Pediatric Bipolar DisorderAndel V. Nicasio, MSEd

University of Central Florida7936 Child Psychopathology

October 9, 2013

1. Review the current DSM-5 definition and criteria for bipolar disorder

2. Highlight major historical developments in the scientific understanding of bipolar disorder

3. Illustrate the evolution of bipolar diagnosis on the DSM

4. Review the literature on pediatric bipolar disorder

5. Present a new theoretical model for pediatric bipolar disorder

Aims of this presentation

• Review the current DSM-5 definition and criteria for bipolar disorder

Aim 1

What is Bipolar Disorder?

“Also known as manic-depressive illness, is a brain disorder that causes unusual shifts in mood, energy, activity levels, and the ability to carry out day-to-day tasks.” NIH

DSM-5 Classification of BP

Bipolar I – (Depression & Mania) Bipolar II – (Depression and Hypomania) Cyclothymic Disorder Substance/Medication-Induced Bipolar and

Related Disorders Bipolar and Related Disorder Due to Another

Medical Condition Other Specified Bipolar and Related

Disorder Unspecified Bipolar and Related Disorder

Bipolar Disorder in the DSM-5 DSM-5 highlights that

children and adolescents who experience bipolar-like symptoms may not meet criteria for BP-I, BP-2, and cyclothymic disorders. However, they may meet criteria for Other Specified Bipolar and Related Disorder.

Bipolar I – DSM-5 Criteria Manic Episode – may have been preceded by and

many be followed by hypomanic or MD episodes.

A. A distinct period of abnormally and persistently elevated, expansive or irritable mood and persistently increased goal-directed activity or energy, lasting at least 1 week and present most day, nearly every day.

B. During the period of mood disturbance and increased energy or activity (three or more) of the following symptoms (4 if the mood is only irritable) are present…

Bipolar I – Manic Episode Inflated self-esteem or grandiosity Decreased need for sleep More talkative than usual or pressure to keep talking Flight of ideas or subjective experience that thoughts are

racing. Distractibility Increase in goal-directed activity or psychomotor

agitation Excessive involvement in activities that have a high

potential for painful consequences

C. The mood disturbance is sufficient severe to cause marked impairment in social or occupational functioning or requires hospitalization…or there are psychotic features.

D. The episode is attributable to the physiological effects of a substance or another medical condition.

Hypomanic Episode A. A distinct period of abnormality and persistently

elevated, expansive or irritable mood and persistently increased goal-directed activity energy or energy, lasting at least 1 week 4 consecutive days and present most day, nearly every day.

B. During the period of mood disturbance and increased energy or activity (three or more) of the following symptoms (4 if the mood is only irritable) are present… Same list of symptoms as Mania

C. The episode is associated with an unequivocal change in functioning that is uncharacteristic of the individual when not symptomatic.

Cont…Hypomania D. The disturbance in mood

and the change in functioning are observable by others.

E. Episode is not severe enough to cause marked impairment in social or occupational functioning or necessitate hospitalization…

F. Episode is not attributable to the use of a substance…

Child with Bipolar DisorderVIDEO

http://www.youtube.com/watch?v=Y4GYwymtbUU

Features a child who has been playing since 1:30am - 10:30am. Video taken around 10:30am

Manic Depressive Episode A. Five (or more) of the following symptoms have been

present the same 2-week period and represent a change in previous functioning; at least one of the Sxs is depressed mood or loss of interest or pleasure. Depressed mood most of the day Markedly lost of interest or pleasure in all, or almost all Significant weight lost Insomnia or hypersomnia Psychomotor agitation or retardation nearly everyday Fatigue or loss of energy Feelings of worthlessness...guilt Diminished ability to think or concentrate... Recurrent thoughts of death, suicidal ideation...

B. Sxs cause significant distress or impairment… C. The episode is not attributable to a substance or

another medical condition.

