Pediatric Bipolar Affective Disorder 

Updated: Mar 28, 2018
Author: Bettina E Bernstein, DO; Chief Editor: Caroly Pataki, MD 

Overview

Background

Bipolar disorder is a mood disorder in which feelings, thoughts, behaviors, and perceptions are altered in the context of episodes of mania and depression. Previously known as manic depression, bipolar disorder was once thought to occur rarely in youth. However, approximately 20% of adults with bipolar disorder had symptoms beginning in adolescence. Polygenic investigations indicate that this disorder is phenotypically separate (with or without psychosis) from schizoaffective disorders and schizophrenia.[1]

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) does not distinguish adult-onset from childhood- or adolescent-onset symptoms of bipolar disorder. The diagnostic criteria for bipolar disorder are the same regardless of the patient’s age at the onset of symptoms.[2]

DSM-5 uses universal symptoms to define the diagnostic criteria for mood episodes, including major depressive and manic episodes. At least 1 true manic episode, with or without psychotic features, is the necessary and sufficient criterion for type I bipolar disorder (BPI). A depressive episode is insufficient for this diagnosis, even in the presence of a strong family history of bipolar disorder. Type II bipolar disorder (BPII) is diagnosed on the basis of at least 1 hypomanic episode.

Therefore, bipolar disorders are viewed as having a spectrum of symptoms that range from mild hypomania to the most extreme mania, which may include life-threatening behaviors, dysphoria, and psychotic features. Outcome studies show that compared with unipolar depression, bipolar disorder causes more work disability and overall poorer outcome 15 years after an index hospitalized manic episode even when mania is in remission for at least 1 year.[3] Randomized controlled trials of combination mood stabilizer treatment (more than one mood stabilizer such as atypicals + lithium + valproate) suggest this may improve outcome by increasing the time to relapse for any mood episode compared with monotherapy as maintenance therapy for Bipolar I.[4]

Early identification of medication nonresponders would be extremely helpful in the treatment of bipolar disorder. Genome-wide association studies (GWASs) potentially can help to identify whether lithium is likely to be effective or if other medication such as atypical antipsychotic medication or antiepileptic medication will be more likely effective in 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.[5]

Go to Bipolar Affective Disorder for complete information on this topic.

Diagnostic criteria

Hallmark symptoms of mania include an abnormal, often expansive, and elevated mood lasting for at least 1 week. They may also include a decreased need for sleep, racing thoughts or a sense that thoughts are out of control, rapid and often pressured speech, increased goal-directed activities or projects, hypersexuality, reckless behaviors and risk-taking, and delusions of grandeur. Associated delusions frequently center on an expansive sense of self that goes well beyond narcissism (eg, believing oneself to have special powers or to be the chosen leader of the world or universe).

For some, the elevated and elated mood may transform into a state of dysphoria during which agitated and irritable behaviors may develop. Cognitive impairment in mania may manifest as episodes of confusion with a flight of ideas and disorganization of thought. In addition, increased risk-taking may involve physical, emotional, or financial endangerment.

Poor insight into one’s disorder or behaviors and poor judgment accompany mania. Therefore, the person’s financial accounts or important relationships may be in such disarray as to lead to adverse outcomes, including loss of important friends and family support or connections, serious financial setbacks, job losses, legal problems, and homelessness.

Especially in older children and adolescents, bipolar disorder may be a more severe form with increased risk of suicide attempts and the adverse effects of the disorder can contribute to dysfunction in the school setting, potentially leading to expulsion or peer rejection. In addition, adverse health outcomes have recently been associated with psychotic states, including psychosis associated with mania.[6]

Such effects include poor eating habits and an increased likelihood of substance abuse, including nicotine dependence, which is known to be associated with serious health consequences, such as early death due to cardiovascular complications of arteriosclerosis, stroke, diabetic ketoacidosis, and cancer.

DSM-5 criteria for a manic episode are as follows.

First, the individual has a distinct period of abnormally and persistently elevated, expansive, or irritable mood lasting at least 1 week (or any duration if hospitalization is necessary).

Second, during the period of mood disturbance, 3 or more of the following symptoms persisted (4 if the mood is only irritable) and have been present to a significant degree:

  • Inflated self-esteem to levels of grandiosity

  • Decreased need for sleep

  • More talkativeness than usual, often characterized by pressured speech with a sense of a need to keep talking

  • Flight of ideas or a subjective feeling that thoughts are racing

  • Distractibility

  • Increased goal-directed activity or psychomotor agitation

  • Excessive involvement in pleasurable activity that has a high potential for painful consequences (eg, hypersexuality, excessive spending, impetuous traveling)

Third, the symptoms do not meet the criteria for a mixed episode.

Fourth, the mood disturbance is severe enough to cause marked social impairment in occupational functioning, social activities, or relationships with others. Hospitalization may be necessary to prevent harm to self or others or if psychotic features are present.

Fifth, the symptoms are not due to the direct physiologic effects of a substance or a general medical condition.

Hypomania is somewhat similar to true mania but is less severe and less debilitating. As such, it is defined as an elevated mood during which (1) no hospitalization has ever been necessary, and (2) no state of delusional or other psychotic thinking ever coincided with the elevated mood. Hypomanic and manic states must impair normal functioning to be considered pathologic states and are often more difficult to recognize and diagnose in children than in adults. Some of the difficulty arises in recognizing atypical symptoms, including irritability, tantrums, physical aggression, and other behavioral problems (eg, expressions of mood disruptions) and may include difficulty in differentiating bipolar mania from hyperactivity as found in ADHD or irritability as found in DMDD. Parental history of ADHD increases the risk of DMDD by 4 times that in control populations, however, risk of DMDD is 20 times higher in families where there are offspring with DMDD.[7]

Comorbid diagnosis of autism spectrum disorder (ASD), especially with ADHD symptoms, are predictive of a more challenging clinical course that may require multiple different medications for remission.[8]

The strongest predictors of bipolar prodrome appear to be baseline anxiety/depression with proximal affective lability and full or subsyndromal manic symptoms, increasing the risk of bipolar prodrome from 2% (baseline risk due to family history) to 49%.[9]

An abnormal behavioral episode may be designated a bipolar disorder after the frequency and type of abnormal mood are considered. Therefore, an episode may be reported as a bipolar disorder with a single manic episode, with recurrent manic episodes, or by the mood state of the most recent episode (eg, depressed, mixed, hypomanic, manic). Descriptors such as "with psychosis" or "without psychosis" are used to further clarify and reflect the severity of the state of the disorder.

