Pediatric Bipolar Disorder

David Camenisch, MD/MPHPAL Conference

Jackson, WYMay 5, 2012

Pediatric Bipolar Disorder

May 5, 2012PAL Conference

Cody (RR 2.5) - History6 year old mixed-race (NA/AA) boy new to your

practiceADHD diagnosis at age 4. On and off stimulants for 2 years. Has been tried on both methylphenidate and

amphetamine preparations. They tend to work for a while but then things “go

back to normal.” He has always been “moody.” Struggling at school socially but “really smart.” Per

mom, “He reads real history books and remembers everything.”


Cody – Presentation Mom thinks he is bipolar. She just got

diagnosed and medications have really helped her.

Mom says she can’t control him at home. A little better with mom’s boyfriend of who has been in and out of the picture for 2 years.

Actually, mom just stopped stimulants because she heard they can make things worse if your kid has bipolar. She thinks he is doing better.

She asks you to prescribe “something” to treat his bipolar mood swings……


What To Do?What role should a primary care provider take

regarding the question of child bipolar disorder?Psychoeducation?Referral?Treatment?

How do you assess for childhood bipolar disorder?

When does it make sense to… WaitPrescribe a mood stabilizer?Refer to a therapist? Refer to a (child and adolescent) psychiatrist?


Bipolar Is A Hot TopicBipolar disorder in kids is much talked

about“Child Anxiety Disorder” on Google

26,600,000 hits (3,120,000)“Child Bipolar Disorder” on Google

33,100,000 hits (4,370,000)(Camenisch 2012, Camenisch 2011)

Child anxiety disorders are actually about 10 times more common than child bipolar disorder

40 fold increase in office visits for child bipolar disorder from 1994 to 2003 (Also 40-fold increase in diagnosis.)

National Center for Health Statistics May 5, 2012PAL Conference

Frequency of Childhood BipolarVery controversial Some assert a high frequency of all children

have bipolar disorder“The Bipolar Child” by Papolos and Papolos

Assert 1/3 of all children with ADHDStates about 6% of all children are bipolar

“Is Your Child Bipolar” by McDonnell and WozniakStates more than 3 million US kids have itBased on their estimates, incidence is 4%.


Quoted Child Rates Don’t Match Our Adult Knowledge

Adult Lifetime prevalence rates of bipolar disorder 1 to 2%

Greater diagnostic certainty with adultsBipolar disorder is a lifelong diagnosis – need

plausible explanation if pediatric bipolar is 3-6X > adult bipolar

Lessons from Great Smoky Mountain data set child bipolar NOS ≠ bipolar adult

Kids with bad mood swings cannot all have “true” bipolar disorder


Why is diagnosis so challenging?Symptom overlap + high rates of co-morbidityConfounding developmental issuesEnvironmental influences Limited ability of (many) children to verbalize

emotionsMany different “expert” opinionsInfluence of popular media/pharmaceutical

industryRequires extensive history – assessment of

both current symptoms and past episodes (subject to recall bias.)


DSM-IV TR (Hypo)Manic Episode

Manic Episode – 7 days + impairment, or hospitalization or psychosisDistinct period of abnormal and persistently

elevated*, expansive or irritable mood Plus 3 (4 if “irritable-only” mood) of the following:

DistractibleGrandiose/inflated self-esteem*Decrease need for sleep (< 3 hrs)More talkative/pressured speechIndiscretions/risk taking Flight of ideas/racing thoughts Increased goal directed activities/PMA

Hypomanic Episode – 4 days. No hospitalizations. No impairment.


Depressive Episode5 or more of following in same 2 week

period + depressed/irritable mood OR lost of interest/anhedonia

Sleep InterestGuilt Energy (fatigue)ConcentrationAttentionPMA/PMR (observable)Suicidal thoughts/feelings/behaviors

Functional ImpairmentNo Mixed Episode, R/O Substance, R/O

GMC, R/O BereavementMay 5, 2012PAL Conference

Diagnosis of Mood DisordersCurrent

None MDE Hypo Manic MixedPastNone No Dx MDD No Dx BP1 BP1MDE MDD MDD BP2 BP1 BP1Hypo No Dx BP2 BP, NOS BP1 BP1Manic BP1 BP1 BP1 BP1 BP1Mixed BP1 BP1 BP1 BP1 BP1

Remember to ask about past mood symptoms, otherwise bipolar will be misdiagnosed as depression.


