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Bipolar Disorder:
Complex, chronic, life-longspectrum of disorders
that are inheritedbut are also
strongly influenced by environmental factors
Stanley Foundation Study
• 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 conditionthat often, ultimately
deteriorates into a chronic,
treatment-resistantdepression
3
Psychiatric Co-Morbidity
• 50-93% Anxiety Disorder50-93% Anxiety Disorder• 71% Substance Use/abuse71% Substance Use/abuse• 30% Binge Eating Disorder30% Binge Eating Disorder
Nat’l. Depression and BipolarSupport Alliance Survey
(2000)
• 69% Misdiagnosed 69% Misdiagnosed as Unipolar MDDas Unipolar MDD• 35% Symptomatic 10+ years35% Symptomatic 10+ years before correct Dx and Txbefore correct Dx and Tx
Frequently Frequently Mis-diagnosedMis-diagnosed
Only 20%:Only 20%:correct Diagnosis in correct Diagnosis in
first yearfirst yearand why it mattersand why it matters
8
Treating Bipolar With Antidepressants
• Ineffective• Cause cycle acceleration• Provoke mania (switching)
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Chronicity: Bipolar IJudd et al. 2003; Frey, 2004
• 13 year follow-up study13 year follow-up study• 47% of weeks: Symptomatic47% of weeks: Symptomatic• 32% weeks: Depressed32% weeks: Depressed• 9%: Manic9%: Manic• 6%: Mixed states6%: Mixed states
Chronicity: Bipolar IIJudd et al. 2003
• 13 year follow-up study13 year follow-up study• 54% of weeks: Symptomatic54% of weeks: Symptomatic• 53% weeks: Depressed53% weeks: Depressed• 1.3%: hypomanic1.3%: hypomanic
High Index ofHigh Index ofSuspicionSuspicion
With Major With Major DepressionsDepressions
Unipolar vs. BipolarUnipolar vs. Bipolar14
Family History• 11stst. Degree relatives. Degree relatives• Blood relatives with:Blood relatives with: > Substance Abuse> Substance Abuse > Psych Hospitalizations> Psych Hospitalizations > 3+ Marriages> 3+ Marriages > Suicides> Suicides > 4+ jobs before age 40> 4+ jobs before age 40 > Hyperthymia> Hyperthymia
Hyper-thymia• EnergeticEnergetic• TalkativeTalkative• OutgoingOutgoing• Sleeps < 6 hours/nightSleeps < 6 hours/night• ImpulsiveImpulsive• Risk-takingRisk-taking• ““Natural Grandiosity”Natural Grandiosity”
Think Bipolar When…
• Family Hx of BipolarFamily Hx of Bipolar• Hx of childhood onsetHx of childhood onset• Post-partum onsetPost-partum onset• Post-hysterectomyPost-hysterectomy (total hysterectomy)(total hysterectomy)
Think Bipolar When…• Treatment resistant to Treatment resistant to antidepressantsantidepressants• Antidepressants cause Antidepressants cause agitation,irritabilityagitation,irritability
Think Bipolar When…• History of + response toHistory of + response to antidepressants, butantidepressants, but loss of efficacy afterloss of efficacy after a month or twoa month or two
Think Bipolar When…• Clear Seasonal PatternClear Seasonal Pattern• MDD with racing thoughtsMDD with racing thoughts
Think Bipolar When…• Psychotic SymptomsPsychotic Symptoms• Frequent recurrenceFrequent recurrence more than one a yearmore than one a year … ….almost 100%.almost 100%• Atypical Symptoms…Atypical Symptoms…
Atypical Depression
• Hyper-somniaHyper-somnia• Extreme FatigueExtreme Fatigue• Increased AppetiteIncreased Appetite > Carbo Craving> Carbo Craving > Weight Gain> Weight Gain
Atypical DepressionPerugi, Toni, et al., 2003
• 78% ultimately meet78% ultimately meet criteria for bipolarcriteria for bipolar• Especially BP IIEspecially BP II
BIPOLAR SPECTRUM DISORDERSBIPOLAR SPECTRUM DISORDERS
BIPOLAR I Bipolar II (most common)
Bipolar IIICyclothymia
Substance induced maniaSchizoaffective disorderChildhood-Onset Bipolar
