Pediatric Bipolar Disorder: Combination Pharmacotherapy, Adverse Effects, and Treatment of High-Risk Youth

Pediatric Bipolar Disorder: Combination Pharmacotherapy, Adverse Effects, and Treatment of High-Risk Youth

Kiki D. Chang, MD

Treating bipolar disorder in pediatric patients is challenging because data from rigorous trials of pharmacotherapy in this population are still not plentiful enough. Furthermore, the treatment of children and adolescents is complicated by the frequent need to combine pharmacotherapies to address all bipolar symptoms as well as this population’s elevated risk for experiencing side effects. Additionally, young patients with depressive episodes who are at high risk for developing bipolar disorder need careful treatment to prevent or delay the emergence of mania. Despite these challenges, clinicians should evaluate the existing pediatric literature, extrapolate evidence obtained from adult patients, and draw from clinical experience to guide treatment decisions for children and adolescents with bipolar disorder.

(J Clin Psychiatry 2016;77[suppl E1]:e03)

From the Department of Psychiatry and Behavioral Sciences, Child and Adolescent Psychiatry, Stanford University School of Medicine, California.

This article is derived from the planning teleconference series "Recognition and Treatment of Pediatric Bipolar Disorder," which was held in August and September 2015 and supported by an educational grant from Forest Laboratories, Inc.

Dr Chang is a consultant for Sunovion, Actavis, Bristol-Myers Squibb, Janssen, and GlaxoSmithKline.

Corresponding author: Kiki D. Chang, MD, Child and Adolescent Psychiatry Clinic, 401 Quarry Rd MC5719, Stanford, CA 94305 ([email protected]).

dx.doi.org/10.4088/JCP.15017su1c.03

© Copyright 2016 Physicians Postgraduate Press, Inc.

A greater number of rigorous clinical trials on which to base recommendations for treating pediatric patients with bipolar disorder are needed. Until this body of evidence grows, treatment recommendations regarding safe and effective combination pharmacotherapy, side effect management, and treatment of youth at high risk for developing bipolar disorder must be drawn from the available studies, extrapolated from data on the treatment of adults with bipolar disorder, and based on clinical experience.

COMBINATION PHARMACOTHERAPY

Available practice guidelines for pediatric bipolar disorder are somewhat outdated.1,2 These guidelines recommend monotherapy with a traditional mood stabilizer or atypical antipsychotic as first-line treatment for acute manic or mixed episodes. The basic idea of these guidelines—that monotherapy is the preferred treatment in this patient population—is unchanged, but currently atypical antipsychotics tend to be the initial treatment of choice rather than mood stabilizers because of greater evidence of efficacy.3-5 Although guidelines recommend monotherapy, in actual practice, combination pharmacotherapy is more common for treating pediatric bipolar disorder.6,7 Potter and colleagues6 found that pediatric patients being treated specifically for mania or mixed states received an average (mean ± SD) of 1.4 ± 0.9 medications.6 In many cases, monotherapy will lead to only partial response.8

When treating pediatric patients with bipolar disorder, common sense should dictate using as few medications as possible at the lowest dose needed to stabilize the patient. However, the goal should be to resolve the patient’s mania quickly, and clinicians, therefore, may decide to use higher doses or combinations of medications to prevent the patient from being in a prolonged manic state, but these treatment strategies should only be used in the short term.

• Avoid combination therapy as much as possible.
• Select an agent from a different class, begin at a low dose, and carefully monitor side effects if combination therapy is required to address all symptoms.
• Obtain baseline health measures and monitor for changes throughout treatment.
• Assess all patients for side effects.
• Before prescribing an antidepressant to a pediatric patient with mood symptoms, determine if the patient is at high risk for bipolar disorder.
• Emphasize psychotherapy and/or behavioral interventions when treating patients at high risk for bipolar disorder.

