Approach

Bipolar I disorder interferes with the child's family and peer relationships and academic functioning. In the case of a clear manic episode, treatment is aimed at controlling and ending the episode as quickly as possible. It is important for the child and family to understand the behaviors and symptoms being targeted.

Environmental circumstances that are exacerbating the problems need to be modified (e.g., poor sleep habits, retaliating responses, inappropriate class placements). Baseline information noting frequency, intensity, and number and duration of rage outbursts needs to be obtained and monitored with treatment.

Treatment should be designed for the individual patient so that efficacy, tolerability, and compliance are maximized. Patients should be monitored with regular follow-up to monitor target symptoms, outcomes, and adverse effects.

If the child has comorbid disorders such as ADHD, autism spectrum disorder, anxiety, or oppositional defiant/conduct disorder, these conditions must be addressed. If the parent(s) have a mental illness, this should be evaluated and treated.[120]

Overview of pharmacotherapy

Pharmacotherapy is the mainstay of treatment for children and adolescents with bipolar disorder. Choice of drug should be based on:[18]

  • Evidence of effectiveness

  • Phase of illness

  • Subtype of disorder (psychosis, mixed episode, rapid cycling)

  • Adverse effect profile with respect to the particular patient

  • Patient's history of medication response

  • Possibly, also a family member's history of medication response.

Because all psychotropic drugs are associated with important adverse effects, a careful risk/benefit analysis is essential before initiating treatment. In particular, few studies have examined the effect of antimanic medications in children younger than 10 years of age; therefore, particular caution is warranted in this age group.[121] One small trial in preschool children with bipolar disorder and mania demonstrated that risperidone, but not divalproex, was more efficacious than placebo for the treatment of mixed or manic episodes in children ages 3-7 years.[122] However, laboratory and weight findings suggested that younger children were more sensitive to the effects of both psychotropics, and caution should be exerted in the use of these medications in this age group. One US study reported that, although the use of atypical antipsychotics in children <6 years of age has declined from its peak in one state, it remains substantial. Of additional concern was the finding that providers other than child psychiatrists were reported to be prescribing atypical antipsychotics, and there was a marked geographic variation in use, suggesting this population needs improved systems of mental health care.[123]

If the child is taking a medication that has been implicated in causing mania, the medication should be withdrawn, if possible. If manic symptoms subside, a decision must be made regarding whether the child was experiencing true mania or medication-induced activation.[18][120]

One consideration that is relevant to teenage girls who might become pregnant is that many drugs used in the treatment of bipolar I disorder are teratogenic. Divalproex is associated with the highest rate of major congenital malformations (6.2% to 16.0%). The relative risk (RR) of neural tube defects with divalproex and carbamazepine is reported as approximately 1% to 5% and 0.5% to 1%, respectively.[124] Preliminary evidence suggests that the RR for oral clefts (cleft lip or palate) is increased with lamotrigine relative to other anticonvulsant drugs, at approximately 0.4%. The rate of major congenital malformations is higher in fetuses exposed to anticonvulsant drug polytherapy (i.e., ≥2 drugs) in comparison with anticonvulsant drug monotherapy.[124] Adverse neurobehavioral effects are insufficiently reported for most agents. Exposure to divalproex in utero is associated with a greater risk of developmental difficulty resulting in decreased verbal IQ scores and the need for special education interventions. In the US, standard practice is that valproate and its analogs are only prescribed for the treatment of manic episodes associated with bipolar disorder during pregnancy, if other alternative medications are not acceptable or not effective.[125] Divalproex is not recommended for use in girls and women of childbearing potential by the World Health Organization (WHO).​[126] ​Other international guidelines stipulate that valproate and its analogs must not be used in female patients of childbearing potential unless other options are unsuitable, there is a pregnancy prevention program in place, and certain conditions are met.[118]​[127]​​​​

Lithium treatment in pregnancy is associated with a higher rate of cardiovascular anomalies in the offspring, including the Ebstein anomaly.[128][129] The major congenital malformation rate with chlorpromazine and second-generation (atypical) antipsychotics is not established as being higher than a nonexposed group; the teratogenic risks associated with the olanzapine/fluoxetine combination are unknown.[124]

