Bipolar Disorder: Complex, chronic, life-long spectrum of disorders that are inherited but are also strongly influenced by environmental factors

1
Bipolar DisorderComplex, chronic,
life-longspectrum of disorders that are
inheritedbut are also strongly influenced by
environmental factors
2
Stanley Foundation Study

• Prospective study
• 2/3 rds have symptoms all of the time
• Chronic, fluctuating symptoms
• Inter-episode chronic low grade
• mixed statesdysphoric hypomania

3
An episodic conditionthat often, ultimately
deteriorates into a chronic,treatment-resistant
depression
4
Complexspectrum ofdisorders and95
haveco-morbidity
5
Psychiatric Co-Morbidity

• 50-93 Anxiety Disorder
• 71 Substance Use/abuse
• 30 Binge Eating Disorder

6
Frequently Mis-diagnosed
7
Natl. Depression and BipolarSupport Alliance
Survey(2000)

• 69 Misdiagnosed
• as Unipolar MDD
• 35 Symptomatic 10 years
• before correct Dx and Tx

8
Frequently Mis-diagnosedOnly 20correct
Diagnosis in first yearand why it matters
9
First Episodes Major Depression

• Childhood onset 70
• Adolescent / adult onset 60

10
Treating Bipolar With Antidepressants

• Ineffective
• Cause cycle acceleration
• Provoke mania (switching)

11
Chronicity Bipolar IJudd et al. 2003 Frey, 2004

• 13 year follow-up study
• 47 of weeks Symptomatic
• 32 weeks Depressed
• 9 Manic
• 6 Mixed states

12
Chronicity Bipolar IIJudd et al. 2003

• 13 year follow-up study
• 54 of weeks Symptomatic
• 53 weeks Depressed
• 1.3 hypomanic

13
DiagnosticIssues
14
High Index ofSuspicion

• With Major
• Depressions
• Unipolar vs. Bipolar

15
Family History

• 1st. Degree relatives
• Blood relatives with
• gt Substance Abuse
• gt Psych Hospitalizations
• gt 3 Marriages
• gt Suicides
• gt 4 jobs before age 40
• gt Hyperthymia

16
Hyper-thymia

• Energetic
• Talkative
• Outgoing
• Sleeps lt 6 hours/night
• Impulsive
• Risk-taking
• Natural Grandiosity

17
Think Bipolar When

• Family Hx of Bipolar
• Hx of childhood onset
• Post-partum onset
• Post-hysterectomy
• (total hysterectomy)

18
Think Bipolar When

• Treatment resistant to
• antidepressants
• Antidepressants cause
• agitation,irritability

19
Think Bipolar When

• History of response to
• antidepressants, but
• loss of efficacy after
• a month or two

20
Think Bipolar When

• Clear Seasonal Pattern
• MDD with racing thoughts

21
Think Bipolar When

• Psychotic Symptoms
• Frequent recurrence
• more than one a year
• .almost 100
• Atypical Symptoms

22
Atypical Depression

• Hyper-somnia
• Extreme Fatigue
• Increased Appetite
• gt Carbo Craving
• gt Weight Gain

23
Atypical DepressionPerugi, Toni, et al., 2003

• 78 ultimately meet
• criteria for bipolar
• Especially BP II

24
Life ChartingNational Institute of Mental
Health
25
BIPOLAR SPECTRUM DISORDERS

• BIPOLAR I ?
• Bipolar II (most common)
• Bipolar III
• Cyclothymia
• Substance induced mania
• Schizoaffective disorder
• Childhood-Onset Bipolar

26
1 Lifetime Prevalence
27
4 lifetime prevalence
28
Bipolar IINew Diagnostic criterionhypomania
2 daysMost commonly misdiagnosedas recurrent
or chronicmajor depression
29
Screening for a History of Mania
orHypomaniagt Mood Disorder ?aire
30
BIPOLAR SPECTRUM DISORDERS

• BIPOLAR III
• (Pseudo-unipolar depression)
• (highly recurrent major depression)

31
(No Transcript)
32
Substance InducedMania

• 95 have bipolar

33
Adverse MedicationEffectsActivation,Switching,
and Cycle Acceleration
34
Warning Signs of Switching

• Racing thoughts
• that prevent
• sleep onset

35
CycleAcceleration
36
Antidepressants

• The most commonly
• Prescribed drugs in
• the USA for
• Bipolar Disorders

37
(Hirshfield, et al., 2003)23judged to have
hadantidepressants causecycle acceleration
38
MANIA SUBTYPES

• CLASSIC MANIA
• 60
• MIXED / DYSPHORIC
• 40 ?