Mood disturbances in children and adolescents are often more difficult to recognize and diagnose than those in adults. Some of the difficulty arises in recognizing atypical symptoms, including irritability, tantrums, physical aggression, and other behavioral problems (eg, expressions of mood disruptions). Perhaps this difficulty is best demonstrated in symptom recognition as there has been recent controversy over potential overdiagnosis of bipolar disorder in youths due to recent US National trends of an increase as much as 40-fold of bipolar diagnosis in youth in outpatient settings and up to a 4-fold increase in inpatient psychiatric hospitalization of youth with bipolar disorder.[6]

The classic symptoms of mania, including racing thoughts, pressured speech, hypersexuality, and grandiosity, more often match the presentation of bipolar disorder in late adolescence. In childhood- or prepubertal-onset bipolar disorder, such a classic cluster of symptoms is uncommon. Nonetheless, as early as 1921, Kraepelin reported that 38% of his 900 patients who had manic episodes had symptom onset when younger than 20 years, and 0.4% had onset of symptoms when younger than 10 years.

Despite Kraepelin’s early observation and description of childhood-onset and adolescent-onset bipolar disorders, the controversy about diagnosing bipolar disorder in young persons persists. This is partially driven by the requirement of discrete episodes of disturbed mood to diagnose bipolar disorder.

Unlike what is noted in adults, well-defined and discrete episodes of abnormal mood are often missing in children and adolescents with this disorder. In particular, according to DSM-5 criteria at least 1 discrete episode of mania or hypomania is necessary to diagnose BPI or BPII. Childhood-onset bipolar disorder frequently has an insidious onset with affective storms often associated with the presentation of mental illness.

Clinicians often use the diagnosis of bipolar disorder not otherwise specified (NOS) in children and adolescents with a chronically mixed or vacillating mood state. Children with this diagnosis may have clinically significant impairment though they do not meet specific criteria for BPI or BPII. However, in the DSM-5, children with chronically irritable mood states and aggression can be diagnosed with disruptive mood dysregulation disorder instead of bipolar NOS, which is hoped to decrease the numbers of children and adolescents diagnosed with bipolar disorder who do not actually have that disorder.

Pathophysiology

Bipolar disorder and other mood disorders are increasingly understood in the context of neurochemical imbalances in the brain that may interact with underlying anatomical changes in the brain that adversely impact neural functional connectivity. 

Smaller subfield hippocampal volumes may reflect underlying pathophysiology of bipolar disorder and impact long term functioning.[10]

Alterations in functional connectivity of areas of the brain involved in executive functioning, decision making – so-called default and salience networks – are other areas being studied. 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.[11]

Exciting research areas also include the identification of youth at higher risk of bipolar disorder.

In Australia, it appeared that the use of ultra–high-risk criteria for bipolar disorder, also called bipolar at-risk (BAR), may provide the possibility of identification of persons prior to the onset of mania/hypomania.[12]

Objective testing, including the use of brain scanning techniques and magnetoencephalography (MEG), can be used to look at preattentive auditory dysfunction as a potential trait marker of severe bipolar disorder symptoms. Preattentive auditory dysfunction was reflected by the presence of reduced pitch-MMNm responses.[13]

Mood lability may be a result or the cause of brain changes seen on neuroimaging, such as reduction in grey matter volume and decreased amygdala and prefrontal functional connectivity.[14]

This may help to understand the underlying mechanism of 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.

A relatively small (N=82) functional MRI study (subjects average age, 13-14 years) analyzed whether differences in brain function could be detected when comparing youths with different diagnoses to one another. The study used a cognitive task involving response reversal to see if cognitive flexibility differed as reflected in differences in brain activation of areas reflective of differences in neural network activation, such as a lack of appropriate activation in areas such as the (right) inferior frontal gyrus and caudate between healthy youths, youths with bipolar disorder, youths with severe mood dysregulation (youths who did not meet criteria for bipolar disorder but had significant chronic irritability), and youths who had attention-deficit/hyperactivity disorder (ADHD) and either severe mood dysregulation or bipolar disorder.

Although the study attempted to correct for the presence of opposition defiant disorder (ODD) and ADHD, it did include youths treated with medication and the types of medication were not separated out as the data appeared to be pooled, so the results may not be completely generalizable. It is possible that medication influenced emotion processing; however, the study did seem to show that cognitive inflexibility can, to some extent, be objectively measured using functional MRI techniques looking at connectivity of neural networks.[15]

Although the circuits of the brain that modulate mood, cognition, and behavior are not yet fully defined, the database of neuroimaging studies, especially resting state connectivity studies, that 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 are ongoing.[16]

A study found that the Bipolar Prodrome Symptom Interview and Scale-Prospective (BPSS-P), the first specific interview for emerging BP symptoms, in 205 youth aged 12-23 years and/or their caregivers showed good internal consistency for the BPSS-P mania (Cronbach's α = 0.87), depression (Cronbach's α = 0.89), and general symptom indices (Cronbach's α = 0.74) and high inter-rater reliability for the BPSS-P total score (intraclass correlation [ICC] = 0.939) and BPSS-P mania (ICC = 0.934), depression (ICC = 0.985), and general (ICC = 0.981) indices. The BPSS-P total score discriminated BPI/BPII/cyclothymia from depression spectrum patients, and the BPSS-Mania Index differentiated all three bipolar spectrum groups from depression spectrum patients.[17]

An association of neurotransmitters acts upon various brain regions and circuits to modify and regulate brain activity. Central nervous system (CNS) neurotransmitters in brain circuits and their putative effects in activity modification include the following:

  • Serotonin - Mood (happy, sad, euthymic)

  • Dopamine - Pleasure (hedonia, anhedonia)

  • Norepinephrine - Alertness, energy level (lethargy, frenzy, vigilance)

  • Acetylcholine - Memory and cognition

  • Gamma-aminobutyric acid (GABA) - Inhibition of CNS neurons

  • Glutamate - Excitation of CNS neurons

One proposal suggests that several neurotransmitters acting in unison but with dynamic balance act as modulators of mood states. In particular, serotonin, dopamine, and norepinephrine appear to modify mood, cognition, and sense of pleasure or displeasure.

Neither the neural nor the genetic basis of bipolar disorder has been definitively elucidated; however, interest has been focused on potential abnormalities in the corpus callosum,[18] amygdala,[16] decreased protein kinase in platelets,[19] and dopamine D4 receptor genotype and abnormalities of the dopamine transporter gene SLC6A3.[20]

Pharmacotherapy for the regulation of bipolar mood swings is thought to be based on the 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, including regular exercise, may also indirectly modulate receptor sensitivity and resting state connectivity as well as neurotransmitter levels impacting endogenous opioid and nicotinic receptor function.