Bipolar II Disorder Criteria have been met for at least one

hypomanic episode and at least one MD episode…

There has never been a manic episode. The occurrence of hypomanic and MD is not

better explained by schizoaffective disorder… The Sxs of depression or the alternation between

periods (MD and hypomania) causes clinically significant distress or impairment…

Diagnostic Coding Specifiers for BP-I and BP-II*:

Current or Most Recent Episode* Severity: Mild, Moderate, Severe* With psychotic features In partial remission, full remission* With anxious distress* With mixed features* With rapid cycling* With melancholic features With atypical features With mood-congruent psychotic

features* With mood-incongruent psychotic

features* With catatonia* With peripartum onset* With seasonal pattern*

Other Specified Bipolar and Related Disorder This Dx is used when Sxs of Bipolar Disorder

Spectrum are present, but do not meet criteria for any one in particular.

Clinicians can specify the reasons why Sxs do not meet criteria for other BPs, by using the other specified designation: Short-duration hypomanic episodes (2-3

days) and MD episodes Hypomanic episodes with insufficient Sxs

and MD episodes Hypomanic episode without prior major

depressive episode Short-duration cyclothymia (less than 24

months)

DSM-5 Model

What is the prognosis of child diagnosed with bipolar disorder?

http://www.youtube.com/watch?v=WYxO8IjpF9k

Dr. Gabrielle Carlson (Feb. 2013)VIDEO

Aim 2 & 3• Highlight major historical

developments in the scientific understanding of bipolar disorder

• Illustrate the evolution of bipolar diagnosis on the DSM

History - Hippocrates (460–337 BC)

Probably the first to systematically describe melancholia and mania.

Formulated the first classification of mental disorders: melancholia, mania, and paranoia.

Suggested a connection between mania and melancholia using humoral theories.

‘‘Black bile’’ could generate a variety of phenomena, depending on the temperature.

Marneros , A. & Angst, J. (2000)

History – Relationship between Manic and Melancholic States

Aretaeus of Cappadocia (2nd Century AD) - considered the ‘‘father of bipolar disorder.’’ First to clearly described mania and melancholia as being two components of one disease. ‘‘It appears to me that melancholy is the commencement and a

part of mania.’’ Jean-Pierre Falret (1854) - “folie circulaire” - formally

described the sequential change from mania to melancholia and vice versa and the symptom-free interval in between as a separate disease.

Jules Baillarger (1857) - ‘‘folie _a double forme’’ - mania and melancholia changed into one another, but the interval between was felt to have no meaning.

Falret and Baillarger (1894) - credited for discovering the bipolar disorder.

Marneros, A. & Angst, J. (2000)

History – Manic-depressive Illness

Emil Kraepelin (1921) Dichotomized the ‘‘endogeneous’’

psychoses into ‘‘dementia praecox’’ and manic-depressive insanity.

Conducted systematic observations of over 900 patients suffering from "manic-depressive insanity“.

First to raise the possibility that children could develop mania.

Children – prevalence rate higher among 15-20 y/o and only 0.4% in children < 10 y/o.

Kraepelin E. (1921). “Manic-depressive insanity and paranoia”

History – Unipolar vs. Bipolar

Karl Leonhard (1957) – classified Unipolar Disorder (major depressive disorder) and Bipolar Disorder.

Research by Karl Leonhard (German), Jules Angst (Swiss), and Carlo Perris (Scandinavian) supported: The nosology and family hx

differentiation between unipolar and bipolar.

There is no unanimity even now about the validity of these separations.

Manic Depression in US Psychiatry was heavily

influenced by Psychoanalytic theories and the theories of Adolf Meyer

Meyer (first half of 1900s) emphasized the interaction between an individual’s biologic and genetic characteristics and the social environment.

This notion is included in the DSM-1 (1952), which includes a diagnosis of ‘‘manic-depressive reaction.’’

Kanner L. (1935).