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Bipolar IIBipolar IINew Diagnostic criterionNew Diagnostic criterion
hypomania: 2+ dayshypomania: 2+ days
Most commonly misdiagnosed:Most commonly misdiagnosed:as recurrent or chronicas recurrent or chronic
major depressionmajor depression 28
Screening for a History of Screening for a History of Mania orMania or
HypomaniaHypomania
> Mood Disorder ?aire> Mood Disorder ?aire
29
BIPOLAR SPECTRUM DISORDERS
BIPOLAR IIIBIPOLAR III (Pseudo-unipolar depression)(Pseudo-unipolar depression)
(highly recurrent major depression)(highly recurrent major depression)
Warning Signs of Switching:
Racing thoughtsRacing thoughtsthat prevent that prevent sleep onsetsleep onset
AntidepressantsThe most commonlyThe most commonlyPrescribed drugs in Prescribed drugs in
the USA for the USA for Bipolar DisordersBipolar Disorders
Mixed State• Unrelenting dysphoriaUnrelenting dysphoria• Marked Irritability Marked Irritability • Severe Agitation / anxietySevere Agitation / anxiety• Intractable InsomniaIntractable Insomnia• High Suicide RiskHigh Suicide Risk
Rapid Cycling
• 4 or more episodes4 or more episodes per yearper year• Ultra-Rapid Cycling:Ultra-Rapid Cycling: 4 per month4 per month• Ultradian: DailyUltradian: Daily
Rapid Cycling(Arch. Gen Psych.)
(Gitlin, 2002)
• N= 919 patients: followed: 7 yearsN= 919 patients: followed: 7 years• 19% were Rapid Cyclers19% were Rapid Cyclers• Of these only 18% had more Of these only 18% had more than two years of RCthan two years of RC• Only 2% had continuous RCOnly 2% had continuous RC• ““Flair up” not continuousFlair up” not continuous
Rapid CyclingAssociated With:
• Delayed treatment Delayed treatment (11 vs 7 years)(11 vs 7 years)
• History of child abuseHistory of child abuse• Thyroid diseaseThyroid disease• Substance AbuseSubstance Abuse * *
Bipolar Disorder:Age of OnsetNIMH: STEP-BD (2004)
• Pre-pubertal: 27%Pre-pubertal: 27%• Adolescent Adolescent (13-18)(13-18) 38% 38%• After age 18 35% After age 18 35%
By age 15-16
Bipolar PresentationBipolar PresentationIs “Adult Onset”Is “Adult Onset”
VersionVersion
Bipolar in Children(Anthony, 2001)
• 70% first episode is MDD70% first episode is MDD• 1% “Classic mania”1% “Classic mania”• 29% Mixed mania29% Mixed mania
MANIA in CHILDREN
• NOT EPISODICNOT EPISODIC• CHRONIC DYSPHORIACHRONIC DYSPHORIA• EXTREME IRRITABILITYEXTREME IRRITABILITY• INTENSE EPISODICINTENSE EPISODIC RAGES…RAGES…
Discriminating Symptoms
• Decreased Need for Sleep Decreased Need for Sleep (40% vs 6%)(40% vs 6%)
• Hypersexuality Hypersexuality (43% vs 6%)(43% vs 6%)
• Intense, prolonged Rage Attacks Intense, prolonged Rage Attacks (92% vs 0%) (92% vs 0%)
• Morbid DreamsMorbid Dreams• Predictable am activity: ADHDPredictable am activity: ADHD
Realistic MedicalRealistic MedicalProphylaxisProphylaxis
• Chronic treatment after first Chronic treatment after first episodeepisode• What is realisticWhat is realistic
““I’m doing a lot better nowI’m doing a lot better nowthat I am back in denial”that I am back in denial”
Realistic MedicalRealistic MedicalProphylaxisProphylaxis
• 30% true cessation of episodes• Realistic Good Outcome: > 75% reduction in episode frequencies > Reduce severity and hospitalizations
Medication AdherenceMedication AdherenceScott and Pope, (2002)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 JamisonGoodwin and Jamison• Marked CircadianMarked Circadian
VulnerabilityVulnerability
Circadian IntegrityThe Most Critical Features
• Regular Times:Regular Times: To Bed & AwakeningTo Bed & Awakening• Early Morning Bright LightEarly Morning Bright Light• Adequate SleepAdequate Sleep