Although relatively small (N=28; after dropouts, n=21), one study attempted to explain why mood stabilizers such as divalproex and atypical antipsychotics such as risperidone are helpful in bipolar mania in youth. Compared with healthy controls, 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. A replication study will be helpful to confirm these results.[21]

Etiology

Genetic and familial factors play an important role in the development of bipolar disorder. Early age of onset of bipolar disorder predicts a higher rate of mood disorder among first-degree relatives. Adolescents who have onset of true mania with childhood-associated symptoms, such as aggression, mood shifts, or attention difficulties, are at a greater genetic risk (family loading) for BPI than adolescents with more adult-related psychotic symptoms, such as grandiosity.

Youths with early-onset bipolar disorder tend to have a poorer or less effective response to usual medications such as lithium (administered as eskalith), valproic acid, or atypical antipsychotic medications and an associated increased risk of alcohol-related disorders in the family members of the probands even though lithium appears to be more chemoprotective of suicide than other agents used.[22]

There appears to be increased psychopathology in children who have at least one biologic parent with BPI or BPII; 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 (hazard ratio [HR] = 20.89; P = .04), major depressive disorder (HR = 17.16; P = .004), anxiety (HR = 2.20; P = .03), sleep (HR = 28.21; P = .02), and substance use disorders (HR = 2.60; P = .05) compared with controls. Offspring from lithium-nonresponsive parents specifically developed psychotic disorders. Childhood anxiety disorder predicted an increased risk of major mood disorder, and evidence supported a progressive transition through clinical stages, from nonspecific psychopathology to depressive, and thenmanic or psychotic episodes.

There is increased psychopathology in children who have at least one biologic parent with BPI or BPII. Specifically, 28% of the children examined had attention deficit/hyperactivity disorder (ADHD), far above the prevalence of 3-5% in the general population of school-aged children. In addition, 15% of the children had a bipolar disorder or cyclothymia. Approximately 90% of children who have bipolar disorders had comorbid ADHD. Moreover, both bipolar disorder and ADHD were more likely to be diagnosed in boys than in girls.

Studies of bipolar disorder in twins showed a 14% concordance rate in dizygotic twins and a 65% concordance rate (range, 33-90%) 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%.[23] Children with bipolar disorder show a higher incidence of psychotic features than older adolescents or adults.[24, 25, 26]

Faraone et al further delineated the differences among children with mania, adolescents with childhood-onset mania, and adolescents with adolescence-onset mania.[27] Socioeconomic status was statistically lower in families of children with mania and adolescents with childhood-onset mania than in others. Increased energy was twice as common in childhood mania as in other forms, euphoria was most common in adolescents with childhood-onset mania, and irritability was least common in adolescents with adolescent-onset mania.

On statistical analysis, adolescents with adolescent-onset mania abused psychoactive drugs and had more impaired parent-child relationships than individuals in the other 2 groups with mania.[27] ADHD was more common in children and adolescents with childhood-onset mania than in patients with adolescent-onset mania, and in some youth ADHD symptoms may be a marker for juvenile-onset mania.

Data from this and other studies[28] 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.

There are concerns that early-onset mania may be misdiagnosed as ADHD or that more children have comorbid ADHD and bipolar disorder, with a higher rate of familial transmission. One controversy is whether youths who are later diagnosed with bipolar disorder 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.[9, 29]

Cognitive and neurodevelopmental factors also seem to be involved in the development of bipolar disorder, especially in preschool-aged children who later go on to develop bipolar disorder.[30, 23, 31]

Preschool children with early behavioral disinhibition[32] and decreased frustration tolerance may be at a 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.[33, 34] Emotion processing seems to be impaired in individuals with bipolar disorder because of a lack of flexibility in thought processing.[35, 34, 16]

A case-cohort study of adolescents with affective disorders revealed that neurodevelopmental delays are overrepresented in early-onset bipolar disorders, as well as in their "unaffected" siblings.[36] These delays occur in language, social, and motor development approximately 10-18 years before affective symptoms appear.[37]

Adolescents who had early developmental antecedents were at a higher risk of developing psychotic symptoms. In addition, intelligence quotient (IQ) scores were significantly 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).

Finally, a statistically significant difference in the mean verbal IQ and mean performance IQ was found only in patients with bipolar disorder. The reason for this discrepancy is unclear but should be the subject of further investigation.

Overall, patients with severe bipolar disorder had a mean IQ lower than that of patients with mild-to-moderate forms of the disorder.

Environmental factors also contribute to the development of bipolar disorder. These may be behavioral, educational, family related, toxic, or substance abuse induced. Wilens et al (2008) implicated smoking as a potential causal element in patients with bipolar disorder.[38]

Diagnoses of mental health problems increase the risk of suicide in adolescents compared with their healthy peers. Adolescent patients in whom bipolar disorder is diagnosed are at higher risk of suicide than adolescents with other behavioral illnesses. Family conflict and substance abuse exponentially increase this risk.[29, 39, 9]

Another risk factor for suicide in youths is legal problems. One study showed that 24% of adolescents who attempted suicide had faced legal charges or consequences in the preceding 12 months.[38]

Males with bipolar disorder are at higher risk of death from suicide than are females, who are more likely to attempt suicide numerous times unsuccessfully. This does not imply that suicide attempts in females should not be of concern; rather, 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.

Incarcerated youths have an inordinately high prevalence of mental illnesses. Some are facing legal consequences as a direct result of behaviors that arise from uncontrolled or untreated mental disorders. The manic state of bipolar disorder can be particularly problematic for adolescents, as the disinhibited risk-taking behaviors driven by the disorder can easily lead to legal problems, such as public disorderly conduct, theft, drug seeking or use, and an agitated and irritable mood that results in verbal and physical altercations.

Future research directions include the impact of the microbiome and intestinal microbiota in causing depression and irritability, which has so far only been proven in animal models. If the intestinal microbiota of humans is determined to play a causal role, then dietary interventions and testing of the microbiome might help with both diagnosis and treatment of bipolar disorder.[40]

Epidemiology

Rates of early-onset bipolar disorder in youth range between 1 and 1.8% according to one meta-analysis. The overall prevalence of BPI in adolescents is approximately 1%, whereas the prevalence in children is 0.2–0.4%. Bipolar disorder has roughly equal prevalence across different cultures.[7, 9]

Most patients with bipolar disorder present in early adulthood (age 20–30 years). The second most common age group at presentation is 15–19 years.

