- Paediatric bipolar disorder (PBD) is characterized by recurrent episodes of alternating moods between mania/hypomania and depression in children. It is associated with negative outcomes like academic and social difficulties. - The prevalence of PBD is estimated to be 1-1.8% in children and 0.2-0.4% in adolescents. It commonly co-occurs with disorders like ADHD, oppositional defiant disorder, anxiety disorders, and substance abuse. - Diagnosis involves using rating scales and interviews to assess mood episodes, symptoms, impairment, and risk factors while ruling out medical and neurological conditions. A thorough family and developmental history is also important.

1. PAEDIATRIC BIPOLAR
DISORDER PBD
DR. Reham Abd Elmohsen
Senior Consultant psychiatrist
Consultant child and adolescent
psychiatrist

2. DEFINITION
◦ presence of recurrent episodes of alternating moods, manic and
hypomanic to a depressed mood in children. No sexual predilection, more
males referred for treatment.
◦ associated with negative outcomes, difficulties in academic achievement
and interpersonal relationships, leading to expulsion or peer rejection.
psychosis associated with mania. increased use of health services and high
rates of suicide attempts.
◦ poor eating habits and an increased likelihood of substance abuse,
including nicotine dependence, associated with serious health
consequences.
◦ hard to distinguish PBD from other disorders that have similar symptoms.
◦ childhood onset of bipolar symptoms may have a course of illness more
severe, chronic, and refractory.
◦ increased risk of mixed mood states (combined symptoms of depression
and mania simultaneously) and rapid cycling (≥3 episodes of mania in 1
year).

3. Epidemiology
◦ (PBD) is an affective disorder affecting 1-1.8%. The overall prevalence
of BPI in adolescents is approximately 1%, whereas the prevalence in
children is 0.2–0.4%. 2011 meta-analysis
◦ The second most common age group at presentation is 15–19 years.
◦ 20% of adults with bipolar disorder had symptoms beginning in
adolescence. WHO survey
◦ 20% of youths in whom a major depressive disorder was previously
diagnosed develop symptoms consistent with a manic state at a later
age.

4. ◦ The clinical diagnosis of PBD increased approximately 40-fold during 1994–2003
to US mental health providers . These data coincide with the transition from DSM-
III-R to DSM-IV(added bipolar II and BP-NOS categories), changing diagnostic
criteria may contribute to the increase.
◦ However, the increasing rates may partly be due to increased awareness of BP and
better access to healthcare, rather than increasing disease prevalence.
◦ The National Comorbidity Survey for Adolescents 6.2% lifetime prevalence of BP
disorders, as they included subthreshold BP in a sample of 10,148 adolescents
between 13 and 17 years of age.
◦ community sample of US adolescents reported that 2.5% of youth met the criteria
for lifetime bipolar I or II disorder, 1.7% met the criteria for mania.
◦ The 12-month rates of mania with and without depression were 2.2 and 1.3%,
Canadian study in 2010

7. Bipolar spectrum DSM-5
◦ Bipolar I the occurrence of at least one lifetime
manic episode; the manic episode may occur
before or after hypomania, depression or a
mixture of these states, or the disorder can
remit and the person can function as normal.
◦ ICD requires multiple episodes of mania to
confirm a diagnosis of bipolar I.

8. ◦ Bipolar II the symptoms have met full criteria for both
a hypomanic episode and a major depressive episode
at some time.
◦ either or both of the hypomanic and depressive
episodes can carry the ‘mixed specifier’. If the
individual ever displays a full manic episode, the
diagnosis changes to bipolar I disorder.
◦ DSM-5 added the condition ‘hypomania under
antidepressant treatment’ explicitly as a form of
bipolar II disorder – provided that mood/energy
problems continue at fully syndromal levels beyond
the physiological effect of the treatment.

9. ◦ Cyclothymic hypomanic and depressive symptoms for
an extended period of time ( more than 1 year in
youths),with symptoms present more than 50% of the
time and not the individual not being symptom free for
more than 2 months.
◦ cyclothymic disorder is difficult to diagnose:
◦ the hypomanic symptoms cannot become too severe or
pronounced; full mania results in the diagnosis of
bipolar I. By the same token, the depressive symptoms
cannot progress to a full-blown major depressive
episode; if so, it either results in the diagnosis of bipolar
II or a major depressive episode, perhaps with a mixed
specifier.

10. ◦ Other specified bipolar & related disorders DSM-5
renamed BP-NOS as OS-BRD. emphasizing a change in
energy as a key feature and adding the mixed specifier.
◦ In addition to three other prototypes:
◦ (short-duration hypomanic episodes of 2–3 days,
◦ hypomanic or manic episodes with an insufficient
number of symptoms
◦ recurrent hypomanic episodes without history of major
depressive episode),
◦ OS-BRD also adds a fourth prototype of short duration
cyclothymia for presentations lasting less than 12
months in youths.

11. ◦ DMDD, that evolved from severe mood dysregulation (SMD)
which was added to slow a growing tendency to misdiagnose
troubled, disruptive kids with bipolar disorder.
◦ symptoms overlap with ODD. The core feature of DMDD is
chronic, severe persistent irritability. This severe irritability has
two prominent clinical manifestations, frequent temper
outbursts. These outbursts typically occur in response to
frustration and can be verbal or behavioral (aggression against
property, self or others). with a family history of ADHD, CD
or odd.
◦ the longitudinal course of the core symptoms is the central
feature differentiating DMDD and PBD: Bipolar disorders are
episodic; DMDD is not.
◦ In DSM-5, the DMDD diagnosis cannot be assigned to someone
who has ever experienced a full-duration hypomanic or manic
episode(irritable or euphoric) or who has ever had manic or
hypomanic symptoms lasting more than 1 day.

12. Pathophysiology
◦ Smaller subfield hippocampal volumes impact long term
functioning in Adolescent.
◦ Alterations in functional connectivity of areas of the brain
involved in executive functioning, decision making –
default and salience networks.
◦ The clinical implications of impaired default mode and
salience network functioning in bipolar disorder may be
helpful in both diagnosis and treatment of mania
especially in the presence of co-morbid ADHD as well as
possible markers of the disorder.

13. Cognitive and neurodevelopmental factors
◦ In Australia, use of ultra–high-risk criteria for bipolar disorder, bipolar at-risk (BAR),
identification of persons prior to the onset of mania/hypomania.
◦ magnetoencephalography (MEG), to look at preattentive auditory dysfunction as a
potential trait marker of severe bipolar disorder symptoms. reflected by the presence
of reduced pitch-MMNm responses.
◦ Mood lability may be a result or the cause of reduction in grey matter volume and
decreased amygdala and prefrontal functional connectivity.
◦ why some youths experience chronic irritability and thus anticipate or trigger, by their
behaviors, negative social interactions with others (eg, rejection) by misinterpreting the
emotional valence of others and, specifically, facial emotional expression. abnormal
neural activation for faces with negative emotions along with face-processing deficits.