Thus, clinicians should first maximize the dose of the initial monotherapy.1 Patients who show no response to first-line treatment should be switched to an agent from a different class.1 If patients show a partial response to first-line treatment, clinicians should augment the initial treatment with a medication from a different class. That is, if a patient shows only partial response to an atypical antipsychotic, a mood stabilizer should be added. If the patient responds only partially to a mood stabilizer, an atypical antipsychotic should be added. Atypical antipsychotics, however, should not be combined because this strategy has not been well studied and may increase the risk for neuroleptic malignant syndrome.9 Combining mood stabilizers was somewhat common in practice, but this treatment strategy has been largely supplanted as evidence of atypical antipsychotic efficacy has grown.3,10 Once a patient has remained euthymic for 12 to 18 months on combination therapy, one medication can be slowly tapered off,5 but if combination therapy is required in order for the patient to recover, it may also be required as maintenance treatment to prevent a recurrence of symptoms.11

Combining drugs from different classes with different mechanisms of action broadens the therapeutic effect. Excessive dopaminergic activity in limbic areas has been implicated in the pathophysiology of bipolar disorder, and atypical antipsychotics are believed to derive their efficacy by reducing dopamine transmission through loosely binding with dopamine D2 receptors,12,13 Mood stabilizers have different mechanisms of action, and the mechanisms by which they derive their therapeutic effect in bipolar disorder are not fully understood.14 Lithium may affect signal transduction by inhibiting secondary messenger enzymes. Anticonvulsants such as divalproex sodium, carbamazepine, and lamotrigine are thought to act by blocking or diminishing the flow of ions through voltage-sensitive sodium channels, which are thought to be overly active in bipolar disorder.14

Few studies investigating combination pharmacotherapy in pediatric patients with bipolar disorder have been conducted. Findling and colleagues15 conducted an open-label trial of combination treatment with lithium and divalproex sodium in 90 patients aged 5 to 17 years who were diagnosed with bipolar I or II disorder. At week 8, participants showed significant improvement in manic symptoms, depressive symptoms, and functioning (P < .0001), and nearly half (46.7%) achieved clinical remission. Fifteen participants withdrew from the study due to tolerability issues, but, overall, the treatment was well tolerated. In a follow-up study, Findling and colleagues16 randomly assigned 60 of the patients who had been stabilized on combination treatment to receive either lithium or divalproex sodium monotherapy. The patients were followed for up to 76 weeks, and the investigators found that more than half of the patients in each group had relapsed within the first 3 to 4 months of the study, and no significant difference between lithium or divalproex sodium in time until reemergence of symptoms was observed.16 Thus, patients who are stabilized on a combination of lithium and divalproex sodium may require maintenance treatment with both agents in order to maintain remission. In an additional open-label follow-up study, Findling and colleagues17 resumed combination treatment in 38 of the patients who had relapsed on monotherapy in the previous study. Nearly all of the patients (89.5%) were successfully restabilized on combination pharmacotherapy within 8 weeks, and treatment was well tolerated with no participants withdrawing due to adverse events.

Although combination therapy with a mood stabilizer and an atypical antipsychotic is common in practice,18 this has not been well tested in clinical trials. My colleagues and I observed 3 prepubertal children with bipolar disorder who had experienced a manic relapse after treatment with either lithium or divalproex sodium.19 After adding 2.5-5 mg/d of olanzapine to their mood stabilizer treatment, all 3 patients experienced symptom resolution within 5 days, but sedation and weight gain were reported. DelBello and colleagues20 randomly assigned adjunctive quetiapine or placebo to 30 patients aged 12 to 18 years who were experiencing an acute manic or mixed episode and who were currently being treated with divalproex sodium monotherapy. After 8 weeks, the patients receiving divalproex sodium plus quetiapine experienced significantly greater improvement in Young Mania Rating Scale scores than those receiving divalproex sodium plus placebo (P = .03). The divalproex sodium plus quetiapine group did, however, report more sedation. Pavuluri and colleagues have conducted 2 open-label trials of risperidone combined with mood stabilizers and found both risperidone plus lithium21,22 and risperidone plus divalproex sodium22 to be safe and effective treatments for pediatric patients experiencing a manic or mixed episode. Although these studies have found preliminary evidence for the efficacy and safety of mood stabilizer and atypical antipsychotic combinations, large controlled trials are needed.