39
Mixed State

• Unrelenting dysphoria
• Marked Irritability
• Severe Agitation / anxiety
• Intractable Insomnia
• High Suicide Risk

40
Rapid Cycling

• 4 or more episodes
• per year
• Ultra-Rapid Cycling
• 4 per month
• Ultradian Daily

41
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

42
Rapid CyclingAssociated With

• Delayed treatment (11 vs 7 years)
• History of child abuse
• Thyroid disease
• Substance Abuse

43
Bipolar DisorderAge of OnsetNIMH STEP-BD
(2004)

• Pre-pubertal 27
• Adolescent (13-18) 38
• After age 18 35

44
By age 15-16

• Bipolar Presentation
• Is Adult Onset
• Version

45
Bipolar in Children(Anthony, 2001)

• 70 first episode is MDD
• 1 Classic mania
• 29 Mixed mania

46
MANIA in CHILDREN

• NOT EPISODIC
• CHRONIC DYSPHORIA
• EXTREME IRRITABILITY
• INTENSE EPISODIC
• RAGES

47
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

48
Realistic MedicalProphylaxis

• Chronic treatment after first episode
• What is realistic

49
Im doing a lot better nowthat I am back in
denial
50
Realistic MedicalProphylaxis

• 30 true cessation of episodes
• Realistic Good Outcome
• gt 75 reduction in episode
• frequencies
• gt Reduce severity and
• hospitalizations

51
Medication AdherenceScott and Pope, (2002)

• 18 month study
• Required repeated hospitalizations
• gt Partial Adherence 81
• gt Adherent 9
• Overall 50 are compliant
• Main problem Long-term tolerability

52
Instability Model

• Goodwin and Jamison
• Marked Circadian
• Vulnerability

53
Circadian IntegrityThe Most Critical Features

• Regular Times
• To Bed Awakening
• Early Morning Bright Light
• Adequate Sleep

54
Circadian IntegrityThe Most Critical Features

• Maintain Social Rhythms
• Eating
• Exercise
• Bright light exposure

55
for Bipolar

• Shift work
• Time Zone Changes
• Substance Abuse
• Disrupted Sleep

56
Empirically ValidatedPsychotherapies

• Psycho-educational family Tx
• Interpersonal and Social
• Rhythm Therapy (IPSRT)

57
Family focusedPsycho-educationMiklowitz, et al.
2003

• N 101
• Fewer hospitalizations 12 vs 60
• (two year follow-up)
• Relapses (one year follow-up)
• gt Tx as usual 53
• gt Family Tx Psy. Ed. 29
• Better Med Compliance p lt 0.04

58
IPSRTInterpersonal 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

59
Outcomes IPSRT(Kupfer, et al., 2000)

• Time to stabilization N 151
• Treatment as usual 40 weeks
• IPSRT 22 weeks
• Significantly different 0.05 level

60
STEP-BD

• Systematic Treatment
• Enhancement Program for
• Bipolar Disorder
• N 5000currently 1000
• NIMH supported study

61
Systematic Trials
62
Aggressive Treatmentvs.Compliance Considerations
63
Episode resolutionvsFunctional Recovery
64
Average Time toFull ResolutionNIMH
Collaborative Study Data

• Mania 11 weeks
• Depression 19 weeks
• Mixed State 36 weeks
• up to

65
Full Resolution of Mania

• Time Adults Children
• 6 months 85 14
• 1 year 92 36
• 2 years 98 65

66
Poly-PharmacologySTEP-BP programonly 11
monotherapy
67
TREATMENT and PHASES of BIPOLAR DISORDER
68
(No Transcript)
69
Ideal Mood Stabilizer

• Prevents relapse and
• cycle acceleration
• do no harm

70
Lithium30 started onprevented
relapseSeroquel
(Swann, et al., 2002)
71
FDA ApprovedMedications for Bipolar Disorder

72

• FDA Acute Mania
• 1970 Lithium
• 1973 Thorazine
• 1995 Depakote
• 2000 Zyprexa
• 2003 Risperdal
• 2004 Seroquel
• 2004 Abilify
• 2005 Geodon
• 2005 Equetro (Tegretol)

73

• FDA Acute
• Bipolar Depression
• 2004 Symbyax
• (Prozac and Zyprexa)
• 2007 Seroquel