Circadian IntegrityThe Most Critical Features
• Maintain Social RhythmsMaintain Social Rhythms• EatingEating• ExerciseExercise• Bright light exposureBright light exposure
for Bipolar
• Shift workShift work• Time Zone ChangesTime Zone Changes• Substance AbuseSubstance Abuse• Disrupted SleepDisrupted Sleep
Empirically ValidatedPsychotherapies
• Psycho-educational family TxPsycho-educational family Tx• Interpersonal and SocialInterpersonal and Social Rhythm Therapy (IPSRT)Rhythm Therapy (IPSRT)
Family focusedPsycho-education
Miklowitz, et al. 2003
• N: 101N: 101• Fewer hospitalizations: 12% vs 60%Fewer hospitalizations: 12% vs 60% (two year follow-up)(two year follow-up)• Relapses (one year follow-up):Relapses (one year follow-up): > Tx as usual: 53%> Tx as usual: 53% > Family Tx Psy. Ed. 29%> Family Tx Psy. Ed. 29%• Better Med Compliance: p < 0.04Better Med Compliance: p < 0.04
IPSRTInterpersonal and Social Rhythm Therapy
(Frank and Ehlers)
• Support medication adherenceSupport medication adherence• Stabilize environmental factorsStabilize environmental factors• Develop and maintain “socialDevelop and maintain “social rhythms”rhythms”• Manage provocative social Manage provocative social interactions andinteractions and Interpersonal problemsInterpersonal problems
Outcomes: IPSRT(Kupfer, et al., 2000)
• 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
Average Time toFull Resolution
NIMH Collaborative Study Data
• Mania: 11 weeksMania: 11 weeks• Depression: 19 weeksDepression: 19 weeks• Mixed State: 36 weeks*Mixed State: 36 weeks* * * up toup to
Full Resolution of Mania
Time Adults ChildrenTime Adults Children6 months 85% 14%6 months 85% 14%1 year 92% 36%1 year 92% 36%2 years 98% 65%2 years 98% 65%
Ideal Mood Stabilizer • Prevents relapse andPrevents relapse and cycle accelerationcycle acceleration “ “do no harm”do no harm”
FDA:FDA: Acute Mania Acute Mania * 1970: Lithium* 1970: Lithium * 1973: Thorazine * 1973: Thorazine * 1995: Depakote* 1995: Depakote * 2000: Zyprexa * 2000: Zyprexa * 2003: Risperdal * 2003: Risperdal * 2004: Seroquel* 2004: Seroquel * 2004: Abilify* 2004: Abilify * 2005: Geodon* 2005: Geodon * 2005: Equetro (Tegretol)* 2005: Equetro (Tegretol)
FDA: Acute FDA: Acute Bipolar DepressionBipolar Depression
* 2004: Symbyax* 2004: Symbyax (Prozac and Zyprexa)(Prozac and Zyprexa) * 2007: Seroquel* 2007: Seroquel
FDA:FDA: Maintenance Maintenance
* 1974: Lithium: both* 1974: Lithium: both * 2003: Lamictal:* 2003: Lamictal: depressiondepression * 2004: Zyprexa: both * 2004: Zyprexa: both * 2005: Abilify: both* 2005: Abilify: both
Acute Mania and Prophylaxis
• Lithium• Depakote *• Tegretol (Equatro) *• Trileptal *• Antipsychotics (all)
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Dysphoric ManiaDysphoric Mania
Rapid CyclingRapid Cycling
DepakoteDepakote, Lithium, Lithiumor antipsychoticsor antipsychotics
LamictalLamictal77
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
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Medications for Bipolar Mania:
Not Effective
•NeurontinNeurontin• GabitrilGabitril
(seizures)(seizures)
Severe Agitation
• Benzodiazepines Benzodiazepines (e.g. Ativan, Klonopin)(e.g. Ativan, Klonopin)
• AntipsychoticsAntipsychotics• ECTECT
Efficacy: Treatment of Mania
• Lithium (pooled): 58%Lithium (pooled): 58%• Depakote (pooled): 54%Depakote (pooled): 54%• Tegretol (pooled): 52%Tegretol (pooled): 52%• Other agents: open studiesOther agents: open studies
Side Effect Management
• Sustained release (Sustained release ( peaks) peaks) or twice a day dosing or twice a day dosing • dose with maintenancedose with maintenance• Drug combos !!!!!!!…..Drug combos !!!!!!!…..