In contrast to the 1921 report stating that 38% of patients had an onset when younger than 20 years, more recent estimates are that 20–30% of adults with BPI had symptom onset when younger than 20 years. In addition, approximately 20% of youths in whom a major depressive disorder was previously diagnosed develop symptoms consistent with a manic state at a later age. Therefore, an adolescent or child who initially presents with depression may have a hidden bipolar disorder that becomes obvious later in life.

Patients with a childhood onset of bipolar symptoms may have a course of illness that is more severe, chronic, and refractory than that of patients with a later onset of symptoms of bipolar disorder. In addition, an early onset of bipolar symptoms seems to be associated with increased risk of mixed mood states (combined symptoms of depression and mania simultaneously) and rapid cycling (≥3 episodes of mania in 1 year).

Pediatric and adolescent bipolar disorder does not appear to have a sexual predilection, although more males with the disorder than females are referred for treatment.[41, 42]

Go to Bipolar Affective Disorder for complete information on this topic.

Prognosis

In general, 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.

An emerging body of evidence indicates that optimal treatment for the genetic or familial form of bipolar disorder may differ from other treatment modalities of other bipolar conditions.

Adverse outcomes of an early onset of bipolar disorder are as follows: (1) The course is generally more severe than that of late-onset disorder, and (2) the course of illness is more refractory to treatment than when the onset starts in adulthood.

As with so many psychiatric and medical disorders in children and adolescents, 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.

All persons with bipolar disorder have an 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 15-25 years.

The exact increase of the risk in youths is unknown; however, in young adults with 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. For example, serious cardiovascular complications (eg, stroke and myocardial infarction) and an increased risk for cancer and diabetes can result from poor dietary choices and higher rates of alcohol and nicotine use and abuse.

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.

A 2017 article in the Journal of Clinical Psychology ephasizes 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 preceeded by negative parental interactions that youths perceive to be rejcting and criticizing.[43]

Patient Education

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.

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.

Families and patients can learn about adolescent or childhood bipolar disorders at the American Academy of Child and Adolescent Psychiatry Web site, in the section titled "Resources for Families." This section provides a user-friendly fact and information sheet to families about bipolar disorder and its treatment in the pediatric population.

The Balanced Mind Parent Network (formerly known as the Child & Adolescent Bipolar Foundation [CABF]) provides important information and resources for families and clinicians.

Another resource is the Depressive and Manic-Depressive Association, a support group for patients and families of patients who have bipolar disorder. This group is mostly for adults, and parents are far more likely than adolescents or children to benefit from this group.

Other sources of information include Web sites such as the American Psychological Association, National Alliance on Mental Illness, and Depression and Bipolar Support Alliance.

For patient education resources, see the Depression Center, as well as Depression and Bipolar Disorder.

 

Presentation

History

Gathering the history of present and past disturbances of mood, behavior, and thought is critical to proper diagnosis of a psychiatric condition such as bipolar disorder. Unlike clinicians working in other areas of medicine, who often rely on laboratory or imaging studies to identify or characterize a disorder, mental health professionals rely almost exclusively on descriptive symptom clusters to diagnose mental disorders. As a consequence, the history is an essential part of the patient examination.

The fundamental problem might be classified as being primarily related to a physical health issue or primarily related to a mental health issue. Thus, the appropriate first step in evaluating a person for a psychiatric disorder is to ensure that no other medical condition is causing the mood or thought disturbance. Therefore, evaluation of the patient is best started by obtaining their oral history of current and past medical and behavioral symptoms and treatments.

To further clarify the problem, gathering additional information from family, friends, and perhaps other physicians who know the patient is always urged for a person experiencing an altered mood or behavioral state. Because bipolar disorder may cause a transient but marked impairment of judgment, insight, and recall, several sources of information are crucial to understand a particular patient. Therefore, family members, friends, teachers, caregivers, or other physicians or mental healthcare workers may be interviewed to fill out the clinical picture.

Nonetheless, the patient's subjective experience is essential in the evaluation and treatment processes, and the establishment of a therapeutic alliance and trust early in the assessment is vital to obtaining an accurate and useful history from the patient.

Knowledge of the family's psychiatric history is another essential part of the patient’s history because bipolar disorder has genetic transmission and familial patterns. A genogram may be developed to further describe a particular patient’s risk bipolar disorder based on familial and genetic attributes in the family system.

While obtaining the history, the physician must explore the possibilities that substance abuse or dependence, trauma to the brain in the present or past, or seizure disorders may be contributing to or causing the current symptoms of illness. Central nervous system (CNS) insults, such as encephalopathy or medication-induced mood changes (ie, steroid-induced mania), must also be considered.

Delirium should be excluded first in persons presenting with altered mental states or acute disturbances of mood and conduct, especially when encephalopathy of an infectious, metabolic, or toxic origin is possible. It is critical to take a careful history of alcohol use or abuse, including substance-abuse patterns, as acute drug-intoxication states may mimic bipolar disorder. There is as high as a 60% lifetime prevalence of bipolar disorder and substance misuse disorders in the United States.[44]

In communities of lower socioeconomic status or in the presence of stressful life events, parental substance use or disruptive behavior, substance use should be part of the differential diagnosis, especially huffing and ingestion of toxic substances such as methyl alcohol (wood alcohol, gasoline), glue, and sprays. Use of these substances is extremely common among adolescents and can result in a very rapid deterioration of mental status. In addition, such activities may result in hypoxia, potentially leading to permanent brain damage. In this setting, appropriate screening tests of blood, urine, and arterial blood oxygen and organ system function may be life-saving.[45]

Sleep disturbances often aid in defining abnormal mood states of bipolar disorder in either the manic or the depressed state. As such, it is helpful to determine the patient’s baseline euphoric state sleep pattern (eg, does the patient often get up early or stay up late?).

A profoundly decreased need for sleep in the absence of a sense of fatigue is a strong indicator of a manic state. A change in the patient’s usual sleep pattern (eg, from being a "night owl" to an "early riser") may predict a significant change in the patient’s mood state. Sleep studies of the CLOCK genetic areas have utilized functional magnetic resonance imaging (fMRI) to differentiate groups of children and adolescents with bipolar disorder.[46]

An uncomfortable reduction of sleep is a pattern of an atypical depression episode in which more sleep is wanted but cannot be achieved. Conversely, a typical depression episode may be indicated by hypersomnolence, an excessive and irresistible need for sleep.[26]

The biology that drives these sleep anomalies in mood disturbances is not fully appreciated. Some suggest that neurochemical and neurobiologic shifts cause these episodic sleep disturbances in conjunction with other shifts that occur in the evolution of manic or depressed states.

