity associated
with increased serum level
• Atypical Antipsychotic: increased mortality
in elderly / demented patients
78
Medications for Bipolar Mania:
Efficacy
not Established
• Trileptal
• Topamax
Medications for
Bipolar Mania:
Not Effective
• Neurontin
• Gabitril
(seizures)
Treating Acute
Manic Episodes
Severe Agitation
• Benzodiazepines
(e.g. Ativan, Klonopin)
• Antipsychotics
• ECT
Caution !
Xanax
may provoke mania
Efficacy: Treatment of Mania
• Lithium (pooled):
58%
• Depakote (pooled): 54%
• Tegretol (pooled): 52%
• Other agents: open studies
Side Effects
Side Effect Management
• Sustained release ( peaks)
or twice a day dosing 
•  dose with maintenance
• Drug combos !!!!!!!…..
Once a day dosing
Two drugs
Compliance:
Mono vs Combo Treatments
(Goodwin, 2004; P. Keck, 2002)
• N= 140 Bipolar I
• Lithium or Depakote monotherapy
compliance rates: 50-60%
• Combined (lower doses)
Compliance rates: 40% better
compliance
Compliance:
Mono vs Combo Treatments
(Goodwin, 2004; P. Keck, 2002)
Sometimes
2+2=5
Lithium
Lithium Side Effects
• Weight Gain (50%)
• Sedation
• Cognitive Blunting
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 creativity; drive
Tremor (65%)
Weakness (transient)
Nausea (50%)
Diarrhea, vomiting
Lithium Side Effects
• Fatigue
• Sexual Dys. (10%)
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W
e
i
g
h
t
G
 Thirst, polydipsia (40%)
Polyuria (40%)
Dermatological
Hypothyroid
Renal (Kidney) Effects (?)
Average Length of
Lithium Continuation
Johnson, 1996
Average Length of
Lithium Continuation
Johnson, 1996
Lithium Levels
0.8-1.2
Lithium Toxicity
• 1.5-2.0: ataxia, coarse tremor,
confusion, drowsiness
slurred speech
• 2.0+: coma, seizures,
stupor, kidney failure
• 4.0:
death
• No antidote, but can treat with
hemo-dialysis or
peritoneal dialysis
Maintenance Doses
(maybe)
• Levels: 0.6: Bipolar II
0.8: Bipolar I
Lithium trivia question:
If you discontinue your
lithium how can you
still use your medication?
Anti-Convulsant
Bipolar Medications
Anti-convulsants
• Depakote
• Tegretol (Equetro)
• Trileptal
• Topamax
• Neurontin
• Lamictal (not for mania)
Side Effects Common to
Most Anticonvulsant
Mood Stabilizers
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Lethargy/Sedation
Tremor
Weight Gain
Nausea
Rash
Depakote
PREDICTORS OF GOOD
DEPAKOTE RESPONSE
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“CLASSIC” MANIA = LITHIUM
RAPID CYCLING
DYSPHORIC / MIXED MANIA
USE FOR RAPID ONSET OF
ACTIONS
Depakote Levels
• Levels: 50-125
Poly-cystic Ovaries
• Women under 20: 80%
• Often associated with:
weight gain
• Pre-treatment sonogram
• Watch for: weight gain
and irregular menses
Tegretol
Trileptal
Targeting Co-morbidity:
Topamax
>
>
>
>
>
>
Bulimia
Binge eating
Obesity
Neuropathic pain
Migraine prophylaxis
Alcohol dependence
Targeting Co-morbidity:
Neurontin
> Social anxiety
> Panic disorder
(not OCD)
> Neuropathic pain
> Substance withdrawal
Atypical Antipsychotics
Not just for
Psychotic Symptoms
Antipsychotics
Anti-psychotic
Anti-manic
Anti-aggression
111
Atypical Antipsychotics
SEROQUEL
RISPERDAL
ZYPREXA
GEODON
ABILIFY
INVEGA
FANAPT
SAPHRIS
112
Atypical Antipsychotics:
Side Effect Issues
• Weight gain
• Increased Cholesterol
and triglycerides
• Hyperglycemia
• Type II Diabetes …….