14. ◦ cognitive inflexibility measured using fMRI (a lack of appropriate activation in areas such as the
(right) inferior frontal gyrus and caudate in BPD, chronic irritability, and youths who had ADHD) .
◦ resting state connectivity studies, facilitate increased appreciation of possible modulating
pathways (particularly in the amygdala) that connect several brain regions to work in unison to
regulate thoughts, feelings, and behaviors.
◦ An association of neurotransmitters to modify and regulate brain activity:
◦ Serotonin - Mood (happy, sad, euthymic) Dopamine - Pleasure (hedonia, anhedonia)
◦ Norepinephrine - Alertness, energy level (lethargy, frenzy, vigilance)
◦ Acetylcholine - Memory and cognition
◦ GABA - Inhibition of CNS neurons Glutamate - Excitation of CNS neurons
◦ Bipolar Prodrome Symptom Interview and Scale-Prospective (BPSS-P) total score discriminated
BPI/BPII/cyclothymia from depression spectrum patients

15. ◦ potential abnormalities in the corpus callosum myelination and enlarged ventricles with an
increased number of hyperintensities. amygdala, decreased protein kinase in platelets, and
dopamine D4 receptor genotype and abnormalities of the dopamine transporter gene SLC6A3.
◦ use of medications that facilitate the regulation of neurotransmitters as well as receptor
sensitivity and perhaps other neurochemical modulators to restore normal mood and cognition.
◦ Meditation and deep relaxation, regular exercise, may also indirectly modulate receptor
sensitivity and resting state connectivity as well as neurotransmitter levels impacting
endogenous opioid and nicotinic receptor function.
◦ youth with mania had a reduction in Young Mania Rating Scale (YMRS) score with increased
brain activity in the ventrolateral prefrontal cortex also the left inferior frontal gyrus. This speaks
to the effect of medication in possibly decreasing impulsive risk taking behaviors in those with
bipolar disorder.

16. ◦
◦ Preschool children with early behavioral disinhibition and decreased frustration
tolerance greater risk for bipolar disorder in adolescence or adulthood, as this may
reflect underlying early abnormalities of temperament that reflect increased risk for
both bipolar disorder and ADHD.
◦ Emotion processing impaired because of a lack of flexibility in thought processing.
◦ neurodevelopmental delays in early-onset bipolar disorders in preschool-aged children
, as well as in their "unaffected" siblings. These delays occur in language, social, and
motor development approximately 10-18 years before affective symptoms appear.
◦ Adolescents who had early developmental antecedents were at a higher risk of
developing psychotic symptoms.
◦ (IQ) lower in patients with early-onset bipolar disorder (mean full-scale IQ, 88.8) than in
patients with unipolar depression (mean full-scale IQ, 105.8).
◦ difference in verbal IQ and performance IQ in patients with bipolar disorder.
◦ patients with severe bipolar disorder had a mean IQ lower than patients with mild-to-
moderate forms of the disorder.

17. Family risk
◦ Adolescents who have onset of true mania with childhood-associated symptoms, are at a greater
genetic risk (family loading) for BPI than adolescents with more adult-related psychotic symptoms.
◦ high-risk offspring (defined by having 1 parent with confirmed bipolar disorder) had an increased
lifetime risk of a broad spectrum of disorders, including bipolar disorder , major depressive disorder,
anxiety, sleep, sud, ADHD). Offspring from lithium-nonresponsive parents specifically developed
psychotic disorders.
◦ 14% concordance rate in dizygotic twins and a 65% concordance rate in monozygotic twins. The risk
for bipolar disorder in the offspring of a couple in which 1 parent has bipolar disorder was estimated
to be 30-35%. For an offspring of a couple in which both parents have bipolar disorder, the risk was
approximately 70-75%. Children with bipolar disorder show a higher incidence of psychotic features
than older adolescents or adults.
◦ Socioeconomic status lower in families of children with mania and adolescents with childhood-onset
mania . Increased energy was twice as common in childhood mania , euphoria was most common in
adolescents with childhood-onset mania, and irritability was least common in adolescents with
adolescent-onset mania.
◦ adolescent-onset mania abused psychoactive drugs, impaired parent-child relationships. in some
youth ADHD symptoms marker for juvenile-onset mania.
◦ suggest that a subtype of bipolar disorder may exist. This subtype may have a high familial
transmission rate, and affected individuals present with childhood-onset of mania symptoms
suggestive of ADHD. (Faraone et al )

18. ◦ Environmental factors (behavioral, educational, family related, toxic, substance abuse.
◦ Wilens et al (2008) implicated smoking as a potential causal element in patients with bipolar
disorder. Family conflict and substance abuse increase this risk.
◦ higher risk of suicide than adolescents with other behavioral illnesses. suicide attempts in males
occur less often, as they tend to be suicide completers. In females, the disorder is also
associated with social rejection from female peers.
◦ Another risk factor for suicide in youths is legal problems. as the disinhibited risk-taking
behaviors easily lead to legal problems
◦ Steiner estimated that 2% of incarcerated juveniles have bipolar I disorder (BPI), whereas 4%
have bipolar II disorder (BPII).

19. Lifestyle risk factors
◦ Eating patterns emerge as potent lifestyle-related risks for overweight/obesity as early as
preadolescence, which may be a result of dysfunctional reward mechanisms contributing
to poor food choices and overeating.
◦ Obesity is significantly more common among individuals with bipolar disorder than
healthy controls. Preliminary findings from a pediatric longitudinal sample found that 42%
of participants with PBD were overweight/obese.
◦ Obesity appears to be a nonspecific risk factor, as it is also associated with depression,
psychosis, heart disease and cancer.

20. Symptoms Predictors
◦ Biederman et al noted that the combination of conduct disorder and major depression in adolescence
could be predictive of bipolar disorder in a 4-year follow-up assessment of those patients.
◦ children with ADHD who later develop bipolar disorder have increased rates of other psychiatric
conditions, including ODD. combination of ADHD with ODD, correlated with a future onset of bipolar
symptoms, (including depression and psychosis )at a rate of 7%, whereas there was a 5% correlation
for ADHD alone.
◦ Overall, the combined symptoms of severe ADHD, unstable affect, and aggression may be predictive
of bipolar disorder later in life among children in whom ADHD is already diagnosed.
◦ School refusal- impaired sleep and (DBD)
◦ The strongest predictors baseline anxiety/depression with proximal affective lability and full or
subsyndromal manic symptoms
◦ In summary, sustained symptoms of conduct and impulse control problems may be warning signs of
a prepubertal onset of bipolar disorder.
Pediatric Bipolar Affective Disorder,medscape2018

21. Major co morbidity with PBD
◦ ADHD 62% -8.3% of youths with ADHD also met BP diagnosis. both ADHD and manic
symptoms appear to be distributed along a continuum rather than in categories or
distinct clusters flowing from the same developmental pathological process
◦ Oppositional Disorder. 53%
◦ psychosis 42%,
◦ Anxiety Disorder 27%
◦ Conduct Disorder. 19%
◦ Substance use Disorder and suicide risk in adolescents. 40%
◦ Epilepsy 8% inter ictal mania may be more prevalent

22. Differential diagnoses
◦Psychiatric Conditions
◦ (ADHD) may have a prodromal phase in early life that appears to be ADHD or
another behavioral disturbance or whether many simply have bipolar disorder
and comorbid ADHD. with a higher rate of familial transmission
◦ conduct disorder.
◦ Childhood-Onset schizophrenia or schizoaffective disorder,
◦ PTSD)
◦ Drug or alcohol abuse, or anxiety states (e.g., generalized anxiety
disorder, social anxiety disorder and Selective Mutism).

23. Self-esteem Inflated Deflated/irritable Inflated and/or
deflated
Inflated
and/or
deflated
Pleasure Euphoric in
mania
Dysphoric in
mixed or
depressed state
variable Often dysphoric
or euthymic
Pleasure in
violating
societal
norms,
especially if
not caught
Attention Distractible Distractible Distractible Normal to
vigilant
Hyperactivity Goal directed Variable Unproductive Goal
directed
Sleep Episodic
disturbances
Often poor due
to avoiding
Chronic poor
sleep; often late
Not known
to be

24. Manic Behaviors and Overlapping
Diagnoses

25. Differential Diagnosis
◦ Medical conditions
◦ Drugs: antidepr.- amphet.
Corticost.- sympathomimetics.
◦ Endocrine Disorders hyperthyroidism
◦ Neurologic conditions TBI- stroke
rt hemisphere lesions,
seizures- tumors

26. Diagnosis and assessment
◦ Brief rating scales combined with information about risk factors and prevalence, the
developmental course and common comorbidities are sufficient to rule PBD out in most
settings
◦ Semi structured interviews gold standard for assessing : KSADS- MINI-Kid
◦ Jacobson etal. developed a psychometrically informed framework for evaluating clinically
significant change, There are two parts to their definition: reliable change and moving
past a benchmark(energy and mood, identifying stressors and triggers, changes in drug
use and suicidal ideation
◦ Progress measures such as the Youth Top Problems scale can also be a method of
monitoring for relapse
◦ Clinical triggers such as family history, early-onset depression, antidepressant-
coincident mania, episodic mood lability, episodic aggressive behavior, psychotic
features and sleep disturbance should trigger a thorough evaluation of possible PBD.