Physical Examination

After interviewing the patient, perform a physical examination. The examination must include a general neurologic examination, including examination of the cranial nerves, muscular bulk, and tone and deep tendon reflexes. Cardiovascular, pulmonary, and abdominal examinations are also essential because abnormal pulmonary function or poor vascular perfusion of the brain may cause abnormal mood, behavior, or cognition.

Both physical and laboratory thyroid examination should be performed because of the potential mood alteration in hypothyroid and hyperthyroid states and because of the need for baseline studies to ensure safety before and during medication treatment (see Workup).

If the physical examination does not reveal a medical condition contributing to the patient’s mental state, a thorough mental health evaluation is appropriate. Through observation and interviewing, mental health professionals may learn of mood, behavioral, cognitive, or judgment and reasoning abnormalities.

The mental status examination (MSE) is the essential component of a mental health evaluation. This examination goes beyond the mini-mental status examination (MMSE) often used in the emergency department (ED). Rather, the MSE is used to assess the general appearance and demeanor, speech, movement, and interpersonal relatedness of the patient with the examiner and others.

Mood and cognitive abilities (eg, orientation to circumstance; attentiveness; immediate-, short-, and long-term modes of memory) are assessed in the MSE. The assessment should be age-appropriate (eg, serial 3s test in younger children).

Some of the most important components of the MSE are those addressing issues of safety of individuals and members of a community. Therefore, suicidal and homicidal issues are explored. Likewise, screens for the more subtle forms of psychosis, such as paranoid or delusional states, in addition to screens for overt psychosis, such as observing the patient responding to unseen others or other non–reality-based internal stimuli, are explored.

Finally, insights into the patient’s mental and physical states, current circumstances of medical or mental healthcare, and ability to show age-appropriate insight and judgment are assessed and integrated into the evaluation of the patient’s global mental state at that moment. As examples, a child might be evaluated on his or her ability to verbalize potential environmental dangers (eg, explaining why not to accept candy from a stranger, why not to run into the street, or how to avoid picking a fight with an older peer).

Complications

Sexual and/or physical abuse is common with bipolar disorder, especially in very young children (< 6 years) and particularly in individuals with comorbid posttraumatic stress disorder (PTSD), psychosis, or conduct disorder. A positive family history of abuse may increase the risk for suicide.[47] Prompt identification and treatment are warranted.{ref39

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.[48]

Many persons with bipolar disorder exhibit excessive risk-taking behaviors, potentially predisposing them to injury or dehydration. In contrast, individuals who experience periods of depression may be at higher risk of developing deep venous thrombosis (DVT) and cardiovascular complications due to hypersomnia and excessive bedrest.

In general, a protracted and severe course of illness is associated with an early age of onset of bipolar disorder.[29]

There have been isolated cases of neuroleptic malignant syndrome associated with quetiapine treatment of bipolar disorder in youth.[49]

 

 

DDx

Diagnostic Considerations

Upon presentation to health care services, youths with bipolar disorder exhibit behaviors that mimic and overlap those of other diagnoses, particularly attention deficit/hyperactivity disorder (ADHD) and conduct disorder. In the early stages of ADHD and conduct disorder, as in patients with bipolar disorder, activity is increased, and self-esteem may be inflated. Societal and educational responses to the behaviors of ADHD and conduct disorder may ultimately reduce self-esteem in these patients compared with those with bipolar disorder.

Comparison of the characteristic behaviors noted in these 4 important disorders that affect young individuals may help in establishing the diagnosis of bipolar disorder (see the table below).[50] .

Table 1. Characteristic Behaviors Associated With Bipolar Disorder, DMDD, ADHD, and Conduct Disorder (Open Table in a new window)

Behavior Bipolar DMDD ADHD

Conduct Disorder

Self-esteem Inflated Deflated/irritable Inflated and/or deflated Inflated and/or deflated
Pleasure

Euphoric in mania

Dyphoric 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 such as decreased need in mania Often poor due to avoiding bedtime Chronic poor sleep; often late bedtimes Not known to be disrupted except with substance abuse
Speech Pressured or rapid in mania; slow in depression Rapid/normal rate Often rapid; may be pressured May be normal
Impulsivity Externally driven/reactive Reactionary Internally driven May engage in predatory or reactionary acts
Social Often good Often poor Often poor Often poor
Academic Often good Varies Often poor Often poor
Psychomotor activity Agitated in mania or mixed states; retarded in depressed states Easily agitated Chronically agitated Easily agitated
ADHD—attention deficit/hyperactivity disorder        

Additional consideration must be given to the possibility of schizophrenia or schizoaffective disorder, posttraumatic stress disorder (PTSD), substance abuse, or anxiety states (eg, generalized anxiety disorder, social anxiety disorder). Any of these disorders may transiently mimic bipolar disorder. Rarely is dementia an issue in youths, but it may have to be excluded in some patients (particularly after head trauma).

Psychometric instruments can be helpful in diagnosis of bipolar disorder, particularly if coexisting ADHD is possible and if other disorders (eg, schizophrenia, intellectual disability) need to be ruled out.[51]

Comorbid conditions

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.[52] An estimated 10-15% of adolescents who present with recurrent episodes of major depression are later diagnosed with bipolar disorder. In addition, children with ADHD who later develop bipolar disorder have increased rates of other psychiatric conditions, including opposition defiant disorder (ODD).

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.

An important predictor of bipolar disorder in youth was impaired sleep and disruptive behavior disorder (DBD), as well as impaired frustration tolerance.[53, 42]

The data specifically suggested that the combination of ADHD with ODD, correlated with a future onset of bipolar symptoms at a rate of 7%, whereas there was a 5% correlation for ADHD alone. When ADHD was present with ODD that progressed to conduct disorder, the occurrence of bipolar disorder dramatically increased to 44%. That is, approximately 55% of adolescents who have a diagnosis of comorbid ADHD, ODD, and conduct disorder do not have an onset of bipolar symptoms.

