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Background Treatment effects of conventional approaches with antipsychotics or psychosocial interventions are limited when it comes to reducing negative and cognitive symptoms in schizophrenia. While there is emerging clinical evidence that new, augmented protocols based on theta-burst stimulation can increase rTMS efficacy dramatically in depression, data on similar augmented therapies are limited in schizophrenia. The different patterns of network impairments in subjects may underlie that some but not all patients responded to given stimulation locations. Methods Therefore, we propose an augmented theta-burst stimulation protocol in schizophrenia by stimulating both locations connected to negative symptoms: (1) the left Dorsolateral Prefrontal Cortex (DLPFC), and (2) the vermis of the cerebellum. Ninety subjects with schizophrenia presenting negative symptoms and aging between 18–55 years will be randomized to active and sham stimulation in a 1:1 ratio. The TBS parameters we adopted follow the standard TBS protocols, with 3-pulse 50-Hz bursts given every 200 ms (at 5 Hz) and an intensity of 100% active motor threshold. We plan to deliver 1800 stimuli to the left DLPFC and 1800 stimuli to the vermis daily in two 9.5-minute blocks for four weeks. The primary endpoint is the change in negative symptom severity measured by the Positive and Negative Syndrome Scale (PANSS). Secondary efficacy endpoints are changes in cognitive flexibility, executive functioning, short-term memory, social cognition, and facial emotion recognition. The safety outcome is the number of serious adverse events. Discussion This is a double-blind, sham-controlled, randomized medical device study to assess the efficacy and safety of an augmented theta-burst rTMS treatment in schizophrenia. We hypothesize that social cognition and negative symptoms of patients on active therapy will improve significantly compared to patients on sham treatment. Trial registration The study protocol is registered at 'clinicaltrials.gov 'with the following ID: NCT05100888. All items from the World Health Organization Trial Registration Data Set are registered. Initial release: 10/19/2021.

Background Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune limbic encephalitis, where psychiatric symptoms are often dominant in the initial phase. These patients are usually treated in psychiatric wards, due to first episode psychosis (FEP). The antibodies responsible for the symptoms, can be identified from the patients’ sera. During the past decade multiple studies had been launched to investigate whether anti-NMDAR antibodies were present in the sera of patients, treated with the diagnosis of schizophrenia, although results have not confirmed this hypothesis. It is possible, however, that autoimmune antibodies, which are not yet known, play a role in FEP, similarly to anti-NMDAR antibodies, therefore there is a rationale behind screening for other antibodies among these patients. The aim of our study is to screen patients with FEP for anti-NMDAR antibodies. We also would like to check whether there are any other potentially pathogenic antibodies, which are not yet known, but could be responsible for psychotic symptoms. Methods So far 26 patients have been recruited with FEP (with symptoms of schizophrenia), the total number of healthy controls involved in the study is currently 21. All of the patients were treated at Semmelweis University, Department of Psychiatry. Patients with affective psychosis, drug-related psychotic disorder and patients with clear signs of encephalitis had been excluded from the study. The patients’ blood samples were centrifuged, after which serum was separated from whole blood. Serum samples were then tested with EUROIMMUN immune fluorescent assays for anti-NMDAR antibodies. A different, non-specific method was also used to test anti-brain antibody activity on monkey-cerebellum and rat-hippocampus to show possibly relevant (but not yet known) antibodies. All of the immunological laboratory investigations were done at Semmelweis University, Central Laboratory and immunfluorescent slides were evaluated by an expert in this field. Further differentiation of this non-specific activity was not part of our current study. All of the samples had been freezed on -80 degrees Celsius and are stored for possible further investigations in the future. IL-6 levels will be checked in the next phase of our study. Results None of the samples from the 26 patients, nor any of the samples collected from healthy controls contained anti-NMDAR antibodies. However it should be noted that during the period of the study 3 patients were diagnosed with anti-NMDAR encephalitis, but as it was described earlier these cases had not been included in our study, because we focused on patients with pure psychotic symptoms. 11 of the patients’ serum showed positive reaction of the neuroendothelium (6 strong, 5 moderate), whereas only 4 of the samples collected from healthy controls showed similar pattern (all of them showed moderate or mild activity). These results suggest that there is a significant difference between the groups, however we will need to increase our sample size to verify these findings. There were other non-specific reactions in both groups in low numbers. Discussion None of the serum samples of the 26 patients proved positive for anti-NMDAR antibodies, which is in agreement with previous studies in the literature. However, a higher proportion of samples form patients showed activity on the neuroendothelium of non-specific immune fluorescent assays compared to healthy controls. We plan to increase our samples sizes in the near future and check the serum samples for interleukins and cytokines.

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