74

• FDA Maintenance
• 1974 Lithium both
• 2003 Lamictal
• depression
• 2004 Zyprexa both
• 2005 Abilify both

75
Off-LabelUse
76
Acute Mania and Prophylaxis

• Lithium
• Depakote
• Tegretol (Equatro)
• Trileptal
• Antipsychotics (all)

77
Dysphoric ManiaRapid Cycling

• Depakote, Lithium
• or antipsychotics
• Lamictal

78
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

79
Medications for Bipolar Mania Efficacynot
Established

• Trileptal
• Topamax

80
Medications for Bipolar ManiaNot Effective

• Neurontin
• Gabitril
• (seizures)

81
Treating AcuteManic Episodes
82
Severe Agitation

• Benzodiazepines
• (e.g. Ativan, Klonopin)
• Antipsychotics
• ECT

83
Xanaxmay provoke mania

• Caution !

84
Efficacy Treatment of Mania

• Lithium (pooled) 58
• Depakote (pooled) 54
• Tegretol (pooled) 52
• Other agents open studies

85
Side Effects
86
Side Effect Management

• Sustained release (? peaks)
• or twice a day dosing ?
• ? dose with maintenance
• Drug combos !!!!!!!..

87
Once a day dosing
88
Two drugs
89
ComplianceMono 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

90
ComplianceMono vs Combo Treatments(Goodwin,
2004 P. Keck, 2002)

• Sometimes
• 225

91
Lithium
92
Lithium Side Effects

• Weight Gain (50)
• Sedation
• Cognitive Blunting
• ? creativity drive
• Tremor (65)
• Weakness (transient)
• Nausea (50)
• Diarrhea, vomiting

93
Lithium Side Effects

• Fatigue
• Sexual Dys. (10)
• ? Thirst, polydipsia (40)
• Polyuria (40)
• Dermatological
• Hypothyroid
• Renal (Kidney) Effects (?)

• Weight Gain (60)
• Weakness (transient)
• Sedation
• Cognitive Blunting
• ? creativity drive
• Tremor (65)
• Nausea (50)
• Diarrhea, vomiting
• Metallic Taste

94
Average Length ofLithium Continuation

• Johnson, 1996

?
95
Average Length ofLithium Continuation

• Johnson, 1996

65 Days !
96
Lithium Levels

• 0.8-1.2

97
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

98
Maintenance Doses(maybe)

• Levels 0.6 Bipolar II
• 0.8 Bipolar I

99
Lithium trivia questionIf you discontinue
yourlithium how can youstill use your
medication?
100
Anti-ConvulsantBipolar Medications
101
Anti-convulsants

• Depakote
• Tegretol (Equetro)
• Trileptal
• Topamax
• Neurontin
• Lamictal (not for mania)

102
Side Effects Common toMost Anticonvulsant Mood
Stabilizers

• Lethargy/Sedation
• Tremor
• Weight Gain
• Nausea
• Rash

103
Depakote
104
PREDICTORS OF GOODDEPAKOTE RESPONSE

• CLASSIC MANIA LITHIUM
• RAPID CYCLING
• DYSPHORIC / MIXED MANIA
• USE FOR RAPID ONSET OF
• ACTIONS

105
Depakote Levels

• Levels 50-125

106
Poly-cystic Ovaries

• Women under 20 80
• Often associated with
• weight gain
• Pre-treatment sonogram
• Watch for weight gain
• and irregular menses

107
TegretolTrileptal
108
Targeting Co-morbidity

• Topamax
• gt Bulimia
• gt Binge eating
• gt Obesity
• gt Neuropathic pain
• gt Migraine prophylaxis
• gt Alcohol dependence

109
Targeting Co-morbidity

• Neurontin
• gt Social anxiety
• gt Panic disorder
• (not OCD)
• gt Neuropathic pain
• gt Substance withdrawal

110
Atypical Antipsychotics

• Not just for
• Psychotic Symptoms

111
Antipsychotics

• Anti-psychotic
• Anti-manic
• Anti-aggression

112
Atypical Antipsychotics

• SEROQUEL
• RISPERDAL
• ZYPREXA
• GEODON
• ABILIFY
• INVEGA
• FANAPT
• SAPHRIS

113
Atypical AntipsychoticsSide Effect Issues

• Weight gain
• Increased Cholesterol
• and triglycerides
• Hyperglycemia
• Type II Diabetes .