Bipolar, NOS DSM-IV TRRapid alternation between manic and

depressive symtpoms that do not meet duration criteria

Recurrent hypomanic episodes w/o depressive symptoms

Manic or mixed episode in context of thought disorder

Hypomanic episodes w/ chronic depressive symptoms

Hypomanic/manic symptoms but haven’t yet been able to rule out influence of substance use or general medical condition.


Bipolar Disorder, NOSContributes to the current bipolar “epidemic”Label often given to impulsive, aggressive

kidsPrognosis could be normal, MDD, or (rarely)

true bipolarDiagnosis confused with:

ADHDDepressionAbuse (current and PTSD)Anxiety DisordersDisruptive Behaviors Disorders Reactive Attachment Disorder Intermittent Explosive Disorder


Why is Bipolar, NOS so common? Broad Category/catch-allNot (yet) another more suitable diagnosis

that captures complex behavioral picture (SMD, TDDD)

Sounds better to us than “I don’t know”Justifies the limited(medication) treatment

options.If we give a child medicine as if bipolar, parents

often report improvementBipolar medicines have many non-specific

effectsAll decrease impulsivity and aggression


If not bipolar, then what? DepressionOngoing abuse/neglect Post-trauma symptoms or syndrome Environmental Instability (frequent change in living

arrangement/primary care giver; parental mental illness)Disordered Attachment (RAD) Temperament Mismatch (Parent-Child Relational

Problem)Anxiety (especially brief, episodic, reactive “mood

swings” )Disruptive Behavior Disorders (ADHD,ODD) Affective lability in context of autism spectrum disorder

(co-morbidity versus core disorder attribution)May 5, 2012PAL Conference

Severe Mood Dysregulation (SMD)Clinical syndrome not a diagnosis (3.3%

lifetime prevalence ages 9-19)“chronically irritable children whose diagnosis

is in doubt.” (Often the “Bipolar, NOS crew) IS real and confers risk of psychopathology

down the line, but is NOT bipolar disorder (also not Axis II)

Presence of SMD increases risk of depressive disorder and GAD at 20 year follow-up. Stringaris et al, 2010


Bipolar Disorder Frequency Depends On Where You Look

Prevalence of “true” adolescent bipolar0.6% of high school students 1% in general outpatient practice 6 % of child psychiatry outpatients (CMHC)22% incarcerated adolescents 26-34% of child psychiatry inpatients manic

symptoms(1996-2004 CDC survey of discharge diagnosis)

Youngstrom et al, CAPC Vol 18


Cody – The QuestionsTest out whether un/under-treated ADHD (haven’t

found right medication, right dose; hasn’t had behavioral help, parenting support) or do you need to consider mood disorder?

Or co-morbidity (depression, anxiety, ODD) Ask for more detail than just “labile moods” (hyper-

arousal)and “won’t listen” (distractibility)How is his mood most of the day? What causes (if anything) his mood to change? When not upset, what does he look like? Can he “pull out of it”Does he “listen” when he is asked to do something he wants to

do?


Cody – The AnswersMom says he “never listens to me” especially

when asked to do chore/homework/go to bed. Goes into rages when doesn’t get his wayThrows things at mom, hits her. Says “I hate

you.” Tried “everything,” even spanking, taking

away the Xbox. With dad or other adults he behaves better.

Some talking back, but manageable. Knows he needs to cool it or he going to get in trouble.


Cody – At School In 2nd grade, teacher said he was not

listening well in beginning of year, is better now

In kindergarten he didn’t follow rules wellPerforming at grade level Not having rages at school Generally more of a problem at home

more than at school


Cody – Social History and Development Mom is primary caregiver.1 younger brother, mom thinks she might be

pregnant. No contact with dad. Left before Cody was born. Mom has few supports. Mom’s family and tribe

“disowned” her and Cody because his father is AA.

Developmental milestones were OK“Read early. Very verbal. Reads “anything

about history” and “remembers everything.” No in utero drug exposure identified.