Acute mania/mixed mania

Recommendations in line with Food and Drug Administration (FDA) indications for initial treatment include either risperidone, aripiprazole, olanzapine, lithium, or quetiapine at the lowest starting doses, as well as increasing the dose while observing for improvement and adverse effects. In areas outside the US, recommendations may vary. For example, in the UK, only aripiprazole is licensed for this indication to be used for up to 12 weeks of treatment for moderate to severe manic episodes in young people aged 13 years and older with bipolar I disorder; in line with this, the UK National Institute for Health and Care Excellence (NICE) guidelines do not routinely recommend treating this patient population for more than 12 weeks.[130] Positive placebo-controlled trials in children and adolescents have been reported for these second-generation antipsychotics,and the efficacy of the second-generation antipsychotics appears to be greater in mania than for psychotic symptoms in schizophrenia.[130][131][132][133][134][135][136][137][138][139][140][141][142][143][144]

The potential benefits of medication need to be considered alongside possible risks.[121][145][146] The adverse effect profile usually governs which medication is most likely to be used.[138][142][147][148]

Lithium is a first-line treatment for bipolar disorder in adults, and is an effective treatment for reducing the risk of suicide in adults with mood disorders.[119][149][129][150] However, there is less evidence in children with regard to efficacy.[18][151][144][152] One small, 8-week multicenter randomized controlled trial (RCT) in pediatric participants (ages 7-17 years) with bipolar I disorder and manic or mixed episodes reported that lithium was superior to placebo in reducing manic symptoms in this population.[144]

One RCT in 290 children, ages 6 to 15 years, diagnosed with bipolar I disorder (having mixed or manic symptoms) showed that risperidone was more effective than lithium or divalproex sodium for the initial treatment of pediatric mania. The discontinuation rate was higher for lithium than for risperidone or divalproex sodium. Those treated with risperidone gained more weight than those on the other medications.[152] With regard to divalproex, data from a placebo-controlled trial were negative, and risperidone was superior to divalproex in a small double-blind trial.[153][154]​ One meta-analysis demonstrated no significant difference in response rates to divalproex, compared with placebo, for treatment of acute mania in children and adolescents, although the quality of evidence was very low.[155] In the US, standard practice is that valproate and its analogs are only prescribed for the treatment of manic episodes associated with bipolar disorder during pregnancy, if other alternative medications are not acceptable or not effective.[125]​ Divalproex is not recommended for use in girls and women of childbearing potential by the WHO.[126] Other international guidelines stipulate that valproate and its analogs must not be used in female patients of childbearing potential unless other options are unsuitable, there is a pregnancy prevention program in place, and certain conditions are met.[118]​​[127]​​ Some therapeutic response is expected within 1-2 weeks.[156]

For patients failing to respond to one of the initial approaches, consideration of dose optimization and medication adherence is recommended prior to moving on to the next pharmacotherapy options.[117][157] If there is no response, or the drug is not tolerated due to adverse effects, it is recommended that a different drug among the recommended initial treatments is tried. If the first drug that was tried was a second-generation antipsychotic and was shown to be only partially effective, lithium or divalproex can be added. Divalproex has been found to reduce levels of aripiprazole and olanzapine when given as combination treatment in adults.[158]

The impact of comorbid disorders should be addressed, as this can also affect response to treatment. Comorbid ADHD has been shown to be associated with a lower response to lithium and divalproex, and comorbid anxiety has been shown to be associated with a significantly lower likelihood of syndromic recovery.[159][160][161] Combined treatment with a selective serotonin-reuptake inhibitor (SSRI) and cognitive behavioral therapy (CBT) is the most efficacious strategy in treating anxiety. Therefore, the use of SSRIs needs to be considered in the presence of anxiety, albeit under close supervision, because comorbid anxiety appears to be associated with a higher risk of treatment-emergent mania.[16]

Other pharmacotherapy options include substituting a first-generation (typical) antipsychotic agent such as haloperidol (although this should be avoided in very young children due to the possibility of tardive dyskinesia) or an alternative second-generation antipsychotic (e.g., paliperidone), adding a benzodiazepine such as lorazepam (useful in cases of agitated mania), and/or adding a mood stabilizer (e.g., carbamazepine). There is no evidence that oxcarbazepine is effective for acute bipolar disorder and its use is not recommended.[86][162] Gabapentin can be useful for children and adolescents with sleeping problems but can cause disinhibition. These off-label treatments appear in many treatment guidelines, but data supporting their efficacy in mania are largely absent. A specialist should be consulted for guidance on suitable drug combinations and the doses for these treatments.