Nonetheless, a potential complication to note in youths who have comorbid ADHD and ODD is the development of bipolar features, including depression and psychosis. In addition, the combination of ADHD and ODD increases the likelihood that the patient will become involved in illegal activities and incarceration. Therefore, bipolar symptoms already exist or may develop in some incarcerated youths.[54, 29]

In a prospective study of 26 prepubertal youths in whom bipolar disorder and conduct disorder manifested at age 8-13 years, Kovacs and Polack found at their 12-year follow-up evaluation that the lifetime comorbidity for these 2 disorders was 69%. Additional review of the pattern of psychiatric pathology revealed that of the patients in whom both disorders began when they were younger than 13 years, 42% were diagnosed first with conduct disorder, whereas 27% were diagnosed first with bipolar disorder.[55]

Because clinicians are often concerned that conduct disorder increases the risk of antisocial personality disorder, careful screening and monitoring for the comorbid conditions of bipolar disorder and conduct disorder may be necessary in youths who present with either of these disorders. Such screening may help to identify and treat these youths so they may avoid incarceration and perhaps erroneous labeling as antisocial adults rather than as individuals with coexisting bipolar disorder and conduct disorder.[54]

Incarcerated youths have a disproportionately high prevalence of bipolar disorders compared with youths in the general population. Steiner estimated that 2% of incarcerated juveniles have bipolar I disorder (BPI), whereas 4% have bipolar II disorder (BPII).[56]

ADHD is a commonly observed comorbid diagnosis in youths with bipolar disorder. Among prepubertal youths presenting with bipolar symptoms, some studies have shown that as many as 90% have a diagnosis of ADHD, although other researchers have found lower comorbid incidences of ADHD. Among adolescents, the highest reported percentage of concurrent ADHD in those with bipolar disorder is 30%.[57, 26]

The most reliable predictor of DMDD is chronic irritability combined with a lack of history of mania along with a family history of ADHD, conduct disorder or oppositional defiant disorder.[50]

Comorbid conditions should be assessed in a timely fashion. Autism spectrum disorder and pediatric anxiety disorder may present with mood disturbances.[53] Comorbid substance abuse, especially nicotine abuse, presents along with ADHD.[38]

In summary, sustained symptoms of conduct and impulse control problems may be warning signs of a prepubertal onset of bipolar disorder.

Other conditions to be considered include the following:

  • Delinquency/truancy

  • Oppositional defiant disorder

  • School refusal

  • Thyrotoxicosis

Differential Diagnoses

 

Workup

Approach Considerations

Initial tests for substance and alcohol abuse are usually necessary to exclude drugs and alcohol as causative agents for behavior. No specific blood or other laboratory tests aid in diagnosing bipolar disorder. Among bipolar youth aged 9 years and older, frequency of comorbid alcohol or drug use is significant. In one study, 34% of bipolar youth used alcohol at least once and 11.9% reported regular alcohol use; 30.1% used drugs at least once and 16.2% reported regular drug use.[45]

Go to Bipolar Affective Disorder for complete information on this topic.

Blood Studies

Thyroid hormones

Thyroid studies may help to rule out a thyroid disorder as a cause of an altered mood. Triiodothyronine (T3) levels may be elevated in agitated patients who have normal thyroid function. Additional thyroid tests, such as thyroid-stimulating hormone (TSH) and thyroxine (T4) studies, can be helpful, as well as consultation with an endocrinologist.

Serum blood chemistries

Serum blood chemistries, such as basic metabolic panels and liver function tests, may help assess renal and hepatic health before certain medications are started or continued to help regulate or ameliorate bipolar symptoms.

Mania and depression may both involve states of malnutrition secondary to the psychiatrically diminished awareness of or ability to maintain one’s health and well-being. Thus, a metabolic panel, in addition to thiamine, albumin, and prealbumin studies (in extreme cases), may help determine the extent of self-neglect and compromised nutritional state. levels of vitamin D, folate, vitamin B-12, vitamin B-6, and total protein can also be abnormal and should be checked, especially in the presence of acute mania or hypomania.

Other tests

Routine screening for substance misuse is not indicated; however, clinical history of substance misuse or pregnancy may indicate the need for such screening such as urine or blood testing for substances of abuse and alcohol. In patients with known hypersexuality, a very careful sexual history should be taken. An HIV test should also be administered, as well as HIV prevention counseling.

Serum cortisol levels may be elevated, but this is neither of diagnostic nor clinical value.

Drug Level Monitoring

After pharmacotherapy is implemented, periodic laboratory tests may be required to monitor drug levels and to ensure that no adverse response to the medication is harming renal or hepatic function or bone marrow. Medications that are strong CYP2D6 inhibitors such as fluoxetine, bupropion, and lamotrigine may cause increases in risperidone concentration and increased risk of adverse side effects, such as elevated prolactin, especially in individuals who are poor metabolizers.[58, 59]

Neuroimaging

Initial studies suggest that developmental changes with maturity in children and adolescents with bipolar disorder differ from those in healthy peers. Neuroimaging modalities are not yet diagnostically helpful in diagnosing bipolar disorder in individuals, but studies are ongoing to determine if they would be helpful in diagnosis.

In some studies, neuroimaging (ie, functional magnetic resonance imaging [fMRI]) in child and adolescent patients with bipolar disorder has shown abnormal neural activation for faces with negative emotions along with face-processing deficits.[60] Adolescent patients failed to show normal developmental maturity changes with respect to total hippocampal volume in comparison to healthy controls.

Other studies have shown abnormal corpus callosum myelination and enlarged ventricles with an increased number of hyperintensities compared with healthy control subjects.[33]

Electrocardiography and Echocardiography

Before a psychotropic medication is started, baseline electrocardiography (ECG) and echocardiography, with measures of cardiac contractility, should be performed; many medications (lithium, trazodone, ziprasidone, risperidone, quetiapine, verapamil) may alter QT intervals or other features of the cardiac rhythm, thereby affecting cardiac contractility and output. This is especially critical if the patient has a family history of a structural or electrical heart abnormality.

 

Treatment

Approach Considerations

The treatment and management of bipolar disorder are complicated. Hence, most children and adolescents with this diagnosis require referral to a psychiatrist specializing in their age group. In general, a team approach is used in the clinical setting because several factors need to be addressed, including medication, family issues, social and school functioning, and, when present, substance abuse.

In general, the treatment of bipolar disorder may be thought of as a 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, and (4) attainment and maintenance of euthymia.

The treatment of adolescent or juvenile patients with bipolar disorder is modeled after treatments provided to adults; it appears that adult bipolar disorder is continuous with pediatric bipolar disorder.[61]

The goals of inpatient or outpatient treatment are to control and minimize symptoms of bipolar disorder, to prolong normal mood states or euthymia, to minimize the number of needed hospitalizations, to eliminate or minimize medication adverse effects to a tolerable level, and to optimize the quality of life (QOL) for the patient.

