To evaluate the efficacy and safety of lurasidone in children and adolescents with bipolar depression.
Patients 10 to 17 years old with a DSM-5 diagnosis of bipolar I depression were randomized to 6 ...weeks of double-blind treatment with flexible doses of lurasidone 20 to 80 mg/day. The primary endpoint was change from baseline to week 6 in the Children’s Depression Rating Scale–Revised (CDRS-R) total score, evaluated by a mixed-model repeated-measures analysis.
A total of 347 patients were randomized and received at least 1 dose of lurasidone (n = 175; mean age 14.2 years; mean dose 33.6 mg/day) or placebo (n = 172; mean age 14.3 years). At week 6, treatment with lurasidone was associated with statistically significant improvement compared with placebo in CDRS-R total score (−21.0 versus −15.3; p < .0001; effect size 0.45). Lurasidone also was associated with statistically significant improvement in the Clinical Global Impression-Bipolar Severity depression score (key secondary measure) and in measures of anxiety, quality of life, and global functioning. Study completion rates were 92.0% in the lurasidone group and 89.7% in the placebo group; discontinuation rates due to adverse events were the same for the 2 groups (1.7%). The 2 most common adverse events on lurasidone were nausea and somnolence. Treatment with lurasidone was associated with few effects on weight and metabolic parameters.
In this placebo-controlled study, monotherapy with lurasidone, in the dose range of 20 to 80 mg/day, significantly decreased depressive symptoms in children and adolescents with bipolar depression. Lurasidone was well tolerated, with minimal effects on weight and metabolic parameters.
Clinical trial registration information—Lurasidone Pediatric Bipolar Study; http://Clinicaltrials.gov; NCT02046369.
To assess the relative efficacy and safety of second-generation antipsychotics for treating major depressive episodes in youths with bipolar disorder.
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).
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.
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.
To assess the efficacy and safety of olanzapine/fluoxetine combination (OFC) for the acute treatment of bipolar depression in children and adolescents.
Patients 10 to 17 years of age with bipolar I ...disorder (BP-I), depressed episode, baseline Children’s Depression Rating Scale–Revised (CDRS-R) total score ≥40, Young Mania Rating Scale (YMRS) total score ≤15, and YMRS-item 1 ≤2 were randomized to OFC (6/25–12/50 mg/day olanzapine/fluoxetine; n = 170) or placebo (n = 85) for up to 8 weeks of double-blind treatment. The primary efficacy measure was mean change in CDRS-R using mixed-model repeated-measures methodology.
Baseline-to-week-8 least-squares mean change in CDRS-R total score was greater for OFC-treated patients than for placebo-treated patients (−28.4 versus −23.4, p = .003; effect size = .46), with between-group differences statistically significant at week 1 (p = .02) and all subsequent visits (all p < .01). Rates of and times to response and remission were statistically significantly greater for OFC- than for placebo-treated patients. The most frequent treatment-emergent adverse events in the OFC group were weight gain, increased appetite, and somnolence. Mean weight gain at patient’s endpoint was significantly greater for OFC- than for placebo-treated patients (4.4 kg versus 0.5 kg, p < .001). Treatment-emergent hyperlipidemia was very common among OFC-treated patients. Abnormal increases in hepatic analytes, prolactin, and corrected QT interval (QTc) were also common or very common but generally not clinically significant.
In this study, OFC was superior to placebo, and has been approved by the US Food and Drug Administration (FDA) for the acute treatment of bipolar I depression in patients 10 to 17 years of age. Benefits should be weighed against the risk of adverse events, particularly weight gain and hyperlipidemia.
Clinical trial registration information—A Study for Assessing Treatment of Patients Ages 10-17 with Bipolar Depression; http://clinicaltrials.gov; NCT00844857.
In pediatric patients with anxiety disorders, existing symptom inventories are either not freely available or require extensive time and effort to administer. We sought to evaluate a brief ...self-report scale-the Generalized Anxiety Disorder 7-item scale (GAD-7)-in adolescents with generalized anxiety disorder (GAD).
The Pediatric Anxiety Rating Scale (PARS) and the GAD-7 were administered to youth with GAD (confirmed by structured interview). Relationships between the measures were assessed, and sensitivity and specificity was determined with regard to a global symptom severity measure (Clinical Global Impression-Severity).
In adolescents with GAD (N = 40; mean age, 14.8 ± 2.8), PARS and GAD-7 scores strongly correlated (R = 0.65, P ≤ .001) and a main effect for symptom severity was observed (P ≤ .001). GAD-7 scores ≥11 and ≥17 represented the optimum specificity and sensitivity for detecting moderate and severe anxiety, respectively.
The PARS and GAD-7 similarly reflect symptom severity. The GAD-7 is associated with acceptable specificity and sensitivity for detecting clinically significant anxiety symptoms. GAD-7 scores may be used to assess anxiety symptoms and to differentiate between mild and moderate GAD in adolescents, and may be more efficient than the PARS.
The tolerability of antidepressants is poorly characterized in children and adolescents with depressive and anxiety disorders. Among adverse events that affect the tolerability of antidepressants in ...youth is activation, a cluster of symptoms that represent a hyperarousal event characterized by impulsivity, restlessness, and/or insomnia. This cluster of symptoms was first identified as a side effect of selective serotonin and selective serotonin norepinephrine inhibitors (SSRIs and SSNRIs) in the early 1990s; however, activation remains poorly characterized in terms of prevalence, risk factors, and pathophysiology. This article describes the pathophysiology of antidepressant-related activation, predictors of activation and its clinical management in youth with depressive and anxiety disorders who are treated with antidepressant medications.
Objectives
Previous studies and meta‐analyses suggested that N‐acetylcysteine (NAC) was superior to placebo in improving depression in bipolar disorder. However, more recent data, including two ...larger trials, found that NAC was no more effective than placebo. We conducted a meta‐analysis to appraise the possible efficacy of NAC in treating bipolar depression.
Methods
A systematic review and meta‐analysis of double‐blind, placebo‐controlled trials of NAC as a treatment augmentation strategy for bipolar depression was carried out in PubMed (1966–2020). We utilized random‐effect analysis to evaluate improvement in depressive symptoms from baseline to endpoint as the primary efficacy measure.
Results
Six trials including 248 patients were included. Treatment augmentation with NAC showed a moderate effect size favoring NAC over placebo (d = 0.45, 95% C.I.: 0.06–0.84). There was substantial heterogeneity (I2 = 49%). Meta‐regression analyses did not identify any moderator that might explain variation in heterogeneity, including baseline depressive symptom scores, mean NAC dose, or duration of study.
Conclusions
Results from six clinical trials suggest that treatment augmentation with NAC for bipolar depression appears to be superior to placebo, with a moderate effect size, but a large confidence interval. Larger clinical trials, investigating possible moderating factors, such as NAC dose, treatment duration, baseline depression severity, or chronicity of illness, are warranted.
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