Treatment of Bipolar Depression in Children and Adolescents

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Bipolar disorder in children and adolescents is a serious illness that adversely affects family, peers, and academic functioning. It increases risk for suicidality and is associated with high rates of occurrence. Bipolar depression presents a significant treatment challenge for clinicians. Although selective serotonin reuptake inhibitors are effective in the treatment of depression, they pose a risk of mania in children with bipolar disorder. There are now two FDA-approved medications: lurasidone and olanzapine/fluoxetine for the treatment of bipolar I depression in children and adolescents aged 10 to 17 years.

Lurasidone

The efficacy and safety of lurasidone was investigated in a double-blind, placebo-controlled study of 347 youth aged 10 to 17 years with a diagnosis of bipolar I depression.¹ Patients were randomized to lurasidone (n = 175) or placebo (n = 172) in this 6-week treatment study: 92% of the lurasidone group and 89.7% of the placebo group completed 6 weeks of treatment. The dose range of lurasidone was 20 to 80 mg daily, with a mean dose of 33.6 mg daily.

There was a statically significant difference from baseline to week 6 in the primary efficacy measure, Children’s Depression Rating Scale-Revised (CDRS-R) total score, between the lurasidone and placebo groups, favoring lurasidone. The effect size was medium, 0.45. Response rates (defined as ≥50% reduction from baseline to week 6 in CDRS-R total score) were significantly higher in the lurasidone group compared with the placebo group (59.5% vs 36.5%). The most frequent adverse events for the lurasidone were nausea and somnolence. There were no significant differences between the lurasidone and placebo groups on measures of suicidality, treatment-emergent mania, akathisia and extrapyramidal symptoms, cognitive function, weight and BMI, and lipid, glucose and prolactin levels.

Olanzapine/fluoxetine

The efficacy and safety of the olanzapine/fluoxetine combination (OFC) was evaluated in a double-blind placebo-controlled trial of 255 youths aged 10 to 17 years with bipolar I depression.² Patients were randomized to OFC (n = 170) or placebo (n = 85) in this 8-week trial: 68.2% of the OFC group and 70.5% of the placebo group completed 8 weeks of treatment. The dose range of OFC was 6/25 to 12/50 mg daily with a mean dose of 7.7/37.6 mg daily.

There was a statically significant difference from baseline to week 8 in the primary efficacy measure, CDRS-R total score, between the OFC and placebo groups, favoring OFC. The effect size was medium, 0.46. Response rates (defined as ≥ 50% reduction from baseline to week 8 in CDRS-R total score and Young Mania Rating Scale item 1 score ≤2 at endpoint) were more significantly higher in the OFC group compared with the placebo group (78.2% vs 59.2%). Adverse events that were statistically significantly more in the OFC than the placebo-treated patients were weight gain, appetite increase, somnolence, sedation, and tremor. Mean weight gain for OFC-treated patients compared with placebo-treated patients was significantly greater (4.4 kg vs 0.5 kg). Patients in the OFC group had significantly greater increase in fasting total cholesterol, triglycerides, prolactin, and hepatic analytes. There were no significant differences in extrapyramidal symptoms and measures of suicidality between the patients receiving OFC and those patients receiving placebo.

Quetiapine

Immediate release and extended release formulations of quetiapine have not demonstrated superiority to placebo in the treatment of adolescents with bipolar 1 depression. In a study of immediate release quetiapine, 32 adolescents were randomized to quetiapine 300 to 600 mg daily or placebo for an 8-week trial.³ There was no statically significant difference in CDRS-R scores from baseline to endpoint between the quetiapine and placebo groups.

In a study of extended release quetiapine, 193 patients were randomized to quetiapine extended release or placebo for an 8-week trial.⁴ There was no statistical significant difference in CDRS-R scores from baseline to endpoint between the quetiapine extended release and placebo groups. Potentially clinically significant elevations in triglycerides (9.3% quetiapine XR; 1.4% placebo) and thyroid stimulating hormone (4.7% quetiapine XR; 0% placebo) were reported.

Lithium

The effectiveness of lithium for the treatment of 27 adolescents with bipolar depression was evaluated in an open-label 6-week study.5 Patients received lithium 30 mg/kg (twice daily dosing) to achieve a serum level of 1.0 to 1.2 mEq/L. There was a significant decrease in CDRS-R scores from baseline to endpoint. Response rate (defined as ≥ 50% reduction in CDRS-R scores from baseline to endpoint) was 48%. The most common adverse events were headache, nausea, vomiting, stomachache, and abdominal cramps.

Lithium is a potential agent in the treatment of bipolar depression in youth, however double-blind placebo-controlled studies of lithium are warranted to establish the efficacy of lithium in treating bipolar depression in youth.

Lamotrigine

Lamotrigine has been evaluated for the treatment of bipolar depression in adolescents as adjunct or monotherapy.⁶ Twenty adolescents with bipolar depression participated in a 8-week open-label trial of lamotrigine adjunct or monotherapy. The mean dose of lamotrigine was 131.6 mg daily. Response rate based on criterion of a ≥50% decrease in CDRS-R scores was 63%. The most common adverse effects were headache, fatigue, nausea, sweating, and difficulty sleeping. No rashes were attributed to lamotrigine.

Double-blind placebo-controlled trials of lamotrigine are needed to determine the efficacy of lamotrigine adjunct or monotherapy for adolescent bipolar depression.

Uridine

In an open-label case series of 7 adolescents with bipolar depression treated with uridine 500 mg twice daily for 6 weeks, there was improvement in CDRS-R scores.⁷ Meanwhile, recruitment has been completed for a randomized, double-blind placebo-controlled 6-week trial of uridine as treatment for adolescents with bipolar depression.⁸

Disclosures:

Dr. Wagner is Professor and Chair, Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch, Galveston, TX. She is President of the American Academy of Child and Adolescent Psychiatry.

References:

1. DelBello MP, Goldman R, Phillips D, et al. Efficacy and safety of lurasidone in children and adolescents with bipolar I depression: a double-blind, placebo-controlled study. J Am Acad Child Adol Psychiatry. 2017;56:1015-1025.

2. Detke HC, DelBello MP, Landry J, Usher RW. Olanzapine/fluoxetine combination in children and adolescents with bipolar I depression: a randomized, double-blind, placebo-controlled trial. J Am Acad Child Adol Psychiatry. 2015;54:217-224.

3. DelBello MP, Chang K, Welge JA, et al. A double-blind, placebo-controlled pilot study of quetiapine for depressed adolescents with bipolar disorder. Bipolar Disord. 2009;11:483-493.

4. Findling RL, Pathak S, Earley WR, et al. Efficacy and safety of extended-release quetiapine fumarate in youth with bipolar depression: an 8 week, double-blind, placebo-controlled trial. J Am Acad Child Adol Psychiatry. 2014;24:325-335.

5. Patel NC, DelBello MP, Bryan HS, et al. Open-label lithium for the treatment of adolescents with bipolar depression. J Am Acad Child Adol Psychiatry. 2006;45:289-297.

6. Chang K, Saxena K, Howe M. An open-label study of lamotrigine adjunct or monotherapy for the treatment of adolescents with bipolar depression. J Am Acad Child Adol Psychiatry. 2006;45:298-304.

7. Kondo DG, Sung YH, Hellem TL, et al. Open-label uridine for treatment of depressed adolescents with bipolar disorder. J Am Acad Child Adol Psychiatry. 2011;21:171-175.

8. University of Utah. Uridine Adolescent Bipolar Depression Randomized Controlled Trial. https//:clinicaltrials.gov/ct2/show/study/NCT01805440. Accessed July 9, 2018.