How to answer Mom’s Question if this is Bipolar Disorder?Difficult diagnosis (no “tests”)Diagnosis best made “over time” ; usually not

point-in-time diagnosis --especially with chronic presentation

Many different opinions, even among specialistsDown side of labeling too early If you think NOT bipolar, continue with…

Psycho-education. (Non-specific nature of “mood swings” and “irritability” e.g. cough analogy)

Reasonable to consider treatment depending on potential consequences. (Sx-driven versus dx-driven treatment*)


Consider the large differential for each of these Mania symptoms in kids:

DistractibleIndiscretions/risk takingGrandioseFlight of ideas/racing thoughts Activity (goal directed) increaseSleep need decreasedTalkative (pressured speech)

Which can mimic ADHD symptoms? May 5, 2012PAL Conference

Manic symptoms versus ADHD (Kowatch et al, 2005)

Symptom ADHD PBD*Irritability 72% 98%Accelerated Speech 82% 97%Distractibility 96% 94%Unusual Energy 95% 100%

* Pediatric Bipolar Disorder


Diagnostic PerspectiveExperience with adult mania helps, but can

be challenging to translate to kids. (Different patterns of diagnosis between Adult and C&A psychiatrists?)

Compare child to a prototypic “manic” patientPressured speech -- not just talkativeHaving no doubt about their grandiose ideas --

impaired reality testing/lack of insight)Thought process is fast and jumping around Episodes that most commonly last days not minutes or

hoursLittle need for sleep (versus poor sleep.)


Look for Episodes and Patterns

Individual episodes represent a clear departure from baseline with some hallmark symptoms

Hopefully, the presence of hallmark symptoms will help distinguish irritable mania from irritable depression

The correct mood diagnosis (and treatment) requires establishing the pattern of mood episodes, not just presenting (current) episode.


Rapid Cycling Controversy Typical adult pattern is episodic. Rapid cycling is

rare in adult bipolar populations. Kids are more reactive and more common to get

story of “rapid cycling.” Consider “rapid cycling” in kids if there is no trigger

identifiable for the mood changesWhere many “episodes” become static, chronic

mood state is controversial.ADHD plus irritability should not generate a bipolar

diagnosisYouth with BP do spend more time cycling and have

more changes in mood polarity that adult populations. (Birmaher et al, 2006)


Chronic versus Episodic IrritabilityObjective: Test validity of distinction between chronic

and episodic irritability. (Central debate in pediatric bipolar)

Method: Community sample of 776 children and adolescents interviewed at 3 points in time (T0, T2y, T7y). Irritability rating scales used to tease out chronic versus episodic irritability. Association with age, gender and diagnosis were examined.

(Liebenluft et al, 2006)


Chronic vs Episodic Irritability Those with episodic irritability were more likely

than those with chronic irritability to have:A parent diagnosed with Bipolar Disorder Experienced elation and/or grandiosityMore symptoms of mania Psychotic symptomsHad a depressive episodeMade a suicide attempt



Irritability and Later PsychopathologyChronic irritability at TI - associated with ADHD at T2 and depression at T3Episodic Irritability – associate with simple phobia at T2 and mania at T3

Conclusions: - Episodic and chronic irritability are distinct constructs. - Episodic irritability is associated with bipolar disorder and confers higher risk of future manic episodes than chronic irritability.



Irritability Controversy Geller: Irritability is not diagnostic of PBD;

it is very common and shows high sensitivity, but poor specificity for PBD

Wozniak: irritability may be primary mood symptom; episodicity not relevant.

Leibenluft: In diagnosing PBD, episodic irritability is more suggestive of PBD than is chronic irritability

Hunt/Birmaher – episodic irritability alone can represent manic phase of illness; “irritable-only” mania exists but is rare; more common in younger children. (COBY).


Look for “Hallmark” SymptomsIncreased specificityMore likely bipolar…

Elation HyperactivityGrandiosityHypersexualityDecreased need for sleep


Bipolar Diagnostic AidesRating Scales

Young Mania Rating ScaleUseful for monitoring symptoms over timeNot a diagnostic tool (very low specificity)

DISC or KSADSUsed in research, have flawsImpractical for your office practice

Rating scales are too misleading to recommend for diagnostic use and are intentionally excluded from the PAL guide.