114
Metabolic Side Effects

• Most common
• gt Clozaril
• gt Zyprexa (Symbyax)
• Moderate
• gt Seroquel, Risperdal. Invega
• Least Likely
• gt Abilify, Geodon

115
The Real ChallengeIn TreatingBipolar
DisorderBipolar DepressionThe greatest
morbidity
116
Bipolar Depression(Not necessarily the same as
Unipolar)
117
BIPOLAR DEPRESSION

• Do No Harm
• Ineffective
• Switching
• Cycle Acceleration

118
BIPOLAR DEPRESSION

• APA Guidelines
• Do not recommend
• antidepressants for
• first line treatment

119
Switch Rates

• STEP-BD program
• 37 report hx of switching

120
Bipolar Meds withAntidepressant Actions

• Lamictal
• Symbyax
• Seroquel
• Lithium
• if above 0.8

121
Bipolar Meds withAntidepressant Actions

• Lamictal
• Symbyax
• Seroquel
• Lithium

122
Stevens-Johnson Syndrome
123
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

124
Lamictal Rash

• Prevalence
• benign 12
• Stevens Johnson 1/1000
• adults and teens
• 2 in Children

125
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

126
SymbyaxSeroquel

• Zyprexa-Prozac Combo
• Quick onset of action

127
Bipolar Depression AlgorithmsIf Bipolar
Irecent mania or history ofswitching,
stronglyrecommend an antimanic agent first line
?
128
Algorithm BP I

• gt Lamictal and Anti-manic
• gt Symbyax or Seroquel
• gt Add lithium
• gt ECT

129
Algorithm BP II

• gt Lamictal
• gt Symbyax or Seroquel
• gt Add lithium
• gt ECT

130
Maintenance
131
Tolerability, Safety and Efficacy

• Seroquel and Lamictal
• combination long-term
• maintenance
• Lithium for suicide prevention

132
Time to Next Manic Episode(Keck and McElroy,
2002 Bowden, et al., 2004)

• Combo Therapy (Li and Depakote)
• 6 x longer vs. monotherapy

133
Childhood-Onset Bipolar Disorder
Is this the same as later-onset bipolar
disorder ?
134
Childhood Onset Bipolar

• Diagnostic confusion !!!!!
• Guarded prognosis

135
Narrow phenotype Bipolar

• Meet DSM-IV criteria for
• bipolar
• Most have a bipolar parent
• Versus broad phenotype

136
Chronic Rapid Cycling (J. Walkup, 2002)

• Chronic lability due to any mixture of ADHD,
  anxiety, depression, poor self-control, adverse
  life circumstances, fetal drug/alcohol exposure,
  substance abuse, lack of supervision, family
  dysfunction.

137
Drug Exposed Babies
138
Severe Early Neglect
139
Temper Dysregulation Disorderwith 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

140
Temper Dysregulation Disorderwith Dysphoria
DSM-V

• Onset after 6 and before 10
• Mood between temper outbursts
• gt Nearly every day angry,
• irritable and/or sad
• Continuous symptoms for at
• least 12 months

141
Temper Dysregulation Disorderwith 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

142
Temper Dysregulation Disorderwith Dysphoria
DSM-V

• No history of
• gt decreased need for sleep
• gt grandiosity
• gt pressured speech

143
Temper Dysregulation Disorderwith Dysphoria
DSM-V

• Can co-exist with ADHD, conduct
• disorder, oppositional-defiant
• disorder and substance abuse
• disorder

144
Target symptomapproach
145
Bipolar Meds with KidsMonotherapy

• Two studies ages 10-17bipolar I
• Trileptal Am. J. Psychiatry (2006)
• Depakote J. Am. Acad. Child and Adol. Psychiatry
  (2009)
• Neither different than placebo

146
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

147
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

148
Full Resolution of Mania

• Time Adults Children
• 6 months 85 14
• 1 year 92 36
• 2 years 98 65

149
Two Year OutcomeChildren with Bipolar(Geller
and Craney, 2002)

• Average age 10.9N89
• 55 relapsed after recovery
• gt Mean time to relapse
• 28 weeks

150
Seroquel

• Childhood onset bipolar
• Broad efficacy and tolerability
• Bipolar Network News (2008)
• Am. College of neuropsychopharmacology
• Open label studies
• De Bello, et al. (2008)

151
Trivia Question

• What is the favorite flavor
• of snow cone syrup
• used to flavor liquid
• Antipsychotic medications?

152
Raspberry
153
V