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Hi! David Rosenberg here for the Psychopharmacology Institute. In this Child and Adolescent Psychiatry Smart Take, we will look at a very understudied area, treating major depressive episodes in youth with bipolar disorder. Very dangerous, right? Moreover, we know that some antidepressants used in bipolar depression are more likely to trigger mania, and some, perhaps bupropion, are less likely to do so. However, studying this in children and adolescents is challenging, and questions arise.
What do we do in children and adolescents with a first-degree relative with bipolar disorder? Obviously, we will look at what nonmedication treatments can be beneficial, but we also have to look at medications. It is not uncommon for second-generation antipsychotic medicines, such as olanzapine, quetiapine, lurasidone, and others, to be used.
This article conducts a meta-analysis where they review existing trials of second-generation antipsychotics in youth 10–18 years of age. Moreover, they found that lurasidone was the most preferred treatment for bipolar depression compared with all other medicines that were looked at—in this case, quetiapine and olanzapine. Interestingly, lurasidone was significantly less likely than olanzapine or quetiapine to be associated with weight gain, cholesterol, and triglyceride change. We know that weight gain, particularly in children and adolescents, is a real concern with atypical antipsychotics. Perhaps not surprisingly, youth with bipolar depression treated with olanzapine were more likely to discontinue treatment because of an adverse event, and olanzapine in particular can be associated with high weight gain. I always recommend that patients have an exercise and diet program before starting olanzapine or any atypical antipsychotic.
I would add that, perhaps surprisingly, there were no significant differences and changes in glucose levels among antipsychotics, and we know that atypical antipsychotics or second-generation antipsychotics have been associated with increased risk for diabetes. So, this is something to consider. Interestingly, in this particular study, quetiapine did not significantly improve depressive symptoms in youth with bipolar depression. Lurasidone treatment was also associated with fewer changes in prolactin levels compared with olanzapine, but no difference was noted with quetiapine.
So, what do we make of this study? Despite it having some strengths looking at controlled trials, there are huge limitations. The length of follow-up for the study was no more than 8 weeks, which is problematic, as youth with bipolar depression continue on these medicines long term. The authors acknowledge that that is a limitation of this study. They also included only 4 randomized clinical trials of 3 second-generation antipsychotics, and none of these trials were head-to-head trials. So, they are extrapolating the comparisons here, and we do not know whether populations were similar.
Furthermore, head-to-head comparisons have many benefits over meta-analysis reviews. This was supported by studies in obsessive-compulsive disorder, where meta-analyses suggested very compellingly that clomipramine, a non-selective serotonin reuptake inhibitor, was superior to the other selective serotonin reuptake inhibitors, like sertraline and fluvoxamine. However, when the head-to-head active comparator trials were done, guess what happened? There was no significant difference between the SSRIs and clomipramine in terms of effectiveness. Also, not surprisingly, fewer side effects were seen with the SSRIs than with clomipramine. So, again, as Thomas Huxley—the eminent British biologist—likes to say, there is nothing like an ugly fact to slay a beautiful hypothesis. We must be cautious when interpreting meta-analyses; no matter how well the authors say the statistical analyses and analyses were done, these studies are fraught with a problem.
Finally, I have to say that this study was funded by Sunovian Pharmaceuticals, which produces lurasidone. This does not mean that the findings have to be completely discounted, but recognition of this is needed since the compound reported to do best, lurasidone, is produced by Sunovian Pharmaceuticals. Sunovian Pharmaceuticals also funded editorial and medical writing support. Moreover, no statement indicates that the authors made the study’s final content and editorial approval.
Bottom line, there is interest in what to do in bipolar depression. And is there one second-generation antipsychotic better than the other for particular side effects and efficacy? Right now, this study provides intriguing possibilities, but further controlled studies are clearly warranted, particularly in a population where the risk of lethality and suicide is so high. So, we cannot make any definitive recommendations at this time other than to say that before using these second-generation antipsychotics, we have to recognize that their effectiveness still remains to be determined, particularly one vs the other. Furthermore, in terms of side effects, it is incumbent upon us to do what we can to mitigate weight gain, diabetes, and other metabolic complications by having our patients and their parents know of these risks, get them involved in exercise and diet programs beforehand, and monitor these patients very closely when they are on medication.
Abstract
Systematic Review and Network Meta-analysis: Efficacy and Safety of Second-Generation Antipsychotics in Youths With Bipolar Depression
Melissa P DelBello, Aditi Kadakia, Vincent Heller, Rajpal Singh, Katsuhiko Hagi, Tadashi Nosaka, Antony Loebel
Objective: To assess the relative efficacy and safety of second-generation antipsychotics for treating major depressive episodes in youths with bipolar disorder.
Method: A systematic literature review using PRISMA guidelines and network meta-analysis (NMA) of randomized controlled trials (RCTs) of second-generation antipsychotics for bipolar depression in youths 10 to 18 years of age was conducted. Efficacy measures included Children’s Depression Rating Scale, Revised (CDRS-R) and Clinical Global Impressions-Bipolar Disorder-Severity Depression (CGI-BP-S-depression) and Overall (CGI-BP-S-overall) scores. Available safety outcomes included discontinuations (all-cause, lack of efficacy, adverse events), metabolic parameters (weight change, cholesterol, triglycerides, glucose), changes in prolactin, and somnolence. Results from the NMA were reported as mean changes from baseline or odds ratios (OR) with 95% credible intervals (CrIs).
Results: Four RCTs comparing placebo to lurasidone, quetiapine (1 each for immediate- and extended-release), and the olanzapine-fluoxetine combination (OFC) met all of the inclusion criteria. Lurasidone and OFC demonstrated similar and statistically significant improvements in CDRS-R, but quetiapine did not (lurasidone: -5.70 [-8.66, -2.76]; OFC: -5.01 [-8.63, -1.38]; quetiapine: -1.85 [-5.99, 2.27]). Lurasidone was associated with smaller changes in weight, cholesterol, and triglycerides from baseline compared to OFC and quetiapine. There were no differences in changes in glucose levels among antipsychotics. In addition, lurasidone was associated with smaller change in prolactin levels compared to OFC but not quetiapine.
Conclusion: Evidence from 4 studies in this NMA indicated that lurasidone and OFC, but not quetiapine, were efficacious for the treatment of bipolar depression in youths. Lurasidone was associated with less weight gain and smaller impacts on cholesterol and triglycerides compared with quetiapine and OFC.
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Reference
DelBello, M. P., Kadakia, A., Heller, V., Singh, R., Hagi, K., Nosaka, T., & Loebel, A. (2022). Systematic review and network meta-analysis: Efficacy and safety of second-generation antipsychotics in youths with bipolar depression. Journal of the American Academy of Child & Adolescent Psychiatry, 61(2), 243-254.