Cody Rage episodes seem directed mostly at

mom, and mom’s attempts to set limits at home

Mood changes occur mostly in response to frustrations

There are not any hallmark symptoms of grandiosity, euphoria, hypersexuality

No history of days-long episodesHe is very young to diagnose as bipolar


What about Family History?Mom says she has been diagnosed with bipolar

and his uncle is bipolar, “just like him”

Avoid overcalling a positive family historymany adults who call themselves bipolar may not

have that illnessfirst degree relative bipolar disorder, increases OR by

5second degree relative bipolar, increase OR by 2.5given a generous prevalence of 2% bipolar in the

population, most children of a bipolar parent (~90%) will not have bipolar disorder

Youngstrom E & Duax J, JAACAP 44:7, 2005


Looking back at adult bipolar….Several studies have asked adults with

bipolar about onset of their symptoms retrospectively

Bipolar adults look back and note symptoms became bipolar-like in their teen years (50-66%)

Many bipolar adults had major depression episodes as children

The younger the child’s first major depression, the more likely bipolar disorder is in the future


What if a “Bipolar” Child Really is Bipolar?Though rare in a PCP practice, becomes

more likely the older the child.Typical pattern is early onset

depression, and during teenage years getting first symptoms of mania.

Expect mood “episodes”. COBY study established validity of episodic course.

Assemble a team. Real deal bipolar disorder is a big problem.


Course Of True Bipolar DisorderSuicidalilty

up to 15% eventually complete suicideSubstance Abuse in up to 60%Anxiety disorders in up to 50%Psychotic features in up to 50%Relationship DisruptionsWork DisruptionsHospitalizations

Stern TA and Herman JB, 2004May 5, 2012PAL Conference

Bipolar TreatmentIf clear manic episodes, strongly

recommend get them to child psychiatristManagement difficult because:

High rate of substance abuseHigh rate of medication non-complianceEven with medication, recurrences happen

High rates of family disruption from the illness

Suicidal behavior is common

Brent et al, 1988, 1993


If No Child Psychiatrist Can Assume Care, Then What?Get collateral evaluations to help

establish correct diagnosisStrongly advise against rushing to offer diagnosis

of bipolar disorder.Seek consultant advice on medication

(when they are appropriate to consider)Preferred model of care:

MH specialist is primary prescriberPCP is a partner in the treatment team

Call the Provider Access Line. Sometimes PCP is left holding the bag


Bipolar Treatments (for when you are left holding the bag)

Atypical antipsychoticsMood StabilizersCombination therapyAntidepressants if used cautiouslyFamily therapy (support/education/adherence)Sleep hygeine Psychotherapy for:

depression treatmentcoping skillssupporting medication treatment adherence


Bipolar Medications


What Is A Mood Stabilizer?Includes both atypical anti-psychotics and anti-

epileptic drugs (AEDs)Generic term – clarify what they mean when

taking history and what you mean when proposing treatment.

FDA does not recognize this term As relates to treatment of bipolar disorder, ideally

treats both depressive and manic episodes as well as prevents recurrence of mood episodes.

Since no one compound does this well, multiple meds are often used together (but little evidence base to support it.)


Mood Stabilizers are Non-Specific to PBDMaladaptive aggression

Mental retardation (lithium, risperidone) Autism (risperidone, aripiprazole)Conduct Disorder (risperidone, valproic acid,

lithium) Seizure Disorders – kindling hypothesis;

neuroprotective effects in mood disorders (lithium)

Depression (risperidone, aripiprazole, quetiapine, lamotrigine)

Psychosis (primary, mood disorder, delirium) OCD (refractory) PTSD (intrusive thoughts)


Pharmacotherapy of Pediatric Bipolar (Liu et al, JAACAP 2011)


Positive Randomized Trials Blinded RCT knowledge base in kids is lowAytpical anti-psychotics

OlanzapineAripiprazole (2) Quetiapine (3)Risperidone (1)

AEDsDivalproex sodium (Depakote) Li (maintenance)


Atypical Antipsychoticsrisperidone, quetiapine, olanzapine,

aripiprazole, ziprasidone11 OTs with 53% response rate8 DBRCTs with 66% response rate N = 1474

That DBRCTs showed greater efficacy than placebo is encouraging and noteworthy

Better tolerated than AEDs as a group.


