Pediatric Bipolar Affective Disorder Treatment & Management

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. ^[63]

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. ^{[31, 9, 59]} 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. ^[24]

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

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. ^{[31, 64]}

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.

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. ^[65]

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. ^[66] 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)

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. ^[67]

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. ^{[66, 68, 64]} 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. ^{[68, 34, 69]}

Therapy with atypical antipsychotics may predispose to neuroleptic malignant syndrome (NMS) in children and adolescents; patients should be closely observed for such effects. ^[70]

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. ^{[71, 72, 73, 74, 75]}

Family conflict may decrease response to medication treatment and so should be addressed in a timely fashion. ^{[32, 76]}

In one study, predictors of response to monotherapeutic approaches to bipolar depression (such as with quetiapine) showed a correlation between lower left dorsolateral prefrontal cortex baseline activation and greater left ventrolateral prefrontal cortex baseline activation. ^[77]

Family Focused care also appeared to delay episodes of bipolar depression as compared to regular enhanced care. ^[78]

Therapeutic interventions that appear to be helpful in bipolar disorder include social rhythm therapy, ^[41] 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. ^[59]

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.

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. ^{[71, 72, 79]}

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.

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.

Adequate protein intake may be protective of cognitive function in bipolar disorder. ^[80]   

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 ^{[81, 66, 31, 79]}

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.

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. ^[82]