Bipolar Disorder

History• “Manic depressive insanity” used by Kraepelin (1921)• Manic depression rare in children• “The universal experience is striking, that the attacks of manic-

depressive insanity…never lead to profound dementia, not even when they continue throughout life almost without interruption…As a rule, the disease runs its course in isolated attacks more or less sharply defined from each other or from health, which are either like or unlike, or even very frequently are the perfect antithesis.”

• Was misdiagnosed as schizophrenia (1978)• Retrospective reports show that 3-5% of adults had onset of

symptoms before age 10

DSM-V Criteria• Seen as a bridge between schizophrenia disorders and depressive

disorders• Many disorders fall under the Bipolar umbrella• Criterion A: 1+ manic episode(s), symptoms nearly all day every day

for a week or a hospitalization• Elevated or irritable mood, more energetic, possible psychotic

symptoms• Criterion B: Must have 3 of 7 symptoms during change in mood:• Inflated self-esteem/grandiosity• Decreased need for sleep (different from insomnia)• More talkative than usual, pressure to keep talking• Thoughts racing, flight of ideas• Increase in goal-directed activity or psychomotor agitation• Risk-taking behavior (spending sprees, sexual behavior)

• Depressive mood possible but not required.

DSM-V Criteria

• Bipolar II involves episodes of hypomania and depression• Hypomania requires the same symptoms as mania – just

shorter duration (4-6 days rather than 7+ days).• Criterion B stays the same

• Child experiencing (hypo)manic episode

DSM SchematicEnvironmental

Factors• Circadian rhythm

disruption• Stress

Genetics• Exact genetics

unknown

Neurobiological Substrate

• Catecholamine deficiency/dysfunction

• Amygdala dysfunction

Core Features• Mania• Depressed, irritable mood

Secondary Features• Risk taking• Inattention• Poor academic

performance• Social difficultues• Suicidal ideation

Medication• Lithium• Other mood

stabilizers• Antipsychotics

Psychotherapy

Onset and Course• Onset often follows stressful events, often depressive mood first• Sleep loss may mediate link

• Average age of onset is 18• Remission gets shorter as time goes on, especially if left

untreated• Those with a diagnosis of bipolar disorder have a 15x higher risk

of suicide attempts than the general population• Some studies (COBY) report 35% higher

• Functionality between episodes can vary greatly Bipolar disorder associated with delayed motor milestones, speech problems and delays, reduced psychomotor functioning, and low educational achievement, (Sigurdsson et al 1999, van Os et al 1997)

Onset and Course• Kids with a Diagnosis of BD I or II will likely persist with a BD

diagnosis in adulthood• Depends on phenotype

• Lower performance on cognitive tests• Could lead to impairment in work function commonly seen,

which would lead to lower SES also observed in adult populations of BD

• Could be due to attentional difficulties

Differences in Children• More chronic course• Episodes have shorter duration (hours) • Kids spend more time symptomatic overall • Irritability – question of whether it is a necessary condition• Kids may take on many new projects, have inappropriate

sexual thoughts• Not due to abuse

• Higher rates of comorbidity• May be because symptoms overlap too much in the DSM

• Higher levels of emotional and behavioral dysregulation

ComorbidityDisorder % of BD children with disorder

ADHD 11-75%

Oppositional Defiant Disorder 46.4-75%

Conduct Disorder 5.6-37%

Anxiety Disorders 12.5-56%

Substance Abuse Disorders 0-40%

Diagnostic Difficulties• Diagnostic difficulties in children • Euphoria particularly difficult

• Look for behavior that is recurrent, inappropriate in context, above and beyond the child’s normal behavior – i.e. change from his or her baseline

• Can be difficult to see in a clinical setting.• May experience irritability instead

• Grandiose beliefs usually take the form of best in the class, smartest in the school, best at their sport, etc. Kids can exaggerate like this anyway.• Younger kids can’t distinguish between fantasy and reality • Poor social skills

• Symptom counting is not enough – a global picture is necessary for a diagnosis

• Low concordance rate of parent/child ratings for mania• Episodes are key to diagnosis• Diagnosis can greatly depend on what assessments are used

Prevalence• Estimated to be 0.6% of the population with no real

differences between males and females (DSM)• Men may have an earlier onset• Males and females may differ in symptom presentation

• The number of adolescents (0-19) diagnosed with BD increased 40x in 9 years (25 diagnosed to 1003 diagnosed), (Moreno, Laje, Blanco, Jiang, Schmidt, & Olfson 2007)• Is this due to a true increase, more recognition, or misdiagnoses?