Compliance:Mono vs Combo Treatments
(Goodwin, 2004; P. Keck, 2002)
• N= 140 Bipolar IN= 140 Bipolar I• Lithium or Depakote monotherapyLithium or Depakote monotherapy compliance rates: 50-60%compliance rates: 50-60%• CombinedCombined (lower doses)(lower doses)
Compliance rates: 40% betterCompliance rates: 40% better compliancecompliance
Lithium Side Effects• Weight GainWeight Gain (50%) (50%)• SedationSedation• Cognitive BluntingCognitive Blunting creativity; drivecreativity; drive• TremorTremor (65%) (65%)• Weakness (transient)• Nausea (50%)• Diarrhea, vomiting
Lithium Side Effects
•Weight Gain Weight Gain (60%)(60%)
•Weakness Weakness (tr ansient(tr ansient))
•SedationSedation
•Cognitive Cognitive BluntingBlunting
creativit y; dr ivecreativit y; dr ive•
Tremor Tremor (65%)(65%)
•Nausea Nausea (50%)(50%)
•Diar rhea, Diar rhea, vomitingvomiting
•Metallic Metallic TasteTaste
• FatigueFatigue• Sexual Dys.Sexual Dys. (10%) (10%)• Thirst, polydipsia (40%)• Polyuria (40%)• Dermatological• Hypothyroid• Renal (Kidney) Effects (?)
Lithium Toxicity• 1.5-2.01.5-2.0: ataxia, coarse tremor, : ataxia, coarse tremor, confusion, drowsinessconfusion, drowsiness slurred speechslurred speech• 2.0+:2.0+: coma, seizures, coma, seizures, stupor, kidney failurestupor, kidney failure• 4.0:4.0: death death• No antidoteNo antidote, but can treat with , but can treat with hemo-dialysis orhemo-dialysis or peritoneal dialysis peritoneal dialysis
Maintenance Doses(maybe)
• Levels: 0.6: Bipolar IILevels: 0.6: Bipolar II 0.8: Bipolar I0.8: Bipolar I
Anti-convulsantsAnti-convulsants
• Depakote• Tegretol (Equetro)• Trileptal• Topamax• Neurontin• Lamictal (not for mania)
Side Effects Common toMost Anticonvulsant
Mood Stabilizers
• Lethargy/SedationLethargy/Sedation• TremorTremor• Weight GainWeight Gain• Nausea• Rash
PREDICTORS OF GOODDEPAKOTE RESPONSE
• ““CLASSIC” MANIA = LITHIUMCLASSIC” MANIA = LITHIUM• RAPID CYCLINGRAPID CYCLING• DYSPHORIC / MIXED MANIADYSPHORIC / MIXED MANIA• USE FOR RAPID ONSETRAPID ONSET OF ACTIONS
Poly-cystic Ovaries• Women under 20: 80%Women under 20: 80%• Often associated with:Often associated with: weight gain weight gain • Pre-treatment sonogramPre-treatment sonogram• Watch for: weight gainWatch for: weight gain and irregular menses and irregular menses
Targeting Co-morbidity:
TopamaxTopamax > Bulimia> Bulimia > Binge eating> Binge eating > Obesity> Obesity > Neuropathic pain> Neuropathic pain > Migraine prophylaxis> Migraine prophylaxis > Alcohol dependence> Alcohol dependence
Targeting Co-morbidity:
NeurontinNeurontin
> Social anxiety> Social anxiety > Panic disorder> Panic disorder (not OCD)(not OCD) > Neuropathic pain> Neuropathic pain > Substance withdrawal > Substance withdrawal
Atypical AntipsychoticsAtypical Antipsychotics
SEROQUELRISPERDALZYPREXAGEODONABILIFYINVEGAFANAPTSAPHRIS 112
Atypical Antipsychotics:Side Effect Issues
• Weight gainWeight gain• Increased CholesterolIncreased Cholesterol and triglyceridesand triglycerides• HyperglycemiaHyperglycemia• Type II Diabetes …….Type II Diabetes …….