29. Work up
◦ first step is to ensure that no other medical condition or alcohol use or abuse, including
substance-abuse
◦ sleep pattern
◦ Sexual and/or physical abuse is common with bipolar disorder, especially in very young children
(< 6 years) and particularly in individuals with comorbid (PTSD), psychosis, or conduct disorder.
◦ A positive family history of abuse may increase the risk for suicide.
◦ Polymorphism of the Val66Met BDNF gene may be associated with early experiences of
adversity and maladaptive rumination, increasing the risk of suicide for some individuals.
◦ Many persons with bipolar disorder exhibit excessive risk-taking behaviors, predisposing them
to injury or dehydration.

31. Integrated Approach
to Management
Pharmacotherapy
Psychotherapy
Pharmacotherapy

32. Approach Considerations
◦ Psychotherapy and psychopharmacology
◦ Hospitalization
◦ Baseline laboratory studies
CBC - Kidney F- Liver F- Thyroid F- electrolytes-ECG-Drug Level Monitoring
Family consent, patient assent, explaining condition and medication side effects
◦ Lithium salts
◦ Carbamazepine
◦ Valproic acid
◦ Clonazepam
ECT
Family consent, patient assent, explaining condition and medication side effects

33. Goals of Treatment
 Achieve remission.
 Prevent relapse.
Prevent recurrence.
Development of personality

34. Multimodal Approach
o High degree of co morbidity.
 Psychosocial consequences.
o Academic consequences.
 Psychological “scars” in youths.
 Untreated depression increases likelihood
of personality disorders.

35. 4-phase process
◦ several factors need to be addressed, including medication, family issues, social and school functioning,
and, substance abuse. adult bipolar disorder is continuous with pediatric bipolar disorder
◦ 4-phase process:
◦ (1) evaluation and diagnosis of presenting symptoms,
◦ (2) acute care and crisis stabilization for psychosis or suicidal or homicidal ideas or acts,
◦ (3) movement toward full recovery from a depressed or manic state,
◦ (4) attainment and maintenance of euthymia. to minimize the number of needed hospitalizations, to
eliminate or minimize medication adverse effects, and to optimize (QOL):
◦ QOL issues for a young person include meaningful relationships with family, peers, coaches, and
teachers; optimal academic performance; and optimal occupational performance as it pertains to
endeavors such as music, art, dance, athletics, or other personally rewarding areas from which the
adolescent derives a sense of competency, mastery, and pleasure.

36. Inpatient indications
◦ present at times of family or youth despair or family crises surrounding their behaviors.
◦ psychotic features and in almost all patients who have suicidal or homicidal ideations or plans,
have access to firearms in their homes or communities and in those who abuse substances,
particularly alcohol.
◦ Inpatient treatment usually requires locked-unit care to assist in safety regulation. Rarely are
young persons physically restrained in hospitals, but seclusion rooms should remain available in
the event of severely agitated states that may culminate in threats or overt expression of
physical aggression to self or others.

37. Pharmacotherapy
◦ higher metabolism than adults because of the efficiency of their hepatic functions.
◦ faster renal clearance rates than adults. For example, lithium carbonate has an elimination half-life of 30-36 hours
in an elderly patient, 24 hours in an adult, 18 hours in an adolescent, and less than 18 hours in children.
◦ Steady states are also achieved earlier in children than in adolescents and earlier in adolescents than in adults.
Therefore, plasma levels may be drawn and assessed earlier in children and adolescents than in adults.
◦ The efficient metabolizing and clearance systems of young individuals have 2 important consequences:
Anticipated peak plasma drug levels may be higher in young patients than in adults.
Anticipated plasma trough levels may be lower in young patients than in adults.
Therefore, children may require increased dosages of medications (mg/kg/d) to attain a therapeutic
response. Special precautions must be taken when one doses psychiatric medications to treat
adolescents and children to achieve therapeutic effect while staying safely below toxic levels.

38. Pharmacotherapy
◦ use of medication with a low (single digit below 10) desirable NNT
(number needed to treat) compared with placebo and high NNH
(number needed to harm; above 10 desirable).
◦ Pediatric treatment guidelines ,The Child Psychiatric Workgroup on
Bipolar Disorder established guidelines involve algorithm-based use of
mood stabilizers and atypical antipsychotic agents alone or in various
combinations.
◦ All medications used in pediatric bipolar disorder pose a risk of adverse
effects or interactions with other medications . These risks should be
clearly discussed with patients and families and weighed against the
potential benefits. Medication should be started only after informed
consent is obtained.

39. ◦ Mood stabilizers for control of manic episodes occurring in bipolar disorder.
◦ Lithium carbonate is effective in 60-70% and remains the first-line therapy for
long-term prophylaxis in classic bipolar disorder with euphoric mania.
◦ treat acute mania, though it cannot be up titrated to an effective level as quickly as
valproic acid.
◦ antisuicide effect.
◦ Berk et al. suggest that lithium may be more effective than quetiapine by slowing
or reversing the core brain dysfunction found in neuroimaging causing acute
mania: reduced grey matter in the orbitofrontal cortex, anterior cingulate, inferior
frontal gyrus, and cerebellum, and reduced internal capsule white matter volume.
◦ lithium therapy can restore white matter microstructure (fractional anisotropy
(FA) in cingulum hippocampus (CGH) white matter was significantly lower),
improved scores on Clinical Global Impressions ratings in relation to
depression and mania severity at Week 8

40. ◦ lithium has FDA approval for bipolar I disorder in youths aged 12 years and older. Findling etal.
investigated the efficacy of lithium for the treatment of youths aged 7 to 17 years with bipolar I
disorder, mixed or manic episode in an 8-week double-blind, placebo-controlled trial. Fifty-three
youths were randomized to treatment with lithium, and 28 youths were randomized to placebo. The
mean lithium serum level at study endpoint was 0.98 mEq/L.
◦ The lithium-treated youths had a significantly greater change in Young Mania Rating Scale (YMRS)
scores. On the basis of Clinical Global Impression-Improvement scores, 47% of lithium-treated youth
were very much improved.
◦ The most common adverse effects of lithium were vomiting , nausea , headache, increase in
thyrotropin concentration (3 mIU/L). 15% of children receiving lithium have enuresis, primarily
nocturnal enuresis. In those whose condition does not respond to lithium, sodium divalproex is
generally the next agent of choice.
◦ lithium may be an alternative for youths who experience significant weight gain with an atypical
antipsychotic.
◦ Monitoring of blood levels is critical.
Karen Dineen Wagner, 2016

