Bipolar Depression Research Review

Long-term Effectiveness of Lurasidone in Pediatric Bipolar Depression: Response, Remission, and Recovery

Singh MK, et al. CNS Spectr. 2021;26:148-149.

Background
Bipolar I disorder has an early onset, with an estimated 1.8% prevalence in children and adolescents. Relatively few prospective studies are available that evaluate the long-term efficacy of AAPs in achieving and sustaining response or remission in pediatric patients with bipolar depression. This post hoc analysis was conducted to evaluate the long-term efficacy of lurasidone in achieving response or remission in children and adolescents with bipolar depression followed over 2 years.

Methods
Patients 10-17 years of age with bipolar I depression who completed a 6-week, double-blind study of lurasidone vs placebo were eligible to enroll on a 2-year, open-label extension study in which patients were continued on flexibly dosed lurasidone (20-80 mg/day) or switched from placebo to lurasidone. Efficacy measures included the Children’s Depression Rating Scale, Revised (CDRS-R) and the Clinical Global Impression, Bipolar Depression Severity scale (CGI-BP-S). Functioning was evaluated using the Healthcare professional-Rated Children’s Global Assessment Scale (CGAS) score, with a score >70 indicating no clinically meaningful functional impairment. Responder criteria were met if a patient achieved 50% reduction from double-blind baseline in the CDRS-R total score; remission criteria were met if a patient achieved a CDRS-R Total Score of 28 and a Young Mania Rating Scale (YMRS) total score of 8 and CGI-BP-S depression score of 3, and patients were considered to have met recovery criteria if they achieved remission with a CGAS score >70. In addition, a more stringent outcome, sustained remission, was also analyzed, which required patients to meet remission criteria for 24 consecutive weeks.

Results
A total of 306 patients completed the 6-week, double-blind study and entered the extension study; 195 (63.7%) patients completed 1 year of treatment and 168 (54.9%) patients completed 2 years of treatment. Responder rates at baseline, 1 year, and 2 years were: 51.0%, 88.4%, and 91.1%, respectively; remission rates were 24.3%, 61.3%, and 75.6%, respectively; and recovery rates were 17.7%, 53.8%, and 73.8%. Statistical analysis revealed a strong inverse relationship between CDRS-R total score and global functioning as measured by the CGAS. Sustained remission was achieved by 37.2% of patients at 1 year and 57% of patients after 2 years.

Conclusions
In children and adolescents with bipolar depression, up to 2 years of treatment with lurasidone was associated with continued improvement in depressive symptoms, resulting in progressively higher rates of response, remission, recovery, and the more rigorously calculated outcome of sustained remission.

Clinical Commentary by Sanjay Gupta, MD
Bipolar depression often begins in the teenage years and is usually treated as a major depressive disorder. There are limited options to treat this condition. This study was a post hoc analysis. A prospective study is unlikely to happen. The sample size was a large one (N = 306). One hundred sixty-eight patients completed (54%) the study. This study used objective rating scales to assess symptoms and functioning. Lurasidone and the olanzapine/fluoxetine combination are the only 2 agents approved by the FDA for bipolar depression in children and adolescents.

Clinical Insights

• It was heartening to see that objective rating scale–based assessments showed improvement in depression that resulted in improved functioning.
• The remission rate continues to increase with the duration of therapy getting to 74% at Week 104. This suggests ongoing efficacy.
• Favorable benefit: Recovery begets recovery! Lurasidone reduces depression severity and keeps it low for up to 2 years after starting the drug.
• Favorable risk: Lurasidone appears to maintain its favorable safety profile during the 2-year follow-up. Being on maintenance lurasidone therapy does not appear to increase the risk for adverse events in patients 10-17 years of age.
• Lurasidone has the advantage of an impressive metabolic profile compared with the other AAPs including the olanzapine/fluoxetine combination (the only other agent FDA approved). It is well known that children and adolescents have a higher likelihood of weight gain compared with adults when receiving antipsychotic medications.
• Hypomania/mania was noted in 5.2% of patients. Healthcare professionals should monitor for treatment-emergent mania/hypomania when treating bipolar depression.

Summary
Based on these data, careful screening of children and adolescents presenting with depression for the presence of bipolar disorder is recommended. A careful longitudinal history, including a family history, is required for accurate diagnosis of a difficult-to-diagnose disease. Lurasidone within the dose range of 20-80 mg/day being FDA indicated/approved should be considered based on these data including the long-term (2-year) follow-up. The need for the medication to be taken with meals should be emphasized to prevent erratic absorption of the drug. In addition, grapefruit juice (CYP3A4 interaction) should be avoided.

Clinical Commentary by Roger McIntyre MD, FRCPC
Pediatric bipolar disorder is severely disabling and associated with impairment in school function and interpersonal development of the adolescent. Healthcare professionals know first-hand the morbidity of an increased risk of suicide that exists in younger persons presenting with bipolar disorder, which is a common age of presentation. Lurasidone has documented efficacy in the treatment of bipolar depression in adults as a monotherapy. Long-term symptomatic and functional outcomes in younger people with bipolar disorder, who remain on a safe and effective treatment, was especially notable considering the high recurrence risk in functional deterioration observed in suboptimally treated persons with bipolar disorder.

Clinical Insights

• Lurasidone was highly effective at achieving response and sustained remission and recovery in pediatric populations with bipolar disorder.
• The rate of response of the percentage of persons who remained on treatment at 1 year (ie, 64%) and 2 years (54.9%) speaks to the acceptability of lurasidone in younger populations (ie, 10-17 years of age) with bipolar disorder.
• The response rates at 1 year (88.4%) and 2 years (91.1%) speak to the significant symptomatic control.
• The recovery rates of 53.8% and 73.8% at 1 and 2 years, respectively, speaks to not only symptomatic improvement but also the functional improvement that can be expected with lurasidone, which is critical considering the severe functional impairment seen in pediatric patients with bipolar disorder.
• The benefit of symptomatic control was especially illustrated by the sustained remission rates, which is an underemphasized important health outcome in bipolar disorder speaking to the stability of response.

Summary
Lurasidone is highly acceptable to individuals 10-17 years of age with pediatric bipolar depression insofar as there is a high level of fidelity to staying on the treatment for 1-2 years, and when able to do so, individuals with bipolar disorder at 10-17 years of age exhibit very significant response remission and sustained remission recovery rates. This study suggests that staying on this effective treatment for bipolar depression, children and adolescents have a better chance to return to a normal trajectory of development.