QOL issues for a young person include meaningful relationships with family, peers, mentors, 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.

The goals of individual therapy and family therapy should be individualized. Nonetheless, 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.[29, 9, 57] 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. In mental healthcare centers and in private practices, most patients and their families receive care from many professionals.

Psychiatrists, psychologists, behavioral and developmental pediatricians, social workers, and many other therapists are involved in treating the patient, monitoring the response to and tolerance of medications, and providing psychotherapy to the family and the patient. In the ideal situation, these professionals work together in a team approach so optimal care can be attained in the medical, educational, family, and social realms.

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.[22]

Go to Bipolar Affective Disorder for complete information on this topic.

Inpatient Hospital Treatment

Adolescents and children with bipolar disorders often present at times of family or youth despair or family crises surrounding their behaviors. In such critical times, inpatient care is often indicated to assess the patient, diagnose the condition, and ensure the safety of the patient or others.

Hospitalization is necessary for most patients with psychotic features and in almost all patients who have suicidal or homicidal ideations or plans. Inpatient care should always be considered in young persons who have suicidal or homicidal ideation and have access to firearms in their homes or communities and in those who abuse substances, particularly alcohol.[29, 62]

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.

Pharmacotherapy

The principles of pharmacotherapy include 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), as the NNH should be larger than NNT.

Although it is common for children and adolescents with bipolar disorder to be treated with medications, risperidone, ziprasidone, aripiprazole, valproate, and lithium (in patients as young as 12 years) have received approval from the US Food and Drug Administration (FDA) for this application. Lurasidone was approved in 2018 for the treatment of major depressive episodes associated with bipolar I disorder (bipolar depression) in children and adolescents aged 10 to 17 years.[63]

Pediatric treatment guidelines have evolved on the basis of empirically derived plans. The Child Psychiatric Workgroup on Bipolar Disorder established guidelines based on the most up-to-date evidence.[64] In general, these 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 (see the table below). 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.

Table 2. Medications for Pediatric Bipolar Disorder: Common Adverse Effects and Special Concerns (Open Table in a new window)

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 disease; drug-drug interactions and sodium intake may alter therapeutic serum levels

Approved for patients 12 y and older

Sodium divalproex/valproic acid (Depakote, Depakene)

Sedation, platelet dysfunction, liver disease, alopecia, weight gain

15-30 mg/kg/d; dose must be adjusted by monitoring serum levels; up-titrate on twice- or thrice-daily schedule

Elevated liver enzymes or liver disease, drug-drug interactions, bone marrow suppression

Approved for patients 12 y and older

Aripiprazole (Abilify, Abilify Discmelt)

Less likely to cause prolactinemia than risperidone; may cause Stevens-Johnson syndrome; as with other atypical antipsychotics, may cause tardive dyskinesia, dystonia, parkinsonism, hyperglycemia; use with caution in seizure disorders and cardiac disorders, including problems with cardiac contractility and electrical activity

2 mg once daily can be increased to 5 mg, 10 mg, 15 mg, to a maximum of 30 mg to start

titrate upwards at weekly to bimonthly intervals

levels may need to be adjusted in patients who are concurrently receiving lamotrigine, topiramate, Depakote, lithium, or other serotonin-norepinephrine reuptake, selective serotonin reuptake, or cytochrome P450 inhibitors

Do not administer if there is an unstable seizure disorder

Approved for patients 12 y and older

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 SL 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 10 y and older

Risperidone (Risperdal, Risperdal Consta, Risperdal M-Tab)

Weight gain, sedation, orthostasis

0.25 mg bid or 0.5 mg at bedtime initially; titrate as tolerated to target dosage of 2-4 mg/d; not to exceed 6 mg/d

Galactorrhea, extrapyramidal symptoms

Approved for patients 10 y and older

Quetiapine (Seroquel, Seroquel XR)

Sedation, orthostasis, weight gain

50 mg bid initially; titrate as tolerated to target dosage of 400-600 mg/d

Decrease dosage with hepatic impairment, may cause neuroleptic malignant syndrome or hyperglycemia

Approved for patients 10 y and older

Olanzapine (Zyprexa, Zyprexa Zydis, Zyprexa Relprevv)

Weight gain, dyslipidemia, sedation, or orthostasis

2.5-5 mg at bedtime initially; titrate as tolerated to target dosage of 10-20 mg/d

Metabolic syndrome, extrapyramidal symptoms

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 20 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 to 40 mg (not to exceed 60 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 individuals with a family history of cardiac sudden death related to cardiac conduction abnormalities

WBC—white blood cell.

The use of mood-stabilizing agents in children and adolescents has unique considerations. In general, adolescents and children have higher metabolism than adults because of the efficiency of their hepatic functions. In addition, adolescents and children have 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.

Mood stabilizers and/or atypical antipsychotics can be used as primary treatment for bipolar disorders in adolescents or children, and emerging evidence from large-scale controlled studies include the use of lithium carbonate, valproic acid or sodium divalproex, and carbamazepine.

Lithium carbonate is effective in approximately 60-70% of adolescents and children with bipolar disorder and remains the first-line therapy in many settings. Approximately 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.

As in adults with bipolar disorder, 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; thus, it is usually only used after atypical antipsychotics and/or valproate/sodium divalproex and/or lithium carbonate have been tried at optimal doses for a sufficient period and are ineffective or if there are contraindications to the use of other medications to stabilize an acute mood disorder or for long-term maintenance.

Lamotrigine is also 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) have had mixed results in adults with bipolar disorder and are not yet indicated in case reports and studies. However, studies are beginning to show the potential usefulness of these medications in pediatric patients with bipolar disorder.

Atypical antipsychotic agents may be used due to demonstrated antimanic properties in pediatric patients with bipolar disorder who present with or without psychosis. These include asenapine (Saphris), risperidone (Risperdal), olanzapine (Zyprexa), and quetiapine (Seroquel) and may be considered first-line alternatives to lithium, valproate, or carbamazepine.

Clozapine (Clozaril) may be considered only in treatment-refractory cases. It is believed to provide protection against suicidality similar to that provided by 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.

A 2012 multicenter study from the TEAM study group (Treatment of Early Age Mania) is one of the first studies 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. The study found that 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 thyrotropin-stimulating hormone levels implying that thyroid function should be closely monitored in children treated with lithium.[65]

Limited data indicate that 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. Metformin and troglitazone (oral antiglycemic agents) may be helpful in treating the secondary hyperglycemia, and atorvastatin (Lipitor) may be helpful in treating or reversing the abnormalities of serum lipids (hypertriglyceridemia, hypercholesterolemia) caused by therapy with atypical medications.