Metabolic Side Effects
• Most common:
> Clozaril
> Zyprexa (Symbyax)
• Moderate:
> Seroquel, Risperdal. Invega
• Least Likely:
> Abilify, Geodon
The Real Challenge
In Treating
Bipolar Disorder:
Bipolar
Depression
The greatest morbidity
Bipolar Depression
(Not necessarily the same as Unipolar)
BIPOLAR DEPRESSION
• “Do No Harm”
• Ineffective
• Switching
• Cycle Acceleration
BIPOLAR DEPRESSION
APA Guidelines
Do not recommend
antidepressants for
first line treatment
Switch Rates
• STEP-BD program
• 37% report hx of switching
Bipolar Meds with
Antidepressant Actions
• Lamictal
• Symbyax
• Seroquel
• Lithium
if above 0.8
Bipolar Meds with
Antidepressant Actions
• Lamictal
• Symbyax *
• Seroquel *
• Lithium *
Stevens-Johnson Syndrome
Lamictal: Dosing
• Dosing: 25 mg week one and two
50 mg week three…
100 mg bid
(see PDR…)
• Target Dosing: 75-225 mg per day
• Onset of Actions: 3-4 weeks
Lamictal: Rash
• Prevalence:
* benign: 12%
* Stevens Johnson: 1/1000
adults and teens
* 2% in Children
How Risky is Lamictal ?
German Rash Registry
• Since slow titration started
• Benign: 9% drug, 8% placebo
• Serious rash: placebo: 0.06%
drug; 0.09%
• No cases of Stevens-Johnson
adults and teens
• Children: 3/10,000
Symbyax
• Zyprexa-Prozac Combo
• Quick onset of action
Seroquel
Bipolar Depression Algorithms
If Bipolar I:
recent mania or history of
switching, strongly
recommend an antimanic agent:
first line 
Algorithm: BP I
> Lamictal and Anti-manic
> Symbyax or Seroquel
> Add lithium
> ECT
Algorithm: BP II
> Lamictal
> Symbyax or Seroquel
> Add lithium
> ECT
Maintenance
Tolerability, Safety and Efficacy
• Seroquel and Lamictal
combination: long-term
maintenance
• Lithium: for suicide prevention
Time to Next
Manic Episode
(Keck and McElroy, 2002; Bowden, et al., 2004)
• Combo Therapy (Li and Depakote):
6 x longer vs. monotherapy
Childhood-Onset Bipolar Disorder
Childhood Onset Bipolar
•Diagnostic confusion !!!!!
•Guarded prognosis
134
Narrow phenotype
Bipolar
• Meet DSM-IV criteria for
bipolar
• Most have a bipolar parent
• Versus broad phenotype
135
Chronic Rapid Cycling
(J. Walkup, 2002)
• Chronic lability due to any mixture of:
ADHD, anxiety, depression, poor selfcontrol, adverse life circumstances,
fetal drug/alcohol exposure, substance
abuse, lack of supervision, family
dysfunction….
136
137
138
Temper Dysregulation Disorder
with Dysphoria: DSM-V
• Severe temper outbursts
• Grossly out of proportion in
intensity and duration
• In response to common stressors
• 3 or more times per week
Temper Dysregulation Disorder
with Dysphoria: DSM-V
• Onset: after 6 and before 10
• Mood between temper outbursts:
> Nearly every day: angry,
irritable and/or sad
• Continuous symptoms: for at
least 12 months
Temper Dysregulation Disorder
with Dysphoria: DSM-V
• Present in at least 2 settings
(e.g. home and school)
• Never a period of time with
abnormally elevated or expansive
mood
Temper Dysregulation Disorder
with Dysphoria: DSM-V
• No history of
> decreased need for sleep
> grandiosity
> pressured speech
Temper Dysregulation Disorder
with Dysphoria: DSM-V
• Can co-exist with ADHD, conduct
disorder, oppositional-defiant
disorder and substance abuse
disorder
Target symptom
approach
144
Bipolar Meds with Kids:
Monotherapy
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•
•
•
Two studies: ages 10-17…bipolar I
Trileptal: Am. J. Psychiatry (2006)
Depakote: J. Am. Acad. Child and Adol. Psychiatry (2009)
Neither different than placebo
145
Medication Combinations
• Children and adolescents
• Lithium and atypical antipsychotic
only slightly better than
lithium and placebo
• Very high rates of relapse: monotherapy
• Lithium and Depakote:
effective in 40%
BNN, V. 13, 2009
BNN, V.12, 2008
146
Experimental
Lithium treatment
• Teens and adults:
Li blood level: 1.0…..brain level: 1.0
• Children:
Li blood level: 1.0…..brain level: 0.5
• May require dosing up to 2.0 Li level
to achieve adequate levels
in the brain
BNN, V. 12, 2008
147
Full Resolution of Mania
Time
Adults
6 months 85%
1 year
92%
2 years
98%
Children
14%
36%
65%
148
Two Year Outcome:
Children with Bipolar
(Geller and Craney, 2002)
• Average age: 10.9…N=89
• 55% relapsed after recovery
> Mean time to relapse:
28 weeks
149
Seroquel
• Childhood onset bipolar
• Broad efficacy and tolerability
• Bipolar Network News (2008)
Am. College of neuropsychopharmacology
• Open label studies
• De Bello, et al. (2008)
150
Trivia Question
What is the favorite flavor
of snow cone syrup
used to flavor liquid
Antipsychotic medications?
Raspberry
V