Some patients and their families may be interested in adding non-psychotropic agents to pharmacologic treatment. Omega-3 fatty acids may be able to stabilize mood in patients with pediatric bipolar disorder. Omega-3 fatty acids are obtained from both plant and animal dietary sources, but Western diets do not contain adequate levels of these nutrients. Gracious and colleagues23 conducted a 16-week study in which 51 patients with bipolar disorder, aged 6 to 17 years, took either flax oil, a plant-derived source of omega-3 fatty acid, or placebo, either as monotherapy or in addition to pharmacologic treatment. The study failed to reveal a significant difference in bipolar symptoms between the flax oil and placebo groups. However, the investigators assessed serum omega-3 fatty acid levels and found that only 8 patients had adequate exposure to flax oil, and this group did show improvement in overall illness and mania. The investigators concluded that future studies should explore fish oil as an omega-3 fatty acid supplement because fish oil is richer in the types of fatty acids more easily used by the body than plant-based sources.

MANAGEMENT OF ADVERSE EFFECTS

Effective management of adverse effects in pediatric populations is critical and is even more important when the patient is receiving combination therapy. Clinicians must be aware that side effects of drugs may manifest differently in pediatric patients than in adults.24 In order to effectively manage adverse events, clinicians need to be familiar with the side effects that children often experience during treatment with different medications.

Lithium

In my clinical experience, lithium generally appears to be better tolerated in pediatric patients than in adults. The following side effects may be associated with lithium: gastrointestinal irritation, sedation, tremors, headache, acne, psoriasis, weight gain, cognitive impairment, thyroid dysfunction, polyuria, polydipsia, enuresis, and, if used during pregnancy, Ebstein’s anomaly.25 Acne can be particularly distressing in this population because teenagers are usually socially sensitive. Lithium-induced hypothyroidism affects about one-third of adult patients, but available data indicate that this condition may affect only about one-quarter of pediatric patients.26 Thyroid dysfunction is usually reversible once lithium treatment is stopped; however, if the patient is responding to treatment but the lithium is causing reduced levels of circulating thyroid hormones, the patient can be treated with thyroid hormone replacement therapy.27 During lithium treatment, polyuria, polydipsia, and enuresis are fairly common side effects and are not necessarily indicative of renal dysfunction. However, because renal issues are possible with lithium treatment, clinicians should regularly assess renal function.25,26

Lamotrigine

Although lamotrigine is not approved for the treatment of pediatric bipolar disorder, the use of this medication in this population has grown.28 Lamotrigine is generally well tolerated, with little or no weight gain29,30 or cognitive impairment,31 but gastrointestinal symptoms and headaches have been reported in pediatric populations.3 The most commonly reported adverse effect is skin rashes, and children are more vulnerable to this than adults.32 Typically, these rashes are minor and transient, but in rare instances this drug has been associated with potentially serious skin rashes, including Stevens-Johnson syndrome.32,33 Slow and careful titration of lamotrigine diminishes the risk of skin rash, which is especially important in children who are also receiving valproate,33 and because the risk is low, this medication should be considered a viable treatment option because of its otherwise favorable tolerability profile.30

Atypical Antipsychotics

Several side effects are common with atypical antipsychotics as a class, but may be more pronounced in certain medications.34 These common adverse effects include sedation, gastrointestinal issues, hyperprolactinemia, extrapyramidal symptoms, neuroleptic malignant syndrome, weight gain, and metabolic syndrome.3,5,27,34,35 Sedation may initially be a helpful side effect to restore normal sleep patterns but could become problematic if it interferes with school or regular functioning.

