WASHINGTON — Lurasidone (Latuda, Sunovion Pharmaceuticals Inc), which received US Food and Drug Administration approval last month as the first single-agent formulation indicated for bipolar depression in children and adolescents, is also safe and effective over the longer term, new research suggests.
The serotonin dopamine antagonist was previously approved for bipolar depression and for schizophrenia in adults, and for schizophrenia in teens aged 13 to 17 years. As reported by Medscape Medical News, its approval in children with bipolar depression was based on 6-week findings from a phase 3 randomized, double-blind, placebo-controlled trial.
A new interim analysis of treatment for up to 28 weeks, part of the ongoing 2-year, open-label extension of the study, was presented here at Anxiety and Depression Association of America (ADAA) 2018.
Results showed continued improvement of depressive symptoms between open-label baseline and week 28 for patients who continued receiving lurasidone and improvement for those switched to lurasidone from placebo.
The treatment was also generally well tolerated; 10.3% of patients discontinued because of an adverse event (AE). Headache, nausea, and anxiety were the most commonly reported treatment-related AEs.
Parsh Sachdeva, PharmD, director and medical science liaison at Sunovion Pharmaceuticals, Marlborough, Massachusetts, told Medscape Medical News that lurasidone also appears to have minimal effects on body weight and metabolic parameters.
"A clear advantage is there are very little weight differences seen between the 6-week data and the 28-week results, suggesting very minimal weight changes in both groups," said Sachdeva.
Safety at 28 Weeks
In the original 6-week double-blind study, 347 pediatric patients with a DSM-5 diagnosis of bipolar I depression were randomly assigned to receive lurasidone 20 to 80 mg/day or matching placebo.
The study reached its primary efficacy endpoint of change from baseline to week 6 on the Children's Depression Rating Scale, Revised (CDRS-R) total score (-21.0 in the lurasidone group vs -15.3 in the placebo group; effect size, 0.45; P < .0001).
In the extension study, the original lurasidone group continued to receive the drug, and patients in the original placebo group were switched.
Of 223 patients enrolled in the extension study, 155 (69.5%) completed 28 weeks of treatment (mean age, 14.3 years). The mean daily dose of treatment drug was 52.6 mg.
The most common reasons for discontinuation included psychiatric events (in 18 patients), akathisia (in three patients), and abdominal pain, overdose, and pruritus (in one patient each). The psychiatric events included suicide ideation and suicide attempt (in five patients each) and mania (in two patients).
The most common AEs among those who received lurasidone for the entire 28 weeks and those who switched after taking placebo for 6 weeks included headache (22.6% and 16.7%, respectively), nausea (12.2% and 16.7%), and anxiety (12.2% and 7.4%).
Extrapyramidal symptoms (nonakathisia) were reported by 3.5% and 11.1% of the groups, respectively.
In terms of metabolic measures, small median changes from baseline to week 28 for the lurasidone and placebo/lurasidone groups were found in levels of total cholesterol (-5.0 and -3.0 mg/dL, respectively), low-density lipoprotein cholesterol (-3.0 and -2.5 mg/dL), triglycerides (-5.0 and -1.0 mg/dL), and glucose (+1.0 mg/dL in each group).
Mean changes in weight at week 28 in the lurasidone and placebo/lurasidone groups were +2.6 and +3.4 kg, respectively, compared with an expected weight gain of +2.4 and +2.2 kg, based on normative data from the Centers for Disease Control and Prevention, the authors note.
Median changes in prolactin from baseline to week 28 were +1.55 and +2.60 ng/mL, respectively, for the girls and +1.25 and +1.80 ng/mL for the boys. No patients were found to have a prolonged QTc interval.
The findings also showed continued symptom improvement, with only 0.9% of patients discontinuing treatment prior to week 28 because of a lack of efficacy.
Whereas patients in the lurasidone group showed greater mean improvement than those in the placebo/lurasidone group in CDRS-R scores from the original baseline to the beginning of the open-label period (-23.4 vs -17.4, respectively), both groups showed significant mean changes from the open-label baseline to week 28 (-7.3 and -12.5).
Mean changes in Clinical Global Severity, Bipolar (CGI-BP-S) depression scores from open-label baseline to week 28 were -1.0 and -1.2 for the groups, respectively.
Response was defined as a 50% or greater reduction from the double-blind baseline in CDRS-R total score. In the lurasidone group, 84% of patients responded to treatment from the double-blind baseline to week 28, vs 86.1% in the placebo/lurasidone group.
Remission rates, defined as a CDRS-R total score of 28 or less, a Young Mania Rating Scale total score of 8 or lower, and a CGI-BP-S depression score of 3 or less, were also similar in the two groups at 28 weeks (58.7% and 57.0%, respectively).
Overall, the findings offer encouraging evidence of sustained safety and efficacy with longer-term use, said Sachdeva.
"We could see that in the initial 6 weeks, there was a significant separation in the luradisone group compared to the placebo group," he said.
"And while there was some drop in efficacy in the placebo group in the first 6 weeks, after switching to lurasidone in the open-label part of the study, we see that at 28 weeks, their symptoms improve," he said.
Commenting on the findings for Medscape Medical News, Mani Pavuluri, MD, PhD, professor and director of the Pediatric Mood Disorders Program in the Department of Psychiatry at the University of Illinois at Chicago, said the approval of lurasidone for bipolar depression in children and adolescents could be an important addition in a field where treatment options are limited.
"The approval is significant because depression is a larger component of bipolar diathesis, and selective serotonin reuptake inhibitors are often harmful and aggravate mania and mixed episodes," he told Medscape Medical News.
In addition, "suicide and self-harm are significant in youth bipolar disorder. Therefore, having this indication means we have a safer alternative tool than traditional choices for unipolar depression to treat bipolar depression," Pavuluri said.
He noted that although the weight gain data are encouraging and objective, other studies have also demonstrated favorable weight results, yet outcomes in real-world practice have been less favorable.
"We have aripiprazole, for example, where the corresponding industry trial showed no significant weight gain," said Pavuluri.
"Yet, in clinical practice, we see weight gain on an individual basis with both lurasidone and aripiprazole. There could be individual factors separate from the potential medication effects of H1 and 5HT2c receptor antagonism responsible for potential weight gain," he said.
Regarding concerns about the use of these types of medications in developing children and adolescents, Pavuluri noted that the benefits of treatment need to be strongly considered, given the seriousness of bipolar depression.
"First of all, if there is a chemical imbalance, you try to set it right with these medications. So in fact, developmentally, you are helping the patient by potentially repairing such an imbalance without leaving them untreated and with resulting incapacity," he said.
Ultimately, however, the clinician's challenge is to try to get to the source, or sources, of a patient's depression and tailor treatment accordingly, said Pavuluri.
"There could be myriad psychosocial factors that need to be addressed which have nothing to do with chemical imbalance," he said.
"Therefore, a clinician is fully justified in not relying entirely on a drug like lurasidone to treat depression. That said, having a safer agent like lurasidone is a welcome choice."
The study was sponsored by Sunovion Pharmaceuticals Inc. Dr Sachdeva is an employee of Sunovion. Dr Pavuluri has disclosed no relevant financial relationships.
Anxiety and Depression Association of America (ADAA) 2018. Abstracts S1-085 and S2-061, presented April 6 and 7, 2018.
Medscape Medical News © 2018
Cite this: Lurasidone Appears Safe at 28 Weeks in Kids With Bipolar Depression - Medscape - Apr 18, 2018.