Department of Psychiatry, Amsterdam University Medical Center, Amsterdam, Netherlands; GGZ inGeest Mental Health Care, Amsterdam, Netherlands; Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, Netherlands.
Department of Psychiatry, UMC Utrecht Brain Centre, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands.
Lancet Psychiatry. 2024 Oct;11(10):828-838. doi: 10.1016/S2215-0366(24)00249-9.
Antibodies against the N-methyl-D-aspartate receptor (NMDAR) have been described in the serum of people with schizophrenia spectrum disorders (schizophrenia). However, the prevalence and clinical relevance of these antibodies in schizophrenia is unclear. This knowledge gap includes the possibility of such antibodies being associated with a distinct clinical profile, which in turn might warrant a distinct treatment approach. We aimed to assess the seroprevalence of anti-NMDAR antibodies in schizophrenia, and compare symptoms and psychosocial functioning between patients with schizophrenia who were seropositive and seronegative for these antibodies.
In this case-control comparison, by combining new and existing studies, we included patients diagnosed with schizophrenia from four independent cohorts for whom anti-NMDAR serostatus had been assessed (or could be assessed by us) with live cell-based assays. Included cohorts were from the EULAST study (a trial conducted across 15 European countries and Israel), the OPTiMiSE study (an interventional study in Europe), and the PPiP1 and PPiP2 studies (conducted in the UK). Patients from these cohorts were analysed if they had complete Positive and Negative Syndrome Scale (PANSS) data. No participant had been diagnosed with autoimmune encephalitis or received treatment for this condition. After calculating the prevalence of serum anti-NMDAR antibodies, we examined possible differences in PANSS scores (negative, positive, and general symptom subscales, and total score) between anti-NMDAR-seropositive and anti-NMDAR-seronegative patients. Psychosocial functioning as measured by Personal Social Performance (PSP) score was also compared. All analyses were exploratory and no adjustment was done for multiple testing. People with lived experience were not involved in the conduct of this study.
We collected individual patient data from 1114 patients with schizophrenia across the four cohorts. The study population had a mean age of 28·6 years (SD 7·6) and comprised 382 (34·3%) women and 732 (65·7%) men, including patients of White (929 [83·4%]), Asian (54 [4·8%]), Black (68 [6·1%]), and other (62 [5·6%]) ethnicities. Overall, 41 (3·7%) participants (range 3·1-4·0% across cohorts) tested positive for serum anti-NMDAR antibodies. Lower symptom severity on the negative symptoms PANSS subscale was observed for anti-NMDAR-seropositive patients (mean score 15·8 [SD 6·4]) than for anti-NMDAR-seronegative patients (18·2 [6·8]; Cohen's d=0·36; p=0·026), as well as on the general symptoms PANSS subscale (32·9 [8·9] vs 36·1 [10·1]; d=0·33; p=0·029) and total PANSS score (65·5 [18·5] vs 72·6 [19·3]; d=0·37; p=0·013). Mean PSP score was better in anti-NMDAR-positive patients (62·0 [17·0]) than in anti-NMDAR-negative patients (53·5 [16·3]; d=0·52; p=0·014).
Serum NMDAR antibodies are present in 3-4% of patients with schizophrenia and are associated with relatively low severity of negative symptoms and relatively good psychosocial functioning. Thus, although the findings await replication in cohorts from other geographical regions, serum anti-NMDAR antibodies might be associated with a different form of psychotic illness. These findings could inform future prognostic and interventional studies examining whether anti-NMDAR antibodies are associated with a specific course of illness or with treatment response.
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抗 N-甲基-D-天冬氨酸受体（NMDAR）抗体已在精神分裂谱系障碍（精神分裂症）患者的血清中被描述。然而，这些抗体在精神分裂症中的患病率和临床相关性尚不清楚。这一知识空白包括这些抗体是否与独特的临床特征相关的可能性，而这反过来可能需要独特的治疗方法。我们旨在评估抗 NMDAR 抗体在精神分裂症中的血清患病率，并比较这些抗体阳性和阴性的患者的症状和社会心理功能。
在这项病例对照比较中，我们通过结合新的和现有的研究，纳入了来自四个独立队列的被诊断为精神分裂症的患者，这些队列曾使用活细胞检测方法评估过抗 NMDAR 血清状态（或我们可以评估）。包括的队列来自 EULAST 研究（在 15 个欧洲国家和以色列进行的一项试验）、OPTiMiSE 研究（在欧洲进行的一项干预性研究）以及 PPiP1 和 PPiP2 研究（在英国进行）。如果这些队列中的患者有完整的阳性和阴性综合征量表（PANSS）数据，我们将对其进行分析。没有参与者被诊断为自身免疫性脑炎或接受过这种疾病的治疗。在计算血清抗 NMDAR 抗体的患病率后，我们检查了抗 NMDAR 阳性和抗 NMDAR 阴性患者的 PANSS 评分（阴性、阳性和一般症状子量表以及总分）之间可能存在的差异。还比较了个人社会表现（PSP）评分所衡量的社会心理功能。所有分析均为探索性分析，未对多次检测进行调整。具有生活体验的人没有参与这项研究的进行。
我们从四个队列中的 1114 名精神分裂症患者中收集了个体患者数据。研究人群的平均年龄为 28.6 岁（标准差 7.6），包括 382 名（34.3%）女性和 732 名（65.7%）男性，包括白人（929 名[83.4%]）、亚洲人（54 名[4.8%]）、黑人（68 名[6.1%]）和其他人种（62 名[5.6%]）。总的来说，41 名（3.7%）参与者（各队列的范围为 3.1-4.0%）血清抗 NMDAR 抗体检测呈阳性。抗 NMDAR 阳性患者的阴性症状 PANSS 子量表的症状严重程度较低（平均得分 15.8 [6.4]），低于抗 NMDAR 阴性患者（18.2 [6.8]；Cohen's d=0.36；p=0.026），以及一般症状 PANSS 子量表（32.9 [8.9] 与 36.1 [10.1]；d=0.33；p=0.029）和总 PANSS 评分（65.5 [18.5] 与 72.6 [19.3]；d=0.37；p=0.013）。抗 NMDAR 阳性患者的平均 PSP 评分较好（62.0 [17.0]），高于抗 NMDAR 阴性患者（53.5 [16.3]；d=0.52；p=0.014）。
血清 NMDAR 抗体存在于 3-4%的精神分裂症患者中，与较低的阴性症状严重程度和较好的社会心理功能相关。因此，尽管这些发现有待其他地理区域的队列进行复制，但血清抗 NMDAR 抗体可能与不同形式的精神病相关。这些发现可以为未来的预后和干预研究提供信息，这些研究可以检验抗 NMDAR 抗体是否与特定的疾病过程或治疗反应相关。
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