DSM-I (1952)DEPRESSION Psychotic Disorders

Involutional psychotic reaction Affective reactions Manic depressive reactions

Manic depressive reaction, manic type Manic depressive reaction, depressed type Manic depressive reaction, other

Psychotic depressive reaction Psychoneurotic Disorders

Depressive reaction

DSM-II (1968)

Psychoses Not Attributed To Physical Conditions 296 Major affective disorders

Manic-depressive illnesses Manic-depressive illness, manic type Manic-depressive illness, depressed

type Manic-depressive illness, circular type Manic-depressive illness, circular type,

manic Manic-depressive illness, circular type,

depressed

US vs European Countries Results from the landmark US/UK comparison study

(1972): Indicated that Bipolar disorder in the US was

markedly under-recognized as compared with European diagnostic systems.

Sparked an increased interest in developing systematic/operational diagnostic criteria to improve the reliability of diagnosis.

Operationalized diagnostic criteria were developed: Research Diagnostic Criteria DSM-II-R

Cooper, J. E., Kendall, R. E., Gurland, B. J., et al. (1972)

Developing a diagnostic criteria for children First attempt to develop diagnostic criteria

for manic-depressive psychosis in children was done by Anthony and Scott (1960): Reviewed 28 papers (1884-1954) and

created a 10 criteria for manic Only 3 in 60 cases met the developed

criteria. These criteria basically eradicated the

diagnosis of manic depression in children, until subsequent studies using Lithium appeared.

Anthony, E. J. & Scott, P. (1960)

Cont…Developing a diagnostic criteria for children

Psychopharmacologic studies in the 1970s restored the concept of childhood-onset bipolar disorder

Weinberg and Brumback (1976) Davis (1979) Coll & Bland, 1979 (CANADA) 1. Euphoric or irritable mood, AND 2. Three or more of the following, which should reflect a change from the child’s normal behavior: a. hyperactive, intrusive behavior b. push of speech c. flight of ideas d. grandiosity e. decreased amount of sleep or unusual pattern of sleep f. distractibility g. symptom duration of 1 month

1. affective storms, defined as a loss of control that is highly intense, disruptive, and transient 2. significant family histories of affective disturbances 3. mental, verbal, and physical hyperactivity 4. high level of distractibility 5. rapid talk or a ‘‘rapid progression of interest’’

1. Euphoria (either 1 or both [1-2] and 3 or more from 3-8) a. Denial of problems or illness b. Inappropriate feelings of well-being, inappropriate cheerfulness 2. Irritability and/or agitation 3. Hyperactivity, intrusiveness 4. Push of speech, garrulousness 5. Flight of ideas 6. Grandiosity (may be delusional) 7. Sleep disturbance (decreased sleep and unusual sleep pattern) 8. Distractibility (short attention span).

Weinberg, W. A. & Brumback, R. A. (1976); Davis, R. E. (1979); Coll, P. G. & Bland, M. B. (1979)

DSM-III (1980) & DSM-III-R (1987)

“Manic-depression” substituted by “Bipolar”

Mania symptoms required to be present for a week.

DSM-III-R Bipolar Disorder-Mixed, Bipolar Disorder-Manic, Bipolar Disorder-Depressed, Bipolar Disorder-Not Otherwise Specified, and Cyclothymia.

DSM-IV & DSM-IV-R (1987) DSM-IV to DSM-IV-TR - no major

changes. DSM-5

Criterion A for manic and hypomanic episodes includes an emphasis on changes in activity and energy as well as mood.

Bipolar I, mixed episode eliminated; instead a new specifier is included: “with mixed features”.

Anxious Distress Specifier (new) NOS eliminated; instead “Other

Specified Bipolar and Related Disorder”

Aim 4• Review the literature on pediatric

bipolar disorder

Bipolar Disorder Runs in Families…

BP Runs in Families… One of the most hereditable psychiatric conditions

as evidenced by twins and other studies. Higher concordances for BP among MZ twins,

compared with DZ twins; estimated heritability >80% (Craddock and Jones, 1999).

