The Zucker Hillside Hospital New York, 75-59 263rd St, Queens, NY 11004, USA; The Feinstein Institutes for Medical Research, 350 Community Dr, Manhasset, NY 11030, USA; The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA.
Lundbeck Pharmaceuticals LLC, 6 Parkway N, Deerfield, IL 60015, USA.
Schizophr Res. 2022 Oct;248:271-278. doi: 10.1016/j.schres.2022.09.012. Epub 2022 Sep 14.
Treatment resistance constitutes the highest burden of disease within schizophrenia. We hypothesized that the synergistic activity of Lu AF35700 at dopamine D and D receptors might provide superior antipsychotic effects versus first-line antipsychotic therapy in patients with treatment resistant schizophrenia (TRS), with a benign tolerability profile.
This was a randomized, double-blind, active-controlled clinical trial (NCT02717195) followed by a one year open-label safety extension (NCT02892422). Following prospective confirmation of treatment resistance, patients were randomized (1:1:1) to 10 weeks double-blind treatment with Lu AF35700 10 mg or 20 mg, or active comparator (risperidone or olanzapine).
1628 patients were screened for TRS, of which 1092 entered the prospective confirmation period. Of these, 697 were randomized (Lu AF35700 10 mg n = 235, 20 mg n = 232, comparator n = 230) and 395 discontinued before randomization, including 264 (24 %) who responded to treatment. 586 patients completed the double-blind phase, of which 524 entered the open-label extension and 318 completed 1-year of open-label treatment. At the end of the double-blind phase, the mean ± SE change in positive and negative syndrome scale (PANSS) total score was -10.1 ± 0.96 for Lu AF35700 10 mg, -8.22 ± 0.98 for Lu AF35700 20 mg, and - 9.90 ± 0.97 for the comparator group. Treatment differences [95 % CI] versus comparator treatment were non-significant (-0.12 [-2.37; 2.13] and 1.67 [-0.59; 3.94], respectively). The most common adverse events with Lu AF35700 were increased weight and headache. Prolactin values decreased by ≥50 % in both sexes treated with Lu AF35700.
Despite evidence of antipsychotic efficacy, treatment with Lu AF35700 failed to differentiate from conventional antipsychotic treatment for patients with TRS.
治疗抵抗构成精神分裂症患者最高的疾病负担。我们假设 Lu AF35700 在多巴胺 D 和 D 受体上的协同活性可能在治疗抵抗性精神分裂症（TRS）患者中提供优于一线抗精神病治疗的抗精神病作用，具有良性的耐受性特征。
这是一项随机、双盲、阳性对照临床试验（NCT02717195），随后进行了为期一年的开放性安全扩展（NCT02892422）。在对治疗抵抗进行前瞻性确认后，患者按 1:1:1 随机分配（Lu AF35700 10mg 或 20mg，或阳性对照药[利培酮或奥氮平]），进行 10 周的双盲治疗。
1628 名患者被筛选为 TRS，其中 1092 名进入前瞻性确认期。其中，697 名患者被随机分配（Lu AF35700 10mg n=235，20mg n=232，对照药 n=230），395 名患者在随机分组前停药，其中 264 名（24%）对治疗有反应。586 名患者完成了双盲阶段，其中 524 名进入开放标签扩展期，318 名完成了 1 年的开放标签治疗。双盲阶段结束时，Lu AF35700 10mg、Lu AF35700 20mg 和对照组的阳性和阴性综合征量表（PANSS）总分平均变化分别为-10.1±0.96、-8.22±0.98 和-9.90±0.97。与对照组治疗相比，治疗差异[95%CI]无显著性（分别为-0.12[-2.37；2.13]和 1.67[-0.59；3.94]）。Lu AF35700 最常见的不良反应是体重增加和头痛。Lu AF35700 治疗的两性患者催乳素值均下降≥50%。
尽管有抗精神病作用的证据，但 Lu AF35700 治疗未能在治疗抵抗的精神分裂症患者中与常规抗精神病治疗区分开来。
