How to Choose a Mood Stabilizer for Children

RESEARCH UPDATE

Lithium is a first-line treatment in adult bipolar disorder, but I often read that it is less effective in children. In the first part of this series, I suggested that the difference depends on whether we focus on lithium’s preventative or acute effects. In long-term studies, lithium outperforms other mood stabilizers in both children and adults.^1,2 The younger the patient, the more important prevention is, but long-term data is scarcer in child psychiatry, so short-term trials may bias the field because the data is more abundant, and the studies are better controlled.

Unlike the long-term research, which points toward lithium across the lifespan, the results of acute manic trials diverge for children and adults. In the Treatment of Early Age Mania (TEAM) study, a large randomized controlled trial of childhood mania, risperidone outperformed both lithium and valproate by a 2:1 margin.³ A meta-analysis arrived at the same conclusion.⁴ The number needed to treat (NNT) to achieve a response in acute pediatric mania was twice as high for lithium and the anticonvulsants (NNT = 8) as it was for the atypical antipsychotics (NNT = 4). No such difference is seen in adult patients, either in meta-analyses or head-to-head trials.^4-6

Is age the deciding factor, or is age just a marker for something else that is influencing response? To answer that question, we’ll need to understand two types of bipolar disorder: classic and atypical. These two forms can occur in bipolar I or bipolar II. They differ in their age of onset, genetics, and treatment response, so much so that many experts think of them as different illnesses.⁷

Classic and atypical bipolar disorder

Among adults, patients with classic manic symptoms are more likely to respond to lithium, while those with atypical presentations fare better with atypical antipsychotics. Atypical bipolar is marked by multiple comorbidities, mixed states, rapid cycling, mood-incongruent psychosis, and a lack of full recovery between episodes. In contrast, in classic bipolar disorder there is a clean separation of manic and depressive episodes, and a relative lack of comorbidities and mixed states. Classic manias present as though they walked out of the bipolar textbook: euphoric, grandiose, energetic, and impulsive.

Another difference between these forms might explain the divergence of the child and adult data. In classic bipolar, the symptoms begin around age 15 to 20 years and arise out of a healthy baseline. In atypical cases the illness starts earlier, during or before puberty, and unfolds insidiously upon a background of social and academic problems, colored by a revolving carousel of psychiatric symptoms including ADHD, conduct disorder, and anxiety.^8,9

Turning back to Geller and colleagues’ landmark TEAM study,³ it’s no surprise that risperidone outperformed lithium. The study cut off at aged 15 years, and the average subject was 10 years old. The sample appears loaded with atypical cases: 93% had mixed mania; 77% psychosis; 93% ADHD; and 90% oppositional defiant disorder. In a reanalysis of the data that adjusted for comorbid ADHD, the differences between lithium and risperidone disappeared.¹⁰ Three earlier naturalistic studies arrived at a similar conclusion: premorbid ADHD lowered the rate of response to lithium approximately 2-fold.^11-13 The onset of bipolar disorder symptoms also tends to occur earlier in children with ADHD.

ADHD is the strongest predictor of poor lithium response in children. Other markers of poor response include prepubertal onset, conduct disorder, anxiety, psychotic features, cluster A traits, and lack of full recovery between episodes.⁹ When it comes to adults, we know a lot more about the features that favor lithium response, but the available studies suggest that the same predictors apply across the ages.

The bottom line

Classic bipolar disorder is an adult illness that begins in the mid-teens, and child psychiatrists are often the first to intervene. These patients are uniquely responsive to lithium, and when they respond, they tend to remain in remission.^1,2 Blanket recommendations to avoid lithium in pediatric patients may cause harm, because starting lithium early (after the first episode) significantly improves the odds of success.¹⁴ Antipsychotics work better with an earlier onset of illness-around or before puberty-and atypical features. Lithium is a better choice for the classic cases that strike in mid- to late-adolescence.

Disclosures:

Dr. Aiken is the Director of the Mood Treatment Center, Editor in Chief of The Carlat Psychiatry Report, and Instructor in Clinical Psychiatry at the Wake Forest University School of Medicine. He does not accept honoraria from pharmaceutical companies but he receives honoraria from W.W. Norton & Co. for Bipolar, Not So Much, a book he coauthored with Jim Phelps, MD.

References:

1. Miura T, Noma H, Furukawa TA, et al. Comparative efficacy and tolerability of pharmacological treatments in the maintenance treatment of bipolar disorder: a systematic review and network meta-analysis.Lancet Psychiatry. 2014;1:351-359.

2. Geller B, Tillman R, Bolhofner K, et al. Pharmacological and non-drug treatment of child bipolar I disorder during prospective eight-year follow-up.Bipolar Disord. 2010;12:164-171.

3. Geller B, Luby JL, Joshi P, et al. A randomized controlled trial of risperidone, lithium, or divalproex sodium for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents.Arch Gen Psychiatry. 2012;69:515-528.

4. Correll CU, Sheridan EM, DelBello MP. Antipsychotic and mood stabilizer efficacy and tolerability in pediatric and adult patients with bipolar I mania: a comparative analysis of acute, randomized, placebo-controlled trials.Bipolar Disord. 2010;12:116-141.

5. Segal J, Berk M, Brook S. Risperidone compared with both lithium and haloperidol in mania: a double-blind randomized controlled trial.Clin Neuropharmacol. 1998;21:176-180.

6. Bowden CL, Grunze H, Mullen J, et al. A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder.J Clin Psychiatry. 2005;66:111-121.

7. Malhi GS, Geddes JR. Carving bipolarity using a lithium sword.Br J Psychiatry, 2014;205:337-339.

8. Marneros A, Goodwin F. Bipolar Disorders: Mixed States, Rapid Cycling and Atypical Forms. Cambridge, UK: Cambridge University Press; 2005.

9. Duffy A. Lithium treatment in children and adolescents: a selected review and integration of research findings. In: Bauer M, Grof P, Muller-Oerlinghausen B, eds. Lithium in Neuropsychiatry: The Comprehensive Guide. Oxford, UK: Informa; 2006.

10. Vitiello B, Riddle MA, Yenokyan G, et al. Treatment moderators and predictors of outcome in the Treatment of Early Age Mania (TEAM) study. J Am Acad Child Adolesc Psychiatry. 2012;51:867-878.

11. Strober M, Morrell W, Burroughs J, et al. A family study of bipolar I disorder in adolescence. Early onset of symptoms linked to increased familial loading and lithium resistance.J Affect Disord. 1988;15:255-268.

12. Strober M, DeAntonio M, Schmidt-Lackner S, et al. Early childhood attention deficit hyperactivity disorder predicts poorer response to acute lithium therapy in adolescent mania.J Affect Disord. 1998;51:145-151.

13. Masi G, Perugi G, Millepiedi S, et al. Pharmacological response in juvenile bipolar disorder subtypes: A naturalistic retrospective examination.Psychiatry Res. 2010;177:192-198.

14. Kessing LV, Vradi E, Andersen PK. Starting lithium prophylaxis early v. late in bipolar disorder.Br J Psychiatry. 2014;205:214-220.