Children and adolescents are increasingly being diagnosed with bipolar disorder (BD). Recent U.S. national trends suggest a 40-fold increase in the diagnosis of BD in youth in office-based settings over the last ten years,[1
] and a 4-fold increase in BD-related inpatient hospitalizations among adolescents,[2
] suggesting a rapidly increasing clinical identification of this disorder in paediatric populations. An early onset of BD in youth has been linked with a more severe course of illness, rapid cycling, an increased risk for psychosis, suicide attempts and substance abuse, as well as the presence of comorbidities and complications such as poor academic and job performance, interpersonal conflicts, or legal problems.[3
] In spite of vigorous efforts to find effective treatments for this condition in youths, treatment challenges are frequent and illness carries a high morbidity and mortality.[8
Comprehensive treatment plans are often required for individuals with BD to address a complex array of symptoms and associated morbidities. In general, a multimodal treatment approach combining pharmacological agents and psychosocial interventions is suggested, with the goal to improve symptoms, provide psychoeducation about BD, and promote treatment adherence for relapse prevention and attenuation of long term complications from the illness.[9
] Clinicians are encouraged to advocate for prevention, early intervention, and biopsychosocial treatments that promote the healthy growth and development of all children affected by BD, in any cultural context.
This article concentrates on the use of atypical antipsychotics for the treatment of BD in children and adolescents, and reviews some new controlled trials that have recently emerged, primarily for the treatment of acute manic or mixed BD episodes with this class of drugs. Studies were found through a systematic search on PubMed and in conference proceedings, and compared for analysis of efficacy and safety where there was clinical homogeneity and comparable trial duration.
Expert opinion, including the American Academy of Child and Adolescent Psychiatry (AACAP)[10
] guideline for the treatment of paediatric BD, endorses the use of a either a mood stabilizer such as lithium, valproate (divalproex) or carbamazepine, or an atypical antipsychotic such as olanzapine, risperidone or quetiapine as optimal first-line agents for the treatment of acute mania. Since the AACAP practice parameters were published, new data with other atypical antipsychotics like ziprasidone and aripiprazole have emerged, necessitating an update on existing clinical parameters and guidelines. Clinicians are currently being recommended to initiate medications that are already US FDA approved for the treatment of BD in adults. Atypical antipsychotics have demonstrated efficacy and are FDA-indicated for the treatment of mania (olanzapine, risperidone, quetiapine and aripiprazole as monotherapy and adjunctive therapy, and ziprasidone and asenapine as monotherapy), depression (olanzapine plus fluoxetine combination, and quetiapine as monotherapy) and maintenance therapy (olanzapine, aripiprazole, and long-acting injectable risperidone as monotherapy, and quetiapine, ziprasidone and long-acting injectable risperidone as adjunctive therapy) for adults with BD.[10
As a collective class of pharmacological agents, several lines of evidence support the safety and efficacy of atypical antipsychotics for treating paediatric BD.12
] Specifically, the second-generation antipsychotics risperidone, aripiprazole, olanzapine, quetiapine and ziprasidone all have multicentre, randomized, double-blind, placebo-controlled studies demonstrating efficacy as monotherapy in paediatric acute mania. As of 2009, risperidone, aripiprazole, and quetiapine have been approved as monotherapy for the treatment of acute manic and mixed episodes in children and adolescents aged 10–17 years.[12
] Olanzapine has been approved for a similar indication in adolescents aged 13-17 years.[12
] Aripiprazole has also been approved for acute mania adjunct to lithium or valproate and for maintenance treatment in paediatric BD,[12
] with maintenance efficacy extrapolated from adult data[13
] and from comparisons of pharmacokinetic parameters between adults and children for aripiprazole. To date, there are no published placebo-controlled studies that are available for atypical antipsychotics for acute bipolar depression or maintenance treatment in children and adolescents, and as such these topics will not be discussed further in this review. Consensus pathways for the treatment of paediatric BD generally suggest starting with monotherapy and then progressing to a combined treatment from two different classes of medication for the treatment of acute mania in children.[9
This paper will provide a brief review of each of the atypical antipsychotics that have become available for youths with acute manic or mixed states of mania and depression combined. The efficacy of an atypical antipsychotic will be defined in terms of treatment response rates or remission of illness. Response rates are commonly reported as a change in a symptom score as determined by clinical assessments of mania from baseline to endpoint. The Young Mania Rating Scale (YMRS) is a commonly used validated instrument to determine the degree of manic symptomatology.[15
] The response rate for the treatment of acute manic or mixed states is commonly defined as the proportion of patients with a ≥50% reduction in YMRS score from baseline to endpoint of the clinical trial. The remission rate is often defined as the proportion of patients with a YMRS score of <12 at endpoint.
After summarizing the efficacy of each antipsychotic, the most common adverse events associated with the medication are considered and dosing is discussed. In general, the incidence of extrapyramidal symptoms (EPS) or neuroleptic malignant syndrome is lower with atypical antipsychotics than with the conventional antipsychotics, but may still occur and should be monitored.[11
] As a group, these medications may cause significant weight gain in youths, and subsequent metabolic problems such as an increased risk of developing type II (non-insulin dependent) diabetes mellitus and the metabolic syndrome.[11
] Clinically significant treatment-emergent weight gain in most studies on atypical antipsychotics has been defined as a ≥7% increase in weight from baseline.
To assess treatment response and risk for adverse events, this review will also determine the numbers needed to treat (NNT) and the numbers needed to harm (NNH) at clinical outcome of each medication tested by randomized controlled design.[16
] The NNT is the number of individuals who need to be treated with a specific agent to yield one additional good outcome compared with placebo, computed as 1/(pdrug
), where pdrug
is the probability of response in the group assigned to the atypical antipsychotic, and pplacebo
is the probability of response in the placebo group at the endpoint of the study. The lower the NNT, the more effective the treatment is at yielding a good outcome. FDA-approved treatments for bipolar disorder have single digit NNTs for response compared with placebo, representing at least 10% superiority over placebo.
Conversely, the NNH indicates how many individuals need to be exposed to a risk factor to cause harm in one patient that would not otherwise have been harmed. NNH is computed as 1/(pdrug − pplacebo), where pdrug is the probability of an adverse event with exposure to drug and pplacebo is the probability of an adverse event with exposure to placebo at endpoint. The higher the NNH, the less likely are adverse events to occur. Clearly, the NNH ought to be higher than the NNT if there is to be a greater likelihood of good than harm. In most instances double digit NNHs are acceptable, representing no more than a 10% increase in risk compared with placebo.
NNTs and NNHs are commonly rounded up to the next whole number, but in this article will be reported to the first decimal place. NNTs and NNHs are effect sizes and hence independent of statistical significance, and are thus most meaningful when there is a significant difference between active drug and placebo. In some articles NNTs and NNHs are reported with 95% confidence intervals, with intervals that do not cross zero or include infinity representing significant differences between active drug and placebo. These data are summarized in and .
Treatment response for placebo-controlled trials of atypical antipsychotics used in pediatric mania
Rates of weight gain for available placebo-controlled trials of atypical antipsychotics used in pediatric mania
As increasing evidence for the use of atypical antipsychotic medications in children and adolescents emerges, a critical evaluation of the efficacy and tolerability for these medications may help clinicians and patients make prudent decisions about proceeding with a particular treatment which may expose patients to adverse events while providing therapeutic benefits.[17
] NNT and NNH data need to be integrated with individual patient factors and preferences to provide personalized qualitative evidence-based care. With these considerations in mind, dosing recommendations and guidelines for titration are also provided.