Calcium channel blockers (Verapamil), angiotensin-converting enzyme (ACE) inhibitors, and phenytoin (Dilantin) may be helpful in some individuals but have not been proven effective and have not been tested in children or adolescents for use in bipolar disorder.

Benzodiazepines, such as clonazepam (Klonopin) and lorazepam (Ativan), 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 (Xanax).

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.

Depressive episodes are frequently the first presentation of bipolar disorders in youths. In these situations, the clinician is wise to recall that approximately 20% of adolescents who have a diagnosis of depression later reveal manic symptoms; 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.[64, 66, 62] An antidepressant with a potentially lowered risk of inducing mania is bupropion (Wellbutrin).

Selective serotonin reuptake inhibitors (SSRIs) should be used cautiously, owing to the risk of mania; doses should be low and titration slow. However, this agent should be used carefully in patients with bipolar disorder because of its long half-life and because of its potential to cause significant weight gain and/or to exacerbate manic symptoms.

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.

Complications of drug treatment

Treatment with mood stabilizers is a vital part of maintaining optimal functioning in children and adolescents with bipolar disorder; however, side effects such as weight gain and acne are particularly problematic with agents such as lithium, olanzapine, and valproate.[66, 32, 67]

Therapy with atypical antipsychotics may predispose to neuroleptic malignant syndrome (NMS) in children and adolescents; patients should be closely observed for such effects.[68]

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.[69, 70, 71, 72, 73]

Family conflict may decrease response to medication treatment and so should be addressed in a timely fashion.[30, 74]

Behavioral Therapy

Therapeutic interventions that appear to be helpful in bipolar disorder include social rhythm therapy,[39] interpersonal therapy (IPT), dialectical behavior therapy (DBT), cognitive behavior therapy (CBT), family therapy, group therapy. Supportive psychotherapy or psychoanalysis should be reserved for individuals who are more likely to respond to those therapies.[57]

Electroconvulsive Therapy

Although electroconvulsive therapy (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 because it is most frequently used in patients with severe or refractory disease, who are likely to require hospitalization more often. Still, ECT may be started at any point in treatment because each ECT treatment can be performed 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. All ECT treatments require the presence of an anesthesiologist or anesthetist throughout the administration of therapy. 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 has been demonstrated to be both safe and therapeutic in adolescents and children. One favorable aspect of ECT is its therapeutic response time, which is more rapid than that of medications (days rather than weeks). One drawback is the associated memory loss surrounding the time just before and after treatments.

Other Treatments

Studies of complementary medications, such as omega-3 fatty acids (PUVA) to reduce symptoms of depression with less risk of mania and herbal preparations to increase sleep, are ongoing and appear promising; however, data are still being gathered regarding long-term safety considerations for children and adolescents. Concerns exist over long-term exposure risks associated with these medications in this population.[69, 70, 75]

Trials of deep brain stimulation for refractory depression are promising, 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.

Dietary Measures

Many individuals with bipolar disorder forget to eat or excessively consume a very unbalanced diet (eg, "empty" calories without adequate fiber or vitamins) during agitated manic states. This can 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.

Prevention

The following measures may help prevent or minimize episodes of bipolar affective disorder:

  • 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[76, 64, 29, 75]

Consultations

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.

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.[77]

 

Medication

Medication Summary

Mood stabilizers, such as lithium carbonate, sodium divalproex, and carbamazepine, have traditionally been the mainstays of treatment of patients with bipolar disorder. However, atypical antipsychotics are increasingly used in bipolar disorder, with or without psychotic symptoms. This class of medications includes asenapine, risperidone, quetiapine, olanzapine, aripiprazole, ziprasidone, and clozapine. In 2018, the FDA approved lurasidone for the treatment of major depressive episodes associated with bipolar I disorder in children and adolescents aged 10 to 17 years.[63] Benzodiazepines may be used to improve sleep and to modulate agitation during hospitalization.

Potential problems include the possibility of neuroleptic malignant syndrome with treatment with valproate.[78]

Mood stabilizers

Class Summary

Mood stabilizers are indicated for control of manic episodes occurring in bipolar disorder. They include lithium carbonate, valproic acid or sodium divalproex, and carbamazepine.

Lithium (Lithobid)

Lithium is considered a first-line agent for long-term prophylaxis in bipolar illness, especially classic bipolar disorder with euphoric mania. It is also used to treat acute mania, though it cannot be up titrated to an effective level as quickly as valproic acid can. Evidence suggests that lithium, unlike any other mood stabilizer, may have a specific antisuicide effect. Monitoring of blood levels is critical with this medication.

Anticonvulsants

Class Summary

Anticonvulsants have been effective in preventing mood swings associated with bipolar disorder.

Valproic acid (Depacon, Depakene, Depakote)

Valproic acid has proven effectiveness in treating and preventing mania. It is classified as a mood stabilizer and can be 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%.

Carbamazepine (Equetro)

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.

Atypical Antipsychotics

Class Summary

Atypical antipsychotics are being used increasingly for treatment of both acute mania and mood stabilization.

Aripiprazole (Abilify, Abilify Discmelt)

Aripiprazole is an atypical antipsychotic that is approved for bipolar disorder in children aged 10-17 years. It can be used as monotherapy or adjunctively with lithium or valproate. For children younger than 10 years, the safety and efficacy has not been established. It is a partial dopamine D2 and serotonin 5HT1A agonist, and it antagonizes serotonin 5HT2A.

Risperidone (Risperdal, Risperdal Consta, Risperdal M-Tab)

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 (Seroquel, Seroquel XR)

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.

Olanzapine (Zyprexa, Zyprexa Zydis, Zyprexa Relprew)

Olanzapine's mechanism of action for acute manic episodes associated with bipolar I disorder is unknown. It is approved by the US Food and Drug Administration (FDA) for adolescents with bipolar I disorder. It is available in tablet, oral disintegrating tablets (Zyprexa, Zydis), and intramuscular (IM) dosage forms. It is approved for children aged 13 years and older.

Ziprasidone (Geodon)

Indicated 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. Although effective for bipolar disorder, the mechanism of action in bipolar disorder is unknown.

Asenapine (Saphris)

Asenapine is an atypical antipsychotic. It is indicated as monotherapy for the acute treatment of manic or mixed episodes associated with bipolar I disorder in pediatric patients aged 10-17 years. Its mechanism of action is unknown, but is thought that its efficacy is attributed to antagonism of dopamine-2 and serotonin-2a receptors.