This study sought to investigate associations between levels of high-sensitivity c-reactive protein (hsCRP) prior to treatment and change in depressive symptoms and cognition in a short-term, double-blind, placebo-controlled study of lurasidone in children and adolescents with bipolar I depression. Patients 10-17 years of age with a DSM-5 diagnosis of bipolar I depression were randomized to 6 weeks of double-blind treatment with flexibly dosed lurasidone (20-80 mg/day) (n=173) or placebo (n=170). The primary efficacy measure was change from baseline to week 6 in the Children's Depression Rating Scale, Revised (CDRS-R). Treatment response was defined as 50% or greater improvement on the CDRS-R from baseline to week 6. Cognitive function was evaluated with the computerized Brief Cogstate Battery at baseline and week 6. Analyses were adjusted for baseline BMI, as well as age. HsCRP was evaluated as a logarithmically transformed continuous variable and as a categorical variable dichotomized into lower (< 1 mg/L) and higher (≥ 1 mg/L) subgroups. A significant interaction was found between baseline hsCRP and treatment group for change in CDRS-R score at study endpoint, with larger placebo-corrected effect sizes for lurasidone in the higher baseline hsCRP group (≥ 1 mg/L). A significant BMI-by-hsCRP-by-treatment interaction was found for response rate with higher baseline hsCRP levels associated with greater antidepressant response to lurasidone (vs. placebo) in the normal BMI range subgroup (NNT=2 in higher hsCRP vs. NNT=5 in lower hsCRP groups) but not in the overweight/obese patients (NNT=6 in higher hsCRP vs. NNT=5 in lower hsCRP). Similarly, a significant interaction effect was observed for the combination of hsCRP and BMI on the procognitive effect of lurasidone, with higher baseline hsCRP levels being associated with improvement in cognitive function for lurasidone (vs placebo) in the normal BMI range subgroup but not in overweight/obese patients. These results suggest that young patients with bipolar depression with normal weight and higher levels of pre-treatment CRP may show a greater placebo-adjusted improvement in depressive symptoms and cognitive performance when treated with lurasidone. If these findings are confirmed in future prospective studies, CRP and BMI may prove to be useful diagnostic and predictive biomarkers in the treatment with lurasidone of children and adolescents with bipolar depression.

中文翻译：

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患有双相 I 型抑郁症的儿童和青少年的 C 反应蛋白和对鲁拉西酮治疗的反应：安慰剂对照试验的结果

本研究旨在调查在儿童和青少年中进行的鲁拉西酮短期、双盲、安慰剂对照研究中治疗前高敏 c 反应蛋白 (hsCRP) 水平与抑郁症状和认知变化之间的关联。双相 I 型抑郁症。DSM-5 诊断为双相 I 型抑郁症的 10-17 岁患者随机接受 6 周灵活剂量的鲁拉西酮双盲治疗（20-80 毫克/天）（n=173）或安慰剂（n=170） ）。主要疗效指标是修订版儿童抑郁量表 (CDRS-R) 从基线到第 6 周的变化。治疗反应定义为 CDRS-R 从基线到第 6 周有 50% 或更大的改善。在基线和第 6 周使用计算机化的 Brief Cogstate Battery 评估认知功能。对基线 BMI 和年龄的分析进行了调整。HsCRP 被评估为对数转换的连续变量和分类变量，分为较低 (< 1 mg/L) 和较高 (≥ 1 mg/L) 亚组。在研究终点时，基线 hsCRP 和治疗组之间的 CDRS-R 评分变化存在显着的相互作用，在较高的基线 hsCRP 组（≥ 1 mg/L）中，鲁拉西酮的安慰剂校正效应量更大。在正常 BMI 范围亚组（较高 hsCRP 与 NNT 中，NNT=2）中，基线 hsCRP 水平越高，对鲁拉西酮（与安慰剂相比）的抗抑郁反应越大，响应率与 BMI 与 hsCRP 与治疗之间的显着相互作用被发现=5 在较低 hsCRP 组中），但在超重/肥胖患者中则不然（较高 hsCRP 中 NNT=6，而较低 hsCRP 中 NNT=5）。相似地，观察到 hsCRP 和 BMI 的组合对 lurasidone 的预测作用有显着的交互作用，在正常 BMI 范围亚组中，较高的基线 hsCRP 水平与 lurasidone（相对于安慰剂）的认知功能改善相关，但与超重/肥胖者无关耐心。这些结果表明，体重正常且治疗前 CRP 水平较高的年轻双相抑郁症患者在接受鲁拉西酮治疗时，可能会显示出更大的安慰剂调整后抑郁症状和认知能力的改善。如果这些发现在未来的前瞻性研究中得到证实，CRP 和 BMI 可能会被证明是治疗双相抑郁症儿童和青少年卢拉西酮的有用诊断和预测生物标志物。