Hopkins Seth C, Tomioka Sasagu, Ogirala Ajay, Loebel Antony, Koblan Kenneth S, Marder Stephen R
Translational Medicine, Sunovion Pharmaceuticals Inc., Marlborough, MA, USA.
Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior at UCLA and the VA Desert Pacific Mental Illness Research, Education and Clinical Center, Los Angeles, CA, USA.
Schizophr Bull Open. 2022 Apr 7;3(1):sgac027. doi: 10.1093/schizbullopen/sgac027. eCollection 2022 Jan.
Drug trials for negative symptoms in schizophrenia select patients based on the severity and stability of negative symptoms, using criteria that are not suitable for trials of acute exacerbation of schizophrenia. Here we present a method to prognostically enrich subjects having a predefined factor structure in PANSS and apply it to the measurement of negative symptoms specifically in trials of acute schizophrenia. A vector of 1335 elements based on between- and within-item variances, covariances, and differences of PANSS items was created to calculate an index of heterogeneity and to enrich for a predetermined symptom construct in PANSS. Using prerandomization PANSS scores across = 4876 subjects in 13 trials of acute schizophrenia, we demonstrate an ability to select for a subpopulation having the greatest amount of variance explained across the 7-items of the Marder PANSS negative symptom (MPNS) construct. Network analyses on subjects enriched for MPNS construct confirm that negative symptoms were most influential in overall psychopathology, distinct from subjects without the MPNS construct. As expected for D2 antagonists, drug-placebo differences on negative symptoms with lurasidone were not specific to the subpopulation having the MPNS construct. In contrast, the novel TAAR1 agonist ulotaront demonstrated specific improvements in negative symptoms which were greatest in the MPNS subpopulation. These results demonstrate the utility of a novel prognostic enrichment strategy that can address heterogeneity in clinical trials, where patients can be selected on the basis of a greater likelihood of having the measured symptom construct (negative symptoms) related to the disorder (schizophrenia). ClinicalTrials.gov Identifiers: NCT0296938, NCT00088634, NCT00549718, NCT00615433, NCT00790192.
精神分裂症阴性症状的药物试验根据阴性症状的严重程度和稳定性来选择患者，所使用的标准并不适用于精神分裂症急性加重期的试验。在此，我们提出一种方法，用于对具有阳性和阴性症状评定量表（PANSS）中预定义因子结构的受试者进行预后富集，并将其应用于急性精神分裂症试验中阴性症状的测量。基于PANSS项目之间和项目内的方差、协方差以及差异，创建了一个1335元素的向量，以计算异质性指数，并富集PANSS中预先确定的症状结构。利用13项急性精神分裂症试验中4876名受试者随机分组前的PANSS评分，我们证明了能够选择出在马德PANSS阴性症状（MPNS）结构的7个项目中具有最大可解释方差量的亚组。对富集了MPNS结构的受试者进行的网络分析证实，阴性症状在整体精神病理学中最具影响力，这与没有MPNS结构的受试者不同。正如对D2拮抗剂的预期那样，鲁拉西酮在阴性症状上的药物 - 安慰剂差异并非特定于具有MPNS结构的亚组。相比之下，新型TAAR1激动剂乌洛托品在阴性症状方面显示出特定的改善，在MPNS亚组中最为显著。这些结果证明了一种新型预后富集策略的实用性，该策略可以解决临床试验中的异质性问题，即在临床试验中，可以根据患者更有可能具有与疾病（精神分裂症）相关的测量症状结构（阴性症状）来选择患者。临床试验注册编号：NCT0296938、NCT00088634、NCT00549718、NCT00615433、NCT00790192。