Metabolic Side Effects
• Most common:Most common: > Clozaril> Clozaril > Zyprexa (Symbyax)> Zyprexa (Symbyax)• Moderate: Moderate: > Seroquel, Risperdal. Invega> Seroquel, Risperdal. Invega• Least Likely:Least Likely: > Abilify, Geodon> Abilify, Geodon
BIPOLAR DEPRESSION
• ““Do No Harm”Do No Harm”• IneffectiveIneffective• SwitchingSwitching• Cycle Acceleration Cycle Acceleration
BIPOLAR DEPRESSION
APA GuidelinesAPA GuidelinesDo Do notnot recommend recommendantidepressants forantidepressants forfirst line treatmentfirst line treatment
Bipolar Meds withAntidepressant Actions
• LamictalLamictal• SymbyaxSymbyax• SeroquelSeroquel• LithiumLithium if above 0.8if above 0.8
Bipolar Meds withBipolar Meds withAntidepressant ActionsAntidepressant Actions
• Lamictal• Symbyax *• Seroquel *• Lithium *
Lamictal: DosingLamictal: Dosing• Dosing: 25 mg week one and twoDosing: 25 mg week one and two 50 mg week three…50 mg week three… 100 mg bid100 mg bid (see PDR…)(see PDR…)
• Target Dosing: 75-225 mg per dayTarget Dosing: 75-225 mg per day• Onset of Actions: 3-4 weeksOnset of Actions: 3-4 weeks
Lamictal: RashLamictal: Rash• Prevalence:Prevalence: * benign: 12%* benign: 12% * Stevens Johnson: 1/1000* Stevens Johnson: 1/1000 adults and teensadults and teens * 2% in Children* 2% in Children
How Risky is Lamictal ?How Risky is Lamictal ?German Rash RegistryGerman Rash Registry
• Since slow titration startedSince slow titration started• Benign: 9% drug, 8% placeboBenign: 9% drug, 8% placebo• Serious rash: placebo: 0.06% Serious rash: placebo: 0.06% drug; 0.09%drug; 0.09%• No cases of Stevens-JohnsonNo cases of Stevens-Johnson adults and teensadults and teens• Children: 3/10,000Children: 3/10,000
SymbyaxSymbyax
SeroquelSeroquel
• Zyprexa-Prozac ComboZyprexa-Prozac Combo• Quick onset of actionQuick onset of action
Bipolar Depression AlgorithmsBipolar Depression Algorithms
If Bipolar IIf Bipolar I::recent mania or history ofrecent mania or history of
switching, stronglyswitching, stronglyrecommend an antimanic agent: recommend an antimanic agent:
first line first line
Algorithm: BP IAlgorithm: BP I
> Lamictal and Anti-manic> Lamictal and Anti-manic > Symbyax or Seroquel> Symbyax or Seroquel > Add lithium> Add lithium > ECT> ECT
Algorithm: BP IIAlgorithm: BP II
> Lamictal > Lamictal > Symbyax or Seroquel> Symbyax or Seroquel > Add lithium> Add lithium > ECT> ECT
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 TherapyCombo Therapy (Li and Depakote): (Li and Depakote):
6 x longer vs. monotherapy6 x longer vs. monotherapy
Narrow phenotype Bipolar
•Meet DSM-IV criteria for bipolar •Most have a bipolar parent• Versus broad phenotype
135
Chronic Rapid CyclingChronic Rapid Cycling (J. Walkup, 2002)(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….
136
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
Temper Dysregulation Disorderwith 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 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
Temper Dysregulation Disorderwith Dysphoria: DSM-V
• No history of > decreased need for sleep > grandiosity > pressured speech
Temper Dysregulation Disorderwith Dysphoria: DSM-V
• Can co-exist with ADHD, conduct disorder, oppositional-defiant disorder and substance abuse disorder
Bipolar Meds with Kids:Monotherapy
• 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 ManiaFull Resolution of Mania
Time Adults Children6 months 85% 14%1 year 92% 36%2 years 98% 65%
148
Two Year Outcome:Children with Bipolar
(Geller and Craney, 2002)(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 QuestionWhat is the favorite flavorWhat is the favorite flavor
of snow cone syrupof snow cone syrupused to flavor liquidused to flavor liquid
Antipsychotic medications?Antipsychotic medications?