41. ◦ Sodium valproate (VPA) decreased amygdala volume, lateral orbito-frontal region, the medial
orbitofrontal, the caudal anterior cingulate, and the posterior cingulate region over a 6-week treatment
period in children with bipolar disorder, according to structural (MRI).
◦ Although lithium for the acute treatment and prophylaxis of mania has demonstrated efficacy in
pediatric bipolar disorder, VPA is often more effective as therapy for mixed states.
◦ treating and preventing mania. used alone or in combination with lithium. It is useful in treating rapid-
cycling bipolar disorders and has been used to treat aggressive or behavioral disorders. A combination
of valproic acid and valproate has been effective in treating persons in manic phase, with a success rate
of 49%.
◦ Valproic acid treatment led to increased weight , and decreased total red blood cells, hemoglobin level,
hematocrit, and albumin level. Mood lability was associated with higher plasma levels of valproic acid
Cazala F, et al. Effects of valproate on brain volumes in pediatric bipolar disorder: a
preliminary study. Psychiatry Res Neuroimaging. 2018

42. ◦ carbamazepine is not a first-line choice, due to its safety profile including an increased risk of
Stevens-Johnson syndrome and/or possible association with agranulocytosis and/or meningitis
◦ Carbamazepine's anticonvulsant action may involve depressing activity in the nucleus ventralis
anterior of the thalamus, reducing polysynaptic responses and blocking posttetanic potentiation.
Carbamazepine reduces sustained, high-frequency, repetitive neural firing. It is a potent enzyme
inducer that can induce its own metabolism. Because of potentially serious blood dyscrasias, weigh
benefit and risk before therapy.
◦ Therapeutic plasma levels are 4-12 µg/mL for analgesic and antiseizure response. Serum levels peak
in 4-5 h. Serum half-life is 12-17 h with repeated doses. Carbamazepine is metabolized in the liver to
its active metabolite (epoxide derivative) with a half-life of 5-8 h. Metabolites are excreted in feces
and urine.
◦ Carbamazepine is effective in cases that do not respond to lithium therapy. It has been effective in
treating rapid-cycling bipolar disorder.

43. ◦ Lamotrigine not a preferred first choice due to an increased risk of Stevens-Johnson syndrome
and/or possible association with agranulocytosis and/or meningitis and/or increased suicidal
ideation, and although it has been approved for bipolar maintenance therapy in adults, initial
data in pediatric patients suggest it does not prevent mania.
◦ Other antiepileptic medications (eg, gabapentin, oxcarbazepine, topiramate) studies are
beginning to show the potential usefulness of these medications in pediatric patients with
bipolar disorder.
◦ Add-on lamotrigine for maintenance treatment of bipolar I disorder in youths aged 7 to 17
years was recently examined, lamotrigine delayed the time to occurrence of a bipolar event
significantly more than for the 10- to 12-year-old group.?

44. ◦ Atypical antipsychotics are being used increasingly for treatment of both acute mania and mood
stabilization. may be considered first-line alternatives to lithium, valproate or carbamazepine.
◦ Aripiprazole is approved for bipolar disorder in children 10-17 years. It can be used as monotherapy or
adjunctively with lithium or valproate. It is a partial dopamine D2 and serotonin 5HT1A agonist, and it
antagonizes serotonin 5HT2A.
◦ Risperidone binds dopamine D2-receptor with a 20 times lower affinity than it has for 5-HT2 receptor. It is
indicated for short-term (3-wk) treatment of acute mania associated with bipolar disorder. It may be used
alone or combined with lithium or valproate. Risperidone is approved for bipolar mania in children aged 10-
17 years.
◦ Quetiapine is indicated for acute treatment of manic episodes that are associated with bipolar I disorder. It is
approved for bipolar mania in children aged 10-17 years. Quetiapine may act by antagonizing dopamine
and serotonin effects. It is a newer antipsychotic used for long-term management. Improvements over
earlier antipsychotics include fewer anticholinergic effects and less dystonia, parkinsonism, and tardive
dyskinesia. There have been isolated cases of neuroleptic malignant syndrome associated with
quetiapine treatment of bipolar disorder in youth.
◦ Olanzapine's approved for children 13 years and older.
◦ Ziprasidone for acute bipolar mania, including manic and mixed episodes. Antagonizes dopamine D2, D3, 5-
HT2A, 5-HT2C, 5-HT1A, 5-HT1D, alpha1 adrenergic. Has moderate antagonistic effect for histamine H1.
Moderately inhibits reuptake of serotonin and norepinephrine.

45. ◦ Asenapine FDA approval for the treatment of bipolar I disorder in youths aged 10 to 17 years.
◦ The combination of somnolence, sedation, and hypersomnia, oral hypoesthesia with dysgeusia, oral paresthesia,
and increased appetite. weight gain The mean changes from baseline in fasting insulin, metabolic parameters, and
glucose were greater for asenapine-treated youth. The incidence of akathisia and extrapyramidal symptoms was
not higher in the asenapine. antagonism of dopamine-2 and serotonin-2a receptors.
◦ Lurasidone was approved in 2018 for major depressive episodes associated with bipolar I disorder (bipolar
depression) in children and adolescents aged 10 to 17 years.
◦ Clozapine in treatment-refractory cases. It is believed to provide protection against suicidality similar to lithium;
however, it should not be a first-line medication, because of the significant risk for agranulocytosis and the
resulting need for frequent hematologic monitoring.
◦ An important consideration with atypical antipsychotics is the potential for weight gain and metabolic syndrome.
The patient’s weight should be measured, and a fasting lipid profile and serum glucose level should be taken
before these agents are started. These values should be monitored periodically during treatment, and if the
patient’s BMI increases by 5%, switching to a different agent or the use of medication, such as metformin, or
behavioral measures to decrease weight gain should be considered. Patients and families should be advised of the
need to appropriately manage diet and exercise.

46. ◦ A 2012 multicenter study from the TEAM study group (Treatment of Early Age Mania) to compare whether there are
differences in efficacy between risperidone, lithium or divalproex in the treatment of manic or mixed states in children aged
6 to 15 years. risperidone was significantly more efficacious than lithium or divalproex, however adverse metabolic effects,
such as weight gain and hyperprolactinemia, were more significant with risperidone. These adverse effects may be even
more problematic as the study did not follow the children beyond week 6.
◦ Lithium and divalproex did not seem to cause as much weight gain; however lithium did cause clinically significant
elevation of TSH levels implying that thyroid function should be closely monitored in children treated with lithium.
risperidone was more effective and produced an earlier clinical response than valproic acid in the treatment of bipolar
disorder in young children
◦ ziprasidone and aripiprazole may have a low potential for these adverse effects and that they may be considered in
patients at high risk because of a family or personal history of metabolic abnormalities. Atypical antipsychotics also pose a
potential risk for extrapyramidal symptoms and tardive dyskinesia.
◦ These medications should be used cautiously during pregnancy, especially because of the potential for birth defects and
impact on blood sugar levels.
◦ Calcium channel blockers (Verapamil), (ACE) inhibitors, and phenytoin not tested in children or adolescents for use in
bipolar disorder.
wagner Bipolar Disorder, Child Adolescent Psychiatry, Neuropsychiatry

47. ◦ 3-Benzodiazepines, such as clonazepam and lorazepam, are
generally avoided in children because of the long-term risk
of dependence, but they may be temporarily useful (< 2 wk
maximum) in restoring sleep or in modulating irritability or
agitation not caused by psychosis. Because of the slow-on
and slow-off action of clonazepam, the risk of abuse is lower
with this drug than with fast-acting benzodiazepines such as
lorazepam and alprazolam.
◦ In the outpatient setting, clonazepam may be preferred
because of the efficacy and the lowered risks of abuse by the
patient or others. Clonazepam can be dosed in the range of
0.01-0.04 mg/kg/d and it is often administered once per day
at bedtime or twice per day. Lorazepam is dosed to 0.04-0.09
mg/kg/d and administered 3 times per day because of its
short half-life.