Risks common to all Atypical Antipsychotics (Correll, JAACAP. 2008)

Sedation (olanzapine, quetiapine)Tardive Dyskinesia (0.4% annual incidence)Increased Cholesterol/ Triglycerides (olanzapine) Akathesia (aripiprazole) (youth<adults)Increase glucose (olanzapine, quetiapine)EPS (risperidone)Lower seizure threshold (mildly)QT interval change (~20ms for ziprasidone)Weight gain (olanzapine > quetiapine,

risperidone >the rest)Neuroleptic Malignant Syndrome


Atypical Heterogeneity


Adverse and Therapeutic Effects of Occupancy and Withdrawal

(Correll, JAACAP. 2008)


Risperidone (Risperdal)PROSQD-BID dosing (T½ = 20 hours)FDA for mania > 10 years old, irritability/aggression in

ASDMultiple dosage forms (liquid, dissolving tab, tabs,

depot) Low doses (<2 mg) adequate for non-specific aggressionTD incidence reported less than 0.5%CONS Weight gain and sedation commonHyperprolactinemia riskRelatively high rates of dystonic reactions/EPS


Aripiprazole (Abilify)PROSQD-BID dosing ( T½=75 hrs) But kids may do better

BIDFDA for mania (>10 yrs) and limited RCT supportMixed agonist/antagonist (less dystonia/EPS)Often less sedationCONSLimited dosage formsMisperception of less weight gain/metabolic SEAgitation/activation not uncommonHigher rates of akithesiaLong T ½ -may take longer to see impact of changes


Quetiapine (Seroquel)PROS Lower potency - may be experienced as “milder”FDA approval (>10 years old)/limited RCT

evidenceEffective anxiolyticCross indication for bipolar and unipolar

depressionCONSShort half-life (T½ = 6 hours); multiple daily dose;

mixed results w/ XR preparationLarge tablets - may be hard to swallowEffective sleep aide (high risk, high cost sleep

aide) Cataract risk


Olanzapine (Zyprexa)PROS QD-BID dosing (T½ = 30 hours)FDA approval (> 13 years) and limited RCT evidence Multiple dosage forms (tablets, oral disintegrating,

IM)Very effective for acute stabilization of mania and

psychosisCONSWeight gain (dose related, less of plateau than

others)High rates of metabolic side effectsSedation common


Ziprasidone (Geodon)PROSOften less sedatingMost weight neutralFewer metabolic side effects Unique receptor profile CONSBID-QID dosing (T ½ = 7 hrs)No FDA approval for pediatric maniaNo pediatric RCT support Concern for EKG changes has lowered its usage


Monitoring for all atypical antipsychotics: AIMS exam at baseline and Q6months due to risk of tardive dyskinesia. Warn of dystonia risk. Weight checks, fasting glucose/lipid panel Q6months at minimum.


Anti-convulsantsLithium (Li), divalproex sodiumm(VPA),

carbamazepine (CBZ)14 OTs (41% response rate) 6 RCTs (40 % response rate) n = 915Only RCTs for divalproex sodiumNo RCTs for Li or CBZ

Lamotrigine, oxcarbazepine, topiramate3 OTs (43% response rate) 2 RCTs (39%)n = 244


LithiumPROSFDA approved for mania >12 years Some evidence in refractory depressionAnti-suicide propertiesSome EB dosing guidelines (adjust for age/GFR)CONSNarrow therapeutic index (close monitoring for toxicity w/

illness/dehydration; no NSAIDs) Usually best in combination, so committing to

polypharmacy if you start here (best w/ atypical or VPA) SE in therapeutic range similar to early toxicity (tremor,

diarrhea)SE often limit use (weight gain, acne, GI); HS dosing can

minimizeHard to predict who will respondNo evidence for maintenance treatment /slow anti-manic

effects May 5, 2012PAL Conference

Early

Signs


Valproic Acid (Depakote)PROSSingle daily dosing can be effective (Depakote ER)Can be useful for maladaptive/non-specific

aggressionStudies suggest helpful, usually in combinationCONS Requires blood draws (levels, LFTs, amylase, CBC) Risk of hepatotoxicity (highest in first 6 months)High side-effect burden (weight gain, GI, tremor,

sedation, rash)Less ideal for females (risk of birth defects (NTD),

PCOS)


DepakoteHow well does it work?

