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


1
Bipolar Disorder Complex, chronic,
life-long spectrum of disorders that are
inherited but 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 condition that often, ultimately
deteriorates into a chronic, treatment-resistant
depression
4
Complex spectrum of disorders and 95
have co-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 Bipolar Support Alliance
Survey (2000)
  • 69 Misdiagnosed
  • as Unipolar MDD
  • 35 Symptomatic 10 years
  • before correct Dx and Tx

8
Frequently Mis-diagnosed Only 20 correct
Diagnosis in first year and 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 I Judd 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 II Judd et al. 2003
  • 13 year follow-up study
  • 54 of weeks Symptomatic
  • 53 weeks Depressed
  • 1.3 hypomanic

13
Diagnostic Issues
14
High Index of Suspicion
  • 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 Depression Perugi, Toni, et al., 2003
  • 78 ultimately meet
  • criteria for bipolar
  • Especially BP II

24
Life Charting National 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 II New Diagnostic criterion hypomania
2 days Most commonly misdiagnosed as recurrent
or chronic major depression
29
Screening for a History of Mania
or Hypomania gt Mood Disorder ?aire
30
BIPOLAR SPECTRUM DISORDERS
  • BIPOLAR III
  • (Pseudo-unipolar depression)
  • (highly recurrent major depression)

31
(No Transcript)
32
Substance Induced Mania
  • 95 have bipolar

33
Adverse Medication Effects Activation, Switching,
and Cycle Acceleration
34
Warning Signs of Switching
  • Racing thoughts
  • that prevent
  • sleep onset

35
Cycle Acceleration
36
Antidepressants
  • The most commonly
  • Prescribed drugs in
  • the USA for
  • Bipolar Disorders

37
(Hirshfield, et al., 2003) 23 judged to have
had antidepressants cause cycle 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 Cycling Associated With
  • Delayed treatment (11 vs 7 years)
  • History of child abuse
  • Thyroid disease
  • Substance Abuse

43
Bipolar Disorder Age of Onset NIMH 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 Medical Prophylaxis
  • Chronic treatment after first episode
  • What is realistic

49
Im doing a lot better now that I am back in
denial
50
Realistic Medical Prophylaxis
  • 30 true cessation of episodes
  • Realistic Good Outcome
  • gt 75 reduction in episode
  • frequencies
  • gt Reduce severity and
  • hospitalizations

51
Medication Adherence Scott 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 Integrity The Most Critical Features
  • Regular Times
  • To Bed Awakening
  • Early Morning Bright Light
  • Adequate Sleep

54
Circadian Integrity The 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 Validated Psychotherapies
  • Psycho-educational family Tx
  • Interpersonal and Social
  • Rhythm Therapy (IPSRT)

57
Family focused Psycho-education Miklowitz, 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
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

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 Treatment vs. Compliance Considerations
63
Episode resolution vs Functional Recovery
64
Average Time to Full Resolution NIMH
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-Pharmacology STEP-BP program only 11
monotherapy
67
TREATMENT and PHASES of BIPOLAR DISORDER
68
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69
Ideal Mood Stabilizer
  • Prevents relapse and
  • cycle acceleration
  • do no harm

70
Lithium 30 started on prevented
relapse Seroquel
(Swann, et al., 2002)
71
FDA Approved Medications 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-Label Use
76
Acute Mania and Prophylaxis
  • Lithium
  • Depakote
  • Tegretol (Equatro)
  • Trileptal
  • Antipsychotics (all)

77
Dysphoric Mania Rapid 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 Efficacy not
Established
  • Trileptal
  • Topamax

80
Medications for Bipolar Mania Not Effective
  • Neurontin
  • Gabitril
  • (seizures)

81
Treating Acute Manic Episodes
82
Severe Agitation
  • Benzodiazepines
  • (e.g. Ativan, Klonopin)
  • Antipsychotics
  • ECT

83
Xanax may 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
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

90
Compliance Mono 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 of Lithium Continuation
  • Johnson, 1996

?
95
Average Length of Lithium 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 question If you discontinue
your lithium how can you still use your
medication?
100
Anti-Convulsant Bipolar Medications
101
Anti-convulsants
  • Depakote
  • Tegretol (Equetro)
  • Trileptal
  • Topamax
  • Neurontin
  • Lamictal (not for mania)

102
Side Effects Common to Most Anticonvulsant Mood
Stabilizers
  • Lethargy/Sedation
  • Tremor
  • Weight Gain
  • Nausea
  • Rash

103
Depakote
104
PREDICTORS OF GOOD DEPAKOTE 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
Tegretol Trileptal
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 Antipsychotics Side 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 Challenge In Treating Bipolar
Disorder Bipolar Depression The 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 with Antidepressant Actions
  • Lamictal
  • Symbyax
  • Seroquel
  • Lithium
  • if above 0.8

121
Bipolar Meds with Antidepressant 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
Symbyax Seroquel
  • Zyprexa-Prozac Combo
  • Quick onset of action

127
Bipolar Depression Algorithms If Bipolar
I recent mania or history of switching,
strongly recommend 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 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

140
Temper Dysregulation Disorder with 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 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

142
Temper Dysregulation Disorder with Dysphoria
DSM-V
  • No history of
  • gt decreased need for sleep
  • gt grandiosity
  • gt pressured speech

143
Temper Dysregulation Disorder with Dysphoria
DSM-V
  • Can co-exist with ADHD, conduct
  • disorder, oppositional-defiant
  • disorder and substance abuse
  • disorder

144
Target symptom approach
145
Bipolar Meds with Kids Monotherapy
  • 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 Outcome Children 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
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