48. ◦ Depressive episodes are frequently the first presentation of bipolar disorders in youths thus,
antidepressant therapy in a depressed youth should be initiated with a warning to the patient
and family of the possibility of later development of mania symptoms.
◦ If a history of a manic state is known or suggested in a patient who is currently depressed, a
mood stabilizer should be started first. Once a therapeutic level and response to the mood
stabilizer are attained, an antidepressant may be considered as additional treatment needed for
the current state of depression, with close monitoring for antidepressant-induced mania. An
antidepressant with a potentially lowered risk of inducing mania is bupropion.
◦ (SSRIs) should be used cautiously, owing to the risk of mania; doses should be low and titration
slow.
◦ After symptoms of psychosis, suicidality, or homicidality are absent or sufficiently diminished to
a safe and manageable level, the patient is discharged to outpatient care.

49. Medication Common Adverse
Effects
Pediatric Doses Special Concerns
Lithium carbonate
(Lithobid)
GI distress, lethargy or
sedation, tremor,
enuresis, weight gain,
alopecia, cognitive
blunting
10-30 mg/kg/d; dose
must be adjusted by
monitoring serum level
and patient response;
up-titrate on twice-daily
schedule
Hypothyroidism,
diabetes insipidus, toxic
in dehydration, polyuria,
polydipsia, renal
drug-drug interactions
and sodium intake may
alter therapeutic serum
levels
Approved for patients
y and older
Sodium
divalproex/valproic acid
(Depakote, Depakene)
Sedation, platelet
dysfunction, liver
disease, alopecia,
gain
15-30 mg/kg/d; dose
must be adjusted by
monitoring serum
up-titrate on twice- or
thrice-daily schedule
Elevated liver enzymes
or liver disease, drug-
drug interactions, bone
marrow suppression
Approved for patients

50. Carbamazepine
(Equetro)
Suppressed WBCs,
dizziness, drowsiness,
rashes, liver toxicity
(rare)
10-20 mg/kg/d; dose
must be adjusted by
monitoring serum blood
levels; up-titrate on
twice-daily schedule
Drug-drug interactions,
bone marrow
suppression
Asenapine (Saphris) Somnolence, oral
paraesthesia
2.5 mg SL q12h initially;
may increase to 5 mg
q12hr after 3 days and
to 10 mg SL q12hr after
3 additional days
Pediatric patients are
more sensitive to
dystonia with initial
dosing when
recommended
escalation schedule not
followed
Approved for patients
y and older
Risperidone (Risperdal,
Risperdal Consta,
Risperdal M-Tab)
Weight gain, sedation,
orthostasis
0.25 mg bid or 0.5 mg
bedtime initially; titrate
as tolerated to target
dosage of 2-4 mg/d;
to exceed 6 mg/d
Galactorrhea,
extrapyramidal
symptoms
Approved for patients

51. Clonazepam (Klonopin) Sedation, abnormal
coordination, ataxia
0.01-0.04 mg/kg/d PO
at bedtime or divided
bid
Caution with
renal/hepatic
impairment and asthma
Fluoxetine (Prozac) Headache, nausea,
insomnia, anorexia,
anxiety, asthenia,
diarrhea, somnolence
10 mg PO qd; may
consider increasing to
mg/d after 1 wk
Long half-life; potential
to exacerbate manic
symptoms when not
coadministered with an
antimanic or mood-
stabilizing agent
Ziprasidone (Geodon) Akathisia, nausea Off-label: 20 mg PO at
bedtime; can increase
40 mg (not to exceed
mg), usually in 2 divided
doses for children
Risk of sudden cardiac
death due to torsades
des pointes due to
prolonged QT
prolongation, which
makes this medication
undesirable for

52. ◦ Early identification of medication non responders by Genome-wide association studies (GWASs)
would be helpful in the treatment of bipolar disorder to stabilize mood.
◦ A GWAS study in China differentiated patients with a good response and those with a poor
response to lithium with a sensitivity of 93% and showed the strongest association with a
response to lithium when the exons, exon-intron boundaries, and part of the promoter of the
gene encoding glutamate decarboxylase-like protein 1 (GADL1) was sequenced for association
with a single-nucleotide polymorphism (SNP) of two SNPs in high-linkage disequilibrium,
rs17026688 and rs17026651, that are located in the introns of GADL1.

53. Complications of drug treatment
◦ side effects such as weight gain and acne are particularly problematic with lithium, olanzapine,
and valproate.
◦ Therapy with atypical antipsychotics may predispose to neuroleptic malignant syndrome (NMS)
in children and adolescents; patients should be closely observed for such effects.
◦ Caution should be used when anticonvulsants and atypical antipsychotics are administered
together because of the increased risk of hematologic side effects. Administration of multiple
classes of anticonvulsants together should also be avoided, when possible.
◦ Family conflict may decrease response to medication treatment and so should be addressed in a
timely fashion.

54. ECT
◦ Although (ECT) is well documented as an effective and safe treatment option in patients with depressive
or psychotic states, most clinicians do not consider it a first-line intervention in children or adolescents.
◦ ECT is often initially administered on an inpatient basis, can be in a day-treatment setting.
◦ Therapy requires at least a 4-hour visit for pre-ECT preparations, delivery of the ECT, and monitoring
during recovery from both ECT and anesthesia. An ECT treatment episode may involve 3-8 or more
sessions, usually at a rate of 1 session every other day or 3 sessions per week. Despite the rapid effect of
ECT on mood and psychotic symptoms, medications are still required in the maintenance phase of
treatment.
◦ ECT safe and therapeutic in adolescents and children. more rapid than medications (days rather than
weeks). One drawback is the associated memory loss surrounding the time just before and after
treatments.

55. complementary medications
◦ omega-3 fatty acids (PUVA) to reduce symptoms of depression with less risk of mania and herbal preparations to
increase sleep. Concerns over long-term exposure risks associated with these medications in this population.
◦ during agitated manic states. lead to depletion of nutritional stores of iron, vitamin B-6, vitamin B-12, and folate
and can increase the risk of diabetes or long-term complications of hyperglycemia or hypoglycemia.
◦ Higher rates of fish consumption during pregnancy associated with lower rates of aggression in children, and fish
consumption later in life correlates with lower rates of mood disorder and suicide.
◦ High levels of vitamin D-binding protein (DBP) may be a significant characteristic of pediatric bipolar disorder . Its
early detection—in use as a biomarker—may help differentiate pediatric PD from other mood disorders—(MDD)—
and boost timely intervention. serum vitamin D concentrations were inversely associated with BMI
◦ deep brain stimulation for refractory depression, as this treatment may potentially lower the risk of mania and
related medication adverse effects, such as weight gain, insulin resistance, sexual dysfunction, and decreased
cognition due to impairment of memory and attention. This treatment also has no risk of potential overdose
because it is a nonmedication treatment.

56. Prognosis
◦ the onset of bipolar disorder in childhood and adolescence has revealed a stronger family history for bipolar disorder than
later onset; therefore, individuals are at increased genetic and familial risk from the beginning of life.
◦ optimal treatment for the genetic or familial form of bipolar disorder may differ from other treatment modalities of other
bipolar conditions.
◦ increased stress in home, school, and social settings may precipitate or exaggerate early mood disturbances of bipolar
disorder. As the patient ages, the tendency for stress to contribute to a mood episode declines, and mood disruptions may
occur spontaneously, even with medication and treatment compliance. This trend seems to be found in adults and not in
children or adolescents; it is thought to be the result of kindling.
◦ increased risk of suicide. In the general population, suicide remains one of the top 10 causes of death in adolescents and
young adults. It is the fourth most common cause of death in persons aged 10-15 years and the third most common cause
of death in persons aged 15-25y.
◦ bipolar disorder, suicide has a higher incidence in males within the first few years of the diagnosis. Current suicide rates in
patients with bipolar disorder are 10-15%.
◦ In adults, treatment with lithium reduces the suicide rate; similar studies in adolescents and children do not exist, but
lithium has been demonstrated to reduce substance use in adolescents with bipolar disorder.
◦ Other sources of morbidity and mortality are associated with poor judgment exercised by individuals with acute mania or
psychosis.