If one parent has BP, the risk of a child to have BP is between 10-25%; higher risk if both parents have BP (Goldstein et al., 2010; Goldwin & Jamison, 2007).

Risk increases during young adulthood (Birmaher et al., 2009) .

First-degree relatives of youth with BP are at higher risk of developing BP…compared with families of health children or children with MDD or ADHD (Geller et al., 2006)

Genetics The study with the largest sample of

pedigrees with BP found: Two chromosomal regions that meet stringent

criteria for genomewide significance (P<.05) on chromosomes 17q and 6q, and

Three regions with suggestive evidence of linkage (P<.10) on chromosomes 2p, 3q, and 8q.

Sample: 1,152 individuals and 250 families; 10 sites.

Dick et al., 2003

Perinatal Risk Factors

Prenatal exposure to drugs or birth complications, increase the risk of having a child with BP diagnosis more than six-fold (Pavuluri et al., 2006).

BP Brain Plasticity Voxelwise meta-analysis, included 21

studies, 660 BD patients and 770 healthy control subjects (Bora et al., 2010). Found gray matter deficits in BD, but only

in two regions (right fronto-insular and left anterior cingulate).

Another studies reported cerebellar vermal size was smaller in multiple-episode patients with BP compared with first-episode and healthy subjects (Del Bello et al. 1999, ; Mills et al. , 2005)

Cont…Brain Plasticity

(de Oliveira et al., 2009; Kauer-Sant’Anna et al., 2009)

Serum Brain-Derived Neurotrophic Factor (BDNF) levels were significantly lower in both medicated and unmedicated patients with bipolar disorder, compared with healthy controls (P<0.0001). 22 adults with bipolar disorder; medication-free, 22 medicated adults with bipolar disorder, and 22 healthy controls

Another study reported that BDNF levels were decreased only in patients with bipolar disorder with late stage of illness.

Cont…Brain Plasticity A study compared the

progression of abnormalities in white matter tract integrity 10 children with BP; 7

children at risk for BP (first-degree relative with BP); 8 healthy controls

Compared with health children, children with BP exhibited decreased fractional anisotropy (FA) in right and left superior frontal tracts, left orbital frontal, and right corpus callosum (P<0.05)

Frazier, J. A. et al. 2007

Cont … Brain Plasticity

Frazier, J. A. et al. 2007

Cont … Brain Plasticity

Frazier, J. A. et al. 2007

Pediatric BD Onset > 50% of adults with bipolar report

onset of Sxs in childhood (Perlis et al., 2009).

Age 15 to 19 years old (Goodwin & Jamison, 2007).

Average age of onset in US is reported as 19.4 years versus 25.2 years in European samples (Post et al., 2008).

However, BP has a lifelong onset; condition could flourish in children and adults as old as over 60 y/o

Prevalence 1996 – BP was the least frequent diagnosis (in-

patient children), BUT in 2004 – was the most frequent diagnosis (Blader & Carlson, 2007).

Based on a recent meta-analysis the rate of BP spectrum disorders in youth is 1.8%, and for BP-I 1.2%; no significant rate difference among UK and US (Van Meter, Moreira, Youngstrom, 2011). 1-3% prevalence rate (Birmaher, 2013)

This is consistent with other studies (Stringaris et al., 2010; Kozloff et al., 2010)

Bipolar I and Bipolar NOS are more common in children than Bipolar II (Birmaher et al., 2006)

Depression or Mania…Which Emerges First?

Depression seems to flourish first in youth, and the rate of conversion to BP is 32%–50% (Ghaemi, 2008; Lewinsohn et al., 2000).

This is higher than the conversion rate for adults (12.6% to 20%) (Akiskal et al., 1995; Ghaemi, 2008).

A prospective study followed 1,037 subjects from childhood through age 26 (Kim-Cohen et al., 2003). Clinical interviews at age 11, 13, 15, 16, 18, 21, and 26. Diagnoses between ages 11 and 15 for those becoming

manic included: conduct disorder (38%), anxiety (35%), and depression (20%).