• Strong genetic component

Etiology• Strong genetic link• Heritability rates hover around 67-72% based on twin studies• Family history is one of the strongest and most consistent risk

factors• Adult relatives of those with BD (1st-degree) have a 10x

increase of diagnosis• Likely shares a genetic origin with mood disorders – some

combination of genetics predisposes one to an affective disorder

Genetics/Family Influences• Romero (2005) compared healthy families (27) to families

where at least one parent had Bipolar Disorder (23)• 3.7% of HF had a child with a mood disorder• 71% of BPD families had a child with a mood disorder• 38% BPD I or II• 13% depression• Also saw cyclothymic disorder, dysthymic disorder

• Used the Family Environment Scale (FES)• Compared to normative FES data, BPD families had higher

independence and conflict, lower cohesion and expressiveness

Social/Environmental Contributions• Hard to determine• Slightly more common in high-income countries (DMS reports

1.4% prevalence vs 0.7%)• Childhood abuse may affect development of disorder• Garner, Goldberg, Ramirez, & Ritzler (2005) studied childhood

abuse in children with BD• N = 100 (BD I – 73, BD II = 27)• Appx half identified either childhood physical, sexual, or

emotional abuse, and/or physical or emotional neglect• Median age of first (hypo)manic episode = 17.5• Kids with severe abuse had significantly lower age on onset,

higher severity of current level of manic symptoms, higher risk of substance use, more rapid cycling

• Increasing number of abuse forms positively associated with number of suicide attempts

Social/Environmental Contributions

• Childhood depression with psychotic features may predispose children to later development of mania

• Goldberg, Harrow, & Whiteside study• 15-year study of 74 patients hospitalized for unipolar depression

• 41% of cohort experienced mania or hypomania• 15% had manic episode

• Patients with family history of BD showed higher rates of conversion to BD themselves• Findings were nonsignificant

• Psychotic features during depression seem to be an additional risk factor

Neurobiological Substrate• No single underlying hypothesis for pathophysiology (“No smoking gun, but a

biological crime scene.”)• Decreased cerebral blood flow and metabolism as compared to controls and

patients with unipolar depression • State dependent

• Decrease in DLPFC metabolism and blood flow• Executive functions such as working memory, planning, abstract reasoning

• Enlarged ventricles – connected to mania?• Smaller amygdala• Possible deficiency in one or more monoamines

• Treatment that increases these can precipitate mania• In a postmortem study, no differences in norepinepherine, serotonin, or dopamine were

found• Decrease in BDNF• Increased white matter hyperintensities

• Seen in normal aging and linked to mild cognitive decline• Seen in patients with BD and MDD

• Similar HPA-axis disregulation as found in unipolar depression

Neuropsychological Deficits• Comobidities make it challenging to assess. • Impaired perception of facial expression seen in both child and

adult populations (narrow phenotype, while euthymic).• Children seem to have more difficulties with adult faces as

opposed to child faces (McClure 2005).• Impairments in working memory and processing speed• Impaired verbal learning• Particularly in kids with comorbid ADHD

• No differences in brain anatomy of BD kids with comorbid ADHD as compared to those without (DelBello 2004)

• Lithium probably impairs psychomotor speed, verbal memory

Neuropsychological Deficits• Dickstein (2004) studied children with BD and gender- and

age-matched controls (n = 42, ages 10-15, 13 euthymic, 8 hypomanic)

• Found impaired attentional set-shifting and visuospatial memory

Phenotypic Differences• Liebenluft et al proposed four subtypes for bipolar disorder• Narrow – meet DSM criteria• Hypomania NOS – Short episodes, hallmark symptoms• Irritable hypomania – irritability instead of euphoria, episodic• Broad – chronic hyperarousal/irritability

• This phenotype is the most controversial• Also called Severe Mood Dysregulation

• Probably means different etiologies, genetic contributions, course, treatment response, outcome

The Irritability Question• Wozniak, Biederman, et al (1995) study found mania present in 16% (43)

of referred children (n = 262)• Used K-SADS

• These kids exhibited impaired psychosocial functioning• High comorbidity (depression, psychosis, ADHD, anxiety disorders, CD,

ODD)• Children were predominantly irritable/mixed mood• 84% mixed mood• 77% extreme, persistent irritable mood• 5% manic

• Of 43 manic children, 42 also diagnosed with ADHD• 70% of manic children had onset before age 5• Course• 84% chronic• 16% episodic• 23% had symptoms that were always present