57. Prevention
◦ Avoidance of prescribing medications that can precipitate acute mania if a
diagnosis of bipolar disorder is unclear
◦ Avoidance of situations (including substance abuse) that precipitate or aggravate
decreased sleep duration, such as work or social situations that encourage or cause
sleep deprivation or significant alterations of sleep pattern
◦ Prompt medical and psychiatric attention upon development of symptoms such as
pressured speech, psychosis, or lack of need for sleep or food
◦ Adjunctive techniques such as meditation or muscle relaxation or deep breathing to
lower stress and anxiety levels
◦ Consultations with a neurologist, nephrologist, cardiologist, or endocrinologist may
be needed if the patient fails to respond to first-line treatment or develops
complications or adverse reactions to medications. Psychological testing may be
indicated.

58. ◦ Studies in the United States have also shown that many persons with serious mental illness (estimates
upward of 40%), especially psychosis, obtain substandard medical care owing to noncompliance with
medical treatment or the lack of resources to obtain needed treatment.
◦ Episodic mood events should be anticipated throughout the life cycle after bipolar disorder is
diagnosed. The frequency and severity of each episode are not readily predictable, but trends have
emerged. In the presence of medication and treatment compliance, relapses may occur, and
hospitalization may be required. In the absence of compliance, the course of the illness can be more
severe than it would be otherwise.
◦ A potentially reassuring aspect of bipolar disorder is that patients may potentially have a full and
normal life during the periods between mood swings. Therefore, many persons with bipolar disorder
may continue their college education and careers with success, and they may foster and nurture
strong relationships.
◦ Inpatient and outpatient psychiatrists, psychologists, social workers, and other therapists involved in
the care of the youth and the family should be able to aid the patient and family in the understanding
and management of bipolar disorder in a loved one.

59. Psychotherapy helps patient and family to
◦ Consolidate learned skills.
◦ Cope with psychosocial sequelae.
◦ Address environmental stressors.
◦ Understand inner conflicts.
◦ Foster medication compliance.
◦ Recognize early signs of relapse.

60. Behavioral Therapy
◦ Long-Term Monitoring
◦ Randomized controlled trials have recommended individual cognitive behavior therapy in
children and adolescents to focus on suicide prevention, as well as to monitor and manage
medication if family conflict and negative expressed emotions are absent.
◦ Parent-focused interpersonal therapy and guidance are important when one or both parents
have significant mood and/or anxiety disorder. If there is negative emotional expressivity in
family interactions, family therapy should be added
◦ social rhythm therapy, (IPT), (DBT), (CBT), family therapy, group therapy. Supportive
psychotherapy or psychoanalysis should be reserved for individuals who are more likely to
respond to those therapies.

61. family therapy
◦ The goals of individual therapy and family therapy should be individualized. common goal themes include
reduction of family stress, improvement of family communications, and a discussion of unresolved feelings of fear,
hurt, or loss caused by a loved family member having a mental disorder.
◦ Family-focused therapy with a cognitive behavioral component is encouraged, in that having a child with bipolar
disorder requires the parents, the identified child, and siblings to adjust to the impact on the family system,
necessitating a focus on improved communication. In family and individual sessions, medication issues and
compliance should also be addressed so that optimal care can be attained in the outpatient setting.
◦ The patient and family need psychoeducation about bipolar disorder and its management, including management
of medication side effects and sleep hygiene.
◦ A 2017 article in the Journal of Clinical Psychology emphasizes the role of family-focused therapy to reduce the risk
of suicide for bipolar youth by decreasing the negative effects of perceived criticism; often, suicide attempts are
preceded by negative parental interactions that youths perceive to be rejecting and criticizing.
◦ Psychoeducation of parents and patients is an important aspect of treating an adolescent or child in whom bipolar
disorder is diagnosed. The young person must be given the relevant facts in an age-appropriate and
developmentally appropriate manner. The diagnosis, benefits of treatment, and detriment of treatment
noncompliance should be made clear and understandable.

62. Juvenile Bipolar Disorder
◦ Accurate recognition and diagnosis.
◦ Lithium vs mood stabilizers.
◦ Antipsychotics especially atypicals.
◦ Long term follow up.
◦ Handling comorbidity.

63. Considerations for treating co
morbidities
Hierarchy
1- Address manic/ or psychotic symptoms.
2- Treat depression.
3- Focus on symptoms of anxiety and ADHD.
4- Combined treatment is often necessary.

64.  What to do
1- Optimize mood stabilizers untreated psychosis/mania can mimic ADHD traits.
2- Add ADHD ttt if potential benefits outweigh risks.
3- In history of remote psychosis, prophylactic neuroleptics are given first.
4- Start ADHD ttt in lower doses and increase cautiously. PBD and ADHD can be safely treated
with mixed amphetamine salts after stabilizing manic symptoms by mood stabilizers

65. ◦ Mood stabilizers alone are not effective in ttt of co morbid ADHD.
◦ Mood stabilizers or atypical antipsychotics.
◦ Adolescents with childhood ADHD who develop BPD respond poorly to lithium.