Comorbidity Bipolar disorder is often accompanied by other

psychiatric disorders (20%-80%). Disruptive Behavior Disorders ADHD Anxiety Disorders Substance Abuse Disorders

Children vs. AdolescentsC. ADHD and Oppositional Defiant Disorder > common A. Conduct and Substance Abuse Disorders > common

Birmaher, 2013)

(Axelson et al., 2006)

Comorbidity – Anxiety Disorder

Common comorbidity in children and youth with BP: N=446, 7-17 y/o; BP 1=260, BP 2=32, BP

NOS=154 At least 1 lifetime AD (44%), most commonly

separation anxiety (24%), and GAD (16%) 2 or more AD, nearly 20% AD predated the onset of BP; those with BP 2

were more likely to have comorbid AD, longer duration of sxs, more severe ratings of depression, and family hx of depression.

Sala, R. et al. (2010)

Comorbidity: Conduct Disorder & Psychosis

CD High rates of conduct disorder reported among youth

with BP (Weller et al., 2004). 42%-69% of clinic-referred youth with BP also had

CD.

Psychosis Co-occurrence rate is between 16% to 60% (Pavuluri et al.,

2004) Delusional grandiosity, persecutory and religious

delusions, hallucinations, and thought disorder.

Comorbidity - ADHD Most common comorbid condition among youths

with BP; studies report 60%-98% rates (Evans et al., 2005; Geller et al.,1998).

Uncommon in children with ADHD: (Hassan, A. et al., 2011) UK sample: n=200, 170 M, 30 F; 6-18 y/o,

mean 11.15, SD 2.95 Only a 9-year-old boy, met diagnostic criteria

for both ICD–10 hypomania and DSM–IV bipolar disorder not otherwise specified.

Main Features of BP in Youth Tend to show mixed episodes rather than distinct

episodes of mania and depression. Tend to describe their mood episodes as feeling “tired but wired”(Biederman et al., 2004).

Sample: 298 children with BP, none with clear-cut mania or depressive episodes.

Tend to cycle fairly frequently from one mood state to the next. Family members describe it as “mood swings” (Biederman et al., 2004; Geller et al., 2000).

Onset – typically develops slowly over time. Often show chronic and continuous mood problems.

Cost to Society and Individuals with BP

High rates of suicide, substance abuse, and neurocognitive deficits associated with poor school functioning (Pavuluri et al 2005; Tolan and Dodge 2005).

Risk of suicide attempt is increased by severe features of BP illness and comorbidity (Goldstein et al., 2005).

Nearly one-half of individuals with bipolar disorder attempt suicide (Jamison, 1999).

Worldwide, it currently accounts for 14 million years of healthy life lost owing to mortality and disability, nearly as much as schizophrenia (WHO, World Health Report 2002).

Does BP exist in younger children? Duffy (2007) – argues lack of supporting evidence

for the hypothesis that BD, as currently defined, exists in very young children. In some cases, there may be nonspecific

prodromal symptoms, including anxiety and sleep and cognitive disturbances antecedent to the manifestation of BD.

BD often starts in adolescence with an episode of major depression.

Duffy, A. (2007)

• Present a new theoretical model for pediatric bipolar disorder

Aim 5

Core Patterns of BP Disorder

Malhi, G. S. et al 2009

Stratified Model of BP Disorder

Malhi, G. S. et al 2012

Functional Neuroanatomy of BP: A Consensus Model

Strakowski, S. M. et al (2012). Schematic of the proposed ventrolateral and ventromedial prefrontal networks underlying human emotional control [adapted with permission from Oxford University Press (17)]. G. = globus; PFC = prefrontal cortex; OFC = orbitofrontal cortex; BA = Brodmanns area.