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Although atypical antipsychotics are less likely to cause hyperprolactinemia than conventional antipsychotics, atypical agents do sometimes have this adverse effect, and youth may have a higher risk than adults.27 Risperidone appears to be the most likely atypical antipsychotic and aripiprazole the least likely to induce hyperprolactinemia (AV 1).27,36 Clinicians, however, must be aware that any antipsychotic can raise prolactin levels and that they should remain alert for signs of prolactin elevation such as galactorrhea or gynecomastia. If these signs appear, prolactin levels should be assessed and monitored during treatment regimen adjustments.37 Sometimes, antipsychotic-induced prolactin elevation will diminish or even normalize after continued treatment.27

Extrapyramidal symptoms (EPS) include tremor, muscular rigidity, parkinsonian features, or akathisia. Although these symptoms occur more frequently with older neuroleptics, they can occur with any atypical antipsychotic, and children seem to be more vulnerable to EPS than adults.37 The incidence of EPS is more common with aripiprazole, ziprasidone, paliperidone, and risperidone than with the other atypical antipsychotics.5,34,38 The ideal way to address EPS is to reduce the antipsychotic dose,5 but if the patient requires the higher dose for mood stabilization, a secondary agent may be added. Anticholinergics such as benztropine are the best options for patients experiencing multiple EPS; β blockers such as propranolol or benzodiazepines such as clonazepam may be used for patients experiencing akathisia.5,39 However, treating a side effect with an additional medication can be risky because the new medication will have side effects of its own and may lead to an overly anticholinergic state (eg, weight gain). If an additional agent is used to treat acute EPS, this agent should be slowly tapered over several weeks to avoid additional side effects. Alternatively, EPS may be addressed by switching the patient to a different atypical antipsychotic and thus avoiding the potential for compounding side effects.

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Weight gain and metabolic syndrome are related adverse events. Children may be more vulnerable than adults to weight gain associated with antipsychotic treatment.27 Weight gain in growing children is expected, but their body mass index (which factors in height) should be checked against norms for their age and gender. Criteria for metabolic syndrome vary slightly between adults and pediatric patients.27 Available data, not including all of the antipsychotics, suggest that clozapine and olanzapine, followed by risperidone and quetiapine, are most commonly associated with weight gain and the development of metabolic syndrome. Aripiprazole and ziprasidone are least associated with these adverse events.27 When initiating antipsychotic treatment, the patient’s family history of diabetes or cardiac problems should be assessed, and baseline body mass index, fasting blood glucose, and vital signs should be recorded and monitored at regular intervals.37 To prevent weight gain and metabolic side effects, the patient (and family) should be advised to eat a healthy diet and exercise regularly (AV 2),27 but these practices are difficult for most people and may be particularly difficult for a teenager with bipolar disorder.

TREATMENT-EMERGENT MANIA AMONG YOUTH WITH OR AT HIGH RISK FOR BIPOLAR DISORDER

Treatment-emergent mania is a problematic side effect among some patients who either are at risk for developing bipolar disorder or who already have it. If patients with major depressive disorder (MDD) or anxiety who have risk factors for bipolar disorder are treated with antidepressants (eg, selective serotonin reuptake inhibitors [SSRIs]), they could enter a mixed or manic state and then appear to meet the diagnostic criteria for bipolar disorder.40 However, the criteria for a manic episode necessitates ruling out medical causes, of which an SSRI exposure would be one such cause.41 The same reaction could occur among patients receiving stimulant medications, typically used for attention-deficit/hyperactivity disorder.42 Baumer and colleagues40 interviewed 52 pediatric patients, who had either bipolar disorder or subthreshold manic symptoms, and their parents about the children’s reactions to antidepressant medications. All of the patients had a parent with bipolar disorder. The investigators found that the majority of patients had a past negative reaction to antidepressants. These negative reactions included new onset or worsening of a manic or mixed episode, and new onset of suicidal ideation. Faedda and colleagues42 reviewed records of 82 children with bipolar disorder and discovered a 58% rate of treatment-emergent mania after exposure to antidepressants or stimulants. This reaction had led to the recognition of bipolar disorder in 17% of those children.42

