REVIEW OF: Patel RS et al, J Child Adolesc Psychopharmacol 2021;31(8):521–530 

STUDY TYPE: Systemic review and meta-analysis

Pediatric bipolar depression (PBD) is difficult to treat (see Dr. Charuvastra’s article, "Bipolar Spectrum Disorders in Children and Adolescents," on page 1) and often broadly defined. Currently there are only two FDA-approved medications: lurasidone and olanzapine/fluoxetine combination (OFC). In this meta-analysis, researchers sought well-designed studies of second-generation antipsychotics (SGAs) to see if there are alternatives to the currently approved treatments. 

The authors reviewed randomized controlled trials comparing SGAs to placebo in youth (<20 years old) with PBD and used Children’s Depression Rating Scale-Revised scores to calculate treatment response and number needed to treat (NNT). Of 569 studies, only four met complete inclusion criteria—one of OFC, one of lurasidone, and two of quetiapine—and all four were industry funded. 

The meta-analysis included 826 youths with PBD who received short-term treatment (six to eight weeks) with an SGA or placebo. Only those administered lurasidone or OFC were significantly more likely than their placebo counterparts to be treatment responders. The NNT was 4.3 for lurasidone and 5.3 for OFC. A subgroup analysis found effect sizes for lurasidone treatment that were five-fold higher in older teens versus younger children (DelBello MP et al, J Am Acad Child Adolesc Psychiatry 2017;56(12):1015–1025). A subsequent meta-analysis of the same four trials reported that lurasidone was associated with smaller increases in weight, cholesterol, triglycerides, and prolactin compared to OFC (DelBello MP et al, J Am Acad Child Adolesc Psychiatry 2022;61(2):243–254). Quetiapine was not more effective than placebo for PBD. 

Carlat Take
While we accept that lurasidone has fewer metabolic side effects, we are wary of the other results. PBD remains a controversial diagnosis, widening the boundaries from classical bipolar disorder and likely including cases of oppositional-defiant disorder, disruptive mood dysregulation disorder, complex posttraumatic stress disorder, and borderline personality disorder. The four trials and this review come from authors who advocate for this PBD construct, and this heterogeneous mixture probably includes cases that are less responsive to SGAs. The other concern is that we have not seen the raw data, and industry-funded studies may manipulate research design. We need independent studies on treatment of classical bipolar I depression that are not industry funded to give us firmer guidance in this area. (Editor’s note: See “Reading Research: Details Matter” in The Carlat Child Psychiatry Report, July/Aug/Sept 2021.)