Pediatric Bipolar Disorder ModelNicasio, A. (2013)

References Akiskal, H.S., (1995). Toward a temperament-based approach to depression: implications for neurobiologic

research. Adv. Bio-chem. Psychopharmacol. 49, 99–112. Anthony, E. J., Scott, P. (1960). Manic-depressive psychosis in childhood. J Child Psychol Psychiatry,1, 53–72. Axelson, D., Birmaher, B., Strober, M., Gill, M. K., Valeri, S. Chiappetta, L., … Keller, M., (2003).

Phenomenology of Children and Adolescents With Bipolar Spectrum Disorders. Arch Gen Psychiatry, 63, 1139-1148.

Biederman, J., Mick, E., Faraone, S. V., Van Patten, S., Burback, M., & Wozniak, J. (2004). A prospective follow-up study of pediatric bipolar disorder in boys with attention-deficit/hyperactivity disorder. Journal of Affective Disorder, 82(1), 17-23.

Birmaher, B., Axelson, D., Strober, M., et al. (2006). Clinical course of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry, 63(2),175-183.

Birmaher, B., Axelson, D., Goldstein, B., Strober, M., Kay Gill, M., Hunt, J., . . .Keller, M. (2009). Four-Year Longitudinal Course of Children and Adolescents With Bipolar Spectrum Disorders: The Course and Outcome of Bipolar Youth (COBY) Study. Am J Psychiatry, 166(7), 795-804.

Birmaher B., Goldstein B. I., Axelson D. A., Monk K., Hickey M. B., Fan J., . . . Kupfer D. J. (2013). Mood lability among offspring of parents with bipolar disorder and community controls. Bipolar Disord, 15(2). doi: 10.1111/bdi.12060.

Blader, J. C., & Carlson, G. A. (2007). Increased rates of bipolar disorder diagnoses among U.S. child, adolescent, and adult inpatients, 1996-2004. Biological Psychiatry, 62, 107-114

Bora E., Fornito, A., Yucel, M., Pantelis, C. (2010). Voxelwise meta-analysis of gray matter abnormalities in bipolar disorder. Biol. Psychiatry 67, 1097–1105. doi: 10.1016/j.biopsych.2010.01.020

Coll, P. G., Bland, M. B. (1979). Manic-depressive illness in adolescence and childhood: review and case report. Can J Psychiatry, 24, 255–62.

Cooper, J. E., Kendall, R. E., Gurland, B. J., et al. (1972). Psychiatric diagnosis in New York and London: a comparative study of mental hospital admissions. Institute of Psychiatry, Maudsley Monographs, p20.

References Craddock, N. & Jones, I. (1999) The genetics of bipolar disorder. Journal of Medical Genetics, 36, 585-

594. Davis, R. E. (1979). Manic-depressive variant syndrome of childhood. Am J Psychiatry,136, 702– 6. de Oliveira, G. S., Cereser, K. M., Fernandes, B. S., et al. (2009). Decreased brain-derived neurotrophic

factor in medicated and drug-free bipolar patients. J Psychiatr Res., 43(14), 1171-1174. Del Bello, M. P., Strakowski, S. M., Zimmerman, M. E., et al. (1999). MRI analysis of the cerebellum in

bipolar disorder: a pilot study. Neuropsychopharmacology, 21(1), 63-68. Dick, D. M., Foroud, T., Flury, L., Bowman, E.S., Miller, M. J., Rau, N. L., Moe, P. R. , et al (2003).

Genomewide linkage analysis of bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health genetics initiative. Am J Hum Genet 73,107–114.

Duffy, A. Does Bipolar Disorder Exist in Children? A Selected Review. Can J Psychiatry, 52, 409-417. Evans, D. L., Foa, E. B., Gur, R. E., Hendin, H., O'Brien, C. P., Seligman, M. E., et al. (2005). Treating and

preventing adolescent mental health disorders: What we know and what we don't know: A research agenda for improving the mental health of our youth. New York: Oxford University Press.

Frazier, J. A., Breeze, J.L., Papadimitriou, G., Kennedy, D. N., Hodge, S. M., Moore, C. M. …Makris, N., (2007). White matter abnormalities in children with and at risk for bipolar disorder. Bipolar Disord, 9(8), 799-809.

