Baltzersen Olga B, Meltzer Herbert Y, Frokjaer Vibe G, Raghava Jayachandra M, Baandrup Lone, Fagerlund Birgitte, Larsson Henrik B W, Fibiger H Christian, Glenthøj Birte Y, Knudsen Gitte M, Ebdrup Bjørn H
Centre for Neuropsychiatric Schizophrenia Research (CNSR), Centre for Clinical Intervention & Neuropsychiatric Schizophrenia Research (CINS), Mental Health Centre Glostrup, Glostrup, Denmark.
Departments of Psychiatry and Behavioral Sciences, Pharmacology, and Physiology, School of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States.
Front Pharmacol. 2020 Apr 30;11:591. doi: 10.3389/fphar.2020.00591. eCollection 2020.
All current approved antipsychotic drugs against schizophrenia spectrum disorders share affinity for the dopamine receptor (D2R). However, up to one-third of these patients respond insufficiently, and in some cases, side-effects outweigh symptom reduction. Previous data have suggested that a subgroup of antipsychotic-naïve patients will respond to serotonin 2A receptor (2AR) blockade.
This investigator-initiated, translational, proof-of-concept study has overall two aims; 1) To test the clinical effectiveness of monotherapy with the newly approved drug against Parkinson's disease psychosis, pimavanserin, in antipsychotic-free patients with first-episode schizophrenia spectrum disorders; 2) To characterize the neurobiological profile of responders to pimavaserin.
Forty patients will be enrolled in this 6-week open label, one-armed trial with the selective serotonin 2AR antagonist (pimavanserin 34 mg/day). At baseline, patients will undergo: positron emission tomography (PET) imaging of the serotonin 2AR using the radioligand [¹¹C]Cimbi-36; structural magnetic resonance imaging (MRI); MR spectroscopy of cerebral glutamate levels and diffusion tensor imaging; cognitive and psychopathological examinations; electrocardiogram, and blood sampling for genetic- and metabolic analyses.
The primary clinical endpoint will be reduction in the Positive and Negative Syndrome Scale (PANSS) positive score. Secondary clinical endpoints comprise multiple clinical ratings (positive and negative symptoms, depressive-, obsessive-compulsive symptoms, quality of life, social functioning, sexual functioning, and side-effects). PET, MRI, and cognitive parameters will be used for in-depth neuropsychiatric characterization of pimavanserin response.
Clinically, we expect pimavanserin to reduce psychotic symptoms with similar effect as observed with conventional antipsychotics, for which we have comparable historical data. We expect pimavanserin to induce minimal side-effects. Neurobiologically, we expect psychotic symptom reduction to be most prominent in patients with low frontal serotonin 2AR binding potential at baseline. Potential pro-cognitive and brain structural effects of pimavanserin will be explored.
Sub-Sero will provide unique information about the role serotonin 2AR in antipsychotic-free, first-episode psychosis. If successful, Sub-Sero will aid identification of a "serotonergic subtype" of schizophrenia spectrum patients, thereby promoting development of precision medicine in clinical psychiatry.
ClinicalTrials, identifier NCT03994965.
目前所有获批用于治疗精神分裂症谱系障碍的抗精神病药物都对多巴胺受体（D2R）具有亲和力。然而，这些患者中高达三分之一的人反应不充分，而且在某些情况下，副作用超过了症状减轻的效果。先前的数据表明，一部分未服用过抗精神病药物的患者会对5-羟色胺2A受体（2AR）阻断产生反应。
这项由研究者发起的转化性概念验证研究总体有两个目的；1）测试新获批的用于治疗帕金森病精神病的药物匹莫范色林单药治疗对首发精神分裂症谱系障碍且未服用过抗精神病药物患者的临床疗效；2）描述对匹莫范色林有反应者的神经生物学特征。
40名患者将参加这项为期6周的开放标签、单臂试验，使用选择性5-羟色胺2AR拮抗剂（匹莫范色林34毫克/天）。在基线时，患者将接受：使用放射性配体[¹¹C]Cimbi-36对5-羟色胺2AR进行正电子发射断层扫描（PET）成像；结构磁共振成像（MRI）；脑谷氨酸水平的磁共振波谱分析和扩散张量成像；认知和精神病理学检查；心电图，以及用于基因和代谢分析的血液采样。
主要临床终点将是阳性和阴性症状量表（PANSS）阳性评分的降低。次要临床终点包括多项临床评分（阳性和阴性症状、抑郁、强迫症状、生活质量、社会功能、性功能和副作用）。PET、MRI和认知参数将用于对匹莫范色林反应进行深入的神经精神特征分析。
在临床上，我们预计匹莫范色林能减轻精神病症状，其效果与传统抗精神病药物相似，我们有可比的历史数据。我们预计匹莫范色林产生的副作用最小。在神经生物学方面，我们预计在基线时额叶5-羟色胺2AR结合潜力低的患者中，精神病症状减轻最为显著。将探索匹莫范色林潜在的促认知和脑结构效应。
Sub-Sero研究将提供关于5-羟色胺2AR在未服用过抗精神病药物的首发精神病中的作用的独特信息。如果成功，Sub-Sero研究将有助于识别精神分裂症谱系患者的“5-羟色胺能亚型”，从而推动临床精神病学中精准医学的发展。
ClinicalTrials，标识符NCT03994965。
Zotero 插件