Anti-NMDAR antibodies as a new piece in schizophrenia’s puzzle

Schizophrenia is a chronic psychiatric disorder marked by psychotic symptoms (i.e., hallucinations and delusions), behavioral changes (e.g., apathy, social withdrawal) and cognitive dysfunction (e.g., executive impairment) [1]. Affecting roughly 1% of the general population, schizophrenia exerts a significant socioeconomic burden due to its severity. From an etiopathogenic perspective, schizophrenia can be conceptualized as the clinical outcome of a series of genetic and/or environmental factors impairing brain development. Accordingly, environmental factors influencing the early development of the CNS, such as maternal infection, maternal stress, nutritional deficiency, among others, would play a major role in schizophrenia development as indicated by epidemiological studies [2]. Interestingly, it has been proposed that a common link between maternal infection/stress and the late development of schizophrenia would be a pro-inflammatory immune response [3]. In the last decade, a great attention has been dedicated to the role played by the immune system in the pathophysiology of schizophrenia. Indeed, different approaches implicate immune dysfunction in schizophrenia: post-mortem studies in patients showing microglial activation and enhanced expression of inflammatory molecules in areas implicated in the genesis of schizophrenic symptoms [4]; PET studies reporting microglial activation in vivo [5]; consistent changes in the blood profile of cytokines and lymphocytes toward a proinflammatory response and/or immune activation [6–8]; genome-wide association studies reporting association between schizophrenia and genetic loci of the major histocompatibility complex and other immune-related genes [9]; and positive results of trials with anti-inflammatorybased strategies [10]. It is worth emphasizing that if a major role of the immune system is confirmed in the pathophysiology of schizophrenia, this may open new venues for therapeutics in an area in high need of novel interventions. Recently, a new piece has been added to the complex puzzle of the immunology of schizophrenia. In the largest cross-sectional study of its kind, Lennox et al. [11] assessed a series of neuronal cell surface antibodies (anti-NMDAR, anti-LGI1, anti-CASPR2, anti-GABA A R and anti-AMPAR) in the serum of 228 young subjects (aged 14–35 years) presenting with a first-episode psychosis and 105 healthy controls. The antibodies were determined by live cell-based assays that, in contrast to other routine serological methods as ELISA and Western blot, allow identification of conformational epitopes. Twenty (9%) of the patients had one or more of the neuronal cell surface antibodies in comparison with four (4%) of the controls, a difference that did not reach statistical significance even when adjusting for potential confounding Anti-NMDAR antibodies as a new piece in schizophrenia’s puzzle