Geller, B., Williams, M., Zimerman, B., Frazier, J., Beringer, L., Warner, K. L. (1998). Prepubertal and early adolescent bipolarity dif-ferentiate from ADHD by manic symptoms, grandiose delusions, ultrarapid or ultradian cycling. J Affect Disord, 51, 81-91,

Geller, B., Bolhofner, K., Craney, J. L., Williams, M., DelBello, M. P., Gundersen, K (2000). Psychosocial functioningin a prepubertaland early adolescent bipolar disorder phenotype. J Am Acad Child Adolesc Psychiatry, 39, 1543– 1548.

Geller, B., Tillman, R., Bolhofner, K., Zimerman, B., Strauss, N. A., Kaufmann, P. (2006). Controlled, blindly rated, direct-interview family study of a prepubertal and early-adolescent bipolar I disorderphenotype: morbid risk, age at onset, and comorbidity. ArchGen Psychiatry, 63,1130-1138.

References Ghaemi, S. N., (2008). Treatment of rapid-cycling bipolar disorder:Are antidepressants mood

detabilizers? The American Journal of Psychiatry, 165(3), 300-302 Goldstein, B. I., Shamseddeen, W., Axelson, D.A., Kalas, C., Monk, K., Brent, D.A., Et al. (2010). Clinical,

demographic, and familial correlates of bipolar spectrum disorders among offspring of parents with bipolar disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 49, 388-396.

Goldstein, T. R., Birmaher, B., Axelson, D., Ryan, N. D., Strober, M. A., Gill, M.K., …Keller, M. (2005). History of suicide attempts in pediatric bipolar disorder: factors associated with increased risk. Bipolar Disord, 7(6), 525-535.

Goodwin, F. K., & Jamison, K. R., (2007). Manic depressive illness: bipolar disorders and recurrent depression. 2nd edition. New York: Oxford University Press, p. 3.

Hassan, A., Agha, S. S., Langley, K. & Thapar, A. (2011). Prevalence of bipolar disorder in children and adolescents with attention-deficit hyperactivity disorder. The British Journal of Psychiatry, 198, 195-198. DOI: 10.1192/bjp.bp.110.078741

Jamison, K. R. (1999). Night falls fast: understanding suicide. Vintage Books, New York. Kanner L. (1935). Child psychiatry. Springfield(IL): CC Thomas, p. 502–7. Kauer-Sant’Anna, M., Kapczinski, F., Andreazza, A. C., et al. (2009). Brain-derived neurotrophic factor and

inflammatory markers in patients with early- vs. late-stage bipolar disorder. Int J Neuropsychopharmacol,12(4), 447-458.

Kim-Cohen, J., Caspi, A., Moffitt, TE. ., et al (2003). Prior juvenile diagnoses in adults with mental disorder: developmental follow-back of a prospective-longitudinal cohort. Archives of General Psychiatry; 60, 709–17.

Kozloff, N., Cheung, A. H., Schaffer, A., Cairney, J., Dewa, C., Veldhuizen, S., … Anthony, J. (2010). Bipolar disorder among adolescents and young adults: Results from an epidemiological sample. Journal of Affective Disorders, 125(1-3), 350-354.

Kraepelin E. (1921). Manic-depressive insanity and paranoia [Barclay M, trans.] Edinburgh (UK): Livingstone.

Lewinsohn, P. M., Klein, D. N., & Seeley, J. R. (2000). Bipolar disorder during adolescence and young adulthood in a community sample. Bipolar Disorders, 2(3), 281-293. DOI: 10.1034/j.1399-5618.2000.20309.x

References Malhi, G. S., Bargh, D. M., Cashman, E., Frye, M. A., Gitlin, M. (2012). The clinical management of bipolar

disorder complexity using a stratified model. Bipolar Disord, 14(2), 66-89. doi: 10.1111/j.1399-5618.2012.00993.x.