Fair, usually works best in adolescents in combination with an antipsychotic (better than either one alone)

Some RCT’s have suggested that it works better than lithium on acute manic symptoms

Broad effects: also used for externalizing behavior disorders, conduct disorder

Lost in head-to-head trial with quetiapineSimilar long-term stabilizing effect to Lithium

after stabilization with both divalproex and lithium

DelBello MP et al, 2002, 2006Bowden C et al, 2004Rana M et al, 2005Findling, R et al 2005


Carbamazepine (Tegretol)PROSSome empirical supports for aggression2 OTs Similar response rates as Li and VPA (38%)

(Kowatch et al, 2005)

CONSDrug/drug interactions (OCPs, Lithium)Blood draws to check levels (auto-induced

metabolism) Weak evidence of benefit in bipolar (McClellan and

Werry, 1997)Risk of aplasia and liver failure


Hard to Compare Effectiveness

42 child outpatients with Bipolar 1 or 2, randomized to one of three open label treatments R Kowatch et al, 2000 May 5, 2012PAL Conference

Lamotrigine (Lamictal)PROSBipolar depression treatmentLess sedation and lower side effect profile in

general

CONSNot helpful for manic phaseRequires monitoring of CBC and liver

functionSignificant rash riskSlow titration (age >12)


Oxcarbazepine (Trileptal)PROSFDA approval for adults bipolar disorderWeight neutralLess risks/side effects than carbamazepineMonitoring of levels not required CONSLevels do not correlate well with efficacy or

toxicityNegative adolescent bipolar trial (Cochrane Review.

Vasudev et al. 2008)Hyponatremia not uncommon


Anticonvulsants Shown Not To Help In Adult Bipolar Disorder topiramate (Topamax) (1 negative

pediatric trial)gabapentin (Neurontin)levetiracetam (Keppra) - can cause

psychiatric symptomszonisamide (Zonegran)pregabalin (Lyrica)felbamate (Felbatol) - can cause

psychiatric symptomsMay 5, 2012PAL Conference

Bipolar Take-Home MessageDiagnosis of bipolar disorder made with relative

confidence in the presence of manic (Bipolar I) or hypomanic (Bipolar II) episodes. It gets tricky after that.

Mood episodes (all) involve distinct change from baseline with alternations in behavior and evidence of impairment.

Bipolar diagnosis is a serious diagnosis that has a life-long course and many management challenges.

True bipolar has high rates of morbidity and mortality. If suspected, strongly recommend involving a child

and adolescent psychiatrist .If you, as PCP, are playing central role in management,

check-in frequently to monitor side effects of medication(s) and surveillance of mood symptoms.


“Not-Bipolar” Take-Home MessageCurrently, there is no single diagnosis for chronically

dysregulated or irritable kids. Evidence is more suggestive of current and/or future depressive disorder.

Kids with severe, non-episodic irritability differ from those with bipolar in course, family history and performance in many cognitive tasks linked to more severe psychopathology.

Still a major role for parent support/training and mental health support. These kids can be draining and are high risk.

There can be a role for medications to decrease maladaptive aggression and affective instability.


At PCP level, recommend….…keeping in mind many possible causes of

mood swings and irritability. …resisting temptation to label impulsive,

difficult kids as “bipolar.”…reminding yourself and parents who are

struggling that most disruptive, irritable children do not have bipolar disorder but can still benefit from help.

…getting help with diagnostic and treatment questions as often as necessary.


Selected BibliographyPharmacologic Treatments for Pediatric

Bipolar Disorder: A Review and Meta-Analysis. Liu et al. JAACAP. August 2011.

Practitioner Review: The Assessment of Bipolar Disorder in Children and Adolescents. Baroni et al. JCPP. 2009.

Antipsychotic Use in Children and Adolescents:Minimizing Adverse Effects to Maximize Outcomes. Correll. JAACAP. January 2008.


Documents

Pediatric Bipolar Disorder