Bipolar NOS

• Brotman et al drew data from the Great Smoky Mountains Study

• N = 1420, 96 had the broad phenotype, or SMD• None experienced a classic (hypo)manic episode • 2% of their parents were diagnosed with BD• Development of MDD was the only statistically significant

association (odds ratio 7.2, CI 1.3-38.8)• Youths with BD I or II diagnoses tend to keep the diagnosis

throughout their lives (Birmaher et al 2006)• i.e. Clinical course differs

Bipolar NOS• COBY study - 4-year longitudinal study of bipolar youth• Question over whether euphoria could/would be observed in

children, or if child BD only includes irritability• Studied youth with Bipolar Disorders I, II, and NOS• NOS kids were irritable but had episodic irritability, which distinguishes

them from constantly irritable BD-NOS group• Episodic irritability lasted for about 2 days, which doesn’t qualify for

hypomania• 1/5 of BP-II converted to BP-I• 1/4 of BP-NOS converted to BP-I or II• Euphoria in 92% of children, irritability in 84%• Age of onset, duration of mood symptoms, low SES, and psychosis all

predicted outcome• Compared youth to adults, youth spent more time symptomatic and

had more episodes and mood symptom changes

Bipolar NOS• Stringaris et al. followed children with BD narrowly defined

(93) and SMD (84) at 6-month intervals for average of 2 years• 50 BD children had a manic or mixed episode during follow-up• 1 SMD child had manic or mixed episode• SMD kids did develop MDD• Suggests they are from different populations

Treatment - Medication• Early studies found lithium to be effective in teens (Annell

1969)• Lithium flows into neurons during depolarization• Can conceptualize as decreasing sensitivity to fire• May increase cell growth in the hippocampus (like SSRI’s)

• Animal study supports this – Yoneyama et al 2014• Lethal doses can be as small as twice theraputic dose

• Anticonvulsants, atypical (2nd generation) antipsychotics sometimes used

Treatment - Psychotherapy• In adjunct to medications, not a substitute for• Interpersonal and social rhythm therapy (IPSRT)• Developed specifically for BD• Individuals vulnerable to disrupted circadian rhythms, abnormal

sleep-wake cycles, stressful events, medication nonadherence• Sleep deprivation can precipitate mania• Therapy targets these issues

• Some empirical evidence, not greatly studied

Treatment - Psychotherapy• Frank et al studied IPSRT and Clinical Management (CM) in 82

patients with BD• All patients were on medication• Treatment was done in two phases – acute and preventative• Some patients kept the same therapy, some switched• Four groups:• Acute IPSRT and preventative IPSRT• Acute IPSRT and preventative CM• Acute CM and preventative IPSRT• Acute CM and preventative CM

• 34% experienced recurrence over 1 year• Outcomes did not depend on type of treatment• Switching treatment was significantly associated with relapse

Treatment - Psychotherapy• Child Family Focused CBT• Family dynamics act as a moderator between treatment response

and relapse rates• 12 sessions, 1 hour each, child and parents• Talk about communication skills, sticking to a routine, medication

adherence• Pavulurti (2004) study of 34 families showed reduction in

problems as compared to pre-treatment

New Schematic

Bipolar Disorder• Narrow

• Episodes of mania• Hypomania NOS

• Shorter episodes• Hallmark symptoms

• Irritable hypomania• Episodic irritability

Secondary Features

• Inattention• Poor academics• Peer difficulties• Suicidal ideation• Family conflict• Restlessness• Increased

psychomotor agitation

SMD• Chronic irritability

and arousal• Severe reactions to

stimuli, rages

Environment• Sleep loss• Stress• Interpersonal conflict• Abuse• Changes in routine

Genetics• Abnormalities

providing common link between mood disorders

Neurobiological Substrate

• Monomine deficiency• HPA dysfunction• Decreased cerebral

blood flow and metabolism

• Enlarged ventricles• White matter

hyperintensities• Smaller amygdala• Decrease in BDNF

Outcome• MDD• Dysthymia

Outcome• BD I and II• Anxiety Disorders• Substance abuse

PsychotherapyMedicationsOther Genetics

Challenges

• Differential diagnosis• Criterion B symptoms include decreased need for sleep, high

distractability, and more energy• This can look a lot like other disorders• BD and schizophrenia can look similar, particularly if there is

psychosis in BD• No consensus on standardized screening instrument. For

example, Biederman frequently uses the Child Behavior Checklist. He finds high scores on attention problems, aggression, and depression/anxiety.

• Youngstrom prefers the Parent General Behavior Inventory and Child Mania Rating Scale

Challenges• Few longitudinal studies• Those that do exist are childhood to adolescence or adolescence

to adulthood, generally not both• Many studies combine children and adolescents • Not many studies compare children to adults• Disorder may be better viewed dimensionally rather than

dichotomously• When diagnosing, be careful to ask the right person the right

questions. For example, parents won’t know as much about homicidal thoughts as the children in question

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