Malhi, G. S., Adams, D., Lampe, L. et al. (2009). Clinical practice recommendations for bipolar disorder. Acta Psychiatrica Scandinavica, Supplementum,119(439), 27–46

Marneros, A., Angst, J. (2000). Bipolar disorders: roots and evolution. In: Marneros A, Angst J, editors. Bipolar disorders: 100 years after manic depressive insanity. AA Dordrecht (The Netherlands): Kluwer Academic Publishers, p. 1–35.

Pavuluri, M. N., Herbener, E. S., Sweeney, A. J. (2004). Psychotic features in pediatric bipolar disorder. J Affect Disord, 80(19), 19-28.

Pavuluri, M. N., Henry, D. B., Nadimpalli, S. S., O’Connor, M. M., Sweeney, J. A. (2006). Biological risk factors in pediatric bipolar disorder. Biol Psychiatry, 60(9), 936-41.

Pavuluri, M. N., Birmaher, B., Naylor, M., (2005). Pediatric Bipolar Disorder: Ten Year Review. Journal of American Academy of Child and Adolescent Psychiatry, 44 (9), 846-871.

Post, R. M., Luckenbaugh, D. A., Leverich, G. S., Altshuler, L. L., Frye, M. A., Suppes, T. . . . Walden, J. (2008). Incidence of childhood-onset bipolar illness in the USA and Europe. Br J Psychiatry, 192(2), 150-1. doi: 10.1192/bjp.bp.107.037820.

Mills, N. P., Del Bello, M. P., Adler, C. M., et al. (2005). MRI analysis of cerebellar vermal abnormalities in bipolar disorder. Am J Psychiatry, 62(8), 1530-1532.

Sala, R., Axelson, D., Castro-Fornieles, J., Goldstein, T., Goldstein, B., Ha, W., … Birmaher, B. (2010). Comornid anxiety in children and adolescents with Bipolar spectrum disorders” Prevalence and clinical correlates. Journal of Clinical Psychiatry, 71(10), 1344-1350.

Sala, R., Axelson, D., Castro-Fornieles, J., Goldstein, T., Goldstein, B., Ha, W., … Birmaher, B. (2012). Factors associated with the persistence and the onset of new anxiety disorders in youth with bipolar spectrum disorders. J Clin Psychiatry, 73(1), 87-94. doi: 10.4088/JCP.10m06720. Epub 2011 Dec 13.

References Strakowski, S. M., Adler, C. M., Almeida, J., Altshuler, L. L., Blumberg, H.P., Chang, K. D., …Townsend, J. D.

(2012). The functional neuroanatomy of bipolar disorder: a consensus model disorder: a consensus model. Bipolar Disord, 14, 313–325.

Stringaris, A., Santosh, P., Leibenluft, E., Goodman, R. (2010). Youth meeting episodic symptom and impairment criteria for bipolar disorder: an epidemiologic inquiry. Journal of Child Psychology and Psychiatry, 51, 31-38.

Tolan, P. H., Dodge, K. A. (2005). Children’s Mental Health as a Primary Care and Concern: A System for Comprehensive Support and Service. Am Psychol, 60, 601–614.

Van Meter, A. R., Moreira, A. L., Youngstrom, E.A. (2011). Meta-analysis of epidemiologic studies of pediatric bipolar disorder. J Clin Psychiatry, 72(9), 1250-6. doi: 10.4088/JCP.10m06290.

Weller, E.B.; Weller, R.A.; Danielyan, A.K. (2004). "Mood disorders in prepubertal children." In Wiener, J.M., Dulcan, M.D. (editors). Textbook of child and adolescent psychiatry. Washington, D,C.: American Psychiatric Publishing: 418.

Weinberg WA, Brumback RA. Mania in childhood: case studies and literature review. American Journal of Disorders in Children 1976;130:380– 5.

World Health Organization (WHO). (2002). The World Health Report 2002: Reducing Risks, Promoting Healthy Life. Geneva: World Health Organization.