Electroconvulsive therapy has been used in adolescents with refractory depression and mania. There is evidence that ECT significantly improves clinical outcomes for adolescents in acute phase treatment, especially for those diagnosed with a comorbid substance use disorder.[163] Adult guidelines can be followed in cases where the depression or mania resembles those conditions in an adult.[156][164]

For children and adolescents with first onset of psychosis, there is a lack of trial data to guide the choice of treatment. Such data are urgently needed, as extrapolations from adult studies may not be implementable. One head-to-head randomized controlled trial (RCT) comparing quetiapine (extended release) versus aripiprazole in children and adolescents with a first episode of psychosis showed no significant differences between the treatment groups in severity of psychotic symptoms after 12 weeks of treatment, with only a modest improvement in symptoms for both groups. Quetiapine was associated with more metabolic adverse events and aripiprazole was associated with more initial akathisia and, unexpectedly, with more sedation.[165]

Bipolar depression

The depressive phase of the illness remains under-studied in both children and adults, and many frequently used treatments, such as lithium, divalproex, and lamotrigine, have limited or no evidence to support their use for the acute treatment of bipolar depression.[166][167][168] Two RCTs in children and adolescents, ages 10 to 17 years, diagnosed with bipolar depression failed to demonstrate a significant benefit of quetiapine versus placebo.[169][170] One large placebo-controlled trial found that the olanzapine/fluoxetine combination was superior to placebo, and has been approved by the FDA for the acute treatment of bipolar I depression in patients 10 to 17 years of age.[171] However, benefits should be weighed against the risk of adverse events, particularly weight gain and hyperlipidemia.

The FDA has also approved lurasidone, an atypical antipsychotic, for the treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in patients ages 10 to 17 years. This pediatric indication was based on data from a 6-week RCT (n=347).[172] Lurasidone was associated with statistically significant and clinically meaningful improvement in bipolar depression symptoms compared with placebo, based on the primary efficacy end point of change from baseline to week 6 on the Children’s Depression Rating Scale-Revised (CDRS-R) total score. Statistically significant and clinically relevant change from baseline to week 6 on the Clinical Global Impression-Bipolar Version, Severity of Illness (CGI-BP-S) score (depression) at the secondary end point was also seen with lurasidone compared with placebo. The most common treatment-emergent adverse events reported for lurasidone compared with placebo were nausea (16.0% vs. 5.8%), weight gain (6.9% vs. 1.7%), and insomnia (5.1% vs. 2.3%).

Decisions regarding managing children with bipolar depression are made on a case-by-case basis. Various drugs are approved for the treatment of bipolar depression and show efficacy in adults. However, these data cannot necessarily be extrapolated to children and adolescents.[173][174][175][176][177][178] The use of the olanzapine/fluoxetine combination should be carefully monitored.[179][180]

There has been considerable debate regarding the increased risk of suicidality with SSRIs; in addition, antidepressants in adult bipolar depression do not demonstrate a clear favorable risk/benefit ratio.[181][182] Therefore, a careful risk/benefit analysis should be undertaken if SSRIs are to be considered. SSRIs may be indicated in the presence of comorbid anxiety, because they have a more favorable risk/benefit ratio in this disorder and, in addition, comorbid anxiety has been associated with more severe depressive symptoms.[16]

The risk of "switching" or developing mood elevation as a result of most drug therapies used to improve mood is a contentious topic, although there is some evidence that comorbid anxiety is associated with an increased risk of treatment-emergent mania.[16][183][184] Extrapolating from information about activation in studies of SSRIs, activation rates are higher in children, averaging about 10%, than in adolescents and adults.[185][186] Activation is a form of behavioral toxicity in which a drug makes a child more excited and irritable and, in some people's opinions, appear more manic.