66. To conclude
◦ Affective illnesses are first treated,
◦ When effective and stable,
◦ Treat co morbidity.

67. ◦ American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th. Arlington, VA: American Psychiatric Publishing.; 2013.
◦ Goldberg JF, Harrow M. A 15-year prospective follow-up of bipolar affective disorders: comparisons with unipolar nonpsychotic depression. Bipolar Disord. 2011 Mar. 13(2):155-63. [Medline].
◦ Marcus R, Khan A, Rollin L, et al. Efficacy of aripiprazole adjunctive to lithium or valproate in the long-term treatment of patients with bipolar I disorder with an inadequate response to lithium or valproate monotherapy: a multicenter, double-blind, randomized study. Bipolar Disord. 2011 Mar. 13(2):133-44. [Medline].
◦ Chen CH, Lee CS, Lee MT, Ouyang WC, Chen CC, Chong MY, et al. Variant GADL1 and response to lithium therapy in bipolar I disorder. N Engl J Med. 2014 Jan 9. 370(2):119-28. [Medline].
◦ Singh MK, Ketter TA, Chang KD. Atypical antipsychotics for acute manic and mixed episodes in children and adolescents with bipolar disorder: efficacy and tolerability. Drugs. 2010 Mar 5. 70(4):433-42. [Medline]. [Full Text].
◦ Van Meter AR, Burke C, Youngstrom EA, Faedda GL, Correll CU. The Bipolar Prodrome: Meta-Analysis of Symptom Prevalence Prior to Initial or Recurrent Mood Episodes. J Am Acad Child Adolesc Psychiatry. 2016 Jul. 55 (7):543-55. [Medline].
◦ Borue X, Mazefsky C, Rooks BT, Strober M, Keller MB, Hower H, et al. Longitudinal Course of Bipolar Disorder in Youth With High-Functioning Autism Spectrum Disorder. J Am Acad Child Adolesc Psychiatry. 2016 Dec. 55 (12):1064-1072.e6. [Medline].
◦ Hafeman DM, Merranko J, Axelson D, Goldstein BI, Goldstein T, Monk K, et al. Toward the Definition of a Bipolar Prodrome: Dimensional Predictors of Bipolar Spectrum Disorders in At-Risk Youths. Am J Psychiatry. 2016 Jul 1. 173 (7):695-704. [Medline].
◦ Tannous J, Amaral-Silva H, Cao B, Wu MJ, Zunta-Soares GB, Kazimi I, et al. Hippocampal subfield volumes in children and adolescents with mood disorders. J Psychiatr Res. 2018 Mar 12. 101:57-62. [Medline].
◦ Lopez-Larson MP, Shah LM, Weeks HR, King JB, Mallik AK, Yurgelun-Todd DA, et al. Abnormal Functional Connectivity Between Default and Salience Networks in Pediatric Bipolar Disorder. Biol Psychiatry Cogn Neurosci Neuroimaging. 2017 Jan. 2 (1):85-93. [Medline].
◦ Correll CU, Olvet DM, Auther AM, et al. The Bipolar Prodrome Symptom Interview and Scale-Prospective (BPSS-P): description and validation in a psychiatric sample and healthy controls. Bipolar Disord. 2014 May 8. [Medline].
◦ Duffy A, Horrocks J, Doucette S, Keown-Stoneman C, McCloskey S, Grof P. The developmental trajectory of bipolar disorder. Br J Psychiatry. 2014 Feb. 204(2):122-8. [Medline].
◦ Johnston JA, Wang F, Liu J, Blond BN, Wallace A, Liu J, et al. Multimodal Neuroimaging of Frontolimbic Structure and Function Associated With Suicide Attempts in Adolescents and Young Adults With Bipolar Disorder. Am J Psychiatry. 2017 Jan 31. appiajp201615050652. [Medline].
◦ Adleman NE, Kayser R, Dickstein D, Blair RJ, Pine D, Leibenluft E. Neural correlates of reversal learning in severe mood dysregulation and pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2011 Nov. 50(11):1173-1185.e2. [Medline].
◦ Garrett A, Chang K. The role of the amygdala in bipolar disorder development. Dev Psychopathol. 2008 Fall. 20(4):1285-96. [Medline].
◦ Grosso G, Pajak A, Marventano S, Castellano S, Galvano F, Bucolo C, et al. Role of omega-3 Fatty acids in the treatment of depressive disorders: a comprehensive meta-analysis of randomized clinical trials. PLoS One. 2014. 9(5):e96905. [Medline]. [Full Text].
◦ Caetano SC, Silveira CM, Kaur S, Nicoletti M, Hatch JP, Brambilla P, et al. Abnormal corpus callosum myelination in pediatric bipolar patients. J Affect Disord. 2008 Jun. 108(3):297-301. [Medline]. [Full Text].
◦ Pandey GN, Ren X, Dwivedi Y, Pavuluri MN. Decreased protein kinase C (PKC) in platelets of pediatric bipolar patients: effect of treatment with mood stabilizing drugs. J Psychiatr Res. 2008 Jan. 42(2):106-16. [Medline]. [Full Text].
◦ Mick E, Kim JW, Biederman J, Wozniak J, Wilens T, Spencer T, et al. Family based association study of pediatric bipolar disorder and the dopamine transporter gene (SLC6A3). Am J Med Genet B Neuropsychiatr Genet. 2008 Oct 5. 147B(7):1182-5. [Medline].
◦ Sparks GM, Axelson DA, Yu H, Ha W, Ballester J, Diler RS, et al. Disruptive mood dysregulation disorder and chronic irritability in youth at familial risk for bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2014 Apr. 53 (4):408-16. [Medline].
◦ Frazier TW, Demeter CA, Youngstrom EA, Calabrese JR, Stansbrey RJ, McNamara NK, et al. Evaluation and comparison of psychometric instruments for pediatric bipolar spectrum disorders in four age groups. J Child Adolesc Psychopharmacol. 2007 Dec. 17(6):853-66. [Medline].
◦ Biederman J, Faraone S, Milberger S, Guite J, Mick E, Chen L, et al. A prospective 4-year follow-up study of attention-deficit hyperactivity and related disorders. Arch Gen Psychiatry. 1996 May. 53(5):437-46. [Medline].
◦ Pine DS, Guyer AE, Goldwin M, Towbin KA, Leibenluft E. Autism spectrum disorder scale scores in pediatric mood and anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2008 Jun. 47(6):652-61. [Medline]. [Full Text].
◦ Copeland WE, Shanahan L, Costello EJ, Angold A. Childhood and adolescent psychiatric disorders as predictors of young adult disorders. Arch Gen Psychiatry. 2009 Jul. 66(7):764-72. [Medline]. [Full Text].
◦ Sparks GM, Axelson DA, Yu H, Ha W, Ballester J, Diler RS, et al. Disruptive mood dysregulation disorder and chronic irritability in youth at familial risk for bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2014 Apr. 53 (4):408-16. [Medline].
◦ Steiner H. Evaluation and management of violent behavior in bipolar adolescents. Symposium 19D. Chicago, IL: The 153rd Annual Meeting of the American Psychiatric Association; May 14, 2000.
◦ Stanley B, Brown G, Brent DA, Wells K, Poling K, Curry J, et al. Cognitive-behavioral therapy for suicide prevention (CBT-SP): treatment model, feasibility, and acceptability. J Am Acad Child Adolesc Psychiatry. 2009 Oct. 48(10):1005-13. [Medline]. [Full Text].
◦ de Leon J, Armstrong SC, Cozza KL. Clinical guidelines for psychiatrists for the use of pharmacogenetic testing for CYP450 2D6 and CYP450 2C19. Psychosomatics. 2006 Jan-Feb. 47(1):75-85. [Medline].
◦ Thomas T, Stansifer L, Findling RL. Psychopharmacology of pediatric bipolar disorders in children and adolescents. Pediatr Clin North Am. 2011 Feb. 58(1):173-87, xii. [Medline].
◦ Bearden CE, Soares JC, Klunder AD, Nicoletti M, Dierschke N, Hayashi KM, et al. Three-dimensional mapping of hippocampal anatomy in adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2008 May. 47(5):515-25. [Medline]. [Full Text].
◦ Chang K. Adult bipolar disorder is continuous with pediatric bipolar disorder. Can J Psychiatry. 2007 Jul. 52(7):418-25. [Medline].
◦ Baumer FM, Howe M, Gallelli K, Simeonova DI, Hallmayer J, Chang KD. A pilot study of antidepressant-induced mania in pediatric bipolar disorder: Characteristics, risk factors, and the serotonin transporter gene. Biol Psychiatry. 2006 Nov 1. 60(9):1005-12. [Medline].
◦ Brooks M. Lurasidone (Latuda) Gets FDA Nod for Bipolar Depression in Kids. Medscape Medical News. Available at https://www.medscape.com/viewarticle/893542. March 7, 2018; Accessed: March 7, 2018.
◦ [Guideline] Kowatch RA, Fristad M, Birmaher B, Wagner KD, Findling RL, Hellander M. Treatment guidelines for children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2005 Mar. 44(3):213-35. [Medline].
◦ Geller B, Luby JL, Joshi P, Wagner KD, Emslie G, Walkup JT, et al. A randomized controlled trial of risperidone, lithium, or divalproex sodium for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents. Arch Gen Psychiatry. 2012 May. 69(5):515-28. [Medline].
◦ Correll CU. Clinical psychopharmacology of pediatric mood stabilizer and antipsychotic treatment, part 1: challenges and developments. J Clin Psychiatry. 2007 Aug. 68(8):1301-2. [Medline].
◦ Findling RL, Frazier JA, Kafantaris V, Kowatch R, McClellan J, Pavuluri M, et al. The Collaborative Lithium Trials (CoLT): specific aims, methods, and implementation. Child Adolesc Psychiatry Ment Health. 2008 Aug 12. 2(1):21. [Medline]. [Full Text].
◦ Croarkin PE, Emslie GJ, Mayes TL. Neuroleptic malignant syndrome associated with atypical antipsychotics in pediatric patients: a review of published cases. J Clin Psychiatry. 2008 Jul. 69(7):1157-65. [Medline].
◦ Bogarapu S, Bishop JR, Krueger CD, Pavuluri MN. Complementary medicines in pediatric bipolar disorder. Minerva Pediatr. 2008 Feb. 60(1):103-14. [Medline].

