Evidence
Commentary on selected evidence
Commentary on selected evidence
With advice from topic experts we selected 1 study for further commentary.
Managing bipolar disorder in children and young people – Pharmacological interventions
We selected the randomised controlled trial of lithium in paediatric bipolar disorder by Findling et al. (2015) for a full commentary. This study was selected as pharmacological studies in young people are not as common as those in adults. A full commentary may be beneficial as recommendations for children and young people are generally based on evidence and trials from an adult population.
What the guideline recommends
NICE guideline CG185 recommends (see recommendations 1.11.9 and 1.11.15) the use of aripiprazole for the management of moderate to severe manic episodes. For the management of moderate to severe bipolar depression, it advises considering a pharmacological intervention in addition to a psychological intervention.
It is also advises that prescribers follow the recommendations for pharmacological interventions for adults and refer to the BNF for children when making treatment decisions. Routine antipsychotic treatment in children and young people should not continue for longer than 12 weeks.
Methods
The Findling et al. (2015) randomised controlled trial investigated the effects of lithium in the acute treatment of bipolar I disorder in a paediatric population. Participants were recruited from academic medical centres in the US.
Eligible participants were aged 7 to 17, met Diagnostic and Statistical Manual of Mental Disorders IV (DSM‑IV) criteria for current manic or mixed episode, and scored 20 or more on the Young Mania Rating Scale (YMRS). Participants were also required to be drug-free at baseline and during the study. Before participation, psychotropic medications were removed during a washout period. However, to aid recruitment, following 4 weeks of double-blind therapy the treating physician could use their discretion to prescribe psychostimulants to participants with comorbid attention deficit hyperactivity disorder.
Children were excluded from the study if they were clinically stable on a medication regimen for bipolar I disorder or if they were diagnosed with any of the following:
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Schizophrenia or schizoaffective disorder.
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A pervasive developmental disorder.
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Anorexia nervosa.
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Bulimia nervosa.
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Obsessive compulsive disorder.
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Substance dependence.
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Symptoms of mania attributable to a general medical condition or secondary to use of medications.
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Any general medical condition or abnormal laboratory assessments that could affect the use of lithium.
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Serious homicidal/suicidal ideation or hallucinations/delusions causing concerns for safety.
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Any concomitant medications that would interact with lithium or affect the participant's physical or mental status.
Participants were randomised in an unblinded data coordinating centre, which provided the assignments to unblinded site staff through an electronic format. Randomisation to the treatment groups was allocated in a 2 (lithium) to 1 (placebo) ratio and stratified according to study site, age and sex. The lithium group received either 600 mg daily if weighing less than 30 kg or 900 mg daily if more than 30 kg.
The primary outcome of the trial investigated the effects of lithium using changes in scores from baseline to the end of study (week 8) on the YMRS. Secondary outcomes were measured with the Children's Depression Rating Scale-Revised (CDRS‑R), Clinical Global Impression-Severity (CGI‑S), and Clinical Global Impression-Improvement (CGI‑I) scales.
Results
A total of 81 participants were randomised with 53 in the lithium group and 28 in the placebo group. Analyses were based on last observation carried forward values.
A significant difference in YMRS score mean change from baseline to week 8 was found in favour of lithium compared to placebo (p=0.03). The results do not present any further statistical data for this comparison.
The treatment effect size is presented following adjustments for baseline factors (5.51, 95% Confidence Interval [95% CI] 0.51 to 10.50).
For secondary outcomes, only overall CGI‑I scores were significantly different between groups and favoured lithium (p=0.03).
No significant differences were found for the secondary outcomes between groups for CDRS‑R, CGAS or CGI‑S scores. No significant differences between groups was found for response or remission rates.
Strengths and limitations
Strengths
The study population is relevant to the guideline with the inclusion of children with bipolar mania or mixed episodes. The primary and secondary outcomes are also relevant and included within the scope of the guideline.
Limitations
The study methodology is generally unclear with no details of how randomised lists were generated or allocated to participants. Blinding of participants and study personnel is not fully reported. It is also unclear whether outcome assessors were blinded to treatment allocation. These methodological limitations increase the risk of bias in the results.
Full statistical data is not presented in the results making it unclear how the effect sizes were calculated. The data on the primary outcome measure does not include mean change scores or confidence intervals. This data would be beneficial in determining the robustness of the effect sizes.
Impact on guideline
The results suggest a benefit of lithium in reducing mania symptoms for this population. Current guideline recommendations advise using aripiprazole for mania in young people. According to the recommendations for adults, lithium can be used in conjunction with an antipsychotic as a third-line treatment if alternatives are poorly tolerated.
The outcome of this study is unlikely to impact NICE guideline CG185 recommendations due to the methodological limitations. There remains sufficient uncertainty in the effectiveness of lithium in this population to warrant a challenge to the current recommendations.
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