Of particular relevance to children and adolescents is a first episode of depression in those with a family history of bipolar disorder. In these patients, the risks of precipitating a mania/hypomania/bipolar course with an antidepressant must be considered; although generally this risk is considered to be relatively low, it may be greater in young people with a family history of bipolar disorder, and in those with a history of manic symptoms.[187] When there is such a history, the reliability of parent observation, adherence to treatment of the child, and family preference should be carefully considered in the decision-making process.[85]

Long-term preventive treatment

In general, treatment guidelines endorse initiation of maintenance therapy after a single manic episode, and suggest discussing maintenance options in a collaborative fashion with all patients once they are stabilized after an acute episode.[119][146] In young people, this recommendation is more tenuous because of absent data describing the rate of sustained remission after a single episode. However, the greater the risks posed by the illness, and the more classic the episode, the more applicable the adult guidelines are.[18] Medications utilized to stabilize an acute episode may be continued as maintenance therapy for most patients, although it is necessary to remain vigilant for relapse or recurrence as well as any treatment-emergent adverse effects, particularly neurologic (extrapyramidal adverse effects, tardive dyskinesia), metabolic (obesity, diabetes mellitus, dyslipidemias), or toxic effects (renal, hepatic, hematologic, thyroid).[138][148][157][188][189][190][191] Adult data in patients with first-episode schizophrenia who have received long-term antipsychotic treatment demonstrate that antipsychotics have a subtle but measurable influence on brain tissue loss over time, suggesting the importance of careful risk/benefit review of dosage and duration of treatment as well as their off-label use.[192] Although adverse events have usually been minor in the randomized studies of second-generation antipsychotics, longer-term, open label studies have indicated that some adverse events, such as the metabolic effects, may be severe and potentially life-threatening in the long term.[142] All atypical antipsychotics may cause diabetes mellitus; case reports exist, and there is evidence that this may be independent of weight gain.[193] Animal research reports an increased risk of cataracts with quetiapine; although there are no known case reports, regular lens monitoring is recommended.[193]

In adults, lithium and aripiprazole, when given as monotherapy, are more effective in preventing mania than depression. There is evidence for both the antimanic and antidepressant effects of olanzapine and quetiapine.[174] Divalproex is more effective as a maintenance treatment when combined with lithium in people with bipolar disorder.[194] Lamotrigine is more effective in preventing depression than mania.[119][146]

Psychosocial treatment and education

The aims of psychosocial interventions are to enable recognition of future episodes before they progress, enhance treatment adherence, and address environmental stressors that act as possible precipitants to further episodes.

There are 4 models of psychosocial treatment that have been studied in children and adolescents with early onset bipolar disorder:

  • Multifamily and individual family psychoeducation

  • Family-focused therapy for adolescents

  • Child- and family-focused CBT for younger children

  • Collaborative problem-solving.

Each emphasizes the importance of psychoeducation and destigmatization as well as increasing parental collaboration by reducing parent blame for causing the disorder. Other components include helping parents distinguish between normative developmental behavior and bipolar symptoms, taking proactive steps to decrease the risk of relapse, developing tools for effectively managing emotional arousal, improving family communication skills, and teaching adaptive problem-solving strategies.[18][120] There is evidence that multifamily psychoeducation produces improvements in the longer term over routine care, and adult data suggest that psychoeducational interventions appear to be of particular benefit.[156][195][196]

One large network meta-analysis that included nearly 3900 adults and adolescents with bipolar disorder demonstrated that psychotherapy in combination with pharmacotherapy was associated with a 44% reduction in relapse of symptoms at 1-year follow-up compared to pharmacotherapy alone.[197] This article further highlighted that family or group therapy was more beneficial than individual therapy. Dialectical behavior therapy may be effective in treating suicidality and depression in adolescents with, or suspected of having, bipolar disorder, and there is some preliminary evidence for the effectiveness of family-based CBT for manic symptoms and psychosocial functioning in children.[198][199] Interpersonal and social rhythm therapy does not confer any advantage over specialist supportive care in young people with bipolar disorder receiving psychopharmacological treatment.[200] 

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