Several risk factors for bipolar disorder have been identified in pediatric patients experiencing a depressive episode, including subthreshold mania, rapid onset, family history of bipolar disorder, psychomotor retardation, psychotic features, and atypical depression.2 When a child or adolescent presents with a major depressive episode and has any of these risk factors, clinicians are faced with a conundrum. Antidepressants are the standard pharmacologic treatment for depression, but the patient may be at risk for antidepressant-induced mania. Furthermore, depression is frequently the first mood episode experienced by individuals with bipolar disorder, and about 20% of pediatric patients with MDD will experience a manic episode by adulthood.43 Thus, the patient may be experiencing a first bipolar episode that happens to be depressive, and antidepressant treatment may trigger the first manic episode, which likely would have emerged eventually but was hastened by the antidepressant treatment.

Unfortunately, effective treatment alternatives have not yet been established.43 Placebo-controlled studies of lithium44 and divalproex sodium45 failed to find that these treatments were any more effective than placebo for alleviating mood symptoms in pediatric patients at high risk for bipolar disorder. DelBello and colleagues46 conducted a study of quetiapine in 20 adolescents at risk for bipolar I disorder and found that 87% of participants responded to treatment, but these findings are limited by the small sample size and lack of a placebo control.

Despite the limited data on safe and effective pharmacotherapy in pediatric patients at high risk for bipolar disorder, some recommendations can be made. Individual or family therapy should be emphasized because behavioral interventions may help hasten and prolong recovery (for more on this topic, see the articles in this supplement by Mary A. Fristad47 and David Miklowitz48).49 If an antidepressant must be used, the patient should be started at a low dose and carefully monitored for worsening of mood or emergent symptoms of mania.50 Patients and their parents should be educated about signs such as sleep difficulties, agitation, or feelings of euphoria or grandiosity that would indicate that mania is emerging and the medication needs to be discontinued. Practice recommendations and evidence on effective alternative agents for bipolar depression can be extrapolated from studies conducted in adults. Lithium is often used with little evidence of efficacy, but favorable results have been found with lamotrigine and lurasidone.51,52 The olanzapine-fluoxetine combination and quetiapine are also possible treatments.51,52

CONCLUSION

Ideally, pediatric patients with bipolar disorder should receive monotherapy with an agent that has a strong base of evidence of efficacy and safety drawn from rigorous trials in children and adolescents. In reality, these patients often require combination therapy with agents that have not been thoroughly tested in children or adolescents. Clinicians should draw from the available evidence as much as possible, but they should also draw from their own clinical sensibility and experience and remember basic principles such as to optimize the dose of the current medication before adding another, select agents from different classes when combining treatments, and attempt to slowly taper off secondary agents as soon as the patient is stabilized. Clinicians must also remember that all medications have side effects, and combination treatment will increase these side effects. Baseline health measures must be obtained and carefully monitored for changes. Clinicians should be aware of the potential for antidepressants to induce mania. When treating pediatric patients with MDD, clinicians should assess their risk factors for bipolar disorder and if a patient is determined to be at high risk, clinicians should proceed with caution.

Drug names: aripiprazole (Abilify and others), asenapine (Saphris), benztropine (Cogentin and others), carbamazepine (Carbatrol, Equetro, and others), clonazepam (Klonopin and others), clozapine (Clozaril, FazaClo, and others), divalproex sodium (Depakote and others), iloperidone (Fanapt), lamotrigine (Lamictal and others), lithium (Lithobid and others), lurasidone (Latuda), olanzapine (Zyprexa and others), olanzapine-fluoxetine combination (Symbyax and others), paliperidone (Invega and others), propranolol (Inderal, InnoPran, and others), quetiapine (Seroquel and others), risperidone (Risperdal and others), ziprasidone (Geodon and others).

Disclosure of off-label usage: Dr Chang has determined that carbamazepine, clonazepam, divalproex sodium, lamotrigine, lithium, paliperidone, propranolol, ziprasidone, and benztropine are not approved by the US Food and Drug Administration for the treatment of bipolar disorder in children and/or adolescents.

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