68. ◦ Pavuluri MN, Passarotti AM, Fitzgerald JM, Wegbreit E, Sweeney JA. Risperidone and divalproex differentially engage the fronto-striato-temporal circuitry in pediatric mania: a pharmacological functional magnetic resonance imaging study. J Am Acad Child Adolesc Psychiatry. 2012 Feb. 51(2):157-170.e5. [Medline].
◦ Berk M, Dandash O, Daglas R, Cotton SM, Allott K, Fornito A, et al. Neuroprotection after a first episode of mania: a randomized controlled maintenance trial comparing the effects of lithium and quetiapine on grey and white matter volume. Transl Psychiatry. 2017 Jan 24. 7 (1):e1011. [Medline].
◦ Chang KD, Steiner H, Ketter TA. Psychiatric phenomenology of child and adolescent bipolar offspring. J Am Acad Child Adolesc Psychiatry. 2000 Apr. 39(4):453-60. [Medline].
◦ Danielyan A, Pathak S, Kowatch RA, Arszman SP, Johns ES. Clinical characteristics of bipolar disorder in very young children. J Affect Disord. 2007 Jan. 97(1-3):51-9. [Medline].
◦ Chang K, Howe M, Gallelli K, Miklowitz D. Prevention of pediatric bipolar disorder: integration of neurobiological and psychosocial processes. Ann N Y Acad Sci. 2006 Dec. 1094:235-47. [Medline].
◦ Chang KD. The bipolar spectrum in children and adolescents: developmental issues. J Clin Psychiatry. 2008 Mar. 69(3):e9. [Medline].
◦ Faraone SV, Biederman J, Wozniak J, Mundy E, Mennin D, O'Donnell D. Is comorbidity with ADHD a marker for juvenile-onset mania?. J Am Acad Child Adolesc Psychiatry. 1997 Aug. 36(8):1046-55. [Medline].
◦ Strober M, DeAntonio M, Schmidt-Lackner S, Freeman R, Lampert C, Diamond J. Early childhood attention deficit hyperactivity disorder predicts poorer response to acute lithium therapy in adolescent mania. J Affect Disord. 1998 Nov. 51(2):145-51. [Medline].
◦ Birmaher B. Longitudinal course of pediatric bipolar disorder. Am J Psychiatry. 2007 Apr. 164(4):537-9. [Medline].
◦ Demeter CA, Townsend LD, Wilson M, Findling RL. Current research in child and adolescent bipolar disorder. Dialogues Clin Neurosci. 2008. 10(2):215-28. [Medline].
◦ Chang KD. The use of atypical antipsychotics in pediatric bipolar disorder. J Clin Psychiatry. 2008. 69 Suppl 4:4-8. [Medline].
◦ [Guideline] Gleason MM, Egger HL, Emslie GJ, Greenhill LL, Kowatch RA, Lieberman AF, et al. Psychopharmacological treatment for very young children: contexts and guidelines. J Am Acad Child Adolesc Psychiatry. 2007 Dec. 46(12):1532-72. [Medline].
◦ Pavuluri MN, Passarotti A. Neural bases of emotional processing in pediatric bipolar disorder. Expert Rev Neurother. 2008 Sep. 8(9):1381-7. [Medline].
◦ Dickstein DP, Nelson EE, McClure EB, Grimley ME, Knopf L, Brotman MA, et al. Cognitive flexibility in phenotypes of pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2007 Mar. 46(3):341-55. [Medline].
◦ Brotman MA, Skup M, Rich BA, Blair KS, Pine DS, Blair JR, et al. Risk for bipolar disorder is associated with face-processing deficits across emotions. J Am Acad Child Adolesc Psychiatry. 2008 Dec. 47(12):1455-61. [Medline]. [Full Text].
◦ Doyle AE, Wozniak J, Wilens TE, Henin A, Seidman LJ, Petty C, et al. Neurocognitive impairment in unaffected siblings of youth with bipolar disorder. Psychol Med. 2009 Aug. 39(8):1253-63. [Medline]. [Full Text].
◦ Joseph MF, Frazier TW, Youngstrom EA, Soares JC. A quantitative and qualitative review of neurocognitive performance in pediatric bipolar disorder. J Child Adolesc Psychopharmacol. 2008 Dec. 18(6):595-605. [Medline]. [Full Text].
◦ Wilens TE, Biederman J, Adamson JJ, Henin A, Sgambati S, Gignac M, et al. Further evidence of an association between adolescent bipolar disorder with smoking and substance use disorders: a controlled study. Drug Alcohol Depend. 2008 Jun 1. 95(3):188-98. [Medline]. [Full Text].
◦ Miklowitz DJ, Axelson DA, Birmaher B, George EL, Taylor DO, Schneck CD, et al. Family-focused treatment for adolescents with bipolar disorder: results of a 2-year randomized trial. Arch Gen Psychiatry. 2008 Sep. 65(9):1053-61. [Medline]. [Full Text].
◦ Nguyen TT, Kosciolek T, Eyler LT, Knight R, Jeste DV. Overview and systematiOverview of studies of microbiome in schizophrenia and bipolar disorder.e glycoproteins with assembled cytoskeletal proteins in concanavalin A-activated rabbit platelets. J Psychiatr Res. 2018 Apr. 99:50-61. [Full Text].
◦ Duax JM, Youngstrom EA, Calabrese JR, Findling RL. Sex differences in pediatric bipolar disorder. J Clin Psychiatry. 2007 Oct. 68(10):1565-73. [Medline].
◦ Duffy A. The early course of bipolar disorder in youth at familial risk. J Can Acad Child Adolesc Psychiatry. 2009 Aug. 18(3):200-5. [Medline]. [Full Text].
◦ Hooley JM, Miklowitz DJ. Perceived Criticism in the Treatment of a High-Risk Adolescent. J Clin Psychol. 2017 Jan 23. [Medline].
◦ Kendall T, Tyrer P, Whittington C, Taylor C. Assessment and management of psychosis with coexisting substance misuse: summary of NICE guidance. BMJ. 2011 Mar 23. 342:d1351. [Medline].
◦ Horwitz SM, Storfer-Isser A, Young AS, Youngstrom EA, Taylor HG, Frazier TW, et al. Development of Alcohol and Drug Use in Youth With Manic Symptoms. J Am Acad Child Adolesc Psychiatry. 2017 Feb. 56 (2):149-156. [Medline].
◦ Pavuluri MN, O'Connor MM, Harral EM, Sweeney JA. An fMRI study of the interface between affective and cognitive neural circuitry in pediatric bipolar disorder. Psychiatry Res. 2008 Apr 15. 162(3):244-55. [Medline]. [Full Text].
◦ Brodsky BS, Mann JJ, Stanley B, Tin A, Oquendo M, Birmaher B, et al. Familial transmission of suicidal behavior: factors mediating the relationship between childhood abuse and offspring suicide attempts. J Clin Psychiatry. 2008 Apr. 69(4):584-96. [Medline]. [Full Text].
◦ Grierson AB, Hickie IB, Naismith SL, Scott J. The role of rumination in illness trajectories in youth: linking trans-diagnostic processes with clinical staging models. Psychol Med. 2016 Sep. 46 (12):2467-84. [Medline].
◦ Yıldırım V, Direk MÇ, Güneş S, Okuyaz Ç, Toros F. Neuroleptic Malignant Syndrome Associated with Valproate in an Adolescent. Clin Psychopharmacol Neurosci. 2017 Feb 28. 15 (1):76-78. [Medline].

69. Thank you